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@Article{niacaris2003,
  author  = {T. Niacaris},
  title   = "{Serotonin Regulates Repolarization of the \textit{C. elegans} Pharyngeal Muscle}",
  journal = {J Exp Biol.},
  year    = {2003},
  volume  = {206},
  pages   = {223-231},
  issn    = {0022-0949},
  doi     = {10.1242/jeb.00101},
}

@Article{straud2013,
  author          = {Straud, Sarah and Lee, Inhwan and Song, Bomi and Avery, Leon and You, Young-Jai},
  title           = {The jaw of the worm: GTPase-activating protein EAT-17 regulates grinder formation in Caenorhabditis elegans.},
  journal         = {Genetics},
  year            = {2013},
  volume          = {195},
  pages           = {115--125},
  month           = sep,
  issn            = {1943-2631},
  abstract        = {Constitutive transport of cellular materials is essential for cell survival. Although multiple small GTPase Rab proteins are required for the process, few regulators of Rabs are known. Here we report that EAT-17, a novel GTPase-activating protein (GAP), regulates RAB-6.2 function in grinder formation in Caenorhabditis elegans. We identified EAT-17 as a novel RabGAP that interacts with RAB-6.2, a protein that presumably regulates vesicle trafficking between Golgi, the endoplasmic reticulum, and plasma membrane to form a functional grinder. EAT-17 has a canonical GAP domain that is critical for its function. RNA interference against 25 confirmed and/or predicted RABs in C. elegans shows that RNAi against rab-6.2 produces a phenotype identical to eat-17. A directed yeast two-hybrid screen using EAT-17 as bait and each of the 25 RAB proteins as prey identifies RAB-6.2 as the interacting partner of EAT-17, confirming that RAB-6.2 is a specific substrate of EAT-17. Additionally, deletion mutants of rab-6.2 show grinder defects identical to those of eat-17 loss-of-function mutants, and both RAB-6.2 and EAT-17 are expressed in the terminal bulb of the pharynx where the grinder is located. Collectively, these results suggest that EAT-17 is a specific GTPase-activating protein for RAB-6.2. Based on the conserved function of Rab6 in vesicular transport, we propose that EAT-17 regulates the turnover rate of RAB-6.2 activity in cargo trafficking for grinder formation. },
  chemicals       = {Caenorhabditis elegans Proteins, EAT-17 protein, C elegans, GTPase-Activating Proteins, Rab6 protein, rab GTP-Binding Proteins},
  citation-subset = {IM},
  completed       = {2014-03-25},
  country         = {United States},
  doi             = {10.1534/genetics.113.152538},
  issn-linking    = {0016-6731},
  issue           = {1},
  keywords        = {Animals; Caenorhabditis elegans, anatomy & histology, genetics, growth & development, metabolism; Caenorhabditis elegans Proteins, chemistry, genetics, metabolism; GTPase-Activating Proteins, chemistry, genetics, metabolism; Gene Deletion; Pharynx, growth & development, metabolism; Protein Binding; Protein Structure, Tertiary; Protein Transport; Transport Vesicles, metabolism; rab GTP-Binding Proteins, genetics, metabolism; Golgi-endosome trafficking; RAB; RABGAP; grinder formation},
  nlm-id          = {0374636},
  owner           = {NLM},
  pii             = {genetics.113.152538},
  pmc             = {PMC3761295},
  pmid            = {23792950},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-02-20},
}

@Article{song2013,
  author          = {Song, B-M. and Faumont, S. and Lockery, S. and Avery, L.},
  title           = "{Recognition of Familiar Food Activates Feeding via an Endocrine Serotonin Signal in \textit{Caenorhabditis elegans}.}",
  journal         = {eLife},
  year            = {2013},
  volume          = {2},
  pages           = {e00329},
  month           = feb,
  issn            = {2050-084X},
  chemicals       = {SER-7b protein, C elegans, Serotonin, GTP-Binding Protein alpha Subunits, Gs},
  citation-subset = {IM},
  completed       = {2016-04-11},
  country         = {England},
  doi             = {10.7554/eLife.00329},
  issn-linking    = {2050-084X},
  keywords        = {Animals; Bacteria, metabolism; Caenorhabditis elegans, genetics, metabolism; Chemoreceptor Cells, metabolism; Discrimination (Psychology); Eating; Feeding Behavior; Food Preferences; GTP-Binding Protein alpha Subunits, Gs, metabolism; Motor Neurons, metabolism; Mutation; Pharynx, innervation; Recognition (Psychology); Serotonin, metabolism; Signal Transduction; Smell; Taste; Time Factors; C. elegans; Feeding; Food; Nervous system; Serotonin; recognition},
  nlm-id          = {101579614},
  owner           = {NLM},
  pii             = {00329},
  pmc             = {PMC3564447},
  pmid            = {23390589},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2017-07-14},
}

@Article{song2012a,
  author          = {Song, Bo-mi and Avery, Leon},
  title           = {Serotonin activates overall feeding by activating two separate neural pathways in Caenorhabditis elegans.},
  journal         = {The J. Neurosci. : the official journal of the Society for Neuroscience},
  year            = {2012},
  volume          = {32},
  pages           = {1920--1931},
  month           = feb,
  issn            = {1529-2401},
  abstract        = {Food intake in the nematode Caenorhabditis elegans requires two distinct feeding motions, pharyngeal pumping and isthmus peristalsis. Bacteria, the natural food of C. elegans, activate both feeding motions (Croll, 1978; Horvitz et al., 1982; Chiang et al., 2006). The mechanisms by which bacteria activate the feeding motions are largely unknown. To understand the process, we studied how serotonin, an endogenous pharyngeal pumping activator whose action is triggered by bacteria, activates feeding motions. Here, we show that serotonin, like bacteria, activates overall feeding by activating isthmus peristalsis as well as pharyngeal pumping. During active feeding, the frequencies and the timing of onset of the two motions were distinct, but each isthmus peristalsis was coupled to the preceding pump. We found that serotonin activates the two feeding motions mainly by activating two separate neural pathways in response to bacteria. For activating pumping, the SER-7 serotonin receptor in the MC motor neurons in the feeding organ activated cholinergic transmission from MC to the pharyngeal muscles by activating the Gsα signaling pathway. For activating isthmus peristalsis, SER-7 in the M4 (and possibly M2) motor neuron in the feeding organ activated the G(12)α signaling pathway in a cell-autonomous manner, which presumably activates neurotransmission from M4 to the pharyngeal muscles. Based on our results and previous calcium imaging of pharyngeal muscles (Shimozono et al., 2004), we propose a model that explains how the two feeding motions are separately regulated yet coupled. The feeding organ may have evolved this way to support efficient feeding.},
  chemicals       = {Caenorhabditis elegans Proteins, Receptors, Serotonin, serotonin 7 receptor, Serotonin},
  citation-subset = {IM},
  completed       = {2012-03-27},
  country         = {United States},
  doi             = {10.1523/JNEUROSCI.2064-11.2012},
  issn-linking    = {0270-6474},
  issue           = {6},
  keywords        = {Animals; Animals, Genetically Modified; Caenorhabditis elegans, genetics, microbiology, physiology; Caenorhabditis elegans Proteins, physiology; Eating, physiology; Feeding Behavior, physiology; Gene Knockdown Techniques; Motor Neurons, microbiology, physiology; Mutation, physiology; Neural Pathways, microbiology, physiology; Peristalsis, physiology; Pharyngeal Muscles, microbiology, physiology; Receptors, Serotonin, physiology; Serotonin, physiology},
  mid             = {NIHMS357136},
  nlm-id          = {8102140},
  owner           = {NLM},
  pii             = {32/6/1920},
  pmc             = {PMC3463504},
  pmid            = {22323705},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2016-10-19},
}

@Article{oh2011,
  author          = {Oh, Won Chan and Song, Hyun-Ok and Cho, Jeong Hoon and Park, Byung-Jae},
  title           = {ANK repeat-domain of SHN-1 Is indispensable for in vivo SHN-1 function in C. elegans.},
  journal         = {Molecules and cells},
  year            = {2011},
  volume          = {31},
  pages           = {79--84},
  month           = jan,
  issn            = {0219-1032},
  abstract        = {Shank protein is one of the postsynaptic density (PSD) proteins which play a major role in proper localization of proteins at membranes. The shn-1, a homolog of Shank in Caenorhabditis elegans, is expressed in neurons, pharynx, intestine, vulva and sperm. We have previously reported a possible genetic interaction between Shank and IP₃ receptor by examining shn-1 RNAi in IP₃ receptor (itr-1) mutant background. In order to show the direct interaction of Shank and IP₃ receptor as well as to show the direct in vivo function of Shank, we have characterized two different mutant alleles of shn-1, which have different deletions in the different domains. shn-1 mutants were observed for Ca²+-related behavioral defects with itr-1 mutants. We found that only shn-1 mutant defective in ANK repeat-domain showed significant defects in defecation, pharyngeal pumping and fertility. In addition, we found that shn-1 regulates defecation, pharyngeal pumping and probably male fertility with itr-1. Thus, we suggest that Shank ANK repeat-domain along with PDZ may play a crucial role in regulating Ca²+-signaling with IP₃ receptor.},
  chemicals       = {Caenorhabditis elegans Proteins, Inositol 1,4,5-Trisphosphate Receptors, SHN-1 protein, C elegans},
  citation-subset = {IM},
  completed       = {2011-09-20},
  country         = {Korea (South)},
  doi             = {10.1007/s10059-011-0007-9},
  issn-linking    = {1016-8478},
  issue           = {1},
  keywords        = {Alleles; Animals; Ankyrin Repeat; Caenorhabditis elegans, physiology; Caenorhabditis elegans Proteins, genetics, metabolism; Defecation, genetics; Fertility, genetics; Genotype; Inositol 1,4,5-Trisphosphate Receptors, metabolism; Intestines, metabolism; Male; Pharyngeal Muscles, metabolism; Pharynx, metabolism; Phenotype; RNA Interference; Sequence Deletion; Sexual Behavior, Animal; Signal Transduction; Spermatozoa, physiology},
  nlm-id          = {9610936},
  owner           = {NLM},
  pmc             = {PMC3906869},
  pmid            = {21191812},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2015-02-05},
}

@Article{song2009,
  author          = {Song, Hyun-Ok and Lee, Wonhae and An, Kiyoung and Lee, Hye-suk and Cho, Jeong Hoon and Park, Zee-Yong and Ahnn, Joohong},
  title           = {C. elegans STI-1, the homolog of Sti1/Hop, is involved in aging and stress response.},
  journal         = {J. Mol. Biol.},
  year            = {2009},
  volume          = {390},
  pages           = {604--617},
  month           = jul,
  issn            = {1089-8638},
  abstract        = {Environmental and physiological stresses such as heat shock, oxidative stress, heavy metals, and pathogenic conditions induce cellular stress response. This response is often mediated by heat shock proteins that function as molecular chaperones. A stress-inducible cochaperone, Sti1/Hop (Hsp organizer protein), functions as an adaptor protein that simultaneously binds with Hsp70 and Hsp90 to transfer client proteins from Hsp70 to Hsp90. However, the biological role of STI-1 in vivo is poorly understood in metazoans. Here, we report the characterization of the Caenorhabditis elegans homolog of Sti1/Hop, which is approximately 56% identical with human STI-1. C. elegans STI-1 (CeSTI-1) is expressed in the pharynx, intestine, nervous system, and muscle from larvae to adults. Analysis of proteins immunoprecipitated with anti-STI-1 antibody by mass spectrometry revealed that CeSTI-1 can bind with both Hsp70 and Hsp90 homologs like its mammalian counterpart. sti-1 expression is elevated by heat stress, and an sti-1(jh125) null mutant shows decreased fertility under heat stress conditions. These mutants also show abnormally high lethality in extreme heat and may be functioning with DAF-16 in thermotolerance. In addition, sti-1(jh125) mutants have a shortened life span. Our results confirm that CeSTI-1 is a cochaperone protein that may maintain homeostatic functions during episodes of stress and can regulate longevity in nematodes.},
  chemicals       = {Caenorhabditis elegans Proteins, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Heat-Shock Proteins, Molecular Chaperones, STI-1 protein, C elegans, STIP1 protein, human},
  citation-subset = {IM},
  completed       = {2009-09-10},
  country         = {England},
  doi             = {10.1016/j.jmb.2009.05.035},
  issn-linking    = {0022-2836},
  issue           = {4},
  keywords        = {Aging, physiology; Amino Acid Sequence; Animals; Caenorhabditis elegans, growth & development, metabolism; Caenorhabditis elegans Proteins, genetics, physiology; HSP70 Heat-Shock Proteins, metabolism; HSP90 Heat-Shock Proteins, metabolism; Heat-Shock Proteins, genetics, physiology; Heat-Shock Response; Hot Temperature; Humans; Larva, metabolism; Longevity, physiology; Molecular Chaperones, genetics, physiology; Molecular Sequence Data; Mutation; Protein Binding; Stress, Physiological},
  nlm-id          = {2985088R},
  owner           = {NLM},
  pii             = {S0022-2836(09)00620-2},
  pmid            = {19467242},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2009-09-11},
}

@Article{lee2009,
  author          = {Lee, Soo-Ung and Song, Hyun-Ok and Lee, Wonhae and Singaravelu, Gunasekaran and Yu, Jae-Ran and Park, Woo-Yoon},
  title           = {Identification and characterization of a putative basic helix-loop-helix (bHLH) transcription factor interacting with calcineurin in C. elegans.},
  journal         = {Molecules and cells},
  year            = {2009},
  volume          = {28},
  pages           = {455--461},
  month           = nov,
  issn            = {0219-1032},
  abstract        = {Calcineurin is a Ca(2+)/Calmodulin activated Ser/Thr phosphatase that is well conserved from yeast to human. It is composed of catalytic subunit A (CnA) and regulatory subunit B (CnB). C. elegans homolog of CnA and CnB has been annotated to tax-6 and cnb-1, respectively and in vivo function of both genes has been intensively studied. In C. elegans, calcineurin play roles in various signaling pathways such as fertility, movement, body size regulation and serotonin-mediated egg laying. In order to understand additional signaling pathway(s) in which calcineurin functions, we screened for binding proteins of TAX-6 and found a novel binding protein, HLH-11. The HLH-11, a member of basic helix-loop-helix (bHLH) proteins, is a putative counterpart of human AP4 transcription factor. Previously bHLH transcription factors have been implicated to regulate many developmental processes such as cell proliferation and differentiation, sex determination and myogenesis. However, the in vivo function of hlh-11 is largely unknown. Here, we show that hlh-11 is expressed in pharynx, intestine, nerve cords, anal depressor and vuvla muscles where calcineurin is also expressed. Mutant analyses reveal that hlh-11 may have role(s) in regulating body size and reproduction. More interestingly, genetic epistasis suggests that hlh-11 may function to regulate serotonin-mediated egg laying at the downstream of tax-6.},
  chemicals       = {Arabidopsis Proteins, Basic Helix-Loop-Helix Transcription Factors, Caenorhabditis elegans Proteins, HLH-11 protein, Arabidopsis, Protein Subunits, Serotonin, Calcineurin},
  citation-subset = {IM},
  completed       = {2010-03-30},
  country         = {Korea (South)},
  doi             = {10.1007/s10059-009-0145-5},
  issn-linking    = {1016-8478},
  issue           = {5},
  keywords        = {Amino Acid Sequence; Animals; Arabidopsis Proteins, chemistry, genetics, metabolism; Basic Helix-Loop-Helix Transcription Factors, chemistry, genetics, metabolism; Caenorhabditis elegans, drug effects, genetics; Caenorhabditis elegans Proteins, chemistry, genetics, metabolism; Calcineurin, metabolism; Gene Deletion; Gene Expression Profiling; Gene Expression Regulation, drug effects; Humans; Molecular Sequence Data; Ovulation, drug effects; Protein Binding, drug effects; Protein Subunits, chemistry, genetics, metabolism; Sequence Alignment; Sequence Homology, Amino Acid; Serotonin, pharmacology},
  nlm-id          = {9610936},
  owner           = {NLM},
  pmid            = {19855932},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{song2013a,
  author       = {Song, Bo-Mi and Avery, Leon},
  title        = {The pharynx of the nematode C. elegans: A model system for the study of motor control.},
  journal      = {Worm},
  year         = {2013},
  volume       = {2},
  pages        = {e21833},
  month        = jan,
  issn         = {2162-4046},
  abstract     = {Motor control is a complex process that requires interplay among the nervous system, muscles and environment. The simple anatomy, well-characterized muscle movements and ample resources for molecular and cellular dissection make the pharynx of the nematode C. elegans an attractive model system for the study of motor control. The C. elegans pharynx shows two clear muscle movements that are essential for food intake, pharyngeal pumping and isthmus peristalsis. Here, we review our recent findings on the mechanism by which food activates the feeding motions. To understand this process, we characterized the behavior of the feeding motions in response to serotonin, an endogenous pharyngeal pumping activator whose action is triggered by food. We found that: (1) the timing of onset and frequencies of the two feeding motions are distinct; (2) isthmus peristalsis is selectively coupled to the preceding pump; (3) like food, serotonin activates isthmus peristalsis as well as pharyngeal pumping. By genetic analysis, we showed that two separate neural pathways activate the two feeding motions explaining the differences between the two feeding motions. We also proposed a model that explains how the two feeding motions are separately controlled, yet coupled by the interaction between the nervous system and the muscles in the pharynx. Finally, we briefly discuss future approaches to further understand the mechanism that couples the two feeding motions in C. elegans and to possibly understand evolution of motor control in the pharynx by expanding findings in C. elegans to other nematode species. },
  completed    = {2013-09-23},
  country      = {United States},
  doi          = {10.4161/worm.21833},
  issn-linking = {2162-4046},
  issue        = {1},
  keywords     = {feeding activation; motor control; muscle; neural circuit; pharynx; serotonin},
  nlm-id       = {101591366},
  owner        = {NLM},
  pii          = {2012WORM049},
  pmc          = {PMC3670459},
  pmid         = {24058858},
  pubmodel     = {Print},
  pubstatus    = {ppublish},
  revised      = {2017-02-20},
}

@Article{park2001,
  author          = {Park, B J and Lee, D G and Yu, J R and Jung, S K and Choi, K and Lee, J and Lee, J and Kim, Y S and Lee, J I and Kwon, J Y and Lee, J and Singson, A and Song, W K and Eom, S H and Park, C S and Kim, D H and Bandyopadhyay, J and Ahnn, J},
  title           = {Calreticulin, a calcium-binding molecular chaperone, is required for stress response and fertility in Caenorhabditis elegans.},
  journal         = {Molecular biology of the cell},
  year            = {2001},
  volume          = {12},
  pages           = {2835--2845},
  month           = sep,
  issn            = {1059-1524},
  abstract        = {Calreticulin (CRT), a Ca(2+)-binding protein known to have many cellular functions, including regulation of Ca(2+) homoeostasis and chaperone activity, is essential for heart and brain development during embryogenesis in mice. Here, we report the functional characterization of Caenorhabditis elegans calreticulin (crt-1). A crt-1 null mutant does not result in embryonic lethality but shows temperature-dependent reproduction defects. In C. elegans CRT-1 is expressed in the intestine, pharynx, body-wall muscles, head neurons, coelomocytes, and in sperm. crt-1 males exhibit reduced mating efficiency and defects late in sperm development in addition to defects in oocyte development and/or somatic gonad function in hermaphrodites. Furthermore, crt-1 and itr-1 (inositol triphosphate receptor) together are required for normal behavioral rhythms. crt-1 transcript level is elevated under stress conditions, suggesting that CRT-1 may be important for stress-induced chaperoning function in C. elegans.},
  chemicals       = {Caenorhabditis elegans Proteins, Calcium Channels, Calcium-Binding Proteins, Calreticulin, Inositol 1,4,5-Trisphosphate Receptors, Molecular Chaperones, RNA, Messenger, Receptors, Cytoplasmic and Nuclear, Ribonucleoproteins, Calcium},
  citation-subset = {IM},
  completed       = {2001-12-04},
  country         = {United States},
  doi             = {10.1091/mbc.12.9.2835},
  issn-linking    = {1059-1524},
  issue           = {9},
  keywords        = {Animals; Blotting, Northern; Blotting, Western; Caenorhabditis elegans, genetics, metabolism, physiology; Caenorhabditis elegans Proteins, genetics, metabolism; Calcium, metabolism; Calcium Channels, metabolism; Calcium-Binding Proteins, genetics, metabolism; Calreticulin; Fertility, genetics; Gene Deletion; Gene Expression Profiling; Homeostasis; Immunohistochemistry; In Situ Hybridization; Inositol 1,4,5-Trisphosphate Receptors; Intestines, metabolism; Male; Molecular Chaperones, genetics, metabolism; Muscles, metabolism; Pharynx, metabolism; RNA, Messenger, genetics, metabolism; Receptors, Cytoplasmic and Nuclear, metabolism; Ribonucleoproteins, genetics, metabolism; Spermatozoa, metabolism; Temperature},
  nlm-id          = {9201390},
  owner           = {NLM},
  pmc             = {PMC59717},
  pmid            = {11553721},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-06-20},
}

@Article{raizen2012,
  author          = {Raizen, David and Song, Bo-Mi and Trojanowski, Nick and You, Young-Jai},
  title           = {Methods for measuring pharyngeal behaviors.},
  journal         = {WormBook : the online review of C. elegans biology},
  year            = {2012},
  pages           = {1--13},
  month           = dec,
  issn            = {1551-8507},
  abstract        = {The pharynx is a neuromuscular pump at the anterior end of the alimentary tract. It is made up of 20 muscle cells, 20 neurons, and 20 other cells. Pharyngeal activity correlates with food intake. The proper feeding rate, as well as the precise timing of pharyngeal movements, is required for efficient feeding and likely for survival in nature. For most purposes, pharyngeal behavioral analysis requires no more than a routine stereomicroscope and a pair of eyes, but accuracy can be increased by video recording followed by off-line analysis in slow motion. Like other C. elegans behaviors, pharyngeal behavior is sensitive to both the immediate environmental conditions as well as to the history of such conditions.},
  citation-subset = {IM},
  completed       = {2013-05-10},
  country         = {United States},
  doi             = {10.1895/wormbook.1.154.1},
  issn-linking    = {1551-8507},
  keywords        = {Animals; Caenorhabditis elegans, physiology; Feeding Behavior; Peristalsis, physiology; Pharynx, physiology},
  nlm-id          = {101303985},
  owner           = {NLM},
  pmc             = {PMC4781406},
  pmid            = {23255345},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2016-10-19},
}

@Article{hobson2003,
  author          = {Hobson, R. J. and Geng, J. and Gray, A. D. and Komuniecki, R. W.},
  title           = "{SER-7b, a Constitutively Active G$\alpha$s Coupled 5-HT7-like Receptor Expressed in the \textit{Caenorhabditis elegans} M4 Pharyngeal Motorneuron}",
  journal         = {J. Neurochem.},
  year            = {2003},
  volume          = {87},
  pages           = {22--29},
  issn            = {0022-3042},
  abstract        = {Serotonin plays a key role in the regulation of pharyngeal pumping in nematodes. We have isolated a Caenorhabditis elegans cDNA (C09B7.1b, ser-7b) with greatest identity to the 5-HT7 receptor family. Membranes from COS-7 cells expressing SER-7b exhibit saturable [3H]-LSD binding (Kd = 45 nm) that is inhibited by serotonin (5-HT) and tryptamine, but not by other physiological biogenic amines. Expression of SER-7b in COS-7 cells results in dramatic increase in basal cAMP levels over untransfected cells that is dependent on expression level. 5-HT further elevates cAMP levels in a dose-dependent manner (pEC50 = 7.5 +/- 0.5). Mammalian 5-HT7 receptor inverse agonists reduce constitutive activity, with methiothepin the most potent (pIC50 = 7.8 +/- 0.1). Ser-7::GFP transcriptional fusions reveal that SER-7b appears to be expressed solely in the M4 pharyngeal motorneuron after hatching. This is the first report of a Galphas coupled biogenic amine receptor in nematodes and the localization of SER-7b in the M4 pharyngeal motorneuron suggests that SER-7b may play a role in the regulation of pharyngeal pumping.},
  chemicals       = {Caenorhabditis elegans Proteins, Receptors, Serotonin, SER-7b protein, C elegans, Serotonin Antagonists, serotonin 7 receptor, Serotonin, Methiothepin, GTP-Binding Protein alpha Subunits, Gs, Heterotrimeric GTP-Binding Proteins},
  citation-subset = {IM},
  completed       = {2003-11-12},
  country         = {England},
  issn-linking    = {0022-3042},
  issue           = {1},
  keywords        = {Amino Acid Sequence; Animals; Binding, Competitive; COS Cells; Caenorhabditis elegans, metabolism; Caenorhabditis elegans Proteins, biosynthesis; GTP-Binding Protein alpha Subunits, Gs, chemistry, genetics, metabolism; Heterotrimeric GTP-Binding Proteins, metabolism; Methiothepin, pharmacokinetics; Molecular Sequence Data; Motor Neurons, metabolism; Pharynx, metabolism; Phylogeny; Receptors, Serotonin, genetics; Sequence Homology, Amino Acid; Serotonin, pharmacokinetics; Serotonin Antagonists, pharmacokinetics},
  nlm-id          = {2985190R},
  owner           = {NLM},
  pii             = {1967},
  pmid            = {12969249},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{regoes2013,
  author          = {Regős, Ágnes and Lengyel, Katalin and Takács-Vellai, Krisztina and Vellai, Tibor},
  title           = {Identification of novel cis-regulatory regions from the Notch receptor genes lin-12 and glp-1 of Caenorhabditis elegans.},
  journal         = {Gene expression patterns : GEP},
  year            = {2013},
  volume          = {13},
  pages           = {66--77},
  issn            = {1872-7298},
  abstract        = {Notch signaling regulates various cellular processes such as growth, proliferation and differentiation, and plays a key role in tissue patterning during animal development. In humans, defects in Notch signaling have been implicated in cancer, stroke, neurodegeneration, as well as learning and memory deficits. The genome of the nematode Caenorhabditis elegans encodes two members of the Notch transmembrane receptor family, LIN-12 and GLP-1, which have both unique and shared developmental functions. LIN-12 affects diverse cell fate specification events at certain embryonic and larval stages, including the ABplp lineage (a neuronal precursor), intestinal primordium, gonadal anchor cell and secondary vulval precursor cells. In addition to developmental functions, it also operates in the adult nervous system to control locomotion, memory and chemosensory response. Although lin-12 expression was subjected to intense analysis, it was almost not demonstrable in neurons; occasional lin-12 expression was detected only in the two RIG interneurons of young larvae. Here we identify two cis-regulatory regions from lin-12, both of them are specified by the presence of a conserved EXD/HOX composite binding site. One of these regions is located in the first intron and required for driving transgene expression in vulval precursor cell lineages and specific gonadal cells. The other region is located in the second intron and can confer neuronal expression for lin-12 throughout life. The latter regulatory element is highly conserved in the paralogous glp-1 genomic environment, suggesting redundant developmental and physiological roles for the two Notch paralogs in the C. elegans nervous system.},
  chemicals       = {Caenorhabditis elegans Proteins, Glp-1 protein, C elegans, Lin-12 protein, C elegans, Receptors, Notch},
  citation-subset = {IM},
  completed       = {2013-09-04},
  country         = {Netherlands},
  doi             = {10.1016/j.gep.2012.11.002},
  issn-linking    = {1567-133X},
  issue           = {3-4},
  keywords        = {Animals; Binding Sites; Body Patterning, genetics; Caenorhabditis elegans, genetics, metabolism; Caenorhabditis elegans Proteins, genetics, metabolism; Cell Differentiation, genetics; Cell Lineage; Embryonic Development, genetics; Gene Expression Regulation, Developmental; Locomotion, genetics; Nervous System, growth & development, metabolism; Neurons, cytology, metabolism; Receptors, Notch, genetics, metabolism; Regulatory Sequences, Nucleic Acid; Signal Transduction},
  nlm-id          = {101167473},
  owner           = {NLM},
  pii             = {S1567-133X(12)00079-8},
  pmid            = {23305862},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-03-25},
}

@Article{olsen2007,
  author          = {Olsen, D P and Phu, D and Libby, L J M and Cormier, J A and Montez, K M and Ryder, E F and Politz, S M},
  title           = {Chemosensory control of surface antigen switching in the nematode Caenorhabditis elegans.},
  journal         = {Genes, brain, and behavior},
  year            = {2007},
  volume          = {6},
  pages           = {240--252},
  month           = apr,
  issn            = {1601-1848},
  abstract        = {Nematodes change their surface compositions in response to environmental signals, which may allow them to survive attacks from microbial pathogens or host immune systems. In the free-living species Caenorhabditis elegans, wild-type worms are induced to display an L1 (first larval stage) surface epitope at later larval stages when grown on an extract of spent culture medium (Inducible Larval Display or ILD). Before this study, it was not known whether ILD was regulated by the well-characterized, neurologically based chemical senses of C. elegans, which mediate other behavioural and developmental responses to environmental signals such as chemotaxis and formation of the facultatively arrested dauer larva stage. We show here that ILD requires the activities of three genes that are essential for the function of the C. elegans chemosensory neurons. ILD was abolished in chemotaxis-defective che-3, osm-3 and tax-4 mutants. In contrast, chemotaxis-defective mutants altered in a different gene, srf-6, show constitutive display of the L1 epitope on all four larval stages. The ILD-defective che-3, osm-3 and tax-4 mutations blocked the constitutive larval display of an srf-6 mutant. Combining srf-6 and certain dauer-constitutive mutations in double mutants enhanced constitutive dauer formation, consistent with the idea that srf-6 acts in parallel with specific components of the dauer formation pathway. These results taken together are consistent with the hypothesis that ILD is triggered by environmental signals detected by the nematode's chemosensory neurons.},
  chemicals       = {Antigens, Surface, Caenorhabditis elegans Proteins, Chemotactic Factors, Epitopes, Ion Channels, Mutant Proteins, OSM-3 protein, C elegans, tax-4 protein, C elegans, Che-3 protein, C elegans, Dyneins, Kinesin},
  citation-subset = {IM},
  completed       = {2007-08-29},
  country         = {England},
  doi             = {10.1111/j.1601-183X.2006.00252.x},
  issn-linking    = {1601-183X},
  issue           = {3},
  keywords        = {Animals; Antigens, Surface, genetics, metabolism; Caenorhabditis elegans, genetics, immunology, metabolism; Caenorhabditis elegans Proteins, genetics, immunology, metabolism; Chemoreceptor Cells, physiology; Chemotactic Factors, genetics, immunology, metabolism; Chemotaxis, physiology; Dyneins, genetics, immunology, metabolism; Epitopes, genetics, immunology, metabolism; Gene Expression Regulation, Developmental, immunology, physiology; Ion Channels, genetics, metabolism; Kinesin, genetics, metabolism; Larva, growth & development, immunology, metabolism; Mutant Proteins, genetics, immunology, metabolism; Skin, immunology, metabolism; Smell, physiology},
  nlm-id          = {101129617},
  owner           = {NLM},
  pii             = {GBB252},
  pmid            = {16879619},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-11-24},
}

@Article{murakami2001,
  author          = {Murakami, M and Koga, M and Ohshima, Y},
  title           = {DAF-7/TGF-beta expression required for the normal larval development in C. elegans is controlled by a presumed guanylyl cyclase DAF-11.},
  journal         = {Mechanisms of development},
  year            = {2001},
  volume          = {109},
  pages           = {27--35},
  month           = nov,
  issn            = {0925-4773},
  abstract        = {In C. elegans development, unfavorable growth conditions lead a larva to an arrested and enduring form called a dauer. To elucidate components upstream of DAF-7/TGF-beta in this control pathway, we isolated a mutant that was defective in daf-7 promoter::gfp reporter expression and showed an arrested (dauer-constitutive) phenotype. It has a new mutation in the daf-11 gene encoding a transmembrane guanylyl cyclase. We show that daf-11 gene and a related gene daf-21 act upstream of daf-7, and cilium-related genes che-2 and che-3 are placed between daf-11 and daf-7, in the genetic pathway controlling dauer formation. Expression of daf-11 cDNA by cell specific promoters suggests that daf-11 acts cell autonomously in ASI chemosensory neurons for daf-7 expression.},
  chemicals       = {Caenorhabditis elegans Proteins, DAF-7 protein, C elegans, Helminth Proteins, Luminescent Proteins, Transforming Growth Factor beta, Green Fluorescent Proteins, Guanylate Cyclase},
  citation-subset = {IM},
  completed       = {2002-01-22},
  country         = {Ireland},
  issn-linking    = {0925-4773},
  issue           = {1},
  keywords        = {Alleles; Animals; Artificial Gene Fusion; Caenorhabditis elegans, genetics, growth & development, metabolism; Caenorhabditis elegans Proteins; Gene Expression Regulation; Green Fluorescent Proteins; Guanylate Cyclase, genetics, metabolism; Helminth Proteins, genetics; Larva, growth & development; Luminescent Proteins, genetics; Mutagenesis; Neurons; Phenotype; Promoter Regions, Genetic; Transforming Growth Factor beta, genetics},
  nlm-id          = {9101218},
  owner           = {NLM},
  pii             = {S0925-4773(01)00507-X},
  pmid            = {11677050},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2008-11-21},
}

@Article{ren1996,
  author          = {Ren, P and Lim, C S and Johnsen, R and Albert, P S and Pilgrim, D and Riddle, D L},
  title           = {Control of C. elegans larval development by neuronal expression of a TGF-beta homolog.},
  journal         = {Science (New York, N.Y.)},
  year            = {1996},
  volume          = {274},
  pages           = {1389--1391},
  month           = nov,
  issn            = {0036-8075},
  abstract        = {The Caenorhabditis elegans dauer larva is specialized for dispersal without growth and is formed under conditions of overcrowding and limited food. The daf-7 gene, required for transducing environmental cues that support continuous development with plentiful food, encodes a transforming growth factor-beta (TGF-beta) superfamily member. A daf-7 reporter construct is expressed in the ASI chemosensory neurons. Dauer-inducing pheromone inhibits daf-7 expression and promotes dauer formation, whereas food reactivates daf-7 expression and promotes recovery from the dauer state. When the food/pheromone ratio is high, the level of daf-7 mRNA peaks during the L1 larval stage, when commitment to non-dauer development is made.},
  chemicals       = {Caenorhabditis elegans Proteins, DAF-7 protein, C elegans, Helminth Proteins, Ligands, Luminescent Proteins, Pheromones, Transforming Growth Factor beta, Green Fluorescent Proteins},
  citation-subset = {IM},
  completed       = {1996-12-13},
  country         = {United States},
  issn-linking    = {0036-8075},
  issue           = {5291},
  keywords        = {Amino Acid Sequence; Animals; Animals, Genetically Modified; Caenorhabditis elegans, genetics, growth & development, metabolism; Caenorhabditis elegans Proteins; Genes, Helminth; Genes, Reporter; Green Fluorescent Proteins; Helminth Proteins, chemistry, genetics, physiology; Humans; Larva, growth & development, metabolism; Ligands; Luminescent Proteins, genetics; Molecular Sequence Data; Mutation; Neurons, Afferent, metabolism; Phenotype; Pheromones, pharmacology; Temperature; Transforming Growth Factor beta, chemistry, genetics, physiology; Transgenes},
  nlm-id          = {0404511},
  owner           = {NLM},
  pmid            = {8910282},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2007-11-14},
}

@Article{bargmann1991,
  author          = {Bargmann, C. I. and Horvitz, H. R.},
  title           = {Control of larval development by chemosensory neurons in Caenorhabditis elegans.},
  journal         = {Science (New York, N.Y.)},
  year            = {1991},
  volume          = {251},
  pages           = {1243--1246},
  month           = mar,
  issn            = {0036-8075},
  abstract        = {Larval development of the nematode Caenorhabditis elegans is controlled by the activities of four classes of chemosensory neurons. The choice between normal development and development into a specialized larval form called a dauer larva is regulated by competing environmental stimuli: food and a dauer pheromone. When the neuron classes ADF, ASG, ASI, and ASJ are killed, animals develop as dauer larvae regardless of environmental conditions. These neurons might sense food or dauer pheromone, or both, to initiate the specialized differentiation of many cell types that occurs during dauer formation. Entry into and exit from the dauer stage are primarily controlled by different chemosensory neurons. The analysis of mutants defective in dauer formation indicates that the chemosensory neurons are active in the absence of sensory inputs and that dauer pheromone inhibits the ability of these neurons to generate a signal necessary for normal development.},
  citation-subset = {IM},
  completed       = {1991-04-23},
  country         = {United States},
  issn-linking    = {0036-8075},
  issue           = {4998},
  keywords        = {Animals; Caenorhabditis, growth & development; Cell Survival; Larva; Models, Neurological; Mutation; Neurons, Afferent, cytology, physiology},
  nlm-id          = {0404511},
  owner           = {NLM},
  pmid            = {2006412},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2007-11-14},
}

@Article{battu2003,
  author          = {Battu, Gopal and Hoier, Erika Froehli and Hajnal, Alex},
  title           = {The C. elegans G-protein-coupled receptor SRA-13 inhibits RAS/MAPK signalling during olfaction and vulval development.},
  journal         = {Development (Cambridge, England)},
  year            = {2003},
  volume          = {130},
  pages           = {2567--2577},
  month           = jun,
  issn            = {0950-1991},
  abstract        = {In C. elegans, the RAS/MAPK pathway is used in different tissues to regulate various cell fate decisions. Several positive and negative regulators tightly control the activity of the RAS/MAPK pathway at different steps. We demonstrate a link between a G-protein-coupled receptor signalling pathway and the RAS/MAPK cascade. SRA-13, a member of the SRA family of chemosensory receptors, negatively regulates RAS/MAPK signalling during vulval induction and the olfaction of volatile attractants. Epistasis analysis indicates that SRA-13 inhibits the RAS/MAPK pathway at the level or upstream of MAPK. In both tissues, the vulval precursor cells and the chemosensory neurones, SRA-13 acts through the GPA-5 Galpha protein subunit, suggesting a common mechanism of crosstalk. Moreover, we find that vulval induction is repressed by food withdrawal during larval development and that SRA-13 activity is required for the suppression of vulval induction in response to food starvation. Thus, SRA-13 may serve to adapt the activity of the RAS/MAPK pathway to environmental conditions.},
  chemicals       = {Receptors, Cell Surface, Mitogen-Activated Protein Kinases, ras Proteins},
  citation-subset = {IM},
  completed       = {2003-07-31},
  country         = {England},
  issn-linking    = {0950-1991},
  issue           = {12},
  keywords        = {Amino Acid Sequence; Animals; Caenorhabditis elegans, embryology, metabolism; Embryonic Induction, physiology; Female; Mitogen-Activated Protein Kinases, metabolism; Molecular Sequence Data; Neurons, physiology; Phylogeny; Receptors, Cell Surface, metabolism; Sequence Analysis, DNA; Signal Transduction; Smell, physiology; Vulva, embryology, metabolism; ras Proteins, metabolism},
  nlm-id          = {8701744},
  owner           = {NLM},
  pmid            = {12736202},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2009-11-19},
}

@Article{ashton1999,
  author          = {Ashton, F T and Li, J and Schad, G A},
  title           = {Chemo- and thermosensory neurons: structure and function in animal parasitic nematodes.},
  journal         = {Veterinary parasitology},
  year            = {1999},
  volume          = {84},
  pages           = {297--316},
  month           = aug,
  issn            = {0304-4017},
  abstract        = {Nematode parasites of warm-blooded hosts use chemical and thermal signals in host-finding and in the subsequent resumption of development. The free-living nematode Caenorhabditis elegans is a useful model for investigating the chemo- and thermosensory neurons of such parasites, because the functions of its amphidial neurons are well known from laser microbeam ablation studies. The neurons found in the amphidial channel detect aqueous chemoattractants and repellants; the wing cells-flattened amphidial neurons-detect volatile odorants. The finger cells-digitiform amphidial neurons-are the primary thermoreceptors. Two neuron classes, named ADF and ASI, control entry into the environmentally resistant resting and dispersal dauer larval stage, while the paired ASJ neurons control exit from this stage. Skin-penetrating nematode parasites, i.e. the dog hookworm Ancylostoma caninum, and the threadworm, Strongyloides stercoralis, use thermal and chemical signals for host-finding, while the passively ingested sheep stomach worm, Haemonchus contortus, uses environmental signals to position itself for ingestion. Amphidial neurons presumably recognize these signals. In all species, resumption of development, on entering a host, is probably triggered by host signals also perceived by amphidial neurons. In the amphids of the A. caninum infective larva, there are wing- and finger-cell neurons, as well as neurons ending in cilia-like dendritic processes, some of which presumably recognize a sequence of signals that stimulate these larvae to attach to suitable hosts. The functions of these neurons can be postulated, based on the known functions of their homologs in C. elegans. The threadworm, S. stercoralis, has a complex life cycle. After leaving the host, soil-dwelling larvae may develop either to infective larvae (the life-stage equivalent of dauer larvae) or to free-living adults. As with the dauer larva of C. elegans, two neuron classes control this developmental switch. Amphidial neurons control chemotaxis to a skin extract, and a highly modified amphidial neuron, the lamellar cell, appears to be the primary thermoreceptor, in addition to having chemosensory function. The stomach worm, Haemonchus contortus, depends on ingestion by a grazing host. Once ingested, the infective larva is exposed to profound environmental changes in the rumen. These changes stimulate resumption of development in this species. We hypothesize that resumption of development is under the control of the ASJ neuronal pair. Identification of the neurons that control the infective process could provide the basis for entirely new approaches to parasite control involving interference with development at the time and place of initial host-contact.},
  citation-subset = {IM},
  completed       = {1999-10-21},
  country         = {Netherlands},
  issn-linking    = {0304-4017},
  issue           = {3-4},
  keywords        = {Ancylostoma, anatomy & histology; Ancylostomiasis, prevention & control, transmission, veterinary; Animals; Caenorhabditis elegans, anatomy & histology; Dog Diseases, parasitology, prevention & control, transmission; Dogs; Haemonchiasis, prevention & control, transmission, veterinary; Haemonchus, anatomy & histology; Humans; Neurons, physiology, ultrastructure; Sheep; Sheep Diseases, parasitology, prevention & control, transmission; Strongyloides stercoralis, anatomy & histology; Strongyloidiasis, prevention & control, transmission},
  nlm-id          = {7602745},
  owner           = {NLM},
  pii             = {S0304-4017(99)00037-0},
  pmid            = {10456420},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {49},
  revised         = {2007-11-14},
}

@Article{cunningham2012,
  author  = {Cunningham, K. and Hua, Z. and Srinivasan, S. and Liu, J. and Lee, B. H. and Edwards, R. H. and Ashrafi, K.},
  title   = "{AMP-Activated Kinase Links Serotonergic Signaling to Glutamate Release for Regulation of Feeding Behavior in \textit{C. elegans.}}",
  journal = {Cell Metab.},
  year    = {2012},
  volume  = {3},
  number  = {16},
  pages   = {113-121},
}

@Article{rand1989,
  author    = {Rand, J. B.},
  title     = "{Genetic Analysis of the cha-1-unc-17 Gene Xomplex in \textit{Caenorhabditis.}}",
  journal   = {Genetics},
  year      = {1989},
  volume    = {122},
  number    = {1},
  pages     = {73--80},
  publisher = {Genetics Soc America},
}

@Article{alfonso1993,
  author  = {Alfonso, A. and Grundahl, K. and Duerr, J. and Han, H. and Rand, J.},
  title   = {The \textit{Caenorhabditis elegans} unc-17 gene: a putative vesicular acetylcholine transporter},
  journal = {Science},
  year    = {1993},
  volume  = {261},
  pages   = {617-619},
  issn    = {0036-8075},
  doi     = {10.1126/science.8342028},
}

@Article{nonet1998,
  author = {Michael L. Nonet and Owais Saifee and Hongjuan Zhao and James B. Rand and Liping Wei},
  title  = {Synaptic Transmission Deficits inCaenorhabditis elegansSynaptobrevin Mutants},
  year   = {1998},
  volume = {18},
  pages  = {70-80},
  issn   = {0270-6474},
  doi    = {10.1523/jneurosci.18-01-00070.1998},
}

@Article{albertson1976,
  author  = {Albertson, D. G. and Thomson, J. N.},
  title   = {The Pharynx of \texiit{Caenorhabditis elegans}},
  journal = {Phil. Trans. Royal Soc. London},
  year    = {1976},
  volume  = {275},
  pages   = {299-325},
  issn    = {0962-8436},
  doi     = {10.1098/rstb.1976.0085},
}

@Article{yan2012,
  author          = {Yan, Ruofeng and Urdaneta-Marquez, Ludmel and Keller, Kathy and James, Catherine E and Davey, Mary W and Prichard, Roger K},
  title           = {The role of several ABC transporter genes in ivermectin resistance in Caenorhabditis elegans.},
  journal         = {Veterinary parasitology},
  year            = {2012},
  volume          = {190},
  pages           = {519--529},
  month           = dec,
  issn            = {1873-2550},
  abstract        = {The functions of nine ATP-binding cassette (ABC) transporter genes, mrp-1, mrp-4, mrp-6, pgp-2, pgp-3, pgp-4, pgp-5, haf-2 and haf-9, in an ivermectin (IVM) resistant strain of Caenorhabditis elegans were screened by comparing transcription levels between the resistant (IVR10) and wild-type (Bristol N2) strains, and by measuring the effects of RNA interference (RNAi) on the IVM resistant strain, on motility, pharyngeal pumping, egg production and death in the presence or varying concentrations of IVM (0-20 ng/ml). mRNA levels of mrp-1, 2, 4, 5, 6, 7, pgp-1, 2, 4, 12, 14, haf-1, 2 and 3 were significantly increased in IVR10 compared with the N2 strain. At 15 or 20 ng/ml IVM, down regulation of mrp-1, pgp-4, haf-2 and haf-9 significantly increased the effect of IVM to reduce egg production. At low to moderate IVM concentrations, down regulation of mrp-1 and haf-2 reduced the motility of C. elegans. However, at high IVM concentrations motility was increased by down regulation of transcription of pgp-3, pgp-4 and haf-9. Down regulation of expression of mrp-1, pgp-2 and pgp-5 resulted in reduced pharyngeal pumping in the presence of varying concentrations of IVM, while down regulation of mrp-6 and haf-2 increased pharyngeal pumping of the resistant strain irrespective of the IVM concentration used. Although the IVR10 strain was markedly resistant to IVM, compared with the unselected N2 strain, IVM led to the death of the C. elegans in a concentration dependent manner. However, differences in the IVM induced death rate, following RNAi, were not significantly different from the IVR10 strain without RNAi. The study shows that different ABC transporter genes may play a role in modulating the effects of IVM on pharyngeal pumping, motility and egg production, with down regulation of mrp-1 and haf-2 perhaps having the greatest effects. However, down regulation of expression of no individual ABC transporter gene profoundly affected the effect of IVM on mortality in the IVR10 strain. This suggests that some of these ABC transporter genes and their products may play a role in modulating the effects of IVM, but are not, individually, the critical gene responsible for IVM resistance. This study provides a model that may help to understand drug resistance in parasitic nematodes.},
  chemicals       = {ATP-Binding Cassette Transporters, Caenorhabditis elegans Proteins, Ivermectin},
  citation-subset = {IM},
  completed       = {2013-04-08},
  country         = {Netherlands},
  doi             = {10.1016/j.vetpar.2012.06.038},
  issn-linking    = {0304-4017},
  issue           = {3-4},
  keywords        = {ATP-Binding Cassette Transporters, genetics, metabolism; Animals; Caenorhabditis elegans, drug effects; Caenorhabditis elegans Proteins, genetics, metabolism; Drug Resistance, genetics, physiology; Gene Expression Regulation, drug effects; Ivermectin, pharmacology; Mice; Oviposition, drug effects; RNA Interference},
  nlm-id          = {7602745},
  owner           = {NLM},
  pii             = {S0304-4017(12)00352-4},
  pmid            = {22840641},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-12-13},
}

@Article{ghosh2012a,
  author          = {Ghosh, Rajarshi and Andersen, Erik C and Shapiro, Joshua A and Gerke, Justin P and Kruglyak, Leonid},
  title           = {Natural variation in a chloride channel subunit confers avermectin resistance in C. elegans.},
  journal         = {Science (New York, N.Y.)},
  year            = {2012},
  volume          = {335},
  pages           = {574--578},
  month           = feb,
  issn            = {1095-9203},
  abstract        = {Resistance of nematodes to anthelmintics such as avermectins has emerged as a major global health and agricultural problem, but genes conferring natural resistance to avermectins are unknown. We show that a naturally occurring four-amino-acid deletion in the ligand-binding domain of GLC-1, the alpha-subunit of a glutamate-gated chloride channel, confers resistance to avermectins in the model nematode Caenorhabditis elegans. We also find that the same variant confers resistance to the avermectin-producing bacterium Streptomyces avermitilis. Population-genetic analyses identified two highly divergent haplotypes at the glc-1 locus that have been maintained at intermediate frequencies by long-term balancing selection. These results implicate variation in glutamate-gated chloride channels in avermectin resistance and provide a mechanism by which such resistance can be maintained.},
  chemicals       = {Antinematodal Agents, Caenorhabditis elegans Proteins, Chloride Channels, Ligands, glutamate-gated chloride channel 1, C elegans, glutamate-gated chloride channels, abamectin, Ivermectin},
  citation-subset = {IM},
  completed       = {2012-11-02},
  country         = {United States},
  doi             = {10.1126/science.1214318},
  issn-linking    = {0036-8075},
  issue           = {6068},
  keywords        = {Amino Acid Sequence; Animals; Animals, Genetically Modified; Antinematodal Agents, pharmacology; Caenorhabditis elegans, drug effects, genetics, physiology; Caenorhabditis elegans Proteins, chemistry, genetics, metabolism; Chloride Channels, chemistry, genetics, metabolism; Crosses, Genetic; Drug Resistance, genetics; Genes, Helminth; Genome-Wide Association Study; Ivermectin, analogs & derivatives, pharmacology; Ligands; Molecular Sequence Data; Mutation; Polymorphism, Single Nucleotide; Protein Structure, Tertiary; Quantitative Trait Loci; Selection, Genetic; Streptomyces, physiology},
  mid             = {NIHMS342302},
  nlm-id          = {0404511},
  owner           = {NLM},
  pii             = {335/6068/574},
  pmc             = {PMC3273849},
  pmid            = {22301316},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2016-11-25},
}

@Article{dent2000,
  author          = {Dent, J A and Smith, M M and Vassilatis, D K and Avery, L},
  title           = {The genetics of ivermectin resistance in Caenorhabditis elegans.},
  journal         = { Proc. Natl. Acad. Sci. USA of the United States of America},
  year            = {2000},
  volume          = {97},
  pages           = {2674--2679},
  month           = mar,
  issn            = {0027-8424},
  abstract        = {The ability of organisms to evolve resistance threatens the effectiveness of every antibiotic drug. We show that in the nematode Caenorhabditis elegans, simultaneous mutation of three genes, avr-14, avr-15, and glc-1, encoding glutamate-gated chloride channel (GluCl) alpha-type subunits confers high-level resistance to the antiparasitic drug ivermectin. In contrast, mutating any two channel genes confers modest or no resistance. We propose a model in which ivermectin sensitivity in C. elegans is mediated by genes affecting parallel genetic pathways defined by the family of GluCl genes. The sensitivity of these pathways is further modulated by unc-7, unc-9, and the Dyf (dye filling defective) genes, which alter the structure of the nervous system. Our results suggest that the evolution of drug resistance can be slowed by targeting antibiotic drugs to several members of a multigene family.},
  chemicals       = {Antinematodal Agents, Caenorhabditis elegans Proteins, Chloride Channels, Helminth Proteins, OSM-1 protein, C elegans, glutamate-gated chloride channels, Glutamic Acid, Ivermectin},
  citation-subset = {IM},
  completed       = {2000-04-25},
  country         = {United States},
  issn-linking    = {0027-8424},
  issue           = {6},
  keywords        = {Animals; Antinematodal Agents, pharmacology; Caenorhabditis elegans, drug effects, genetics; Caenorhabditis elegans Proteins; Chloride Channels, genetics; Cloning, Molecular; Drug Resistance, genetics; Electrophysiology; Glutamic Acid, pharmacology; Helminth Proteins, genetics; Ivermectin, pharmacology; Models, Biological; Models, Genetic; Mutation; Pharynx, drug effects; Protein Binding},
  nlm-id          = {7505876},
  owner           = {NLM},
  pii             = {97/6/2674},
  pmc             = {PMC15988},
  pmid            = {10716995},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2017-02-19},
}

@Article{urdaneta-marquez2014,
  author          = {Urdaneta-Marquez, Ludmel and Bae, Seong Han and Janukavicius, Patrick and Beech, Robin and Dent, Joseph and Prichard, Roger},
  title           = {A dyf-7 haplotype causes sensory neuron defects and is associated with macrocyclic lactone resistance worldwide in the nematode parasite Haemonchus contortus.},
  journal         = {International journal for parasitology},
  year            = {2014},
  volume          = {44},
  pages           = {1063--1071},
  month           = dec,
  issn            = {1879-0135},
  abstract        = {Heavy reliance on macrocyclic lactones to treat parasitic nematodes has resulted in the evolution of widespread drug resistance that threatens human and animal health. Management strategies have been proposed that would slow the rise of resistance, however testing these strategies has been hampered by the lack of identified strong-effect resistance markers in parasites. We show that the Caenorhabditis elegans gene Cel_dyf-7, necessary for amphid sensory neuron development, also confers macrocyclic lactone sensitivity. In the sheep parasite Haemonchus contortus: (i) strains selected for macrocyclic lactone resistance were enriched in a Hco_dyf-7 haplotype that was rare in the drug-naïve population, (ii) the resistant haplotype correlated with the sensory neuron defects, and (iii) the resistant haplotype was associated with decreased Hco_dyf-7 expression. Resistant field isolates of H. contortus from five continents were enriched for the resistant haplotype, demonstrating the relevance of the Hco_dyf-7 haplotype to practise and indicating that it is a locus of strong effect. Hemizygosity resulting from sex linkage of dyf-7 likely contributes to the rise of resistance in treated populations. },
  chemicals       = {Anthelmintics, Caenorhabditis elegans Proteins, DNA, Helminth, Ivermectin},
  citation-subset = {IM},
  completed       = {2015-07-17},
  country         = {England},
  doi             = {10.1016/j.ijpara.2014.08.005},
  issn-linking    = {0020-7519},
  issue           = {14},
  keywords        = {Animals; Anthelmintics, pharmacology, therapeutic use; Caenorhabditis elegans Proteins, genetics; Chi-Square Distribution; DNA, Helminth, chemistry, genetics; Drug Resistance; Female; Haemonchiasis, drug therapy, genetics, parasitology, veterinary; Haemonchus, genetics, physiology; Haplotypes; Humans; Ivermectin, pharmacology, therapeutic use; Male; Models, Genetic; Organisms, Genetically Modified; Polymerase Chain Reaction; Sensory Receptor Cells, physiology; Sheep; Sheep Diseases, drug therapy, genetics, parasitology; Amphids; Caenorhabditis elegans; Dyf-7; Haemonchus contortus; Ivermectin; Macrocyclic-lactone; Nematodes; Resistance},
  nlm-id          = {0314024},
  owner           = {NLM},
  pii             = {S0020-7519(14)00227-6},
  pmid            = {25224687},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2014-12-02},
}

@Article{zhang2015,
  author = {Zhang, J. and Yan, Y-J. and An, J. and Huang, S.X. and Wang, X-J. and Xiang, W-S.},
  title  = {Designed biosynthesis of 25-methyl and 25-ethyl ivermectin with enhanced insecticidal activity by domain swap of avermectin polyketide synthase.},
  journal = {Microbial cell factories},
  year    = {2015},
  volume  = {14},
  pages   = {152},
  doi             = {10.1186/s12934-015-0337-y},
  revised         = {2015-09-28},
}

@Article{cornejo2014,
  author          = {Cornejo, Isabel and Andrini, Olga and Niemeyer, María Isabel and Marabolí, Vanessa and González-Nilo, F Danilo and Teulon, Jacques and Sepúlveda, Francisco V and Cid, L Pablo},
  title           = {Identification and functional expression of a glutamate- and avermectin-gated chloride channel from Caligus rogercresseyi, a southern Hemisphere sea louse affecting farmed fish.},
  journal         = {PLoS pathogens},
  year            = {2014},
  volume          = {10},
  pages           = {e1004402},
  month           = sep,
  issn            = {1553-7374},
  abstract        = {Parasitic sea lice represent a major sanitary threat to marine salmonid aquaculture, an industry accounting for 7% of world fish production. Caligus rogercresseyi is the principal sea louse species infesting farmed salmon and trout in the southern hemisphere. Most effective control of Caligus has been obtained with macrocyclic lactones (MLs) ivermectin and emamectin. These drugs target glutamate-gated chloride channels (GluCl) and act as irreversible non-competitive agonists causing neuronal inhibition, paralysis and death of the parasite. Here we report the cloning of a full-length CrGluClα receptor from Caligus rogercresseyi. Expression in Xenopus oocytes and electrophysiological assays show that CrGluClα is activated by glutamate and mediates chloride currents blocked by the ligand-gated anion channel inhibitor picrotoxin. Both ivermectin and emamectin activate CrGluClα in the absence of glutamate. The effects are irreversible and occur with an EC(50) value of around 200 nM, being cooperative (n(H) = 2) for ivermectin but not for emamectin. Using the three-dimensional structure of a GluClα from Caenorabditis elegans, the only available for any eukaryotic ligand-gated anion channel, we have constructed a homology model for CrGluClα. Docking and molecular dynamics calculations reveal the way in which ivermectin and emamectin interact with CrGluClα. Both drugs intercalate between transmembrane domains M1 and M3 of neighbouring subunits of a pentameric structure. The structure displays three H-bonds involved in this interaction, but despite similarity in structure only of two these are conserved from the C. elegans crystal binding site. Our data strongly suggest that CrGluClα is an important target for avermectins used in the treatment of sea louse infestation in farmed salmonids and open the way for ascertaining a possible mechanism of increasing resistance to MLs in aquaculture industry. Molecular modeling could help in the design of new, more efficient drugs whilst functional expression of the receptor allows a first stage of testing of their efficacy.},
  chemicals       = {Chloride Channels, Insecticides, glutamate-gated chloride channels, Glutamic Acid, Ivermectin, avermectin},
  citation-subset = {IM},
  completed       = {2015-12-08},
  country         = {United States},
  doi             = {10.1371/journal.ppat.1004402},
  issn-linking    = {1553-7366},
  issue           = {9},
  keywords        = {Amino Acid Sequence; Animals; Caenorhabditis elegans, genetics, growth & development, metabolism; Chloride Channels, chemistry, genetics, metabolism; Cloning, Molecular; Copepoda, drug effects, physiology; Electrophysiology; Female; Fish Diseases, genetics, metabolism, parasitology; Fishes, growth & development, metabolism, parasitology; Glutamic Acid, pharmacology; Insecticides, pharmacology; Ivermectin, analogs & derivatives, pharmacology; Models, Molecular; Molecular Docking Simulation; Molecular Sequence Data; Oocytes, cytology, drug effects, metabolism; Sequence Homology, Amino Acid; Xenopus laevis, genetics, growth & development, metabolism},
  nlm-id          = {101238921},
  owner           = {NLM},
  pii             = {PPATHOGENS-D-14-00288},
  pmc             = {PMC4177951},
  pmid            = {25255455},
  pubmodel        = {Electronic-eCollection},
  pubstatus       = {epublish},
  revised         = {2014-09-26},
}

@Article{janssen2013,
  author          = {Janssen, I Jana I and Krücken, Jürgen and Demeler, Janina and Basiaga, Marta and Kornaś, Sławomir and von Samson-Himmelstjerna, Georg},
  title           = {Genetic variants and increased expression of Parascaris equorum P-glycoprotein-11 in populations with decreased ivermectin susceptibility.},
  journal         = {PloS one},
  year            = {2013},
  volume          = {8},
  pages           = {e61635},
  issn            = {1932-6203},
  abstract        = {Macrocyclic lactones (MLs) represent the major drug class for control of parasitic infections in humans and animals. However, recently reports of treatment failures became more frequent. In addition to human and ruminant parasitic nematodes this also is the case for the horse-nematode Parascaris equorum. Nevertheless, to date the molecular basis of ML resistance is still not understood. Unspecific resistance mechanisms involving transporters such as P-glycoproteins (Pgps) are expected to contribute to ML resistance in nematodes. Here, complete sequences of two P. equorum Pgps were cloned and identified as orthologs of Caenorhabditis elegans Ppg-11 and an unnamed Caenorhabditis briggsae Pgp designated as Pgp-16 using phylogenetic analysis. Quantitative real-time PCR was used to compare expression between tissues. Significantly higher PeqPgp-11 expression was found in the gut for both genders, whereas for PeqPgp-16 the body wall was identified as predominant expression site. Furthermore, Pgps were analyzed regarding their participation in resistance development. Using SeqDoC analyses, Pgp-sequences of P. equorum populations with different ML susceptibility were compared. This approach revealed three single nucleotide polymorphisms (SNPs) causing missense mutations in the PeqPgp-11 sequence which correlated with decreased ML susceptibility. However, no resistance associated differences in mRNA expression levels were detected between embryonated eggs of these populations. In contrast, comparison of two pre-adult groups with different ivermectin (IVM) susceptibility revealed the presence of the three SNPs and in addition statistically significant PeqPgp-11 overexpression in the group of worms with reduced susceptibility. These results indicate that Pgp-11 might be involved in IVM resistance in P. equorum as it shows increased expression in an IVM exposed life-cycle stage of an IVM resistant population as well as occurrence of putatively resistance associated SNPs in populations with reduced IVM susceptibility. These SNPs are promising diagnostic candidates for detection of ML resistance with potential also for other parasitic nematode species.},
  chemicals       = {ATP Binding Cassette Transporter, Sub-Family B, Antinematodal Agents, RNA, Messenger, Ivermectin},
  citation-subset = {IM},
  completed       = {2013-12-09},
  country         = {United States},
  doi             = {10.1371/journal.pone.0061635},
  issn-linking    = {1932-6203},
  issue           = {4},
  keywords        = {ATP Binding Cassette Transporter, Sub-Family B, genetics; Alleles; Animals; Antinematodal Agents, pharmacology; Ascaridoidea, classification, drug effects, genetics; Drug Resistance, genetics; Female; Gene Expression; Gene Expression Regulation, drug effects; Gene Frequency; Genetic Variation; Horses, parasitology; Ivermectin, pharmacology; Male; Organ Specificity, genetics; Phylogeny; Polymorphism, Single Nucleotide; RNA, Messenger, genetics},
  nlm-id          = {101285081},
  owner           = {NLM},
  pii             = {PONE-D-13-01239},
  pmc             = {PMC3634834},
  pmid            = {23637871},
  pubmodel        = {Electronic-Print},
  pubstatus       = {epublish},
  revised         = {2018-03-21},
}

@Article{barnes1997,
  author          = {Barnes, T M and Hekimi, S},
  title           = {The Caenorhabditis elegans avermectin resistance and anesthetic response gene unc-9 encodes a member of a protein family implicated in electrical coupling of excitable cells.},
  journal         = {J. Neurochem.},
  year            = {1997},
  volume          = {69},
  pages           = {2251--2260},
  month           = dec,
  issn            = {0022-3042},
  abstract        = {Mutations in the unc-9 gene of the nematode Caenorhabditis elegans cause abnormal forward locomotion and an egg-retention phenotype. unc-9 mutations also reduce the worms' sensitivity to avermectin and block a form of hypersensitivity to volatile anesthetics. We report here the cloning and molecular characterization of unc-9 and show that it encodes a member of the OPUS family of proteins that is 56% identical to another OPUS protein, UNC-7. It is significant that unc-9 mutants share all phenotypes with unc-7 mutants. Mutants in another gene, unc-124, also share all tested phenotypes with unc-9 mutants, including identical locomotory and egg-laying defects, suggesting that multiple genes are required for the same biochemical function. OPUS proteins are implicated in the function of invertebrate gap junctions, and, based on a new alignment including 24 members from C. elegans, we present a refined model for the structure of OPUS proteins suggesting that oligomers could form a hydrophilic pore. We also show that alteration of highly conserved proline residues in UNC-9 leads to a cold sensitivity that likely affects a step in protein expression rather than function. Finally, we speculate on the basis of the avermectin resistance and anesthetic response phenotypes.},
  chemicals       = {Anesthetics, Anthelmintics, Caenorhabditis elegans Proteins, Helminth Proteins, Membrane Proteins, Unc-9 protein, C elegans, Ivermectin, avermectin},
  citation-subset = {IM},
  completed       = {1997-12-12},
  country         = {England},
  issn-linking    = {0022-3042},
  issue           = {6},
  keywords        = {Alleles; Amino Acid Sequence; Anesthetics, pharmacology; Animals; Anthelmintics, pharmacology; Caenorhabditis elegans, drug effects, genetics, physiology; Caenorhabditis elegans Proteins; Cloning, Molecular; Female; Gap Junctions, physiology; Helminth Proteins, genetics; Insecticide Resistance, genetics; Ivermectin, analogs & derivatives, pharmacology; Membrane Proteins, genetics; Molecular Sequence Data; Motor Activity, physiology; Mutation, genetics; Oviposition, physiology},
  nlm-id          = {2985190R},
  owner           = {NLM},
  pmid            = {9375655},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2006-11-15},
}

@Article{mccavera2009,
  author          = {McCavera, Samantha and Rogers, Adrian T and Yates, Darran M and Woods, Debra J and Wolstenholme, Adrian J},
  title           = {An ivermectin-sensitive glutamate-gated chloride channel from the parasitic nematode Haemonchus contortus.},
  journal         = {Molecular pharmacology},
  year            = {2009},
  volume          = {75},
  pages           = {1347--1355},
  month           = jun,
  issn            = {1521-0111},
  abstract        = {Nematode glutamate-gated chloride channels are targets of the macrocyclic lactones, the most important group of anthelmintics available. In Xenopus laevis oocytes, channels formed by the GluClalpha3B subunit from the parasite Haemonchus contortus were more sensitive to l-glutamate (EC(50) = 27.6 +/- 2.7 microM) than those formed by the homologous subunit from Caenorhabditis elegans (EC(50) = 2.2 +/- 0.12 mM). Ibotenate was a partial agonist (EC(50) = 87.7 +/- 3.5 microM). The H. contortus channels responded to low concentrations of ivermectin (estimated EC(50) = approximately 0.1 +/- 1.0 nM), opening slowly and irreversibly in a highly cooperative manner: the rate of channel opening was concentration-dependent. Responses to glutamate and ivermectin were inhibited by picrotoxinin and fipronil. Mutating an N-terminal domain amino acid, leucine 256, to phenylalanine increased the EC(50) for l-glutamate to 92.2 +/- 3.5 microM, and reduced the Hill number from 1.89 +/- 0.35 to 1.09 +/- 0.16. It increased the K(d) for radiolabeled ivermectin binding from 0.35 +/- 0.1 to 2.26 +/- 0.78 nM. Two other mutations (E114G and V235A) had no effect on l-glutamate activation or ivermectin binding: one (T300S) produced no detectable channel activity, but ivermectin binding was similar to wild-type. The substitution of any aromatic amino acid for Leu256 had similar effects in the radioligand binding assay. Molecular modeling studies suggested that the GluCl subunits have a fold similar to that of other Cys-loop ligand-gated ion channels and that amino acid 256 was unlikely to play a direct role in ligand binding but may be involved in mediating the allosteric properties of the receptor.},
  chemicals       = {Anthelmintics, Chloride Channel Agonists, Chloride Channels, Protein Subunits, glutamate-gated chloride channels, Glutamic Acid, Ivermectin},
  citation-subset = {IM},
  completed       = {2009-06-15},
  country         = {United States},
  doi             = {10.1124/mol.108.053363},
  issn-linking    = {0026-895X},
  issue           = {6},
  keywords        = {Animals; Anthelmintics, pharmacology; COS Cells; Cercopithecus aethiops; Chloride Channel Agonists; Chloride Channels, genetics; Drug Resistance; Female; Glutamic Acid, pharmacology; Haemonchus, metabolism; Ion Channel Gating; Ivermectin, pharmacology; Models, Molecular; Mutagenesis, Site-Directed; Mutation; Oocytes, drug effects, physiology; Patch-Clamp Techniques; Protein Conformation; Protein Subunits, physiology; Radioligand Assay; Xenopus laevis},
  nlm-id          = {0035623},
  owner           = {NLM},
  pii             = {mol.108.053363},
  pmc             = {PMC2684884},
  pmid            = {19336526},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-10-19},
}

@Article{gilleard2006,
  author          = {Gilleard, John Stuart},
  title           = {Understanding anthelmintic resistance: the need for genomics and genetics.},
  journal         = {International journal for parasitology},
  year            = {2006},
  volume          = {36},
  pages           = {1227--1239},
  month           = oct,
  issn            = {0020-7519},
  abstract        = {Anthelmintic resistance is a major problem for the control of many parasitic nematode species and has become a major constraint to livestock production in many parts of the world. In spite of its increasing importance, there is still a poor understanding of the molecular and genetic basis of resistance. It is unclear which mutations contribute most to the resistance phenotype and how resistance alleles arise, are selected and spread in parasite populations. The main strategy used to identify mutations responsible for anthelmintic resistance has been to undertake experimental studies on candidate genes. These genes have been chosen predominantly on the basis of our knowledge of drug mode-of-action and the identification of mutations that can confer resistance in model organisms. The application of these approaches to the analysis of benzimidazole and ivermectin resistance is reviewed and the reasons for their relative success or failure are discussed. The inherent limitation of candidate gene studies is that they rely on very specific and narrow assumptions about the likely identity of resistance-associated genes. In contrast, forward genetic and functional genomic approaches do not make such assumptions, as illustrated by the successful application of these techniques in the study of insecticide resistance. Although there is an urgent need to apply these powerful approaches to anthelmintic resistance research, the basic methodologies and resources are still lacking. However, these are now being developed for the trichostrongylid nematode Haemonchus contortus and the current progress and research priorities in this area are discussed.},
  chemicals       = {Anthelmintics, Benzimidazoles, Insecticides, Ivermectin, benzimidazole},
  citation-subset = {IM},
  completed       = {2007-09-26},
  country         = {England},
  doi             = {10.1016/j.ijpara.2006.06.010},
  issn-linking    = {0020-7519},
  issue           = {12},
  keywords        = {Animals; Anthelmintics, therapeutic use; Benzimidazoles, therapeutic use; Caenorhabditis elegans, genetics; Drug Resistance, genetics; Genes, Helminth, genetics; Genetics, Population, methods; Genomics, methods; Haemonchus, drug effects, genetics; Insecticide Resistance, genetics; Insecticides, pharmacology; Ivermectin, therapeutic use; Models, Animal; Mutation, genetics; Nematoda, drug effects; Polymorphism, Genetic, genetics},
  nlm-id          = {0314024},
  owner           = {NLM},
  pii             = {S0020-7519(06)00240-2},
  pmid            = {16889782},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  references      = {95},
  revised         = {2012-11-15},
}

@Article{vassilatis1997,
  author          = {Vassilatis, D K and Arena, J P and Plasterk, R H and Wilkinson, H A and Schaeffer, J M and Cully, D F and Van der Ploeg, L H},
  title           = {Genetic and biochemical evidence for a novel avermectin-sensitive chloride channel in Caenorhabditis elegans. Isolation and characterization.},
  journal         = {J. Biol. Chem.},
  year            = {1997},
  volume          = {272},
  pages           = {33167--33174},
  month           = dec,
  issn            = {0021-9258},
  abstract        = {Avermectins are a class of macrocyclic lactones that is widely used in Crop Prot. and to treat helminth infections in man and animals. Two complementary DNAs (GluClalpha and GluClbeta) encoding chloride channels that are gated by avermectin and glutamate, respectively, were isolated from Caenorhabditis elegans. To study the role of these subunits in conferring avermectin sensitivity we isolated a mutant C. elegans strain with a Tc1 transposable element insertion that functionally inactivated the GluClalpha gene (GluClalpha::Tc1). GluClalpha::Tc1 animals exhibit a normal phenotype including typical avermectin sensitivity. Xenopus oocytes expressing GluClalpha::Tc1 strain mRNA elicited reduced amplitude avermectin and glutamate-dependent chloride currents. Avermectin binding assays in GluClalpha::Tc1 strain membranes showed the presence of high affinity binding sites, with a reduced Bmax. These experiments suggest that GluClalpha is a target for avermectin and that additional glutamate-gated and avermectin-sensitive chloride channel subunits exist in C. elegans. We isolated a cDNA (GluClalpha2) encoding a chloride channel that shares 75% amino acid identity with GluClalpha. This subunit forms homomeric channels that are gated irreversibly by avermectin and reversibly by glutamate. GluClalpha2 coassembles with GluClbeta to form heteromeric channels that are gated by both ligands. The presence of subunits related to GluClalpha may explain the low level and rarity of target site involvement in resistance to the avermectin class of compounds.},
  chemicals       = {Chloride Channels, RNA, Messenger, glutamate-gated chloride channels, Ivermectin, avermectin, Ribonuclease H},
  citation-subset = {IM},
  completed       = {1998-01-23},
  country         = {United States},
  issn-linking    = {0021-9258},
  issue           = {52},
  keywords        = {Amino Acid Sequence; Animals; Base Sequence; Caenorhabditis elegans; Chloride Channels, chemistry, isolation & purification; Chromosome Mapping; Chromosomes, Artificial, Yeast; Ivermectin, analogs & derivatives, metabolism, pharmacology; Molecular Sequence Data; Phenotype; RNA, Messenger; Ribonuclease H, metabolism; Xenopus},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pmid            = {9407104},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2007-11-15},
}

@Article{williamson2012,
  author          = {Williamson, S M and Wolstenholme, A J},
  title           = {P-glycoproteins of Haemonchus contortus: development of real-time PCR assays for gene expression studies.},
  journal         = {Journal of helminthology},
  year            = {2012},
  volume          = {86},
  pages           = {202--208},
  month           = jun,
  issn            = {1475-2697},
  abstract        = {P-glycoproteins (P-gps) are proteins that function as efflux pumps, removing lipophilic xenobiotic compounds from cells. There is evidence that P-gps play a role in the resistance of parasitic nematodes to anthelmintic drugs such as benzimidazoles and macrocyclic lactones. As anthelmintic resistance becomes more common, it is important to identify candidate resistance genes with the aim of understanding the molecular basis of resistance, and of developing assays to detect these resistance-associated changes. We identified several sequences from the genome of the parasite Haemonchus contortus with convincing homology to the known P-gp coding genes of the model nematode Caenorhabditis elegans. Nine of these sequences were successfully amplified by polymerase chain reaction (PCR) and shown to be most similar to the C. elegans sequences for pgp-1, pgp-2, pgp-3, pgp-4, pgp-9, pgp-10, pgp-11, pgp-12 and pgp-14. These partial P-gp sequences from H. contortus were used to design and optimize a quantitative real-time PCR assay to investigate potential changes in the expression levels of P-gp transcripts associated with drug resistance. No significant changes in P-gp mRNA expression levels were found in a rapidly selected ivermectin-resistant parasite isolate compared to its drug-sensitive parent, but the assay has the potential to be used on other isolates in the future to further investigate resistance-associated changes in P-gp gene expression.},
  chemicals       = {ATP Binding Cassette Transporter, Sub-Family B, Anthelmintics, DNA Primers, DNA, Helminth, Helminth Proteins},
  citation-subset = {IM},
  completed       = {2012-08-23},
  country         = {England},
  doi             = {10.1017/S0022149X11000216},
  issn-linking    = {0022-149X},
  issue           = {2},
  keywords        = {ATP Binding Cassette Transporter, Sub-Family B, biosynthesis, genetics; Animals; Anthelmintics, pharmacology; Caenorhabditis elegans, genetics; DNA Primers, genetics; DNA, Helminth, chemistry, genetics; Drug Resistance; Gene Expression Profiling, methods; Haemonchus, genetics; Helminth Proteins, biosynthesis, genetics; Molecular Sequence Data; Phylogeny; Real-Time Polymerase Chain Reaction, methods; Sequence Analysis, DNA; Sequence Homology, Amino Acid},
  nlm-id          = {2985115R},
  owner           = {NLM},
  pii             = {S0022149X11000216},
  pmid            = {21729384},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@Article{martin2012,
  author          = {Martin, Richard J and Robertson, Alan P and Buxton, Samuel K and Beech, Robin N and Charvet, Claude L and Neveu, Cédric},
  title           = {Levamisole receptors: a second awakening.},
  journal         = {Trends in parasitology},
  year            = {2012},
  volume          = {28},
  pages           = {289--296},
  month           = jul,
  issn            = {1471-5007},
  abstract        = {Levamisole and pyrantel are old (1965) but useful anthelmintics that selectively activate nematode acetylcholine ion channel receptors; they are used to treat roundworm infections in humans and animals. Interest in their actions has surged, giving rise to new knowledge and technical advances, including an ability to reconstitute receptors that reveal more details of modes of action/resistance. We now know that the receptors are plastic and may form diverse species-dependent subtypes of receptor with different sensitivities to individual cholinergic anthelmintics. Understanding the biology of the levamisole receptors is expected to inform other studies on anthelmintics (ivermectin and emodepside) that act on ion channels.},
  chemicals       = {Anthelmintics, Depsipeptides, Ion Channels, Receptors, Cholinergic, Levamisole, Pyrantel, emodepside},
  citation-subset = {IM},
  completed       = {2012-10-15},
  country         = {England},
  doi             = {10.1016/j.pt.2012.04.003},
  issn-linking    = {1471-4922},
  issue           = {7},
  keywords        = {Animals; Anthelmintics, pharmacology; Caenorhabditis elegans, drug effects, genetics, metabolism; Calcium Signaling; Depsipeptides, pharmacology; Drug Resistance; Genes, Helminth; Humans; Ion Channel Gating; Ion Channels, drug effects, metabolism; Levamisole, pharmacology; Models, Molecular; Pyrantel, pharmacology; Receptors, Cholinergic, drug effects, metabolism; Species Specificity; Xenopus, genetics, metabolism},
  mid             = {NIHMS378876},
  nlm-id          = {100966034},
  owner           = {NLM},
  pii             = {S1471-4922(12)00067-0},
  pmc             = {PMC3378725},
  pmid            = {22607692},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@Article{mounsey2006,
  author          = {Mounsey, K E and Holt, D C and McCarthy, J and Walton, S F},
  title           = {Identification of ABC transporters in Sarcoptes scabiei.},
  journal         = {Parasitology},
  year            = {2006},
  volume          = {132},
  pages           = {883--892},
  month           = jun,
  issn            = {0031-1820},
  abstract        = {We have identified and partially sequenced 8 ABC transporters from an EST dataset of Sarcoptes scabiei var. hominis, the causative agent of scabies. Analysis confirmed that most of the known ABC subfamilies are represented in the EST dataset including several members of the multidrug resistance protein subfamily (ABC-C). Although P-glycoprotein (ABC-B) sequences were not found in the EST dataset, a partial P-glycoprotein sequence was subsequently obtained using a degenerate PCR strategy and library screening. Thus a total of 9 potential S. scabiei ABC transporters representing the subfamilies A, B, C, E, F and H have been identified. Ivermectin is currently used in the treatment of hyper-infested (crusted) scabies, and has also been identified as a potentially effective acaricide for mass treatment programmes in scabies-endemic communities. The observation of clinical and in vitro ivermectin resistance in 2 crusted scabies patients who received multiple treatments has raised serious concerns regarding the sustainability of such programmes. One possible mechanism for ivermectin resistance is through ABC transporters such as P-glycoprotein. This work forms an important foundation for further studies to elucidate the potential role of ABC transporters in ivermectin resistance of S. scabiei.},
  chemicals       = {ATP-Binding Cassette Transporters, ATP-Binding Cassette, Sub-Family B, Member 1, DNA Primers},
  citation-subset = {IM},
  completed       = {2006-07-25},
  country         = {England},
  doi             = {10.1017/S0031182005009716},
  issn-linking    = {0031-1820},
  issue           = {Pt 6},
  keywords        = {ATP-Binding Cassette Transporters, genetics, isolation & purification; ATP-Binding Cassette, Sub-Family B, Member 1, genetics; Amino Acid Sequence; Animals; Caenorhabditis elegans, genetics; Cluster Analysis; DNA Primers, chemistry; Drosophila melanogaster, genetics; Expressed Sequence Tags; Gene Library; Molecular Sequence Data; Phylogeny; Polymerase Chain Reaction, veterinary; Sarcoptes scabiei, physiology},
  nlm-id          = {0401121},
  owner           = {NLM},
  pii             = {S0031182005009716},
  pmid            = {16454864},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-12-13},
}

@Article{mccavera2007,
  author          = {McCavera, S. and Walsh, T. K. and Wolstenholme, A. J.},
  title           = {Nematode ligand-gated chloride channels: an appraisal of their involvement in macrocyclic lactone resistance and prospects for developing molecular markers.},
  journal         = {Parasitology},
  year            = {2007},
  volume          = {134},
  issue           = {Pt 8},
  pages           = {1111--1121},
  issn            = {0031-1820},
  doi             = {10.1017/S0031182007000042},
  abstract        = {SUMMARYLigand-gated chloride channels, including the glutamate-(GluCl) and GABA-gated channels, are the targets of the macrocyclic lactone (ML) family of anthelmintics. Changes in the sequence and expression of these channels can cause resistance to the ML in laboratory models, such as Caenorhabditis elegans and Drosophila melanogaster. Mutations in multiple GluCl subunit genes are required for high-level ML resistance in C. elegans, and this can be influenced by additional mutations in gap junction and amphid genes. Parasitic nematodes have a different complement of channel subunit genes from C. elegans, but a few genes, including avr-14, are widely present. A polymorphism in an avr-14 orthologue, which makes the subunit less sensitive to ivermectin and glutamate, has been identified in Cooperia oncophora, and polymorphisms in several subunits have been reported from resistant isolates of Haemonchus contortus. This has led to suggestions that ML resistance may be polygenic. Possible reasons for this, and its consequences for the development of molecular tests for resistance, are explored.},
  chemicals       = {Anthelmintics, Chloride Channels, Lactones, Macrocyclic Compounds},
  citation-subset = {IM},
  completed       = {2007-09-27},
  country         = {England},
  issn-linking    = {0031-1820},
  keywords        = {Animals; Anthelmintics, pharmacology; Chloride Channels, metabolism; Drug Resistance, genetics; Lactones, pharmacology; Macrocyclic Compounds, pharmacology; Nematoda, drug effects, metabolism},
  nlm-id          = {0401121},
  owner           = {NLM},
  pii             = {S0031182007000042},
  pmid            = {17608971},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {80},
  revised         = {2007-07-04},
}

@Article{harder2003,
  author          = {Harder, Achim and Schmitt-Wrede, Hans-Peter and Krücken, Jürgen and Marinovski, Predrag and Wunderlich, Frank and Willson, James and Amliwala, Kiran and Holden-Dye, Lindy and Walker, Robert},
  title           = {Cyclooctadepsipeptides--an anthelmintically active class of compounds exhibiting a novel mode of action.},
  journal         = {International journal of antimicrobial agents},
  year            = {2003},
  volume          = {22},
  pages           = {318--331},
  month           = sep,
  issn            = {0924-8579},
  abstract        = {There are three major classes of anthelmintics for veterinary use: the benzimidazoles/prebenzimidazoles, the tetrahydropyrimidines/imidazothiazoles, and the macrocyclic lactones. In nematodes, there are five targets for the existing anthelmintics: the nicotinergic acetylcholine receptor which is the target of tetrahydropyrimidines/imidazothiazoles and indirectly that of the acetylcholineesterase inhibitors; the GABA receptor which is the target of piperazine, the glutamate-gated chloride channel as the target of the macrocyclic lactones, and beta-tubulin as the target of prebenzimidazoles/benzimidazoles. All these anthelmintics are now in serious danger because of the worldwide spread of resistant nematodes in sheep, cattle, horses and pigs. The class of cyclooctadepsipeptides has entered the scene of anthelmintic research in the early 1990s. PF1022A, the first anthelmintically active member, is a natural compound from the fungus Mycelia sterilia that belongs to the microflora of the leaves of the Camellia japonica. PF1022A contains 4 N-Methyl-L-leucines, 2 D-lactic acids and 2-D-phenyllactic acids arranged as a cyclic octadepsipeptide with an alternating L-D-L-configuration. Emodepside is a semisynthetic derivative of PF1022A with a morpholine ring at each of the two D-phenyllactic acids in para position. The anthelmintic activity is directed against gastrointestinal nematodes in chicken, mice, rats, meriones, dogs, cats, sheep, cattle and horses. Moreover, emodepside is active against Trichinella spiralis larvae in muscles, microfilariae and preadult filariae and Dictyocaulus viviparus. PF1022A and emodepside are fully effective against benzimidazole-, levamisole or ivermectin-resistant nematodes in sheep and cattle. In Ascaris suum both cyclooctadepsipeptides lead to paralysis indicating a neuropharmacological action of these compounds. Using a PF1022A-ligand immunoscreening of a cDNA library from Haemonchus contortus a cDNA clone of 3569 base pairs could be identified. This clone codes for a novel 110 kDa heptahelical transmembrane receptor, named HC110R. Database- and phylogenetic analysis reveals that this receptor is a homolog to B0457.1 from Caenorhabditis elegans and has significant similarity to latrophilins from human, cattle and rat. HC110R is located in the plasma membrane and in lysosomes and endosomes. Alpha-latrotoxin, the poison of the black widow spider, binds at a 54 kDa aminoterminal fragment of HC110R. After binding a Ca2+-influx into HEK293 cells is induced which can be blocked by EGTA, Cd2+ or nifedipin. PF1022A or emodepside also bind to this 54 kDa aminoterminal region of HC110R and interact with the functional responses of alpha-latrotoxin. In C. elegans antibodies against the C-or N-terminus of HC110R bind to the B0457.1 protein located in the pharynx. Electrophysiological studies reveal that emodepside inhibits pharyngeal pumping of the nematodes in a concentration dependent way with an IC(50) value of about 4 nM. Thus, it is tempting to speculate that emodepside exerts its action on nematodes via a latrophilin-like receptor which might have an important regulatory function on pharyngeal pumping.},
  chemicals       = {Anthelmintics, Depsipeptides, Helminth Proteins, Peptides, Cyclic, PF 1022A},
  citation-subset = {IM},
  completed       = {2004-01-20},
  country         = {Netherlands},
  issn-linking    = {0924-8579},
  issue           = {3},
  keywords        = {Animals; Anthelmintics, chemistry, classification, pharmacology; Binding Sites; Depsipeptides; Drug Resistance; Helminth Proteins, genetics, metabolism; Helminthiasis, drug therapy; Helminthiasis, Animal, drug therapy; Helminths, drug effects; Humans; Nematoda, drug effects; Peptides, Cyclic, chemistry, pharmacology; Phylogeny},
  nlm-id          = {9111860},
  owner           = {NLM},
  pii             = {S092485790300219X},
  pmid            = {13678839},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {52},
  revised         = {2005-11-16},
}

@Article{bhatla2015,
  author          = {Bhatla, N. and Droste, R. and Sando, S. R. and Huang, A. and Horvitz, H. R.},
  title           = "{Distinct Neural Circuits Control Rhythm Inhibition and Spitting by the Myogenic Pharynx of \textit{C.elegans}.}",
  journal         = {Curr. Biol.},
  year            = {2015},
  volume          = {25},
  pages           = {2075--2089},
  month           = aug,
  issn            = {1879-0445},
  abstract        = {Neural circuits have long been known to modulate myogenic muscles such as the heart, yet a mechanistic understanding at the cellular and molecular levels remains limited. We studied how light inhibits pumping of the Caenorhabditis elegans pharynx, a myogenic muscular pump for feeding, and found three neural circuits that alter pumping. First, light inhibits pumping via the I2 neuron monosynaptic circuit. Our electron microscopic reconstruction of the anterior pharynx revealed evidence for synapses from I2 onto muscle that were missing from the published connectome, and we show that these "missed synapses" are likely functional. Second, light inhibits pumping through the RIP-I1-MC neuron polysynaptic circuit, in which an inhibitory signal is likely transmitted from outside the pharynx into the pharynx in a manner analogous to how the mammalian autonomic nervous system controls the heart. Third, light causes a novel pharyngeal behavior, reversal of flow or "spitting," which is induced by the M1 neuron. These three neural circuits show that neurons can control a myogenic muscle organ not only by changing the contraction rate but also by altering the functional consequences of the contraction itself, transforming swallowing into spitting. Our observations also illustrate why connectome builders and users should be cognizant that functional synaptic connections might exist despite the absence of a declared synapse in the connectome.},
  citation-subset = {IM},
  completed       = {2016-05-16},
  country         = {England},
  doi             = {10.1016/j.cub.2015.06.052},
  issn-linking    = {0960-9822},
  issue           = {16},
  keywords        = {Animals; Caenorhabditis elegans, physiology, ultrastructure; Feeding Behavior; Microscopy, Electron, Transmission; Motor Neurons, physiology, ultrastructure; Muscles, physiology, ultrastructure; Pharynx, physiology, ultrastructure; Synapses, physiology, ultrastructure},
  mid             = {NIHMS705398},
  nlm-id          = {9107782},
  owner           = {NLM},
  pii             = {S0960-9822(15)00746-0},
  pmc             = {PMC4546535},
  pmid            = {26212880},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-02-20},
}

@Article{trojanowski2014,
  author          = {Trojanowski, Nicholas F and Padovan-Merhar, Olivia and Raizen, David M and Fang-Yen, Christopher},
  title           = {Neural and genetic degeneracy underlies Caenorhabditis elegans feeding behavior.},
  journal         = {J. Neurophys.},
  year            = {2014},
  volume          = {112},
  issue           = {4},
  month           = aug,
  pages           = {951--961},
  issn            = {1522-1598},
  doi             = {10.1152/jn.00150.2014},
  abstract        = {Degenerate networks, in which structurally distinct elements can perform the same function or yield the same output, are ubiquitous in biology. Degeneracy contributes to the robustness and adaptability of networks in varied environmental and evolutionary contexts. However, how degenerate neural networks regulate behavior in vivo is poorly understood, especially at the genetic level. Here, we identify degenerate neural and genetic mechanisms that underlie excitation of the pharynx (feeding organ) in the nematode Caenorhabditis elegans using cell-specific optogenetic excitation and inhibition. We show that the pharyngeal neurons MC, M2, M4, and I1 form multiple direct and indirect excitatory pathways in a robust network for control of pharyngeal pumping. I1 excites pumping via MC and M2 in a state-dependent manner. We identify nicotinic and muscarinic receptors through which the pharyngeal network regulates feeding rate. These results identify two different mechanisms by which degeneracy is manifest in a neural circuit in vivo. },
  chemicals       = {Receptors, Muscarinic, Receptors, Nicotinic},
  citation-subset = {IM},
  completed       = {2015-04-10},
  country         = {United States},
  issn-linking    = {0022-3077},
  keywords        = {Animals; Caenorhabditis elegans, genetics, metabolism, physiology; Feeding Behavior; Ganglia, Invertebrate, cytology, physiology; Nerve Net, cytology, physiology; Neurons, metabolism, physiology; Optogenetics; Pharynx, innervation, physiology; Receptors, Muscarinic, metabolism; Receptors, Nicotinic, metabolism; behavior; feeding; neural circuits; optogenetics},
  nlm-id          = {0375404},
  owner           = {NLM},
  pii             = {jn.00150.2014},
  pmc             = {PMC4122747},
  pmid            = {24872529},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-10-19},
}

@Article{li2012,
  author          = {Li, Z. and Li, Y. and Yi, Y. and Huang, W. and Yang, S. and Niu, W. and Zhang, L. and Xu, Z. and Qu, A. and Wu, Z. and Xu, T.},
  title           = "{Dissecting a Central Flip-Flop Circuit That Integrates Contradictory Sensory Cues in \textit{C. elegans} Feeding Regulation}",
  journal         = {Nat. Commun.},
  year            = {2012},
  volume          = {3},
  pages           = {776},
  issn            = {2041-1723},
  doi             = {10.1038/ncomms1780},
  abstract        = {Feeding behaviour is modulated by both environmental cues and internal physiological states. Appetite is commonly boosted by the pleasant smell (or appearance) of food and destroyed by a bad taste. In reality, animals sense multiple environmental cues at the same time and it is not clear how these sensory inputs are integrated and a decision is made to regulate feeding behaviour accordingly. Here we show that feeding behaviour in Caenorhabditis elegans can be either facilitated by attractive odours or suppressed by repellents. By identifying mutants that are defective for sensory-mediated feeding regulation, we dissected a central flip-flop circuit that integrates two contradictory sensory inputs and generates bistable hormone output to regulate feeding behaviour. As feeding regulation is fundamental to animal survival, we speculate that the basic organizational logic identified here in C. elegans is likely convergent throughout different phyla.},
  chemicals       = {Caenorhabditis elegans Proteins},
  citation-subset = {IM},
  completed       = {2012-07-26},
  country         = {England},
  issn-linking    = {2041-1723},
  keywords        = {Animals; Caenorhabditis elegans, genetics, physiology; Caenorhabditis elegans Proteins, genetics, metabolism; Feeding Behavior; Odorants, analysis; Sensory Receptor Cells, physiology; Smell},
  nlm-id          = {101528555},
  owner           = {NLM},
  pii             = {ncomms1780},
  pmid            = {22491324},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2017-02-20},
}

@WWW{boulin2001,
  author = {Boulin, T.},
  title  = {The mind of a worm. In WormAtlas.},
  year   = {2001},
  url    = {http://www.wormatlas.org/MoW_built0.92/cells/il2.html},
}

@Article{serrano-saiz2013,
  author    = {Serrano-Saiz, E. and Poole, R. J. and Felton, T. and Zhang, F. and De La Cruz, E. Daniel. and Hobert, O.},
  title     = "{Modular Control of Glutamatergic Neuronal Identity in \textit{C. elegans} by Distinct Homeodomain Proteins}",
  journal   = {Cell},
  year      = {2013},
  volume    = {155},
  number    = {3},
  pages     = {659--673},
  publisher = {Elsevier},
}

@Article{Kindt2007,
  author    = {Kindt, K. S. and Viswanath, V. and Macpherson, L. and Quast, K. and Hu, H. and Patapoutian, A. and Schafer, W. R.},
  title     = "{\textit{Caenorhabditis elegans} TRPA-1 Functions in Mechanosensation}",
  journal   = {Nat. Neurosci.e},
  year      = {2007},
  volume    = {10},
  number    = {5},
  pages     = {568},
  publisher = {Nature Publishing Group},
}

@Article{Talavera2009,
  author    = {Talavera, K. and Gees, M. and Karashima, Y. and Meseguer, V. M. and Vanoirbeek, J. A. J. and Damann, N. and Everaerts, W. and Benoit, M. and Janssens, A. and Vennekens, R. and others},
  title     = {Nicotine activates the chemosensory cation channel T{RPA}1},
  journal   = {Nat. Neurosci.e},
  year      = {2009},
  volume    = {12},
  number    = {10},
  pages     = {1293},
  publisher = {Nature Publishing Group},
}

@Article{Liu2004,
  author    = {Liu, L. and Zhu, W. and Zhang, Z-S. and Yang, T. and Grant, A. and Oxford, G. and Simon, S. A.},
  title     = {Nicotine inhibits voltage-dependent sodium channels and sensitizes vanilloid receptors},
  journal   = {J. Neurophys.},
  year      = {2004},
  volume    = {91},
  number    = {4},
  pages     = {1482--1491},
  publisher = {American Physiological Society},
}

@Article{Nurrish1999,
  author    = {Nurrish, S. and S{\'e}galat, L. and Kaplan, J. M.},
  title     = {Serotonin inhibition of synaptic transmission: G$\alpha$o decreases the abundance of U{NC}-13 at release sites},
  journal   = {Neuron},
  year      = {1999},
  volume    = {24},
  number    = {1},
  pages     = {231--242},
  publisher = {Elsevier},
}

@Article{Hallam2000,
  author    = {Hallam, Steven and Singer, Emily and Waring, David and Jin, Yishi},
  title     = "{The \textit{C. elegans} NeuroD homolog cnd-1 Functions in Multiple Aspects of Motor Neuron Fate Specification}",
  journal   = {Development},
  year      = {2000},
  volume    = {127},
  number    = {19},
  pages     = {4239--4252},
  publisher = {The Company of Biologists Ltd},
}

@Article{starich1996,
  author          = {Starich, T A and Lee, R Y and Panzarella, C and Avery, L and Shaw, J E},
  title           = {eat-5 and unc-7 represent a multigene family in Caenorhabditis elegans involved in cell-cell coupling.},
  journal         = {J. Cell. Biol.},
  year            = {1996},
  volume          = {134},
  issue           = {2},
  month           = jul,
  pages           = {537--548},
  issn            = {0021-9525},
  abstract        = {The Drosophila melanogaster genes Passover and l(1)ogre and the Caenorhabditis elegans gene unc-7 define a gene family whose function is not known. We have isolated and characterized the C. elegans gene eat-5, which is required for synchronized pharyngeal muscle contractions, and find that it is a new member of this family. Simultaneous electrical and video recordings reveal that in eat-5 mutants, action potentials of muscles in the anterior and posterior pharynx are unsynchronized. Injection of carboxyfluorescein into muscles of the posterior pharynx demonstrates that all pharyngeal muscles are dye-coupled in wild-type animals; in eat-5 mutants, however, muscles of the anterior pharynx are no longer dye-coupled to posterior pharyngeal muscles. We show that a gene fusion of eat-5 to the green fluorescent protein is expressed in pharyngeal muscles. unc-7 and eat-5 are two of at least sixteen members of this family in C. elegans as determined by database searches and PCR-based screens. The amino acid sequences of five of these members in C. elegans have been deduced from cDNA sequences. Polypeptides of the family are predicted to have four transmembrane domains with cytoplasmic amino and carboxyl termini. We have constructed fusions of one of these polypeptides with beta-galactosidase and with green fluorescent protein. The fusion proteins appear to be localized in a punctate pattern at or near plasma membranes. We speculate that this gene family is required for the formation of gap junctions.},
  chemicals       = {Caenorhabditis elegans Proteins, Connexins, DNA, Complementary, Drosophila Proteins, Helminth Proteins, Insect Hormones, Membrane Proteins, Nerve Tissue Proteins, Unc-7 protein, C elegans, eat-5 protein, C elegans, optic ganglion reduced protein, Drosophila, shakB protein, Drosophila},
  citation-subset = {IM},
  completed       = {1996-09-10},
  country         = {United States},
  issn-linking    = {0021-9525},
  keywords        = {Action Potentials; Amino Acid Sequence; Animals; Base Sequence; Caenorhabditis elegans, genetics, metabolism; Caenorhabditis elegans Proteins; Cloning, Molecular; Connexins, genetics, metabolism; DNA, Complementary; Drosophila Proteins; Helminth Proteins, genetics, metabolism; Insect Hormones, genetics; Membrane Proteins, genetics, metabolism; Molecular Sequence Data; Multigene Family; Mutation; Nerve Tissue Proteins, genetics; Pharyngeal Muscles, physiology; Pharynx, physiology; Polymerase Chain Reaction; Sequence Homology, Amino Acid},
  nlm-id          = {0375356},
  owner           = {NLM},
  pmc             = {PMC2120886},
  pmid            = {8707836},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2017-02-19},
}

@Article{Dillon2013,
  author          = {Dillon, J. and Andrianakis, I. and Mould, R. and Ient, B. and Liu, W. and James, C. and O'Connor, V. and Holden-Dye, L.},
  title           = {Distinct molecular targets including SLO-1 and gap junctions are engaged across a continuum of ethanol concentrations in Caenorhabditis elegans.},
  journal         = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
  year            = {2013},
  volume          = {27},
  issue           = {10},
  month           = oct,
  pages           = {4266--4278},
  issn            = {1530-6860},
  doi             = {10.1096/fj.11-189340},
  abstract        = {Ethanol (alcohol) interacts with diverse molecular effectors across a range of concentrations in the brain, eliciting intoxication through to sedation. Invertebrate models including the nematode worm Caenorhabditis elegans have been deployed for molecular genetic studies to inform on key components of these alcohol signaling pathways. C. elegans studies have typically employed external dosing with high (>250 mM) ethanol concentrations: A careful analysis of responses to low concentrations is lacking. Using the C. elegans pharyngeal system as a paradigm, we report a previously uncharacterized continuum of cellular and behavioral responses to ethanol from low (10 mM) to high (300 mM) concentrations. The complexity of these responses indicates that the pleiotropic action of ethanol observed in mammalian brain is conserved in this invertebrate model. We investigated two candidate ethanol effectors, the calcium-activated K(+) channel SLO-1 and gap junctions, and show that they contribute to, but are not sole determinants of, the low- and high-concentration effects, respectively. Notably, this study shows cellular and whole organismal behavioral responses to ethanol in C. elegans that directly equate to intoxicating through to supralethal blood alcohol concentrations in humans and provides an important benchmark for interpretation of paradigms that seek to inform on human alcohol use disorders.},
  chemicals       = {Caenorhabditis elegans Proteins, Large-Conductance Calcium-Activated Potassium Channels, slo-1 protein, C elegans, Ethanol},
  citation-subset = {IM},
  completed       = {2013-12-16},
  country         = {United States},
  issn-linking    = {0892-6638},
  keywords        = {Action Potentials, drug effects, physiology; Animals; Caenorhabditis elegans, drug effects, metabolism; Caenorhabditis elegans Proteins, genetics, metabolism; Dose-Response Relationship, Drug; Ethanol, pharmacology; Feeding Behavior, drug effects; Gap Junctions, physiology; Gene Expression Regulation; Large-Conductance Calcium-Activated Potassium Channels, genetics, metabolism; Muscle Cells, drug effects; alcohol; anesthesia; calcium-activated K+ channel; electrophysiology; intoxication; pharynx},
  nlm-id          = {8804484},
  owner           = {NLM},
  pii             = {fj.11-189340},
  pmc             = {PMC4046189},
  pmid            = {23882127},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-10-19},
}

@Article{avery1987,
  author    = "{Avery, L. and H. R. Horvitz}",
  title     = "{A Cell That Dies During Wild-Type \textit{C. elegans} Development Can Function as a Neuron In a \textit{ced-3} Mutant}",
  journal   = {Cell},
  year      = {1987},
  volume    = {51},
  number    = {6},
  pages     = {1071--1078},
  publisher = {Elsevier},
}

@Article{ochoa1989,
  author    = {Ochoa, Enrique LM and Chattopadhyay, Amitabha and McNamee, Mark G},
  title     = {Desensitization of the nicotinic acetylcholine receptor: molecular mechanisms and effect of modulators},
  journal   = {Cellular and molecular neurobiology},
  year      = {1989},
  volume    = {9},
  number    = {2},
  pages     = {141--178},
  publisher = {Springer},
}

@Article{quick2002,
  author    = {Quick, Michael W and Lester, Robin AJ},
  title     = {Desensitization of neuronal nicotinic receptors},
  journal   = {Journal of neurobiology},
  year      = {2002},
  volume    = {53},
  number    = {4},
  pages     = {457--478},
  publisher = {Wiley Online Library},
}

@Article{towers2005,
  author    = {Towers, P. R. and Edwards, B. and Richmond, J. E. and Sattelle, D. B.},
  title     = "{The \textit{Caenorhabditis elegans} lev-8 Gene Encodes a Novel Type of Nicotinic Acetylcholine Receptor $\alpha$ Subunit}",
  journal   = {J. Neurochem.},
  year      = {2005},
  volume    = {93},
  number    = {1},
  pages     = {1--9},
  publisher = {Wiley Online Library},
}

@Article{baron2017,
  author    = {Baron, G. L. and Raine, N. E. and Brown, M. J. F.},
  title     = {General and species-specific impacts of a neonicotinoid insecticide on the ovary development and feeding of wild bumblebee queens},
  journal   = {Proc. R. Soc. B},
  year      = {2017},
  volume    = {284},
  number    = {1854},
  pages     = {20170123},
  publisher = {The Royal Society},
}

@Article{thompson2015,
  author    = {Thompson, Helen M and Wilkins, Selwyn and Harkin, Sarah and Milner, Sarah and Walters, Keith FA},
  title     = {Neonicotinoids and bumblebees (Bombus terrestris): effects on nectar consumption in individual workers},
  journal   = {Pest Manag Sci},
  year      = {2015},
  volume    = {71},
  number    = {7},
  pages     = {946--950},
  publisher = {Wiley Online Library},
}

@Article{dalliere2015,
  author    = {Dalliere, N. and Bhatla, N. and Luedtke, Z. and Ma, D. K. and Woolman, J. and Walker, R. J. and Holden-Dye, L. and O’Connor, V.},
  title     = "{Multiple Excitatory and Inhibitory Neural Signals Converge to Fine-Tune \textit{Caenorhabditis elegans} Feeding to Food Availability}",
  journal   = {The FASEB Journal},
  year      = {2015},
  volume    = {30},
  number    = {2},
  pages     = {836--848},
  publisher = {Federation of American Societies for Experimental Biology Bethesda, MD, USA},
}

@Article{sugiura2005,
  author    = {Sugiura, M. and Fuke, S. and Suo, S. and Sasagawa, N. and Van Tol, H. H. M. and Ishiura, S.},
  title     = "{Characterization of a Novel D2-like Dopamine Receptor with a Truncated Splice Variant and a D1-like Dopamine Receptor Unique to Invertebrates from \textit{Caenorhabditis elegans}}",
  journal   = {J. Neurochem.},
  year      = {2005},
  volume    = {94},
  number    = {4},
  pages     = {1146--1157},
  publisher = {Wiley Online Library},
}

@Article{liu2011,
  author    = {Liu, X. and Testa, B. and Fahr, A.},
  title     = {Lipophilicity and its relationship with passive drug permeation},
  journal   = {Pharmaceutical research},
  year      = {2011},
  volume    = {28},
  number    = {5},
  pages     = {962--977},
  publisher = {Springer},
}

@Article{iyaniwura1991,
  author    = {Iyaniwura, T. T.},
  title     = {Non-target and environmental hazards of pesticides},
  journal   = {Reviews on environmental health},
  year      = {1991},
  volume    = {9},
  number    = {3},
  pages     = {161--176},
  publisher = {De Gruyter},
}

@Article{chagnon2015,
  author    = {Chagnon, Madeleine and Kreutzweiser, David and Mitchell, Edward AD and Morrissey, Christy A and Noome, Dominique A and Van der Sluijs, Jeroen P},
  title     = {Risks of large-scale use of systemic insecticides to ecosystem functioning and services},
  journal   = {Environ. Sci. Pollut. Res. Int.},
  year      = {2015},
  volume    = {22},
  number    = {1},
  pages     = {119--134},
  publisher = {Springer},
}

@Article{volkov2007,
  author  = {Volkov, E. M. and Nurullin, L. F. and Nikolsky, E. and Vysko{\v{c}}il, F.},
  title   = {Miniature excitatory synaptic ion currents in the earthworm Lumbricus terrestris body wall muscles.},
  journal = {Physiological research},
  year    = {2007},
  volume  = {56},
  number  = {5},
}

@Book{rand2007,
  author    = {Rand, J. B.},
  title     = {Acetylcholine in WormBook},
  year      = {2007},
  number    = {suppl\_1},
  publisher = {The C. elegans Research Community},
  chapter   = {Acetylcholine},
  pages     = {www.wormbook.org},
  doi       = {doi/10.1895/wormbook},
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@Article{liman1992,
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  journal         = {Neuron},
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  abstract        = {The subunit stoichiometry of the mammalian K+ channel KV1.1 (RCK1) was examined by linking together the coding sequences of 2-5 K+ channel subunits in a single open reading frame and tagging the expression of individual subunits with a mutation (Y379K or Y379R) that altered the sensitivity of the channel to block by external tetraethylammonium ion. Two lines of evidence argue that these constructs lead to K+ channel expression only through the formation of functional tetramers. First, currents expressed by tetrameric constructs containing a single mutant subunit have a sensitivity to tetraethylammonium that is well fitted by a single site binding isotherm. Second, a mutant subunit (Y379K) that expresses only as part of a heteromultimer contributes to the expression of functional channels when coexpressed with a trimeric construct but not a tetrameric construct.},
  chemicals       = {Macromolecular Substances, Potassium Channels, Tetraethylammonium Compounds, Tetraethylammonium, DNA},
  citation-subset = {IM},
  completed       = {1992-12-17},
  country         = {United States},
  issn-linking    = {0896-6273},
  keywords        = {Amino Acid Sequence; Animals; DNA, chemistry, genetics; Electric Conductivity; Gene Expression; Genetic Vectors; Macromolecular Substances; Molecular Sequence Data; Mutagenesis, Site-Directed; Oocytes, metabolism; Potassium Channels, chemistry, genetics, physiology; Tetraethylammonium; Tetraethylammonium Compounds, pharmacology; Thermodynamics; Xenopus},
  nlm-id          = {8809320},
  owner           = {NLM},
  pii             = {0896-6273(92)90239-A},
  pmid            = {1419000},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2006-11-15},
}

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  issn            = {0026-895X},
  doi             = {10.1124/mol.105.020198},
  abstract        = {alpha4beta2 nicotinic acetylcholine receptors (nAChRs) are recognized as the principal nicotine binding site in brain. Recombinant alpha4beta2 nAChR demonstrate biphasic concentration-response relationships with low- and high-EC50 components. This study shows that untranslated regions (UTR) can influence expression of high-sensitivity subforms of alpha4beta2 and alpha3beta2 nAChR. Oocytes injected with alpha4 and beta2 RNA lacking UTR expressed biphasic concentration-response relationships for acetylcholine with high-sensitivity EC50 values of 0.5 to 2.5 microM (14-24% of the population) and low-sensitivity EC50 values of 110 to 180 microM (76-86%). In contrast, message with UTR expressed exclusively the high-sensitivity alpha4beta2 nAChR subform with an acetylcholine EC50 value of 2.2 microM. Additional studies revealed pharmacological differences between high- and low-sensitivity alpha4beta2 subforms. Whereas the antagonists dihydro-beta-erythroidine (IC50 of 3-6 nM) and methyllycaconitine (IC50 of 40-135 nM) were not selective between high- and low-sensitivity alpha4beta2, chlorisondamine, mecamylamine, and d-tubocurarine were, respectively, 100-, 8-, and 5-fold selective for the alpha4beta2 subform with low sensitivity to acetylcholine. Conversely, agonists that selectively activated the high-sensitivity alpha4beta2 subform with respect to efficacy as well as potency were identified. Furthermore, two of these agonists were shown to activate mouse brain alpha4beta2 as well as the ferret high-sensitivity alpha4beta2 expressed in Xenopus laevis oocytes. With the use of UTR-containing RNA, exclusive expression of a novel high-sensitivity alpha3beta2 nAChR was also achieved. These studies 1) provide further evidence for the existence of multiple subforms of alpha4beta2 nAChR, 2) extend that to alpha3beta2 nAChR, 3) demonstrate UTR influence on beta2-containing nAChR properties, and 4) reveal compounds that interact with alpha4beta2 in a subform-selective manner.},
  chemicals       = {5' Untranslated Regions, Nicotinic Agonists, Nicotinic Antagonists, Protein Isoforms, Protein Subunits, Receptors, Nicotinic, nicotinic receptor alpha3beta2, nicotinic receptor alpha4beta2, methyllycaconitine, Dihydro-beta-Erythroidine, Estradiol, Nicotine, Chlorisondamine, Acetylcholine, Tubocurarine, Aconitine},
  citation-subset = {IM},
  completed       = {2006-10-24},
  country         = {United States},
  issn-linking    = {0026-895X},
  keywords        = {5' Untranslated Regions, genetics; Acetylcholine, pharmacology; Aconitine, analogs & derivatives, pharmacology; Animals; Chlorisondamine, pharmacology; Dihydro-beta-Erythroidine, pharmacology; Dose-Response Relationship, Drug; Estradiol, pharmacology; Female; Ferrets; Gene Expression, drug effects; Membrane Potentials, drug effects; Mice; Mice, Inbred C57BL; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Nicotinic Antagonists, pharmacology; Oocytes, drug effects, metabolism, physiology; Protein Isoforms, genetics, physiology; Protein Subunits, genetics, physiology; Receptors, Nicotinic, genetics, physiology; Tubocurarine, pharmacology; Xenopus laevis},
  nlm-id          = {0035623},
  owner           = {NLM},
  pii             = {mol.105.020198},
  pmid            = {16569710},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{lewis1997,
  author          = {Lewis, T M and Harkness, P C and Sivilotti, L G and Colquhoun, D and Millar, N S},
  title           = {The ion channel properties of a rat recombinant neuronal nicotinic receptor are dependent on the host cell type.},
  journal         = { J. Physiol.},
  year            = {1997},
  volume          = {505 ( Pt 2)},
  month           = dec,
  pages           = {299--306},
  issn            = {0022-3751},
  abstract        = {1. A stable mammalian cell line (L-alpha 3 beta 4) has been established which expresses the cloned rat neuronal nicotinic acetylcholine receptor (nAChR) subunits alpha 3 and beta 4, which are the most abundant in autonomic ganglia. Ion channel properties of nAChRs expressed in L-alpha 3 beta 4 cells were investigated by single-channel and whole-cell recording techniques, and compared with both rat alpha 3 beta 4 nAChRs expressed in Xenopus oocytes, and endogenous nicotinic receptors in rat superior cervical ganglion (SCG) neurones, using identical solutions for all cell types. 2. Acetylcholine (ACh) caused activation of single ion channel currents with a range of amplitudes. Some channels had high conductances (30-40 pS), and relatively brief lifetimes; these resembled the predominant native channel from SCG. Other channels had low conductances (20-26 pS) and long bursts of openings which were quite unlike native channels, but which were similar to channels formed by alpha 3 beta 4 in oocytes. Both types often occurred in the same patch. 3. Cytisine was about 3 times more potent than ACh (low-concentration potency ratio) in L-alpha 3 beta 4 cells, which is not dissimilar to the 5-fold potency ratio found in both SCG and oocytes, whereas 1,1-dimethyl-4-phenylpiperazinium (DMPP) was less potent than ACh in some cells (as in the oocyte), but more potent in others (as in SCG). 4. While the channels expressed in L-alpha 3 beta 4 cells do not mimic exactly those expressed in rat SCG, they differ considerably from the same subunit combination expressed in oocytes. Larger conductance, SCG-like channels were detected frequently in L-alpha 3 beta 4, but were rarely, if ever, seen in oocytes injected with alpha 3 and beta 4 mRNA. Our results indicate that ion channel properties such as single-channel conductance can be influenced by the choice of heterologous expression system.},
  chemicals       = {Ion Channels, Nicotinic Agonists, RNA, Messenger, Receptors, Nicotinic, Recombinant Proteins, Dimethylphenylpiperazinium Iodide, Acetylcholine, Calcium},
  citation-subset = {IM},
  completed       = {1998-02-17},
  country         = {England},
  issn-linking    = {0022-3751},
  keywords        = {Acetylcholine, pharmacology; Animals; Calcium, metabolism; Cell Line; Cloning, Molecular; Dimethylphenylpiperazinium Iodide, pharmacology; Female; Ganglia, Autonomic, physiology; Ion Channels, drug effects, physiology; L Cells (Cell Line); Membrane Potentials, drug effects; Mice; Neurons, physiology; Nicotinic Agonists, pharmacology; Oocytes, physiology; Patch-Clamp Techniques; RNA, Messenger, metabolism; Rats; Receptors, Nicotinic, biosynthesis, physiology; Recombinant Proteins, biosynthesis; Transfection; Xenopus},
  nlm-id          = {0266262},
  owner           = {NLM},
  pmc             = {PMC1160064},
  pmid            = {9423173},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{blumenthal1997,
  author          = {Blumenthal, E. M. and Conroy, W. G. and Romano, S. J. and Kassner, P. D. and Berg, D. K.},
  title           = {Detection of functional nicotinic receptors blocked by alpha-bungarotoxin on P{C}12 cells and dependence of their expression on post-translational events.},
  journal         = {The J. Neurosci.},
  year            = {1997},
  volume          = {17},
  issue           = {16},
  pages           = {6094--6104},
  issn            = {0270-6474},
  abstract        = {A major class of nicotinic receptors in the nervous system is one that binds alpha-bungarotoxin and contains the alpha7 gene product. PC12 cells, frequently used to study nicotinic receptors, express the alpha7 gene and have binding sites for the toxin, but previous attempts to elicit currents from the putative receptors have failed. Using whole-cell patch-clamp recording techniques and rapid application of agonist, we find a rapidly desensitizing acetylcholine-induced current in the cells that can be blocked by alpha-bungarotoxin. The current amplitude varies dramatically among three populations of PC12 cells but correlates well with the number of toxin-binding receptors. In contrast, the current shows no correlation with alpha7 transcript; cells with high levels of alpha7 mRNA can be negative for toxin binding and yet have other functional nicotinic receptors. Northern blot analysis and reverse transcription-PCR reveal no defects in alpha7 RNA from the negative cells, and immunoblot analysis demonstrates that they contain full-length alpha7 protein, although at reduced levels. Affinity purification of toxin-binding receptors from cells expressing them confirms that the receptors contain alpha7 protein. Transfection experiments demonstrate that PC12 cells lacking native toxin-binding receptors are deficient at producing receptors from alpha7 gene constructs, although the same cells can produce receptors from other transfected gene constructs. The results indicate that nicotinic receptors that bind alpha-bungarotoxin and contain alpha7 subunits require additional gene products to facilitate assembly and stabilization of the receptors. PC12 cells offer a model system for identifying those gene products.},
  chemicals       = {Bungarotoxins, Carrier Proteins, Cyclosporins, Nicotinic Antagonists, RNA, Messenger, Receptors, Nicotinic, Amino Acid Isomerases, Peptidylprolyl Isomerase},
  citation-subset = {IM},
  completed       = {1997-08-28},
  country         = {United States},
  issn-linking    = {0270-6474},
  keywords        = {Amino Acid Isomerases, pharmacology; Animals; Binding Sites, physiology; Bungarotoxins, pharmacology; Carrier Proteins, pharmacology; Cyclosporins, pharmacology; Gene Expression Regulation, physiology; Neurons, chemistry, physiology; Nicotinic Antagonists, pharmacology; PC12 Cells; Patch-Clamp Techniques; Peptidylprolyl Isomerase; Protein Processing, Post-Translational, physiology; RNA, Messenger, analysis; Rats; Receptors, Nicotinic, analysis, chemistry, genetics; Transfection},
  nlm-id          = {8102140},
  owner           = {NLM},
  pmid            = {9236221},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2007-11-14},
}

@Article{drago2003,
  author          = {Drago, J and McColl, C D and Horne, M K and Finkelstein, D I and Ross, S A},
  title           = {Neuronal nicotinic receptors: insights gained from gene knockout and knockin mutant mice.},
  journal         = {Cellular and molecular life sciences : CMLS},
  year            = {2003},
  volume          = {60},
  issue           = {7},
  month           = jul,
  pages           = {1267--1280},
  issn            = {1420-682X},
  abstract        = {Neuronal nicotinic acetylcholine receptors are ligand-gated ion channels that subserve a range of functions in the brain and peripheral nervous system. They are pentamers variously composed of alpha (alpha2-alpha10) and beta subunits (beta2-beta4). Pharmacological and ligand-binding studies have shown that the different subunits vary in their distribution and channel properties, but precise delineation of the in vivo function of individual subunits has been hampered by lack of subunit-specific antagonists. The development of transgenic mice with targeted deletions of specific subunits (knockout mice) or mutations in critical receptor domains (knockin mice) has extended understanding of nicotinic receptors, revealing that some subunits are necessary for viability, whereas others mediate modulatory effects on learning and memory, locomotion, anxiety, nociception, dopaminergic neurotransmission, seizure threshold, development of the visual system and autonomic function. In some cases, studies of transgenic mice have confirmed expectations derived from pharmacological and expression studies, but in other cases, compensation by related subunits has revealed a degree of functional redundancy not predicted by previous approaches.},
  chemicals       = {Ligands, Receptors, Nicotinic},
  citation-subset = {IM},
  completed       = {2003-09-24},
  country         = {Switzerland},
  issn-linking    = {1420-682X},
  keywords        = {Animals; Binding Sites; Ligands; Mice; Mice, Knockout; Mice, Transgenic; Neurons, physiology; Phenotype; Protein Conformation; Receptors, Nicotinic, chemistry, deficiency, genetics, physiology},
  nlm-id          = {9705402},
  owner           = {NLM},
  pmid            = {12943217},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {106},
  revised         = {2004-11-17},
}

@Article{maskos2005,
  author          = {Maskos, U and Molles, B E and Pons, S and Besson, M and Guiard, B P and Guilloux, J-P and Evrard, A and Cazala, P and Cormier, A and Mameli-Engvall, M and Dufour, N and Cloëz-Tayarani, I and Bemelmans, A-P and Mallet, J and Gardier, A M and David, V and Faure, P and Granon, S and Changeux, J-P},
  title           = {Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.},
  journal         = {Nature},
  year            = {2005},
  volume          = {436},
  issue           = {7047},
  month           = jul,
  pages           = {103--107},
  issn            = {1476-4687},
  doi             = {10.1038/nature03694},
  abstract        = {Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction, but nicotine is also known to enhance cognitive performance. Identifying the molecular mechanisms involved in nicotine reinforcement and cognition is a priority and requires the development of new in vivo experimental paradigms. The ventral tegmental area (VTA) of the midbrain is thought to mediate the reinforcement properties of many drugs of abuse. Here we specifically re-expressed the beta2-subunit of the nicotinic acetylcholine receptor (nAChR) by stereotaxically injecting a lentiviral vector into the VTA of mice carrying beta2-subunit deletions. We demonstrate the efficient re-expression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in dopamine-containing neurons of the VTA, together with the recovery of nicotine-elicited dopamine release and nicotine self-administration. We also quantified exploratory behaviours of the mice, and showed that beta2-subunit re-expression restored slow exploratory behaviour (a measure of cognitive function) to wild-type levels, but did not affect fast navigation behaviour. We thus demonstrate the sufficient role of the VTA in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.},
  chemicals       = {Receptors, Adrenergic, beta-2, Receptors, Nicotinic, Nicotine, Morphine, Dopamine},
  citation-subset = {IM},
  completed       = {2005-07-19},
  country         = {England},
  issn-linking    = {0028-0836},
  keywords        = {Animals; Cognition, drug effects, physiology; Dopamine, metabolism; Exploratory Behavior, drug effects, physiology; Gene Expression; Locomotion, physiology; Mice; Morphine, administration & dosage, pharmacology; Neurons, drug effects, metabolism; Nicotine, administration & dosage, metabolism, pharmacology; Receptors, Adrenergic, beta-2, deficiency, genetics, metabolism; Receptors, Nicotinic, deficiency, genetics, metabolism; Ventral Tegmental Area, cytology, drug effects, physiology},
  nlm-id          = {0410462},
  owner           = {NLM},
  pii             = {nature03694},
  pmid            = {16001069},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{sloan2015,
  author          = {Sloan, M. A. and Reaves, B. J. and Maclean, M. J. and Storey, B. E. and Wolstenholme, A. J.},
  title           = "{Expression of Nicotinic Acetylcholine Receptor Subunits from Parasitic Nematodes in \textit{Caenorhabditis elegans}.}",
  journal         = {Mol Biochem Parasit},
  year            = {2015},
  volume          = {204},
  issue           = {1},
  pages           = {44--50},
  issn            = {1872-9428},
  doi             = {10.1016/j.molbiopara.2015.12.006},
  abstract        = {The levamisole-sensitive nicotinic acetylcholine receptor present at nematode neuromuscular junctions is composed of multiple different subunits, with the exact composition varying between species. We tested the ability of two well-conserved nicotinic receptor subunits, UNC-38 and UNC-29, from Haemonchus contortus and Ascaris suum to rescue the levamisole-resistance and locomotion defects of Caenorhabditis elegans strains with null deletion mutations in the unc-38 and unc-29 genes. The parasite cDNAs were cloned downstream of the relevant C. elegans promoters and introduced into the mutant strains via biolistic transformation. The UNC-38 subunit of H. contortus was able to completely rescue both the locomotion defects and levamisole resistance of the null deletion mutant VC2937 (ok2896), but no C. elegans expressing the A. suum UNC-38 could be detected. The H. contortus UNC-29.1 subunit partially rescued the levamisole resistance of a C. elegans null mutation in unc-29 VC1944 (ok2450), but did cause increased motility in a thrashing assay. In contrast, only a single line of worms containing the A. suum UNC-29 subunit showed a partial rescue of levamisole resistance, with no effect on thrashing. },
  chemicals       = {Antinematodal Agents, Caenorhabditis elegans Proteins, Carrier Proteins, DNA, Complementary, DNA, Helminth, Protein Subunits, Receptors, Nicotinic, UNC-29 protein, C elegans, Unc-38 protein, C elegans, Levamisole},
  citation-subset = {IM},
  completed       = {2016-08-31},
  country         = {Netherlands},
  issn-linking    = {0166-6851},
  keywords        = {Animals; Antinematodal Agents, pharmacology; Ascaris suum, drug effects, genetics; Biolistics; Caenorhabditis elegans, genetics; Caenorhabditis elegans Proteins, genetics; Carrier Proteins, genetics; Cloning, Molecular; DNA, Complementary, genetics; DNA, Helminth, genetics; Drug Resistance, genetics; Haemonchus, drug effects, genetics; Levamisole, pharmacology; Locomotion, genetics; Protein Subunits, genetics; Receptors, Nicotinic, genetics; Sequence Deletion; Ascaris suum; Caenorhabditis elegans; Haemonchus contortus; Levamisole; Nicotinic acetylcholine receptor},
  mid             = {NIHMS750696},
  nlm-id          = {8006324},
  owner           = {NLM},
  pii             = {S0166-6851(15)30047-5},
  pmc             = {PMC4729587},
  pmid            = {26747395},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{cooper1997,
  author          = {Cooper, S. T. and Millar, N. S.},
  title           = {Host cell-specific folding and assembly of the neuronal nicotinic acetylcholine receptor alpha7 subunit.},
  journal         = {J. Neurochem.},
  year            = {1997},
  volume          = {68},
  issue           = {5},
  month           = may,
  pages           = {2140--2151},
  issn            = {0022-3042},
  abstract        = {Expression of the cloned neuronal nicotinic acetylcholine receptor (nAChR) alpha7 subunit in several cultured mammalian cell lines has revealed that the folding, assembly, and subcellular localization of this protein are critically dependent upon the nature of the host cell. In all cell lines that were examined, high levels of alpha7 protein were detected by metabolic labelling and immunoprecipitation after transfection with the cloned alpha7 cDNA. In contrast, elevated levels of alpha-bungarotoxin binding could be detected in only two of the nine cell lines. Both of these "alpha7-permissive" cell lines [rat phaeochromocytoma (PC12) and human neuroblastoma (SH-SY5Y)] express an endogenous alpha7 subunit. However, by expression of an epitope-tagged alpha7 subunit, it has been possible to show that the elevation in surface alpha-bungarotoxin binding in these two cell lines is due to expression of cDNA-encoded alpha7. The cell-specific misfolding of the neuronal nAChR alpha7 subunit is a phenomenon that is not shared by either the hetero-oligomeric muscle nAChR or the homooligomeric serotonin receptor 5-HT3 subunit. Our data also indicate that the cell-specific misfolding cannot be explained by a requirement for the coassembly with other known nAChR subunits and cannot be alleviated by treatments that have been reported to affect the assembly efficiency of other neurotransmitter-gated ion channels.},
  chemicals       = {Antibodies, Monoclonal, Bungarotoxins, DNA, Complementary, Receptors, Nicotinic, Cyclic AMP},
  citation-subset = {IM},
  completed       = {1997-05-15},
  country         = {England},
  issn-linking    = {0022-3042},
  keywords        = {Animals; Antibodies, Monoclonal, immunology; Bungarotoxins, metabolism; Cell Line; Chickens; Cyclic AMP, metabolism; DNA, Complementary; Endoplasmic Reticulum, metabolism; Humans; Intracellular Membranes, metabolism; Molecular Conformation; Muscles, metabolism; Neurons, metabolism, physiology; PC12 Cells; Protein Folding; Rats; Receptors, Nicotinic, chemistry, genetics, physiology; Subcellular Fractions, metabolism; Tissue Distribution},
  nlm-id          = {2985190R},
  owner           = {NLM},
  pmid            = {9109542},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{alvarez2007,
  author    = {Alvarez, L. I. and Mottier, M. L. and Lanusse, C. E.},
  title     = {Drug transfer into target helminth parasites},
  journal   = {Trends in parasitology},
  year      = {2007},
  volume    = {23},
  number    = {3},
  pages     = {97--104},
  publisher = {Elsevier},
}

@Article{baines2017,
  author    = {Baines, Danica and Wilton, Emily and Pawluk, Abbe and Gorter, Michael and Chomistek, Nora},
  title     = {Neonicotinoids act like endocrine disrupting chemicals in newly-emerged bees and winter bees},
  journal   = {Sci. Rep.},
  year      = {2017},
  volume    = {7},
  number    = {1},
  pages     = {10979},
  publisher = {Nature Publishing Group},
}

@Article{bao2018,
  author    = {Bao, H. and Xu, X. and Liu, W. and Yu, N. and Liu, Z.},
  title     = {Dual effects of insect nAChR chaperone RIC-3 on hybrid receptor: Promoting assembly on endoplasmic reticulum but suppressing transport to plasma membrane on Xenopus oocytes},
  journal   = {Neurochem . Int.},
  year      = {2018},
  volume    = {115},
  pages     = {24--30},
  publisher = {Elsevier},
}

@Article{vehovszky2018,
  author    = {Vehovszky, {\'A}gnes and Farkas, Anna and Csik{\'o}s, Vivien and Sz{\'e}k{\'a}cs, Andr{\'a}s and M{\"o}rtl, M{\'a}ria and Gy{\H{o}}ri, J{\'a}nos},
  title     = {Neonicotinoid insecticides are potential substrates of the multixenobiotic resistance (MXR) mechanism in the non-target invertebrate, Dreissena sp.},
  journal   = {Aquatic Toxicology},
  year      = {2018},
  volume    = {205},
  pages     = {148--155},
  publisher = {Elsevier},
}

@Article{gyori2017,
  author    = {Gy{\H{o}}ri, J{\'a}nos and Farkas, Anna and Stolyar, Oksana and Sz{\'e}k{\'a}cs, Andr{\'a}s and M{\"o}rtl, M{\'a}ria and Vehovszky, {\'A}gnes},
  title     = {Inhibitory effects of four neonicotinoid active ingredients on acetylcholine esterase activity},
  journal   = {Acta Biologica Hungarica},
  year      = {2017},
  volume    = {68},
  number    = {4},
  pages     = {345--357},
  publisher = {Akad{\'e}miai Kiad{\'o}},
}

@Article{hampton2002,
  author    = {Hampton, R. Y.},
  title     = {ER-associated degradation in protein quality control and cellular regulation},
  journal   = {Current opinion in cell biology},
  year      = {2002},
  volume    = {14},
  number    = {4},
  pages     = {476--482},
  publisher = {Elsevier},
}

@Article{baier2006,
  author    = {Baier, C. J. and Barrantes, F. J.},
  title     = {Sphingolipids are necessary for nicotinic acetylcholine receptor export in the early secretory pathway},
  journal   = {J. Neurochem.},
  year      = {2006},
  volume    = {99},
  pages     = {2},
  publisher = {J. Neurochem.},
}

@Article{eimer2007,
  author    = {Eimer, S. and Gottschalk, A. and Hengartner, M. and Horvitz, H. R. and Richmond, J. and Schafer, W. R. and Bessereau, J.},
  title     = {Regulation of nicotinic receptor trafficking by the transmembrane Golgi protein U{NC}-50},
  journal   = {The EMBO journal},
  year      = {2007},
  volume    = {26},
  number    = {20},
  pages     = {4313--4323},
  publisher = {EMBO Press},
}

@Article{papke2002,
  author          = {Papke, R. L. and Porter-Papke, J. K.},
  title           = {Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.},
  journal         = {Br. J. Pharmacol.},
  year            = {2002},
  volume          = {137},
  issue           = {1},
  month           = sep,
  pages           = {49--61},
  issn            = {0007-1188},
  doi             = {10.1038/sj.bjp.0704833},
  abstract        = {1. Pharmacological studies of alpha7 nicotinic acetylcholine receptors are confounded by the fact that rapid desensitization to high agonist concentration causes alpha7 peak responses to occur well in advance of complete solution exchange. For this reason, peak currents are an invalid measure of response to applied agonist concentrations. We show that results comparable to those that have been corrected for instantaneous concentration are obtained if net charge is used as the measure of receptor response. 2. Dose response curves obtained with these methods indicate that alpha7 receptors are approximately 10 fold more sensitive to agonist than previously reported. The agonists, ACh, choline, cytisine, GTS-21, 4OH-GTS-21 and 4-MeO-CA have the same rank order potency for both human and rat receptors: 4-MeO-CA > 4OH-GTS-21 > GTS-21 > cytisine > ACh > choline. However, differences in efficacy exist between rat and human receptors. GTS-21 is more efficacious for rat than human alpha7 receptors and cytosine more efficacious for human than rat alpha7 receptors. 3. Choline is the least potent agonist for both human and rat alpha7, with a potency approximately 10 fold lower than that of ACh. While the EC50 for the activation of alpha7 receptors by choline (400-500 microM) is outside the normal physiological range (10-100 microM), choline can nonetheless produce detectable levels of channel activation in the physiological concentration range. Since these concentrations are relatively non-desensitizing, the contribution of choline-activated alpha7 receptor current may play a significant role in the regulation of calcium homeostasis in alpha7-expressing neurons.},
  chemicals       = {3-(4-dimethylaminocinnamylidene)anabaseine, 3-(4-hydroxy-2-methoxybenzylidene)anabaseine, Benzylidene Compounds, Chrna7 protein, human, Chrna7 protein, rat, Nicotinic Agonists, Pyridines, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, 3-(2,4-dimethoxybenzylidene)anabaseine, Anabasine},
  citation-subset = {IM},
  completed       = {2003-03-19},
  country         = {England},
  issn-linking    = {0007-1188},
  keywords        = {Anabasine, analogs & derivatives, pharmacology; Animals; Benzylidene Compounds, metabolism, pharmacology; Dose-Response Relationship, Drug; Electrophysiology; Humans; Kinetics; Nicotinic Agonists, metabolism, pharmacology; Oocytes; Pyridines, metabolism, pharmacology; Rats; Receptors, Nicotinic, drug effects, metabolism, physiology; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {7502536},
  owner           = {NLM},
  pmc             = {PMC1573461},
  pmid            = {12183330},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{briggs1996,
  author  = "{Briggs, C. A. and D. G. McKenna}",
  title   = {Effect of M{K}-801 at the human {a}lpha7 nicotinic acetylcholine receptor.},
  journal = {Neuropharm.},
  year    = {1996},
  volume  = {35},
  issue   = {4},
  pages   = {407-414},
}

@Article{abongwa2016,
  author          = {Abongwa, M. and Buxton, S. K. and Courtot, E. and Charvet, C. L. and Neveu, C. and McCoy, C. J. and Verma, S. and Robertson, A. P. and Martin, R. J.},
  title           = {Pharmacological profile of Ascaris suum ACR-16, a new homomeric nicotinic acetylcholine receptor widely distributed in Ascaris tissues.},
  journal         = {Br. J. Pharmacol.},
  year            = {2016},
  volume          = {173},
  issue           = {16},
  month           = aug,
  pages           = {2463--2477},
  issn            = {1476-5381},
  doi             = {10.1111/bph.13524},
  abstract        = {Control of nematode parasite infections relies largely on anthelmintic drugs, several of which act on nicotinic ACh receptors (nAChRs), and there are concerns about the development of resistance. There is an urgent need for development of new compounds to overcome resistance and novel anthelmintic drug targets. We describe the functional expression and pharmacological characterization of a homomeric nAChR, ACR-16, from a nematode parasite. Using RT-PCR, molecular cloning and two-electrode voltage clamp electrophysiology, we localized acr-16 mRNA in Ascaris suum (Asu) and then cloned and expressed acr-16 cRNA in Xenopus oocytes. Sensitivity of these receptors to cholinergic anthelmintics and a range of nicotinic agonists was tested. Amino acid sequence comparison with vertebrate nAChR subunits revealed ACR-16 to be most closely related to α7 receptors, but with some striking distinctions. acr-16 mRNA was recovered from Asu somatic muscle, pharynx, ovijector, head and intestine. In electrophysiological experiments, the existing cholinergic anthelmintic agonists (morantel, levamisole, methyridine, thenium, bephenium, tribendimidine and pyrantel) did not activate Asu-ACR-16 (except for a small response to oxantel). Other nAChR agonists: nicotine, ACh, cytisine, 3-bromocytisine and epibatidine, produced robust current responses which desensitized at a rate varying with the agonists. Unlike α7, Asu-ACR-16 was insensitive to α-bungarotoxin and did not respond to genistein or other α7 positive allosteric modulators. Asu-ACR-16 had lower calcium permeability than α7 receptors. We suggest that ACR-16 has diverse tissue-dependent functions in nematode parasites and is a suitable drug target for development of novel anthelmintic compounds.},
  chemicals       = {Nicotinic Antagonists, RNA, Messenger, Receptors, Nicotinic},
  citation-subset = {IM},
  completed       = {2017-10-12},
  country         = {England},
  issn-linking    = {0007-1188},
  keywords        = {Amino Acid Sequence; Animals; Ascaris suum, drug effects, genetics, metabolism; Female; Nicotinic Antagonists, chemistry, pharmacology; RNA, Messenger, genetics, metabolism; Receptors, Nicotinic, chemistry, genetics, metabolism},
  nlm-id          = {7502536},
  owner           = {NLM},
  pmc             = {PMC4959957},
  pmid            = {27238203},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{holden-dye2013,
  author          = {Holden-Dye, L. and Joyner, M. and O'Connor, V. and Walker, R. J.},
  title           = {Nicotinic acetylcholine receptors: a comparison of the nAChRs of Caenorhabditis elegans and parasitic nematodes.},
  journal         = {Parasitology international},
  year            = {2013},
  volume          = {62},
  issue           = {6},
  month           = dec,
  pages           = {606--615},
  issn            = {1873-0329},
  doi             = {10.1016/j.parint.2013.03.004},
  abstract        = {Nicotinic acetylcholine receptors (nAChRs) play a key role in the normal physiology of nematodes and provide an established target site for anthelmintics. The free-living nematode, Caenorhabditis elegans, has a large number of nAChR subunit genes in its genome and so provides an experimental model for testing novel anthelmintics which act at these sites. However, many parasitic nematodes lack specific genes present in C. elegans, and so care is required in extrapolating from studies using C. elegans to the situation in other nematodes. In this review the properties of C. elegans nAChRs are reviewed and compared to those of parasitic nematodes. This forms the basis for a discussion of the possible subunit composition of nAChRs from different species of parasitic nematodes. Currently our knowledge on this is largely based on studies using heterologous expression and pharmacological analysis of receptor subunits in Xenopus laevis oocytes. It is concluded that more information is required regarding the subunit composition and pharmacology of endogenous nAChRs in parasitic nematodes.},
  chemicals       = {Anthelmintics, Helminth Proteins, Protein Subunits, Receptors, Nicotinic, Levamisole},
  citation-subset = {IM},
  completed       = {2015-04-23},
  country         = {Netherlands},
  issn-linking    = {1383-5769},
  keywords        = {Animals; Anthelmintics, pharmacology; Ascariasis, parasitology; Ascaris suum, drug effects, genetics, metabolism; Caenorhabditis elegans, drug effects, genetics, metabolism; Gene Expression; Haemonchiasis, parasitology; Haemonchus, drug effects, genetics, metabolism; Helminth Proteins, drug effects, genetics, metabolism; Levamisole, pharmacology; Oocytes; Protein Subunits, genetics; Receptors, Nicotinic, drug effects, genetics, metabolism; Xenopus laevis; Anthelmintic; Ascaris suum; Caenorhabditis elegans; Haemonchus contortus; Levamisole; Nicotine; nAChRs},
  nlm-id          = {9708549},
  owner           = {NLM},
  pii             = {S1383-5769(13)00033-0},
  pmid            = {23500392},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-10-14},
}

@Article{jeschke2008,
  author          = {Jeschke, Peter and Nauen, Ralf},
  title           = {Neonicotinoids-from zero to hero in insecticide chemistry.},
  journal         = {Pest Manag Sci},
  year            = {2008},
  volume          = {64},
  issue           = {11},
  month           = nov,
  pages           = {1084--1098},
  issn            = {1526-498X},
  doi             = {10.1002/ps.1631},
  abstract        = {In recent years, neonicotinoids have been the fastest-growing class of insecticides in modern Crop Prot., with widespread use against a broad spectrum of sucking and certain chewing pests. As potent agonists, they act selectively on insect nicotinic acetylcholine receptors, their molecular target site. The discovery of neonicotinoids can be considered as a milestone in insecticide research and facilitates greatly the understanding of the functional properties of insect nicotinic acetylcholine receptors. Because of the relatively low risk for non-target organisms and environment, the high target specificity of neonicotinoid insecticides and their versatility in application methods, this important class has to be maintained globally for integrated pest management strategies and insect resistance management programmes. This review comprehensively describes particularly the origin, structure and bonding as well as associated properties of neonicotinoid insecticides.},
  chemicals       = {Insecticides, Nicotinic Agonists},
  citation-subset = {IM},
  completed       = {2009-01-07},
  country         = {England},
  issn-linking    = {1526-498X},
  keywords        = {Animals; Insect Control, trends; Insecta; Insecticide Resistance; Insecticides, chemistry, pharmacokinetics; Nicotinic Agonists, chemistry, pharmacokinetics},
  nlm-id          = {100898744},
  owner           = {NLM},
  pmid            = {18712805},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {130},
  revised         = {2017-11-16},
}

@Article{bonmatin2015,
  author          = {Bonmatin, J-M and Giorio, C and Girolami, V and Goulson, D and Kreutzweiser, D P and Krupke, C and Liess, M and Long, E and Marzaro, M and Mitchell, E A D and Noome, D A and Simon-Delso, N and Tapparo, A},
  title           = {Environmental fate and exposure; neonicotinoids and fipronil.},
  journal         = {Environ Sci Pollut Res Int},
  year            = {2015},
  volume          = {22},
  issue           = {1},
  month           = jan,
  pages           = {35--67},
  issn            = {1614-7499},
  doi             = {10.1007/s11356-014-3332-7},
  abstract        = {Systemic insecticides are applied to plants using a wide variety of methods, ranging from foliar sprays to seed treatments and soil drenches. Neonicotinoids and fipronil are among the most widely used pesticides in the world. Their popularity is largely due to their high toxicity to invertebrates, the ease and flexibility with which they can be applied, their long persistence, and their systemic nature, which ensures that they spread to all parts of the target crop. However, these properties also increase the probability of environmental contamination and exposure of nontarget organisms. Environmental contamination occurs via a number of routes including dust generated during drilling of dressed seeds, contamination and accumulation in arable soils and soil water, runoff into waterways, and uptake of pesticides by nontarget plants via their roots or dust deposition on leaves. Persistence in soils, waterways, and nontarget plants is variable but can be prolonged; for example, the half-lives of neonicotinoids in soils can exceed 1,000 days, so they can accumulate when used repeatedly. Similarly, they can persist in woody plants for periods exceeding 1 year. Breakdown results in toxic metabolites, though concentrations of these in the environment are rarely measured. Overall, there is strong evidence that soils, waterways, and plants in agricultural environments and neighboring areas are contaminated with variable levels of neonicotinoids or fipronil mixtures and their metabolites (soil, parts per billion (ppb)-parts per million (ppm) range; water, parts per trillion (ppt)-ppb range; and plants, ppb-ppm range). This provides multiple routes for chronic (and acute in some cases) exposure of nontarget animals. For example, pollinators are exposed through direct contact with dust during drilling; consumption of pollen, nectar, or guttation drops from seed-treated crops, water, and consumption of contaminated pollen and nectar from wild flowers and trees growing near-treated crops. Studies of food stores in honeybee colonies from across the globe demonstrate that colonies are routinely and chronically exposed to neonicotinoids, fipronil, and their metabolites (generally in the 1-100 ppb range), mixed with other pesticides some of which are known to act synergistically with neonicotinoids. Other nontarget organisms, particularly those inhabiting soils, aquatic habitats, or herbivorous insects feeding on noncrop plants in farmland, will also inevitably receive exposure, although data are generally lacking for these groups. We summarize the current state of knowledge regarding the environmental fate of these compounds by outlining what is known about the chemical properties of these compounds, and placing these properties in the context of modern agricultural practices. },
  chemicals       = {Insecticides, Nicotinic Agonists, Pyrazoles, Soil, Soil Pollutants, Water Pollutants, Chemical, fipronil},
  citation-subset = {IM},
  completed       = {2015-06-15},
  country         = {Germany},
  issn-linking    = {0944-1344},
  keywords        = {Agriculture; Animals; Insecta, drug effects; Insecticides, chemistry, metabolism, toxicity; Nicotinic Agonists, chemistry, metabolism, toxicity; Plants, metabolism; Pyrazoles, chemistry, metabolism, toxicity; Soil, chemistry; Soil Pollutants, chemistry, metabolism, toxicity; Water Pollutants, Chemical, chemistry, metabolism, toxicity},
  nlm-id          = {9441769},
  owner           = {NLM},
  pmc             = {PMC4284396},
  pmid            = {25096486},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-02},
}

@Article{wu2015,
  author          = {Wu, Zhong-shan and Cheng, Hao and Jiang, Yi and Melcher, Karsten and Xu, H Eric},
  title           = {Ion channels gated by acetylcholine and serotonin: structures, biology, and drug discovery.},
  journal         = {Acta pharmacologica Sinica},
  year            = {2015},
  volume          = {36},
  issue           = {8},
  month           = aug,
  pages           = {895--907},
  issn            = {1745-7254},
  doi             = {10.1038/aps.2015.66},
  abstract        = {The nicotinic acetylcholine receptors (nAChRs) and the 5-HT3 receptors (5-HT3Rs) are cation-selective members of the pentameric ligand-gated ion channels (pLGICs), which are oligomeric protein assemblies that convert a chemical signal into an ion flux through postsynaptic membrane. They are critical components for synaptic transmission in the nervous system, and their dysfunction contributes to many neurological disorders. The diverse subunit compositions of pLGICs give rise to complex mechanisms of ligand recognition, channel gating, and ion-selective permeability, which have been demonstrated in numerous electrophysiological and molecular biological studies, and unraveled by progress in studying the structural biology of this protein family. In this review, we discuss recent insights into the structural and functional basis of two cation-selective pLGICs, the nAChR and the 5-HT3R, including their subunit compositions, ligand binding, and channel gating mechanisms. We also discuss their relevant pharmacology and drug discovery for treating various neurological disorders. Finally, we review a model of two alternative ion conducting pathways based on the latest 5-HT3A crystal structure. },
  chemicals       = {Receptors, Cholinergic, Receptors, Serotonin, 5-HT3, Serotonin, Acetylcholine},
  citation-subset = {IM},
  completed       = {2016-07-22},
  country         = {United States},
  issn-linking    = {1671-4083},
  keywords        = {Acetylcholine, metabolism; Allosteric Site, drug effects; Amino Acid Sequence; Animals; Drug Discovery, methods; Humans; Ion Channel Gating, drug effects; Models, Molecular; Molecular Sequence Data; Protein Conformation; Receptors, Cholinergic, chemistry, metabolism; Receptors, Serotonin, 5-HT3, chemistry, metabolism; Sequence Alignment; Serotonin, metabolism},
  nlm-id          = {100956087},
  owner           = {NLM},
  pii             = {aps201566},
  pmc             = {PMC4564887},
  pmid            = {26238288},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{olsen2014,
  author          = {Olsen, J. A and Balle, T. and Gajhede, M. and Ahring, P. K. and Kastrup, J. S.},
  title           = {Molecular recognition of the neurotransmitter acetylcholine by an acetylcholine binding protein reveals determinants of binding to nicotinic acetylcholine receptors.},
  journal         = {PloS one},
  year            = {2014},
  volume          = {9},
  issue           = {3},
  pages           = {e91232},
  issn            = {1932-6203},
  doi             = {10.1371/journal.pone.0091232},
  abstract        = {Despite extensive studies on nicotinic acetylcholine receptors (nAChRs) and homologues, details of acetylcholine binding are not completely resolved. Here, we report the crystal structure of acetylcholine bound to the receptor homologue acetylcholine binding protein from Lymnaea stagnalis. This is the first structure of acetylcholine in a binding pocket containing all five aromatic residues conserved in all mammalian nAChRs. The ligand-protein interactions are characterized by contacts to the aromatic box formed primarily by residues on the principal side of the intersubunit binding interface (residues Tyr89, Trp143 and Tyr185). Besides these interactions on the principal side, we observe a cation-π interaction between acetylcholine and Trp53 on the complementary side and a water-mediated hydrogen bond from acetylcholine to backbone atoms of Leu102 and Met114, both of importance for anchoring acetylcholine to the complementary side. To further study the role of Trp53, we mutated the corresponding tryptophan in the two different acetylcholine-binding interfaces of the widespread α4β2 nAChR, i.e. the interfaces α4(+)β2(-) and α4(+)α4(-). Mutation to alanine (W82A on the β2 subunit or W88A on the α4 subunit) significantly altered the response to acetylcholine measured by oocyte voltage-clamp electrophysiology in both interfaces. This shows that the conserved tryptophan residue is important for the effects of ACh at α4β2 nAChRs, as also indicated by the crystal structure. The results add important details to the understanding of how this neurotransmitter exerts its action and improves the foundation for rational drug design targeting these receptors. },
  chemicals       = {Carrier Proteins, Neurotransmitter Agents, Receptors, Nicotinic, Tumor Suppressor Protein p53, Acetylcholine},
  citation-subset = {IM},
  completed       = {2015-01-06},
  country         = {United States},
  issn-linking    = {1932-6203},
  keywords        = {Acetylcholine, chemistry, metabolism; Animals; Binding Sites; Carrier Proteins, chemistry, metabolism; Evoked Potentials, genetics; Models, Molecular; Molecular Conformation; Mutation; Neurotransmitter Agents, chemistry, metabolism; Oocytes, metabolism; Protein Binding; Receptors, Nicotinic, chemistry, genetics, metabolism; Tumor Suppressor Protein p53, chemistry, metabolism},
  nlm-id          = {101285081},
  owner           = {NLM},
  pii             = {PONE-D-13-39235},
  pmc             = {PMC3956608},
  pmid            = {24637639},
  pubmodel        = {Electronic-eCollection},
  pubstatus       = {epublish},
  revised         = {2018-11-13},
}

@Article{bourne2010,
  author          = {Bourne, Yves and Radic, Zoran and Aráoz, Rómulo and Talley, Todd T and Benoit, Evelyne and Servent, Denis and Taylor, Palmer and Molgó, Jordi and Marchot, Pascale},
  title           = {Structural determinants in phycotoxins and AChBP conferring high affinity binding and nicotinic AChR antagonism.},
  journal         = { Proc. Natl. Acad. Sci. USA of the United States of America},
  year            = {2010},
  volume          = {107},
  issue           = {13},
  month           = mar,
  pages           = {6076--6081},
  issn            = {1091-6490},
  doi             = {10.1073/pnas.0912372107},
  abstract        = {Spirolide and gymnodimine macrocyclic imine phycotoxins belong to an emerging class of chemical agents associated with marine algal blooms and shellfish toxicity. Analysis of 13-desmethyl spirolide C and gymnodimine A by binding and voltage-clamp recordings on muscle-type alpha1(2)betagammadelta and neuronal alpha3beta2 and alpha4beta2 nicotinic acetylcholine receptors reveals subnanomolar affinities, potent antagonism, and limited subtype selectivity. Their binding to acetylcholine-binding proteins (AChBP), as soluble receptor surrogates, exhibits picomolar affinities governed by diffusion-limited association and slow dissociation, accounting for apparent irreversibility. Crystal structures of the phycotoxins bound to Aplysia-AChBP ( approximately 2.4A) show toxins neatly imbedded within the nest of ar-omatic side chains contributed by loops C and F on opposing faces of the subunit interface, and which in physiological conditions accommodates acetylcholine. The structures also point to three major features: (i) the sequence-conserved loop C envelops the bound toxins to maximize surface complementarity; (ii) hydrogen bonding of the protonated imine nitrogen in the toxins with the carbonyl oxygen of loop C Trp147 tethers the toxin core centered within the pocket; and (iii) the spirolide bis-spiroacetal or gymnodimine tetrahydrofuran and their common cyclohexene-butyrolactone further anchor the toxins in apical and membrane directions, along the subunit interface. In contrast, the se-quence-variable loop F only sparingly contributes contact points to preserve the broad receptor subtype recognition unique to phycotoxins compared with other nicotinic antagonists. These data offer unique means for detecting spiroimine toxins in shellfish and identify distinctive ligands, functional determinants and binding regions for the design of new drugs able to target several receptor subtypes with high affinity.},
  chemicals       = {Carrier Proteins, Heterocyclic Compounds, 3-Ring, Hydrocarbons, Cyclic, Imines, Ligands, Macromolecular Substances, Marine Toxins, Nicotinic Antagonists, Receptors, Nicotinic, Spiro Compounds, gymnodimine, Acetylcholine},
  citation-subset = {IM},
  completed       = {2010-04-28},
  country         = {United States},
  issn-linking    = {0027-8424},
  keywords        = {Acetylcholine, metabolism; Animals; Aplysia, metabolism; Carrier Proteins, chemistry, metabolism; Crystallography, X-Ray; Electric Organ, metabolism; Female; Heterocyclic Compounds, 3-Ring, chemistry, metabolism, pharmacology; Humans; Hydrocarbons, Cyclic, chemistry, metabolism, pharmacology; Imines, chemistry, metabolism, pharmacology; In Vitro Techniques; Kinetics; Ligands; Macromolecular Substances; Marine Toxins, chemistry, metabolism, pharmacology; Models, Molecular; Molecular Structure; Nicotinic Antagonists, chemistry, metabolism, pharmacology; Oocytes, drug effects, metabolism; Receptors, Nicotinic, metabolism; Spiro Compounds, chemistry, metabolism, pharmacology; Torpedo, metabolism; Xenopus, metabolism},
  nlm-id          = {7505876},
  owner           = {NLM},
  pii             = {0912372107},
  pmc             = {PMC2851920},
  pmid            = {20224036},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{blum2010,
  author          = {Blum, A. P. and Lester, H. A. and Dougherty, D. A.},
  title           = {Nicotinic pharmacophore: the pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone {NH}.},
  journal         = { Proc. Natl. Acad. Sci. USA of the United States of America},
  year            = {2010},
  volume          = {107},
  issue           = {30},
  month           = jul,
  pages           = {13206--13211},
  issn            = {1091-6490},
  doi             = {10.1073/pnas.1007140107},
  abstract        = {Pharmacophore models for nicotinic agonists have been proposed for four decades. Central to these models is the presence of a cationic nitrogen and a hydrogen bond acceptor. It is now well-established that the cationic center makes an important cation-pi interaction to a conserved tryptophan, but the donor to the proposed hydrogen bond acceptor has been more challenging to identify. A structure of nicotine bound to the acetylcholine binding protein predicted that the binding partner of the pharmacophore's second component was a water molecule, which also hydrogen bonds to the backbone of the complementary subunit of the receptors. Here we use unnatural amino acid mutagenesis coupled with agonist analogs to examine whether such a hydrogen bond is functionally significant in the alpha4beta2 neuronal nAChR, the receptor most associated with nicotine addiction. We find evidence for the hydrogen bond with the agonists nicotine, acetylcholine, carbamylcholine, and epibatidine. These data represent a completed nicotinic pharmacophore and offer insight into the design of new therapeutic agents that selectively target these receptors.},
  chemicals       = {Bridged Bicyclo Compounds, Heterocyclic, Nicotinic Agonists, Pyridines, RNA, Messenger, Receptors, Nicotinic, nicotinic receptor alpha4beta2, Nicotine, Carbon, Carbachol, epibatidine, Acetylcholine, pyridine},
  citation-subset = {IM},
  completed       = {2010-09-27},
  country         = {United States},
  issn-linking    = {0027-8424},
  keywords        = {Acetylcholine, chemistry, metabolism, pharmacology; Animals; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic, chemistry, metabolism, pharmacology; Carbachol, chemistry, metabolism, pharmacology; Carbon, chemistry, metabolism; Female; Hydrogen Bonding; Membrane Potentials, drug effects, physiology; Microinjections; Models, Molecular; Molecular Structure; Mutation; Nicotine, chemistry, metabolism, pharmacology; Nicotinic Agonists, chemistry, metabolism, pharmacology; Oocytes, metabolism, physiology; Protein Structure, Tertiary; Pyridines, chemistry, metabolism, pharmacology; RNA, Messenger, administration & dosage, genetics; Rats; Receptors, Nicotinic, chemistry, genetics, metabolism; Xenopus laevis},
  nlm-id          = {7505876},
  owner           = {NLM},
  pii             = {1007140107},
  pmc             = {PMC2922130},
  pmid            = {20616056},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{blum2011,
  author          = {Blum, A. P. and Gleitsman, K. R. and Lester, H. A. and Dougherty, D. A.},
  title           = {Evidence for an extended hydrogen bond network in the binding site of the nicotinic receptor: role of the vicinal disulfide of the alpha1 subunit.},
  journal         = {J. Biol. Chem.},
  year            = {2011},
  volume          = {286},
  issue           = {37},
  month           = sep,
  pages           = {32251--32258},
  issn            = {1083-351X},
  doi             = {10.1074/jbc.M111.254235},
  abstract        = {The defining feature of the α subunits of the family of nicotinic acetylcholine receptors is a vicinal disulfide between Cys-192 and Cys-193. Although this structure has played a pivotal role in a number of pioneering studies of nicotinic receptors, its functional role in native receptors remains uncertain. Using mutant cycle analysis and unnatural residue mutagenesis, including backbone mutagenesis of the peptide bond of the vicinal disulfide, we have established the presence of a network of hydrogen bonds that extends from that peptide NH, across a β turn to another backbone hydrogen bond, and then across the subunit interface to the side chain of a functionally important Asp residue in the non-α subunit. We propose that the role of the vicinal disulfide is to distort the β turn and thereby properly position a backbone NH for intersubunit hydrogen bonding to the key Asp.},
  chemicals       = {Disulfides, Peptides, Receptors, Nicotinic, Xenopus Proteins},
  citation-subset = {IM},
  completed       = {2011-11-22},
  country         = {United States},
  issn-linking    = {0021-9258},
  keywords        = {Animals; Disulfides, chemistry; Hydrogen Bonding; Peptides, chemistry, genetics, metabolism; Protein Structure, Secondary; Receptors, Nicotinic, chemistry, genetics, metabolism; Xenopus Proteins; Xenopus laevis},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pii             = {M111.254235},
  pmc             = {PMC3173184},
  pmid            = {21757705},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{dennis2018,
  author    = {Dennis, E. J. and Dobosiewicz, M. and Jin, X. and Duvall, L. B. and Hartman, P. S. and Bargmann, C. I. and Vosshall, L. B.},
  title     = {A natural variant and engineered mutation in a GPCR promote DEET resistance in C. elegans},
  journal   = {Nature},
  year      = {2018},
  volume    = {562},
  number    = {7725},
  pages     = {119},
  publisher = {Nature Publishing Group},
}

@Article{lee2017,
  author    = {Lee, Kyung Suk and Iwanir, Shachar and Kopito, Ronen B and Scholz, Monika and Calarco, John A and Biron, David and Levine, Erel},
  title     = "{Serotonin-Dependent Kinetics of Feeding Bursts Underlie a Graded Response to Food Availability in \textit{C. elegans}}",
  journal   = {Nat. Commun.},
  year      = {2017},
  volume    = {8},
  pages     = {14221},
  publisher = {Nature Publishing Group},
}

@Article{bodereau-dubois2012,
  author    = {Bodereau-Dubois, B{\'e}atrice and List, Olivier and Calas-List, Delphine and Marques, Olivier and Communal, Pierre-Yves and Thany, Steeve H and Lapied, Bruno},
  title     = {Transmembrane potential polarization, calcium influx, and receptor conformational state modulate the sensitivity of the imidacloprid-insensitive neuronal insect nicotinic acetylcholine receptor to neonicotinoid insecticides},
  journal   = {J. Pharmacol. Exp. Ther.},
  year      = {2012},
  volume    = {341},
  number    = {2},
  pages     = {326--339},
  publisher = {ASPET},
}

@Article{marotta2014,
  author    = {Marotta, C. B. and Rreza, I. and Lester, H. A. and Dougherty, D. A.},
  title     = {Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors},
  journal   = {ACS chemical biology},
  year      = {2014},
  volume    = {9},
  number    = {5},
  pages     = {1153--1159},
  publisher = {ACS Publications},
}

@Article{harpsoe2013,
  author    = {Harps{\o}e, K. and Hald, H. and Timmermann, D. B. and Jensen, M. L. and Dyhring, T. and Nielsen, E. {\O}. and Peters, D. and Balle, T. and Gajhede, M. and Kastrup, J. S. and others},
  title     = {Molecular determinants of subtype-selective efficacies of cytisine and the novel compound NS3861 at heteromeric nicotinic acetylcholine receptors},
  journal   = {J. Biol. Chem.},
  year      = {2013},
  volume    = {288},
  number    = {4},
  pages     = {2559--2570},
  publisher = {ASBMB},
}

@Article{morales-perez2016,
  author    = {Morales-Perez, C. L. and Noviello, C. M. and Hibbs, R. E.},
  title     = {X-ray structure of the human $\alpha$4$\beta$2 nicotinic receptor},
  journal   = {Nature},
  year      = {2016},
  volume    = {538},
  number    = {7625},
  pages     = {411},
  publisher = {Nature Publishing Group},
}

@Article{hansen2004,
  author    = {Hansen, S. B. and Talley, T. T. and Radi{\'c}, Z. and Taylor, P.},
  title     = "{Structural and Ligand Recognition Characteristics of an Acetylcholine-Binding Protein from \textit{Aplysia californica}}",
  journal   = {J. Biol. Chem.},
  year      = {2004},
  volume    = {279},
  number    = {23},
  pages     = {24197--24202},
  publisher = {ASBMB},
}

@Booklet{wonnacott2007,
  author = {Wonnacott, S. and Baric, J.},
  editor = {Tocris Bioscience},
  title  = "{Nicotinic ACh Receptors}",
  year   = {2007},
  url    = {https://www.tocris.com/literature/scientific-reviews/nicotinic-ach-receptors}
}

@Article{cartereau2018,
  author    = {Cartereau, A. and Martin, C. and Thany, S. H.},
  title     = {Neonicotinoid insecticides differently modulate acetycholine-induced currents on mammalian $\alpha$7 nicotinic acetylcholine receptors},
  journal   = {Br. J. Pharmacol.},
  year      = {2018},
  volume    = {175},
  number    = {11},
  pages     = {1987--1998},
  publisher = {Wiley Online Library},
}

@Article{bartos2006,
  author    = {Bartos, M. and Rayes, D. and Bouzat, C.},
  title     = {Molecular determinants of pyrantel selectivity in nicotinic receptors},
  journal   = {Molecular pharmacology},
  year      = {2006},
  publisher = {ASPET},
}

@Article{bao2015,
  author    = {Bao, H. and Sun, H. and Xiao, Y. and Zhang, Y. and Wang, X. and Xu, X. and Liu, Z. and Fang, J. and Li, Z.},
  title     = {Functional interaction of nicotinic acetylcholine receptors and Na+/K+ ATPase from Locusta migratoria manilensis (Meyen)},
  journal   = {Sci. Rep.},
  year      = {2015},
  volume    = {5},
  pages     = {8849},
  publisher = {Nature Publishing Group},
}

@Article{wuestenberg2004,
  author    = {W{\"u}stenberg, D. G. and Gr{\"u}newald, B.},
  title     = {Pharmacology of the neuronal nicotinic acetylcholine receptor of cultured Kenyon cells of the honeybee, Apis mellifera},
  journal   = {Journal of Comparative Physiology A},
  year      = {2004},
  volume    = {190},
  number    = {10},
  pages     = {807--821},
  publisher = {Springer},
}

@Article{wegener2004,
  author    = {Wegener, Christian and Hamasaka, Yasutaka and Nassel, Dick R},
  title     = {Acetylcholine increases intracellular Ca2+ via nicotinic receptors in cultured PDF-containing clock neurons of Drosophila},
  journal   = {J. Neurophys.},
  year      = {2004},
  volume    = {91},
  number    = {2},
  pages     = {912--923},
  publisher = {American Physiological Society},
}

@Article{chamaon2002,
  author    = {Chamaon, K. and Smalla, Karl-H. and Thomas, U. and Gundelfinger, E. D.},
  title     = {Nicotinic acetylcholine receptors of Drosophila: three subunits encoded by genomically linked genes can co-assemble into the same receptor complex},
  journal   = {J. Neurochem.},
  year      = {2002},
  volume    = {80},
  number    = {1},
  pages     = {149--157},
  publisher = {Wiley Online Library},
}

@Article{albert1993,
  author    = {Albert, J. L. and Lingle, C. J.},
  title     = {Activation of nicotinic acetylcholine receptors on cultured \textit{Drosophila} and other insect neurones.},
  journal   = { J. Physiol.},
  year      = {1993},
  volume    = {463},
  number    = {1},
  pages     = {605--630},
  publisher = {Wiley Online Library},
}

@Article{kagabu2000,
  author    = {Kagabu, S. and Maienfisch, P. and Zhang, A. and Granda-Minones, J. and Haettenschwiler, J. and Kayser, H. and Maetzke, T. and Casida, J. E.},
  title     = {5-Azidoimidacloprid and an acyclic analogue as candidate photoaffinity probes for mammalian and insect nicotinic acetylcholine receptors},
  journal   = {Journal of medicinal chemistry},
  year      = {2000},
  volume    = {43},
  number    = {26},
  pages     = {5003--5009},
  publisher = {ACS Publications},
}

@Article{unwin2012,
  author    = {Unwin, N. and Fujiyoshi, Y.},
  title     = {Gating movement of acetylcholine receptor caught by plunge-freezing},
  journal   = {J. Mol. Biol.},
  year      = {2012},
  volume    = {422},
  number    = {5},
  pages     = {617--634},
  publisher = {Elsevier},
}

@Article{taylor1978,
  author    = {Taylor, A. L. and Sasser, J. N.},
  title     = {Biology, identification and control of root-knot nematodes},
  journal   = {North Carolina State University Graphics},
  year      = {1978},
  volume    = {111},
  publisher = {Citeseer},
}

@Article{lin2006,
  author    = {Lin, L. Y. and Ching, C. L. and Chin, K. H. and Chou, S. H. and Chan, N. L.},
  title     = "{Crystal Structure of the Conserved Hypothetical Cytosolic Protein Xcc0516 from \textit{Xanthomonas campestris} Reveals a Novel Quaternary Structure Assembled by Five Four-Helix Bundles}",
  journal   = {Proteins: Structure, Function, and Bioinformatics},
  year      = {2006},
  volume    = {65},
  number    = {3},
  pages     = {783--786},
  publisher = {Wiley Online Library},
}

@Book{arndt2012,
  author    = {Arndt, C. and Koristka, S. and Bartsch, H. and Bachmann, M.},
  title     = {Protein Electrophoresis. Methods in Molecular Biology (Methods and Protocols)},
  year      = {2012},
  volume    = {869},
  publisher = {Humana Press, Totowa, NJ},
  chapter   = {Native Polyacrylamide Gels},
}

@Article{zouridakis2014,
  author  = {Zouridakis, M. and Giastas, P. and Zarkadas, E. and Chroni-Tzartou, D. and Bregestovski, P. and Tzartos, S. J.},
  title   = {Crystal Structure of the Extracellular Domain of the Human Alpha9 Nicotinic Acetylcholine Receptor In Complex with Methyllycaconitine.},
  journal = {Nat Struct Mol Biol},
  year    = {2014},
  volume  = {21},
  number  = {976},
}

@Article{berman2000,
  author  = {Berman, H. M. and Westbrook, J. and Feng, Z. and Gilliland, G. and Bhat, N. T. and Weissig, H. and Shindyalov, I. N. and Bourne, P. E.},
  title   = {The Protein Data Bank},
  journal = {Nucleic Acids Research},
  year    = {2000},
  volume  = {28},
  number  = {1},
}

@Article{kouvatsos2014,
  author          = {Kouvatsos, N. and Niarchos, A. and Zisimopoulou, P. and Eliopoulos, E. and Poulas, K. and Tzartos, S.},
  title           = {Purification and functional characterization of a truncated human $\alpha$4$\beta$2 nicotinic acetylcholine receptor.},
  journal         = {Inter. J. Biol. Macromol.},
  year            = {2014},
  volume          = {70},
  month           = sep,
  pages           = {320--326},
  issn            = {1879-0003},
  doi             = {10.1016/j.ijbiomac.2014.06.058},
  abstract        = {Nicotinic acetylcholine receptors (nAChR) are abundant in the brain and are essential in cognitive function, learning and memory. Previous efforts on α4β2 nAChR had been focused on functional and pharmacological characterization, where high expression yield is not essential. For structural studies though, large amounts of pure protein is important but heterologous overexpression of membrane proteins can be a burdensome task, especially if high amounts are required. In the current study, a truncated mutant of the human α4β2 nAChR was designed in order to improve expression and solubility and to obtain material suitable for high resolution structural studies. We showed that the wild type α4β2 nAChR presented low expression and solubilization yield both of which were improved with the truncated construct. The truncated nAChR showed similar binding profile to the wild type, was purified by a two-step chromatography and isolated in high purity and adequate quantity. },
  chemicals       = {Bridged Bicyclo Compounds, Heterocyclic, Ligands, Pyridines, Receptors, Nicotinic, nicotinic receptor alpha4beta2, epibatidine},
  citation-subset = {IM},
  completed       = {2015-05-22},
  country         = {Netherlands},
  issn-linking    = {0141-8130},
  keywords        = {Animals; Bridged Bicyclo Compounds, Heterocyclic, chemistry, metabolism; Cell Line; Cloning, Molecular; Gene Expression; Humans; Ligands; Protein Binding; Pyridines, chemistry, metabolism; Receptors, Nicotinic, chemistry, genetics, isolation & purification, metabolism; Solubility; Baculovirus expression system; Ion channel receptor; Membrane protein; Protein engineering; α4β2 nAChR},
  nlm-id          = {7909578},
  owner           = {NLM},
  pii             = {S0141-8130(14)00441-3},
  pmid            = {25014634},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-11-25},
}

@Article{abraham2016,
  author          = {Abraham, N. and Paul, B. and Ragnarsson, L. and Lewis, R. J.},
  title           = {\textit{Escherichia coli} Protein Expression System for Acetylcholine Binding Proteins (AChBPs)},
  journal         = {PloS one},
  year            = {2016},
  volume          = {11},
  issue           = {6},
  pages           = {e0157363},
  issn            = {1932-6203},
  doi             = {10.1371/journal.pone.0157363},
  abstract        = {Nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels, identified as therapeutic targets for a range of human diseases. Drug design for nAChR related disorders is increasingly using structure-based approaches. Many of these structural insights for therapeutic lead development have been obtained from co-crystal structures of nAChR agonists and antagonists with the acetylcholine binding protein (AChBP). AChBP is a water soluble, structural and functional homolog of the extracellular, ligand-binding domain of nAChRs. Currently, AChBPs are recombinantly expressed in eukaryotic expression systems for structural and biophysical studies. Here, we report the establishment of an Escherichia coli (E. coli) expression system that significantly reduces the cost and time of production compared to the existing expression systems. E. coli can efficiently express unglycosylated AChBP for crystallography and makes the expression of isotopically labelled forms feasible for NMR. We used a pHUE vector containing an N-terminal His-tagged ubiquitin fusion protein to facilitate AChBP expression in the soluble fractions, and thus avoid the need to recover protein from inclusion bodies. The purified protein yield obtained from the E. coli expression system is comparable to that obtained from existing AChBP expression systems. E. coli expressed AChBP bound nAChR agonists and antagonists with affinities matching those previously reported. Thus, the E. coli expression system significantly simplifies the expression and purification of functional AChBP for structural and biophysical studies. },
  chemicals       = {AChBP protein, Lymnaea, Carrier Proteins, Ligands, Receptors, Nicotinic, Recombinant Fusion Proteins, Acetylcholine},
  citation-subset = {IM},
  completed       = {2017-07-24},
  country         = {United States},
  issn-linking    = {1932-6203},
  keywords        = {Acetylcholine, metabolism; Amino Acid Sequence; Animals; Base Sequence; Carrier Proteins, chemistry, genetics, metabolism; Crystallography, X-Ray; Escherichia coli, genetics; Gene Expression; Genetic Vectors, genetics; Humans; Ligands; Pichia, genetics; Protein Binding; Receptors, Nicotinic, chemistry, genetics, metabolism; Recombinant Fusion Proteins, chemistry, genetics, metabolism},
  nlm-id          = {101285081},
  owner           = {NLM},
  pii             = {PONE-D-15-54243},
  pmc             = {PMC4909209},
  pmid            = {27304486},
  pubmodel        = {Electronic-eCollection},
  pubstatus       = {epublish},
  revised         = {2018-11-13},
}

@Article{tillman2016,
  author          = {Tillman, T. S. and Alvarez, F. J. D. and Reinert, N. J. and Liu, C. and Wang, D. and Xu, Y. and Xiao, K. and Zhang, P. and Tang, P.},
  title           = {Functional Human α7 Nicotinic Acetylcholine Receptor (nAChR) Generated from Escherichia coli.},
  journal         = {J. Biol. Chem.},
  year            = {2016},
  volume          = {291},
  issue           = {35},
  month           = aug,
  pages           = {18276--18282},
  issn            = {1083-351X},
  doi             = {10.1074/jbc.M116.729970},
  abstract        = {Human Cys-loop receptors are important therapeutic targets. High-resolution structures are essential for rational drug design, but only a few are available due to difficulties in obtaining sufficient quantities of protein suitable for structural studies. Although expression of proteins in E. coli offers advantages of high yield, low cost, and fast turnover, this approach has not been thoroughly explored for full-length human Cys-loop receptors because of the conventional wisdom that E. coli lacks the specific chaperones and post-translational modifications potentially required for expression of human Cys-loop receptors. Here we report the successful production of full-length wild type human α7nAChR from E. coli Chemically induced chaperones promote high expression levels of well-folded proteins. The choice of detergents, lipids, and ligands during purification determines the final protein quality. The purified α7nAChR not only forms pentamers as imaged by negative-stain electron microscopy, but also retains pharmacological characteristics of native α7nAChR, including binding to bungarotoxin and positive allosteric modulators specific to α7nAChR. Moreover, the purified α7nAChR injected into Xenopus oocytes can be activated by acetylcholine, choline, and nicotine, inhibited by the channel blockers QX-222 and phencyclidine, and potentiated by the α7nAChR specific modulators PNU-120596 and TQS. The successful generation of functional human α7nAChR from E. coli opens a new avenue for producing mammalian Cys-loop receptors to facilitate structure-based rational drug design.},
  chemicals       = {1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea, Bungarotoxins, Escherichia coli Proteins, Isoxazoles, Molecular Chaperones, Phenylurea Compounds, Recombinant Proteins, alpha7 Nicotinic Acetylcholine Receptor, QX-222, Lidocaine, Phencyclidine},
  citation-subset = {IM},
  completed       = {2017-05-12},
  country         = {United States},
  issn-linking    = {0021-9258},
  keywords        = {Animals; Bungarotoxins, chemistry, pharmacology; Escherichia coli, genetics, metabolism; Escherichia coli Proteins, biosynthesis, chemistry, genetics; Humans; Isoxazoles, chemistry, pharmacology; Lidocaine, analogs & derivatives, chemistry, pharmacology; Molecular Chaperones, biosynthesis, chemistry, genetics; Phencyclidine, chemistry, pharmacology; Phenylurea Compounds, chemistry, pharmacology; Recombinant Proteins, biosynthesis, chemistry, genetics, isolation & purification; Xenopus; alpha7 Nicotinic Acetylcholine Receptor, biosynthesis, chemistry, genetics, isolation & purification; Cys-loop receptor; electron microscopy (EM); ion channel; nicotinic acetylcholine receptors (nAChR); pLGICs; pentameric ligand-gated ion channels; recombinant protein expression; α7 nAChR; α7nAChR},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pii             = {M116.729970},
  pmc             = {PMC5000075},
  pmid            = {27385587},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{fischer2001,
  author          = {Fischer, M. and Corringer, P. J. and Schott, K. and Bacher, A. and Changeux, J. P.},
  title           = {A method for soluble overexpression of the alpha7 nicotinic acetylcholine receptor extracellular domain.},
  journal         = { Proc. Natl. Acad. Sci. USA of the United States of America},
  year            = {2001},
  volume          = {98},
  issue           = {6},
  month           = mar,
  pages           = {3567--3570},
  issn            = {0027-8424},
  doi             = {10.1073/pnas.041594798},
  abstract        = {We describe the construction of a soluble protein carrying the N-terminal extracellular domain (ECD) of the alpha7 subunit of the nicotinic acetylcholine receptor. The approach was to fuse the alpha7 ECD at the C and N termini of several monomeric and pentameric soluble carrier proteins and to investigate the soluble expression of the product in Escherichia coli. An initial screening of six carrier proteins resulted in the selection of a fusion protein comprising, from the N to the C terminus, the maltose binding protein, a 17-aa linker containing an enterokinase binding site, and the alpha7 ECD. This protein is soluble upon expression in bacteria and is purified by affinity chromatography. It binds the competitive nicotinic antagonist alpha-bungarotoxin with 2.5 microM affinity and displays a CD spectrum corresponding to a folded protein. The method might be suitable to produce large quantities of protein for crystallization and immunochemical experiments.},
  chemicals       = {ATP-Binding Cassette Transporters, Bungarotoxins, Carrier Proteins, Escherichia coli Proteins, Maltose-Binding Proteins, Monosaccharide Transport Proteins, Nicotinic Antagonists, Receptors, Nicotinic, Recombinant Fusion Proteins, alpha7 Nicotinic Acetylcholine Receptor, maltose transport system, E coli},
  citation-subset = {IM},
  completed       = {2001-12-04},
  country         = {United States},
  issn-linking    = {0027-8424},
  keywords        = {ATP-Binding Cassette Transporters; Base Sequence; Binding Sites; Bungarotoxins, metabolism; Carrier Proteins, genetics, metabolism; Escherichia coli; Escherichia coli Proteins; Gene Expression; Genetic Vectors; Maltose-Binding Proteins; Molecular Sequence Data; Monosaccharide Transport Proteins; Nicotinic Antagonists, metabolism; Protein Structure, Secondary; Receptors, Nicotinic, chemistry, genetics, isolation & purification, metabolism; Recombinant Fusion Proteins, chemistry, genetics, isolation & purification, metabolism; Solubility; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {7505876},
  owner           = {NLM},
  pii             = {98/6/3567},
  pmc             = {PMC30693},
  pmid            = {11248118},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{san-miguel2013,
  author  = {San-Miguel, T. and Pérez-Bermúdez, P. and Gavidia, I.},
  title   = {Production of soluble eukaryotic recombinant proteins in E. coli is favoured in early log-phase cultures induced at low temperature},
  journal = {SpringerPlus},
  year    = {2013},
  volume  = {2},
  number  = {89},
}

@Article{dumon-seignovert2004,
  author          = {Dumon-Seignovert, Laurence and Cariot, Guillaume and Vuillard, Laurent},
  title           = {The toxicity of recombinant proteins in Escherichia coli: a comparison of overexpression in BL21(DE3), C41(DE3), and C43(DE3).},
  journal         = {Protein Express. Purif.},
  year            = {2004},
  volume          = {37},
  issue           = {1},
  month           = sep,
  pages           = {203--206},
  issn            = {1046-5928},
  doi             = {10.1016/j.pep.2004.04.025},
  abstract        = {Two mutant strains of Escherichia coli BL21(DE3), called C41(DE3) and C43(DE3) and originally described by Miroux and Walker, are frequently used to overcome the toxicity associated with overexpressing recombinant proteins using the bacteriophage T7 RNA polymerase expression system. Even when the toxicity of the plasmids is so high that it prevents transformation in the strain BL21(DE3), the toxic proteins can often be expressed successfully in C41(DE3) and/or C43(DE3). In this work, using a range of plasmids coding for several types of proteins, we investigated in BL21(DE3), C41(DE3), and C43(DE3) their ability to undergo transformation and to express. While transformation was always possible in C41(DE3) and C43(DE3), we could not obtain transformants in BL21(DE3) for 62% of the expression vectors tested. Moreover, after induction, the expression of heterologous proteins in both mutant strains is generally better than in BL21(DE3). In this study, we also enhanced the stability of plasmids in culture during the expression of proteins by adding the par locus from the plasmid pSC101 to the vector backbone. The stability of a subset of the plasmids (measured 3 h after induction) was determined in C41(DE3) and C43(DE3) and varies from 62 to 92% for C43(DE3) and from 10 to 90% for C41(DE3). This study demonstrates the usefulness of these strains C41(DE3) and C43(DE3) in solving the problem of plasmid instability during the expression of toxic recombinant proteins.},
  chemicals       = {Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2005-08-30},
  country         = {United States},
  issn-linking    = {1046-5928},
  keywords        = {Escherichia coli, genetics, metabolism; Humans; Microbial Sensitivity Tests; Plasmids, genetics, metabolism, toxicity; Recombinant Proteins, genetics, metabolism, toxicity; Transformation, Genetic},
  nlm-id          = {9101496},
  owner           = {NLM},
  pii             = {S1046592804001779},
  pmid            = {15294299},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2006-11-15},
}

@Article{jia2016,
  author          = {Jia, Baolei and Jeon, Che Ok},
  title           = {High-throughput recombinant protein expression in Escherichia coli: current status and future perspectives.},
  journal         = {Open biology},
  year            = {2016},
  volume          = {6},
  issue           = {8},
  month           = aug,
  issn            = {2046-2441},
  doi             = {10.1098/rsob.160196},
  abstract        = {The ease of genetic manipulation, low cost, rapid growth and number of previous studies have made Escherichia coli one of the most widely used microorganism species for producing recombinant proteins. In this post-genomic era, challenges remain to rapidly express and purify large numbers of proteins for academic and commercial purposes in a high-throughput manner. In this review, we describe several state-of-the-art approaches that are suitable for the cloning, expression and purification, conducted in parallel, of numerous molecules, and we discuss recent progress related to soluble protein expression, mRNA folding, fusion tags, post-translational modification and production of membrane proteins. Moreover, we address the ongoing efforts to overcome various challenges faced in protein expression in E. coli, which could lead to an improvement of the current system from trial and error to a predictable and rational design.},
  chemicals       = {RNA, Messenger, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2017-11-21},
  country         = {England},
  issn-linking    = {2046-2441},
  keywords        = {Cloning, Molecular; Escherichia coli, genetics; Gene Expression; Protein Engineering, methods; Protein Processing, Post-Translational; RNA Folding; RNA, Messenger, chemistry; Recombinant Proteins, genetics, metabolism; 5′UTR and N-terminal codons; Escherichia coli; fusion tag; high-throughput; membrane protein; recombinant protein expression},
  nlm-id          = {101580419},
  owner           = {NLM},
  pii             = {160196},
  pmc             = {PMC5008019},
  pmid            = {27581654},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2019-01-09},
}

@Article{delic2014,
  author          = {Delic, Marizela and Göngrich, Rebecca and Mattanovich, Diethard and Gasser, Brigitte},
  title           = {Engineering of protein folding and secretion-strategies to overcome bottlenecks for efficient production of recombinant proteins.},
  journal         = {Antioxidants \& redox signaling},
  year            = {2014},
  volume          = {21},
  issue           = {3},
  month           = jul,
  pages           = {414--437},
  issn            = {1557-7716},
  doi             = {10.1089/ars.2014.5844},
  abstract        = {Recombinant protein production has developed into a huge market with enormous positive implications for human health and for the future direction of a biobased economy. Limitations in the economic and technical feasibility of production processes are often related to bottlenecks of in vivo protein folding. Based on cell biological knowledge, some major bottlenecks have been overcome by the overexpression of molecular chaperones and other folding related proteins, or by the deletion of deleterious pathways that may lead to misfolding, mistargeting, or degradation. While important success could be achieved by this strategy, the list of reported unsuccessful cases is disappointingly long and obviously dependent on the recombinant protein to be produced. Singular engineering of protein folding steps may not lead to desired results if the pathway suffers from several limitations. In particular, the connection between folding quality control and proteolytic degradation needs further attention. Based on recent understanding that multiple steps in the folding and secretion pathways limit productivity, synergistic combinations of the cell engineering approaches mentioned earlier need to be explored. In addition, systems biology-based whole cell analysis that also takes energy and redox metabolism into consideration will broaden the knowledge base for future rational engineering strategies.},
  chemicals       = {Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2015-02-21},
  country         = {United States},
  issn-linking    = {1523-0864},
  keywords        = {Cytosol, metabolism; Endoplasmic Reticulum, genetics, metabolism; Escherichia coli, genetics, metabolism; Eukaryotic Cells, metabolism; Humans; Protein Engineering; Protein Folding; Proteolysis; Recombinant Proteins, biosynthesis, genetics, metabolism},
  nlm-id          = {100888899},
  owner           = {NLM},
  pmid            = {24483278},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2014-07-03},
}

@Article{baneyx2004,
  author          = {Baneyx, François and Mujacic, Mirna},
  title           = {Recombinant protein folding and misfolding in Escherichia coli.},
  journal         = {Nature biotechnology},
  year            = {2004},
  volume          = {22},
  issue           = {11},
  month           = nov,
  pages           = {1399--1408},
  issn            = {1087-0156},
  doi             = {10.1038/nbt1029},
  abstract        = {The past 20 years have seen enormous progress in the understanding of the mechanisms used by the enteric bacterium Escherichia coli to promote protein folding, support protein translocation and handle protein misfolding. Insights from these studies have been exploited to tackle the problems of inclusion body formation, proteolytic degradation and disulfide bond generation that have long impeded the production of complex heterologous proteins in a properly folded and biologically active form. The application of this information to industrial processes, together with emerging strategies for creating designer folding modulators and performing glycosylation all but guarantee that E. coli will remain an important host for the production of both commodity and high value added proteins.},
  chemicals       = {Escherichia coli Proteins, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2005-03-22},
  country         = {United States},
  issn-linking    = {1087-0156},
  keywords        = {Escherichia coli, genetics, metabolism; Escherichia coli Proteins, chemistry, genetics, metabolism; Gene Expression Regulation, Bacterial, physiology; Inclusion Bodies, genetics, metabolism; Protein Engineering, methods; Protein Folding; Protein Transport, physiology; Recombinant Proteins, chemistry, metabolism; Signal Transduction, physiology},
  nlm-id          = {9604648},
  owner           = {NLM},
  pii             = {nbt1029},
  pmid            = {15529165},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {124},
  revised         = {2006-11-15},
}

@Article{peng2017,
  author          = {Peng, S and Chu, Z and Lu, J and Li, D and Wang, Y and Yang, S and Zhang, Y},
  title           = {Heterologous Expression of Chaperones from Hyperthermophilic Archaea Inhibits Aminoglycoside-Induced Protein Misfolding in Escherichia coli.},
  journal         = {Biochem.},
  year            = {2017},
  volume          = {82},
  issue           = {10},
  month           = oct,
  pages           = {1169--1175},
  issn            = {1608-3040},
  doi             = {10.1134/S0006297917100091},
  abstract        = {Aminoglycoside antibiotics affect protein translation fidelity and lead to protein aggregation and an increase in intracellular oxidative stress level as well. The overexpression of the chaperonin GroEL/GroES system promotes short-term tolerance to aminoglycosides in Escherichia coli. Here, we demonstrated that the coexpression of prefoldin or Hsp60 originating from the hyperthermophilic archaeon Pyrococcus furiosus in E. coli cells can rescue cell growth and inhibit protein aggregation induced by streptomycin exposure. The results of our study show that hyperthermophilic chaperones endow E. coli with a higher tolerance to streptomycin than the GroEL/GroES system, and that they exert better effects on the reduction of intracellular protein misfolding, indicating that these chaperones have unique features and functions.},
  chemicals       = {Chaperonin 10, Chaperonin 60, Molecular Chaperones, Recombinant Proteins, prefoldin, Streptomycin},
  citation-subset = {IM},
  completed       = {2017-11-16},
  country         = {United States},
  issn-linking    = {0006-2979},
  keywords        = {Chaperonin 10, genetics, metabolism; Chaperonin 60, genetics, metabolism; Escherichia coli, metabolism; Membrane Potentials, drug effects; Molecular Chaperones, genetics, metabolism; Protein Folding, drug effects; Pyrococcus furiosus, metabolism; Recombinant Proteins, biosynthesis, chemistry; Streptomycin, pharmacology},
  nlm-id          = {0376536},
  owner           = {NLM},
  pii             = {BCM82101522},
  pmid            = {29037137},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2017-11-28},
}

@Article{dwyer2014,
  author          = {Dwyer, Robert S and Malinverni, Juliana C and Boyd, Dana and Beckwith, Jon and Silhavy, Thomas J},
  title           = {Folding LacZ in the periplasm of Escherichia coli.},
  journal         = {J. Bacteriol.},
  year            = {2014},
  volume          = {196},
  issue           = {18},
  month           = sep,
  pages           = {3343--3350},
  issn            = {1098-5530},
  doi             = {10.1128/JB.01843-14},
  abstract        = {Targeted, translational LacZ fusions provided the initial support for the signal sequence hypothesis in prokaryotes and allowed for selection of the mutations that identified the Sec translocon. Many of these selections relied on the fact that expression of targeted, translational lacZ fusions like malE-lacZ and lamB-lacZ42-1 causes lethal toxicity as folded LacZ jams the translocation pore. However, there is another class of targeted LacZ fusions that do not jam the translocon. These targeted, nonjamming fusions also show toxic phenotypes that may be useful for selecting mutations in genes involved in posttranslocational protein folding and targeting; however, they have not been investigated to the same extent as their jamming counterparts. In fact, it is still unclear whether LacZ can be fully translocated in these fusions. It may be that they simply partition into the inner membrane where they can no longer participate in folding or assembly. In the present study, we systematically characterize the nonjamming fusions and determine their ultimate localization. We report that LacZ can be fully translocated into the periplasm, where it is toxic. We show that this toxicity is likely due to LacZ misfolding and that, in the absence of the periplasmic disulfide bond catalyst DsbA, LacZ folds in the periplasm. Using the novel phenotype of periplasmic β-galactosidase activity, we show that the periplasmic chaperone FkpA contributes to LacZ folding in this nonnative compartment. We propose that targeted, nonjamming LacZ fusions may be used to further study folding and targeting in the periplasm of Escherichia coli. },
  chemicals       = {Escherichia coli Proteins, Membrane Proteins, Recombinant Proteins, Peptidylprolyl Isomerase, FkpA protein, E coli},
  citation-subset = {IM},
  completed       = {2014-12-16},
  country         = {United States},
  issn-linking    = {0021-9193},
  keywords        = {Escherichia coli, genetics, metabolism; Escherichia coli Proteins, genetics, metabolism; Gene Expression Regulation, Bacterial, physiology; Genotype; Lac Operon, physiology; Membrane Proteins, genetics, metabolism; Peptidylprolyl Isomerase, genetics, metabolism; Protein Folding; Recombinant Proteins; Signal Transduction; Translocation, Genetic},
  nlm-id          = {2985120R},
  owner           = {NLM},
  pii             = {JB.01843-14},
  pmc             = {PMC4135689},
  pmid            = {25002543},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{ferrer-miralles2015,
  author          = {Ferrer-Miralles, Neus and Saccardo, Paolo and Corchero, José Luis and Xu, Zhikun and García-Fruitós, Elena},
  title           = {General introduction: recombinant protein production and purification of insoluble proteins.},
  journal         = {Methods in molecular biology (Clifton, N.J.)},
  year            = {2015},
  volume          = {1258},
  pages           = {1--24},
  issn            = {1940-6029},
  doi             = {10.1007/978-1-4939-2205-5_1},
  abstract        = {Proteins are synthesized in heterologous systems because of the impossibility to obtain satisfactory yields from natural sources. The production of soluble and functional recombinant proteins is among the main goals in the biotechnological field. In this context, it is important to point out that under stress conditions, protein folding machinery is saturated and this promotes protein misfolding and, consequently, protein aggregation. Thus, the selection of the optimal expression organism and the most appropriate growth conditions to minimize the formation of insoluble proteins should be done according to the protein characteristics and downstream requirements. Escherichia coli is the most popular recombinant protein expression system despite the great development achieved so far by eukaryotic expression systems. Besides, other prokaryotic expression systems, such as lactic acid bacteria and psychrophilic bacteria, are gaining interest in this field. However, it is worth mentioning that prokaryotic expression system poses, in many cases, severe restrictions for a successful heterologous protein production. Thus, eukaryotic systems such as mammalian cells, insect cells, yeast, filamentous fungus, and microalgae are an interesting alternative for the production of these difficult-to-express proteins.},
  chemicals       = {Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2015-07-15},
  country         = {United States},
  issn-linking    = {1064-3745},
  keywords        = {Animals; Bacteria, genetics, metabolism; Biotechnology, methods; Eukaryota, genetics, metabolism; Humans; Protein Folding; Recombinant Proteins, genetics, isolation & purification, metabolism},
  nlm-id          = {9214969},
  owner           = {NLM},
  pmid            = {25447856},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2014-12-02},
}

@Article{martinez-alonso2010,
  author          = {Martínez-Alonso, Mónica and Gómez-Sebastián, Silvia and Escribano, José M and Saiz, Juan-Carlos and Ferrer-Miralles, Neus and Villaverde, Antonio},
  title           = {DnaK/DnaJ-assisted recombinant protein production in Trichoplusia ni larvae.},
  journal         = {Applied microbiology and biotechnology},
  year            = {2010},
  volume          = {86},
  issue           = {2},
  month           = mar,
  pages           = {633--639},
  issn            = {1432-0614},
  doi             = {10.1007/s00253-009-2305-0},
  abstract        = {The DnaK/DnaJ Escherichia coli chaperone pair, co-produced along with recombinant proteins, has been widely used to assist protein folding in bacterial cells, although with poor consensus about the ultimate effect on protein quality and its general applicability. Here, we have evaluated for the first time these bacterial proteins as folding modulators in a highly promising recombinant protein platform based on insect larvae. Intriguingly, the bacterial chaperones enhanced the solubility of a reporter, misfolding-prone GFP, doubling the yield of recombinant protein that can be recovered from the larvae extracts in a production process. This occurs without negative effects on the yield of total protein (extractable plus insoluble), indicative of a proteolytic stability of the chaperone substrate. It is in contrast with what has been observed in bacteria for the same reporter protein, which is dramatically degraded in a DnaK-dependent manner. The reported data are discussed in the context of the biotechnological potential and applicability of prokaryotic chaperones in complex, eukaryotic factories for recombinant protein production.},
  chemicals       = {DnaJ protein, E coli, Escherichia coli Proteins, HSP40 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, Recombinant Proteins, Green Fluorescent Proteins, dnaK protein, E coli},
  citation-subset = {IM},
  completed       = {2010-05-04},
  country         = {Germany},
  issn-linking    = {0175-7598},
  keywords        = {Animals; Biotechnology, methods; Escherichia coli, enzymology, genetics; Escherichia coli Proteins, genetics, metabolism; Genes, Reporter; Green Fluorescent Proteins, genetics, metabolism; HSP40 Heat-Shock Proteins, genetics, metabolism; HSP70 Heat-Shock Proteins, genetics, metabolism; Larva, genetics, metabolism; Lepidoptera, genetics, metabolism; Protein Folding; Recombinant Proteins, metabolism},
  nlm-id          = {8406612},
  owner           = {NLM},
  pmid            = {19876625},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2010-02-22},
}

@Article{gupta2010,
  author          = {Gupta, Rashmi and Lakshmipathy, Sathish Kumar and Chang, Hung-Chun and Etchells, Stephanie A and Hartl, F Ulrich},
  title           = {Trigger factor lacking the PPIase domain can enhance the folding of eukaryotic multi-domain proteins in Escherichia coli.},
  journal         = {FEBS letters},
  year            = {2010},
  volume          = {584},
  issue           = {16},
  month           = aug,
  pages           = {3620--3624},
  issn            = {1873-3468},
  doi             = {10.1016/j.febslet.2010.07.036},
  abstract        = {Recombinant expression of eukaryotic proteins in bacteria often results in misfolding and aggregation. The ribosome-binding Trigger factor (TF) is the first molecular chaperone that interacts with nascent polypeptide chains in bacteria. Here we show that mutant TF lacking the PPIase domain (TFNC) is more efficient than wild-type TF in enhancing the folding yield of multi-domain proteins such as firefly luciferase. We find that TFNC has a shorter residence time on nascent chains, thus facilitating co-translational folding. By delaying folding relative to translation, the PPIase domain may increase the propensity of misfolding for certain eukaryotic proteins that rely on a mechanism of co-translational, domain-wise folding.},
  chemicals       = {Escherichia coli Proteins, Molecular Chaperones, Recombinant Proteins, Luciferases, Firefly, Tetrahydrofolate Dehydrogenase, ras Proteins, trigger factor, E coli, Peptidylprolyl Isomerase},
  citation-subset = {IM},
  completed       = {2010-09-03},
  country         = {England},
  issn-linking    = {0014-5793},
  keywords        = {Animals; Escherichia coli, genetics, metabolism; Escherichia coli Proteins, chemistry, genetics, metabolism; Luciferases, Firefly, chemistry, genetics, metabolism; Models, Molecular; Molecular Chaperones, chemistry, genetics, metabolism; Mutation; Peptidylprolyl Isomerase, chemistry, genetics, metabolism; Protein Biosynthesis; Protein Folding; Protein Structure, Tertiary; Recombinant Proteins, chemistry, genetics, metabolism; Sequence Deletion; Tetrahydrofolate Dehydrogenase, chemistry, genetics, metabolism; ras Proteins, chemistry, genetics, metabolism},
  nlm-id          = {0155157},
  owner           = {NLM},
  pii             = {S0014-5793(10)00594-6},
  pmid            = {20659464},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2010-08-16},
}

@Article{bandyopadhyay2017,
  author          = {Bandyopadhyay, Boudhayan and Goldenzweig, Adi and Unger, Tamar and Adato, Orit and Fleishman, Sarel J and Unger, Ron and Horovitz, Amnon},
  title           = {Local energetic frustration affects the dependence of green fluorescent protein folding on the chaperonin GroEL.},
  journal         = {J. Biol. Chem.},
  year            = {2017},
  volume          = {292},
  issue           = {50},
  month           = dec,
  pages           = {20583--20591},
  issn            = {1083-351X},
  doi             = {10.1074/jbc.M117.808576},
  abstract        = {The GroE chaperonin system in   comprises GroEL and GroES and facilitates ATP-dependent protein folding   and   Proteins with very similar sequences and structures can differ in their dependence on GroEL for efficient folding. One potential but unverified source for GroEL dependence is frustration, wherein not all interactions in the native state are optimized energetically, thereby potentiating slow folding and misfolding. Here, we chose enhanced green fluorescent protein as a model system and subjected it to random mutagenesis, followed by screening for variants whose   folding displays increased or decreased GroEL dependence. We confirmed the altered GroEL dependence of these variants with   folding assays. Strikingly, mutations at positions predicted to be highly frustrated were found to correlate with decreased GroEL dependence. Conversely, mutations at positions with low frustration were found to correlate with increased GroEL dependence. Further support for this finding was obtained by showing that folding of an enhanced green fluorescent protein variant designed computationally to have reduced frustration is indeed less GroEL-dependent. Our results indicate that changes in local frustration also affect partitioning   between spontaneous and chaperonin-mediated folding. Hence, the design of minimally frustrated sequences can reduce chaperonin dependence and improve protein expression levels.},
  chemicals       = {Chaperonin 10, Chaperonin 60, Escherichia coli Proteins, GroE protein, E coli, Heat-Shock Proteins, Protein Subunits, Recombinant Proteins, enhanced green fluorescent protein, Green Fluorescent Proteins},
  citation-subset = {IM},
  completed       = {2018-01-25},
  country         = {United States},
  issn-linking    = {0021-9258},
  keywords        = {Amino Acid Substitution; Chaperonin 10, chemistry, genetics, metabolism; Chaperonin 60, chemistry, genetics, metabolism; Computational Biology; Crystallography, X-Ray; Databases, Protein; Escherichia coli, metabolism; Escherichia coli Proteins, chemistry, genetics, metabolism; Green Fluorescent Proteins, chemistry, genetics, metabolism; Heat-Shock Proteins, chemistry, genetics, metabolism; Kinetics; Models, Molecular; Mutation; Protein Conformation; Protein Engineering; Protein Folding; Protein Refolding; Protein Stability; Protein Subunits, chemistry, genetics, metabolism; Protein Transport; Recombinant Proteins, chemistry, metabolism; Solubility; Structural Homology, Protein; GroEL; chaperone; chaperonin; kinetics; protein design; protein folding},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pii             = {M117.808576},
  pmc             = {PMC5733594},
  pmid            = {29066625},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-15},
}

@Article{oreilly2014,
  author          = {O'Reilly, A O and Cole, A R and Lopes, J L S and Lampert, A and Wallace, B A},
  title           = {Chaperone-mediated native folding of a β-scorpion toxin in the periplasm of Escherichia coli.},
  journal         = {Biochimica et biophysica acta},
  year            = {2014},
  volume          = {1840},
  issue           = {1},
  month           = jan,
  pages           = {10--15},
  issn            = {0006-3002},
  doi             = {10.1016/j.bbagen.2013.08.021},
  abstract        = {Animal neurotoxin peptides are valuable probes for investigating ion channel structure/function relationships and represent lead compounds for novel therapeutics and insecticides. However, misfolding and aggregation are common outcomes when toxins containing multiple disulfides are expressed in bacteria. The β-scorpion peptide toxin Bj-xtrIT from Hottentotta judaica and four chaperone enzymes (DsbA, DsbC, SurA and FkpA) were co-secreted into the oxidizing environment of the Escherichia coli periplasm. Expressed Bj-xtrIT was purified and analyzed by HPLC and FPLC chromatography. Its thermostability was assessed using synchrotron radiation circular dichroism spectroscopy and its crystal structure was determined. Western blot analysis showed that robust expression was only achieved when cells co-expressed the chaperones. The purified samples were homogenous and monodisperse and the protein was thermostable. The crystal structure of the recombinant toxin confirmed that it adopts the native disulfide connectivity and fold. The chaperones enabled correct folding of the four-disulfide-bridged Bj-xtrIT toxin. There was no apparent sub-population of misfolded Bj-xtrIT, which attests to the effectiveness of this expression method. We report the first example of a disulfide-linked scorpion toxin natively folded during bacterial expression. This method eliminates downstream processing steps such as oxidative refolding or cleavage of a fusion-carrier and therefore enables efficient production of insecticidal Bj-xtrIT. Periplasmic chaperone activity may produce native folding of other extensively disulfide-reticulated proteins including animal neurotoxins. This work is therefore relevant to venomics and studies of a wide range of channels and receptors.},
  chemicals       = {Bj-xtrIT toxin, Disulfides, Insect Proteins, Molecular Chaperones, Neurotoxins, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2014-03-13},
  country         = {Netherlands},
  issn-linking    = {0006-3002},
  keywords        = {Amino Acid Sequence; Animals; Blotting, Western; Circular Dichroism; Crystallography, X-Ray; Disulfides, metabolism; Escherichia coli, metabolism; Insect Proteins, chemistry, metabolism; Models, Molecular; Molecular Chaperones, metabolism; Molecular Sequence Data; Neurotoxins, chemistry, metabolism; Periplasm, metabolism; Protein Conformation; Protein Folding; Protein Multimerization; Recombinant Proteins, chemistry, metabolism; Scorpions, metabolism; Structure-Activity Relationship; Chaperones; Crystal structure; Disulfide-linked toxin; Protein expression; Protein folding; Synchrotron radiation circular dichroism spectroscopy},
  nlm-id          = {0217513},
  owner           = {NLM},
  pii             = {S0304-4165(13)00365-6},
  pmc             = {PMC3898981},
  pmid            = {23999087},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{narayanan2009,
  author          = {Narayanan, Niju and Chou, C Perry},
  title           = {Alleviation of proteolytic sensitivity to enhance recombinant lipase production in Escherichia coli.},
  journal         = {Applied and environmental microbiology},
  year            = {2009},
  volume          = {75},
  issue           = {16},
  month           = aug,
  pages           = {5424--5427},
  issn            = {1098-5336},
  doi             = {10.1128/AEM.00740-09},
  abstract        = {Two amino acids, Leu149 and Val223, were identified as proteolytically sensitive when Pseudozyma antarctica lipase (PalB) was heterologously expressed in Escherichia coli. The functional expression was enhanced using the double mutant for cultivation. However, the recombinant protein production was still limited by PalB misfolding, which was resolved by DsbA coexpression.},
  chemicals       = {Escherichia coli Proteins, Recombinant Proteins, Lipase, Peptide Hydrolases, Protein Disulfide-Isomerases, dsbA protein, E coli, Leucine, Valine},
  citation-subset = {IM},
  completed       = {2009-10-19},
  country         = {United States},
  issn-linking    = {0099-2240},
  keywords        = {Amino Acid Substitution; Escherichia coli, enzymology, genetics; Escherichia coli Proteins, genetics, metabolism; Gene Expression Regulation, Bacterial; Industrial Microbiology, methods; Leucine, genetics; Lipase, chemistry, genetics, metabolism; Peptide Hydrolases, metabolism; Protein Disulfide-Isomerases, genetics, metabolism; Protein Engineering, methods; Protein Folding; Recombinant Proteins, genetics, metabolism; Ustilaginales, enzymology, genetics; Valine, genetics},
  nlm-id          = {7605801},
  owner           = {NLM},
  pii             = {AEM.00740-09},
  pmc             = {PMC2725454},
  pmid            = {19542329},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{ami2009,
  author          = {Ami, D and Natalello, A and Schultz, T and Gatti-Lafranconi, P and Lotti, M and Doglia, S M and de Marco, A},
  title           = {Effects of recombinant protein misfolding and aggregation on bacterial membranes.},
  journal         = {Biochimica et biophysica acta},
  year            = {2009},
  volume          = {1794},
  issue           = {2},
  month           = feb,
  pages           = {263--269},
  issn            = {0006-3002},
  doi             = {10.1016/j.bbapap.2008.10.015},
  abstract        = {The expression of recombinant proteins is known to induce a metabolic rearrangement in the host cell. We used aggregation-sensitive model systems to study the effects elicited in Escherichia coli cells by the aggregation of recombinant glutathione-S-transferase and its fusion with the green fluorescent protein that, according to the expression conditions, accumulate intracellularly as soluble protein, or soluble and insoluble aggregates. We show that the folding state of the recombinant protein and the complexity of the intracellular aggregates critically affect the cell response. Specifically, protein misfolding and aggregation induce changes in specific host proteins involved in lipid metabolism and oxidative stress, a reduction in the membrane permeability, as well as a rearrangement of its lipid composition. The temporal evolution of the host cell response and that of the aggregation process pointed out that the misfolded protein and soluble aggregates are responsible for the membrane modifications and the changes in the host protein levels. Interestingly, native recombinant protein and large insoluble aggregates do not seem to activate stress markers and membrane rearrangements.},
  chemicals       = {Membrane Lipids, Recombinant Fusion Proteins, Green Fluorescent Proteins, Glutathione Transferase, beta-Galactosidase},
  citation-subset = {IM},
  completed       = {2009-03-23},
  country         = {Netherlands},
  issn-linking    = {0006-3002},
  keywords        = {Cell Membrane, physiology; Cell Membrane Permeability; Escherichia coli, enzymology; Genes, Reporter; Glutathione Transferase, metabolism; Green Fluorescent Proteins, genetics; Membrane Lipids, metabolism; Oxidative Stress; Protein Folding; Recombinant Fusion Proteins, biosynthesis, genetics; Spectroscopy, Fourier Transform Infrared; beta-Galactosidase, genetics},
  nlm-id          = {0217513},
  owner           = {NLM},
  pii             = {S1570-9639(08)00336-1},
  pmid            = {19059501},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-11-26},
}

@Article{martinez-alonso2010a,
  author          = {Martínez-Alonso, Mónica and García-Fruitós, Elena and Ferrer-Miralles, Neus and Rinas, Ursula and Villaverde, Antonio},
  title           = {Side effects of chaperone gene co-expression in recombinant protein production.},
  journal         = {Microbial cell factories},
  year            = {2010},
  volume          = {9},
  month           = sep,
  pages           = {64},
  issn            = {1475-2859},
  doi             = {10.1186/1475-2859-9-64},
  abstract        = {Insufficient availability of molecular chaperones is observed as a major bottleneck for proper protein folding in recombinant protein production. Therefore, co-production of selected sets of cell chaperones along with foreign polypeptides is a common approach to increase the yield of properly folded, recombinant proteins in bacterial cell factories. However, unbalanced amounts of folding modulators handling folding-reluctant protein species might instead trigger undesired proteolytic activities, detrimental regarding recombinant protein stability, quality and yield. This minireview summarizes the most recent observations of chaperone-linked negative side effects, mostly focusing on DnaK and GroEL sets, when using these proteins as folding assistant agents. These events are discussed in the context of the complexity of the cell quality network and the consequent intricacy of the physiological responses triggered by protein misfolding.},
  chemicals       = {Bacterial Proteins, Chaperonin 60, Escherichia coli Proteins, HSP70 Heat-Shock Proteins, Molecular Chaperones, Recombinant Proteins, dnaK protein, E coli},
  citation-subset = {IM},
  completed       = {2010-12-08},
  country         = {England},
  issn-linking    = {1475-2859},
  keywords        = {Bacterial Proteins, genetics, metabolism; Chaperonin 60, genetics, metabolism; Escherichia coli Proteins, genetics, metabolism; HSP70 Heat-Shock Proteins, genetics, metabolism; Molecular Chaperones, chemistry, genetics, metabolism; Protein Folding; Protein Stability; Recombinant Proteins, biosynthesis, chemistry, genetics},
  nlm-id          = {101139812},
  owner           = {NLM},
  pii             = {1475-2859-9-64},
  pmc             = {PMC2944165},
  pmid            = {20813055},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2018-11-13},
}

@Article{jahn2018,
  author          = {Jahn, Markus and Tych, Katarzyna and Girstmair, Hannah and Steinmaßl, Maximilian and Hugel, Thorsten and Buchner, Johannes and Rief, Matthias},
  title           = {Folding and Domain Interactions of Three Orthologs of Hsp90 Studied by Single-Molecule Force Spectroscopy.},
  journal         = {Structure (London, England : 1993)},
  year            = {2018},
  volume          = {26},
  issue           = {1},
  month           = jan,
  pages           = {96--105.e4},
  issn            = {1878-4186},
  doi             = {10.1016/j.str.2017.11.023},
  abstract        = {The heat-shock protein 90 (Hsp90) molecular chaperones are highly conserved across species. However, their dynamic properties can vary significantly from organism to organism. Here we used high-precision optical tweezers to analyze the mechanical properties and folding of different Hsp90 orthologs, namely bacterial Hsp90 (HtpG) and Hsp90 from the endoplasmic reticulum (ER) (Grp94), as well as from the cytosol of the eukaryotic cell (Hsp82). We find that the folding rates of Hsp82 and HtpG are similar, while the folding of Grp94 is slowed down by misfolding of the N-terminal domain. Furthermore, the domain interactions mediated by the charged linker, involved in the conformational cycles of all three orthologs, are much stronger for Grp94 than for Hsp82, keeping the N-terminal domain and the middle domain in close proximity. Thus, the ER resident Hsp90 ortholog differs from the cytosolic counterparts in basic functionally relevant structural properties.},
  chemicals       = {Escherichia coli Proteins, HSP70 Heat-Shock Proteins, HSP82 protein, S cerevisiae, HSP90 Heat-Shock Proteins, HtpG protein, E coli, Membrane Proteins, Recombinant Proteins, Saccharomyces cerevisiae Proteins, glucose-regulated proteins},
  citation-subset = {IM},
  completed       = {2018-11-26},
  country         = {United States},
  issn-linking    = {0969-2126},
  keywords        = {Amino Acid Sequence; Animals; Cloning, Molecular; Crystallography, X-Ray; Cytosol, chemistry, metabolism; Dogs; Endoplasmic Reticulum, chemistry, metabolism; Escherichia coli, genetics, metabolism; Escherichia coli Proteins, chemistry, genetics, metabolism; Gene Expression; Genetic Vectors, chemistry, metabolism; HSP70 Heat-Shock Proteins, chemistry, genetics, metabolism; HSP90 Heat-Shock Proteins, chemistry, genetics, metabolism; Kinetics; Membrane Proteins, chemistry, genetics, metabolism; Optical Tweezers; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Folding; Protein Interaction Domains and Motifs; Protein Multimerization; Recombinant Proteins, chemistry, genetics, metabolism; Saccharomyces cerevisiae, genetics, metabolism; Saccharomyces cerevisiae Proteins, chemistry, genetics, metabolism; Spectrum Analysis, methods; Thermodynamics; chaperones; conformational dynamics; heat-shock protein 90; optical tweezers; protein folding; single molecule},
  nlm-id          = {101087697},
  owner           = {NLM},
  pii             = {S0969-2126(17)30397-0},
  pmid            = {29276035},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-26},
}

@Article{marco2007,
  author          = {de Marco, Ario and Deuerling, Elke and Mogk, Axel and Tomoyasu, Toshifumi and Bukau, Bernd},
  title           = {Chaperone-based procedure to increase yields of soluble recombinant proteins produced in E. coli.},
  journal         = {BMC biotechnology},
  year            = {2007},
  volume          = {7},
  month           = jun,
  pages           = {32},
  issn            = {1472-6750},
  doi             = {10.1186/1472-6750-7-32},
  abstract        = {The overproduction of recombinant proteins in host cells often leads to their misfolding and aggregation. Previous attempts to increase the solubility of recombinant proteins by co-overproduction of individual chaperones were only partially successful. We now assessed the effects of combined overproduction of the functionally cooperating chaperone network of the E. coli cytosol on the solubility of recombinant proteins. A two-step procedure was found to show the strongest enhancement of solubility. In a first step, the four chaperone systems GroEL/GroES, DnaK/DnaJ/GrpE, ClpB and the small HSPs IbpA/IbpB, were coordinately co-overproduced with recombinant proteins to optimize de novo folding. In a second step, protein biosynthesis was inhibited to permit chaperone mediated refolding of misfolded and aggregated proteins in vivo. This novel strategy increased the solubility of 70% of 64 different heterologous proteins tested up to 42-fold. The engineered E. coli strains and the two-step procedure presented here led to a remarkable increase in the solubility of a various recombinant proteins and should be applicable to a wide range of target proteins produced in biotechnology.},
  chemicals       = {Escherichia coli Proteins, Molecular Chaperones, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2007-07-25},
  country         = {England},
  issn-linking    = {1472-6750},
  keywords        = {Escherichia coli, genetics, metabolism; Escherichia coli Proteins, chemistry, genetics, metabolism; Genetic Enhancement, methods; Molecular Chaperones, chemistry, genetics, metabolism; Protein Engineering, methods; Recombinant Proteins, chemistry, genetics, metabolism; Solubility},
  nlm-id          = {101088663},
  owner           = {NLM},
  pii             = {1472-6750-7-32},
  pmc             = {PMC1904446},
  pmid            = {17565681},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2018-11-13},
}

@Article{paul2008,
  author          = {Paul, S and Chaudhuri, T K},
  title           = {Chaperone mediated solubilization of 69-kDa recombinant maltodextrin glucosidase in Escherichia coli.},
  journal         = {Journal of applied microbiology},
  year            = {2008},
  volume          = {104},
  issue           = {1},
  month           = jan,
  pages           = {35--41},
  issn            = {1365-2672},
  doi             = {10.1111/j.1365-2672.2007.03519.x},
  abstract        = {To investigate the factors affecting expression and solubilization of Escherichia coli maltodextrin glucosidase in E. coli. Expression level and solubilization of the recombinant E. coli maltodextrin glucosidase was studied in E. coli at different temperatures, in presence of overexpressed GroEL, GroES and externally supplemented glycerol. Aggregation of maltodextrin glucosidase in the cytoplasm was partially prevented by the co-expression of GroEL and GroES, and using externally supplemented glycerol or lowering the culture temperature. Co-expression of GroEL and GroES or simultaneous presence of overexpressed GroEL, GroES and externally supplemented glycerol together resulted significant increase of the activity of maltodextrin glucosidase. The growth rate of E. coli was inhibited by the formation of inclusion bodies whereas the presence of overexpressed GroEL, GroES alone or together with glycerol enhanced the growth rate of E. coli substantially. The results indicated that lowering the temperature, use of GroEL, GroES and glycerol could be few controlling factors for the solubilization of recombinant aggregation-prone maltodextrin glucosidase in E. coli. Our study could help in developing the strategy for enhancing the production of soluble industrial enzymes and finding the therapeutic agents against protein misfolding diseases.},
  chemicals       = {Chaperonin 10, Chaperonin 60, Escherichia coli Proteins, Molecular Chaperones, Recombinant Proteins, Glycoside Hydrolases, malZ protein, E coli, Glycerol},
  citation-subset = {IM},
  completed       = {2008-04-29},
  country         = {England},
  issn-linking    = {1364-5072},
  keywords        = {Bioreactors, microbiology; Chaperonin 10; Chaperonin 60; Escherichia coli, growth & development, metabolism; Escherichia coli Proteins, chemistry; Glycerol, pharmacology; Glycoside Hydrolases, chemistry; Industrial Microbiology; Molecular Chaperones; Protein Folding; Recombinant Proteins, metabolism; Temperature},
  nlm-id          = {9706280},
  owner           = {NLM},
  pii             = {JAM3519},
  pmid            = {18171380},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{hill2017,
  author          = {Hill, Shannon E and Nguyen, Elaine and Donegan, Rebecca K and Patterson-Orazem, Athéna C and Hazel, Anthony and Gumbart, James C and Lieberman, Raquel L},
  title           = {Structure and Misfolding of the Flexible Tripartite Coiled-Coil Domain of Glaucoma-Associated Myocilin.},
  journal         = {Structure (London, England : 1993)},
  year            = {2017},
  volume          = {25},
  issue           = {11},
  month           = nov,
  pages           = {1697--1707.e5},
  issn            = {1878-4186},
  doi             = {10.1016/j.str.2017.09.008},
  abstract        = {Glaucoma-associated myocilin is a member of the olfactomedins, a protein family involved in neuronal development and human diseases. Molecular studies of the myocilin N-terminal coiled coil demonstrate a unique tripartite architecture: a Y-shaped parallel dimer-of-dimers with distinct tetramer and dimer regions. The structure of the dimeric C-terminal 7-heptad repeats elucidates an unexpected repeat pattern involving inter-strand stabilization by oppositely charged residues. Molecular dynamics simulations reveal an alternate accessible conformation in which the terminal inter-strand disulfide limits the extent of unfolding and results in a kinked configuration. By inference, full-length myocilin is also branched, with two pairs of C-terminal olfactomedin domains. Selected variants within the N-terminal region alter the apparent quaternary structure of myocilin but do so without compromising stability or causing aggregation. In addition to increasing our structural knowledge of naturally occurring extracellular coiled coils and biomedically important olfactomedins, this work broadens the scope of protein misfolding in the pathogenesis of myocilin-associated glaucoma.},
  chemicals       = {Cytoskeletal Proteins, Eye Proteins, Glycoproteins, Recombinant Proteins, trabecular meshwork-induced glucocorticoid response protein},
  citation-subset = {IM},
  completed       = {2018-07-24},
  country         = {United States},
  issn-linking    = {0969-2126},
  keywords        = {Amino Acid Sequence; Binding Sites; Cloning, Molecular; Crystallography, X-Ray; Cytoskeletal Proteins, chemistry, genetics, metabolism; Escherichia coli, genetics, metabolism; Eye Proteins, chemistry, genetics, metabolism; Gene Expression; Genetic Vectors, chemistry, metabolism; Glycoproteins, chemistry, genetics, metabolism; Humans; Molecular Dynamics Simulation; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Folding; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Stability; Protein Structure, Quaternary; Recombinant Proteins, chemistry, genetics, metabolism; Sequence Alignment; Sequence Homology, Amino Acid; X-ray crystallography; chemical crosslinking; coiled coil; extracellular matrix; glaucoma; molecular dynamics simulations; protein design; protein misfolding; small-angle X-ray scattering; trabecular meshwork},
  mid             = {NIHMS907762},
  nlm-id          = {101087697},
  owner           = {NLM},
  pii             = {S0969-2126(17)30299-X},
  pmc             = {PMC5685557},
  pmid            = {29056483},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{son2015,
  author          = {Son, Ahyun and Choi, Seong Il and Han, Gyoonhee and Seong, Baik L},
  title           = {M1 RNA is important for the in-cell solubility of its cognate C5 protein: Implications for RNA-mediated protein folding.},
  journal         = {RNA biology},
  year            = {2015},
  volume          = {12},
  issue           = {11},
  pages           = {1198--1208},
  issn            = {1555-8584},
  doi             = {10.1080/15476286.2015.1096487},
  abstract        = {It is one of the fundamental questions in biology how proteins efficiently fold into their native conformations despite off-pathway events such as misfolding and aggregation in living cells. Although molecular chaperones have been known to assist the de novo folding of certain types of proteins, the role of a binding partner (or a ligand) in the folding and in-cell solubility of its interacting protein still remains poorly defined. RNase P is responsible for the maturation of tRNAs as adaptor molecules of amino acids in ribosomal protein synthesis. The RNase P from Escherichia coli, composed of M1 RNA and C5 protein, is a prototypical ribozyme in which the RNA subunit contains the catalytic activity. Using E. coli RNase P, we demonstrate that M1 RNA plays a pivotal role in the in-cell solubility of C5 protein both in vitro and in vivo. Mutations in either the C5 protein or M1 RNA that affect their interactions significantly abolished the folding of C5 protein. Moreover, we find that M1 RNA provides quality insurance of interacting C5 protein, either by promoting the degradation of C5 mutants in the presence of functional proteolytic machinery, or by abolishing their solubility if the machinery is non-functional. Our results describe a crucial role of M1 RNA in the folding, in-cell solubility, and, consequently, the proteostasis of the client C5 protein, giving new insight into the biological role of RNAs as chaperones and mediators that ensure the quality of interacting proteins. },
  chemicals       = {Escherichia coli Proteins, Intrinsically Disordered Proteins, RNA, Bacterial, Recombinant Proteins, Ribonuclease P, ribonuclease P, E coli},
  citation-subset = {IM},
  completed       = {2016-09-15},
  country         = {United States},
  issn-linking    = {1547-6286},
  keywords        = {Amino Acid Sequence; Escherichia coli Proteins, chemistry, genetics, metabolism; Intrinsically Disordered Proteins, chemistry, metabolism; Models, Biological; Molecular Sequence Data; Mutation; Protein Binding; Protein Folding; Protein Interaction Domains and Motifs; Protein Refolding; Protein Stability; RNA, Bacterial, metabolism; Recombinant Proteins; Ribonuclease P, chemistry, genetics, metabolism; Sequence Alignment; Solubility; C5 protein; M1 RNA; RNA-mediated chaperoning function; RNase P; aggregation; protein folding},
  nlm-id          = {101235328},
  owner           = {NLM},
  pmc             = {PMC4829320},
  pmid            = {26517763},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{vera2007,
  author          = {Vera, Andrea and González-Montalbán, Nuria and Arís, Anna and Villaverde, Antonio},
  title           = {The conformational quality of insoluble recombinant proteins is enhanced at low growth temperatures.},
  journal         = {Biotechnology and bioengineering},
  year            = {2007},
  volume          = {96},
  issue           = {6},
  month           = apr,
  pages           = {1101--1106},
  issn            = {0006-3592},
  doi             = {10.1002/bit.21218},
  abstract        = {Protein aggregation is a major bottleneck during the bacterial production of recombinant proteins. In general, the induction of gene expression at sub-optimal growth temperatures improves the solubility of aggregation-prone polypeptides and minimizes inclusion body (IB) formation. However, the effect of low temperatures on the quality of the recombinant protein, especially within the insoluble cell fraction, has been hardly ever explored. In this work, we have examined the conformational status of a recombinant GFP protein when produced in Escherichia coli below 37 degrees C. As expected, the fraction of aggregated protein largely decreased at lower temperatures, while the conformational quality of both soluble and aggregated GFP, as reflected by its specific fluorescence emission, progressively improved. This observation indicates that physicochemical conditions governing protein folding affect concurrently the quality of the soluble and the aggregated forms of a misfolding-prone protein, and that protein misfolding and aggregation are clearly not coincident events.},
  chemicals       = {Recombinant Proteins, Green Fluorescent Proteins},
  citation-subset = {IM},
  completed       = {2007-05-17},
  country         = {United States},
  issn-linking    = {0006-3592},
  keywords        = {Cold Temperature; Escherichia coli, metabolism; Green Fluorescent Proteins, biosynthesis, chemistry, isolation & purification; Inclusion Bodies, chemistry; Protein Conformation; Recombinant Proteins, biosynthesis, chemistry, isolation & purification; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship},
  nlm-id          = {7502021},
  owner           = {NLM},
  pmid            = {17013944},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2008-11-21},
}

@Article{faburay2014,
  author          = {Faburay, Bonto and Tark, Dongseob and Kanthasamy, Anumantha G and Richt, Juergen A},
  title           = {In vitro amplification of scrapie and chronic wasting disease PrP(res) using baculovirus-expressed recombinant PrP as substrate.},
  journal         = {Prion},
  year            = {2014},
  volume          = {8},
  issue           = {6},
  pages           = {393--403},
  issn            = {1933-690X},
  doi             = {10.4161/19336896.2014.983753},
  abstract        = {Protein misfolding cyclic amplification (PMCA) is an in vitro simulation of prion replication, which relies on the use of normal brain homogenate derived from host species as substrate for the specific amplification of abnormal prion protein, PrP(Sc). Studies showed that recombinant cellular PrP, PrP(C), expressed in Escherichia coli lacks N-glycosylation and an glycophosphatidyl inositol anchor (GPI) and therefore may not be the most suitable substrate in seeded PMCA reactions to recapitulate prion conversion in vitro. In this study, we expressed 2 PRNP genotypes of sheep, V136L141R154Q171 and A136F141R154Q171, and one genotype of white-tailed deer (Q95G96, X132,Y216) using the baculovirus expression system and evaluated their suitability as substrates in seeded-PMCA. It has been reported that host-encoded mammalian RNA molecules and divalent cations play a role in the pathogenesis of prion diseases, and RNA molecules have also been shown to improve the sensitivity of PMCA assays. Therefore, we also assessed the effect of co-factors, such as prion-specific mRNA molecules and a divalent cation, manganese, on protein conversion. Here, we report that baculovirus-expressed recombinant PrP(C) shows a glycoform and GPI-anchor profile similar to mammalian brain-derived PrP(C) and supports amplification of PrP(Sc) and PrP(CWD) derived from prion-affected animals in a single round of seeded PMCA in the absence of exogenous co-factors. Addition of species-specific in vitro transcribed PrP mRNA molecules stimulated the conversion efficiency resulting in increased PrP(Sc) or PrP(CWD) production. Addition of 2 to 20 μM of manganese chloride (MnCl2) to unseeded PMCA resulted in conversion of recombinant PrP(C) to protease-resistant PrP. Collectively, we demonstrate, for the first time, that baculovirus expressed sheep and deer PrP can serve as a substrate in protein misfolding cyclic amplification for sheep and deer prions in the absence of additional exogenous co-factors. },
  chemicals       = {Cations, Chlorides, Detergents, Manganese Compounds, Prions, RNA, Messenger, Recombinant Proteins, Polyethylene Glycols, Manganese, Nonidet P-40, Type C Phospholipases, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase, manganese chloride},
  citation-subset = {IM},
  completed       = {2015-09-28},
  country         = {United States},
  issn-linking    = {1933-6896},
  keywords        = {Animals; Baculoviridae, metabolism; Brain, metabolism, pathology; Cations; Chlorides, chemistry; Cloning, Molecular; Deer, genetics; Detergents, chemistry; Escherichia coli, metabolism; Genotype; Insecta; Manganese, chemistry; Manganese Compounds, chemistry; Microscopy, Fluorescence; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase, metabolism; Polyethylene Glycols, chemistry; Prion Diseases, metabolism, pathology; Prions, genetics, metabolism; Protein Folding; RNA, Messenger, metabolism; Recombinant Proteins, metabolism; Sheep, genetics; Type C Phospholipases, metabolism; PrPSc, PrPCWD; PrPres; prion; protein misfolding cyclic amplification; recombinant PrPC},
  nlm-id          = {101472305},
  owner           = {NLM},
  pmc             = {PMC4601224},
  pmid            = {25495764},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-12-02},
}

@Article{petersson2004,
  author          = {Petersson, Lisa and Carrió, M Mar and Vera, Andrea and Villaverde, Antonio},
  title           = {The impact of dnaKJ overexpression on recombinant protein solubility results from antagonistic effects on the control of protein quality.},
  journal         = {Biotechnology letters},
  year            = {2004},
  volume          = {26},
  issue           = {7},
  month           = apr,
  pages           = {595--601},
  issn            = {0141-5492},
  abstract        = {We have produced increasing levels of DnaK and its co-chaperone DnaJ along with the model VP1LAC misfolding-prone protein, to explore the role of DnaK on the management of Escherichia coli inclusion bodies. While relative solubility of VP1LAC is progressively enhanced, the heat-shock response is down-regulated as revealed by decreasing levels of GroEL. This is accompanied by an increasing yield of VP1LAC and a non-regular evolution of its insoluble fraction, at moderate levels of DnaK resulting in more abundant inclusion bodies. Also, the impact of chaperone co-expression is much more pronounced in wild type cells than in a DnaK- mutant, probably due to the different background of heat shock proteins in these cells. The involvement of DnaK in the supervision of misfolding proteins is then pictured as a dynamic balance between its immediate holding and folding activities, and the side-effect downregulation of the heat shock response though the limitation of other chaperone and proteases activities.},
  chemicals       = {DnaJ protein, E coli, Escherichia coli Proteins, HSP40 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, Heat-Shock Proteins, Recombinant Proteins, dnaK protein, E coli},
  citation-subset = {IM},
  completed       = {2005-01-25},
  country         = {Netherlands},
  issn-linking    = {0141-5492},
  keywords        = {Dimerization; Escherichia coli, enzymology, genetics; Escherichia coli Proteins, chemistry, genetics, metabolism; Gene Expression Regulation, Bacterial, physiology; Gene Expression Regulation, Enzymologic, physiology; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins, chemistry, genetics, metabolism; Heat-Shock Proteins; Heat-Shock Response, physiology; Inclusion Bodies, chemistry, genetics, metabolism; Protein Binding; Protein Engineering, methods; Recombinant Proteins, chemistry, metabolism; Solubility},
  nlm-id          = {8008051},
  owner           = {NLM},
  pmid            = {15168861},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2006-11-15},
}

@Article{xu2005,
  author          = {Xu, Yali and Hsieh, Ming-Yi and Narayanan, Niju and Anderson, William A and Scharer, Jeno M and Moo-Young, Murray and Chou, C Perry},
  title           = {Cytoplasmic overexpression, folding, and processing of penicillin acylase precursor in Escherichia coli.},
  journal         = {Biotechnology progress},
  year            = {2005},
  volume          = {21},
  issue           = {5},
  pages           = {1357--1365},
  issn            = {8756-7938},
  doi             = {10.1021/bp0501120},
  abstract        = {Penicillin acylase (PAC) precursor, proPAC, was overproduced in a soluble or insoluble form in the cytoplasm of Escherichia coli through the expression of the leader-less pac gene (ll-pac) devoid of the coding region for the signal peptide of PAC. Also, a portion of the overexpressed proPAC was further processed to form mature PAC, indicating that the posttranslational processing steps for PAC maturation can occur in both the periplasm and the cytoplasm of E. coli. The cultivation performance for ll-pac expression was limited by several factors, including (1) misfolding of proPAC, resulting in the aggregation of insoluble proPAC as inclusion bodies, (2) intracellular proteolysis, leading to the degradation of the overexpressed gene products, and (3) inefficient PAC maturation, limiting the formation of active PAC. The effect of coexpression of various cytoplasmic chaperones, including trigger factor, GroEL/ES, DnaK/J-GrpE, and their combinations, on ll-pac expression was investigated. Intracellular proteolysis of the overexpressed gene products could be prevented by coexpression of GroEL/ES. On the other hand, coexpression of trigger factor appeared to be able to facilitate the folding of soluble proPAC and to improve PAC maturation. The roles of trigger factor and GroEL/ES could be coordinated to significantly improve ll-pac expression performance. DnaK/J-GrpE had an effect for solublization of proPAC and perhaps, similar to trigger factor, for improving PAC maturation. The ll-pac expression performance was also significantly improved through the simultaneous coexpression of DnaK/J-GrpE and GroEL/ES. The results of the study suggest that the folding and/or processing of proPAC could be a major issue limiting the overproduction of PAC in E. coli and the bottleneck could be eliminated through the coexpression of appropriate chaperone(s).},
  chemicals       = {Protein Precursors, Recombinant Proteins, Penicillin Amidase},
  citation-subset = {IM},
  completed       = {2006-02-27},
  country         = {United States},
  issn-linking    = {1520-6033},
  keywords        = {Bioreactors, microbiology; Cell Culture Techniques, methods; Cytoplasm, metabolism; Escherichia coli, enzymology, genetics; Gene Expression Regulation, Bacterial, physiology; Gene Expression Regulation, Enzymologic, physiology; Penicillin Amidase, biosynthesis, chemistry, genetics, isolation & purification; Protein Engineering, methods; Protein Folding; Protein Precursors, biosynthesis, chemistry, genetics, isolation & purification; Recombinant Proteins, biosynthesis, chemistry, isolation & purification},
  nlm-id          = {8506292},
  owner           = {NLM},
  pmid            = {16209538},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2006-11-15},
}

@Article{dunn2013,
  author          = {Dunn, Linda L and Boyer, Paul L and Clark, Patrick K and Hughes, Stephen H},
  title           = {Mutations in HIV-1 reverse transcriptase cause misfolding and miscleavage by the viral protease.},
  journal         = {Virology},
  year            = {2013},
  volume          = {444},
  issue           = {1-2},
  month           = sep,
  pages           = {241--249},
  issn            = {1096-0341},
  doi             = {10.1016/j.virol.2013.06.017},
  abstract        = {Previous work on mutations in the thumb of HIV-1 reverse transcriptase (RT) showed that the majority of the mutant RTs were degraded (by the viral protease) to various extents in virions. This degradation was, in most cases, temperature sensitive, and presumably was due to a partial unfolding of the protein at 37°C. We used recombinant proteins to investigate the effects of the mutations on the thermal stability and proteolytic degradation of RT. Both subunits contribute to the stability of RT. In general, the differences in stability between the mutants and WT were greater if the mutation was in p51 rather than p66. Expressing the Pol polyprotein containing the RT mutants in Escherichia coli produced results similar to what was seen in virions; the mutant RTs were misfolded and/or degraded at 37°C, but were better folded and processed at 30°C. },
  chemicals       = {Mutant Proteins, Recombinant Proteins, reverse transcriptase, Human immunodeficiency virus 1, HIV Reverse Transcriptase, HIV Protease},
  citation-subset = {IM},
  completed       = {2013-11-06},
  country         = {United States},
  issn-linking    = {0042-6822},
  keywords        = {Enzyme Stability; Escherichia coli, genetics; HIV Protease, metabolism; HIV Reverse Transcriptase, chemistry, genetics, metabolism; HIV-1, enzymology, genetics; Mutant Proteins, genetics, metabolism; Protein Folding; Protein Stability; Proteolysis; Recombinant Proteins, genetics, isolation & purification, metabolism; Temperature; Differential scanning fluorescence; HIV-1; Protease; Reverse transcriptase; Stability},
  mid             = {NIHMS505838},
  nlm-id          = {0110674},
  owner           = {NLM},
  pii             = {S0042-6822(13)00366-8},
  pmc             = {PMC3804327},
  pmid            = {23850459},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{chen2014,
  author          = {Chen, Wei and Jin, Jingjie and Gu, Wei and Wei, Bo and Lei, Yun and Xiong, Sheng and Zhang, Gong},
  title           = {Rational design of translational pausing without altering the amino acid sequence dramatically promotes soluble protein expression: a strategic demonstration.},
  journal         = {Journal of biotechnology},
  year            = {2014},
  volume          = {189},
  month           = nov,
  pages           = {104--113},
  issn            = {1873-4863},
  doi             = {10.1016/j.jbiotec.2014.08.031},
  abstract        = {The production of many pharmaceutical and industrial proteins in prokaryotic hosts is hindered by the insolubility of industrial expression products resulting from misfolding. Even with a correct primary sequence, an improper translation elongation rate in a heterologous expression system is an important cause of misfolding. In silico analysis revealed that most of the endogenous Escherichia coli genes display translational pausing sites that promote correct folding, and almost 1/5 genes have pausing sites at the 3'-termini of their coding sequence. Therefore, we established a novel strategy to efficiently promote the expression of soluble and active proteins without altering the amino acid sequence or expression conditions. This strategy uses the rational design of translational pausing based on structural information solely through synonymous substitutions, i.e. no change on the amino acids sequence. We demonstrated this strategy on a promising antiviral candidate, Cyanovirin-N (CVN), which could not be efficiently expressed in any previously reported system. By introducing silent mutations, we increased the soluble expression level in E. coli by 2000-fold without altering the CVN protein sequence, and the specific activity was slightly higher for the optimized CVN than for the wild-type variant. This strategy introduces new possibilities for the production of bioactive recombinant proteins. },
  chemicals       = {Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2015-08-26},
  country         = {Netherlands},
  issn-linking    = {0168-1656},
  keywords        = {Amino Acid Sequence; Escherichia coli, metabolism; Protein Biosynthesis; Protein Folding; Recombinant Proteins, chemistry, metabolism; Antiviral activity; Cyanovirin-N; Escherichia coli; Protein folding; Synonymous substitutions; Translation pausing},
  nlm-id          = {8411927},
  owner           = {NLM},
  pii             = {S0168-1656(14)00836-0},
  pmid            = {25238722},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2014-12-02},
}

@Article{pan2003,
  author          = {Pan, Kao-Lu and Hsiao, Hsu-Chou and Weng, Chiao-Ling and Wu, Ming-Sheng and Chou, C Perry},
  title           = {Roles of DegP in prevention of protein misfolding in the periplasm upon overexpression of penicillin acylase in Escherichia coli.},
  journal         = {J. Bacteriol.},
  year            = {2003},
  volume          = {185},
  issue           = {10},
  month           = may,
  pages           = {3020--3030},
  issn            = {0021-9193},
  abstract        = {Enhancement of the production of soluble recombinant penicillin acylase in Escherichia coli via coexpression of a periplasmic protease/chaperone, DegP, was demonstrated. Coexpression of DegP resulted in a shift of in vivo penicillin acylase (PAC) synthesis flux from the nonproductive pathway to the productive one when pac was overexpressed. The number of inclusion bodies, which consist primarily of protein aggregates of PAC precursors in the periplasm, was highly reduced, and the specific PAC activity was highly increased. DegP was a heat shock protein induced in response to pac overexpression, suggesting that the protein could possibly suppress the physiological toxicity caused by pac overexpression. Coexpression of DegP(S210A), a DegP mutant without protease activity but retaining chaperone activity, could not suppress the physiological toxicity, suggesting that DegP protease activity was primarily responsible for the suppression, possibly by degradation of abnormal proteins when pac was overexpressed. However, a shortage of periplasmic protease activity was not the only reason for the deterioration in culture performance upon pac overexpression because coexpression of a DegP-homologous periplasmic protease, DegQ or DegS, could not suppress the physiological toxicity. The chaperone activity of DegP is proposed to be another possible factor contributing to the suppression.},
  chemicals       = {Enzyme Precursors, Heat-Shock Proteins, Periplasmic Proteins, Recombinant Proteins, DegP protease, Serine Endopeptidases, Penicillin Amidase},
  citation-subset = {IM},
  completed       = {2003-06-16},
  country         = {United States},
  issn-linking    = {0021-9193},
  keywords        = {Enzyme Precursors, metabolism; Escherichia coli, genetics, metabolism, physiology; Gene Expression Regulation, Bacterial; Heat-Shock Proteins, genetics, metabolism; Inclusion Bodies, metabolism; Penicillin Amidase, chemistry, genetics, metabolism; Periplasm, metabolism; Periplasmic Proteins, genetics, metabolism; Protein Folding; Recombinant Proteins, chemistry, genetics, metabolism; Serine Endopeptidases, genetics, metabolism},
  nlm-id          = {2985120R},
  owner           = {NLM},
  pmc             = {PMC154077},
  pmid            = {12730160},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{kraft2007,
  author          = {Kraft, Mario and Knüpfer, Uwe and Wenderoth, Rolf and Pietschmann, Patricia and Hock, Björn and Horn, Uwe},
  title           = {An online monitoring system based on a synthetic sigma32-dependent tandem promoter for visualization of insoluble proteins in the cytoplasm of Escherichia coli.},
  journal         = {Applied microbiology and biotechnology},
  year            = {2007},
  volume          = {75},
  issue           = {2},
  month           = may,
  pages           = {397--406},
  issn            = {0175-7598},
  doi             = {10.1007/s00253-006-0815-6},
  abstract        = {The expression of heterologous proteins in the cytoplasm of Escherichia coli is often accompanied by limitations resulting in uncontrollable fermentation processes, increased rates of cell lysis, and thus limited yields of target protein. To deal with these problems, reporter tools are required to improve the folding properties of recombinant protein. In this work, the well-known sigma(32)-dependent promoters ibpAB and fxsA were linked in a tandem promoter (ibpfxs), fused with the luciferase reporter gene lucA to allow enhanced monitoring of the formation of misfolded proteins and their aggregates in E. coli cells. Overexpression of MalE31, a folding-defective variant of the maltose-binding protein, and other partially insoluble heterologous proteins showed that the lucA reporter gene was activated in the presence of these misfolded proteins. Contrary to this, the absence of damaged proteins or overexpression of mostly soluble proteins led to a reduced level of luciferase induction. Through performing expression of aggregation-prone proteins, we were able to demonstrate that the ibpfxs::lucA reporter unit is 2.5-4.5 times stronger than the single reporter units ibp::lucA and fxs::lucA. Data of misfolding studies showed that this reporter system provides an adequate tool for in vivo folding studies in E. coli from microtiter up to fermentation scales.},
  chemicals       = {Escherichia coli Proteins, Heat-Shock Proteins, Sigma Factor, heat-shock sigma factor 32, Luciferases},
  citation-subset = {IM},
  completed       = {2007-07-19},
  country         = {Germany},
  issn-linking    = {0175-7598},
  keywords        = {Bioreactors; Biotechnology, methods; Escherichia coli, growth & development, metabolism; Escherichia coli Proteins, genetics, metabolism; Fermentation; Gene Expression Regulation, Bacterial; Genes, Reporter; Heat-Shock Proteins, metabolism; Heat-Shock Response; Luciferases, genetics, metabolism; Online Systems; Promoter Regions, Genetic; Protein Folding; Sigma Factor, metabolism; Solubility},
  nlm-id          = {8406612},
  owner           = {NLM},
  pmid            = {17221192},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2008-11-21},
}

@Article{zou2011,
  author          = {Zou, Zhurong and Fan, Yunliu and Zhang, Chunyi},
  title           = {Preventing protein aggregation by its hyper-acidic fusion cognates in Escherichia coli.},
  journal         = {Protein Express. Purif.},
  year            = {2011},
  volume          = {80},
  issue           = {1},
  month           = nov,
  pages           = {138--144},
  issn            = {1096-0279},
  doi             = {10.1016/j.pep.2011.06.004},
  abstract        = {Preventing protein aggregation is crucial for various protein studies, and has a large potential for remedy of protein misfolding or aggregates-linked diseases. In this study, we demonstrated the hyper-acidic protein fusion partners, which were previously reported to enhance the soluble expression of aggregation-prone proteins, could also significantly prevent aggregation (or improve the solubility) of disease-associated and amyloid/fibril-forming polypeptides such as TEL-SAM and Aβ42 in Escherichia coli cells. Further and most importantly, the solubility of all poorly soluble target proteins examined was greatly elevated by their corresponding highly soluble hyper-acidic fusion cognates when they were co-expressed, in despite of a concomitant compromise of the cognates' solubility. The extent of such a solubility enhancement appeared to be in parallel with the ratio of the levels of co-expressed hyper-acidic fusion cognate and target protein. The hyper-acidic fusion cognates might function as intermolecular solubilizing effectors to prevent aggregation of the target proteins, and a plausible model for interpreting these results is also proposed.},
  chemicals       = {Acids, Amyloid beta-Peptides, Peptide Fragments, Recombinant Fusion Proteins, amyloid beta-protein (1-42)},
  citation-subset = {IM},
  completed       = {2012-01-23},
  country         = {United States},
  issn-linking    = {1046-5928},
  keywords        = {Acids, chemistry; Amyloid beta-Peptides, chemistry, genetics; Escherichia coli, genetics; Gene Expression; Peptide Fragments, chemistry, genetics; Protein Folding; Protein Structure, Tertiary; Recombinant Fusion Proteins, chemistry, genetics; Solubility},
  nlm-id          = {9101496},
  owner           = {NLM},
  pii             = {S1046-5928(11)00151-3},
  pmid            = {21704170},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2011-09-29},
}

@Article{wang2011,
  author          = {Wang, Fei and Wang, Xinhe and Ma, Jiyan},
  title           = {Conversion of bacterially expressed recombinant prion protein.},
  journal         = {Methods (San Diego, Calif.)},
  year            = {2011},
  volume          = {53},
  issue           = {3},
  month           = mar,
  pages           = {208--213},
  issn            = {1095-9130},
  doi             = {10.1016/j.ymeth.2010.12.013},
  abstract        = {The infectivity associated with prion disease sets it apart from a large group of late-onset neurodegenerative disorders that shares the characteristics of protein aggregation and neurodegeneration. The unconventional infectious agent, PrP(Sc), is an aberrantly folded form of the normal prion protein (PrP(C)) and the PrP(C)-to-PrP(Sc) conversion is a critical pathogenic step in prion disease. Using the Protein Misfolding Cyclic Amplification technique, we converted folded bacterially expressed recombinant PrP into a proteinase K-resistant and aggregated conformation (rPrP-res) in the presence of anionic lipid and RNA molecules. Moreover, high prion infectivity was demonstrated by intracerebral inoculation of rPrP-res into wild-type mice, which caused prion disease with a short incubation period. The establishment of the in vitro recombinant PrP conversion assay makes it feasible for us to explore the molecular basis behind the intriguing properties associated with prion infectivity.},
  chemicals       = {Phosphatidylglycerols, PrPC Proteins, PrPSc Proteins, Recombinant Proteins, RNA, 1-palmitoyl-2-oleoylglycero-3-phosphoglycerol, Endopeptidase K},
  citation-subset = {IM},
  completed       = {2011-09-09},
  country         = {United States},
  issn-linking    = {1046-2023},
  keywords        = {Animals; Brain, pathology; Cloning, Molecular, methods; Disease Models, Animal; Endopeptidase K, metabolism; Escherichia coli, metabolism; Female; Mice; Phosphatidylglycerols, chemistry; PrPC Proteins, administration & dosage, biosynthesis, chemistry; PrPSc Proteins, administration & dosage, biosynthesis, chemistry; Prion Diseases, pathology; Protein Folding; RNA, chemistry; Recombinant Proteins, administration & dosage, biosynthesis, chemistry; Sonication},
  mid             = {NIHMS265043},
  nlm-id          = {9426302},
  owner           = {NLM},
  pii             = {S1046-2023(10)00296-3},
  pmc             = {PMC3049836},
  pmid            = {21176786},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{johanssen2012,
  author          = {Johanssen, V A and Barnham, K J and Masters, C L and Hill, A F and Collins, S J},
  title           = {Generating recombinant C-terminal prion protein fragments of exact native sequence.},
  journal         = {Neurochem . Int.},
  year            = {2012},
  volume          = {60},
  issue           = {3},
  month           = feb,
  pages           = {318--326},
  issn            = {1872-9754},
  doi             = {10.1016/j.neuint.2011.12.006},
  abstract        = {Transmissibility and distinctive neuropathology are hallmark features of prion diseases differentiating them from other neurodegenerative disorders, with pathogenesis and transmission appearing closely linked to misfolded conformers (PrP(Sc)) of the ubiquitously expressed cellular form of the prion protein (PrP(C)). Given the apparent pathogenic primacy of misfolded PrP, the utilisation of peptides based on the prion protein has formed an integral approach for providing insights into misfolding pathways and pathogenic mechanisms. In parallel with studies employing prion peptides, similar approaches in other neurodegenerative disorders such as Alzheimer Disease, have demonstrated that differential processing of parent proteins and quite minor variations in the primary sequence of cognate peptides generated from the same constitutive processing (such as Aβ1-40 versus Aβ1-42 produced from γ-secretase activity) can be associated with very different pathogenic consequences. PrP(C) also undergoes constitutive α- or β-cleavage yielding C1 (residues 112-231 human sequence) or C2 (residues 90-231), respectively, with the full cell biological significance of such processing unresolved; however, it is noteworthy that in prion diseases, such as Creutzfeldt-Jakob disease (CJD) and murine models, the moderately extended C2 fragment predominates in the brain suggesting that the two cleavage events and the consequent C-terminal fragments may differ in their pathogenic significance. Accordingly, studies characterising biologically relevant peptides like C1 and C2, would be most valid if undertaken using peptides completely free of any inherent non-native sequence that arises as a by-product of commonly employed recombinant production techniques. To achieve this aim and thereby facilitate more representative biophysical and neurotoxicity studies, we adapted the combination of high fidelity Taq TA cloning with a SUMO-Hexa-His tag-type approach, incorporating the SUMO protease step. This technique consistently produced sufficient yields (∼10 mg/L) of high purity peptides (>95%) equating to C1 and C2 of exact native primary sequence in the α-helical conformation suitable for biological and biophysical investigations.},
  chemicals       = {Peptide Fragments, Prions, Recombinant Proteins, Small Ubiquitin-Related Modifier Proteins, DNA},
  citation-subset = {IM},
  completed       = {2012-06-25},
  country         = {England},
  issn-linking    = {0197-0186},
  keywords        = {Amino Acid Sequence; Blotting, Western; Chromatography, Affinity; Circular Dichroism; DNA, genetics; Escherichia coli, genetics, metabolism; Genetic Vectors; Inclusion Bodies, chemistry; Molecular Sequence Data; Oxidation-Reduction; Peptide Fragments, biosynthesis, chemistry; Prions, biosynthesis, chemistry; Protein Folding; Protein Structure, Secondary; Recombinant Proteins, biosynthesis, chemistry; Small Ubiquitin-Related Modifier Proteins; Spectrometry, Mass, Electrospray Ionization},
  nlm-id          = {8006959},
  owner           = {NLM},
  pii             = {S0197-0186(11)00393-7},
  pmid            = {22197912},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2012-02-20},
}

@Article{bae2013,
  author          = {Bae, Ji-Young and Koo, Bon-Kyung and Ryu, Han-Bong and Song, Jung-A and Nguyen, Minh Tan and Vu, Thu Trang Thi and Son, Young-Jin and Lee, Hyang Kyu and Choe, Han},
  title           = {Cu/Zn incorporation during purification of soluble human EC-SOD from E. coli stabilizes proper disulfide bond formation.},
  journal         = {Applied biochemistry and biotechnology},
  year            = {2013},
  volume          = {169},
  issue           = {5},
  month           = mar,
  pages           = {1633--1647},
  issn            = {1559-0291},
  doi             = {10.1007/s12010-012-0025-x},
  abstract        = {Extracellular superoxide dismutase (EC-SOD) is the only enzyme that removes superoxide radical in the extracellular space. The reduction of EC-SOD is linked to many diseases, suggesting that the protein may have therapeutic value. EC-SOD is reported to be insoluble and to make inclusion bodies when overexpressed in the cytoplasm of Escherichia coli. The refolding process has the advantage of high yield, but has the disadvantage of frequent aggregation or misfolding during purification. For the first time, this study shows that fusion with maltose-binding protein (MBP), N-utilization substance protein A, and protein disulfide isomerase enabled the soluble overexpression of EC-SOD in the cytoplasm of E. coli. MBP-tagged human EC-SOD (hEC-SOD) was purified by MBP affinity and anion exchange chromatography, and its identity was confirmed by MALDI-TOF MS analysis. The purified protein showed good enzyme activity in vitro; however, there was a difference in metal binding. When copper and zinc were incorporated into hEC-SOD before MBP tag cleavage, the enzymatic activity was higher than when the metal ions were bound to the purified protein after MBP tag cleavage. Therefore, the enzymatic activity of hEC-SOD is associated with metal incorporation and protein folding via disulfide bond.},
  chemicals       = {Disulfides, Escherichia coli Proteins, Maltose-Binding Proteins, Peptide Elongation Factors, Recombinant Fusion Proteins, Transcription Factors, Transcriptional Elongation Factors, nusA protein, E coli, Copper, Superoxide Dismutase, Protein Disulfide-Isomerases, Zinc},
  citation-subset = {IM},
  completed       = {2013-08-20},
  country         = {United States},
  issn-linking    = {0273-2289},
  keywords        = {Amino Acid Sequence; Copper, chemistry, metabolism; Cytoplasm, genetics, metabolism; Disulfides, chemistry, metabolism; Escherichia coli, genetics, metabolism; Escherichia coli Proteins, chemistry, genetics, metabolism; Extracellular Space; Gene Expression; Humans; Maltose-Binding Proteins, chemistry, genetics, metabolism; Models, Molecular; Molecular Sequence Data; Peptide Elongation Factors, chemistry, genetics, metabolism; Protein Disulfide-Isomerases, chemistry, genetics, metabolism; Protein Folding; Protein Structure, Secondary; Recombinant Fusion Proteins, chemistry, genetics, metabolism; Solubility; Superoxide Dismutase, chemistry, genetics, metabolism; Transcription Factors, chemistry, genetics, metabolism; Transcriptional Elongation Factors; Zinc, chemistry, metabolism},
  nlm-id          = {8208561},
  owner           = {NLM},
  pmid            = {23329142},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{hultqvist2012,
  author          = {Hultqvist, Greta and Punekar, Avinash S and Morrone, Angela and Chi, Celestine N and Engström, Ake and Selmer, Maria and Gianni, Stefano and Jemth, Per},
  title           = {Tolerance of protein folding to a circular permutation in a PDZ domain.},
  journal         = {PloS one},
  year            = {2012},
  volume          = {7},
  issue           = {11},
  pages           = {e50055},
  issn            = {1932-6203},
  doi             = {10.1371/journal.pone.0050055},
  abstract        = {Circular permutation is a common molecular mechanism for evolution of proteins. However, such re-arrangement of secondary structure connectivity may interfere with the folding mechanism causing accumulation of folding intermediates, which in turn can lead to misfolding. We solved the crystal structure and investigated the folding pathway of a circularly permuted variant of a PDZ domain, SAP97 PDZ2. Our data illustrate how well circular permutation may work as a mechanism for molecular evolution. The circular permutant retains the overall structure and function of the native protein domain. Further, unlike most examples in the literature, this circular permutant displays a folding mechanism that is virtually identical to that of the wild type. This observation contrasts with previous data on the circularly permuted PDZ2 domain from PTP-BL, for which the folding pathway was remarkably affected by the same mutation in sequence connectivity. The different effects of this circular permutation in two homologous proteins show the strong influence of sequence as compared to topology. Circular permutation, when peripheral to the major folding nucleus, may have little effect on folding pathways and could explain why, despite the dramatic change in primary structure, it is frequently tolerated by different protein folds.},
  chemicals       = {Adaptor Proteins, Signal Transducing, DLG1 protein, human, Membrane Proteins, Peptides, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2013-05-13},
  country         = {United States},
  issn-linking    = {1932-6203},
  keywords        = {Adaptor Proteins, Signal Transducing, chemistry, genetics; Amino Acid Sequence; Crystallography, X-Ray; Escherichia coli, genetics; Humans; Kinetics; Membrane Proteins, chemistry, genetics; Models, Molecular; Molecular Sequence Data; PDZ Domains; Peptides, chemistry, genetics; Protein Engineering; Protein Folding; Protein Stability; Protein Structure, Secondary; Protein Unfolding; Recombinant Proteins, chemistry, genetics; Structural Homology, Protein; Thermodynamics},
  nlm-id          = {101285081},
  owner           = {NLM},
  pii             = {PONE-D-12-28083},
  pmc             = {PMC3503759},
  pmid            = {23185531},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{martinez-alonso2009,
  author          = {Martínez-Alonso, Mónica and Toledo-Rubio, Verónica and Noad, Rob and Unzueta, Ugutz and Ferrer-Miralles, Neus and Roy, Polly and Villaverde, Antonio},
  title           = {Rehosting of bacterial chaperones for high-quality protein production.},
  journal         = {Applied and environmental microbiology},
  year            = {2009},
  volume          = {75},
  issue           = {24},
  month           = dec,
  pages           = {7850--7854},
  issn            = {1098-5336},
  doi             = {10.1128/AEM.01532-09},
  abstract        = {Coproduction of DnaK/DnaJ in Escherichia coli enhances solubility but promotes proteolytic degradation of their substrates, minimizing the yield of unstable polypeptides. Higher eukaryotes have orthologs of DnaK/DnaJ but lack the linked bacterial proteolytic system. By coexpression of DnaK and DnaJ in insect cells with inherently misfolding-prone recombinant proteins, we demonstrate simultaneous improvement of soluble protein yield and quality and proteolytic stability. Thus, undesired side effects of bacterial folding modulators can be avoided by appropriate rehosting in heterologous cell expression systems.},
  chemicals       = {DnaJ protein, E coli, Escherichia coli Proteins, HSP40 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, Recombinant Proteins, dnaK protein, E coli},
  citation-subset = {IM},
  completed       = {2010-03-29},
  country         = {United States},
  issn-linking    = {0099-2240},
  keywords        = {Animals; Escherichia coli, genetics, metabolism; Escherichia coli Proteins, biosynthesis, genetics, metabolism; Gene Expression; HSP40 Heat-Shock Proteins, biosynthesis, genetics, metabolism; HSP70 Heat-Shock Proteins, biosynthesis, genetics, metabolism; Protein Folding; Recombinant Proteins, biosynthesis, genetics, metabolism; Spodoptera, cytology, genetics},
  nlm-id          = {7605801},
  owner           = {NLM},
  pii             = {AEM.01532-09},
  pmc             = {PMC2794089},
  pmid            = {19820142},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{thomas2000,
  author          = {Thomas, J G and Baneyx, F},
  title           = {ClpB and HtpG facilitate de novo protein folding in stressed Escherichia coli cells.},
  journal         = {Molecular microbiology},
  year            = {2000},
  volume          = {36},
  issue           = {6},
  month           = jun,
  pages           = {1360--1370},
  issn            = {0950-382X},
  abstract        = {DnaK-DnaJ-GrpE and GroEL-GroES are the best-characterized molecular chaperone systems in the cytoplasm of Escherichia coli. A number of additional proteins, including ClpA, ClpB, HtpG and IbpA/B, act as molecular chaperones in vitro, but their function in cellular protein folding remains unclear. Here, we examine how these chaperones influence the folding of newly synthesized recombinant proteins under heat-shock conditions. We show that the absence of either CIpB or HtpG at 42 degrees C leads to increased aggregation of preS2-beta-galactosidase, a fusion protein whose folding depends on DnaK-DnaJ-GrpE, but not GroEL-GroES. However, only the deltaclpB mutation is deleterious to the folding of homodimeric Rubisco and cMBP, two proteins requiring the GroEL-GroES chaperonins to reach a proper conformation. Null mutations in clpA or the ibpAB operon do not affect the folding of these model substrates. Overexpression of ClpB, HtpG, IbpA/B or ClpA does not suppress inclusion body formation by the aggregation-prone protein preS2-S'-beta-galactosidase in wild-type cells or alleviate recombinant protein misfolding in dnaJ259, grpE280 or groES30 mutants. By contrast, higher levels of DnaK-DnaJ, but not GroEL-GroES, restore efficient folding in deltaclpB cells. These results indicate that ClpB, and to a lesser extent HtpG, participate in de novo protein folding in mildly stressed E. coli cells, presumably by expanding the ability of the DnaK-DnaJ-GrpE team to interact with newly synthesized polypeptides.},
  chemicals       = {Bacterial Proteins, Chaperonin 10, Chaperonin 60, CipA protein, Clostridium, DnaJ protein, E coli, Escherichia coli Proteins, GrpE protein, Bacteria, GrpE protein, E coli, HSP40 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Heat-Shock Proteins, Hepatitis B Surface Antigens, HtpG protein, E coli, IbpA protein, E coli, IbpB protein, E coli, Membrane Proteins, Molecular Chaperones, Protein Precursors, Recombinant Fusion Proteins, presurface protein 2, hepatitis B surface antigen, HtpG protein, bacteria, beta-Galactosidase, Endopeptidase Clp, dnaK protein, E coli, ClpB protein, E coli},
  citation-subset = {IM},
  completed       = {2000-12-01},
  country         = {England},
  issn-linking    = {0950-382X},
  keywords        = {Animals; Bacterial Proteins, genetics, metabolism, physiology; Chaperonin 10, metabolism; Chaperonin 60, metabolism; Endopeptidase Clp; Escherichia coli, genetics, growth & development, metabolism; Escherichia coli Proteins; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins, metabolism; HSP90 Heat-Shock Proteins, genetics, metabolism, physiology; Heat-Shock Proteins, genetics, metabolism, physiology; Hepatitis B Surface Antigens, biosynthesis, genetics; Inclusion Bodies; Membrane Proteins, genetics, metabolism, physiology; Molecular Chaperones, genetics, metabolism, physiology; Protein Folding; Protein Precursors, biosynthesis, genetics; Rabbits; Recombinant Fusion Proteins, genetics, metabolism, physiology; beta-Galactosidase, biosynthesis, genetics},
  nlm-id          = {8712028},
  owner           = {NLM},
  pii             = {mmi1951},
  pmid            = {10931286},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@Article{petrakis2012,
  author          = {Petrakis, Spyros and Raskó, Tamás and Russ, Jenny and Friedrich, Ralf P and Stroedicke, Martin and Riechers, Sean-Patrick and Muehlenberg, Katja and Möller, Angeli and Reinhardt, Anita and Vinayagam, Arunachalam and Schaefer, Martin H and Boutros, Michael and Tricoire, Hervé and Andrade-Navarro, Miguel A and Wanker, Erich E},
  title           = {Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1.},
  journal         = {Plos Genet.},
  year            = {2012},
  volume          = {8},
  issue           = {8},
  pages           = {e1002897},
  issn            = {1553-7404},
  doi             = {10.1371/journal.pgen.1002897},
  abstract        = {Proteins with long, pathogenic polyglutamine (polyQ) sequences have an enhanced propensity to spontaneously misfold and self-assemble into insoluble protein aggregates. Here, we have identified 21 human proteins that influence polyQ-induced ataxin-1 misfolding and proteotoxicity in cell model systems. By analyzing the protein sequences of these modifiers, we discovered a recurrent presence of coiled-coil (CC) domains in ataxin-1 toxicity enhancers, while such domains were not present in suppressors. This suggests that CC domains contribute to the aggregation- and toxicity-promoting effects of modifiers in mammalian cells. We found that the ataxin-1-interacting protein MED15, computationally predicted to possess an N-terminal CC domain, enhances spontaneous ataxin-1 aggregation in cell-based assays, while no such effect was observed with the truncated protein MED15ΔCC, lacking such a domain. Studies with recombinant proteins confirmed these results and demonstrated that the N-terminal CC domain of MED15 (MED15CC) per se is sufficient to promote spontaneous ataxin-1 aggregation in vitro. Moreover, we observed that a hybrid Pum1 protein harboring the MED15CC domain promotes ataxin-1 aggregation in cell model systems. In strong contrast, wild-type Pum1 lacking a CC domain did not stimulate ataxin-1 polymerization. These results suggest that proteins with CC domains are potent enhancers of polyQ-mediated protein misfolding and aggregation in vitro and in vivo.},
  chemicals       = {ATXN1 protein, human, Ataxin-1, Ataxins, MED15 protein, human, Mediator Complex, Nerve Tissue Proteins, Nuclear Proteins, PUM1 protein, human, Peptides, RNA-Binding Proteins, Recombinant Fusion Proteins, polyglutamine},
  citation-subset = {IM},
  completed       = {2012-12-17},
  country         = {United States},
  issn-linking    = {1553-7390},
  keywords        = {Animals; Ataxin-1; Ataxins; COS Cells; Cercopithecus aethiops; Escherichia coli, genetics; Humans; Mediator Complex, chemistry, genetics; Mutation; Nerve Tissue Proteins, chemistry, genetics; Nuclear Proteins, chemistry, genetics; Peptides, chemistry, genetics; Plasmids; Polymerization; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; RNA-Binding Proteins, chemistry, genetics; Recombinant Fusion Proteins, chemistry, genetics; Structure-Activity Relationship; Transfection},
  nlm-id          = {101239074},
  owner           = {NLM},
  pii             = {PGENETICS-D-11-01911},
  pmc             = {PMC3420947},
  pmid            = {22916034},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{montioli2015,
  author          = {Montioli, Riccardo and Oppici, Elisa and Dindo, Mirco and Roncador, Alessandro and Gotte, Giovanni and Cellini, Barbara and Borri Voltattorni, Carla},
  title           = {Misfolding caused by the pathogenic mutation G47R on the minor allele of alanine:glyoxylate aminotransferase and chaperoning activity of pyridoxine.},
  journal         = {Biochimica et biophysica acta},
  year            = {2015},
  volume          = {1854},
  issue           = {10 Pt A},
  month           = oct,
  pages           = {1280--1289},
  issn            = {0006-3002},
  doi             = {10.1016/j.bbapap.2015.07.002},
  abstract        = {Liver peroxisomal alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate (PLP) enzyme, exists as two polymorphic forms, the major (AGT-Ma) and the minor (AGT-Mi) haplotype. Deficit of AGT causes Primary Hyperoxaluria Type 1 (PH1), an autosomal recessive rare disease. Although ~one-third of the 79 disease-causing missense mutations segregates on AGT-Mi, only few of them are well characterized. Here for the first time the molecular and cellular defects of G47R-Mi are reported. When expressed in Escherichia coli, the recombinant purified G47R-Mi variant exhibits only a 2.5-fold reduction of its kcat, and its apo form displays a remarkably decreased PLP binding affinity, increased dimer-monomer equilibrium dissociation constant value, susceptibility to thermal denaturation and to N-terminal region proteolytic cleavage, and aggregation propensity. When stably expressed in a mammalian cell line, we found ~95% of the intact form of the variant in the insoluble fraction, and proteolyzed (within the N-terminal region) and aggregated forms both in the soluble and insoluble fractions. Moreover, the intact and nicked forms have a peroxisomal and a mitochondrial localization, respectively. Unlike what already seen for G41R-Mi, exposure of G47R-Mi expressing cells to pyridoxine (PN) remarkably increases the expression level and the specific activity in a dose-dependent manner, reroutes all the protein to peroxisomes, and rescues its functionality. Although the mechanism of the different effect of PN on the variants G47R-Mi and G41R-Mi remains elusive, the chaperoning activity of PN may be of value in the therapy of patients bearing the G47R mutation. },
  chemicals       = {Apoenzymes, Glyoxylates, Holoenzymes, Recombinant Proteins, Pyridoxal Phosphate, Transaminases, glyoxylate aminotransferase, glyoxylic acid, Pyridoxine, Alanine},
  citation-subset = {IM},
  completed       = {2015-12-01},
  country         = {Netherlands},
  issn-linking    = {0006-3002},
  keywords        = {Alanine, chemistry, metabolism; Alleles; Animals; Apoenzymes, chemistry, genetics, metabolism; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Enzyme Assays; Gene Expression; Glyoxylates, chemistry, metabolism; Holoenzymes, chemistry, genetics, metabolism; Humans; Kinetics; Mutagenesis, Site-Directed; Mutation; Protein Conformation, drug effects; Protein Folding, drug effects; Pyridoxal Phosphate, chemistry, metabolism; Pyridoxine, metabolism, pharmacology; Recombinant Proteins, chemistry, genetics, metabolism; Solubility; Transaminases, chemistry, genetics, metabolism; Alanine:glyoxylate aminotransferase; Pathogenic variant; Primary Hyperoxaluria Type 1; Pyridoxal 5′-phosphate; Pyridoxine treatment},
  nlm-id          = {0217513},
  owner           = {NLM},
  pii             = {S1570-9639(15)00194-6},
  pmid            = {26149463},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-09-22},
}

@Article{xu2005a,
  author          = {Xu, Yali and Weng, Chiao-Ling and Narayanan, Niju and Hsieh, Ming-Yi and Anderson, William A and Scharer, Jeno M and Moo-Young, Murray and Chou, C Perry},
  title           = {Chaperone-mediated folding and maturation of the penicillin acylase precursor in the cytoplasm of Escherichia coli.},
  journal         = {Applied and environmental microbiology},
  year            = {2005},
  volume          = {71},
  issue           = {10},
  month           = oct,
  pages           = {6247--6253},
  issn            = {0099-2240},
  doi             = {10.1128/AEM.71.10.6247-6253.2005},
  abstract        = {Expression of the leaderless pac gene (LL pac), which lacks the coding region for the signal peptide of penicillin acylase (PAC), in Escherichia coli was conducted. It was demonstrated that the PAC precursor, proPAC, can be produced and even processed to form mature PAC in the cytoplasm, indicating that the posttranslational processing steps for PAC maturation can occur in both the periplasm and the cytoplasm of E. coli. The outcome of proPAC folding and PAC maturation could be affected by several factors, such as inducer type, proPAC formation rate, and chaperone availability. Misfolding of proPAC in the cytoplasm could be partially resolved through the coexpression of cytoplasmic chaperones, such as trigger factor, GroEL/ES, or DnaK/J-GrpE. The three chaperones tested showed different extents of the effect on proPAC solublization and PAC maturation, and trigger factor had the most prominent one. However, the chaperone-mediated solublization of proPAC did not guarantee its maturation, which is usually limited by the first autoproteolytic step. It was observed that arabinose could act as an effective inducer for the induction of LL pac expression regulated by the lac-derived promoter system of trc. In addition, PAC maturation could be highly facilitated by arabinose supplementation and coexpression of trigger factor, suggesting that the coordination of chaperone systems with proper culture conditions could dramatically impact recombinant protein production. This study suggests that folding/misfolding of proPAC could be a major step limiting the overproduction of PAC in E. coli and that the problem could be resolved through the search for appropriate chaperones for coexpression. It also demonstrates the analogy in the issues of proPAC misfolding as well as the expression bottleneck occurring in the cytoplasm (i.e., LL pac expression) and those occurring in the periplasm (i.e., wild-type pac expression).},
  chemicals       = {Molecular Chaperones, Protein Precursors, Penicillin Amidase},
  citation-subset = {IM},
  completed       = {2005-12-02},
  country         = {United States},
  issn-linking    = {0099-2240},
  keywords        = {Base Sequence; Cytoplasm, enzymology; Escherichia coli, enzymology, genetics, growth & development; Gene Expression Regulation, Bacterial; Molecular Chaperones, metabolism; Molecular Sequence Data; Penicillin Amidase, genetics, metabolism; Protein Folding; Protein Precursors, genetics, metabolism},
  nlm-id          = {7605801},
  owner           = {NLM},
  pii             = {71/10/6247},
  pmc             = {PMC1265976},
  pmid            = {16204545},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{lesley2002,
  author          = {Lesley, Scott A and Graziano, Jim and Cho, Charles Y and Knuth, Mark W and Klock, Heath E},
  title           = {Gene expression response to misfolded protein as a screen for soluble recombinant protein.},
  journal         = {Protein engineering},
  year            = {2002},
  volume          = {15},
  issue           = {2},
  month           = feb,
  pages           = {153--160},
  issn            = {0269-2139},
  abstract        = {Proper protein folding is key to producing recombinant proteins for structure determination. We have examined the effect of misfolded recombinant protein on gene expression in Escherichia coli. Comparison of expression patterns indicates a unique set of genes responding to translational misfolding. The response is in part analogous to heat shock and suggests a translational component to the regulation. We have further utilized the expression information to generate reporters responsive to protein misfolding. These reporters were used to identify properly folded recombinant proteins and to create soluble domains of insoluble proteins for structural studies.},
  chemicals       = {Heat-Shock Proteins, Proteins, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2002-09-30},
  country         = {England},
  issn-linking    = {0269-2139},
  keywords        = {Animals; Gene Expression; Gene Expression Profiling; Genes, Reporter, genetics; Heat-Shock Proteins, metabolism; Heat-Shock Response, physiology; Hot Temperature; Humans; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Protein Biosynthesis; Protein Conformation; Protein Engineering, methods; Protein Folding; Proteins, chemistry, genetics; Recombinant Proteins, chemistry, genetics, metabolism; Regulatory Sequences, Nucleic Acid; Ribosomes, chemistry; Solubility; Transcription, Genetic},
  nlm-id          = {8801484},
  owner           = {NLM},
  pmid            = {11917152},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2008-11-21},
}

@Article{lee2009a,
  author          = {Lee, Dae-Hee and Kim, Sung-Gun and Kweon, Dae-Hyuk and Seo, Jin-Ho},
  title           = {Folding machineries displayed on a cation-exchanger for the concerted refolding of cysteine- or proline-rich proteins.},
  journal         = {BMC biotechnology},
  year            = {2009},
  volume          = {9},
  month           = mar,
  pages           = {27},
  issn            = {1472-6750},
  doi             = {10.1186/1472-6750-9-27},
  abstract        = {Escherichia coli has been most widely used for the production of valuable recombinant proteins. However, over-production of heterologous proteins in E. coli frequently leads to their misfolding and aggregation yielding inclusion bodies. Previous attempts to refold the inclusion bodies into bioactive forms usually result in poor recovery and account for the major cost in industrial production of desired proteins from recombinant E. coli. Here, we describe the successful use of the immobilized folding machineries for in vitro refolding with the examples of high yield refolding of a ribonuclease A (RNase A) and cyclohexanone monooxygenase (CHMO). We have generated refolding-facilitating media immobilized with three folding machineries, mini-chaperone (a monomeric apical domain consisting of residues 191-345 of GroEL) and two foldases (DsbA and human peptidyl-prolyl cis-trans isomerase) by mimicking oxidative refolding chromatography. For efficient and simple purification and immobilization simultaneously, folding machineries were fused with the positively-charged consecutive 10-arginine tag at their C-terminal. The immobilized folding machineries were fully functional when assayed in a batch mode. When the refolding-facilitating matrices were applied to the refolding of denatured and reduced RNase A and CHMO, both of which contain many cysteine and proline residues, RNase A and CHMO were recovered in 73% and 53% yield of soluble protein with full enzyme activity, respectively. The refolding-facilitating media presented here could be a cost-efficient platform and should be applicable to refold a wide range of E. coli inclusion bodies in high yield with biological function.},
  chemicals       = {Escherichia coli Proteins, Immobilized Proteins, Molecular Chaperones, Proline, Oxygenases, cyclohexanone oxygenase, Ribonuclease, Pancreatic, Peptidylprolyl Isomerase, Protein Disulfide-Isomerases, dsbA protein, E coli, Cysteine},
  citation-subset = {IM},
  completed       = {2009-05-15},
  country         = {England},
  issn-linking    = {1472-6750},
  keywords        = {Circular Dichroism; Cysteine, metabolism; Escherichia coli, metabolism; Escherichia coli Proteins, metabolism; Humans; Immobilized Proteins, metabolism; Molecular Chaperones, metabolism; Oxygenases, isolation & purification, metabolism; Peptidylprolyl Isomerase, metabolism; Plasmids; Proline, metabolism; Protein Disulfide-Isomerases, metabolism; Protein Folding; Ribonuclease, Pancreatic, isolation & purification, metabolism; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization},
  nlm-id          = {101088663},
  owner           = {NLM},
  pii             = {1472-6750-9-27},
  pmc             = {PMC2676282},
  pmid            = {19323835},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2018-11-13},
}

@Article{knockenhauer2015,
  author          = {Knockenhauer, Kevin E and Schwartz, Thomas U},
  title           = {Structural Characterization of Bardet-Biedl Syndrome 9 Protein (BBS9).},
  journal         = {J. Biol. Chem.},
  year            = {2015},
  volume          = {290},
  issue           = {32},
  month           = aug,
  pages           = {19569--19583},
  issn            = {1083-351X},
  doi             = {10.1074/jbc.M115.649202},
  abstract        = {The Bardet-Biedl syndrome protein complex (BBSome) is an octameric complex that transports membrane proteins into the primary cilium signaling organelle in eukaryotes and is implicated in human disease. Here we have analyzed the 99-kDa human BBS9 protein, one of the eight BBSome components. The protein is composed of four structured domains, including a β-stranded N-terminal domain. The 1.8 Å crystal structure of the 46-kDa N-terminal domain reveals a seven-bladed β-propeller. A structure-based homology search suggests that it functions in protein-protein interactions. We show that the Bardet-Biedl syndrome-causing G141R mutation in BBS9 likely results in misfolding of the β-propeller. Although the C-terminal half of BBS9 dimerizes in solution, the N-terminal domain only does so in the crystal lattice. This C-terminal dimerization interface might be important for the assembly of the BBSome. },
  chemicals       = {BBS9 protein, human, Neoplasm Proteins, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2015-11-05},
  country         = {United States},
  issn-linking    = {0021-9258},
  keywords        = {Amino Acid Sequence; Bardet-Biedl Syndrome, metabolism; Crystallography, X-Ray; Escherichia coli, genetics, metabolism; Gene Expression; Humans; Models, Molecular; Molecular Sequence Data; Mutation; Neoplasm Proteins, chemistry, genetics, metabolism; Protein Folding; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Stability; Protein Structure, Secondary; Recombinant Proteins, chemistry, genetics, metabolism; Sequence Alignment; Structural Homology, Protein; analytical ultracentrifugation; chromatography; cilia; crystal structure; genetic disease; protein translocation},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pii             = {M115.649202},
  pmc             = {PMC4528124},
  pmid            = {26085087},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2019-01-08},
}

@Article{garcia-pardo2014,
  author          = {Garcia-Pardo, Javier and Graña-Montes, Ricardo and Fernandez-Mendez, Marc and Ruyra, Angels and Roher, Nerea and Aviles, Francesc X and Lorenzo, Julia and Ventura, Salvador},
  title           = {Amyloid formation by human carboxypeptidase D transthyretin-like domain under physiological conditions.},
  journal         = {J. Biol. Chem.},
  year            = {2014},
  volume          = {289},
  issue           = {49},
  month           = dec,
  pages           = {33783--33796},
  issn            = {1083-351X},
  doi             = {10.1074/jbc.M114.594804},
  abstract        = {Protein aggregation is linked to a growing list of diseases, but it is also an intrinsic property of polypeptides, because the formation of functional globular proteins comes at the expense of an inherent aggregation propensity. Certain proteins can access aggregation-prone states from native-like conformations without the need to cross the energy barrier for unfolding. This is the case of transthyretin (TTR), a homotetrameric protein whose dissociation into its monomers initiates the aggregation cascade. Domains with structural homology to TTR exist in a number of proteins, including the M14B subfamily carboxypeptidases. We show here that the monomeric transthyretin-like domain of human carboxypeptidase D aggregates under close to physiological conditions into amyloid structures, with the population of folded but aggregation-prone states being controlled by the conformational stability of the domain. We thus confirm that the TTR fold keeps a generic residual aggregation propensity upon folding, resulting from the presence of preformed amyloidogenic β-strands in the native state. These structural elements should serve for functional/structural purposes, because they have not been purged out by evolution, but at the same time they put proteins like carboxypeptidase D at risk of aggregation in biological environments and thus can potentially lead to deposition diseases. },
  chemicals       = {Amyloid, Prealbumin, Protein Aggregates, Proteins, Recombinant Proteins, metallocarboxypeptidase D},
  citation-subset = {IM},
  completed       = {2015-03-03},
  country         = {United States},
  issn-linking    = {0021-9258},
  keywords        = {Amino Acid Sequence; Amyloid, chemistry, metabolism; Escherichia coli, genetics, metabolism; Gene Expression; Humans; Hydrogen-Ion Concentration; Kinetics; Models, Molecular; Molecular Sequence Data; Prealbumin, chemistry, genetics, metabolism; Protein Aggregates; Protein Folding; Protein Structure, Quaternary; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins, chemistry, genetics, metabolism; Recombinant Proteins, chemistry, genetics, metabolism; Sequence Alignment; Amyloid; Carboxypeptidase; Protein Aggregation; Protein Misfolding; Protein Stability; Transthyretin},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pii             = {M114.594804},
  pmc             = {PMC4256313},
  pmid            = {25294878},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{temer2017,
  author          = {Temer, Beatriz and Dos Santos, Leandro Vieira and Negri, Victor Augusti and Galhardo, Juliana Pimentel and Magalhães, Pedro Henrique Mello and José, Juliana and Marschalk, Cidnei and Corrêa, Thamy Lívia Ribeiro and Carazzolle, Marcelo Falsarella and Pereira, Gonçalo Amarante Guimarães},
  title           = {Conversion of an inactive xylose isomerase into a functional enzyme by co-expression of GroEL-GroES chaperonins in Saccharomyces cerevisiae.},
  journal         = {BMC biotechnology},
  year            = {2017},
  volume          = {17},
  issue           = {1},
  month           = sep,
  pages           = {71},
  issn            = {1472-6750},
  doi             = {10.1186/s12896-017-0389-7},
  abstract        = {Second-generation ethanol production is a clean bioenergy source with potential to mitigate fossil fuel emissions. The engineering of Saccharomyces cerevisiae for xylose utilization is an essential step towards the production of this biofuel. Though xylose isomerase (XI) is the key enzyme for xylose conversion, almost half of the XI genes are not functional when expressed in S. cerevisiae. To date, protein misfolding is the most plausible hypothesis to explain this phenomenon. This study demonstrated that XI from the bacterium Propionibacterium acidipropionici becomes functional in S. cerevisiae when co-expressed with GroEL-GroES chaperonin complex from Escherichia coli. The developed strain BTY34, harboring the chaperonin complex, is able to efficiently convert xylose to ethanol with a yield of 0.44 g ethanol/g xylose. Furthermore, the BTY34 strain presents a xylose consumption rate similar to those observed for strains carrying the widely used XI from the fungus Orpinomyces sp. In addition, the tetrameric XI structure from P. acidipropionici showed an elevated number of hydrophobic amino acid residues on the surface of protein when compared to XI commonly expressed in S. cerevisiae. Based on our results, we elaborate an extensive discussion concerning the uncertainties that surround heterologous expression of xylose isomerases in S. cerevisiae. Probably, a correct folding promoted by GroEL-GroES could solve some issues regarding a limited or absent XI activity in S. cerevisiae. The strains developed in this work have promising industrial characteristics, and the designed strategy could be an interesting approach to overcome the non-functionality of bacterial protein expression in yeasts.},
  chemicals       = {Chaperonin 60, Escherichia coli Proteins, GroE protein, E coli, Heat-Shock Proteins, Recombinant Proteins, Ethanol, Xylose, Aldose-Ketose Isomerases, xylose isomerase},
  citation-subset = {IM},
  completed       = {2018-05-15},
  country         = {England},
  issn-linking    = {1472-6750},
  keywords        = {Aldose-Ketose Isomerases, chemistry, genetics, metabolism; Chaperonin 60, genetics, metabolism; Escherichia coli Proteins, genetics, metabolism; Ethanol, metabolism; Heat-Shock Proteins, genetics, metabolism; Models, Molecular; Propionibacterium, enzymology; Protein Conformation; Protein Engineering, methods; Recombinant Proteins, genetics, metabolism; Saccharomyces cerevisiae, genetics, metabolism; Xylose, metabolism; Ethanol production; GroEL-GroES chaperonins; Saccharomyces cerevisiae; Xylose fermentation; Xylose isomerase},
  nlm-id          = {101088663},
  owner           = {NLM},
  pii             = {10.1186/s12896-017-0389-7},
  pmc             = {PMC5591498},
  pmid            = {28888227},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2018-11-13},
}

@Article{nawata2017,
  author          = {Nawata, Marina and Tsutsumi, Hirotaka and Kobayashi, Yuta and Unzai, Satoru and Mine, Shouhei and Nakamura, Tsutomu and Uegaki, Koichi and Kamikubo, Hironari and Kataoka, Mikio and Hamada, Daizo},
  title           = {Heat-induced native dimerization prevents amyloid formation by variable domain from immunoglobulin light-chain REI.},
  journal         = {The FEBS journal},
  year            = {2017},
  volume          = {284},
  issue           = {18},
  month           = sep,
  pages           = {3114--3127},
  issn            = {1742-4658},
  doi             = {10.1111/febs.14181},
  abstract        = {Amyloid light-chain (AL) amyloidosis is a protein-misfolding disease characterized by accumulation of immunoglobulin light chains (LCs) into amyloid fibrils. Dimerization of a full length or variable domain (V  ) of LC serves to stabilize the native state and prevent the formation of amyloid fibrils. We here analyzed the thermodynamic properties of dimerization and unfolding reactions by nonamyloidogenic V  from REI LC or its monomeric Y96K mutant using sedimentation velocity and circular dichroism. The data indicate that the equilibrium shifts to native dimerization for wild-type REI V  by elevating temperature due to the negative enthalpy change for dimer dissociation (-81.2 kJ·mol  ). The Y96K mutation did not affect the stability of the monomeric native state but increased amyloidogenicity. These results suggest that the heat-induced native homodimerization is the major factor preventing amyloid formation by wild-type REI V  . Heat-induced native oligomerization may be an efficient strategy to avoid the formation of misfolded aggregates particularly for thermostable proteins that are used at elevated temperatures under conditions where other proteins tend to misfold. Structural data are available in the Protein Data Bank under the accession numbers 5XP1 and 5XQY.},
  chemicals       = {Amyloid, Immunoglobulin Light Chains, Immunoglobulin Variable Region, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2017-10-04},
  country         = {England},
  issn-linking    = {1742-464X},
  keywords        = {Amino Acid Sequence; Amyloid, chemistry, genetics, metabolism; Cloning, Molecular; Crystallography, X-Ray; Escherichia coli, genetics, metabolism; Gene Expression; Hot Temperature; Humans; Immunoglobulin Light Chains, chemistry, genetics, metabolism; Immunoglobulin Variable Region, chemistry, genetics, metabolism; Kinetics; Models, Molecular; Mutation; Protein Folding; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Stability; Protein Structure, Secondary; Protein Unfolding; Recombinant Proteins, chemistry, genetics, metabolism; Scattering, Small Angle; Sequence Alignment; Sequence Homology, Amino Acid; Thermodynamics; X-Ray Diffraction; X-ray crystallography; amyloid; dimer-monomer equilibrium; sedimentation velocity; small-angle X-ray scattering},
  nlm-id          = {101229646},
  owner           = {NLM},
  pmid            = {28736891},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-03-09},
}

@Article{cabantous2008,
  author          = {Cabantous, Stéphanie and Rogers, Yvonne and Terwilliger, Thomas C and Waldo, Geoffrey S},
  title           = {New molecular reporters for rapid protein folding assays.},
  journal         = {PloS one},
  year            = {2008},
  volume          = {3},
  issue           = {6},
  month           = jun,
  pages           = {e2387},
  issn            = {1932-6203},
  doi             = {10.1371/journal.pone.0002387},
  abstract        = {The GFP folding reporter assay uses a C-terminal GFP fusion to report on the folding success of upstream fused polypeptides. The GFP folding assay is widely-used for screening protein variants with improved folding and solubility, but truncation artifacts may arise during evolution, i.e. from de novo internal ribosome entry sites. One way to reduce such artifacts would be to insert target genes within the scaffolding of GFP circular permuted variants. Circular permutants of fluorescent proteins often misfold and are non-fluorescent, and do not readily tolerate fused polypeptides within the fluorescent protein scaffolding. To overcome these limitations, and to increase the dynamic range for reporting on protein misfolding, we have created eight GFP insertion reporters with different sensitivities to protein misfolding using chimeras of two previously described GFP variants, the GFP folding reporter and the robustly-folding "superfolder" GFP. We applied this technology to engineer soluble variants of Rv0113, a protein from Mycobacterium tuberculosis initially expressed as inclusion bodies in Escherichia coli. Using GFP insertion reporters with increasing stringency for each cycle of mutagenesis and selection led to a variant that produced large amounts of soluble protein at 37 degrees C in Escherichia coli. The new reporter constructs discriminate against truncation artifacts previously isolated during directed evolution of Rv0113 using the original C-terminal GFP folding reporter. Using GFP insertion reporters with variable stringency should prove useful for engineering protein variants with improved folding and solubility, while reducing the number of artifacts arising from internal cryptic ribosome initiation sites.},
  chemicals       = {Recombinant Fusion Proteins, Green Fluorescent Proteins},
  citation-subset = {IM},
  completed       = {2008-08-20},
  country         = {United States},
  issn-linking    = {1932-6203},
  keywords        = {Escherichia coli, genetics; Green Fluorescent Proteins, chemistry, genetics; Mycobacterium tuberculosis, genetics; Protein Folding; Recombinant Fusion Proteins, chemistry, genetics},
  nlm-id          = {101285081},
  owner           = {NLM},
  pmc             = {PMC2408556},
  pmid            = {18545698},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2018-11-13},
}

@Article{rotunno2014,
  author          = {Rotunno, Melissa S and Auclair, Jared R and Maniatis, Stephanie and Shaffer, Scott A and Agar, Jeffrey and Bosco, Daryl A},
  title           = {Identification of a misfolded region in superoxide dismutase 1 that is exposed in amyotrophic lateral sclerosis.},
  journal         = {J. Biol. Chem.},
  year            = {2014},
  volume          = {289},
  issue           = {41},
  month           = oct,
  pages           = {28527--28538},
  issn            = {1083-351X},
  doi             = {10.1074/jbc.M114.581801},
  abstract        = {Mutations and aberrant post-translational modifications within Cu,Zn-superoxide dismutase (SOD1) cause this otherwise protective enzyme to misfold, leading to amyotrophic lateral sclerosis (ALS). The C4F6 antibody selectively binds misfolded SOD1 in spinal cord tissues from postmortem human ALS cases, as well as from an ALS-SOD1 mouse model, suggesting that the C4F6 epitope reports on a pathogenic conformation that is common to misfolded SOD1 variants. To date, the residues and structural elements that comprise this epitope have not been elucidated. Using a chemical cross-linking and mass spectrometry approach, we identified the C4F6 epitope within several ALS-linked SOD1 variants, as well as an oxidized form of WT SOD1, supporting the notion that a similar misfolded conformation is shared among pathological SOD1 proteins. Exposure of the C4F6 epitope was modulated by the SOD1 electrostatic (loop VII) and zinc binding (loop IV) loops and correlated with SOD1-induced toxicity in a primary microglia activation assay. Site-directed mutagenesis revealed Asp(92) and Asp(96) as key residues within the C4F6 epitope required for the SOD1-C4F6 binding interaction. We propose that stabilizing the functional loops within SOD1 and/or obscuring the C4F6 epitope are viable therapeutic strategies for treating SOD1-mediated ALS. },
  chemicals       = {Antibodies, Monoclonal, Epitopes, Isoenzymes, Recombinant Proteins, SOD1 protein, human, Sod1 protein, mouse, Superoxide Dismutase, Superoxide Dismutase-1},
  citation-subset = {IM},
  completed       = {2015-02-06},
  country         = {United States},
  issn-linking    = {0021-9258},
  keywords        = {Amyotrophic Lateral Sclerosis, genetics, metabolism, pathology; Animals; Antibodies, Monoclonal, biosynthesis, chemistry, isolation & purification; Epitopes, chemistry, genetics, metabolism; Escherichia coli, genetics, metabolism; Gene Expression; Humans; Hybridomas, immunology; Isoenzymes, chemistry, genetics, metabolism, toxicity; Mice; Microglia, cytology, drug effects, metabolism; Mutagenesis, Site-Directed; Mutation; Oxidation-Reduction; Primary Cell Culture; Protein Binding; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Recombinant Proteins, chemistry, genetics, metabolism, toxicity; Spinal Cord, chemistry, pathology; Superoxide Dismutase, chemistry, genetics, metabolism, toxicity; Superoxide Dismutase-1; Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig Disease); Microglia; Neurodegenerative Disease; Protein Cross-linking; Protein Misfolding; Superoxide Dismutase (SOD)},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pii             = {M114.581801},
  pmc             = {PMC4192504},
  pmid            = {25164820},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{wang2003,
  author          = {Wang, Haoyong and Chong, Shaorong},
  title           = {Visualization of coupled protein folding and binding in bacteria and purification of the heterodimeric complex.},
  journal         = { Proc. Natl. Acad. Sci. USA of the United States of America},
  year            = {2003},
  volume          = {100},
  issue           = {2},
  month           = jan,
  pages           = {478--483},
  issn            = {0027-8424},
  doi             = {10.1073/pnas.0236088100},
  abstract        = {During overexpression of recombinant proteins in Escherichia coli, misfolded proteins often aggregate and form inclusion bodies. If an aggregation-prone recombinant protein is fused upstream (as an N-terminal fusion) to GFP, aggregation of the recombinant protein domain also leads to misfolding of the downstream GFP domain, resulting in a decrease or loss of fluorescence. We investigated whether the GFP domain could fold correctly if aggregation of the upstream protein domain was prevented in vivo by a coupled protein folding and binding interaction. Such interaction has been previously shown to occur between the E. coli integration host factors alpha and beta, and between the domains of the general transcriptional coactivator cAMP response element binding protein (CREB)-binding protein and the activator for thyroid hormone and retinoid receptors. In this study, fusion of integration host factor beta or the CREB-binding protein domain upstream to GFP resulted in aggregation of the fusion protein. Coexpression of their respective partners, on the other hand, allowed soluble expression of the fusion protein and a dramatic increase in fluorescence. The study demonstrated that coupled protein folding and binding could be correlated to GFP fluorescence. A modified miniintein containing an affinity tag was inserted between the upstream protein domain and GFP to allow rapid purification and identification of the heterodimeric complex. The GFP coexpression fusion system may be used to identify novel protein-protein interactions that involve coupled folding and binding or protein partners that can solubilize aggregation-prone recombinant proteins.},
  chemicals       = {Carrier Proteins, Escherichia coli Proteins, Integration Host Factors, Luminescent Proteins, Recombinant Fusion Proteins, citrate-binding transport protein, integration host factor, E coli, Green Fluorescent Proteins},
  citation-subset = {IM},
  completed       = {2003-02-24},
  country         = {United States},
  issn-linking    = {0027-8424},
  keywords        = {Carrier Proteins, chemistry; Dimerization; Escherichia coli, genetics; Escherichia coli Proteins, chemistry; Fluorescence; Green Fluorescent Proteins; Integration Host Factors, chemistry; Luminescent Proteins, chemistry; Protein Folding; Recombinant Fusion Proteins, chemistry},
  nlm-id          = {7505876},
  owner           = {NLM},
  pii             = {0236088100},
  pmc             = {PMC141020},
  pmid            = {12515863},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{vangerven2014,
  author          = {Van Gerven, Nani and Goyal, Parveen and Vandenbussche, Guy and De Kerpel, Maia and Jonckheere, Wim and De Greve, Henri and Remaut, Han},
  title           = {Secretion and functional display of fusion proteins through the curli biogenesis pathway.},
  journal         = {Molecular microbiology},
  year            = {2014},
  volume          = {91},
  issue           = {5},
  month           = mar,
  pages           = {1022--1035},
  issn            = {1365-2958},
  doi             = {10.1111/mmi.12515},
  abstract        = {Curli are functional amyloids expressed as fibres on the surface of Enterobacteriaceae. Contrary to the protein misfolding events associated with pathogenic amyloidosis, curli are the result of a dedicated biosynthetic pathway. A specialized transporter in the outer membrane, CsgG, operates in conjunction with the two accessory proteins CsgE and CsgF to secrete curlin subunits to the extracellular surface, where they nucleate into cross-beta strand fibres. Here we investigate the substrate tolerance of the CsgG transporter and the capability of heterologous sequences to be built into curli fibres. Non-native polypeptides ranging up to at least 260 residues were exported when fused to the curli subunit CsgA. Secretion efficiency depended on the folding properties of the passenger sequences, with substrates exceeding an approximately 2 nm transverse diameter blocking passage through the transport channel. Secretion of smaller passengers was compatible with prior DsbA-mediated disulphide bridge formation in the fusion partner, indicating that CsgG is capable of translocating non-linear polypeptide stretches. Using fusions we further demonstrate the exported or secreted heterologous passenger proteins can attain their native, active fold, establishing curli biogenesis pathway as a platform for the secretion and surface display of small heterologous proteins. },
  chemicals       = {Amyloid, Bacterial Secretion Systems, Escherichia coli Proteins, Peptides, Recombinant Fusion Proteins},
  citation-subset = {IM},
  completed       = {2014-10-23},
  country         = {England},
  issn-linking    = {0950-382X},
  keywords        = {Amyloid, metabolism, ultrastructure; Bacterial Secretion Systems; Biosynthetic Pathways; Blotting, Western; Cell Membrane, metabolism; Escherichia coli, metabolism, ultrastructure; Escherichia coli Proteins, chemistry, metabolism; Peptides, metabolism; Protein Structure, Secondary; Protein Transport; Recombinant Fusion Proteins, chemistry, metabolism, ultrastructure; Substrate Specificity},
  nlm-id          = {8712028},
  owner           = {NLM},
  pmid            = {24417346},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{breitfeld2013,
  author          = {Breitfeld, Jana and Heiker, John T and Böttcher, Yvonne and Schleinitz, Dorit and Tönjes, Anke and Weidle, Kerstin and Krause, Kerstin and Kuettner, E Bartholomeus and Scholz, Markus and Kiess, Wieland and Sträter, Norbert and Beck-Sickinger, Annette G and Stumvoll, Michael and Körner, Antje and Blüher, Matthias and Kovacs, Peter},
  title           = {Analysis of a rare functional truncating mutation rs61757459 in vaspin (SERPINA12) on circulating vaspin levels.},
  journal         = {Journal of molecular medicine (Berlin, Germany)},
  year            = {2013},
  volume          = {91},
  issue           = {11},
  month           = nov,
  pages           = {1285--1292},
  issn            = {1432-1440},
  doi             = {10.1007/s00109-013-1062-9},
  abstract        = {A recent genome-wide association study suggests that genetic variation within the vaspin gene might contribute to the variability in circulating serum visceral adipose tissue-derived serine protease inhibitor (vaspin) concentrations. Here, we analyzed the functional consequences of the rare variant rs61757459 predicting a premature stop codon and its impact on circulating serum vaspin concentrations. In order to identify genetic variation, we sequenced the vaspin gene in 48 nonrelated Caucasian subjects. Rs61757459 was subsequently genotyped in three metabolically well-characterized German cohorts (N = 4,019). We addressed the impact of rs61757459 on the crystal structure of vaspin and investigated its effects on vaspin expression in vivo as well as in vitro using various cell lines (Escherichia coli, HEK293). Along with previously reported common genetic variants, sequencing of vaspin revealed a rare variant (rs61757459; minor allele frequency: 1 %) which predicts a premature stop codon p.R211X. Heterozygous carriers of this mutation had lower circulating vaspin levels when compared with noncarriers. In silico structure analysis of the truncated vaspin, which was estimated to be 24.5 kDa, suggested misfolding and potential instability due to the absence of core structural domains. Indeed, the truncated protein was detected after recombinant expression in E. coli and in lysate, but not in supernatant of HEK293 cells. We conclude that rs61757459 is a functional mutation that results in a truncated protein whose instability likely results in reduced serum vaspin levels. A rare variant (rs61757459) in vaspin coding for the stop codon p.R211X is related to lower circulating vaspin concentrations. Structure analysis suggests misfolding and instability due to the absence of core structural domains. The truncated protein is detectable after recombinant expression in E. coli and in lysate, but not in supernatant of HEK293 cells.},
  chemicals       = {Codon, Terminator, Recombinant Proteins, SERPINA12 protein, human, Serpins},
  citation-subset = {IM},
  completed       = {2014-06-02},
  country         = {Germany},
  issn-linking    = {0946-2716},
  keywords        = {Aged; Codon, Terminator; Cohort Studies; Escherichia coli, genetics; Female; Gene Expression; HEK293 Cells; Humans; Male; Middle Aged; Models, Molecular; Mutation; Phylogeny; Protein Folding; Protein Stability; Recombinant Proteins, analysis, genetics; Serpins, analysis, blood, genetics},
  nlm-id          = {9504370},
  owner           = {NLM},
  pmid            = {23756768},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{ignatova2007,
  author          = {Ignatova, Zoya and Krishnan, Beena and Bombardier, Jeffrey P and Marcelino, Anna Marie C and Hong, Jiang and Gierasch, Lila M},
  title           = {From the test tube to the cell: exploring the folding and aggregation of a beta-clam protein.},
  journal         = {Biopolymers},
  year            = {2007},
  volume          = {88},
  issue           = {2},
  pages           = {157--163},
  issn            = {0006-3525},
  doi             = {10.1002/bip.20665},
  abstract        = {A crucial challenge in present biomedical research is the elucidation of how fundamental processes like protein folding and aggregation occur in the complex environment of the cell. Many new physico-chemical factors like crowding and confinement must be considered, and immense technical hurdles must be overcome in order to explore these processes in vivo. Understanding protein misfolding and aggregation diseases and developing therapeutic strategies to these diseases demand that we gain mechanistic insight into behaviors and misbehaviors of proteins as they fold in vivo. We have developed a fluorescence approach using FlAsH labeling to study the thermodynamics of folding of a model beta-rich protein, cellular retinoic acid binding protein (CRABP) in Escherichia coli cells. The labeling approach has also enabled us to follow aggregation of a modified version of CRABP and chimeras between CRABP and huntingtin exon 1 with its glutamine repeat tract. In this article, we review our recent results using FlAsH labeling to study in-vivo folding and present new observations that hint at fundamental differences between the thermodynamics and kinetics of protein folding in vivo and in vitro.},
  chemicals       = {Multiprotein Complexes, Receptors, Retinoic Acid, Recombinant Proteins, retinoic acid binding protein I, cellular},
  citation-subset = {IM},
  completed       = {2007-05-22},
  country         = {United States},
  issn-linking    = {0006-3525},
  keywords        = {Animals; Drug Stability; Escherichia coli, genetics; In Vitro Techniques; Models, Molecular; Multiprotein Complexes; Mutagenesis, Site-Directed; Protein Folding; Protein Structure, Quaternary; Receptors, Retinoic Acid, chemistry, genetics; Recombinant Proteins, chemistry, genetics},
  mid             = {NIHMS212914},
  nlm-id          = {0372525},
  owner           = {NLM},
  pmc             = {PMC2904568},
  pmid            = {17206628},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{sastry2009,
  author          = {Sastry, M S R and Zhou, Weibin and Baneyx, François},
  title           = {Integrity of N- and C-termini is important for E. coli Hsp31 chaperone activity.},
  journal         = {Protein Sci. : a publication of the Protein Society},
  year            = {2009},
  volume          = {18},
  issue           = {7},
  month           = jul,
  pages           = {1439--1447},
  issn            = {1469-896X},
  doi             = {10.1002/pro.158},
  abstract        = {Hsp31 is a stress-inducible molecular chaperone involved in the management of protein misfolding at high temperatures and in the development of acid resistance in starved E. coli. Each subunit of the Hsp31 homodimer consists of two structural domains connected by a flexible linker that sits atop a continuous tract of nonpolar residues adjacent to a hydrophobic bowl defined by the dimerization interface. Previously, we proposed that while the bowl serves as a binding site for partially folded species at physiological temperatures, chaperone function under heat shock conditions requires that folding intermediates further anneal to high-affinity binding sites that become uncovered upon thermally induced motion of the linker. In support of a mechanism requiring that client proteins first bind to the bowl, we show here that fusion of a 20-residue-long hexahistidine tag to the N-termini of Hsp31 abolishes chaperone activity at all temperatures by inducing reversible structural changes that interfere with substrate binding. We further demonstrate that extending the C-termini of Hsp31 with short His tags selectively suppresses chaperone function at high temperatures by interfering with linker movement. The structural and functional sensitivity of Hsp31 to lengthening is consistent with the high degree of conservation of class I Hsp31 orthologs and will serve as a cautionary tale on the implications of affinity tagging.},
  chemicals       = {Escherichia coli Proteins, His-His-His-His-His-His, Molecular Chaperones, Oligopeptides, Recombinant Fusion Proteins, hchA protein, E coli, Histidine},
  citation-subset = {IM},
  completed       = {2009-09-23},
  country         = {United States},
  issn-linking    = {0961-8368},
  keywords        = {Circular Dichroism; Escherichia coli, genetics, metabolism; Escherichia coli Proteins, chemistry, genetics, metabolism; Histidine, chemistry, genetics, metabolism; Kinetics; Models, Molecular; Molecular Chaperones, chemistry, genetics, metabolism; Oligopeptides, chemistry, genetics, metabolism; Protein Multimerization; Protein Stability; Protein Structure, Tertiary; Recombinant Fusion Proteins, chemistry, genetics, metabolism; Structure-Activity Relationship; Temperature},
  nlm-id          = {9211750},
  owner           = {NLM},
  pmc             = {PMC2775212},
  pmid            = {19517531},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{jaremko2013,
  author          = {Jaremko, Mariusz and Jaremko, Łukasz and Kim, Hai-Young and Cho, Min-Kyu and Schwieters, Charles D and Giller, Karin and Becker, Stefan and Zweckstetter, Markus},
  title           = {Cold denaturation of a protein dimer monitored at atomic resolution.},
  journal         = {Nature chemical biology},
  year            = {2013},
  volume          = {9},
  issue           = {4},
  month           = apr,
  pages           = {264--270},
  issn            = {1552-4469},
  doi             = {10.1038/nchembio.1181},
  abstract        = {Protein folding and unfolding are crucial for a range of biological phenomena and human diseases. Defining the structural properties of the involved transient species is therefore of prime interest. Using a combination of cold denaturation with NMR spectroscopy, we reveal detailed insight into the unfolding of the homodimeric repressor protein CylR2. Seven three-dimensional structures of CylR2 at temperatures from 25 °C to -16 °C reveal a progressive dissociation of the dimeric protein into a native-like monomeric intermediate followed by transition into a highly dynamic, partially folded state. The core of the partially folded state seems critical for biological function and misfolding.},
  chemicals       = {Bacterial Proteins, Cytotoxins, DNA, Bacterial, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2013-05-07},
  country         = {United States},
  issn-linking    = {1552-4450},
  keywords        = {Bacterial Proteins, chemistry, genetics, metabolism; Binding Sites; Cold Temperature; Cytotoxins, chemistry, genetics, metabolism; DNA, Bacterial, chemistry, genetics, metabolism; Enterococcus faecalis, genetics, metabolism; Escherichia coli, genetics; Models, Molecular; Molecular Conformation; Nuclear Magnetic Resonance, Biomolecular; Promoter Regions, Genetic; Protein Binding; Protein Denaturation; Protein Folding; Protein Multimerization; Protein Unfolding; Recombinant Proteins, chemistry, genetics, metabolism},
  mid             = {NIHMS881248},
  nlm-id          = {101231976},
  owner           = {NLM},
  pii             = {nchembio.1181},
  pmc             = {PMC5521822},
  pmid            = {23396077},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{fisher2006,
  author          = {Fisher, Adam C and Kim, Woojin and DeLisa, Matthew P},
  title           = {Genetic selection for protein solubility enabled by the folding quality control feature of the twin-arginine translocation pathway.},
  journal         = {Protein Sci. : a publication of the Protein Society},
  year            = {2006},
  volume          = {15},
  issue           = {3},
  month           = mar,
  pages           = {449--458},
  issn            = {0961-8368},
  doi             = {10.1110/ps.051902606},
  abstract        = {One of the most vexing problems facing structural genomics efforts and the biotechnology enterprise in general is the inability to efficiently produce functional proteins due to poor folding and insolubility. Additionally, protein misfolding and aggregation has been linked to a number of human diseases, such as Alzheimer's. Thus, a robust cellular assay that allows for direct monitoring, manipulation, and improvement of protein folding could have a profound impact. We report the development and characterization of a genetic selection for protein folding and solubility in living bacterial cells. The basis for this assay is the observation that protein transport through the bacterial twin-arginine translocation (Tat) pathway depends on correct folding of the protein prior to transport. In this system, a test protein is expressed as a tripartite fusion between an N-terminal Tat signal peptide and a C-terminal TEM1 beta-lactamase reporter protein. We demonstrate that survival of Escherichia coli cells on selective medium expressing a Tat-targeted test protein/beta-lactamase fusion correlates with the solubility of the test protein. Using this assay, we isolated solubility-enhanced variants of the Alzheimer's Abeta42 peptide from a large combinatorial library of Abeta42 sequences, thereby confirming that our assay is a highly effective selection tool for soluble proteins. By allowing the bacterial Tat pathway to exert folding quality control on expressed target protein sequences, we have generated a powerful tool for monitoring protein folding and solubility in living cells, for molecular engineering of solubility-enhanced proteins or for the isolation of factors and/or cellular conditions that stabilize aggregation-prone proteins.},
  chemicals       = {Amyloid beta-Peptides, Escherichia coli Proteins, Membrane Transport Proteins, Peptide Fragments, Peptide Library, Protein Sorting Signals, Recombinant Fusion Proteins, amyloid beta-protein (1-42), twin-arginine translocase complex, E coli, beta-Lactamases, beta-lactamase TEM-1},
  citation-subset = {IM},
  completed       = {2006-03-22},
  country         = {United States},
  issn-linking    = {0961-8368},
  keywords        = {Amino Acid Sequence; Amyloid beta-Peptides, chemistry, genetics; Escherichia coli, genetics; Escherichia coli Proteins, metabolism; Membrane Transport Proteins, metabolism; Molecular Sequence Data; Peptide Fragments, chemistry, genetics; Peptide Library; Protein Engineering, methods; Protein Folding; Protein Sorting Signals; Protein Transport; Recombinant Fusion Proteins, analysis, chemistry; Sequence Alignment; Solubility; beta-Lactamases, analysis, genetics},
  nlm-id          = {9211750},
  owner           = {NLM},
  pii             = {ps.051902606},
  pmc             = {PMC2249766},
  pmid            = {16452624},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{mohajeri2017,  
  author       = {Mohajeri, A. and Sanaei, S. and Kiafar, F. and Fattahi, A. and Khalili, M. and Zarghami, N.},
  title        = {The Challenges of Recombinant Endostatin in Clinical Application: Focus on the Different Expression Systems and Molecular Bioengineering.},
  journal      = {Advanced pharmaceutical bulletin},
  year         = {2017},
  volume       = {7},
  issue        = {1},
  month        = apr,
  pages        = {21--34},
  issn         = {2228-5881},
  doi          = {10.15171/apb.2017.004},
  abstract     = {Angiogenesis plays an essential role in rapid growing and metastasis of the tumors. Inhibition of angiogenesis is a putative strategy for cancer therapy. Endostatin (Es) is an attractive anti-angiogenesis protein with some clinical application challenges including; short half-life, instability in serum and requirement to high dosage. Therefore, production of recombinant endostatin (rEs) is necessary in large scale. The production of rEs is difficult because of its structural properties and is high-cost. Therefore, this review focused on the different expression systems that involved in rEs production including; mammalian, baculovirus, yeast, and Escherichia coli (E. coli) expression systems. The evaluating of the results of different expression systems declared that none of the mentioned systems can be considered to be generally superior to the other. Meanwhile with considering the advantages and disadvantage of E. coli expression system compared with other systems beside the molecular properties of Es, E. coli expression system can be a preferred expression system for expressing of the Es in large scale. Also, the molecular bioengineering and sustained release formulations that lead to improving of its stability and bioactivity will be discussed. Point mutation (P125A) of Es, addition of RGD moiety or an additional zinc biding site to N-terminal of Es , fusing of Es to anti-HER2 IgG or heavy-chain of IgG, and finally loading of the endostar by PLGA and PEG- PLGA nanoparticles and gold nano-shell particles are the effective bioengineering methods to overcome to clinical changes of endostatin.},
  country      = {Iran},
  issn-linking = {2228-5881},
  keywords     = {Angiogenesis; Bioengineering; Endostatin; Expression system; Molecular targeted therapy},
  nlm-id       = {101578021},
  owner        = {NLM},
  pmc          = {PMC5426730},
  pmid         = {28507934},
  pubmodel     = {Print-Electronic},
  pubstatus    = {ppublish},
  revised      = {2018-11-13},
}

@Article{gu2016,
  author          = {Gu, S. and Matta, J. A. and Lord, B. and Harrington, A. W. and Sutton, S. W. and Davini, W. B. and Bredt, D. S.},
  title           = {Brain $\alpha7$ Nicotinic Acetylcholine Receptor Assembly Requires N{ACHO}.},
  journal         = {Neuron},
  year            = {2016},
  volume          = {89},
  issue           = {5},
  pages           = {948--955},
  issn            = {1097-4199},
  doi             = {10.1016/j.neuron.2016.01.018},
  abstract        = {Nicotine exerts its behavioral and additive actions through a family of brain nicotinic acetylcholine receptors (nAChRs). Enhancing α7-type nAChR signaling improves symptoms in Alzheimer's disease and schizophrenia. The pharmaceutical study of α7 receptors is hampered because these receptors do not form their functional pentameric structure in cell lines, and mechanisms that underlie α7 receptor assembly in neurons are not understood. Here, a genomic screening strategy solves this long-standing puzzle and identifies NACHO, a transmembrane protein of neuronal endoplasmic reticulum that mediates assembly of α7 receptors. NACHO promotes α7 protein folding, maturation through the Golgi complex, and expression at the cell surface. Knockdown of NACHO in cultured hippocampal neurons or knockout of NACHO in mice selectively and completely disrupts α7 receptor assembly and abolishes α7 channel function. This work identifies NACHO as an essential, client-specific chaperone for nAChRs and has implications for physiology and disease associated with these widely distributed neurotransmitter receptors.},
  chemicals       = {1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea, Glial Fibrillary Acidic Protein, Intracellular Signaling Peptides and Proteins, Isoxazoles, MAP2 protein, human, Membrane Proteins, Microtubule-Associated Proteins, Phenylurea Compounds, Protein Subunits, RIC3 protein, human, RNA, Small Interfering, alpha7 Nicotinic Acetylcholine Receptor, Calnexin, Serotonin, Glutamic Acid, Acetylcholine},
  citation-subset = {IM},
  completed       = {2016-07-13},
  country         = {United States},
  issn-linking    = {0896-6273},
  keywords        = {Acetylcholine, pharmacology; Action Potentials, drug effects, genetics; Animals; Calnexin, metabolism; Glial Fibrillary Acidic Protein, genetics, metabolism; Glutamic Acid, pharmacology; HEK293 Cells; Hippocampus, cytology, metabolism; Humans; Intracellular Signaling Peptides and Proteins, genetics, metabolism; Isoxazoles, pharmacology; Male; Membrane Proteins, drug effects, metabolism; Mice; Microtubule-Associated Proteins, genetics, metabolism; Neurons, drug effects, physiology; Phenylurea Compounds, pharmacology; Protein Subunits, genetics, metabolism; RNA, Small Interfering, genetics, metabolism; Serotonin, pharmacology; alpha7 Nicotinic Acetylcholine Receptor, genetics, metabolism},
  nlm-id          = {8809320},
  owner           = {NLM},
  pii             = {S0896-6273(16)00019-2},
  pmid            = {26875622},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-03-04},
}

@Article{daegelen2009,
  author          = {Daegelen, P. and Studier, F. W. and Lenski, R. E. and Cure, S. and Kim, J. F.},
  title           = {Tracing ancestors and relatives of Escherichia coli B, and the derivation of B strains REL606 and BL21(DE3).},
  journal         = {J. Mol. Biol.},
  year            = {2009},
  volume          = {394},
  issue           = {4},
  month           = dec,
  pages           = {634--643},
  issn            = {1089-8638},
  doi             = {10.1016/j.jmb.2009.09.022},
  abstract        = {Antecedents of Escherichia coli B have been traced through publications, inferences, and personal communication to a strain from the Institut Pasteur in Paris used by d'Herelle in his studies of bacteriophages as early as 1918 (a strain not in the current collection). This strain appears to have passed from d'Herelle to Bordet in 1920, and from Bordet to at least three other laboratories by 1925. The strain that Gratia received from Bordet was apparently passed to Bronfenbrenner by 1924 and from him to Luria around 1941. Delbrück and Luria published the first paper calling this strain B in 1942. Its choice as the common host for phages T1-T7 by the phage group that developed around Delbrück, Luria, and Hershey in the 1940s led to widespread use of B along with E. coli K-12, chosen about the same time for biochemical and genetic studies by Tatum and Lederberg. Not all currently available strains related to B are descended from the B of Delbrück and Luria; at least three strains with somewhat different characteristics were derived independently by Hershey directly from the Bronfenbrenner strain, and a strain that appears to have passed from Bordet to Wollman is in the current Collection of the Institut Pasteur. The succession of manipulations and strains that led from the B of Delbrück and Luria to REL606 and BL21(DE3) is given, established in part through evidence from their recently determined complete genome sequences.},
  citation-subset = {IM},
  completed       = {2009-12-21},
  country         = {England},
  issn-linking    = {0022-2836},
  keywords        = {Bacteriology, history; Escherichia coli, genetics, isolation & purification; History, 20th Century; History, 21st Century; Molecular Biology, history},
  nlm-id          = {2985088R},
  owner           = {NLM},
  pii             = {S0022-2836(09)01139-5},
  pmid            = {19765591},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2009-11-25},
}


@Book{bachmann1996,
  author    = {Bachmann, B. J.},
  title     = {Derivations and genotypes of some mutant derivatives of Escherichia coli},
  year      = {1996},
  editor    = {Neidhardt, F. C.},
  edition   = {2},
  publisher = {ASM Press, Washington, DC},
}

@Article{singh2013,
  author          = {Singh, Pranveer and Sharma, Likhesh and Kulothungan, S Rajendra and Adkar, Bharat V and Prajapati, Ravindra Singh and Ali, P Shaik Syed and Krishnan, Beena and Varadarajan, Raghavan},
  title           = {Effect of signal peptide on stability and folding of Escherichia coli thioredoxin.},
  journal         = {PloS one},
  year            = {2013},
  volume          = {8},
  issue           = {5},
  pages           = {e63442},
  issn            = {1932-6203},
  doi             = {10.1371/journal.pone.0063442},
  abstract        = {The signal peptide plays a key role in targeting and membrane insertion of secretory and membrane proteins in both prokaryotes and eukaryotes. In E. coli, recombinant proteins can be targeted to the periplasmic space by fusing naturally occurring signal sequences to their N-terminus. The model protein thioredoxin was fused at its N-terminus with malE and pelB signal sequences. While WT and the pelB fusion are soluble when expressed, the malE fusion was targeted to inclusion bodies and was refolded in vitro to yield a monomeric product with identical secondary structure to WT thioredoxin. The purified recombinant proteins were studied with respect to their thermodynamic stability, aggregation propensity and activity, and compared with wild type thioredoxin, without a signal sequence. The presence of signal sequences leads to thermodynamic destabilization, reduces the activity and increases the aggregation propensity, with malE having much larger effects than pelB. These studies show that besides acting as address labels, signal sequences can modulate protein stability and aggregation in a sequence dependent manner.},
  chemicals       = {Anilino Naphthalenesulfonates, Buffers, Insulin, Protein Sorting Signals, Recombinant Fusion Proteins, Thioredoxins, 1-anilino-8-naphthalenesulfonate, Guanidine},
  citation-subset = {IM},
  completed       = {2013-12-17},
  country         = {United States},
  issn-linking    = {1932-6203},
  keywords        = {Amino Acid Sequence; Anilino Naphthalenesulfonates, metabolism; Buffers; Calorimetry, Differential Scanning; Chromatography, Gel; Circular Dichroism; Electrophoresis, Polyacrylamide Gel; Escherichia coli, metabolism; Guanidine, pharmacology; Insulin, metabolism; Molecular Sequence Data; Protein Denaturation, drug effects; Protein Folding, drug effects; Protein Refolding, drug effects; Protein Sorting Signals; Protein Stability, drug effects; Protein Structure, Quaternary; Proteolysis, drug effects; Recombinant Fusion Proteins, metabolism; Spectrometry, Fluorescence; Temperature; Thioredoxins, chemistry, metabolism},
  nlm-id          = {101285081},
  owner           = {NLM},
  pii             = {PONE-D-12-30695},
  pmc             = {PMC3646739},
  pmid            = {23667620},
  pubmodel        = {Electronic-Print},
  pubstatus       = {epublish},
  revised         = {2018-11-13},
}

@Article{perlman1983,
  author          = {Perlman, D. and Halvorson, H. O.},
  title           = {A putative signal peptidase recognition site and sequence in eukaryotic and prokaryotic signal peptides.},
  journal         = {J. Mol. Biol.},
  year            = {1983},
  volume          = {167},
  issue           = {2},
  month           = jun,
  pages           = {391--409},
  issn            = {0022-2836},
  abstract        = {Presecretory signal peptides of 39 proteins from diverse prokaryotic and eukaryotic sources have been compared. Although varying in length and amino acid composition, the labile peptides share a hydrophobic core of approximately 12 amino acids. A positively charged residue (Lys or Arg) usually precedes the hydrophobic core. Core termination is defined by the occurrence of a charged residue, a sequence of residues which may induce a beta-turn in a polypeptide, or an interruption in potential alpha-helix or beta-extended strand structure. The hydrophobic cores contain, by weight average, 37% Leu: 15% Ala: 10% Val: 10% Phe: 7% Ile plus 21% other hydrophobic amino acids arranged in a non-random sequence. Following the hydrophobic cores (aligned by their last residue) a highly non-random and localized distribution of Ala is apparent within the initial eight positions following the core: (formula; see text) Coincident with this observation, Ala-X-Ala is the most frequent sequence preceding signal peptidase cleavage. We propose the existence of a signal peptidase recognition sequence A-X-B with the preferred cleavage site located after the sixth amino acid following the core sequence. Twenty-two of the above 27 underlined Ala residues would participate as A or B in peptidase cleavage. Position A includes the larger aliphatic amino acids, Leu, Val and Ile, as well as the residues already found at B (principally Ala, Gly and Ser). Since a preferred cleavage site can be discerned from carboxyl and not amino terminal alignment of the hydrophobic cores it is proposed that the carboxyl ends are oriented inward toward the lumen of the endoplasmic reticulum where cleavage is thought to occur. This orientation coupled with the predicted beta-turn typically found between the core and the cleavage site implies reverse hairpin insertion of the signal sequence. The structural features which we describe should help identify signal peptides and cleavage sites in presumptive amino acid sequences derived from DNA sequences.},
  chemicals       = {Amino Acids, Membrane Proteins, Peptides, Protein Sorting Signals, Endopeptidases, Serine Endopeptidases, type I signal peptidase},
  citation-subset = {IM},
  completed       = {1983-08-17},
  country         = {England},
  issn-linking    = {0022-2836},
  keywords        = {Amino Acid Sequence; Amino Acids, analysis; Endopeptidases, metabolism; Membrane Proteins; Models, Molecular; Peptides, metabolism; Protein Conformation; Protein Sorting Signals; Serine Endopeptidases},
  nlm-id          = {2985088R},
  owner           = {NLM},
  pii             = {S0022-2836(83)80341-6},
  pmid            = {6345794},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-01-13},
}

@Article{pugsley1993,
  author          = {Pugsley, A. P.},
  title           = {The complete general secretory pathway in gram-negative bacteria.},
  journal         = {MicroBiol. Rew.},
  year            = {1993},
  volume          = {57},
  issue           = {1},
  month           = mar,
  pages           = {50--108},
  issn            = {0146-0749},
  abstract        = {The unifying feature of all proteins that are transported out of the cytoplasm of gram-negative bacteria by the general secretory pathway (GSP) is the presence of a long stretch of predominantly hydrophobic amino acids, the signal sequence. The interaction between signal sequence-bearing proteins and the cytoplasmic membrane may be a spontaneous event driven by the electrochemical energy potential across the cytoplasmic membrane, leading to membrane integration. The translocation of large, hydrophilic polypeptide segments to the periplasmic side of this membrane almost always requires at least six different proteins encoded by the sec genes and is dependent on both ATP hydrolysis and the electrochemical energy potential. Signal peptidases process precursors with a single, amino-terminal signal sequence, allowing them to be released into the periplasm, where they may remain or whence they may be inserted into the outer membrane. Selected proteins may also be transported across this membrane for assembly into cell surface appendages or for release into the extracellular medium. Many bacteria secrete a variety of structurally different proteins by a common pathway, referred to here as the main terminal branch of the GSP. This recently discovered branch pathway comprises at least 14 gene products. Other, simpler terminal branches of the GSP are also used by gram-negative bacteria to secrete a more limited range of extracellular proteins.},
  chemicals       = {Bacterial Proteins},
  citation-subset = {IM},
  completed       = {1993-05-03},
  country         = {United States},
  gene-symbols    = {pil, prl, pul, sec},
  issn-linking    = {0146-0749},
  keywords        = {Amino Acid Sequence; Bacterial Proteins, chemistry, genetics, metabolism; Biological Transport, physiology; Cell Membrane, metabolism; Fimbriae, Bacterial, metabolism; Genes, Bacterial, physiology; Gram-Negative Bacteria, genetics, metabolism, ultrastructure; Molecular Sequence Data; Sequence Alignment},
  nlm-id          = {7806086},
  owner           = {NLM},
  pmc             = {PMC372901},
  pmid            = {8096622},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {625},
  revised         = {2018-11-13},
}

@Article{samant2014,
  author          = {Samant, Shalaka and Gupta, Gunja and Karthikeyan, Subbulakshmi and Haq, Saiful F and Nair, Ayyappan and Sambasivam, Ganesh and Sukumaran, Sunilkumar},
  title           = {Effect of codon-optimized E. coli signal peptides on recombinant Bacillus stearothermophilus maltogenic amylase periplasmic localization, yield and activity.},
  journal         = {Journal of industrial microbiology \& biotechnology},
  year            = {2014},
  volume          = {41},
  issue           = {9},
  month           = sep,
  pages           = {1435--1442},
  issn            = {1476-5535},
  doi             = {10.1007/s10295-014-1482-8},
  abstract        = {Recombinant proteins can be targeted to the Escherichia coli periplasm by fusing them to signal peptides. The popular pET vectors facilitate fusion of target proteins to the PelB signal. A systematic comparison of the PelB signal with native E. coli signal peptides for recombinant protein expression and periplasmic localization is not reported. We chose the Bacillus stearothermophilus maltogenic amylase (MA), an industrial enzyme widely used in the baking and brewing industry, as a model protein and analyzed the competence of seven, codon-optimized, E. coli signal sequences to translocate MA to the E. coli periplasm compared to PelB. MA fusions to three of the signals facilitated enhanced periplasmic localization of MA compared to the PelB fusion. Interestingly, these three fusions showed greatly improved MA yields and between 18- and 50-fold improved amylase activities compared to the PelB fusion. Previously, non-optimal codon usage in native E. coli signal peptide sequences has been reported to be important for protein stability and activity. Our results suggest that E. coli signal peptides with optimal codon usage could also be beneficial for heterologous protein secretion to the periplasm. Moreover, such fusions could even enhance activity rather than diminish it. This effect, to our knowledge has not been previously documented. In addition, the seven vector platform reported here could also be used as a screen to identify the best signal peptide partner for other recombinant targets of interest. },
  chemicals       = {Bacterial Proteins, Codon, Protein Sorting Signals, Recombinant Fusion Proteins, Glycoside Hydrolases, glucan 1,4-alpha-maltohydrolase},
  citation-subset = {IM},
  completed       = {2014-12-03},
  country         = {Germany},
  issn-linking    = {1367-5435},
  keywords        = {Bacterial Proteins, genetics, metabolism; Codon; Escherichia coli, genetics, metabolism; Gene Expression; Geobacillus stearothermophilus, enzymology, genetics; Glycoside Hydrolases, genetics, metabolism; Periplasm, enzymology, metabolism; Protein Engineering; Protein Sorting Signals; Protein Transport; Recombinant Fusion Proteins, genetics, metabolism},
  nlm-id          = {9705544},
  owner           = {NLM},
  pmid            = {25038884},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-02},
}

@Article{yoon2010,
  author          = {Yoon, S. H. and Kim, S. K. and Kim, J. F.},
  title           = "{Secretory Production of Recombinant Proteins in \textit{Escherichia coli}.}",
  journal         = {Recent Pat. Biotechnol.},
  year            = {2010},
  volume          = {4},
  issue           = {1},
  month           = jan,
  pages           = {23--29},
  issn            = {2212-4012},
  abstract        = {Extracellular production of heterologous proteins using the Escherichia coli cell factory offers several advantages over intracellular production and mammalian culture. Properly folded proteins can be rapidly accumulated in the culture media, and downstream processes for isolation and purification can be much simplified. Efforts to enhance the secretory production of target proteins can be largely classified as selection and modification of the signal peptide, co-expression of proteins to assist translocation and folding, improvement of periplasmic release, and protection of target proteins from degradation and contamination. Here, we review recent patents on the secretory production of recombinant proteins in E. coli.},
  chemicals       = {Protein Sorting Signals, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2010-05-20},
  country         = {United Arab Emirates},
  issn-linking    = {1872-2083},
  keywords        = {Escherichia coli, genetics, metabolism; Patents as Topic; Periplasm, metabolism; Protein Folding; Protein Sorting Signals, genetics, physiology; Recombinant Proteins, genetics, metabolism; Secretory Pathway; Translocation, Genetic},
  nlm-id          = {101309942},
  owner           = {NLM},
  pii             = {BIOT- ABSTRACT 10},
  pmid            = {20201800},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {77},
  revised         = {2011-11-10},
}

@Article{lebendiker2011,
  author          = {Lebendiker, M. and Danieli, T.},
  title           = {Purification of proteins fused to maltose-binding protein.},
  journal         = {Methods in molecular biology (Clifton, N.J.)},
  year            = {2011},
  volume          = {681},
  pages           = {281--293},
  issn            = {1940-6029},
  doi             = {10.1007/978-1-60761-913-0_15},
  abstract        = {Maltose-binding protein (MBP) is one of the most popular fusion partners being used for producing recombinant proteins in bacterial cells. MBP allows one to use a simple capture affinity step on amylose-agarose columns, resulting in a protein that is often 70-90% pure. In addition to protein-isolation applications, MBP provides a high degree of translation and facilitates the proper folding and solubility of the target protein. This chapter describes efficient procedures for isolating highly purified MBP-target proteins. Special attention is given to considerations for downstream applications such as structural determination studies, protein activity assays, and assessing the chemical characteristics of the target protein.},
  chemicals       = {Maltose-Binding Proteins, Recombinant Fusion Proteins, Amylose, Sepharose},
  citation-subset = {IM},
  completed       = {2011-02-07},
  country         = {United States},
  issn-linking    = {1064-3745},
  keywords        = {Amylose, chemistry; Chemical Fractionation, instrumentation, methods; Chromatography, Affinity; Chromatography, Gel; Chromatography, Ion Exchange; Equipment Reuse; Escherichia coli, cytology, genetics; Maltose-Binding Proteins, genetics; Protein Engineering, methods; Recombinant Fusion Proteins, genetics, isolation & purification; Sepharose, chemistry},
  nlm-id          = {9214969},
  owner           = {NLM},
  pmid            = {20978971},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2010-10-27},
}

@Article{nys2016,
  author  = {Nys, M. and Wijckmans, E. and Farinha, A. and Yoluk, O. and Andersson, M. and Brams, M. and Spurny, R. and Peigneur, S. and Tytgat, J. and Lindahl, E. and Ulens, C.},
  title   = {Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine.},
  journal = {PNAS},
  year    = {2016},
  volume  = {113},
  number  = {43},
}

@Article{tsetlin2002,
  author          = {Tsetlin, V. I. and Dergousova, N. I. and Azeeva, E. A. and Kryukova, E. V. and Kudelina, I. A. and Shibanova, E. D. and Kasheverov, I. E. and Methfessel, C.},
  title           = "{Refolding of the \textit{Escherichia coli} Expressed Extracellular Domain of alpha 7 Nicotinic Acetylcholine Receptor.}",
  journal         = {Eur. J. Biochem.},
  year            = {2002},
  volume          = {269},
  issue           = {11},
  month           = jun,
  pages           = {2801--2809},
  issn            = {0014-2956},
  abstract        = {Heterologous expression of the extracellular domains (ECDs) of the nicotinic acetylcholine receptor (AChR) subunits may give large amounts of proteins for studying the functional and spatial characteristics of their ligand-binding sites. The ECD of the alpha 7 subunit of the homo-oligomeric alpha 7 neuronal AChR appears to be a more suitable object than the ECDs of other heteromeric neuronal or muscle-type AChRs. The rat alpha 7 ECDs (amino-acid residues approximately 1-210) were recently expressed in Escherichia coli as fusion proteins with maltose-binding protein [Fischer, M., Corringer, P., Schott, K., Bacher, A. & Changeux, J. (2001) Proc. Natl Acad. Sci. USA 98, 3567-3570] and glutathione S-transferase (GST) [Utkin, Y., Kukhtina, V., Kryukova, E., Chiodini, F., Bertrand, D., Methfessel, C. & Tsetlin, V. (2001) J. Biol. Chem. 276, 15810-15815]. However, these proteins exist in solution mostly as high-molecular mass aggregates rather than monomers or oligomers. In the present work it is found that refolding of GST-alpha 7-(1-208) protein in the presence of 0.1% SDS considerably decreases the formation of high-molecular mass aggregates. The C116S mutation in the alpha 7 moiety was found to further decrease the aggregation and to increase the stability of protein solutions. This mutation slightly increased the affinity of the protein for alpha-bungarotoxin (from Kd approximately 300 to 150 nm). Gel-permeation HPLC was used to isolate the monomeric form of the GST-alpha 7-(1-208) protein and its mutant almost devoid of SDS. CD spectra revealed that the C116S mutation considerably increased the content of beta structure and made it more stable under different conditions. The monomeric C116S mutant appears promising both for further structural studies and as a starting material for preparing the alpha 7 ECD in an oligomeric form.},
  chemicals       = {Chrna7 protein, rat, Cobra Neurotoxin Proteins, Receptors, Nicotinic, Recombinant Fusion Proteins, alpha7 Nicotinic Acetylcholine Receptor, alpha-cobratoxin},
  citation-subset = {IM},
  completed       = {2002-07-26},
  country         = {England},
  issn-linking    = {0014-2956},
  keywords        = {Amino Acid Substitution; Animals; Cobra Neurotoxin Proteins, metabolism; Mutation; Protein Folding; Protein Renaturation; Protein Structure, Tertiary; Rats; Receptors, Nicotinic, chemistry, genetics, metabolism; Recombinant Fusion Proteins, chemistry, genetics, metabolism; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {0107600},
  owner           = {NLM},
  pii             = {2961},
  pmid            = {12047391},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2016-10-17},
}

@Article{utkin2001,
  author  = {Utkin, Y. N. and Kukhtina, V. V. and Kryukova, E. V. and Chiodini, F. and Bertrand, D. and Methfessel, C. and Tsetlin, V. I.},
  title   = {‘Weak toxin’ from Naja kaouthia is a nontoxic antagonist of α7 and muscle–type nicotinic acetylcholine receptors.},
  journal = {J Biol Chem},
  year    = {2001},
  volume  = {276},
  pages   = {15810–15815},
}

@Article{khoury2011,
  author       = {Khoury, G. A. and Baliban, R. C. and Floudas, C. A.},
  title        = {Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot database.},
  journal      = {Sci. Rep.},
  year         = {2011},
  volume       = {1},
  month        = sep,
  issn         = {2045-2322},
  doi          = {10.1038/srep00090},
  abstract     = {Post-translational modifications (PTMs) broadly contribute to the recent explosion of proteomic data and possess a complexity surpassing that of protein design. PTMs are the chemical modification of a protein after its translation, and have wide effects broadening its range of functionality. Based on previous estimates, it is widely believed that more than half of proteins are glycoproteins. Whereas mutations can only occur once per position, different forms of post-translational modifications may occur in tandem. With the number and abundances of modifications constantly being discovered, there is no method to readily assess their relative levels. Here we report the relative abundances of each PTM found experimentally and putatively, from high-quality, manually curated, proteome-wide data, and show that at best, less than one-fifth of proteins are glycosylated. We make available to the academic community a continuously updated resource (http://selene.princeton.edu/PTMCuration) containing the statistics so scientists can assess "how many" of each PTM exists.},
  country      = {England},
  issn-linking = {2045-2322},
  mid          = {NIHMS330285},
  nlm-id       = {101563288},
  owner        = {NLM},
  pii          = {srep00090},
  pmc          = {PMC3201773},
  pmid         = {22034591},
  pubmodel     = {Print},
  pubstatus    = {ppublish},
  revised      = {2018-11-13},
}

@Article{xu2015,
  author          = {Xu, C. and Ng, D. T. W.},
  title           = {Glycosylation-directed quality control of protein folding.},
  journal         = {Nature reviews. Molecular cell biology},
  year            = {2015},
  volume          = {16},
  issue           = {12},
  month           = dec,
  pages           = {742--752},
  issn            = {1471-0080},
  doi             = {10.1038/nrm4073},
  abstract        = {Membrane-bound and soluble proteins of the secretory pathway are commonly glycosylated in the endoplasmic reticulum. These adducts have many biological functions, including, notably, their contribution to the maturation of glycoproteins. N-linked glycans are of oligomeric structure, forming configurations that provide blueprints to precisely instruct the folding of protein substrates and the quality control systems that scrutinize it. O-linked mannoses are simpler in structure and were recently found to have distinct functions in protein quality control that do not require the complex structure of N-linked glycans. Together, recent studies reveal the breadth and sophistication of the roles of these glycan-directed modifications in protein biogenesis. },
  chemicals       = {Glycoproteins, Polysaccharides},
  citation-subset = {IM},
  completed       = {2016-03-23},
  country         = {England},
  issn-linking    = {1471-0072},
  keywords        = {Animals; Endoplasmic Reticulum, metabolism; Glycoproteins, chemistry; Glycosylation; Humans; Polysaccharides, chemistry; Protein Folding; Protein Processing, Post-Translational; Protein Structure, Tertiary; Schizosaccharomyces, metabolism},
  nlm-id          = {100962782},
  owner           = {NLM},
  pii             = {nrm4073},
  pmid            = {26465718},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{dell2010,
  author    = {Dell, A. and Galadari, A. and Sastre, F. and Hitchen, P.},
  title     = {Similarities and differences in the glycosylation mechanisms in prokaryotes and eukaryotes.},
  journal   = {Int. J. Microbiol.},
  year      = {2010},
  volume    = {2010},
  pages     = {148178},
  issn      = {1687-9198},
  doi       = {10.1155/2010/148178},
  abstract  = {Recent years have witnessed a rapid growth in the number and diversity of prokaryotic proteins shown to carry N- and/or O-glycans, with protein glycosylation now considered as fundamental to the biology of these organisms as it is in eukaryotic systems. This article overviews the major glycosylation pathways that are known to exist in eukarya, bacteria and archaea. These are (i) oligosaccharyltransferase (OST)-mediated N-glycosylation which is abundant in eukarya and archaea, but is restricted to a limited range of bacteria; (ii) stepwise cytoplasmic N-glycosylation that has so far only been confirmed in the bacterial domain; (iii) OST-mediated O-glycosylation which appears to be characteristic of bacteria; and (iv) stepwise O-glycosylation which is common in eukarya and bacteria. A key aim of the review is to integrate information from the three domains of life in order to highlight commonalities in glycosylation processes. We show how the OST-mediated N- and O-glycosylation pathways share cytoplasmic assembly of lipid-linked oligosaccharides, flipping across the ER/periplasmic/cytoplasmic membranes, and transferring "en bloc" to the protein acceptor. Moreover these hallmarks are mirrored in lipopolysaccharide biosynthesis. Like in eukaryotes, stepwise O-glycosylation occurs on diverse bacterial proteins including flagellins, adhesins, autotransporters and lipoproteins, with O-glycosylation chain extension often coupled with secretory mechanisms.},
  completed = {2011-07-14},
  country   = {Egypt},
  nlm-id    = {101516125},
  owner     = {NLM},
  pmc       = {PMC3068309},
  pmid      = {21490701},
  pubmodel  = {Print-Electronic},
  pubstatus = {ppublish},
  revised   = {2018-11-13},
}

@Article{duplay1984,
  author          = {Duplay, P and Bedouelle, H and Fowler, A and Zabin, I and Saurin, W and Hofnung, M},
  title           = {Sequences of the malE gene and of its product, the maltose-binding protein of Escherichia coli K12.},
  journal         = {J. Biol. Chem.},
  year            = {1984},
  volume          = {259},
  issue           = {16},
  month           = aug,
  pages           = {10606--10613},
  issn            = {0021-9258},
  abstract        = {The sequences of the malE gene and of its mature product, the maltose-binding protein, have been determined and are in good agreement. The malE gene encodes the pre-protein (396 amino acid residues) which yields, upon cleavage of the NH2-terminal extension (26 amino acid residues), the mature maltose-binding protein (370 amino acid residues). The malE mRNA could form stable stem and loop structures, some of which may account for translational pauses observed by Randall et al. (Randall, L., Josefsson, L. G. & Hardy, S. J. S. (1980) Eur. J. Biochem. 107, 375-379). The sequence change due to an in-frame nonpolar deletion of 765 nucleotides in malE is also presented as well as homologies between the maltose-binding protein and other sugar-binding proteins.},
  chemicals       = {ATP-Binding Cassette Transporters, Carrier Proteins, Escherichia coli Proteins, MalE protein, E coli, Maltose-Binding Proteins, Membrane Proteins, Monosaccharide Transport Proteins, Periplasmic Binding Proteins, RNA, Messenger, maltose transport system, E coli, DNA Restriction Enzymes},
  citation-subset = {IM},
  completed       = {1984-09-28},
  country         = {United States},
  issn-linking    = {0021-9258},
  keywords        = {ATP-Binding Cassette Transporters; Amino Acid Sequence; Base Sequence; Calorimetry; Carrier Proteins, genetics; DNA Restriction Enzymes; Escherichia coli, genetics; Escherichia coli Proteins; Genes; Genes, Bacterial; Maltose-Binding Proteins; Membrane Proteins, genetics; Monosaccharide Transport Proteins; Nucleic Acid Conformation; Periplasmic Binding Proteins; Plasmids; RNA, Messenger, genetics; Species Specificity},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pmid            = {6088507},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2017-12-13},
}

@Article{bedouelle1983,
  author          = {Bedouelle, H},
  title           = "{Mutations in the Promoter Regions of the malEFG and malK-lamB Operons of \textit{Escherichia coli} K12.}",
  journal         = {J. Mol. Biol.},
  year            = {1983},
  volume          = {170},
  issue           = {4},
  month           = nov,
  pages           = {861--882},
  issn            = {0022-2836},
  abstract        = {The malB region of Escherichia coli is composed of two operons, malEFG and malK-lamB, transcribed divergently from a control region located between the malE and malK genes. Expression of the malB operons is under the positive control of the malT gene product (MalT) and maltose and of the crp gene product (CRP) and cyclic AMP. Strains in which the lac genes have been fused to malE or malK are unable to use lactose as carbon source if they have been deleted for malT or crp. Mutations in the malB region allowing such fusion strains to grow on lactose have been isolated. These and previously isolated mutations were genetically characterized. As regards the malEp promoter mutations, malEp9, malEp1 and malEp6 create new promoters that are MalT and CRP independent. malEp9 and malEp1 change residues -1 and -2, respectively, of malEp without altering its activity. malEp6 duplicates six base-pairs between residues -22 and -23. malEp3 improves the -10 region hexamer. malEp5 deletes residues -29 to -62. It creates a new promoter that is MalT independent, CRP dependent, likely by fusing together functional regions of malEp that are normally apart. malEp5 also reduces the expression of malK-lamB, suggesting the existence of a link between the malEp and malKp promoters. As regards the malKp mutations, malKp6 changes residue -81 of malKp without altering its activity. It creates a new promoter, which is MalT independent, CRP dependent, likely by using a pre-existing cyclic AMP/CRP binding site. malKp102 changes residue -36, two bases upstream of the -35 region hexamer. It decreases the activity of malKp by at least four orders of magnitude and likely alters the MalT binding site. These results are discussed in terms of regulatory interactions within the malB control region.},
  chemicals       = {DNA, Bacterial, Maltose, beta-Galactosidase},
  citation-subset = {IM},
  completed       = {1984-01-26},
  country         = {England},
  issn-linking    = {0022-2836},
  keywords        = {Base Sequence; Coliphages, genetics; DNA, Bacterial; Escherichia coli, genetics; Gene Expression Regulation; Lac Operon; Lysogeny; Maltose, genetics; Mutation; Operon; Protein Biosynthesis; Transduction, Genetic; beta-Galactosidase, genetics},
  nlm-id          = {2985088R},
  owner           = {NLM},
  pii             = {S0022-2836(83)80192-2},
  pmid            = {6417341},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-01-13},
}

@Article{planson2003,
  author          = {Planson, A-G. and Guijarro, J. I. and Goldberg, M. E. and Chaffotte, A. F.},
  title           = "{Assistance of Maltose Binding Protein to the \textit{in vivo} Folding of the Disulfide-Rich C-terminal Fragment from \textit{Plasmodium falciparum merozoite} Surface Protein 1 Expressed in \textit{Escherichia coli}.}",
  journal         = {Biochem.},
  year            = {2003},
  volume          = {42},
  issue           = {45},
  month           = nov,
  pages           = {13202--13211},
  issn            = {0006-2960},
  doi             = {10.1021/bi035321c},
  abstract        = {The C-terminal fragment of Plasmodium falciparum merozoite surface protein 1 (F19) is a leading candidate for the development of a malaria vaccine. Successful vaccination trials on primates, immunochemistry, and structural studies have shown the importance of its native conformation for its protective role against infection. F19 is a disulfide-rich protein, and the correct pairing of its 12 half-cystines is required for the native state of the protein. F19 has been produced in the Escherichia coli periplasm, which has an oxidative environment favorable for the formation of disulfide bonds. F19 was either expressed as a fusion with the maltose binding protein (MBP) or directly addressed to the periplasm by fusing it with the MBP signal peptide. Direct expression of F19 in the periplasm led to a misfolded protein with a heterogeneous distribution of disulfide bridges. On the contrary, when produced as a fusion protein with E. coli MBP, the F19 moiety was natively folded. Indeed, after proteolysis of the fusion protein, the resulting F19 possesses the structural characteristics and the immunochemical reactivity of the analogous fragment produced either in baculovirus-infected insect cells or in yeast. These results demonstrate that the positive effect of MBP in assisting the folding of passenger proteins extends to the correct formation of disulfide bridges in vivo. Although proteins or protein fragments fused to MBP have been frequently expressed with success, our comparative study evidences for the first time the helping property of MBP in the oxidative folding of a disulfide-rich protein.},
  chemicals       = {Carrier Proteins, Disulfides, Maltose-Binding Proteins, Merozoite Surface Protein 1, Peptide Fragments, Recombinant Fusion Proteins},
  citation-subset = {IM},
  completed       = {2004-03-04},
  country         = {United States},
  issn-linking    = {0006-2960},
  keywords        = {Animals; Carrier Proteins, chemistry, genetics; Circular Dichroism; Disulfides, chemistry; Escherichia coli, chemistry, genetics; Maltose-Binding Proteins; Merozoite Surface Protein 1, biosynthesis, chemistry, genetics; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments, biosynthesis, chemistry, genetics; Periplasm, chemistry, genetics; Plasmodium falciparum, chemistry, genetics; Protein Conformation; Protein Engineering, methods; Protein Folding; Protein Structure, Tertiary, genetics; Recombinant Fusion Proteins, biosynthesis, chemistry, isolation & purification; Spectrometry, Mass, Electrospray Ionization},
  nlm-id          = {0370623},
  owner           = {NLM},
  pmid            = {14609331},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2010-11-18},
}

@Article{imai1989,
  author          = {Imai, Y and Tsunokawa, Y and Sugimura, T and Terada, M},
  title           = {Purification and DNA-binding properties of human papillomavirus type 16 E6 protein expressed in Escherichia coli.},
  journal         = {Biochemical and biophysical research communications},
  year            = {1989},
  volume          = {164},
  issue           = {3},
  month           = nov,
  pages           = {1402--1410},
  issn            = {0006-291X},
  abstract        = {Unfused human papillomavirus type 16 (HPV 16) E6 protein was expressed in Escherichia coli using a lambda PL promoter system. The protein was isolated from the cells as inclusion bodies, extracted by 6 M guanidine-HCl, and purified by chromatography. The purified protein had high affinity to DNA and was demonstrated for the first time to bind to a specific sequence within the long control region of HPV 16.},
  chemicals       = {DNA-Binding Proteins, Oncogene Proteins, Viral, Recombinant Fusion Proteins, Viral Structural Proteins, protein E6, Bovine papillomavirus},
  citation-subset = {IM},
  completed       = {1989-12-28},
  country         = {United States},
  issn-linking    = {0006-291X},
  keywords        = {Cloning, Molecular; DNA-Binding Proteins, isolation & purification; Enhancer Elements, Genetic; Escherichia coli, genetics; Gene Expression; Genes, Viral; Genetic Vectors; Immunoblotting; Kinetics; Oncogene Proteins, Viral, genetics, isolation & purification, metabolism; Papillomaviridae, genetics, metabolism; Recombinant Fusion Proteins, isolation & purification, metabolism; Restriction Mapping; Viral Structural Proteins, genetics},
  nlm-id          = {0372516},
  owner           = {NLM},
  pii             = {0006-291X(89)91826-3},
  pmid            = {2556128},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2008-11-21},
}

@Article{raran-kurussi2015,
  author          = {Raran-Kurussi, S. and Keefe, K. and Waugh, D. S.},
  title           = {Positional effects of fusion partners on the yield and solubility of M{BP} fusion proteins.},
  journal         = {Protein Express. Purif.},
  year            = {2015},
  volume          = {110},
  pages           = {159--164},
  issn            = {1096-0279},
  doi             = {10.1016/j.pep.2015.03.004},
  abstract        = {Escherichia coli maltose-binding protein (MBP) is exceptionally effective at promoting the solubility of its fusion partners. However, there are conflicting reports in the literature claiming that (1) MBP is an effective solubility enhancer only when it is joined to the N-terminus of an aggregation-prone passenger protein, and (2) MBP is equally effective when fused to either end of the passenger. Here, we endeavor to resolve this controversy by comparing the solubility of a diverse set of MBP fusion proteins that, unlike those analyzed in previous studies, are identical in every way except for the order of the two domains. The results indicate that fusion proteins with an N-terminal MBP provide an excellent solubility advantage along with more robust expression when compared to analogous fusions in which MBP is the C-terminal fusion partner. We find that only intrinsically soluble passenger proteins (i.e., those not requiring a solubility enhancer) are produced as soluble fusions when they precede MBP. We also report that even subtle differences in inter-domain linker sequences can influence the solubility of fusion proteins. },
  chemicals       = {Escherichia coli Proteins, His-His-His-His-His-His, Maltose-Binding Proteins, Oligopeptides, Recombinant Fusion Proteins, Histidine},
  citation-subset = {IM},
  completed       = {2015-12-24},
  country         = {United States},
  issn-linking    = {1046-5928},
  keywords        = {Amino Acid Sequence; Escherichia coli, genetics, metabolism; Escherichia coli Proteins, chemistry, genetics, metabolism; Gene Expression; Histidine, chemistry, genetics; Maltose-Binding Proteins, chemistry, genetics, metabolism; Molecular Sequence Data; Oligopeptides, chemistry, genetics; Plasmids, chemistry, metabolism; Protein Folding; Protein Structure, Tertiary; Recombinant Fusion Proteins, chemistry, genetics, metabolism; Solubility; Structure-Activity Relationship; Fusion protein; Gateway cloning; Inclusion bodies; MBP; Solubility enhancer},
  mid             = {NIHMS672461},
  nlm-id          = {9101496},
  owner           = {NLM},
  pii             = {S1046-5928(15)00044-3},
  pmc             = {PMC4393804},
  pmid            = {25782741},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{makrides1996,
  author          = {Makrides, S. C.},
  title           = {Strategies for achieving high-level expression of genes in Escherichia coli.},
  journal         = {MicroBiol. Rew.},
  year            = {1996},
  volume          = {60},
  issue           = {3},
  month           = sep,
  pages           = {512--538},
  issn            = {0146-0749},
  abstract        = {Progress in our understanding of several biological processes promises to broaden the usefulness of Escherichia coli as a tool for gene expression. There is an expanding choice of tightly regulated prokaryotic promoters suitable for achieving high-level gene expression. New host strains facilitate the formation of disulfide bonds in the reducing environment of the cytoplasm and offer higher protein yields by minimizing proteolytic degradation. Insights into the process of protein translocation across the bacterial membranes may eventually make it possible to achieve robust secretion of specific proteins into the culture medium. Studies involving molecular chaperones have shown that in specific cases, chaperones can be very effective for improved protein folding, solubility, and membrane transport. Negative results derived from such studies are also instructive in formulating different strategies. The remarkable increase in the availability of fusion partners offers a wide range of tools for improved protein folding, solubility, protection from proteases, yield, and secretion into the culture medium, as well as for detection and purification of recombinant proteins. Codon usage is known to present a potential impediment to high-level gene expression in E. coli. Although we still do not understand all the rules governing this phenomenon, it is apparent that "rare" codons, depending on their frequency and context, can have an adverse effect on protein levels. Usually, this problem can be alleviated by modification of the relevant codons or by coexpression of the cognate tRNA genes. Finally, the elucidation of specific determinants of protein degradation, a plethora of protease-deficient host strains, and methods to stabilize proteins afford new strategies to minimize proteolytic susceptibility of recombinant proteins in E. coli.},
  chemicals       = {Recombinant Fusion Proteins, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {1996-12-10},
  country         = {United States},
  issn-linking    = {0146-0749},
  keywords        = {Biotechnology, methods; Cell Compartmentation; Escherichia coli, genetics; Gene Expression; Genetic Vectors; Protein Folding; Recombinant Fusion Proteins, biosynthesis, metabolism; Recombinant Proteins, biosynthesis, metabolism},
  nlm-id          = {7806086},
  owner           = {NLM},
  pmc             = {PMC239455},
  pmid            = {8840785},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {623},
  revised         = {2018-11-30},
}

@Article{dale1994,
  author          = {Dale, G. E. and Broger, C. and Langen, H. and D'Arcy, A. and Stüber, D.},
  title           = {Improving protein solubility through rationally designed amino acid replacements: solubilization of the trimethoprim-resistant type S1 dihydrofolate reductase.},
  journal         = {Protein engineering},
  year            = {1994},
  volume          = {7},
  issue           = {7},
  month           = jul,
  pages           = {933--939},
  issn            = {0269-2139},
  abstract        = {In recent years resistance to the antibacterial agent trimethoprim (Tmp) has become more widespread and several Tmp-resistant (Tmpr) dihydrofolate reductases (DHFRs) have been described from Gram-negative bacteria. In staphylococci, however, only one Tmpr DHFR (type S1 DHFR) has been found so far, and this is located on transposon Tn4003. To help understand the mechanism of resistance, we are interested in determining the 3-D structure of the recombinant enzyme produced in Escherichia coli. However, the production level of the type S1 DHFR was very low and > 95% of the total recombinant protein accumulated in inclusion bodies. Furthermore, as a result of an internal start of translation, a truncated derivative of the enzyme that copurified with the full-length enzyme was produced. We were able to increase the expression level 20-fold by changing 18 N-terminal codons and to eliminate the internal start of translation. In addition, through molecular modelling and subsequent site-directed mutagenesis to replace two amino acids, we constructed a biochemically similar but soluble derivative of the type S1 DHFR that, after production in E.coli, resulted in a 264-fold increase in DHFR activity. The highly overproduced enzyme was purified to homogeneity, characterized biochemically and crystallized.},
  chemicals       = {Bacterial Proteins, Folic Acid Antagonists, Recombinant Fusion Proteins, Trimethoprim, Tetrahydrofolate Dehydrogenase},
  citation-subset = {IM},
  completed       = {1994-12-29},
  country         = {England},
  issn-linking    = {0269-2139},
  keywords        = {Bacterial Proteins, chemistry; Base Sequence; Crystallization; Escherichia coli, metabolism; Folic Acid Antagonists; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Protein Conformation; Protein Engineering; Recombinant Fusion Proteins, chemistry; Solubility; Staphylococcus aureus, enzymology; Tetrahydrofolate Dehydrogenase, chemistry; Trimethoprim, pharmacology; Trimethoprim Resistance},
  nlm-id          = {8801484},
  owner           = {NLM},
  pmid            = {7971955},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{chen2013,
  author          = {Chen, Xiaoying and Zaro, Jennica L and Shen, Wei-Chiang},
  title           = {Fusion protein linkers: property, design and functionality.},
  journal         = {Advanced drug delivery reviews},
  year            = {2013},
  volume          = {65},
  issue           = {10},
  month           = oct,
  pages           = {1357--1369},
  issn            = {1872-8294},
  doi             = {10.1016/j.addr.2012.09.039},
  abstract        = {As an indispensable component of recombinant fusion proteins, linkers have shown increasing importance in the construction of stable, bioactive fusion proteins. This review covers the current knowledge of fusion protein linkers and summarizes examples for their design and application. The general properties of linkers derived from naturally-occurring multi-domain proteins can be considered as the foundation in linker design. Empirical linkers designed by researchers are generally classified into 3 categories according to their structures: flexible linkers, rigid linkers, and in vivo cleavable linkers. Besides the basic role in linking the functional domains together (as in flexible and rigid linkers) or releasing the free functional domain in vivo (as in in vivo cleavable linkers), linkers may offer many other advantages for the production of fusion proteins, such as improving biological activity, increasing expression yield, and achieving desirable pharmacokinetic profiles. },
  chemicals       = {Peptides, Recombinant Fusion Proteins},
  citation-subset = {IM},
  completed       = {2014-05-13},
  country         = {Netherlands},
  issn-linking    = {0169-409X},
  keywords        = {Animals; Drug Delivery Systems; Humans; Peptides, chemistry; Protein Structure, Tertiary; Recombinant Fusion Proteins, administration & dosage, chemistry, metabolism; Bifunctional recombinant proteins; EBFP; EGFP; FIX; FRET; G-CSF; HSA; IFN; LAP; MMP; PD; PDB; PK; Pharmacodynamics; Pharmacokinetics; Protein Data Bank; Spacer; TGN; Tf; V(H); V(L); aa; amino acid; antibody heavy chain variable region; antibody light-chain variable regions; coagulation factor IX; enhanced blue fluorescent protein; enhanced green fluorescent protein; fluorescent resonance energy transfer; granulocyte colony-stimulating factor; hGH; human growth hormone; human serum albumin; interferon; latency associated peptide; matrix metalloproteinase; pharmacodynamic; pharmacokinetic; scFv; single-chain variable fragment; trans-golgi network; transferrin},
  mid             = {NIHMS411484},
  nlm-id          = {8710523},
  owner           = {NLM},
  pii             = {S0169-409X(12)00300-6},
  pmc             = {PMC3726540},
  pmid            = {23026637},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{latifi2015,
  author       = {Latifi, A. M. and Khajeh, K. and Farnoosh, G. and Hassanpour, K. and Khodi, S.},
  title        = {The Cytoplasmic and Periplasmic Expression Levels and Folding of Organophosphorus Hydrolase Enzyme in Escherichia coli.},
  journal      = {Jundishapur journal of microbiology},
  year         = {2015},
  volume       = {8},
  issue        = {12},
  month        = dec,
  pages        = {e17790},
  issn         = {2008-3645},
  doi          = {10.5812/jjm.17790},
  abstract     = {Organophosphorus hydrolase (OPH) is a type of organophosphate-degrading enzyme which is widely used in the bioremediation process. In this study, the periplasmic and cytoplasmic productions and the activity of recombinant OPH in Escherichia coli were investigated and compared using two pET systems (pET21a and pET26b). The sequence encoding the opd gene was synthesized and expressed in the form of inclusion body using pET21a-opd and in the periplasmic space in pET26b-opd. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed a band of about 37 kDa with a maximum expression level at 30°C from pET21a-opd.However, the obtained results of the periplasmic space extraction of OPH (pET26b-opd) showed a very weak band, while the cytoplasmic expression of OPH (pET21a-opd) produced a strong protein band. The activities studied by the production of PNP were determined by following the increase at 410 nm. The maximum PNP was produced at 30°C with an optical density of 10.62 in the presence of cytoplasmic expression of OPH (pET21a-opd). Consequently, our results suggest cytoplasmic expression system as an appropriate candidate with a high amount of OPH in spite of inclusion body formation, which needs an additional refolding step.},
  completed    = {2016-02-12},
  country      = {Iran},
  issn-linking = {2008-3645},
  keywords     = {Cytoplasmic; Escherichia coli; Organophosphorus; Periplasmic},
  nlm-id       = {101515122},
  owner        = {NLM},
  pmc          = {PMC4746795},
  pmid         = {26870308},
  pubmodel     = {Electronic-eCollection},
  pubstatus    = {epublish},
  revised      = {2018-11-13},
}

@Article{wang2011a,
  author          = {Wang, Y. Y. and Fu, Z. B. and Ng, K. L. and Lam, C. C. and Chan, A. K. N. and Sze, K. F. and Wong, W. K. R.},
  title           = {Enhancement of excretory production of an exoglucanase from Escherichia coli with phage shock protein A (PspA) overexpression.},
  journal         = {Journal of microbiology and biotechnology},
  year            = {2011},
  volume          = {21},
  issue           = {6},
  month           = jun,
  pages           = {637--645},
  issn            = {1738-8872},
  abstract        = {Production of recombinant proteins by excretory expression has many advantages over intracellular expression in Escherichia coli. Hyperexpression of a secretory exoglucanase, Exg, of Cellulomonas fimi was previously shown to saturate the SecYEG pathway and result in dramatic cell death of E. coli. In this study, we demonstrated that overexpression of the PspA in the JM101(pM1VegGcexL-pspA) strain enhanced excretion of Exg to 1.65 U/ml using shake-flask cultivation, which was 80% higher than the highest yield previously obtained from the optimized JM101(pM1VegGcexL) strain. A much higher excreted Exg activity of 4.5 U/ml was further achieved with high cell density cultivation using rich media. Furthermore, we showed that the PspA overexpression strain enjoyed an elevated critical value (CV), which was defined as the largest quotient between the intracellular unprocessed precursor and its secreted mature counterpart that was still tolerable by the host cells prior to the onset of cell death, improving from the previously determined CV of 20/80 to the currently achieved CV of 45/55 for Exg. The results suggested that the PspA overexpression strain might tolerate a higher level of precursor Exg making use of the SecYEG pathway for secretion. The reduced lethal effect might be attributable to the overexpressed PspA, which was postulated to be able to reduce membrane depolarization and damage. Our findings introduce a novel strategy of the combined application of metabolic engineering and construct optimization to the attainment of the best possible E. coli producers for secretory/excretory production of recombinant proteins, using Exg as the model protein.},
  chemicals       = {Bacterial Proteins, Culture Media, Escherichia coli Proteins, Heat-Shock Proteins, Membrane Proteins, Recombinant Proteins, phage shock protein, Bacteria, Glucosidases},
  citation-subset = {IM},
  completed       = {2011-11-14},
  country         = {Korea (South)},
  issn-linking    = {1017-7825},
  keywords        = {Bacterial Proteins, genetics, metabolism; Biotechnology, methods; Cellulomonas, enzymology, genetics; Culture Media; Escherichia coli, enzymology, genetics, metabolism; Escherichia coli Proteins, genetics, metabolism; Gene Expression Regulation, Bacterial; Genetic Engineering, methods; Glucosidases, genetics, metabolism; Heat-Shock Proteins, genetics, metabolism; Membrane Proteins, genetics, metabolism; Recombinant Proteins, biosynthesis, genetics, metabolism; Up-Regulation},
  nlm-id          = {9431852},
  owner           = {NLM},
  pii             = {JMB021-06-12},
  pmid            = {21715971},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2011-06-30},
}

@Article{rosano2014,
  author       = {Rosano, G. L. and Ceccarelli, E. A.},
  title        = "{Recombinant Protein Expression in \textit{Escherichia coli}: advances and challenges.}",
  journal      = {Front. Microbiol.},
  year         = {2014},
  volume       = {5},
  pages        = {172},
  issn         = {1664-302X},
  doi          = {10.3389/fmicb.2014.00172},
  abstract     = {Escherichia coli is one of the organisms of choice for the production of recombinant proteins. Its use as a cell factory is well-established and it has become the most popular expression platform. For this reason, there are many molecular tools and protocols at hand for the high-level production of heterologous proteins, such as a vast catalog of expression plasmids, a great number of engineered strains and many cultivation strategies. We review the different approaches for the synthesis of recombinant proteins in E. coli and discuss recent progress in this ever-growing field. },
  completed    = {2014-06-24},
  country      = {Switzerland},
  issn-linking = {1664-302X},
  keywords     = {E. coli expression strains; Escherichia coli; affinity tags; expression plasmid; inclusion bodies; recombinant protein expression},
  nlm-id       = {101548977},
  owner        = {NLM},
  pmc          = {PMC4029002},
  pmid         = {24860555},
  pubmodel     = {Electronic-eCollection},
  pubstatus    = {epublish},
  revised      = {2018-11-13},
}

@Article{stefan2015,
  author          = {Stefan, Alessandra and Ceccarelli, Alessandro and Conte, Emanuele and Montón Silva, Alejandro and Hochkoeppler, Alejandro},
  title           = {The multifaceted benefits of protein co-expression in Escherichia coli.},
  journal         = {Journal of visualized experiments : JoVE},
  year            = {2015},
  issue           = {96},
  month           = feb,
  issn            = {1940-087X},
  doi             = {10.3791/52431},
  abstract        = {We report here that the expression of protein complexes in vivo in Escherichia coli can be more convenient than traditional reconstitution experiments in vitro. In particular, we show that the poor solubility of Escherichia coli DNA polymerase III ε subunit (featuring 3'-5' exonuclease activity) is highly improved when the same protein is co-expressed with the α and θ subunits (featuring DNA polymerase activity and stabilizing ε, respectively). We also show that protein co-expression in E. coli can be used to efficiently test the competence of subunits from different bacterial species to associate in a functional protein complex. We indeed show that the α subunit of Deinococcus radiodurans DNA polymerase III can be co-expressed in vivo with the ε subunit of E. coli. In addition, we report on the use of protein co-expression to modulate mutation frequency in E. coli. By expressing the wild-type ε subunit under the control of the araBAD promoter (arabinose-inducible), and co-expressing the mutagenic D12A variant of the same protein, under the control of the lac promoter (inducible by isopropyl-thio-β-D-galactopyranoside, IPTG), we were able to alter the E. coli mutation frequency using appropriate concentrations of the inducers arabinose and IPTG. Finally, we discuss recent advances and future challenges of protein co-expression in E. coli. },
  chemicals       = {Escherichia coli Proteins, Protein Subunits, Recombinant Proteins, DNA Polymerase III},
  citation-subset = {IM},
  completed       = {2016-08-10},
  country         = {United States},
  issn-linking    = {1940-087X},
  keywords        = {DNA Polymerase III, biosynthesis, chemistry, genetics; Deinococcus, enzymology, genetics; Escherichia coli, enzymology, genetics; Escherichia coli Proteins, biosynthesis, genetics; Protein Subunits, biosynthesis, chemistry, genetics; Recombinant Proteins, biosynthesis, genetics},
  nlm-id          = {101313252},
  owner           = {NLM},
  pmc             = {PMC4354606},
  pmid            = {25742393},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2018-12-02},
}

@Article{ayyar2017,
  author          = {Ayyar, B Vijayalakshmi and Arora, Sushrut and Ravi, Shiva Shankar},
  title           = {Optimizing antibody expression: The nuts and bolts.},
  journal         = {Methods (San Diego, Calif.)},
  year            = {2017},
  volume          = {116},
  month           = mar,
  pages           = {51--62},
  issn            = {1095-9130},
  doi             = {10.1016/j.ymeth.2017.01.009},
  abstract        = {Antibodies are extensively utilized entities in biomedical research, and in the development of diagnostics and therapeutics. Many of these applications require high amounts of antibodies. However, meeting this ever-increasing demand of antibodies in the global market is one of the outstanding challenges. The need to maintain a balance between demand and supply of antibodies has led the researchers to discover better means and methods for optimizing their expression. These strategies aim to increase the volumetric productivity of the antibodies along with the reduction of associated manufacturing costs. Recent years have witnessed major advances in recombinant protein technology, owing to the introduction of novel cloning strategies, gene manipulation techniques, and an array of cell and vector engineering techniques, together with the progress in fermentation technologies. These innovations were also highly beneficial for antibody expression. Antibody expression depends upon the complex interplay of multiple factors that may require fine tuning at diverse levels to achieve maximum yields. However, each antibody is unique and requires individual consideration and customization for optimizing the associated expression parameters. This review provides a comprehensive overview of several state-of-the-art approaches, such as host selection, strain engineering, codon optimization, gene optimization, vector modification and process optimization that are deemed suitable for enhancing antibody expression.},
  chemicals       = {Antibodies, Codon, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2018-02-09},
  country         = {United States},
  issn-linking    = {1046-2023},
  keywords        = {Animals; Antibodies, genetics, isolation & purification; CHO Cells; Codon, chemistry, metabolism; Cricetulus; Escherichia coli, genetics; Gene Expression; Genetic Engineering, methods; Genetic Vectors, chemistry, metabolism; HEK293 Cells; Humans; Pichia, genetics; Plants, Genetically Modified, genetics; Recombinant Proteins, biosynthesis, genetics, isolation & purification; Spodoptera; Antibody expression; Codon optimization; Expression hosts; Gene optimization; Process optimization; Vector modification},
  nlm-id          = {9426302},
  owner           = {NLM},
  pii             = {S1046-2023(17)30034-8},
  pmid            = {28163103},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-05-22},
}

@Article{swartz2001,
  author          = {Swartz, J R},
  title           = {Advances in Escherichia coli production of therapeutic proteins.},
  journal         = {Current opinion in biotechnology},
  year            = {2001},
  volume          = {12},
  issue           = {2},
  month           = apr,
  pages           = {195--201},
  issn            = {0958-1669},
  abstract        = {Escherichia coli offers a means for the rapid and economical production of recombinant proteins. These advantages, coupled with a wealth of biochemical and genetic knowledge, have enabled the production of such economically sensitive products as insulin and bovine growth hormone. Although significant progress has been made in transcription, translation and secretion, one of the major challenges is obtaining the product in a soluble and bioactive form. Recent progress in oxidative cytoplasmic folding and cell-free protein synthesis offers attractive alternatives to standard expression methods.},
  chemicals       = {Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2001-05-24},
  country         = {England},
  issn-linking    = {0958-1669},
  keywords        = {Cell-Free System; Cytoplasm, chemistry; Escherichia coli, genetics, metabolism; Gene Expression Regulation, Bacterial; Genetic Vectors, genetics; Periplasm, chemistry; Promoter Regions, Genetic, genetics; Protein Biosynthesis; Protein Folding; RNA Stability; Recombinant Proteins, biosynthesis, therapeutic use},
  nlm-id          = {9100492},
  owner           = {NLM},
  pii             = {S0958-1669(00)00199-3},
  pmid            = {11287237},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {56},
  revised         = {2008-11-21},
}

@Article{georgiou2005,
  author          = {Georgiou, George and Segatori, Laura},
  title           = {Preparative expression of secreted proteins in bacteria: status report and future prospects.},
  journal         = {Current opinion in biotechnology},
  year            = {2005},
  volume          = {16},
  issue           = {5},
  month           = oct,
  pages           = {538--545},
  issn            = {0958-1669},
  doi             = {10.1016/j.copbio.2005.07.008},
  abstract        = {The expression of heterologous secreted proteins in Escherichia coli is widely employed for laboratory and preparative purposes. Thanks to advances in expression technologies over the past 25 years, many mammalian proteins can now be produced routinely in secreted form with yields in the gram/litre scale. Nonetheless, ensuring efficient secretion across the inner membrane, and preventing proteolytic degradation, incorrect disulfide-bond formation and aggregation into periplasmic inclusion bodies, frequently presents significant challenges. Recent advances in the understanding of the periplasmic folding quality control system are leading to new strategies to facilitate the expression of heterologous secreted proteins. In parallel, protein design and directed evolution approaches are beginning to be exploited for engineering of the cellular protein folding machinery to achieve further improvements in protein expression.},
  chemicals       = {Bacterial Proteins, Escherichia coli Proteins, Membrane Transport Proteins, Molecular Chaperones, Recombinant Proteins, SEC Translocation Channels, Signal Recognition Particle, twin-arginine translocase complex, E coli, SecA protein, Bacteria, Peptide Hydrolases, Adenosine Triphosphatases},
  citation-subset = {IM},
  completed       = {2005-12-16},
  country         = {England},
  issn-linking    = {0958-1669},
  keywords        = {Adenosine Triphosphatases, metabolism; Bacterial Proteins, metabolism; Biotechnology, methods, trends; Directed Molecular Evolution; Escherichia coli, genetics, metabolism; Escherichia coli Proteins, metabolism; Membrane Transport Proteins, metabolism; Molecular Chaperones, genetics, metabolism; Peptide Hydrolases, metabolism; Protein Processing, Post-Translational; Recombinant Proteins, biosynthesis, metabolism; SEC Translocation Channels; Signal Recognition Particle, metabolism},
  nlm-id          = {9100492},
  owner           = {NLM},
  pii             = {S0958-1669(05)00124-2},
  pmid            = {16095898},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {57},
  revised         = {2018-12-01},
}

@Article{friehs1993,
  author          = {Friehs, K and Reardon, K F},
  title           = {Parameters influencing the productivity of recombinant E. coli cultivations.},
  journal         = {Advances in biochemical engineering/biotechnology},
  year            = {1993},
  volume          = {48},
  pages           = {53--77},
  issn            = {0724-6145},
  abstract        = {In the past 10 to 15 years, many of the promises of microbial genetic engineering have been realized: the use of recombinant Escherichia coli has moved from the laboratory to the production facility, and the manufacture of therapeutic recombinant proteins such as human growth hormone and interleukins is a rapidly growing industry. Along with this progress, however, have come new problems to solve: bioreactor operators have discovered that large-scale cultivations of plasmid-containing bacteria do not behave in exactly the same way as those of plasmid-free cells, plasmid stability has been recognized as a major hurdle, and the protein product might not be present in a soluble form but rather as intracellular granules that resist solubilization. These and other difficulties represent a new generation of challenges for genetic engineering. However, genetic engineering can do more than solve these problems. Molecular biological techniques also have the ability to create new opportunities: to produce new compounds, to use cheaper substrates, to facilitate downstream processing, and to optimize production in new ways. The productivity of a cultivation can generally be expressed as the product of the cell density and the specific biological activity. Both of these parameters are influenced by a variety of factors. For recombinant cultivations, though, the level of biological activity, a reflection of the plasmid copy number and expression efficiency, is the more interesting and important consideration and will therefore be given more attention in our review. In this contribution, our general goal is to discuss the factors that influence the productivity of recombinant E. coli cultivations, covering parameters relating to DNA; parameters relating to protein synthesis; parameters relating to proteins; and parameters relating to downstream processing. The object is not to tell the reader how to choose the perfect plasmid, host, and cultivation conditions, but to make known the many variables involved in designing a recombinant process and to point out recent and potential advances made possible by genetic engineering. The discussion focuses on the production of a protein, but many of the same concepts apply to other cultivations of recombinant E. coli, including cases in which the desired product is not a protein or the cells have been designed for a special metabolic capability such as pollutant biodegradation.},
  chemicals       = {Bacterial Proteins, DNA, Bacterial},
  citation-subset = {IM},
  completed       = {1993-04-23},
  country         = {Germany},
  issn-linking    = {0724-6145},
  keywords        = {Bacterial Proteins, metabolism; Biotechnology; Chemical Engineering; DNA, Bacterial, genetics; Escherichia coli, genetics, metabolism; Plasmids; Recombination, Genetic},
  nlm-id          = {8307733},
  owner           = {NLM},
  pmid            = {8460577},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {164},
  revised         = {2006-05-01},
}

@Article{kim2018,
  author       = {Kim, Young-Seok and Son, Ahyun and Kim, Jihoon and Kwon, Soon Bin and Kim, Myung Hee and Kim, Paul and Kim, Jieun and Byun, Young Ho and Sung, Jemin and Lee, Jinhee and Yu, Ji Eun and Park, Chan and Kim, Yeon-Sook and Cho, Nam-Hyuk and Chang, Jun and Seong, Baik L},
  title        = {Chaperna-Mediated Assembly of Ferritin-Based Middle East Respiratory Syndrome-Coronavirus Nanoparticles.},
  journal      = {Frontiers in immunology},
  year         = {2018},
  volume       = {9},
  pages        = {1093},
  issn         = {1664-3224},
  doi          = {10.3389/fimmu.2018.01093},
  abstract     = {The folding of monomeric antigens and their subsequent assembly into higher ordered structures are crucial for robust and effective production of nanoparticle (NP) vaccines in a timely and reproducible manner. Despite significant advances in   design and structure-based assembly, most engineered NPs are refractory to soluble expression and fail to assemble as designed, presenting major challenges in the manufacturing process. The failure is due to a lack of understanding of the kinetic pathways and enabling technical platforms to ensure successful folding of the monomer antigens into regular assemblages. Capitalizing on a novel function of RNA as a molecular chaperone (chaperna: chaperone + RNA), we provide a robust protein-folding vehicle that may be implemented to NP assembly in bacterial hosts. The receptor-binding domain (RBD) of Middle East respiratory syndrome-coronavirus (MERS-CoV) was fused with the RNA-interaction domain (RID) and bacterioferritin, and expressed in   in a soluble form. Site-specific proteolytic removal of the RID prompted the assemblage of monomers into NPs, which was confirmed by electron microscopy and dynamic light scattering. The mutations that affected the RNA binding to RBD significantly increased the soluble aggregation into amorphous structures, reducing the overall yield of NPs of a defined size. This underscored the RNA-antigen interactions during NP assembly. The sera after mouse immunization effectively interfered with the binding of MERS-CoV RBD to the cellular receptor hDPP4. The results suggest that RNA-binding controls the overall kinetic network of the antigen folding pathway in favor of enhanced assemblage of NPs into highly regular and immunologically relevant conformations. The concentration of the ion Fe , salt, and fusion linker also contributed to the assembly  , and the stability of the NPs. The kinetic "pace-keeping" role of chaperna in the super molecular assembly of antigen monomers holds promise for the development and delivery of NPs and virus-like particles as recombinant vaccines and for serological detection of viral infections.},
  country      = {Switzerland},
  issn-linking = {1664-3224},
  keywords     = {Lysyl-tRNA synthetase; Middle East respiratory syndrome coronavirus; RNA-interacting domain of human LysRS; chaperone; ferritin; nanoparticle; receptor-binding domain; virus-like particle},
  nlm-id       = {101560960},
  owner        = {NLM},
  pmc          = {PMC5966535},
  pmid         = {29868035},
  pubmodel     = {Electronic-eCollection},
  pubstatus    = {epublish},
  revised      = {2018-11-14},
}

@Article{nolden2007,
  author          = {Nolden, Lars and Edenhofer, Frank and Peitz, Michael and Brüstle, Oliver},
  title           = {Stem cell engineering using transducible Cre recombinase.},
  journal         = {Methods in molecular medicine},
  year            = {2007},
  volume          = {140},
  pages           = {17--32},
  issn            = {1543-1894},
  abstract        = {Embryonic stem (ES) cells have become a major focus of scientific interest both as a potential donor source for regenerative medicine and as a model system for tissue development and pathobiology. Tight and efficient methods for genetic engineering are required to exploit ES cells as disease models and to generate specific somatic phenotypes by lineage selection or instruction. In 1990s, the application of site-specific recombinases (SSRs) such as Cre has revolutionized mammalian genetics by providing a reliable and efficient means to delete, insert, invert, or exchange chromosomal DNA in a conditional manner. Despite these significant advances, the available technology still suffers from limitations, including unwanted side effects elicited by the random integration of Cre expression vectors and leak activity of inducible or presumptive cell type-specific Cre expression systems. These challenges can be met by combining the Cre/loxP recombination system with direct intracellular delivery of Cre by protein transduction, thus enabling rapid and highly efficient conditional mutagenesis in ES cells and ES cell-derived somatic progeny. Modified recombinant variants of Cre protein induce recombination in virtually 100% of human ES (hES) and mouse ES (mES) cells. Here, we present methods for generating purified transducible Cre protein from Escherichia coli and its transduction into ES cells and their neural progeny.},
  chemicals       = {Cre recombinase, Integrases},
  citation-subset = {IM},
  completed       = {2008-01-28},
  country         = {United States},
  issn-linking    = {1543-1894},
  keywords        = {Animals; Gene Transfer Techniques; Humans; Integrases, genetics, metabolism; Mice; Neurons, cytology, physiology; Stem Cells, cytology, physiology; Tissue Engineering, methods; Transduction, Genetic},
  nlm-id          = {101123138},
  owner           = {NLM},
  pmid            = {18085201},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2007-12-18},
}

@Article{cresswell2011,
  author          = {Cresswell, J. E.},
  title           = {A meta-analysis of experiments testing the effects of a neonicotinoid insecticide (imidacloprid) on honey bees.},
  journal         = {Ecotoxicol.},
  year            = {2011},
  volume          = {20},
  issue           = {1},
  month           = jan,
  pages           = {149--157},
  issn            = {1573-3017},
  doi             = {10.1007/s10646-010-0566-0},
  abstract        = {Honey bees provide important pollination services to crops and wild plants. The agricultural use of systemic insecticides, such as neonicotinoids, may harm bees through their presence in pollen and nectar, which bees consume. Many studies have tested the effects on honey bees of imidacloprid, a neonicotinoid, but a clear picture of the risk it poses to bees has not previously emerged, because investigations are methodologically varied and inconsistent in outcome. In a meta-analysis of fourteen published studies of the effects of imidacloprid on honey bees under laboratory and semi-field conditions that comprised measurements on 7073 adult individuals and 36 colonies, fitted dose-response relationships estimate that trace dietary imidacloprid at field-realistic levels in nectar will have no lethal effects, but will reduce expected performance in honey bees by between 6 and 20%. Statistical power analysis showed that published field trials that have reported no effects on honey bees from neonicotinoids were incapable of detecting these predicted sublethal effects with conventionally accepted levels of certainty. These findings raise renewed concern about the impact on honey bees of dietary imidacloprid, but because questions remain over the environmental relevance of predominantly laboratory-based results, I identify targets for research and provide procedural recommendations for future studies.},
  chemicals       = {Imidazoles, Insecticides, Neonicotinoids, Nitro Compounds, imidacloprid},
  citation-subset = {IM},
  completed       = {2011-05-02},
  country         = {United States},
  issn-linking    = {0963-9292},
  keywords        = {Animals; Bees, drug effects; Environmental Exposure; Imidazoles, toxicity; Insecticides, toxicity; Neonicotinoids; Nitro Compounds, toxicity; Toxicity Tests},
  nlm-id          = {9885956},
  owner           = {NLM},
  pmid            = {21080222},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{godfray2015,
  author          = {Godfray, H. H. J. and Blacquière, T. and Field, L. M. and Hails, R. S. and Potts, S. G. and Raine, N. E. and Vanbergen, A. J. and McLean, A. R.},
  title           = {A restatement of recent advances in the natural science evidence base concerning neonicotinoid insecticides and insect pollinators.},
  journal         = {Proceedings. Biological sciences},
  year            = {2015},
  volume          = {282},
  issue           = {1818},
  month           = nov,
  pages           = {20151821},
  issn            = {1471-2954},
  doi             = {10.1098/rspb.2015.1821},
  abstract        = {A summary is provided of recent advances in the natural science evidence base concerning the effects of neonicotinoid insecticides on insect pollinators in a format (a 'restatement') intended to be accessible to informed but not expert policymakers and stakeholders. Important new studies have been published since our recent review of this field (Godfray et al. 2014 Proc. R. Soc. B 281, 20140558. (doi:10.1098/rspb.2014.0558)) and the subject continues to be an area of very active research and high policy relevance. },
  chemicals       = {Insecticides},
  citation-subset = {IM},
  completed       = {2016-08-11},
  country         = {England},
  issn-linking    = {0962-8452},
  keywords        = {Animals; Bees, drug effects; European Union; Insecta, drug effects; Insecticides, toxicity; Pollination; bumblebee; evidence for policy; honeybee; neonicotinoid; pest management; pollinator},
  nlm-id          = {101245157},
  owner           = {NLM},
  pii             = {20151821},
  pmc             = {PMC4650156},
  pmid            = {26511042},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{spurgeon2016,
  author  = {Spurgeon, D. and Kesketh, H. and LAhive, E. and Svendsen, C. and Baas, J and Robindon, A. and Horton, A. and Heard, M.},
  title   = {Chronic oral lethal and sub‐lethal toxicities of different binary mixtures of pesticides and contaminants in bees (Apis mellifera, Osmia bicornis and Bombus terrestris)},
  journal = {EFSA supporting publication},
  year    = {2016},
  date    = {2016},
  volume  = {EN1076},
}

@Article{byrne2006,
  author    = {Byrne, F. J and Toscano, N. C.},
  title     = {Uptake and persistence of imidacloprid in grapevines treated by chemigation},
  journal   = {Crop Prot.},
  year      = {2006},
  volume    = {25},
  number    = {8},
  pages     = {831--834},
  publisher = {Elsevier},
}

@Article{castle2005,
  author          = {Castle, S. J. and Byrne, F. J. and Bi, J. L. and Toscano, N. C.},
  title           = {Spatial and temporal distribution of imidacloprid and thiamethoxam in citrus and impact on Homalodisca coagulata populations.},
  journal         = {Pest Manag Sci},
  year            = {2005},
  volume          = {61},
  issue           = {1},
  month           = jan,
  pages           = {75--84},
  issn            = {1526-498X},
  doi             = {10.1002/ps.949},
  abstract        = {Titers of two systemic neonicotinoid insecticides in citrus trees were measured in conjunction with conventional evaluations of their impact on glassy-winged sharpshooter (Homalodisca coagulata (Say); GWSS) populations. Xylem fluid samples were collected at regular intervals and from multiple locations within field-grown citrus trees to determine imidacloprid and thiamethoxam concentrations using commercial ELISA kits. Uptake profiles varied considerably with peak mean titers of imidacloprid occurring 6-8 weeks after application compared with 2 weeks for thiamethoxam. The persistence of each compound also varied as near-peak levels of imidacloprid were sustained for another 6-10 weeks before gradually declining. In contrast, thiamethoxam titers declined more rapidly after the initial peak, possibly reflecting an application rate only one-quarter of that used for imidacloprid. Within-tree distributions were more similar for the two compounds, with no significant effect due to height of the sample (upper or lower half) or to the quadrant location within the tree, with the exception of one quadrant in the thiamethoxam-treated trees. Substantial reductions in GWSS nymphs and adults were observed in imidacloprid-treated trees during the 2001 trial and were sustained for 4-5 months after treatment. Treatment effects on nymphs were not as well pronounced in the 2002 trial, when overall GWSS infestations were much reduced from the previous year. However, consistently lower adult infestations were still observed in 2002 for both treatments compared with untreated trees. Information on the spatial and temporal profiles in citrus trees was obtained for both compounds to complement field impact data and improve understanding of their pest management potential.},
  chemicals       = {Imidazoles, Insecticides, Neonicotinoids, Nitro Compounds, Oxazines, Thiazoles, imidacloprid, Thiamethoxam},
  citation-subset = {IM},
  completed       = {2005-04-05},
  country         = {England},
  issn-linking    = {1526-498X},
  keywords        = {Animals; Citrus, metabolism; Hemiptera; Imidazoles, metabolism; Insect Control, methods; Insecticides, metabolism; Neonicotinoids; Nitro Compounds, metabolism; Oxazines, metabolism; Plant Diseases, parasitology; Thiamethoxam; Thiazoles; Time Factors},
  nlm-id          = {100898744},
  owner           = {NLM},
  pmid            = {15593076},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-12-01},
}

@Article{luo1999,
  author    = {Luo, Y. and Zang, Y. and Zhong, Y. and Kong, Z.},
  title     = "{Toxicological Study of Two Novel Pesticides on Earthworm \textit{Eisenia foetida}}",
  journal   = {Chemosphere},
  year      = {1999},
  volume    = {39},
  number    = {13},
  pages     = {2347--2356},
  publisher = {Elsevier},
}

@Article{richmond1999a,
  author    = {Richmond, J. E. and Davis, W. S. and Jorgensen, E. M.},
  title     = {UNC-13 is required for synaptic vesicle fusion in C. elegans},
  journal   = {Nat. Neurosci.e},
  year      = {1999},
  volume    = {2},
  number    = {11},
  pages     = {959},
  publisher = {Nature Publishing Group},
}

@Article{aravamudan1999,
  author    = {Aravamudan, B. and Fergestad, T. and Davis, W. S. and Rodesch, C. K. and Broadie, K.},
  title     = {\texit{Drosophila} UNC-13 is essential for synaptic transmission},
  journal   = {Nat. Neurosci.e},
  year      = {1999},
  volume    = {2},
  number    = {11},
  pages     = {965},
  publisher = {Nature Publishing Group},
}

@Article{richmond2001,
  author    = {Richmond, J. E. and Weimer, R. M. and Jorgensen, E. M.},
  title     = {An open form of syntaxin bypasses the requirement for U{NC}-13 in vesicle priming},
  journal   = {Nature},
  year      = {2001},
  volume    = {412},
  number    = {6844},
  pages     = {338},
  publisher = {Nature Publishing Group},
}

@Article{chase2007,
  author    = {Chase, D. L. and Koelle, M. R.},
  title     = "{Biogenic Amine Neurotransmitters in \textit{C. elegans} in \textit{C. elegans} (February 20, 2007), WormBook, ed. The \textit{C. elegans} Research Community, WormBook}",
  year      = {2007},
  url       = {http://www.wormbook.org},
  doi       = {doi/10.1895/wormbook.1.132.1},
}

@Article{lee1999,
  author    = {Lee, R. Y. N. and Sawin, E. R. and Chalfie, M. and Horvitz, H. R. and Avery, L.},
  title     = "{EAT-4, a Homolog of a Mammalian Sodium-Dependent Inorganic Phosphate Cotransporter, is Necessary for Glutamatergic Neurotransmission in \textit{Caenorhabditis elegans}}",
  journal   = {J. Neurosci.},
  year      = {1999},
  volume    = {19},
  number    = {1},
  pages     = {159--167},
  publisher = {Soc Neuroscience},
}

@Article{lee2008,
  author  = {Lee, D. and Jung, S. and Ryu, J. and Ahnn, J. and Ha, I.},
  title   = {Human vesicular glutamate transporters functionally complement EAT-4 in C. elegans.},
  journal = {Mol Cells.},
  date    = {2008},
  volume  = {25},
  number  = {1},
  pages   = {50-4},
}

@Article{dillon2015,
  author  = {Dillon, J. and Franks, C. J. and Murray, C. and Edwards, R. J. and Calahorro, F. and Ishihara, T. and Katsura, I. and Holden-Dye, L. and O’Connor, V.},
  title   = {Metabotropic glutamate receptors: Modulators of context-dependent feeding behaviour in C. elegans.},
  journal = {J. Biol. Chem.},
  year    = {2015},
  volume  = {24},
  number  = {15},
  pages   = {15052-15065},
}

@Article{calahorro2018,
  author       = {Calahorro, F. and Keefe, F. and Dillon, J. and Holden-Dye, L. and O'Connor, V.},
  title        = {Neuroligin tuning of pharyngeal pumping reveals an extrapharyngeal modulation of the feeding.},
  journal      = {The J Exp Biol},
  year         = {2018},
  month        = dec,
  issn         = {1477-9145},
  doi          = {10.1242/jeb.189423},
  abstract     = {The integration of distinct sensory modalities is essential for behavioural decision making. In   this process is coordinated by neural circuits that integrate sensory cues from the environment to generate an appropriate behaviour at the appropriate output muscles. Food is a multimodal cue that impacts on the microcircuits to modulating feeding and foraging drivers at the level of the pharyngeal and body wall muscle respectively. When food triggers an upregulation in pharyngeal pumping it allows the effective ingestion of food. Here we show that a   mutant in the single orthologous gene of human neuroligins,  , is defective in food induced pumping. This is not explained by an inability to sense food, as   mutants are not defective in chemotaxis towards bacteria. In addition, we show that neuroligin is widely expressed in the nervous system including AIY, ADE, ALA, URX and HSN neurones. Interestingly, despite the deficit in pharyngeal pumping neuroligin is not expressed within the pharyngeal neuromuscular network, which suggests an extrapharyngeal regulation of this circuit. We resolve electrophysiologically the neuroligin contribution to the pharyngeal circuit by mimicking a food-dependent pumping, and show that the   phenotype is similar to mutants impaired in GABAergic and/or glutamatergic signalling. We suggest that neuroligin organizes extrapharyngeal circuits that regulate the pharynx. These observations based on the molecular and cellular determinants of feeding are consistent with the emerging role of neuroligin in discretely impacting functional circuits underpinning complex behaviours.},
  country      = {England},
  issn-linking = {0022-0949},
  keywords     = {EPG; Electropharyngeogram; Sensory cues; Sensory modulation; nlg-1},
  nlm-id       = {0243705},
  owner        = {NLM},
  pii          = {jeb.189423},
  pmid         = {30559302},
  pubmodel     = {Print-Electronic},
  pubstatus    = {aheadofprint},
  revised      = {2018-12-18},
}

@Article{you2006,
  author          = {You, Y. and Kim, J. and Cobb, M. and Avery, L.},
  title           = "{Starvation Activates MAP Kinase Through the Muscarinic Acetylcholine Pathway in \textit{Caenorhabditis elegans} pharynx.}",
  journal         = {Cell Metab.},
  year            = {2006},
  volume          = {3},
  issue           = {4},
  month           = apr,
  pages           = {237--245},
  issn            = {1550-4131},
  doi             = {10.1016/j.cmet.2006.02.012},
  abstract        = {Starvation activates MAPK in the pharyngeal muscles of C. elegans through a muscarinic acetylcholine receptor, Gqalpha, and nPKC as shown by the following results: (1) Starvation causes phosphorylation of MAPK in pharyngeal muscle. (2) In a sensitized genetic background in which Gqalpha signaling cannot be downregulated, activation of the pathway by a muscarinic agonist causes lethal changes in pharyngeal muscle function. Starvation has identical effects. (3) A muscarinic antagonist blocks the effects of starvation on sensitized muscle. (4) Mutations and drugs that block any step of signaling from the muscarinic receptor to MAPK also block the effects of starvation on sensitized muscle. (5) Overexpression of MAPK in wild-type pharyngeal muscle mimics the effects of muscarinic agonist and of starvation on sensitized muscle. We suggest that, during starvation, the muscarinic pathway to MAPK is activated to change the pharyngeal muscle physiology to enhance ingestion of food when food becomes available.},
  chemicals       = {Caenorhabditis elegans Proteins, Cholinergic Agonists, GPB-2 protein, C elegans, GTP-Binding Protein beta Subunits, Muscarinic Agonists, Muscarinic Antagonists, Receptors, Muscarinic, Arecoline, Protein Kinase C, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Acetylcholine},
  citation-subset = {IM},
  completed       = {2006-09-21},
  country         = {United States},
  issn-linking    = {1550-4131},
  keywords        = {Acetylcholine, physiology; Animals; Arecoline, pharmacology; Caenorhabditis elegans, genetics, physiology; Caenorhabditis elegans Proteins, drug effects, genetics, physiology; Cholinergic Agonists, pharmacology; Enzyme Activation, drug effects, physiology; Feeding Behavior; GTP-Binding Protein beta Subunits, genetics, physiology; Gene Expression Regulation, Enzymologic; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1, physiology; Mitogen-Activated Protein Kinases, metabolism; Muscarinic Agonists, pharmacology; Muscarinic Antagonists, pharmacology; Mutation; Pharynx, drug effects, enzymology; Phenotype; Protein Kinase C, physiology; Receptors, Muscarinic, drug effects, physiology; Starvation},
  mid             = {NIHMS355255},
  nlm-id          = {101233170},
  owner           = {NLM},
  pii             = {S1550-4131(06)00093-3},
  pmc             = {PMC3433278},
  pmid            = {16581001},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{maupas1900,
  author  = {Maupas, E.},
  title   = {Modes et formes de reproduction des nematodes.},
  journal = {Archives de Zoologie Experimentale et Generale},
  year    = {1900},
  volume  = {8},
  pages   = {463-624},
}

@Article{stiernagle1999,
  author    = {Stiernagle, T.},
  title     = {Maintenance of C. elegans},
  journal   = {C. elegans},
  year      = {1999},
  volume    = {2},
  pages     = {51--67},
  publisher = {Oxford University Press, Oxford, UK},
}

@Article{mello1991,
  author    = {Mello, C. C. and Kramer, J. M. and Stinchcomb, D. and Ambros, V.},
  title     = {Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences.},
  journal   = {The EMBO journal},
  year      = {1991},
  volume    = {10},
  number    = {12},
  pages     = {3959--3970},
  publisher = {Wiley Online Library},
}

@Article{cuenca2003,
  author    = {Cuenca, Adrian A and Schetter, Aaron and Aceto, Donato and Kemphues, Kenneth and Seydoux, Geraldine},
  title     = {Polarization of the C. elegans zygote proceeds via distinct establishment and maintenance phases},
  journal   = {Development},
  year      = {2003},
  volume    = {130},
  number    = {7},
  pages     = {1255--1265},
  publisher = {The Company of Biologists Ltd},
}

@Article{berry2003,
  author    = {Berry, Katherine L and B{\"u}low, Hannes E and Hall, David H and Hobert, Oliver},
  title     = {A C. elegans CLIC-like protein required for intracellular tube formation and maintenance},
  journal   = {science},
  year      = {2003},
  volume    = {302},
  number    = {5653},
  pages     = {2134--2137},
  publisher = {American Association for the Advancement of Science},
}

@Article{anderson2010,
  author    = {Anderson, Jennifer L and Morran, Levi T and Phillips, Patrick C},
  title     = {Outcrossing and the maintenance of males within C. elegans populations},
  journal   = {Journal of heredity},
  year      = {2010},
  volume    = {101},
  number    = {suppl\_1},
  pages     = {S62--S74},
  publisher = {Oxford University Press},
}

@Article{watts2006,
  author    = {Watts, Jennifer L and Browse, John},
  title     = {Dietary manipulation implicates lipid signaling in the regulation of germ cell maintenance in C. elegans},
  journal   = {Dev. Biol.},
  year      = {2006},
  volume    = {292},
  number    = {2},
  pages     = {381--392},
  publisher = {Elsevier},
}

@Article{buelow2004,
  author    = {B{\"u}low, Hannes E and Boulin, Thomas and Hobert, Oliver},
  title     = {Differential functions of the C. elegans FGF receptor in axon outgrowth and maintenance of axon position},
  journal   = {Neuron},
  year      = {2004},
  volume    = {42},
  number    = {3},
  pages     = {367--374},
  publisher = {Elsevier},
}

@Article{kelly1998,
  author    = {Kelly, William G and Fire, Andrew},
  title     = {Chromatin silencing and the maintenance of a functional germline in Caenorhabditis elegans},
  journal   = {Development},
  year      = {1998},
  volume    = {125},
  number    = {13},
  pages     = {2451--2456},
  publisher = {The Company of Biologists Ltd},
}

@Article{aceto2006,
  author    = {Aceto, Donato and Beers, Melissa and Kemphues, Kenneth J},
  title     = {Interaction of PAR-6 with CDC-42 is required for maintenance but not establishment of PAR asymmetry in C. elegans},
  journal   = {Dev. Biol.},
  year      = {2006},
  volume    = {299},
  number    = {2},
  pages     = {386--397},
  publisher = {Elsevier},
}

@Article{stewart2002,
  author    = {Stewart, Andrew D and Phillips, Patrick C},
  title     = {Selection and maintenance of androdioecy in Caenorhabditis elegans.},
  journal   = {Genetics},
  year      = {2002},
  volume    = {160},
  number    = {3},
  pages     = {975},
  publisher = {Genetics Society of America},
}

@Article{michaelson2000,
  author    = {Michaelson, Louise},
  title     = {C. elegans: A Practical Approach. Ian A. Hope (ed.). Oxford University Press, Oxford. 1999. Pp. 281. Price{\pounds} 29.95, paperback. ISBN 0 19 963738 5.},
  journal   = {Heredity},
  year      = {2000},
  volume    = {85},
  number    = {1},
  pages     = {99--99},
  publisher = {Wiley Online Library},
}

@Article{gracida2013,
  author    = {Gracida, Xicotencatl and Eckmann, Christian R},
  title     = {Fertility and germline stem cell maintenance under different diets requires nhr-114/HNF4 in C. elegans},
  journal   = {Curr. Biol.},
  year      = {2013},
  volume    = {23},
  number    = {7},
  pages     = {607--613},
  publisher = {Elsevier},
}

@Article{etemad-moghadam1995,
  author    = {Etemad-Moghadam, Bijan and Guo, Su and Kemphues, Kenneth J},
  title     = {Asymmetrically distributed PAR-3 protein contributes to cell polarity and spindle alignment in early C. elegans embryos},
  journal   = {Cell},
  year      = {1995},
  volume    = {83},
  number    = {5},
  pages     = {743--752},
  publisher = {Elsevier},
}

@Article{wiegant2009,
  author    = {Wiegant, FAC and Surinova, Silvia and Ytsma, E and Langelaar-Makkinje, M and Wikman, G and Post, JA},
  title     = {Plant adaptogens increase lifespan and stress resistance in C. elegans},
  journal   = {Biogerontology},
  year      = {2009},
  volume    = {10},
  number    = {1},
  pages     = {27--42},
  publisher = {Springer},
}

@Article{kemphues1988,
  author    = {Kemphues, Kenneth J and Priess, James R and Morton, Diane G and Cheng, Niansheng},
  title     = {Identification of genes required for cytoplasmic localization in early C. elegans embryos},
  journal   = {Cell},
  year      = {1988},
  volume    = {52},
  number    = {3},
  pages     = {311--320},
  publisher = {Elsevier},
}

@Article{london2008,
  author    = {London, Timothy BC and Barber, Louise J and Mosedale, Georgina and Kelly, Gavin P and Balasubramanian, Shankar and Hickson, Ian D and Boulton, Simon J and Hiom, Kevin},
  title     = {FANCJ is a structure-specific DNA helicase associated with the maintenance of genomic G/C tracts},
  journal   = {J. Biol. Chem.},
  year      = {2008},
  volume    = {283},
  number    = {52},
  pages     = {36132--36139},
  publisher = {ASBMB},
}

@Article{lynch2009,
  author    = {Lynch, Allison M and Hardin, Jeff},
  title     = {The assembly and maintenance of epithelial junctions in C. elegans},
  journal   = {Frontiers in bioscience: a journal and virtual library},
  year      = {2009},
  volume    = {14},
  pages     = {1414},
  publisher = {NIH Public Access},
}

@Article{goh1991,
  author    = {Goh, PY and Bogaert, THIERRY},
  title     = {Positioning and maintenance of embryonic body wall muscle attachments in C. elegans requires the mup-1 gene},
  journal   = {Development},
  year      = {1991},
  volume    = {111},
  number    = {3},
  pages     = {667--681},
  publisher = {The Company of Biologists Ltd},
}

@Article{shafaq-zadah2012,
  author    = {Shafaq-Zadah, Massiullah and Brocard, Lysiane and Solari, Florence and Michaux, Gr{\'e}goire},
  title     = {AP-1 is required for the maintenance of apico-basal polarity in the C. elegans intestine},
  journal   = {Development},
  year      = {2012},
  pages     = {dev--076711},
  publisher = {Oxford University Press for The Company of Biologists Limited},
}

@Article{carmell2002,
  author    = {Carmell, Michelle A and Xuan, Zhenyu and Zhang, Michael Q and Hannon, Gregory J},
  title     = {The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis},
  journal   = {Genes \& development},
  year      = {2002},
  volume    = {16},
  number    = {21},
  pages     = {2733--2742},
  publisher = {Cold Spring Harbor Lab},
}

@Book{altun2009a,
  author = {Altun, Z. F. and Hall, D. H.},
  title  = {Alimentary System, Pharynx. In WormAtlas},
  year   = {2009},
  editor = {Edited for the web by Laura A. Herndon},
  url    = {http://www.wormatlas.org/hermaphrodite/alimentary/Alimframeset.html},
}

@Article{wolke2007,
  author    = {Wolke, U. and Jezuit, E. A. and Priess, J. R.},
  title     = {Actin-dependent cytoplasmic streaming in C. elegans oogenesis},
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  title     = {CD81 extracellular domain 3D structure: insight into the tetraspanin superfamily structural motifs},
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  title     = {Structure of the complete extracellular domain of the common $\beta$ subunit of the human GM-CSF, IL-3, and IL-5 receptors reveals a novel dimer configuration},
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@Article{mi2011,
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  journal   = {Molecular pharmacology},
  year      = {2007},
  volume    = {71},
  number    = {3},
  pages     = {769--776},
  publisher = {ASPET},
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  title     = {Nicotinic receptors in the development and modulation of CNS synapses},
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  author    = {Mulle, Christophe and Choquet, Daniel and Korn, Henri and Changeux, Jean-Pierre},
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  year      = {1992},
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@Article{katz2000,
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@Article{shen2009,
  author    = {Shen, Jian-xin and Yakel, Jerrel L},
  title     = {Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system},
  journal   = {Acta pharmacologica Sinica},
  year      = {2009},
  volume    = {30},
  number    = {6},
  pages     = {673},
  publisher = {Nature Publishing Group},
}

@Article{fayuk2005,
  author    = {Fayuk, Dmitriy and Yakel, Jerrel L},
  title     = {Ca2+ permeability of nicotinic acetylcholine receptors in rat hippocampal CA1 interneurones},
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  year      = {2005},
  volume    = {566},
  number    = {3},
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@Article{fucile2003,
  author    = {Fucile, Sergio and Renzi, Massimiliano and Lax, Pedro and Eusebi, Fabrizio},
  title     = {Fractional Ca2+ current through human neuronal $\alpha$7 nicotinic acetylcholine receptors},
  journal   = {Cell calcium},
  year      = {2003},
  volume    = {34},
  number    = {2},
  pages     = {205--209},
  publisher = {Elsevier},
}

@Article{katz1957,
  author    = {Katz, B. and Thesleff, S.},
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  title     = "{Aphicidal Activity of Imidacloprid Against a Tobacco Feeding Strain of \textit{Myzus persicae (Homoptera: Aphididae)} from Japan Closely Related to \textit{Myzus nicotianae} and Highly Resistant to Carbamates and Organophosphates}",
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@Article{zhang2004,
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  title     = "{\texztit{Drosophila} Nicotinic Receptors: Evidence for Imidacloprid Insecticide and $\alpha$-bungarotoxin Binding to Distinct Sites}",
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@Article{nauen2001,
  author    = {Nauen, R. and Ebbinghaus-Kintscher, U. and Schmuck, R.},
  title     = {Toxicity and nicotinic acetylcholine receptor interaction of imidacloprid and its metabolites in Apis mellifera (Hymenoptera: Apidae)},
  journal   = {Pest Manag. Sci.: formerly Pestic. Sci.},
  year      = {2001},
  volume    = {57},
  number    = {7},
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}

@Article{bal2010,
  author          = {Bal, Ramazan and Erdogan, Suat and Theophilidis, George and Baydas, Giyasettin and Naziroglu, Mustafa},
  title           = {Assessing the effects of the neonicotinoid insecticide imidacloprid in the cholinergic synapses of the stellate cells of the mouse cochlear nucleus using whole-cell patch-clamp recording.},
  journal         = {Neurotoxicology},
  year            = {2010},
  volume          = {31},
  issue           = {1},
  month           = jan,
  pages           = {113--120},
  issn            = {1872-9711},
  doi             = {10.1016/j.neuro.2009.10.004},
  abstract        = {Imidacloprid (IMI) is widely used systemic insecticide that acts as an agonist on nicotinic acetylcholine receptors (nAChRs). IMI has been reported to be more active against insect nAChRs (EC(50) 0.86-1 microM) than it is against mammalian nAChRs (EC(50) 70 microM). The objective of this study was to determine to what extent IMI affects the nAChRs of the stellate cells of mouse cochlear nucleus (CN), using whole-cell patch-clamp recording. Puff application of 1 microM IMI had no significant effect on the membrane properties of the neurons tested, while a concentration of 10 microM caused a significant depolarizing shift in the membrane potential and resulted in increases in the fluctuation of the membrane potential and in the frequency of miniature postsynaptic potentials (mpps) within less than a minute of exposure. IMI at concentrations >or=50 microM caused a significant depolarizing shift in the membrane potential, accompanied by a marked increase in the frequency of action potential. IMI decreased the membrane input resistance and the membrane time constants. Bath application of 50 microM d-tubocurarine (d-TC) reversibly blocked the depolarizing shift of the resting membrane potential and the spontaneous firing induced by IMI application in current clamp and blocked the inward currents through nicotinic receptors induced by IMI application in voltage clamp. Similarly, 100 nM alpha-bungarotoxin (alpha-BgTx) blocked the spontaneous firing induced by IMI (n=3). The amplitude of the 100 microM IMI-induced inward current at -60 mV holding potential was 115.0+/-16.2 pA (n=7). IMI at a concentration of 10 microM produced 11.3+/-3.4 pA inward current (n=4). We conclude that exposure to IMI at concentrations >or=10 microM for <1 min can change the membrane properties of neurons that have nAChRs and, as a consequence, their function.},
  chemicals       = {Bungarotoxins, Imidazoles, Insecticides, Neonicotinoids, Nicotinic Agonists, Nicotinic Antagonists, Nitro Compounds, Sodium Channel Blockers, imidacloprid, Tetrodotoxin, Nicotine, biocytin, Lysine, Acetylcholine, Tubocurarine},
  citation-subset = {IM},
  completed       = {2010-04-13},
  country         = {Netherlands},
  issn-linking    = {0161-813X},
  keywords        = {Acetylcholine, metabolism; Animals; Animals, Newborn; Bungarotoxins, pharmacology; Cochlear Nucleus, cytology; Dose-Response Relationship, Drug; Imidazoles, pharmacology; In Vitro Techniques; Insecticides, pharmacology; Interneurons, cytology; Lysine, analogs & derivatives; Membrane Potentials, drug effects; Mice; Neonicotinoids; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Nicotinic Antagonists, pharmacology; Nitro Compounds, pharmacology; Patch-Clamp Techniques, methods; Sodium Channel Blockers, pharmacology; Synapses, drug effects; Tetrodotoxin, pharmacology; Tubocurarine, pharmacology},
  nlm-id          = {7905589},
  owner           = {NLM},
  pii             = {S0161-813X(09)00227-7},
  pmid            = {19853623},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@Article{tomizawa2000a,
  author          = {Tomizawa, M and Casida, J E},
  title           = {Imidacloprid, thiacloprid, and their imine derivatives up-regulate the alpha 4 beta 2 nicotinic acetylcholine receptor in M10 cells.},
  journal         = {Toxicol. Appl. Pharm.},
  year            = {2000},
  volume          = {169},
  issue           = {1},
  month           = nov,
  pages           = {114--120},
  issn            = {0041-008X},
  doi             = {10.1006/taap.2000.9057},
  abstract        = {Neonicotinoids are the most important new class of insecticides of the last decade. They act as nicotinic acetylcholine receptor (AChR) agonists. This investigation tests the hypothesis for the first time that neonicotinoid insecticides and their imine derivatives up-regulate the alpha 4 beta 2 nicotinic AChR subtype, which represents >90% of the high-affinity [(3)H]nicotine binding sites in mammalian brain. The alpha 4 beta 2 receptor stably expressed in mouse fibroblast M10 cells was assayed after 3 days' exposure to the test compound, as [(3)H]nicotine binding following immunoisolation by monoclonal antibody (mAb 299) or as [(125)I]mAb 299 labeling for cell surface receptors. We found that imidacloprid (IMI) (one of the most important insecticides) and thiacloprid (THIA) increased [(3)H]nicotine binding levels (up-regulation of the alpha 4 beta 2 AChRs) by five- to eightfold with EC50s of approximately 70,000 and 19,000 nM, respectively, compared with 760 nM for (-)-nicotine. In contrast, two imine analogs [the desnitro metabolite of IMI (DNIMI) and the descyano derivative of THIA] gave up-regulation by eightfold and EC50s of 870 and 500 nM, respectively. The potency order for up-regulation by the five aforementioned compounds was correlated with their in vitro IC50s for inhibiting [(3)H]nicotine binding (r(2) = 0.99, n = 5), indicating that binding to the alpha 4 beta 2 receptor initiates the up-regulation. A potent olefin derivative of the THIA imine up-regulated with an EC50 of 22 nM. DNIMI-induced up-regulation mainly occurred intracellularly rather than at the cell surface. These findings in alpha 4 beta 2-expressing M10 cells indicate the possibility that some neonicotinoid insecticides or their metabolites, on accidental human exposure or when used for flea control on dogs, may also up-regulate the receptor in mammals.},
  chemicals       = {Imidazoles, Insecticides, Neonicotinoids, Nitro Compounds, Pyridines, Receptors, Nicotinic, Thiazines, nicotinic receptor alpha4beta2, Tritium, Colforsin, imidacloprid, Nicotine, Cycloheximide, thiacloprid, Tetradecanoylphorbol Acetate},
  citation-subset = {IM},
  completed       = {2001-01-04},
  country         = {United States},
  issn-linking    = {0041-008X},
  keywords        = {Animals; Cell Line; Colforsin, pharmacology; Cycloheximide, pharmacology; Fibroblasts, drug effects, metabolism; Imidazoles, pharmacology; Insecticides, pharmacology; Mice; Neonicotinoids; Nicotine, metabolism; Nitro Compounds; Pyridines, pharmacology; Receptors, Nicotinic, metabolism; Tetradecanoylphorbol Acetate, pharmacology; Thiazines, pharmacology; Transfection; Tritium; Up-Regulation},
  nlm-id          = {0416575},
  owner           = {NLM},
  pii             = {S0041-008X(00)99057-4},
  pmid            = {11076703},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@Article{sone1994,
  author       = {Sone, S. and Nagata, K. and Tsuboi, S-I. and Shono, T.},
  title        = "{Toxic Symptoms and Neural Effect of a New Class of Insecticide ,Imidacloprid, on the American Cockroach, \textit{Periplaneta ameyicana (L.)}}",
  journaltitle = {J pesticide Sci},
  year         = {1994},
  volume       = {19},
  pages        = {69-72},
}

@Article{nemecz2016,
  author          = {Nemecz, Ákos and Prevost, Marie S and Menny, Anaïs and Corringer, Pierre-Jean},
  title           = {Emerging Molecular Mechanisms of Signal Transduction in Pentameric Ligand-Gated Ion Channels.},
  journal         = {Neuron},
  year            = {2016},
  volume          = {90},
  issue           = {3},
  month           = may,
  pages           = {452--470},
  issn            = {1097-4199},
  doi             = {10.1016/j.neuron.2016.03.032},
  abstract        = {Nicotinic acetylcholine, serotonin type 3, γ-amminobutyric acid type A, and glycine receptors are major players of human neuronal communication. They belong to the family of pentameric ligand-gated ion channels, sharing a highly conserved modular 3D structure. Recently, high-resolution structures of both open- and closed-pore conformations have been solved for a bacterial, an invertebrate, and a vertebrate receptor in this family. These data suggest that a common gating mechanism occurs, coupling neurotransmitter binding to pore opening, but they also pinpoint significant differences among subtypes. In this Review, we summarize the structural and functional data in light of these gating models and speculate about their mechanistic consequences on ion permeation, pathological mutations, as well as functional regulation by orthosteric and allosteric effectors.},
  chemicals       = {Ligand-Gated Ion Channels, Receptors, Glycine},
  citation-subset = {IM},
  completed       = {2017-08-22},
  country         = {United States},
  issn-linking    = {0896-6273},
  keywords        = {Animals; Biophysical Phenomena, physiology; Humans; Ion Channel Gating, physiology; Ligand-Gated Ion Channels, metabolism; Models, Molecular; Receptors, Glycine, metabolism; Signal Transduction, physiology},
  nlm-id          = {8809320},
  owner           = {NLM},
  pii             = {S0896-6273(16)30023-X},
  pmid            = {27151638},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-01-10},
}

@Article{rahman2016,
  author          = {Rahman, Shafiqur and Engleman, Eric A and Bell, Richard L},
  title           = {Recent Advances in Nicotinic Receptor Signaling in Alcohol Abuse and Alcoholism.},
  journal         = {Progress in molecular biology and translational science},
  year            = {2016},
  volume          = {137},
  pages           = {183--201},
  issn            = {1878-0814},
  doi             = {10.1016/bs.pmbts.2015.10.004},
  abstract        = {Alcohol is the most commonly abused legal substance and alcoholism is a serious public health problem. It is a leading cause of preventable death in the world. The cellular and molecular mechanisms of alcohol reward and addiction are still not well understood. Emerging evidence indicates that unlike other drugs of abuse, such as nicotine, cocaine, or opioids, alcohol targets numerous channel proteins, receptor molecules, and signaling pathways in the brain. Previously, research has identified brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of pentameric ligand-gated cation channels expressed in the mammalian brain, as critical molecular targets for alcohol abuse and dependence. Genetic variations encoding nAChR subunits have been shown to increase the vulnerability to develop alcohol dependence. Here, we review recent insights into the rewarding effects of alcohol, as they pertain to different nAChR subtypes, associated signaling molecules, and pathways that contribute to the molecular mechanisms of alcoholism and/or comorbid brain disorders. Understanding these cellular changes and molecular underpinnings may be useful for the advancement of brain nicotinic-cholinergic mechanisms, and will lead to a better translational and therapeutic outcome for alcoholism and/or comorbid conditions. },
  chemicals       = {Receptors, Nicotinic, Nicotine},
  citation-subset = {IM},
  completed       = {2016-12-30},
  country         = {Netherlands},
  issn-linking    = {1877-1173},
  keywords        = {Alcoholism, metabolism; Animals; Animals, Genetically Modified; Humans; Nicotine, administration & dosage; Receptors, Nicotinic, metabolism; Signal Transduction; alcohol dependence; alcoholism; drug addiction; drug targets; molecular mechanisms; nicotinic receptor; translational research},
  mid             = {NIHMS757026},
  nlm-id          = {101498165},
  owner           = {NLM},
  pii             = {S1877-1173(15)00206-9},
  pmc             = {PMC4754113},
  pmid            = {26810002},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{hirata2017,
  author          = {Hirata, Koichi and Jouraku, Akiya and Kuwazaki, Seigo and Kanazawa, Jun and Iwasa, Takao},
  title           = "{The R81T Mutation in the Nicotinic Acetylcholine Receptor of \textit{Aphis gossypii} is Associated with Neonicotinoid Insecticide Resistance with Differential Effects for Cyano- and Nitro-Substituted Neonicotinoids.}",
  journal         = {Pestic. Biochem. Phys.},
  year            = {2017},
  volume          = {143},
  pages           = {57--65},
  issn            = {1095-9939},
  doi             = {10.1016/j.pestbp.2017.09.009},
  abstract        = {The cotton aphid, Aphis gossypii Glover, is one of the most agriculturally important insect pests. Neonicotinoid insecticides and sulfoxaflor have generally shown excellent control of A. gossypii, but these aphids have recently developed resistance against neonicotinoid insecticides. We previously characterized a field-collected A. gossypii Kushima clone that showed higher resistance to nitro-substituted neonicotinoids, such as imidacloprid, than to cyano-substituted neonicotinoids, such as acetamiprid. This Kushima clone harbors the R81T mutation in the nicotinic acetylcholine receptor (nAChR) β1 subunit; this mutation is the source of neonicotinoid insecticide resistance. In the present study, electrophysiological analyses and molecular modeling were employed to investigate the differential effects of the R81T mutation on cyano- and nitro-substituted neonicotinoids and sulfoxaflor. We isolated full-length coding sequences of A. gossypii nAChR α1, α2, and β1 subunits. When co-expressed in Xenopus laevis oocytes with chicken β2 nAChR, A. gossypii α1 evoked inward currents in a concentration-dependent manner in response to acetylcholine (ACh) and showed sensitivity to neonicotinoid and sulfoxaflor. Additionally, the chicken β2 T77R+E79V (equivalent double mutant of R81T) mutation resulted in a lower effect to cyano-substituted neonicotinoids and sulfoxaflor than to nitro-substituted neonicotinoids. Electrophysiological data and nAChR homology modeling analysis suggested that the Kushima clone exhibited different levels of resistance to cyano- and nitro-substituted neonicotinoid insecticides.},
  chemicals       = {Insect Proteins, Insecticides, Neonicotinoids, Protein Subunits, Receptors, Nicotinic},
  citation-subset = {IM},
  completed       = {2018-07-18},
  country         = {United States},
  issn-linking    = {0048-3575},
  keywords        = {Animals; Aphids, genetics; Chickens; Insect Proteins, genetics, physiology; Insecticide Resistance, genetics; Insecticides, chemistry, toxicity; Models, Molecular; Mutation; Neonicotinoids, chemistry, toxicity; Oocytes, physiology; Protein Subunits, genetics, physiology; Receptors, Nicotinic, genetics, physiology; Xenopus laevis; Aphis gossypii; Insecticide resistance; Neonicotinoid; Nicotinic acetylcholine receptor; nAChR modeling},
  nlm-id          = {1301573},
  owner           = {NLM},
  pii             = {S0048-3575(17)30171-2},
  pmid            = {29183611},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-07-18},
}

@Article{charaabi2018,
  author          = {Charaabi, K. and Boukhris-Bouhachem, S. and Makni, M. and Denholm, I.},
  title           = {Occurrence of target-site resistance to neonicotinoids in the aphid \textit{Myzus persicae} in Tunisia, and its status on different host plants.},
  journal         = {Pest Manag. Sci.},
  year            = {2018},
  volume          = {74},
  issue           = {6},
  month           = jun,
  pages           = {1297--1301},
  issn            = {1526-4998},
  doi             = {10.1002/ps.4833},
  abstract        = {The R81T mutation conferring target-site resistance to neonicotinoid insecticides in Myzus persicae was first detected in France and has since spread across much of southern Europe. In response to recent claims of control failure with neonicotinoids in Tunisia, we have used a molecular assay to investigate the presence and distribution of this target-site mutation in samples collected from six locations and six crops attacked by M. persicae. The resistance allele containing R81T was present at substantial frequencies (32-55%) in aphids collected between 2014 and 2016 from northern Tunisia but was much rarer further south. It occurred in aphids collected from the aphid's primary host (peach) and four secondary crop hosts (potato, pepper, tomato and melon). Its absence in aphids from tobacco highlights complexities in the systematics of M. persicae that require further investigation. This first report of R81T from North Africa reflects a continuing expansion of its range around the Mediterranean Basin, although it remains unrecorded elsewhere in the world. Loss of efficacy of neonicotinoids presents a serious threat to the sustainability of aphid control. © 2017 Society of Chemical Industry.},
  chemicals       = {Insect Proteins, Insecticides, Neonicotinoids},
  citation-subset = {IM},
  completed       = {2018-09-07},
  country         = {England},
  issn-linking    = {1526-498X},
  keywords        = {Animals; Aphids, drug effects, genetics; Insect Proteins, genetics, metabolism; Insecticide Resistance, genetics; Insecticides, pharmacology; Mutation; Neonicotinoids, pharmacology; Tunisia; North Africa; Taqman assay; dispersal; gene flow; insecticide resistance; target-site mutation},
  nlm-id          = {100898744},
  owner           = {NLM},
  pmid            = {29266681},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-09-07},
}

@Article{shimomura2005,
  author  = {Shimomura, M. and Satoh, M. and Yokota, M. and Ihara, M. and Matsuda, M. and Sattelle, M.},
  title   = {Insect-vertebrate chimeric nicotinic acetylcholine receptors identify a region, loop B to the N-terminus of the Drosophila Dalpha2 subunit, which contributes to neonicotinoid sensitivity},
  journal = {Neurosci Lett},
  year    = {2005},
  volume  = {385},
  number  = {2},
  doi     = {https://doi.org/10.1016/j.neulet.2005.05.014},
}

@Article{boulin2012,
  author  = {Boulin, T. and Hobert, O.},
  title   = {From genes to function: the C. elegans genetic toolbox.},
  journal = {Wiley Interdiscip Rev Dev Biol},
  year    = {2012},
}



@Article{nelson1973,
  author    = {Nelson, W. C. and Lykins, M. H. and Mackey, J. and Newill, V. A. and Finklea, J. F. and Hammer, D. I.},
  title     = {Mortality among orchard workers exposed to lead arsenate spray: a cohort study},
  journal   = {J. Chronic Dis.},
  year      = {1973},
  volume    = {26},
  number    = {2},
  pages     = {105--118},
  publisher = {Elsevier},
}

@Article{gibb2010,
  author    = {Gibb, H. and Haver, C. and Gaylor, D. and Ramasamy, S. and Lee, J. S. and Lobdell, D. and Wade, T. and Chen, C. and White, P. and Sams, R.},
  title     = {Utility of recent studies to assess the National Research Council 2001 estimates of cancer risk from ingested arsenic},
  journal   = {Environ. Health Perspect.},
  year      = {2010},
  volume    = {119},
  number    = {3},
  pages     = {284--290},
  publisher = {National Institute of Environmental Health Sciences},
}

@Article{argos2010,
  author    = {Argos, M. and Kalra, T. and Rathouz, P. J. and Chen, Y. and Pierce, B. and Parvez, F. and Islam, T. and Ahmed, A. and Rakibuz-Zaman, M. and Hasan, R. and others},
  title     = {Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study},
  journal   = {The Lancet},
  year      = {2010},
  volume    = {376},
  number    = {9737},
  pages     = {252--258},
  publisher = {Elsevier},
}

@Article{haas2006,
  author    = {Haas, M. and Kuhnhold, J.},
  title     = {Field trials with O-TEQ{\textregistered} products, in particular difficult-to-wet crops},
  journal   = {PFLANZENSCHUTZ NACHRICHTEN-BAYER-ENGLISH EDITION},
  year      = {2006},
  volume    = {60},
  number    = {1},
  pages     = {59},
  publisher = {BAYER AG},
}

@Article{wang2015,
  author    = {Wang, K. and Pang, S. and Mu, X. and Qi, S. and Li, D. and Cui, F. and Wang, C.},
  title     = {Biological response of earthworm, Eisenia fetida, to five neonicotinoid insecticides},
  journal   = {Chemosphere},
  year      = {2015},
  volume    = {132},
  pages     = {120--126},
  publisher = {Elsevier},
}

@Article{scheffel2018,
  author          = {Scheffel, Corinna and Niessen, Karin V and Rappenglück, Sebastian and Wanner, Klaus T and Thiermann, Horst and Worek, Franz and Seeger, Thomas},
  title           = {Electrophysiological investigation of the effect of structurally different bispyridinium non-oxime compounds on human α7-nicotinic acetylcholine receptor activity-An in vitro structure-activity analysis.},
  journal         = {Toxicology letters},
  year            = {2018},
  volume          = {293},
  month           = sep,
  pages           = {157--166},
  issn            = {1879-3169},
  doi             = {10.1016/j.toxlet.2017.11.025},
  abstract        = {Organophosphorus compounds, including nerve agents and pesticides, exert their toxicity through irreversible inhibition of acetylcholinesterase (AChE) resulting in an accumulation of acetylcholine and functional impairment of muscarinic and nicotinic acetylcholine receptors. Current therapy comprises oximes to reactivate AChE and atropine to antagonize effects induced by muscarinic acetylcholine receptors. Nicotinic malfunction leading to depression of the central and peripheral respiratory system is not directly treated calling for alternative therapeutic interventions. In the present study, we investigated the electrophysiological properties of the human nAChR subtype α7 (hα7-nAChR) and the functional effect of the 4-tert-butyl bispyridinium (BP) compound MB327 and of a series of novel substituted bispyridinium compounds on the receptors by an automated patch clamp technique. Activation of hα7-nAChRs was induced by nicotine and acetylcholine demonstrating rapid cationic influx up to 100μM. Agonist-induced currents decayed within a few milliseconds revealing fast desensitization of the receptors. Application of higher agonist concentrations led to a decline of current amplitudes which seemed to be due to increasing receptor desensitization. When 100μM of agonist was coapplied with low concentrations of the well characterized α7-specific positive allosteric modulator PNU-120596 (1μM-10μM), the maximum response and duration of nAChR activation were markedly augmented indicating an elongated mean open-time of receptors and prevention of receptor desensitization. However, co-application of increasing PNU-120596 concentrations (>10μM) with agonist induced a decline of potentiated current responses. Although less pronounced than PNU-120596, six of the twenty tested substituted BP compounds, in particular those with a substituent at 3-position and 4-position at the pyridinium moieties, were found to potentiate current responses of hα7-nAChRs, most pronounced MB327.This effect was clearly depended on the presence of the agonist indicating a positive allosteric mechanism of these compounds. Besides potentiation at low concentrations, these compounds seem to interact at different binding sites on hα7-nAChRs since enhancement decreased at high concentrations. The residual fourteen BP compounds, possessing either an isopropyl-group or more than one group at the pyridinium moiety, antagonized nicotinic currents exhibiting IC  of low up to high micromolar concentrations (∼1μM-300μM).},
  chemicals       = {1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea, Isoxazoles, MB327, Nicotinic Agonists, Phenylurea Compounds, Pyridinium Compounds, alpha7 Nicotinic Acetylcholine Receptor},
  citation-subset = {IM},
  completed       = {2018-06-04},
  country         = {Netherlands},
  issn-linking    = {0378-4274},
  keywords        = {Animals; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Electrophysiological Phenomena, drug effects; Isoxazoles, pharmacology; Nicotinic Agonists, pharmacology; Patch-Clamp Techniques; Phenylurea Compounds, pharmacology; Pyridinium Compounds, chemistry, pharmacology; Structure-Activity Relationship; alpha7 Nicotinic Acetylcholine Receptor, drug effects; Activation; Allosteric modulation; Automated patch clamp; Desensitization; Organophosphorus compounds; PNU-120596 (PubChem CID: 311434); acetylcholine iodide (PubChem CID: 75271); nicotine hydrogen tartrate salt (PubChem CID: 24867513); α7-nicotinic acetylcholine receptor},
  nlm-id          = {7709027},
  owner           = {NLM},
  pii             = {S0378-4274(17)31484-4},
  pmid            = {29191791},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-06-04},
}

@Article{ma2018,
  author          = {Ma, Kai-Ge and Lv, Jia and Yang, Wei-Na and Chang, Ke-Wei and Hu, Xiao-Dan and Shi, Li-Li and Zhai, Wan-Ying and Zong, Hang-Fan and Qian, Yi-Hua},
  title           = {The p38 mitogen activated protein kinase regulates β-amyloid protein internalization through the α7 nicotinic acetylcholine receptor in mouse brain.},
  journal         = {Brain res.},
  year            = {2018},
  volume          = {137},
  month           = mar,
  pages           = {41--52},
  issn            = {1873-2747},
  doi             = {10.1016/j.brainresbull.2017.11.006},
  abstract        = {Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. Intracellular β-amyloid protein (Aβ) is an early event in AD. It induces the formation of amyloid plaques and neuron damage. The α7 nicotinic acetylcholine receptor (α7nAChR) has been suggested to play an important role in Aβ caused cognition. It has high affinity with Aβ and could mediate Aβ internalization in vitro. However, whether in mouse brain the p38 MAPK signaling pathway is involved in the regulation of the α7nAChR mediated Aβ internalization and their role in mitochondria remains little known. Therefore, in this study, we revealed that Aβ is internalized by cholinergic and GABAergic neurons. The internalized Aβ were found deposits in lysosomes/endosomes and mitochondria. Aβ could form Aβ-α7nAChR complex with α7nAChR, activates the p38 mitogen activated protein kinase (MAPK). And the increasing of α7nAChR could in return mediate Aβ internalization in the cortex and hippocampus. In addition, by using the α7nAChR agonist PNU282987, the p38 phosphorylation level decreases, rescues the biochemical changes which are tightly associated with Aβ-induced apoptosis, such as Bcl2/Bax level, cytochrome c (Cyt c) release. Collectively, the p38 MAPK signaling pathway could regulate the α7nAChR-mediated internalization of Aβ. The activation of α7nAChR or the inhibition of p38 MAPK signaling pathway may be a beneficial therapy to AD.},
  chemicals       = {Amyloid beta-Peptides, Benzamides, Bridged Bicyclo Compounds, Nicotinic Agonists, PNU-282987, Peptide Fragments, alpha7 Nicotinic Acetylcholine Receptor, amyloid beta-protein (1-42), p38 Mitogen-Activated Protein Kinases},
  citation-subset = {IM},
  completed       = {2018-08-31},
  country         = {United States},
  issn-linking    = {0361-9230},
  keywords        = {Amyloid beta-Peptides, metabolism; Animals; Benzamides, pharmacology; Brain, drug effects, metabolism, pathology; Bridged Bicyclo Compounds, pharmacology; Cholinergic Neurons, drug effects, metabolism, pathology; Endosomes, drug effects, metabolism, pathology; Female; GABAergic Neurons, drug effects, metabolism, pathology; Lysosomes, drug effects, metabolism, pathology; Mice; Mitochondria, drug effects, metabolism, pathology; Nicotinic Agonists, pharmacology; Peptide Fragments, metabolism; Phosphorylation; Random Allocation; alpha7 Nicotinic Acetylcholine Receptor, agonists, antagonists & inhibitors, metabolism; p38 Mitogen-Activated Protein Kinases, metabolism; Alzheimer’s disease; Apoptosis; Aβ internalization; p38 mitogen activated protein kinase; α7 nicotinic acetylcholine receptor},
  nlm-id          = {7605818},
  owner           = {NLM},
  pii             = {S0361-9230(17)30551-8},
  pmid            = {29128415},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-08-31},
}

@Article{scheffel2018a,
  author          = {Scheffel, Corinna and Niessen, Karin V and Rappenglück, Sebastian and Wanner, Klaus T and Thiermann, Horst and Worek, Franz and Seeger, Thomas},
  title           = {Counteracting desensitization of human α7-nicotinic acetylcholine receptors with bispyridinium compounds as an approach against organophosphorus poisoning.},
  journal         = {Toxicology letters},
  year            = {2018},
  volume          = {293},
  month           = sep,
  pages           = {149--156},
  issn            = {1879-3169},
  doi             = {10.1016/j.toxlet.2017.12.005},
  abstract        = {Irreversible inhibition of acetylcholinesterase (AChE) resulting in accumulation of acetylcholine and overstimulation of muscarinic and nicotinic receptors accounts for the acute toxicity of organophosphorus compounds (OP). Accordingly, the mainstay pharmacotherapy against poisoning by OP comprises the competitive muscarinic acetylcholine receptor antagonist atropine to treat muscarinic effects and, in addition, oximes to reactivate inhibited AChE. A therapeutic gap still remains in the treatment of desensitized nicotinic acetylcholine receptors following OP exposure. Hereby, nicotinic effects result in paralysis of the central and peripheral respiratory system if untreated. Thus, these receptors pose an essential target for therapeutic indication to address these life-threatening nicotinic symptoms of the cholinergic crisis. Identification of ligands regulating dynamic transitions between functional states by binding to modulatory sites appears to be a promising strategy for therapeutic intervention. In this patch clamp study, the ability of differently substituted bispyridinium non-oximes to "resensitize" i.e. to recover the activity of desensitized human homomeric α7-type nAChRs stably transfected in CHO cells was investigated and compared to the already described α7-specific positive allosteric modulator PNU-120596. The structures of these bispyridinium analogues were based on the lead structure of the tert-butyl-substituted bispyridinium propane MB327, which has been shown to have a positive therapeutic effect due to a non-competitive antagonistic action at muscle-type nAChRs in vivo and has been found to have a positive allosteric activity at neuronal receptors in vitro. Prior to test compounds, desensitization of hα7-nAChRs was verified by applying an excess of nicotine revealing activation at low, and desensitization at high concentrations. Thereby, desensitization could be reduced by modulation with PNU-120596. Desensitization was further verified by dose-response profiles of agonists, carbamoylcholine and epibatidine in the absence and presence of PNU-120596. Although less pronounced than PNU-120596 and the lead structure MB327, bispyridinium compounds, particularly those substituted at position 3 and 4, resensitized the nicotine desensitized hα7-nAChRs in a concentration-dependent manner and prolonged the mean channel open time. In summary, identification of more potent compounds able to restore nAChR function in OP intoxication is needed for development of a putative efficient antidote.},
  chemicals       = {1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea, Cholinesterase Reactivators, Isoxazoles, MB327, Nicotinic Agonists, Phenylurea Compounds, Pyridinium Compounds, alpha7 Nicotinic Acetylcholine Receptor},
  citation-subset = {IM},
  completed       = {2018-06-04},
  country         = {Netherlands},
  issn-linking    = {0378-4274},
  keywords        = {Animals; CHO Cells; Cholinesterase Reactivators, pharmacology; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Humans; Isoxazoles, therapeutic use; Nicotinic Agonists, pharmacology; Organophosphate Poisoning, drug therapy; Patch-Clamp Techniques; Phenylurea Compounds, therapeutic use; Pyridinium Compounds, chemistry, pharmacology; Structure-Activity Relationship; alpha7 Nicotinic Acetylcholine Receptor, agonists, antagonists & inhibitors; (±)-epibatidine (PubChem CID: 3073763); (−)-nicotine hydrogen tartrate salt (PubChem CID: 24867513); Activation; Allosteric modulation; Automated patch clamp; Desensitization; Human α7-nicotinic acetylcholine receptor; Organophosphorus compounds; PNU-120596 (PubChem CID: 311434); Resensitization; carbamoylcholine (PubChem CID: 5831)},
  nlm-id          = {7709027},
  owner           = {NLM},
  pii             = {S0378-4274(17)31515-1},
  pmid            = {29248576},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-06-04},
}

@Article{andreasen2012,
  author          = {Andreasen, Jesper T and Redrobe, John P and Nielsen, Elsebet Ø},
  title           = {Combined α7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests: a comparison of SSR180711 and PNU-282987.},
  journal         = {Pharmacology, biochemistry, and behavior},
  year            = {2012},
  volume          = {100},
  issue           = {3},
  month           = jan,
  pages           = {624--629},
  issn            = {1873-5177},
  doi             = {10.1016/j.pbb.2011.11.004},
  abstract        = {Emerging evidence points to an involvement of nicotinic acetylcholine receptors (nAChRs) in major depression. Nicotine improves symptoms of depression in humans and shows antidepressant-like effects in rodents. Monoamine release is facilitated by nAChR stimulation, and nicotine-evoked serotonin (5-HT) release has been shown to depend on α7 nAChR activation. The α7 nAChR agonist PNU-282987 shows no antidepressant-like activity when tested alone in the mouse forced swim (mFST) or tail suspension tests (mTST). However, in combination with a sub-active dose of the selective 5-HT reuptake inhibitor citalopram, inducing ~50% 5-HT reuptake inhibition, PNU-282987 has shown marked antidepressant-like effects in the mFST. SSR180711 is a recently described α7 nAChR agonist that has shown antidepressant-like activity in the rat forced swim test. To address the possibility that 5-HT reuptake inhibition contributes to the antidepressant-like profile of SSR180711, we compared the behavioural and biochemical profiles of PNU-282987 and SSR180711. In the mFST and mTST, SSR180711 (3-30 mg/kg, s.c.) showed dose-dependent antidepressant-like activity, while PNU-282987 (3-30 mg/kg, s.c.) showed no significant effect. The ED(50) to displace [³H]α-bungarotoxin binding was 1.7 and 5.5 mg/kg for SSR180711 and PNU-282987, respectively, suggesting that both compounds produce near-maximal α7 nAChR occupancy at the highest dose. While PNU-282987 did not affect ex vivo [³H]5-HT uptake, SSR180711 inhibited [³H]5-HT uptake with an ED₅₀ of 30 mg/kg. This degree of inhibition is similar to that observed with a citalopram dose of ~2.4 mg/kg, a dose that is normally not active in the mFST or mTST. This suggests that the antidepressant-like activity of SSR180711 may involve partial 5-HT reuptake inhibition. SSR180711 therefore represents a compound displaying the synergistic effect of α7 nAChR agonism combined with partial 5-HT reuptake inhibition previously described. The addition of α7 nAChR agonism to classical monoamine-based mechanisms may represent a novel option for the improved treatment of major depression.},
  chemicals       = {Antidepressive Agents, Benzamides, Bridged Bicyclo Compounds, Bridged Bicyclo Compounds, Heterocyclic, Chrna7 protein, human, Chrna7 protein, mouse, Chrna7 protein, rat, Nicotinic Agonists, PNU-282987, Receptors, Nicotinic, SSR180711, Serotonin Plasma Membrane Transport Proteins, Serotonin Uptake Inhibitors, Slc6a4 protein, mouse, alpha7 Nicotinic Acetylcholine Receptor, Citalopram, Serotonin},
  citation-subset = {IM},
  completed       = {2012-05-04},
  country         = {United States},
  issn-linking    = {0091-3057},
  keywords        = {Animals; Antidepressive Agents, administration & dosage, metabolism, pharmacokinetics, therapeutic use; Behavior, Animal, drug effects; Benzamides, administration & dosage, metabolism, pharmacokinetics, therapeutic use; Bridged Bicyclo Compounds, administration & dosage, metabolism, pharmacokinetics, therapeutic use; Bridged Bicyclo Compounds, Heterocyclic, administration & dosage, metabolism, pharmacokinetics, therapeutic use; Cerebral Cortex, drug effects, metabolism; Citalopram, therapeutic use; Depression, drug therapy, metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Mice; Mice, Inbred Strains; Molecular Targeted Therapy; Nicotinic Agonists, administration & dosage, metabolism, pharmacokinetics, therapeutic use; Receptors, Nicotinic, administration & dosage, chemistry, metabolism; Serotonin, metabolism; Serotonin Plasma Membrane Transport Proteins, chemistry; Serotonin Uptake Inhibitors, therapeutic use; Tissue Distribution; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {0367050},
  owner           = {NLM},
  pii             = {S0091-3057(11)00359-5},
  pmid            = {22108649},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-11-25},
}

@Article{gee2017,
  author          = {Gee, Kelvin W and Olincy, Ann and Kanner, Richard and Johnson, Lynn and Hogenkamp, Derk and Harris, Josette and Tran, Minhtam and Edmonds, Stephen A and Sauer, William and Yoshimura, Ryan and Johnstone, Timothy and Freedman, Robert},
  title           = {First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288.},
  journal         = {J. Psychopharmacol.},
  year            = {2017},
  volume          = {31},
  issue           = {4},
  month           = apr,
  pages           = {434--441},
  issn            = {1461-7285},
  doi             = {10.1177/0269881117691590},
  abstract        = {Type I positive allosteric modulators (PAMs) of the alpha7-nicotinic receptor enhance its cholinergic activation while preserving the spatiotemporal features of synaptic transmission and the receptor's characteristic rapid desensitization kinetics. Alpha7-nicotinic receptor agonists have shown promise for improving cognition in schizophrenia, but longer-term trials have been disappointing. Therefore, the type I PAM AVL-3288 was evaluated for safety and preliminary evidence of neurocognitive effect in healthy human subjects. Single-dose oral administration in ascending doses was conducted in a double-blind, placebo-controlled Phase I trial in non-smokers. The trial found indication of positive but non-significant effects on neurocognition at 10 and 30 mg, two doses that produced overlapping peak levels. There was also some evidence for effects on inhibition of the P50 auditory evoked potential to repeated stimuli, a biomarker that responds to alpha7-nicotinic receptor activation. The pharmacokinetic characteristics were consistent between subjects, and there were no safety concerns. The effects and safety profile were also assessed at 3 mg in a cohort of smokers, in whom concurrent nicotine administration did not alter either effects or safety. The trial demonstrates that a type I PAM can be safely administered to humans and that it has potential positive neurocognitive effects in central nervous system (CNS) disorders.},
  chemicals       = {AVL3288, Anilides, Biomarkers, Isoxazoles, Nicotinic Agonists, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, Nicotine},
  citation-subset = {IM},
  completed       = {2018-01-04},
  country         = {United States},
  issn-linking    = {0269-8811},
  keywords        = {Adult; Allosteric Regulation, drug effects; Anilides, adverse effects, pharmacokinetics, therapeutic use; Biomarkers, metabolism; Cognition, drug effects; Double-Blind Method; Female; Humans; Isoxazoles, adverse effects, pharmacokinetics, therapeutic use; Male; Neurocognitive Disorders, drug therapy, metabolism; Nicotine, administration & dosage; Nicotinic Agonists, adverse effects, pharmacokinetics, therapeutic use; Receptors, Nicotinic, metabolism; Schizophrenia, drug therapy, metabolism; Synaptic Transmission, drug effects; Young Adult; alpha7 Nicotinic Acetylcholine Receptor, metabolism; Receptors; allosteric modulators; cognition; drug evaluation; nicotinic; schizophrenia},
  nlm-id          = {8907828},
  owner           = {NLM},
  pmid            = {28196430},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-01-11},
}

@Article{brunzell2014,
  author          = {Brunzell, Darlene H and McIntosh, J Michael and Papke, Roger L},
  title           = {Diverse strategies targeting α7 homomeric and α6β2* heteromeric nicotinic acetylcholine receptors for smoking cessation.},
  journal         = {Annals of the New York Academy of Sciences},
  year            = {2014},
  volume          = {1327},
  month           = oct,
  pages           = {27--45},
  issn            = {1749-6632},
  doi             = {10.1111/nyas.12421},
  abstract        = {Preclinical studies suggest that a diversity of nicotinic acetylcholine receptors (nAChRs) with different sensitivities to nicotine may contribute to tobacco addiction. Using rodent intravenous nicotine self-administration as a preclinical model with good predictive validity for therapeutic efficacy for tobacco cessation, investigators have identified heteromeric α6β2* and homomeric α7 nAChRs as promising novel therapeutic targets to promote smoking abstinence (*denotes possible assembly with other subunits). The data suggest that diverse strategies that target these subclasses of nAChRs, namely inhibition of α6β2* nAChRs and stimulation of α7 nAChRs, will support tobacco cessation. α6β2* nAChRs, members of the high-affinity family of β2* nAChRs, function similarly to α4β2* nAChRs, the primary target of the FDA-approved drug varenicline, but have a much more selective neuroanatomical pattern of expression in catecholaminergic nuclei. Although activation of β2* nAChRs facilitates nicotine self-administration, stimulation of α7 nAChRs appears to negatively modulate both nicotine reinforcement and β2* nAChR function in the mesolimbic dopamine system. Although challenges and caveats must be considered in the development of therapeutics that target these nAChR subpopulations, an accumulation of data suggests that α7 nAChR agonists, partial agonists, or positive allosteric modulators and α6β2* nAChR antagonists, partial agonists, or negative allosteric modulators may prove to be effective therapeutics for tobacco cessation. },
  chemicals       = {Chrna7 protein, human, Nerve Tissue Proteins, Nicotinic Agonists, Nicotinic Antagonists, Receptors, Nicotinic, alpha6beta2 nicotinic acetylcholine receptor, alpha7 Nicotinic Acetylcholine Receptor},
  citation-subset = {IM},
  completed       = {2014-12-23},
  country         = {United States},
  issn-linking    = {0077-8923},
  keywords        = {Allosteric Regulation, drug effects; Animals; Brain, drug effects, metabolism; Dopaminergic Neurons, drug effects, metabolism; Drug Design; Humans; Molecular Targeted Therapy; Nerve Tissue Proteins, agonists, antagonists & inhibitors, metabolism; Nicotinic Agonists, therapeutic use; Nicotinic Antagonists, therapeutic use; Receptors, Nicotinic, chemistry, metabolism; Smoking Cessation, methods; alpha7 Nicotinic Acetylcholine Receptor, agonists, metabolism; drug development; nicotine dependence; nicotinic; smoking cessation; α6; α7},
  mid             = {NIHMS610385},
  nlm-id          = {7506858},
  owner           = {NLM},
  pmc             = {PMC4197117},
  pmid            = {24730978},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{arias2013,
  author          = {Arias, Hugo R and De Rosa, Maria Jose and Bergé, Ignacio and Feuerbach, Dominik and Bouzat, Cecilia},
  title           = {Differential pharmacological activity of JN403 between α7 and muscle nicotinic acetylcholine receptors.},
  journal         = {Biochem.},
  year            = {2013},
  volume          = {52},
  issue           = {47},
  month           = nov,
  pages           = {8480--8488},
  issn            = {1520-4995},
  doi             = {10.1021/bi4012572},
  abstract        = {The differential action of the novel agonist JN403 at neuronal α7 and muscle nicotinic receptors (AChRs) was explored by using a combination of functional and structural approaches. Single-channel recordings reveal that JN403 is a potent agonist of α7 but a very low-efficacy agonist of muscle AChRs. JN403 elicits detectable openings of α7 and muscle AChRs at concentrations ~1000-fold lower and ~20-fold higher, respectively, than that for ACh. Single-channel activity elicited by JN403 is very similar to that elicited by ACh in α7 but profoundly different in muscle AChRs, where openings are brief and infrequent and do not appear in clusters at any concentration. JN403 elicits single-channel activity of muscle AChRs lacking the ε subunit, with opening events being more frequent and prolonged than those of wild-type AChRs. This finding is in line with the molecular docking studies predicting that JN403 may form a hydrogen bond required for potent activation at the α-δ but not at the α-ε binding site. JN403 does not elicit detectable Ca²⁺ influx in muscle AChRs but inhibits (±)-epibatidine-elicited influx mainly by a noncompetitive mechanism. Such inhibition is compatible with single-channel recordings revealing that JN403 produces open-channel blockade and early termination of ACh-elicited clusters, and it is therefore also a potent desensitizing enhancer of muscle AChRs. The latter mechanism is supported by the JN403-induced increase in the level of binding of [³H]cytisine and [³H]TCP to resting AChRs. Elucidation of the differences in activity of JN403 between neuronal α7 and muscle AChRs provides further insights into mechanisms underlying selectivity for α7 AChRs.},
  chemicals       = {(S)-(1-azabicyclo(2.2.2)oct-3-yl)carbamic acid (S)-1-(2-fluorophenyl) ethyl ester, CHRNA1 protein, human, Carbamates, Chrna7 protein, human, Fetal Proteins, Muscle Proteins, Nerve Tissue Proteins, Nicotinic Agonists, Nicotinic Antagonists, Protein Subunits, Quinuclidines, Receptors, Nicotinic, Recombinant Proteins, alpha7 Nicotinic Acetylcholine Receptor},
  citation-subset = {IM},
  completed       = {2014-01-30},
  country         = {United States},
  issn-linking    = {0006-2960},
  keywords        = {Animals; Calcium Signaling, drug effects; Carbamates, metabolism, pharmacology; Cell Line; Fetal Proteins, agonists, chemistry, genetics, metabolism; Humans; Kinetics; Membrane Potentials, drug effects; Mice; Molecular Conformation; Molecular Docking Simulation; Muscle Proteins, agonists, chemistry, genetics, metabolism; Nerve Tissue Proteins, agonists, chemistry, genetics, metabolism; Nicotinic Agonists, metabolism, pharmacology; Nicotinic Antagonists, chemistry, metabolism, pharmacology; Protein Binding; Protein Subunits, agonists, chemistry, genetics, metabolism; Quinuclidines, metabolism, pharmacology; Receptors, Nicotinic, chemistry, genetics, metabolism; Recombinant Proteins, chemistry, metabolism; Torpedo; alpha7 Nicotinic Acetylcholine Receptor, agonists, chemistry, genetics, metabolism},
  nlm-id          = {0370623},
  owner           = {NLM},
  pmid            = {24164482},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-11-26},
}

@Article{cheng2014,
  author          = {Cheng, Qing and Yakel, Jerrel L},
  title           = {Presynaptic α7 nicotinic acetylcholine receptors enhance hippocampal mossy fiber glutamatergic transmission via PKA activation.},
  journal         = {The J. Neurosci.},
  year            = {2014},
  volume          = {34},
  issue           = {1},
  month           = jan,
  pages           = {124--133},
  issn            = {1529-2401},
  doi             = {10.1523/JNEUROSCI.2973-13.2014},
  abstract        = {Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory. However, the mechanism of nicotine's action on cognitive function remains elusive. We performed patch-clamp recordings from hippocampal CA3 pyramidal neurons to determine the effect of nicotine on mossy fiber glutamatergic synaptic transmission. We found that nicotine in combination with NS1738, an α7 nAChR-positive allosteric modulator, strongly potentiated the amplitude of evoked EPSCs (eEPSCs), and reduced the EPSC paired-pulse ratio. The action of nicotine and NS1738 was mimicked by PNU-282987 (an α7 nAChR agonist), and was absent in α7 nAChR knock-out mice. These data indicate that activation of α7 nAChRs was both necessary and sufficient to enhance the amplitude of eEPSCs. BAPTA applied postsynaptically failed to block the action of nicotine and NS1738, suggesting again a presynaptic action of the α7 nAChRs. We also observed α7 nAChR-mediated calcium rises at mossy fiber giant terminals, indicating the presence of functional α7 nAChRs at presynaptic terminals. Furthermore, the addition of PNU-282987 enhanced action potential-dependent calcium transient at these terminals. Last, the potentiating effect of PNU-282987 on eEPSCs was abolished by inhibition of protein kinase A (PKA). Our findings indicate that activation of α7 nAChRs at presynaptic sites, via a mechanism involving PKA, plays a critical role in enhancing synaptic efficiency of hippocampal mossy fiber transmission. },
  chemicals       = {1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea, Benzamides, Bridged Bicyclo Compounds, PNU-282987, Phenylurea Compounds, alpha7 Nicotinic Acetylcholine Receptor, Glutamic Acid, Cyclic AMP-Dependent Protein Kinases},
  citation-subset = {IM},
  completed       = {2014-02-24},
  country         = {United States},
  issn-linking    = {0270-6474},
  keywords        = {Animals; Benzamides, pharmacology; Bridged Bicyclo Compounds, pharmacology; Cyclic AMP-Dependent Protein Kinases, metabolism; Enzyme Activation, drug effects, physiology; Female; Glutamic Acid, metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mossy Fibers, Hippocampal, drug effects, metabolism; Phenylurea Compounds, pharmacology; Presynaptic Terminals, drug effects, metabolism; Synaptic Transmission, drug effects, physiology; alpha7 Nicotinic Acetylcholine Receptor, agonists, antagonists & inhibitors, metabolism},
  nlm-id          = {8102140},
  owner           = {NLM},
  pii             = {34/1/124},
  pmc             = {PMC3866480},
  pmid            = {24381273},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{roncarati2009,
  author          = {Roncarati, Renza and Scali, Carla and Comery, Thomas A and Grauer, Steven M and Aschmi, Suzan and Bothmann, Hendrick and Jow, Brian and Kowal, Dianne and Gianfriddo, Marco and Kelley, Cody and Zanelli, Ugo and Ghiron, Chiara and Haydar, Simon and Dunlop, John and Terstappen, Georg C},
  title           = {Procognitive and neuroprotective activity of a novel alpha7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders.},
  journal         = {The J. Pharmacol. Exp. Ther.},
  year            = {2009},
  volume          = {329},
  issue           = {2},
  month           = may,
  pages           = {459--468},
  issn            = {1521-0103},
  doi             = {10.1124/jpet.108.150094},
  abstract        = {The alpha7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of alpha7 nAChR. SEN12333 shows high affinity for the rat alpha7 receptor expressed in GH4C1 cells (K(i) = 260 nM) and acts as full agonist in functional Ca(2+) flux studies (EC(50) = 1.6 microM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC(50) = 12 microM). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at alpha3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the alpha7-selective antagonist methyllycaconitine, indicating that it is mediated by alpha7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel alpha7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of alpha7 agonists for treatment of neurodegenerative and cognitive disorders.},
  chemicals       = {5-morpholin-4-ylpentanoic acid (4-pyridin-3-ylphenyl)amide, Chrna7 protein, human, Chrna7 protein, rat, Morpholines, Neuroprotective Agents, Nicotinic Agonists, Pyridines, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, Calcium},
  citation-subset = {IM},
  completed       = {2009-05-22},
  country         = {United States},
  issn-linking    = {0022-3565},
  keywords        = {Animals; Behavior, Animal, drug effects; Calcium, metabolism; Cell Line; Cognition, drug effects; Cognition Disorders, drug therapy, metabolism; Humans; Male; Membrane Potentials, drug effects; Molecular Structure; Morpholines, chemistry, pharmacokinetics, pharmacology, therapeutic use; Motor Activity, drug effects; Neurodegenerative Diseases, drug therapy, metabolism; Neuroprotective Agents, chemistry, pharmacokinetics, pharmacology, therapeutic use; Nicotinic Agonists, chemistry, pharmacokinetics, pharmacology, therapeutic use; Patch-Clamp Techniques; Protein Binding; Pyridines, chemistry, pharmacokinetics, pharmacology, therapeutic use; Radioligand Assay; Rats; Rats, Long-Evans; Rats, Wistar; Receptors, Nicotinic, metabolism; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {0376362},
  owner           = {NLM},
  pii             = {jpet.108.150094},
  pmid            = {19223665},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{tsoyi2011,
  author          = {Tsoyi, Konstantin and Jang, Hwa Jin and Kim, Jong Woo and Chang, Hong Kyung and Lee, Young Soo and Pae, Hyun-Ock and Kim, Hye Jung and Seo, Han Geuk and Lee, Jae Heun and Chung, Hun-Taeg and Chang, Ki Churl},
  title           = {Stimulation of alpha7 nicotinic acetylcholine receptor by nicotine attenuates inflammatory response in macrophages and improves survival in experimental model of sepsis through heme oxygenase-1 induction.},
  journal         = {Antioxidants \& redox signaling},
  year            = {2011},
  volume          = {14},
  issue           = {11},
  month           = jun,
  pages           = {2057--2070},
  issn            = {1557-7716},
  doi             = {10.1089/ars.2010.3555},
  abstract        = {Activation of nicotinic acetylcholine receptor alpha7 subunit (α7nAChR) by nicotine leads to the improved survival rate in experimental model of sepsis. Previously, we demonstrated that heme oxygenase (HO)-1 inducers or carbon monoxide significantly increased survival of lipopolysaccharide (LPS)-induced and cecal ligation and puncture-induced septic mice by reduction of high mobility group box 1 release, a late mediator of sepsis. However, that activation of α7nAChR by nicotine provides anti-inflammatory action through HO-1 upregulation has not been elucidated. Here we show that HO-1-inducible effect by nicotine was mediated through sequential event-Ca(2+) influx, classical protein kinase C activation, and reactive oxygen species production-which activates phosphoinositol-3-kinase/Akt/Nrf-2 pathway. In addition, HO-1 is required for nicotine-mediated suppression of tumor necrosis factor-α, inducible nitric oxide synthase, and high mobility group box 1 expression induced by LPS in macrophages, as evidenced by the fact that nicotine failed to inhibit production of these mediators when HO-1 was suppressed. Importantly, nicotine-induced survival rate was reduced by inhibition of HO-1 in LPS- and cecal ligation and puncture-treated septic mice. Collectively, these data suggest that activation of α7nAChR by nicotine is critical in the regulation of anti-inflammatory process, which could be mediated through HO-1 expression. Thus, we conclude that activation of α7nAChR by nicotine provides anti-inflammatory action through HO-1 upregulation.},
  chemicals       = {Anti-Inflammatory Agents, Chrna7 protein, human, Chrna7 protein, mouse, HMGB1 Protein, Lipopolysaccharides, NF-E2-Related Factor 2, Nfe2l2 protein, mouse, Nicotinic Agonists, Reactive Oxygen Species, Receptors, Nicotinic, Tumor Necrosis Factor-alpha, alpha7 Nicotinic Acetylcholine Receptor, Nicotine, Nitric Oxide Synthase Type II, Nos2 protein, mouse, Heme Oxygenase-1, NADPH Oxidases, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Protein Kinase C},
  citation-subset = {IM},
  completed       = {2011-11-01},
  country         = {United States},
  issn-linking    = {1523-0864},
  keywords        = {Animals; Anti-Inflammatory Agents, pharmacology; Calcium Signaling, drug effects; Cell Line; Endotoxemia, genetics, metabolism; Gene Expression Regulation, drug effects; HMGB1 Protein, metabolism; Heme Oxygenase-1, antagonists & inhibitors, genetics, metabolism; Humans; Inflammation, chemically induced, prevention & control; Kaplan-Meier Estimate; Lipopolysaccharides, toxicity; Macrophages, drug effects, metabolism; Male; Mice; Mice, Inbred BALB C; NADPH Oxidases, metabolism; NF-E2-Related Factor 2, metabolism; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Nitric Oxide Synthase Type II, metabolism; Phosphatidylinositol 3-Kinases, metabolism; Protein Kinase C, metabolism; Proto-Oncogene Proteins c-akt, metabolism; Reactive Oxygen Species, metabolism; Receptors, Nicotinic, metabolism; Sepsis, genetics, metabolism; Signal Transduction, drug effects; Tumor Necrosis Factor-alpha, metabolism; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {100888899},
  owner           = {NLM},
  pmid            = {21083424},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@Article{arias2013a,
  author          = {Arias, Hugo R and López, Jhon J and Feuerbach, Dominik and Fierro, Angélica and Ortells, Marcelo O and Pérez, Edwin G},
  title           = {Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms.},
  journal         = {The international journal of biochemistry \& cell biology},
  year            = {2013},
  volume          = {45},
  issue           = {11},
  month           = nov,
  pages           = {2420--2430},
  issn            = {1878-5875},
  doi             = {10.1016/j.biocel.2013.08.003},
  abstract        = {This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca(2+) influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed. The results indicate that the methiodides present the highest affinities for the hα7 nAChR agonist sites, while the same compounds bind preferably to the hα4β2 nAChR ion channel domain. These results indicate that the methiodides are competitive antagonists of the hα7 nAChR but noncompetitive antagonists of the hα4β2 subtype. Docking and molecular dynamics simulations showed that the methiodide derivative 8d binds to the hα7 orthosteric binding sites by forming stable cation-π interactions between the quaternized quinulinuim moiety and the aromatic box in the receptor, whereas compounds 7j and 8j block the hα4β2 AChR ion channel by interacting with a luminal domain formed between the serine (position 6') and valine (position 13') rings that overlaps the imipramine binding site. },
  chemicals       = {Ion Channels, Ligands, Quinuclidines, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, nicotinic receptor alpha4beta2, Calcium},
  citation-subset = {IM},
  completed       = {2014-08-27},
  country         = {Netherlands},
  issn-linking    = {1357-2725},
  keywords        = {Binding Sites; Binding, Competitive, drug effects; Calcium, metabolism; HEK293 Cells; Humans; Ion Channels, metabolism; Ligands; Molecular Docking Simulation; Quinuclidines, chemistry, pharmacology; Radioligand Assay; Receptors, Nicotinic, chemistry, metabolism; Stereoisomerism; Structure-Activity Relationship; Thermodynamics; alpha7 Nicotinic Acetylcholine Receptor, agonists, antagonists & inhibitors, chemistry, metabolism; ACh; CCh; Competitive antagonists; EC(50); Hill coefficient; IC(50); K(i); Nicotinic acetylcholine receptors; Noncompetitive antagonists; Quinuclidines; RMSD; RT; Structure–activity relationship; [(3)H]MLA; [(3)H]methyllycaconitine; acetylcholine; agonist concentration that produces 50% AChR activation; carbamylcholine; inhibition constant; ligand concentration that produces 50% inhibition (of binding or of agonist activation); n(H); nAChR; nicotinic acetylcholine receptor; room temperature; root mean square deviation},
  nlm-id          = {9508482},
  owner           = {NLM},
  pii             = {S1357-2725(13)00256-2},
  pmid            = {23954208},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-10-15},
}

@Article{papke2011,
  author          = {Papke, Roger L and Trocmé-Thibierge, Caryn and Guendisch, Daniela and Al Rubaiy, Shehd Abdullah Abbas and Bloom, Stephen A},
  title           = {Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists.},
  journal         = {The J. Pharmacol. Exp. Ther.},
  year            = {2011},
  volume          = {337},
  issue           = {2},
  month           = may,
  pages           = {367--379},
  issn            = {1521-0103},
  doi             = {10.1124/jpet.110.177485},
  abstract        = {Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between acetylcholine (ACh) and weak partial agonists. Data were best-fit to a basic competition model that included an additional factor for noncompetitive inhibition. Partial agonist effects were compared with the nAChR antagonist bupropion in prolonged bath application experiments that were designed to mimic prolonged drug exposure typical of therapeutic drug delivery. A primary effect of prolonged application of nicotine was to decrease the response of all nAChR subtypes to acute applications of ACh. In addition, nicotine, cytisine, and varenicline produced detectable steady-state activation of α4β2* [(α4)(2)(β2)(3), (α4)(3)(β2)(2), and (α4)(2)(β2)(2)α5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of α7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, "run-up" of α7 ACh responses was also sometimes observed under control conditions. Potential off-target effects of the partial agonists therefore included the modulation of α7 responses by α4β2 partial agonists and decreases in α4β2* responses by α7-selective agonists. These data indicate the dual effects expected for α4β2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development.},
  chemicals       = {Alkaloids, Azocines, Benzazepines, Chrna7 protein, human, DNA, Complementary, Dopamine Uptake Inhibitors, Nicotinic Agonists, Nicotinic Antagonists, Pyridinium Compounds, Quinolizines, Quinoxalines, Receptors, Nicotinic, S 24795, alpha7 Nicotinic Acetylcholine Receptor, nicotinic receptor alpha4beta2, Bupropion, cytisine, Nicotine, Acetylcholine, Varenicline},
  citation-subset = {IM},
  completed       = {2011-06-21},
  country         = {United States},
  issn-linking    = {0022-3565},
  keywords        = {Acetylcholine, pharmacology; Alkaloids, pharmacology; Animals; Azocines, pharmacology; Benzazepines, pharmacology; Bupropion, pharmacology; DNA, Complementary, biosynthesis, genetics; Dopamine Uptake Inhibitors, pharmacology; Electrophysiological Phenomena; Humans; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Nicotinic Antagonists, pharmacology; Oocytes, metabolism; Pyridinium Compounds, pharmacology; Quinolizines, pharmacology; Quinoxalines, pharmacology; Receptors, Nicotinic, drug effects; Smoking Cessation; Varenicline; Xenopus; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {0376362},
  owner           = {NLM},
  pii             = {jpet.110.177485},
  pmc             = {PMC3083103},
  pmid            = {21285282},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{kawahara2011,
  author          = {Kawahara, Ryoji and Yasuda, Masashi and Hashimura, Hiroshi and Amagase, Kikuko and Kato, Shinichi and Takeuchi, Koji},
  title           = {Activation of α7 nicotinic acetylcholine receptors ameliorates indomethacin-induced small intestinal ulceration in mice.},
  journal         = {European journal of pharmacology},
  year            = {2011},
  volume          = {650},
  issue           = {1},
  month           = jan,
  pages           = {411--417},
  issn            = {1879-0712},
  doi             = {10.1016/j.ejphar.2010.10.031},
  abstract        = {Cholinergic anti-inflammatory actions have been shown to result mainly from the activation of α7 nicotinic acetylcholine receptors. Here, we investigated the possible role of α7 nicotinic acetylcholine receptors in the pathogenesis of indomethacin-induced small intestinal ulceration in mice. Male C57BL/6 mice were given indomethacin (10mg/kg, s.c.), and sacrificed 24h later. Nicotine (0.3-3mg/kg) and PNU-282987 (a selective agonist of α7 nicotinic acetylcholine receptors; 1-10mg/kg) were administered i.p. twice, at 0.5h before and 8h after indomethacin treatment, while methyllycaconitine (a selective antagonist of α7 nicotinic acetylcholine receptors; 10mg/kg was administered twice, at 0.5h before each nicotine treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine with marked increases in myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS) expression in the mucosa. Pretreatment with nicotine reduced the severity of intestinal lesions in a dose-dependent manner. The protective effect of nicotine was mimicked by PNU-282987 and significantly attenuated by methyllycaconitine. The increases in MPO activity and iNOS expression induced by indomethacin were also significantly suppressed by nicotine and PNU-282987. Immunohistochemical study showed that the expression of α7 nicotinic acetylcholine receptors was clearly enhanced in the submucosa of the damaged area following indomethacin treatment. These results suggest that the activation of α7 nicotinic acetylcholine receptors ameliorates indomethacin-induced small intestinal ulceration, and that this effect may result from the inhibition of iNOS expression and neutrophil migration.},
  chemicals       = {Anti-Inflammatory Agents, Non-Steroidal, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Benzamides, Bridged Bicyclo Compounds, CD68 antigen, human, Chrna7 protein, human, Chrna7 protein, mouse, Nicotinic Agonists, PNU-282987, RNA, Messenger, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, 3-nitrotyrosine, Tyrosine, Nicotine, Peroxidase, Nitric Oxide Synthase Type II, Indomethacin},
  citation-subset = {IM},
  completed       = {2011-03-24},
  country         = {Netherlands},
  issn-linking    = {0014-2999},
  keywords        = {Animals; Anti-Inflammatory Agents, Non-Steroidal, adverse effects; Antigens, CD, metabolism; Antigens, Differentiation, Myelomonocytic, metabolism; Benzamides, pharmacology; Bridged Bicyclo Compounds, pharmacology; Gene Expression Regulation, Enzymologic, drug effects; Indomethacin, adverse effects; Intestine, Small, drug effects, enzymology, metabolism; Macrophages, drug effects, metabolism; Male; Mice; Mice, Inbred C57BL; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Nitric Oxide Synthase Type II, genetics; Peroxidase, metabolism; RNA, Messenger, genetics, metabolism; Receptors, Nicotinic, metabolism; Tyrosine, analogs & derivatives, biosynthesis; Ulcer, chemically induced, enzymology, metabolism; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {1254354},
  owner           = {NLM},
  pii             = {S0014-2999(10)01053-8},
  pmid            = {20969854},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-11-25},
}

@Article{gopalakrishnan2011,
  author          = {Gopalakrishnan, Sujatha M and Philip, Betsy M and Gronlien, Jens Halvard and Malysz, John and Anderson, David J and Gopalakrishnan, Murali and Warrior, Usha and Burns, David J},
  title           = {Functional characterization and high-throughput screening of positive allosteric modulators of α7 nicotinic acetylcholine receptors in IMR-32 neuroblastoma cells.},
  journal         = {Assay and drug development technologies},
  year            = {2011},
  volume          = {9},
  issue           = {6},
  month           = dec,
  pages           = {635--645},
  issn            = {1557-8127},
  doi             = {10.1089/adt.2010.0319},
  abstract        = {α7 nicotinic acetylcholine receptors (nAChRs) are characterized by relatively low ACh sensitivity, rapid activation, and fast desensitization kinetics. ACh/agonist evoked currents at the α7 nAChR are transient, and, typically, calcium flux responses are difficult to detect using conventional fluorometric assay techniques. One approach to study interactions of agonists with the α7 nAChR is by utilizing positive allosteric modulators (PAMs). In this study, we demonstrate that inclusion of type II PAMs such as PNU-120596, but not type I, can enable detection of endogenous α7 nAChR-mediated calcium responses in human neuroblastoma (IMR-32) cells. Using this approach, we characterized the pharmacological profile of nicotine, epibatidine, choline, and other nAChR agonists such as PNU-282987, SSR-180711, GTS-21, OH-GTS21, tropisetron, NS6784, and A-582941. The rank order potency of agonists well correlated with α7 nAChR binding affinities measured in brain membranes. Inhibition of calcium response by methyllycaconitine in the presence of increasing concentrations of PNU-282987 or PNU-120596 revealed that the IC(50) value of methyllycaconitine was sensitive to varying concentrations of the agonist, but not that of the PAM. This format demonstrated the feasibility of this approach for high-throughput screening to identify small molecule, PAMs, which were further confirmed in electrophysiological assays of human α7 nAChR expressed in oocytes.},
  chemicals       = {Chrna7 protein, human, Chrna7 protein, rat, Nicotinic Agonists, Nicotinic Antagonists, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor},
  citation-subset = {IM},
  completed       = {2012-08-16},
  country         = {United States},
  issn-linking    = {1540-658X},
  keywords        = {Allosteric Regulation, drug effects, physiology; Animals; Animals, Newborn; Cell Line, Tumor; Cells, Cultured; Dose-Response Relationship, Drug; Female; High-Throughput Screening Assays, methods; Humans; Neuroblastoma; Nicotinic Agonists, chemistry, pharmacology; Nicotinic Antagonists, chemistry, pharmacology; Rats; Receptors, Nicotinic, physiology; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {101151468},
  owner           = {NLM},
  pmid            = {21309712},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{russo2014,
  author          = {Russo, Patrizia and Del Bufalo, Alessandra and Frustaci, Alessandra and Fini, Massimo and Cesario, Alfredo},
  title           = {Beyond acetylcholinesterase inhibitors for treating Alzheimer's disease: α7-nAChR agonists in human clinical trials.},
  journal         = {Current pharmaceutical design},
  year            = {2014},
  volume          = {20},
  issue           = {38},
  pages           = {6014--6021},
  issn            = {1873-4286},
  abstract        = {The neuronal nicotinic alpha7-acetylcholine receptor (α7-nAChR) is a promising and attractive drug target for improving cognitive deficits in neuropsychiatric and neurological disorders such as Alzheimer's disease (AD). α7-nAChR belongs to the family of ligand gated ion channels. α7-nAChR is expressed in key brain regions (e.g. pre- and frontal cortex, hippocampus). It is involved in essential cognitive functions such as memory, thinking, comprehension, learning capacity, calculation, orientation, language, and judgment. α7-nAChR binds to amyloid peptide (Aβ) inducing either receptor activation or inhibition in an Aβ concentration-dependent mode. Aβ oligomers induce τ phosphorylation via α7-nAChR activation. α7-nAChR agonists and/or α7-nAChR positive allosteric modulators may be useful in AD therapy. The current review enlightens: (i) α7-nAChR neurobiology, (ii) α7-nAChR role in cognition and (iii) in AD, and (iv) the clinical status of the most promising molecules for the treatment of cognitive dysfunction in AD. },
  chemicals       = {Cholinesterase Inhibitors, Nicotinic Agonists, alpha7 Nicotinic Acetylcholine Receptor},
  citation-subset = {IM},
  completed       = {2015-06-22},
  country         = {United Arab Emirates},
  issn-linking    = {1381-6128},
  keywords        = {Alzheimer Disease, drug therapy, epidemiology; Cholinesterase Inhibitors, administration & dosage; Clinical Trials as Topic, trends; Drug Delivery Systems, trends; Humans; Nicotinic Agonists, administration & dosage; Treatment Outcome; alpha7 Nicotinic Acetylcholine Receptor, agonists},
  nlm-id          = {9602487},
  owner           = {NLM},
  pii             = {CPD-EPUB-59658},
  pmid            = {24641224},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-06-05},
}

@Article{kalkman2016,
  author          = {Kalkman, Hans O and Feuerbach, Dominik},
  title           = {Modulatory effects of α7 nAChRs on the immune system and its relevance for CNS disorders.},
  journal         = {Cellular and molecular life sciences : CMLS},
  year            = {2016},
  volume          = {73},
  issue           = {13},
  month           = jul,
  pages           = {2511--2530},
  issn            = {1420-9071},
  doi             = {10.1007/s00018-016-2175-4},
  abstract        = {The clinical development of selective alpha-7 nicotinic acetylcholine receptor (α7 nAChR) agonists has hitherto been focused on disorders characterized by cognitive deficits (e.g., Alzheimer's disease, schizophrenia). However, α7 nAChRs are also widely expressed by cells of the immune system and by cells with a secondary role in pathogen defense. Activation of α7 nAChRs leads to an anti-inflammatory effect. Since sterile inflammation is a frequently observed phenomenon in both psychiatric disorders (e.g., schizophrenia, melancholic and bipolar depression) and neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, and multiple sclerosis), α7 nAChR agonists might show beneficial effects in these central nervous system disorders. In the current review, we summarize information on receptor expression, the intracellular signaling pathways they modulate and reasons for receptor dysfunction. Information from tobacco smoking, vagus nerve stimulation, and cholinesterase inhibition is used to evaluate the therapeutic potential of selective α7 nAChR agonists in these inflammation-related disorders. },
  chemicals       = {alpha7 Nicotinic Acetylcholine Receptor},
  citation-subset = {IM},
  completed       = {2017-02-15},
  country         = {Switzerland},
  issn-linking    = {1420-682X},
  keywords        = {Animals; Central Nervous System Diseases, drug therapy, immunology, pathology; Drug Discovery; Humans; Immune System, drug effects, immunology, pathology; Signal Transduction, drug effects; alpha7 Nicotinic Acetylcholine Receptor, agonists, analysis, immunology; Autism; CREB; Dyskinesia; GSK3; Lithium; Nrf2; Suicide},
  nlm-id          = {9705402},
  owner           = {NLM},
  pii             = {10.1007/s00018-016-2175-4},
  pmc             = {PMC4894934},
  pmid            = {26979166},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{papke2009,
  author          = {Papke, R. L. and Kem, W. R. and Soti, F. and López-Hernández, G. Y. and Horenstein, N. A.},
  title           = {Activation and desensitization of nicotinic alpha7-type acetylcholine receptors by benzylidene anabaseines and nicotine.},
  journal         = {The J. Pharmacol. Exp. Ther.},
  year            = {2009},
  volume          = {329},
  issue           = {2},
  month           = may,
  pages           = {791--807},
  issn            = {1521-0103},
  doi             = {10.1124/jpet.108.150151},
  abstract        = {Nicotinic receptor activation is inextricably linked to desensitization. This duality affects our ability to develop useful therapeutics targeting nicotinic acetylcholine receptor (nAChR). Nicotine and some alpha7-selective experimental partial agonists produce a transient activation of alpha7 receptors followed by a period of prolonged residual inhibition or desensitization (RID). The object of the present study was to determine whether RID was primarily due to prolonged desensitization or due to channel block. To make this determination, we used agents that varied significantly in their production of RID and two alpha7-selective positive allosteric modulators (PAMs): 5-hydroxyindole (5HI), a type 1 PAM that does not prevent desensitization; and 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxanol-3-yl)-urea (PNU-120596), a type 2 PAM that reactivates desensitized receptors. The RID-producing compounds nicotine and 3-(2,4-dimethoxybenzylidene)anabaseine (diMeOBA) could obscure the potentiating effects of 5HI. However, through the use of nicotine, diMeOBA, and the RID-negative compound 3-(2,4-dihydroxybenzylidene)anabaseine (diOHBA) in combination with PNU-120596, we confirmed that diMeOBA produces short-lived channel block of alpha7 but that RID is because of the induction of a desensitized state that is stable in the absence of PNU-120596 and activated in the presence of PNU-120596. In contrast, diOHBA produced channel block but only readily reversible desensitization, whereas nicotine produced desensitization that could be converted into activation by PNU-120596 but no demonstrable channel block. Steady-state currents through receptors that would otherwise be desensitized could also be produced by the application of PNU-120596 in the presence of a physiologically relevant concentration of choline (60 microM), which may be significant for the therapeutic development of type 2 PAMs.},
  chemicals       = {Benzylidene Compounds, Chrna7 protein, human, Chrna7 protein, rat, Nicotinic Agonists, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, Nicotine, anabaseine, Anabasine},
  citation-subset = {IM},
  completed       = {2009-05-22},
  country         = {United States},
  issn-linking    = {0022-3565},
  keywords        = {Allosteric Regulation; Anabasine, analogs & derivatives, chemistry, pharmacology; Animals; Benzylidene Compounds, chemistry, pharmacology; Dose-Response Relationship, Drug; Female; Humans; Nicotine, chemistry, pharmacology; Nicotinic Agonists, chemistry, pharmacology; Oocytes, metabolism; Rats; Receptors, Nicotinic, genetics, metabolism; Structure-Activity Relationship; Transfection; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {0376362},
  owner           = {NLM},
  pii             = {jpet.108.150151},
  pmc             = {PMC2672872},
  pmid            = {19223664},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{flood2002,
  author          = {Flood, Pamela and Coates, Kristen M},
  title           = {Sensitivity of the alpha7 nicotinic acetylcholine receptor to isoflurane may depend on receptor inactivation.},
  journal         = {Anesthesia and analgesia},
  year            = {2002},
  volume          = {95},
  issue           = {1},
  month           = jul,
  pages           = {83--7, table of contents},
  issn            = {0003-2999},
  abstract        = {In previous studies, we demonstrated that nicotinic acetylcholine receptors (nAChRs) composed of the alpha7 subunit are unaffected by the co-application of isoflurane with agonists at concentrations up to 640 microM (two times the minimum alveolar anesthetic concentration). Modulation of alpha7-nAChR activity by isoflurane might have important behavioral ramifications because these receptors are expressed diffusely in the central and peripheral nervous systems and play pre- and postsynaptic roles in synaptic transmission. Here we have demonstrated that under some potentially physiologically relevant circumstances, the activation of alpha7 nAChRs may be inhibited by clinically relevant concentrations of isoflurane. We evaluated isoflurane inhibition of alpha7 nAChRs from chicks and humans expressed in Xenopus oocytes using two-electrode voltage clamp methodology. We determined the influence of time of preperfusion of isoflurane, agonist concentration, and membrane potential on inhibition by isoflurane. Both activation by a large concentration of agonist and isoflurane preperfusion increased inhibition. The half-maximal inhibitory concentration for isoflurane inhibition of chick alpha7 nAChR with isoflurane preperfusion and activation by 100 microM of acetylcholine was 938 +/- 26, and when activated by 1 mM of acetylcholine, it was 408 +/- 51 microM. The increase in inhibition with isoflurane preexposure and large agonist concentration raises the possibility that isoflurane interacts preferentially with a closed or closed-desensitized state of the channel. Nicotinic receptors expressed in the brain have been considered a possible target for the actions of isoflurane. We studied the effect of isoflurane on alpha7 type nicotinic receptors expressed in Xenopus oocytes. We find that when activated by large concentrations of acetylcholine, alpha7 nicotinic receptors are inhibited by isoflurane at concentrations near MAC.},
  chemicals       = {Anesthetics, Inhalation, Chrna7 protein, human, Nicotinic Agonists, Nicotinic Antagonists, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, Isoflurane, Acetylcholine},
  citation-subset = {AIM, IM},
  completed       = {2002-07-23},
  country         = {United States},
  issn-linking    = {0003-2999},
  keywords        = {Acetylcholine, pharmacology; Anesthetics, Inhalation, pharmacology; Animals; Chick Embryo; Electrophysiology; Humans; Isoflurane, pharmacology; Nicotinic Agonists, pharmacology; Nicotinic Antagonists; Pulmonary Alveoli, metabolism; Receptors, Nicotinic, drug effects; Synapses, drug effects; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {1310650},
  owner           = {NLM},
  pmid            = {12088948},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{ross2016,
  author          = {Ross, Randal G and Hunter, Sharon K and Hoffman, M Camille and McCarthy, Lizbeth and Chambers, Betsey M and Law, Amanda J and Leonard, Sherry and Zerbe, Gary O and Freedman, Robert},
  title           = {Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation.},
  journal         = {The American journal of psychiatry},
  year            = {2016},
  volume          = {173},
  issue           = {5},
  month           = may,
  pages           = {509--516},
  issn            = {1535-7228},
  doi             = {10.1176/appi.ajp.2015.15091188},
  abstract        = {α7-Nicotinic receptors are involved in the final maturation of GABA inhibitory synapses before birth. Choline at levels found in the amniotic fluid is an agonist at α7-nicotinic receptors. The authors conducted a double-blind placebo-controlled trial to assess whether high-dose oral phosphatidylcholine supplementation during pregnancy to increase maternal amniotic fluid choline levels would enhance fetal development of cerebral inhibition and, as a result, decrease childhood behavior problems associated with later mental illness. The authors previously reported that newborns in the phosphatidylcholine treatment group have increased suppression of the cerebral evoked response to repeated auditory stimuli. In this follow-up, they report parental assessments of the children's behavior at 40 months of age, using the Child Behavior Checklist. At 40 months, parent ratings of children in the phosphatidylcholine group (N=23) indicated fewer attention problems and less social withdrawal compared with the placebo group (N=26). The improvement is comparable in magnitude to similar deficits at this age associated with later schizophrenia. The children's behavior is moderated by CHRNA7 variants associated with later mental illness and is related to their enhanced cerebral inhibition as newborns. CHRNA7, the α7-nicotinic acetylcholine receptor gene, has been associated with schizophrenia, autism, and attention deficit hyperactivity disorder. Maternal phosphatidylcholine treatment may, by increasing activation of the α7-nicotinic acetylcholine receptor, alter the development of behavior problems in early childhood that can presage later mental illness.},
  chemicals       = {Phosphatidylcholines, alpha7 Nicotinic Acetylcholine Receptor},
  citation-subset = {AIM, IM},
  completed       = {2017-05-09},
  country         = {United States},
  issn-linking    = {0002-953X},
  keywords        = {Adult; Child Behavior, drug effects; Child, Preschool; Double-Blind Method; Female; Genotype; Humans; Phosphatidylcholines, pharmacology; Pregnancy; Prenatal Exposure Delayed Effects, psychology; Young Adult; alpha7 Nicotinic Acetylcholine Receptor, agonists, genetics},
  mid             = {NIHMS954203},
  nlm-id          = {0370512},
  owner           = {NLM},
  pmc             = {PMC5892450},
  pmid            = {26651393},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{mura2012,
  author          = {Mura, Elisa and Zappettini, Stefania and Preda, Stefania and Biundo, Fabrizio and Lanni, Cristina and Grilli, Massimo and Cavallero, Anna and Olivero, Guendalina and Salamone, Alessia and Govoni, Stefano and Marchi, Mario},
  title           = {Dual effect of beta-amyloid on α7 and α4β2 nicotinic receptors controlling the release of glutamate, aspartate and GABA in rat hippocampus.},
  journal         = {PloS one},
  year            = {2012},
  volume          = {7},
  issue           = {1},
  pages           = {e29661},
  issn            = {1932-6203},
  doi             = {10.1371/journal.pone.0029661},
  abstract        = {We previously showed that beta-amyloid (Aβ), a peptide considered as relevant to Alzheimer's Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer's Disease pathology, evaluating the effect of Aβ (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, α4β2 and α7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA. WE USED A DUAL APPROACH: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Aβ considered (10 µM in vivo and 100 nM in vitro). In vivo administration of 100 nM Aβ (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Aβ and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (α7 and α4β2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Aβ concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Aβ concentrations (1 nM and 100 pM) selectively acted on α7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA. The results reinforce the concept that Aβ has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used.},
  chemicals       = {Amyloid beta-Peptides, Chrna7 protein, human, Chrna7 protein, rat, Neurotransmitter Agents, Nicotinic Agonists, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, nicotinic receptor alpha4beta2, Aspartic Acid, Glutamic Acid, gamma-Aminobutyric Acid, Nicotine, Veratridine, Potassium},
  citation-subset = {IM},
  completed       = {2012-05-29},
  country         = {United States},
  issn-linking    = {1932-6203},
  keywords        = {Amyloid beta-Peptides, metabolism, pharmacology; Animals; Aspartic Acid, metabolism; Glutamic Acid, metabolism; Hippocampus, cytology, drug effects, metabolism; Humans; Immunohistochemistry; Male; Neurotransmitter Agents, metabolism; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Potassium, pharmacology; Rats; Rats, Wistar; Receptors, Nicotinic, metabolism; Time Factors; Veratridine, pharmacology; alpha7 Nicotinic Acetylcholine Receptor; gamma-Aminobutyric Acid, metabolism},
  nlm-id          = {101285081},
  owner           = {NLM},
  pii             = {PONE-D-11-14035},
  pmc             = {PMC3256170},
  pmid            = {22253754},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-01},
}

@Article{chernyavsky2010,
  author          = {Chernyavsky, Alexander I and Arredondo, Juan and Skok, Maryna and Grando, Sergei A},
  title           = {Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors.},
  journal         = {International immunopharmacology},
  year            = {2010},
  volume          = {10},
  issue           = {3},
  month           = mar,
  pages           = {308--315},
  issn            = {1878-1705},
  doi             = {10.1016/j.intimp.2009.12.001},
  abstract        = {Although acetylcholine (ACh) is well known for its neurotransmitter function, recent studies have indicated that it also functions as an immune cytokine that prevents macrophage activation through a 'cholinergic (nicotinic) anti-inflammatory pathway'. In this study, we used the macrophage-like U937 cells to elucidate the mechanisms of the physiologic control of cytokine production by auto/paracrine ACh through the nicotinic class of ACh receptors (nAChRs) expressed in these cells. Stimulation of cells with lipopolysaccharide up-regulated expression of alpha1, alpha4, alpha5, alpha7, alpha10, beta1 and beta3 subunits, down-regulated alpha6 and beta2 subunits, and did not alter the relative quantity of alpha9 and beta4 mRNAs. Distinct nAChR subtypes showed differential regulation of the production of pro- and anti-inflammatory cytokines. While inhibition of the expression of the TNF-alpha gene was mediated predominantly by the alpha-bungarotoxin sensitive nAChRs, that of the IL-6 and IL-18 genes-by the mecamylamine-sensitive nAChRs. Both the Mec- and alphaBtx-sensitive nAChRs regulated expression of the IL-1beta gene equally efficiently. Upregulation of IL-10 production by auto/paracrine ACh was mediated predominantly through alpha7 nAChR. These findings offer a new insight on how nicotinic agonists control inflammation, thus laying a groundwork for the development of novel immunomodulatory therapies based on the nAChR subtype selectivity of nicotinic agonists.},
  chemicals       = {Chrna7 protein, human, Cytokines, Immunologic Factors, Indicators and Reagents, Lipopolysaccharides, Nicotinic Agonists, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, Interleukin-10, Acetylcholine},
  citation-subset = {IM},
  completed       = {2010-06-02},
  country         = {Netherlands},
  issn-linking    = {1567-5769},
  keywords        = {Acetylcholine, pharmacology; Autocrine Communication, drug effects; Blotting, Western; Cytokines, metabolism; Humans; Immunologic Factors, pharmacology; Indicators and Reagents; Inflammation, metabolism; Interleukin-10, biosynthesis; Lipopolysaccharides, pharmacology; Macrophages, drug effects; Nicotinic Agonists, pharmacology; Paracrine Communication, drug effects; Receptors, Nicotinic, drug effects, metabolism; Reverse Transcriptase Polymerase Chain Reaction; U937 Cells; alpha7 Nicotinic Acetylcholine Receptor},
  mid             = {NIHMS165136},
  nlm-id          = {100965259},
  owner           = {NLM},
  pii             = {S1567-5769(09)00366-X},
  pmc             = {PMC2829366},
  pmid            = {20004742},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2019-01-08},
}

@Article{chernyavsky2008,
  author          = {Chernyavsky, Alex I and Arredondo, Juan and Piser, Timothy and Karlsson, Evert and Grando, Sergei A},
  title           = {Differential coupling of M1 muscarinic and alpha7 nicotinic receptors to inhibition of pemphigus acantholysis.},
  journal         = {J. Biol. Chem.},
  year            = {2008},
  volume          = {283},
  issue           = {6},
  month           = feb,
  pages           = {3401--3408},
  issn            = {0021-9258},
  doi             = {10.1074/jbc.M704956200},
  abstract        = {The mechanisms mediating and regulating assembly and disassembly of intercellular junctions is a subject of intensive research. The IgG autoantibodies produced in patients with the immunoblistering skin disease pemphigus vulgaris (PV) can induce keratinocyte (KC) dyshesion (acantholysis) via mechanisms that involve signaling kinases targeting intercellular adhesion molecules, thus providing a useful model to study the physiologic regulation of KC cohesion. Previous studies showed that activation of Src and protein kinase C are the earliest events in the PV IgG-induced intracellular phosphorylation cascades and that cholinergic agonists are effective for treating patients with pemphigus. In this study, we sought to elucidate the molecular mechanisms allowing cholinergic agonists to inhibit PV IgG-induced acantholysis and phosphorylation of KC adhesion molecules. The extent of acantholysis in KC monolayers correlated closely with the degree of PV IgG-induced phosphorylation of p120- and beta-catenins, with classic isoforms of protein kinase C mediating serine phosphorylation of beta-catenin and Src-tyrosine phosphorylation of p120-catenin. The M(1) muscarinic agonist pilocarpine blocked phosphorylation of both catenins, which could be abolised by the M(1) antagonist MT7. The alpha7 nicotinic agonist AR-R17779 inhibited phosphorylation of P120-cateinin. The alpha7 antagonist methyllycaconitine abolished the effect of AR-R17779. Okadaic acid abrogated protective effects of agonists on phosphorylation of beta-catenin, and pervanadate, on that of p120-catenin. Stimulation of KCs with pilocarpine significantly (p < 0.05) elevated both serine/threonine and tyrosine phosphatase activities in KCs. AR-R17779 both stimulated tyrosine phosphatase and decreased PV IgG-induced Src activity. Methyllycaconitine released Src activity in intact KCs and caused acantholysis. Thus, downstream signaling from M(1) abolished PV IgG-dependent catenin phosphorylation due to activation of both serine/threonine and tyrosine phosphatases, whereas alpha7 action involved both activation of tyrosine phosphatase and inhibition of Src. These findings identified novel paradigm of regulation of signaling kinases associated with cholinergic receptors and provided mechanistic explanation of therapeutic activity of cholinomimetics in PV patients.},
  chemicals       = {Chrna7 protein, human, Immunoglobulin G, Receptor, Muscarinic M1, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, beta Catenin, Okadaic Acid, methyllycaconitine, src-Family Kinases, Aconitine},
  citation-subset = {IM},
  completed       = {2008-03-31},
  country         = {United States},
  issn-linking    = {0021-9258},
  keywords        = {Aconitine, analogs & derivatives, pharmacology; Cell Adhesion; Cells, Cultured; Gene Expression Regulation; Humans; Immunoglobulin G, chemistry, metabolism; Keratinocytes, cytology, metabolism; Models, Biological; Okadaic Acid, metabolism; Pemphigus, metabolism; Phosphorylation; Receptor, Muscarinic M1, metabolism; Receptors, Nicotinic, metabolism; alpha7 Nicotinic Acetylcholine Receptor; beta Catenin, metabolism; src-Family Kinases, metabolism},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pii             = {M704956200},
  pmid            = {18073210},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{dajas-bailador2002,
  author          = {Dajas-Bailador, F A and Soliakov, L and Wonnacott, S},
  title           = {Nicotine activates the extracellular signal-regulated kinase 1/2 via the alpha7 nicotinic acetylcholine receptor and protein kinase A, in SH-SY5Y cells and hippocampal neurones.},
  journal         = {J. Neurochem.},
  year            = {2002},
  volume          = {80},
  issue           = {3},
  month           = feb,
  pages           = {520--530},
  issn            = {0022-3042},
  abstract        = {Neuronal nicotinic acetylcholine receptors (nAChR) can modulate many cellular mechanisms, such as cell survival and memory processing, which are also influenced by the serine/threonine protein kinases ERK1/2. In SH-SY5Y cells and hippocampal neurones, nicotine (100 microM) increased the activity of ERK1/2. This effect was Ca2+ dependent, and prevented by the alpha7 nAChR antagonist alpha-bungarotoxin (alpha-Bgt) and an inhibitor (PD98059) of the upstream kinase MEK. To determine the intervening steps linking Ca2+ entry to MEK-ERK1/2 activation, inhibitors of Ca2+-dependent kinases were deployed. In SH-SY5Y cells, selective blockers for PKC (Ro 31-8220), CaM kinase II (KN-62) or PI3 kinase (LY 294002) failed to inhibit the nicotine-evoked increase in ERK1/2 activity. In contrast, two structurally different inhibitors of PKA (KT 5720 and H-89) completely prevented the nicotine-dependent increase in ERK1/2 activity. Inhibition of the nicotine-evoked increase in ERK1/2 activity by H-89 was also observed in hippocampal cultures. Down stream of PKA, the activity of B-Raf was significantly decreased by nicotine in SH-SY5Y cells, as determined by direct measurement of MEK1 phosphorylation or in vitro kinase assays, whereas the modulation of MEK1 phosphorylation by Raf-1 tended to increase. Thus, this study provides evidence for a novel signalling route coupling the stimulation of alpha7 nAChR to the activation of ERK1/2, in a Ca2+ and PKA dependent manner.},
  chemicals       = {Chrna7 protein, human, Nicotinic Agonists, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, Nicotine, Cyclic AMP-Dependent Protein Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases},
  citation-subset = {IM},
  completed       = {2002-04-04},
  country         = {England},
  issn-linking    = {0022-3042},
  keywords        = {Cyclic AMP-Dependent Protein Kinases, metabolism; Hippocampus, cytology; Humans; MAP Kinase Signaling System, drug effects, physiology; Mitogen-Activated Protein Kinase 1, metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases, metabolism; Neuroblastoma; Neurons, cytology, enzymology; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Receptors, Nicotinic, metabolism; Tumor Cells, Cultured; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {2985190R},
  owner           = {NLM},
  pmid            = {11905997},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{briggs1998,
  author          = "{Briggs, C. A. and D. G. McKenna}",
  title           = {Activation and inhibition of the human {a}lpha7 nicotinic acetylcholine receptor by agonists.},
  journal         = {Neuropharm.},
  year            = {1998},
  volume          = {37},
  issue           = {9},
  month           = sep,
  pages           = {1095--1102},
  issn            = {0028-3908},
  abstract        = {To better understand the effects of weak as well as strong agonists at the human alpha7 nicotinic acetylcholine receptor (human alpha7 nAChR), the abilities of several classic nAChR agonists to both activate and inhibit (desensitize) the human alpha7 nAChR expressed in Xenopus oocytes were quantified and compared. Activation was measured during 0.2-20 s agonist application, as required to elicit a peak response. Inhibition was measured as the reduction in the agonist response to 200 microM ACh in the presence of inhibitor during a 5-20 min incubation. Acetylcholine (ACh), (-)-nicotine, (+)-nicotine, and 1,1-dimethyl-4-phenylpiperazinium (DMPP) were 62- to 130-fold more potent as inhibitors than as activators, with excellent correlation between the IC50 and EC50 values (r2 = 0.924). Agonist concentrations that elicited only 0.6-1.2% nAChR activation were sufficient to inhibit the response to ACh by 50%. Thus, even a very weak agonist could appear to be a potent and effective inhibitor through receptor desensitization. (-)-Lobeline, in contrast, acted as an antagonist at the human alpha7 nAChR, eliciting no detectable agonist-like response at concentrations up to 1 mM, but inhibiting the response to ACh with an IC50 value of 8.5 microM. (-)-Cotinine and the novel ligand ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine] acted as weak agonists at the human alpha7 nAChR (1 and 1.5% response at 1 mM, respectively) and inhibited the response to ACh with IC50) values of 175 and 48 microM, respectively. These effects could be explained by receptor desensitization, at least in part.},
  chemicals       = {Nicotinic Agonists, Receptors, Nicotinic, Dimethylphenylpiperazinium Iodide, RNA, Nicotine, Lobeline, Cotinine, Acetylcholine},
  citation-subset = {IM},
  completed       = {1999-02-02},
  country         = {England},
  issn-linking    = {0028-3908},
  keywords        = {Acetylcholine, pharmacology; Animals; Cotinine, pharmacology; Dimethylphenylpiperazinium Iodide, pharmacology; Dose-Response Relationship, Drug; Female; Humans; Lobeline, pharmacology; Membrane Potentials, drug effects; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Oocytes, drug effects, metabolism, physiology; Patch-Clamp Techniques; RNA, administration & dosage, genetics; Receptors, Nicotinic, drug effects, genetics, metabolism; Xenopus},
  nlm-id          = {0236217},
  owner           = {NLM},
  pii             = {S0028390898001105},
  pmid            = {9833639},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{carlisle2007,
  author          = {Carlisle, Diane L and Liu, Xuwan and Hopkins, Toni M and Swick, Michelle C and Dhir, Rajiv and Siegfried, Jill M},
  title           = {Nicotine activates cell-signaling pathways through muscle-type and neuronal nicotinic acetylcholine receptors in non-small cell lung cancer cells.},
  journal         = {Pulmonary pharmacology \& therapeutics},
  year            = {2007},
  volume          = {20},
  issue           = {6},
  pages           = {629--641},
  issn            = {1094-5539},
  doi             = {10.1016/j.pupt.2006.07.001},
  abstract        = {Nicotinic acetylcholine receptors (nAChR) are expressed on non-neuronal cell types, including normal bronchial epithelial cells, and nicotine has been reported to cause Akt activation in cultured normal airway cells. This study documents mRNA and protein expression of subunits known to form a muscle-type nAChR in non-small cell lung cancer (NSCLC) cell lines. In one NSCLC examined, mRNA and protein for a heteropentamer neuronal-type alpha3beta2 nAChR was detected in addition to a muscle-type receptor. Protein for the alpha5 nAChR was also detected in NSCLC cells. Although, mRNA for the alpha7 nAChR subunit was observed in all cell lines, alpha7 protein was not detectable by immunoblot in NSCLC cell extracts. Immunohistochemistry (IHC) of NSCLC primary tissues from 18 patients demonstrated protein expression of nAChR alpha1 and beta1 subunits, but not alpha7 subunit, in lung tumors, indicating preferential expression of the muscle-type receptor. In addition, the beta1 subunit showed significantly increased expression in lung tumors as compared to non-tumor bronchial tissue. The alpha1 subunit also showed evidence of high expression in lung tumors. Nicotine at a concentration of 10 microM caused phosphorylation of mitogen-activated protein kinase (MAPK) (p44/42) that could be inhibited using nAChR antagonists. Inhibition was observed at 100 nM alpha-bungarotoxin (alpha-BTX) or 10 microM hexamethonium (HEX); maximal inhibition was achieved using a combination of alpha-BTX and HEX. Akt was also phosphorylated in NSCLC cells after exposure to nicotine; this effect was inhibited by the PI3K inhibitor LY294002 and antagonists to the neuronal-type nAChR, but not to the muscle-type receptor. Nicotine triggered influx of calcium in the 273T NSCLC cell line, suggesting that L-type calcium channels were activated. 273T cells also showed greater activation of p44/42 MAPK than of Akt in response to nicotine. Cultures treated with nicotine and the EGFR tyrosine kinase inhibitor gefitinib showed a significant increase in the number of surviving cells compared to gefitinib alone. These data indicate that the muscle-type nAChR, rather than the alpha7 type, is highly expressed in NSCLC and leads to downstream activation of the p44/42 MAPK pathway. Neuronal-type receptors are also present and functional, as evidenced by antagonist studies, although, the expression levels are lower than muscle-type nAChR. They also lead to downstream activation of MAPK and Akt. Nicotine may play a role in regulating survival of NSCLC cells and endogenous acetylcholine released locally in the lung and/or chronic nicotine exposure might play a role in NSCLC development. In addition, exposure of NSCLC patients to nicotine through use of nicotine replacement products or use of tobacco products may alter the efficacy of therapy with EGFR inhibitors.},
  chemicals       = {CHRNA1 protein, human, CHRNB1 protein, human, Calcium Channels, L-Type, Chrna7 protein, human, Ganglionic Stimulants, Nicotinic Agonists, Protein Subunits, RNA, Messenger, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, Nicotine, ErbB Receptors, Proto-Oncogene Proteins c-akt, Mitogen-Activated Protein Kinase 1, Acetylcholine},
  citation-subset = {IM},
  completed       = {2008-01-29},
  country         = {England},
  issn-linking    = {1094-5539},
  keywords        = {Acetylcholine, metabolism; Calcium Channels, L-Type, drug effects, metabolism; Carcinoma, Non-Small-Cell Lung, genetics, metabolism; Cell Line, Tumor; Cell Survival, drug effects; ErbB Receptors, antagonists & inhibitors; Ganglionic Stimulants, pharmacology; Gene Expression Regulation, Neoplastic, drug effects; Humans; Lung Neoplasms, genetics, metabolism; Mitogen-Activated Protein Kinase 1, metabolism; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Phosphorylation; Protein Subunits, genetics; Proto-Oncogene Proteins c-akt, drug effects, metabolism; RNA, Messenger, metabolism; Receptors, Nicotinic, drug effects, genetics, metabolism; Signal Transduction, drug effects; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {9715279},
  owner           = {NLM},
  pii             = {S1094-5539(06)00082-4},
  pmid            = {17015027},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-01},
}

@Article{sun2017,
  author          = {Sun, Fen and Johnson, Stephen R and Jin, Kunlin and Uteshev, Victor V},
  title           = {Boosting Endogenous Resistance of Brain to Ischemia.},
  journal         = {Molecular neurobiology},
  year            = {2017},
  volume          = {54},
  issue           = {3},
  month           = apr,
  pages           = {2045--2059},
  issn            = {1559-1182},
  doi             = {10.1007/s12035-016-9796-3},
  abstract        = {Most survivors of ischemic stroke remain physically disabled and require prolonged rehabilitation. However, some stroke victims achieve a full neurological recovery suggesting that the human brain can defend itself against ischemic injury, but the protective mechanisms are unknown. This study used selective pharmacological agents and a rat model of cerebral ischemic stroke to detect endogenous brain protective mechanisms that require activation of α7 nicotinic acetylcholine receptors (nAChRs). This endogenous protection was found to be (1) limited to less severe injuries; (2) significantly augmented by intranasal administration of a positive allosteric modulator of α7 nAChRs, significantly reducing brain injury and neurological deficits after more severe ischemic injuries; and (3) reduced by inhibition of calcium/calmodulin-dependent kinase-II. The physiological role of α7 nAChRs remains largely unknown. The therapeutic activation of α7 nAChRs after cerebral ischemia may serve as an important physiological responsibility of these ubiquitous receptors and holds a significant translational potential.},
  chemicals       = {1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea, Benzylamines, Isoxazoles, KN 92, Phenylurea Compounds, Sulfonamides, alpha7 Nicotinic Acetylcholine Receptor, KN 93, Calcium-Calmodulin-Dependent Protein Kinase Type 2},
  citation-subset = {IM},
  completed       = {2018-02-07},
  country         = {United States},
  issn-linking    = {0893-7648},
  keywords        = {Administration, Intravenous; Allosteric Regulation, drug effects, physiology; Animals; Benzylamines, administration & dosage; Brain, drug effects, metabolism; Brain Ischemia, metabolism, prevention & control; Calcium-Calmodulin-Dependent Protein Kinase Type 2, antagonists & inhibitors, metabolism; Dose-Response Relationship, Drug; Infusions, Intraventricular; Isoxazoles, administration & dosage; Male; Organ Culture Techniques; Phenylurea Compounds, administration & dosage; Rats; Rats, Sprague-Dawley; Sulfonamides, administration & dosage; alpha7 Nicotinic Acetylcholine Receptor, agonists, metabolism; Allosteric modulator; Choline; Neuroprotection; Nicotinic receptors; PNU-120596; PNU120596; Stroke},
  mid             = {NIHMS763357},
  nlm-id          = {8900963},
  owner           = {NLM},
  pii             = {10.1007/s12035-016-9796-3},
  pmc             = {PMC4996768},
  pmid            = {26910820},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{singh2013a,
  author          = {Singh, Nagendra S and Paul, Rajib K and Ramamoorthy, Anuradha and Torjman, Marc C and Moaddel, Ruin and Bernier, Michel and Wainer, Irving W},
  title           = {Nicotinic acetylcholine receptor antagonists alter the function and expression of serine racemase in PC-12 and 1321N1 cells.},
  journal         = {Cellular signalling},
  year            = {2013},
  volume          = {25},
  issue           = {12},
  month           = dec,
  pages           = {2634--2645},
  issn            = {1873-3913},
  doi             = {10.1016/j.cellsig.2013.08.025},
  abstract        = {Western blot analysis demonstrated that PC-12 cells express monomeric and dimeric forms of serine racemase (m-SR, d-SR) and that 1321N1 cells express m-SR. Quantitative RT-PCR and functional studies demonstrated that PC-12 cells express homomeric and heteromeric forms of nicotinic acetylcholine receptors (nAChR) while 1321N1 cells primarily express the α7-nAChR subtype. The effect of nAChR agonists and antagonists on SR activity and expression was examined by following concentration-dependent changes in intracellular d-Ser levels and SR protein expression. Incubation with (S)-nicotine increased d-Ser levels, which were attenuated by the α7-nAChR antagonist methyllycaconitine (MLA). Treatment of PC-12 cells with mecamylamine (MEC) produced a bimodal reduction of d-Ser reflecting MEC inhibition of homomeric and heteromeric nAChRs, while a unimodal curve was observed with 1321N1 cells, reflecting predominant expression of α7-nAChR. The nAChR subtype selectivity was probed using α7-nAChR selective inhibitors MLA and (R,S)-dehydronorketamine and α3β4-nAChR specific inhibitor AT-1001. The compounds reduced d-Ser in PC-12 cells, but only MLA and (R,S)-dehydronorketamine were effective in 1321N1 cells. Incubation of PC-12 and 1321N1 cells with (S)-nicotine, MEC and AT-1001 did not affect m-SR or d-SR expression, while MLA and (R,S)-dehydronorketamine increased m-SR expression but not SR mRNA levels. Treatment with cycloheximide indicated that increased m-SR was due to de novo protein synthesis associated with phospho-active forms of ERK1/2, MARCKS, Akt and rapamycin-sensitive mTOR. This effect was attenuated by treatment with the pharmacological inhibitors U0126, LY294002 and rapamycin, which selectively block the activation of ERK1/2, Akt and mTOR, respectively, and siRNAs directed against ERK1/2, Akt and mTOR. We propose that nAChR-associated changes in Ca(2+) flux affect SR activity, but not expression, and that MLA and (R,S)-dehydronorketamine bind to allosteric sites on the α7-nAChR and promote multiple signaling cascades that converge at mTOR to increase m-SR levels. },
  chemicals       = {Nicotinic Antagonists, Receptors, Nicotinic, methyllycaconitine, Mecamylamine, Nicotine, TOR Serine-Threonine Kinases, Racemases and Epimerases, serine racemase, Aconitine},
  citation-subset = {IM},
  completed       = {2014-12-03},
  country         = {England},
  issn-linking    = {0898-6568},
  keywords        = {Aconitine, analogs & derivatives, pharmacology; Animals; Cell Line; Cell Line, Tumor; Gene Expression Regulation, drug effects; Humans; Mecamylamine, pharmacology; Nicotine, metabolism; Nicotinic Antagonists, pharmacology; PC12 Cells, drug effects, enzymology, metabolism; Racemases and Epimerases, genetics, metabolism; Rats; Receptors, Nicotinic, genetics, metabolism; Signal Transduction, drug effects; TOR Serine-Threonine Kinases, metabolism; DHNK; MEC; MLA; Nicotinic acetylcholine receptors; Serine racemase; d-SR; d-Ser; d-Serine; d-serine; dehydronorketamine; dimeric serine racemase; m-SR; mTOR; mecamylamine; methyllycaconitine; monomeric serine racemase; nAChR; nicotinic acetylcholine receptor},
  mid             = {NIHMS523570},
  nlm-id          = {8904683},
  owner           = {NLM},
  pii             = {S0898-6568(13)00260-X},
  pmc             = {PMC3846540},
  pmid            = {24012499},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{hambsch2014,
  author          = {Hambsch, B and Keyworth, H and Lind, J and Otte, D M and Racz, I and Kitchen, I and Bailey, A and Zimmer, A},
  title           = {Chronic nicotine improves short-term memory selectively in a G72 mouse model of schizophrenia.},
  journal         = {Br. J. Pharmacol.},
  year            = {2014},
  volume          = {171},
  issue           = {7},
  month           = apr,
  pages           = {1758--1771},
  issn            = {1476-5381},
  doi             = {10.1111/bph.12578},
  abstract        = {The prevalence of smoking in schizophrenia patients is exceptionally high; it is not known why but many researchers suggest that smoking constitutes a form of self-medication. Among the symptoms of schizophrenia that may be improved by nicotine are cognitive deficits. Hence, we studied the effects of long-term nicotine administration on cognition in a genetic animal model of schizophrenia susceptibility, G72-transgenic (G72Tg) mice. The effect of long-term nicotine or saline, administered by osmotic minipumps, on different cognitive domains was assessed in G72Tg mice and controls using a battery of behavioural tests. To investigate the mechanism underlying phenotypic differences, quantitative autoradiographic mapping of nACh receptor subtypes was performed in forebrain structures to explore effects of chronic nicotine exposure on nACh receptor density in wild-type (WT) and G72Tg mice. Genotype significantly affected the cognitive effects of chronic nicotine administration. Whereas chronic nicotine disrupted cognitive performance in WT mice, it was effective at restoring impaired prepulse inhibition, working memory and social recognition in G72Tg mice. However, long-term spatial learning was further impaired by nicotine in transgenic animals. In contrast, associative learning was protected by G72-expression against the adverse nicotine effects seen in WT animals. G72-expression did not decisively influence nicotine-induced up-regulation of the α4β2*subtype, whereas α7nACh receptor density was differentially altered by genotype or by a genotype·treatment interaction in specific brain areas, most notably hippocampal subregions. Our data support the hypothesis that nicotine self-medication of schizophrenics improves cognitive symptoms, possibly by facilitating nicotine-induced α7nACh receptor activation in the hippocampus.},
  chemicals       = {Carrier Proteins, Chrna7 protein, mouse, DAOA protein, human, Nicotinic Agonists, Nootropic Agents, alpha7 Nicotinic Acetylcholine Receptor, Nicotine},
  citation-subset = {IM},
  completed       = {2014-11-12},
  country         = {England},
  issn-linking    = {0007-1188},
  keywords        = {Animals; Behavior, Animal, drug effects; Carrier Proteins, genetics, metabolism; Cognition, drug effects; Disease Models, Animal; Drug Administration Schedule; Genotype; Humans; Memory, Short-Term, drug effects; Mice; Mice, Transgenic; Neural Inhibition, drug effects; Nicotine, administration & dosage; Nicotinic Agonists, administration & dosage; Nootropic Agents, administration & dosage; Phenotype; Prosencephalon, drug effects, metabolism; Recognition (Psychology), drug effects; Schizophrenia, diagnosis, drug therapy, genetics; Schizophrenic Psychology; Social Behavior; Time Factors; alpha7 Nicotinic Acetylcholine Receptor, agonists, metabolism; G72 mouse model; G72/G30 gene locus; chronic nicotine; cognition; nicotinic acetylcholine receptor; receptor autoradiography; schizophrenia; self-medication; short-term memory; susceptibility gene},
  nlm-id          = {7502536},
  owner           = {NLM},
  pmc             = {PMC3966754},
  pmid            = {24417347},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{watson2014,
  author          = {Watson, Brittany M and Oliveria, John Paul and Nusca, Graeme M and Smith, Steven G and Beaudin, Sue and Dua, Benny and Watson, Rick M and Assayag, Evelynne Israël and Cormier, Yvon F and Sehmi, Roma and Gauvreau, Gail M},
  title           = {Inhibition of allergen-induced basophil activation by ASM-024, a nicotinic receptor ligand.},
  journal         = {International archives of allergy and immunology},
  year            = {2014},
  volume          = {165},
  issue           = {4},
  pages           = {255--264},
  issn            = {1423-0097},
  doi             = {10.1159/000370068},
  abstract        = {Nicotinic acetylcholine receptors (nAChRs) were identified on eosinophils and shown to regulate inflammatory responses, but nAChR expression on basophils has not been explored yet. We investigated surface receptor expression of nAChR α4, α7 and α1/α3/α5 subunits on basophils. Furthermore, we examined the effects of ASM-024, a synthetic nicotinic ligand, on in vitro anti-IgE and in vivo allergen-induced basophil activation. Basophils were enriched from the peripheral blood of allergic donors and the expression of nAChR subunits and muscarinic receptors was determined. Purified basophils were stimulated with anti-IgE in the presence of ASM-024 with or without muscarinic or nicotinic antagonists for the measurement of CD203c expression and histamine release. The effect of 9 days of treatment with 50 and 200 mg ASM-024 on basophil CD203c expression was examined in the blood of mild allergic asthmatics before and after allergen inhalation challenge. nAChR α4, α7 and α1/α3/α5 receptor subunit expression was detected on basophils. Stimulation of basophils with anti-IgE increased CD203c expression and histamine release, which was inhibited by ASM-024 (10(-5) to 10(-)(3) M, p < 0.05). The effect of ASM-024 was reversed in the presence of muscarinic and nicotinic antagonists. In subjects with mild asthma, ASM-024 inhalation significantly inhibited basophil CD203c expression measured 24 h after allergen challenge (p = 0.03). This study shows that ASM-024 inhibits IgE- and allergen-induced basophil activation through both nicotinic and muscarinic receptors, and suggests that ASM-024 may be an efficacious agent for modulating allergic asthma responses.},
  chemicals       = {ENPP3 protein, human, Nicotinic Agonists, Receptors, Nicotinic, Dimethylphenylpiperazinium Iodide, Phosphoric Diester Hydrolases, Pyrophosphatases},
  citation-subset = {IM},
  completed       = {2015-04-16},
  country         = {Switzerland},
  issn-linking    = {1018-2438},
  keywords        = {Adult; Aged; Asthma, drug therapy, immunology; Basophils, immunology; Cross-Over Studies; Dimethylphenylpiperazinium Iodide, administration & dosage, analogs & derivatives, pharmacology; Double-Blind Method; Female; Flow Cytometry; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Nicotinic Agonists, administration & dosage, pharmacology; Phosphoric Diester Hydrolases, blood; Pyrophosphatases, blood; Random Allocation; Receptors, Nicotinic, immunology; Young Adult},
  nlm-id          = {9211652},
  owner           = {NLM},
  pii             = {000370068},
  pmid            = {25660404},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2015-02-09},
}

@Article{sun2009,
  author          = {Sun, XiaoJuan and Ritzenthaler, Jeffrey D and Zhong, XiaoRong and Zheng, Ying and Roman, Jesse and Han, ShouWei},
  title           = {Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha.},
  journal         = {Cancer research},
  year            = {2009},
  volume          = {69},
  issue           = {16},
  month           = aug,
  pages           = {6445--6453},
  issn            = {1538-7445},
  doi             = {10.1158/0008-5472.CAN-09-1001},
  abstract        = {We previously showed that nicotine stimulates non-small cell lung carcinoma (NSCLC) cell proliferation through nicotinic acetylcholine receptor (nAChR)-mediated signals. Activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) has also been shown to induce NSCLC cell growth. Here, we explore the potential link between nicotine and PPARbeta/delta and report that nicotine increases the expression of PPARbeta/delta protein; this effect was blocked by an alpha7 nAChR antagonist (alpha-bungarotoxin), by alpha7 nAChR short interfering RNA, and by inhibitors of phosphatidylinositol 3-kinase (PI3K; wortmannin and LY294002) and mammalian target of rapamycin (mTOR; rapamycin). In contrast, this effect was enhanced by PUN282987, an alpha7 nAChR agonist. Silencing of PPARbeta/delta attenuated the stimulatory effect of nicotine on cell growth, which was overcome by transfection of an exogenous PPARbeta/delta expression vector. Of note, nicotine induced complex formation between alpha7 nAChR and PPARbeta/delta protein and increased PPARbeta/delta gene promoter activity through inhibition of AP-2alpha as shown by reduced AP-2alpha binding using electrophoretic gel mobility shift and chromatin immunoprecipitation assays. In addition, silencing of Sp1 attenuated the effect of nicotine on PPARbeta/delta. Collectively, our results show that nicotine increases PPARbeta/delta gene expression through alpha7 nAChR-mediated activation of PI3K/mTOR signals that inhibit AP-2alpha protein expression and DNA binding activity to the PPARbeta/delta gene promoter. Sp1 seems to modulate this process. This study unveils a novel mechanism by which nicotine promotes human lung carcinoma cell growth.},
  chemicals       = {Bungarotoxins, Cholinergic Agonists, Chrna7 protein, human, PPAR delta, PPAR-beta, Receptors, Nicotinic, Transcription Factor AP-2, alpha7 Nicotinic Acetylcholine Receptor, Nicotine, Protein Kinases, Phosphatidylinositol 3-Kinases, MTOR protein, human, TOR Serine-Threonine Kinases},
  citation-subset = {IM},
  completed       = {2009-09-15},
  country         = {United States},
  issn-linking    = {0008-5472},
  keywords        = {Bungarotoxins, pharmacology; Carcinoma, Non-Small-Cell Lung, genetics, metabolism; Cell Proliferation, drug effects; Cholinergic Agonists, pharmacology; Enzyme Activation, drug effects, physiology; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms, genetics, metabolism; Models, Biological; Nicotine, pharmacology; PPAR delta, genetics, metabolism; PPAR-beta, genetics, metabolism; Phosphatidylinositol 3-Kinases, metabolism, physiology; Promoter Regions, Genetic, drug effects; Protein Kinases, metabolism, physiology; Receptors, Nicotinic, physiology; TOR Serine-Threonine Kinases; Transcription Factor AP-2, antagonists & inhibitors, metabolism; Tumor Cells, Cultured; Up-Regulation, drug effects; alpha7 Nicotinic Acetylcholine Receptor},
  mid             = {NIHMS128021},
  nlm-id          = {2984705R},
  owner           = {NLM},
  pii             = {0008-5472.CAN-09-1001},
  pmc             = {PMC2745317},
  pmid            = {19654299},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{olincy2006,
  author          = {Olincy, Ann and Harris, Josette G and Johnson, Lynn L and Pender, Vicki and Kongs, Susan and Allensworth, Diana and Ellis, Jamey and Zerbe, Gary O and Leonard, Sherry and Stevens, Karen E and Stevens, James O and Martin, Laura and Adler, Lawrence E and Soti, Ferenc and Kem, William R and Freedman, Robert},
  title           = {Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.},
  journal         = {Archives of general psychiatry},
  year            = {2006},
  volume          = {63},
  issue           = {6},
  month           = jun,
  pages           = {630--638},
  issn            = {0003-990X},
  doi             = {10.1001/archpsyc.63.6.630},
  abstract        = {The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors. Randomized, double-blind crossover trial of 2 drug doses and 1 placebo. General clinical research center. Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count. Administration of DMXB-A. Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating. Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well. An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy.},
  chemicals       = {Benzylidene Compounds, Nicotinic Agonists, Placebos, Pyridines, Receptors, Nicotinic, 3-(2,4-dimethoxybenzylidene)anabaseine},
  citation-subset = {AIM, IM},
  completed       = {2006-06-21},
  country         = {United States},
  issn-linking    = {0003-990X},
  keywords        = {Adult; Benzylidene Compounds, therapeutic use; Cognition Disorders, diagnosis, drug therapy, psychology; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Evoked Potentials, Auditory, drug effects; Female; Humans; Male; Neuropsychological Tests, statistics & numerical data; Nicotinic Agonists, therapeutic use; Placebos; Psychiatric Status Rating Scales; Pyridines, therapeutic use; Receptors, Nicotinic, drug effects; Schizophrenia, drug therapy; Schizophrenic Psychology; Severity of Illness Index},
  nlm-id          = {0372435},
  owner           = {NLM},
  pii             = {63/6/630},
  pmid            = {16754836},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@Article{koukouli2017,
  author          = {Koukouli, Fani and Rooy, Marie and Tziotis, Dimitrios and Sailor, Kurt A and O'Neill, Heidi C and Levenga, Josien and Witte, Mirko and Nilges, Michael and Changeux, Jean-Pierre and Hoeffer, Charles A and Stitzel, Jerry A and Gutkin, Boris S and DiGregorio, David A and Maskos, Uwe},
  title           = {Nicotine reverses hypofrontality in animal models of addiction and schizophrenia.},
  journal         = {Nature medicine},
  year            = {2017},
  volume          = {23},
  issue           = {3},
  month           = mar,
  pages           = {347--354},
  issn            = {1546-170X},
  doi             = {10.1038/nm.4274},
  abstract        = {The prefrontal cortex (PFC) underlies higher cognitive processes that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs. PFC spontaneous default activity is altered in neuropsychiatric disorders, including schizophrenia-a disorder that can be accompanied by heavy smoking. Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia. Mice with altered nAChR gene function exhibit PFC-dependent behavioral deficits, but it is unknown how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying behavior. Here we show that mice expressing a human α5 SNP exhibit neurocognitive behavioral deficits in social interaction and sensorimotor gating tasks. Two-photon calcium imaging in awake mouse models showed that nicotine can differentially influence PFC pyramidal cell activity by nAChR modulation of layer II/III hierarchical inhibitory circuits. In α5-SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased somatostatin (SOM) interneuron inhibitory drive over layer II/III pyramidal neurons. The decreased activity observed in α5-SNP-expressing mice resembles the hypofrontality observed in patients with psychiatric disorders, including schizophrenia and addiction. Chronic nicotine administration reversed this hypofrontality, suggesting that administration of nicotine may represent a therapeutic strategy for the treatment of schizophrenia, and a physiological basis for the tendency of patients with schizophrenia to self-medicate by smoking.},
  chemicals       = {CHRNA5 protein, mouse, Chrna7 protein, mouse, Nicotinic Agonists, Receptors, Adrenergic, beta-2, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, Nicotine},
  citation-subset = {IM},
  completed       = {2017-08-07},
  country         = {United States},
  issn-linking    = {1078-8956},
  keywords        = {Animals; Behavior, Animal, drug effects; CRISPR-Cas Systems; Disease Models, Animal; Fluorescent Antibody Technique; Male; Mice; Mice, Knockout; Mice, Transgenic; Neural Inhibition, drug effects; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Polymorphism, Single Nucleotide; Prefrontal Cortex, drug effects, physiopathology; Prepulse Inhibition, drug effects; Pyramidal Cells, drug effects; Receptors, Adrenergic, beta-2, genetics; Receptors, Nicotinic, genetics; Reflex, Startle, drug effects; Schizophrenia, genetics; Social Behavior; Tobacco Use Disorder, genetics; alpha7 Nicotinic Acetylcholine Receptor, genetics},
  mid             = {NIHMS941848},
  nlm-id          = {9502015},
  owner           = {NLM},
  pii             = {nm.4274},
  pmc             = {PMC5819879},
  pmid            = {28112735},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{revathikumar2016,
  author       = {Revathikumar, Priya and Bergqvist, Filip and Gopalakrishnan, Srividya and Korotkova, Marina and Jakobsson, Per-Johan and Lampa, Jon and Le Maître, Erwan},
  title        = {Immunomodulatory effects of nicotine on interleukin 1β activated human astrocytes and the role of cyclooxygenase 2 in the underlying mechanism.},
  journal      = {Journal of neuroinflammation},
  year         = {2016},
  volume       = {13},
  issue        = {1},
  month        = sep,
  pages        = {256},
  issn         = {1742-2094},
  doi          = {10.1186/s12974-016-0725-1},
  abstract     = {The cholinergic anti-inflammatory pathway (CAP) primarily functions through acetylcholine (ACh)-alpha7 nicotinic acetylcholine receptor (α7nAChR) interaction on macrophages to control peripheral inflammation. Interestingly, ACh can also bind α7nAChRs on microglia resulting in neuroprotective effects. However, ACh effects on astrocytes remain elusive. Here, we investigated the effects of nicotine, an ACh receptor agonist, on the cytokine and cholinesterase production of immunocompetent human astrocytes stimulated with interleukin 1β (IL-1β) in vitro. In addition, the potential involvement of prostaglandins as mediators of nicotine was studied using cyclooxygenase 2 (COX-2) inhibition. Cultured human fetal astrocytes were stimulated with human recombinant IL-1β and treated simultaneously with nicotine at different concentrations (1, 10, and 100 μM). Cell supernatants were collected for cytokine and cholinesterase profiling using ELISA and MesoScale multiplex assay. α7nAChR expression on activated human astrocytes was studied using immunofluorescence. For the COX-2 inhibition studies, enzyme activity was inhibited using NS-398. One-way ANOVA was used to perform statistical analyses. Nicotine treatment dose dependently limits the production of critical proinflammatory cytokines such as IL-6 (60.5 ± 3.3, %inhibition), IL-1β (42.4 ± 1.7, %inhibition), and TNF-α (68.9 ± 7.7, %inhibition) by activated human astrocytes. Interestingly, it also inhibits IL-8 chemokine (31.4 ± 8.5, %inhibition), IL-13 (34.243 ± 4.9, %inhibition), and butyrylcholinesterase (20.8 ± 2.8, %inhibition) production at 100 μM. Expression of α7nAChR was detected on the activated human astrocytes. Importantly, nicotine's inhibitory effect on IL-6 production was reversed with the specific COX-2 inhibitor NS-398. Activation of the cholinergic system through α7nAChR agonists has been known to suppress inflammation both in the CNS and periphery. In the CNS, earlier experimental data shows that cholinergic activation through nicotine inhibits microglial activation and proinflammatory cytokine release. Here, we report similar anti-inflammatory effects of cholinergic activation on human astrocytes, at least partly mediated through the COX-2 pathway. These results confirm the potential for cholinergic neuroprotection, which is looked upon as a promising therapy for neuroinflammation as well as neurodegenerative diseases and stroke. Our data implicates an important role for the prostaglandin system in cholinergic regulatory effects.},
  country      = {England},
  issn-linking = {1742-2094},
  keywords     = {Alpha7 nicotinic acetylcholine receptor; Astrocytes; Cholinergic immune regulation; Cyclooxygenase 2; Neuroinflammation; Nicotine; Prostaglandins},
  nlm-id       = {101222974},
  owner        = {NLM},
  pii          = {10.1186/s12974-016-0725-1},
  pmc          = {PMC5041575},
  pmid         = {27681882},
  pubmodel     = {Electronic},
  pubstatus    = {epublish},
  revised      = {2018-11-13},
}

@Article{spencer2006,
  author          = {Spencer, J P and Weil, A and Hill, K and Hussain, I and Richardson, J C and Cusdin, F S and Chen, Y H and Randall, A D},
  title           = {Transgenic mice over-expressing human beta-amyloid have functional nicotinic alpha 7 receptors.},
  journal         = {Neuroscience},
  year            = {2006},
  volume          = {137},
  issue           = {3},
  month           = feb,
  pages           = {795--805},
  issn            = {0306-4522},
  doi             = {10.1016/j.neuroscience.2005.10.007},
  abstract        = {A potentially major factor in the development of Alzheimer's disease is the enhanced production of soluble beta-amyloid peptide fragments amyloid beta peptide(1-40) and amyloid beta peptide(1-42). These amyloid peptides are generated by cleavage of the amyloid-precursor protein and aggregate spontaneously to form amyloid plaques, which are a classical pathological hallmark in Alzheimer's disease. Although the precise mechanisms are unknown, it is widely believed that amyloid peptides initiate the degenerative process, resulting in subsequent cognitive decline. One interaction of amyloid beta peptide that may contribute to an impairment of cognition is its high affinity binding to the alpha 7 nicotinic receptor; a receptor shown to be important for cognition in a number of studies. There is some controversy, however, whether amyloid beta peptide inhibits or activates this receptor. We have cloned and stably expressed the human alpha 7 receptor and investigated its interaction with amyloid beta peptide using patch clamp electrophysiology. Human alpha 7 was activated in a concentration-dependent fashion by nicotine, acetylcholine and choline and potently inhibited by methyllycaconitine citrate. The responses were inwardly rectifying and exhibited rapid activation, desensitization and deactivation. Amyloid beta peptide(1-42) antagonized human alpha7 responses in a partially reversible fashion; no agonist effects of amyloid beta peptide(1-42) were detected. A similar inhibition of mouse alpha 7 was also observed. In addition, we have assessed the function of native alpha 7 receptors in hippocampal slices prepared from transgenic mice that over-express human amyloid. Despite this clear inhibition of recombinant receptors, hippocampal GABAergic interneurones in slices from beta-amyloid over-expressing mice still possess alpha 7 receptor-mediated currents.},
  chemicals       = {Amyloid beta-Peptides, Chrna7 protein, human, Chrna7 protein, mouse, Nicotinic Agonists, Peptide Fragments, Receptors, Nicotinic, Recombinant Proteins, alpha7 Nicotinic Acetylcholine Receptor, amyloid beta-protein (1-42), Nicotine},
  citation-subset = {IM},
  completed       = {2006-04-12},
  country         = {United States},
  issn-linking    = {0306-4522},
  keywords        = {Amyloid beta-Peptides, biosynthesis, genetics, physiology; Animals; Cell Line; Cloning, Molecular; Electric Stimulation; Electrophysiology; Hippocampus, cytology, metabolism; Humans; In Vitro Techniques; Interneurons, metabolism, physiology; Mice; Mice, Transgenic; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Patch-Clamp Techniques; Peptide Fragments, physiology; Receptors, Nicotinic, genetics, physiology; Recombinant Proteins, genetics, metabolism; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {7605074},
  owner           = {NLM},
  pii             = {S0306-4522(05)01150-4},
  pmid            = {16303255},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{saeed2005,
  author          = {Saeed, Rubina W and Varma, Santosh and Peng-Nemeroff, Tina and Sherry, Barbara and Balakhaneh, David and Huston, Jared and Tracey, Kevin J and Al-Abed, Yousef and Metz, Christine N},
  title           = {Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation.},
  journal         = {The Journal of experimental medicine},
  year            = {2005},
  volume          = {201},
  issue           = {7},
  month           = apr,
  pages           = {1113--1123},
  issn            = {0022-1007},
  doi             = {10.1084/jem.20040463},
  abstract        = {Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Based on recent studies showing that acetylcholine and other cholinergic mediators suppress the production of proinflammatory cytokines via the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) expressed by macrophages and our observations that human microvascular endothelial cells express the alpha7 nAChR, we examined the effect of cholinergic stimulation on endothelial cell activation in vitro and in vivo. Using the Shwartzman reaction, we observed that nicotine (2 mg/kg) and the novel cholinergic agent CAP55 (12 mg/kg) inhibit endothelial cell adhesion molecule expression. Using endothelial cell cultures, we observed the direct inhibitory effects of acetylcholine and cholinergic agents on tumor necrosis factor (TNF)-induced endothelial cell activation. Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial cell activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway. In vitro mechanistic studies revealed that nicotine blocked TNF-induced nuclear factor-kappaB nuclear entry in an inhibitor kappaB (IkappaB)alpha- and IkappaBepsilon-dependent manner. Finally, with the carrageenan air pouch model, both vagus nerve stimulation and cholinergic agonists significantly blocked leukocyte migration in vivo. These findings identify the endothelium, a key regulator of leukocyte trafficking during inflammation, as a target of anti-inflammatory cholinergic mediators.},
  chemicals       = {Cell Adhesion Molecules, Cholinergic Agents, Chrna7 protein, human, Chrna7 protein, mouse, DNA Primers, Nicotinic Antagonists, Receptors, Nicotinic, Tumor Necrosis Factor-alpha, alpha7 Nicotinic Acetylcholine Receptor, Mecamylamine, Nicotine, Carrageenan, Acetylcholine},
  citation-subset = {IM},
  completed       = {2005-06-07},
  country         = {United States},
  issn-linking    = {0022-1007},
  keywords        = {Acetylcholine, pharmacology; Animals; Blotting, Western; Carrageenan; Cell Adhesion Molecules, antagonists & inhibitors, metabolism; Cell Migration Inhibition; Cholinergic Agents, pharmacology; DNA Primers; Endothelial Cells, drug effects, metabolism; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Inflammation, immunology, metabolism; Leukocytes, immunology; Mecamylamine, pharmacology; Mice; Mice, Inbred BALB C; Nicotine, pharmacology; Nicotinic Antagonists; Phagocytes, immunology, metabolism; Receptors, Nicotinic, metabolism; Reverse Transcriptase Polymerase Chain Reaction; Shwartzman Phenomenon, immunology; Tumor Necrosis Factor-alpha, metabolism; Vagus Nerve, metabolism; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {2985109R},
  owner           = {NLM},
  pii             = {jem.20040463},
  pmc             = {PMC2213139},
  pmid            = {15809354},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{alkondon2000,
  author          = {Alkondon, M. and Pereira, E. F. and Eisenberg, H. M. and Albuquerque, E. X.},
  title           = {Nicotinic receptor activation in human cerebral cortical interneurons: a mechanism for inhibition and disinhibition of neuronal networks.},
  journal         = {The J. Neurosci. : the official journal of the Society for Neuroscience},
  year            = {2000},
  volume          = {20},
  issue           = {1},
  month           = jan,
  pages           = {66--75},
  issn            = {1529-2401},
  abstract        = {Cholinergic control of the activity of human cerebral cortical circuits has long been thought to be accounted for by the interaction of acetylcholine (ACh) with muscarinic receptors. Here we report the discovery of functional nicotinic receptors (nAChRs) in interneurons of the human cerebral cortex and discuss the physiological and clinical implications of these findings. The whole-cell mode of the patch-clamp technique was used to record responses triggered by U-tube application of the nonselective agonist ACh and of the alpha7-nAChR-selective agonist choline to interneurons visualized by means of infrared-assisted videomicroscopy in slices of the human cerebral cortex. Choline induced rapidly desensitizing whole-cell currents that, being sensitive to blockade by methyllycaconitine (MLA; 50 nM), were most likely subserved by an alpha7-like nAChR. In contrast, ACh evoked slowly decaying whole-cell currents that, being sensitive to blockade by dihydro-beta-erythroidine (DHbetaE; 10 microM), were most likely subserved by an alpha4beta2-like nAChR. Application of ACh (but not choline) to the slices also triggered GABAergic postsynaptic currents (PSCs). Evidence is provided that ACh-evoked PSCs are the result of activation of alpha4beta2-like nAChRs present in preterminal axon segments and/or in presynaptic terminals of interneurons. Thus, nAChRs can relay inhibitory and/or disinhibitory signals to pyramidal neurons and thereby modulate the activity of neuronal circuits in the human cerebral cortex. These mechanisms, which appear to be retained across species, can account for the involvement of nAChRs in cognitive functions and in certain neuropathological conditions.},
  chemicals       = {Chrna7 protein, human, Excitatory Amino Acid Agonists, GABA Antagonists, Insecticides, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, nicotinic acetylcholine receptor alpha4 subunit, methyllycaconitine, Dihydro-beta-Erythroidine, Tetrodotoxin, gamma-Aminobutyric Acid, Quisqualic Acid, Choline, Acetylcholine, Aconitine, Bicuculline},
  citation-subset = {IM},
  completed       = {2000-01-27},
  country         = {United States},
  issn-linking    = {0270-6474},
  keywords        = {Acetylcholine, pharmacology; Aconitine, analogs & derivatives, pharmacology; Adolescent; Adult; Bicuculline, pharmacology; Cerebral Cortex, cytology, physiology; Child; Choline, pharmacology; Dihydro-beta-Erythroidine, pharmacology; Excitatory Amino Acid Agonists, pharmacology; Excitatory Postsynaptic Potentials, drug effects, physiology; Female; GABA Antagonists, pharmacology; Humans; Insecticides, pharmacology; Interneurons, chemistry, physiology; Male; Middle Aged; Nerve Net, physiology; Neural Inhibition, drug effects, physiology; Organ Culture Techniques; Patch-Clamp Techniques; Quisqualic Acid, pharmacology; Receptors, Nicotinic, physiology; Stimulation, Chemical; Tetrodotoxin, pharmacology; alpha7 Nicotinic Acetylcholine Receptor; gamma-Aminobutyric Acid, pharmacology, physiology},
  nlm-id          = {8102140},
  owner           = {NLM},
  pmid            = {10627582},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{papke2000,
  author          = {Papke, R L and Webster, J C and Lippiello, P M and Bencherif, M and Francis, M M},
  title           = {The activation and inhibition of human nicotinic acetylcholine receptor by RJR-2403 indicate a selectivity for the alpha4beta2 receptor subtype.},
  journal         = {J. Neurochem.},
  year            = {2000},
  volume          = {75},
  issue           = {1},
  month           = jul,
  pages           = {204--216},
  issn            = {0022-3042},
  abstract        = {Human nicotinic acetylcholine (ACh) receptor subtypes expressed in Xenopus oocytes were characterized in terms of their activation by the experimental agonist RJR-2403. Responses to RJR-2403 were compared with those evoked by ACh and nicotine. These agonists were also characterized in terms of whether application of the drugs had the effect of producing a residual inhibition that was manifest as a decrease in subsequent control responses to ACh measured 5 min after the washout of the drug. For the activation of alpha4beta2 receptors, RJR-2403 had an efficacy equivalent to that of ACh and was more potent than ACh. RJR-2403 was less efficacious than ACh for other human receptor subtypes, suggesting that it is a partial agonist for all these receptors. Nicotine activated peak currents in human alpha4beta2 and alpha3beta2 receptors that were 85 and 50% of the respective ACh maximum responses. Nicotine was an efficacious activator of human alpha7 receptors, with a potency similar to ACh, whereas RJR-2403 had very low potency and efficacy for these receptors. At concentrations of <1 mM, RJR-2403 did not produce any residual inhibition of subsequent ACh responses for any receptor subtype. In contrast, nicotine produced profound residual inhibition of human alpha4beta2, alpha3beta2, and alpha7 receptors with IC(50) values of 150, 200, and 150 microM, respectively. Co-expression of the human alpha5 subunit with alpha3 and beta2 subunits had the effect of producing protracted responses to ACh and increasing residual inhibition by ACh and nicotine but not RJR-2403. In conclusion, our results, presented in the context of the complex pharmacology of nicotine for both activating and inhibiting neuronal nicotinic receptor subtypes, suggest that RJR-2403 will be a potent and relatively selective activator of human alpha4beta2 receptors.},
  chemicals       = {Nicotinic Agonists, Nicotinic Antagonists, Receptors, Nicotinic, metanicotine, Nicotine, Acetylcholine},
  citation-subset = {IM},
  completed       = {2000-07-17},
  country         = {England},
  issn-linking    = {0022-3042},
  keywords        = {Acetylcholine, pharmacology; Animals; Electric Conductivity; Female; Humans; Nicotine, analogs & derivatives, pharmacology; Nicotinic Agonists, pharmacology; Nicotinic Antagonists, pharmacology; Receptors, Nicotinic, drug effects, physiology; Xenopus laevis},
  nlm-id          = {2985190R},
  owner           = {NLM},
  pmid            = {10854263},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{takahashi2006,
  author          = {Takahashi, Hideo Kohka and Iwagaki, Hiromi and Hamano, Ryosuke and Yoshino, Tadashi and Tanaka, Noriaki and Nishibori, Masahiro},
  title           = {Effect of nicotine on IL-18-initiated immune response in human monocytes.},
  journal         = {Journal of leukocyte biology},
  year            = {2006},
  volume          = {80},
  issue           = {6},
  month           = dec,
  pages           = {1388--1394},
  issn            = {0741-5400},
  doi             = {10.1189/jlb.0406236},
  abstract        = {Nicotine is thought to inhibit the production of proinflammatory cytokines from macrophages through an anti-inflammatory pathway that is dependent on nicotinic acetylcholine receptor alpha7 subunit (alpha7-nAChR). IL-18, an important proinflammatory cytokine, is reported to induce the expression of adhesion molecules on monocytes, thus enhancing cell-to-cell interactions with T-cells and contributing to IL-18-initiated cytokine production. Accordingly, inhibition of IL-18 suppresses systemic inflammatory responses. In the present study, we found that nicotine inhibited the IL-18-enhanced expression of ICAM-1, B7.2, and CD40 on monocytes, and the production of IL-12, IFN-gamma, and TNF-alpha by PBMC. A nonselective and a selective alpha7-nAChR antagonist, mecamylamine, and alpha-bungarotoxin abolished the effects of nicotine, suggesting that this depends on alpha7-nAChR stimulation. It is reported that nicotine induces prostaglandinE2 (PGE(2)) production in PBMC through the up-regulation of cyclooxygenase (COX)-2 expression. PGE(2) is known to activate the EP2/EP4-receptor, leading to an increase in cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity. Consistent with this, we found that COX-2 and PKA inhibitors prevented the effects of nicotine on adhesion molecule expression and cytokine production, indicating that the mechanism of action of nicotine may be via endogenous PGE(2) production.},
  chemicals       = {Antigens, CD, Chrna7 protein, human, Cytokines, Interleukin-18, Membrane Proteins, Nicotinic Agonists, PTGER2 protein, human, Receptors, Nicotinic, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP2 Subtype, alpha7 Nicotinic Acetylcholine Receptor, Nicotine, Cyclic AMP, Cyclooxygenase 2, PTGS2 protein, human, Cyclic AMP-Dependent Protein Kinases, Dinoprostone},
  citation-subset = {IM},
  completed       = {2007-01-18},
  country         = {United States},
  issn-linking    = {0741-5400},
  keywords        = {Antigens, CD, biosynthesis, immunology; Cells, Cultured; Cyclic AMP, immunology, metabolism; Cyclic AMP-Dependent Protein Kinases, biosynthesis, immunology; Cyclooxygenase 2, biosynthesis, immunology; Cytokines, biosynthesis, immunology; Dinoprostone, biosynthesis, immunology; Gene Expression Regulation, drug effects, immunology; Humans; Interleukin-18, biosynthesis, immunology; Macrophage Activation, drug effects, immunology; Membrane Proteins, biosynthesis, immunology; Monocytes, immunology, metabolism; Nicotine, immunology, pharmacology; Nicotinic Agonists, immunology, pharmacology; Receptors, Nicotinic, immunology, metabolism; Receptors, Prostaglandin E, biosynthesis, immunology; Receptors, Prostaglandin E, EP2 Subtype; Signal Transduction, drug effects, immunology; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {8405628},
  owner           = {NLM},
  pii             = {jlb.0406236},
  pmid            = {16966384},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{arias2009,
  author          = {Arias, H R and Xing, H and Macdougall, K and Blanton, M P and Soti, F and Kem, W R},
  title           = {Interaction of benzylidene-anabaseine analogues with agonist and allosteric sites on muscle nicotinic acetylcholine receptors.},
  journal         = {Br. J. Pharmacol.},
  year            = {2009},
  volume          = {157},
  issue           = {2},
  month           = may,
  pages           = {320--330},
  issn            = {1476-5381},
  doi             = {10.1111/j.1476-5381.2009.00156.x},
  abstract        = {Benzylidene-anabaseines (BAs) are partial agonists of the alpha7 nicotinic acetylcholine receptor (nAChR) but their mechanism(s) of action are unknown. Our study explores several possibilities, including direct interactions of BAs with the nAChR channel. Functional and radioligand-binding assays were used to examine the interaction of two BA analogues, 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA) and its primary metabolite 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine (4OH-DMXBA) with both agonist and non-competitive antagonist (NCA)-binding sites on muscle-type nAChRs. Both BAs non-competitively inhibited ACh activation of human fetal muscle nAChRs and sterically inhibited the specific binding of the NCAs [piperidyl-3,4-3H(N)]-(N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([(3)H]TCP) and [(3)H]dizocilpine to Torpedo nAChRs in the desensitized state. These compounds modulated [(3)H]tetracaine, [(14)C]amobarbital and [(3)H]TCP binding to resting nAChRs by allosteric mechanisms. Both BAs enhanced [(3)H]TCP binding when the nAChR was initially in the resting but activatable state, suggesting that both compounds desensitized the Torpedo nAChR. Although DMXBA failed to activate human fetal muscle nAChRs, 4OH-DMXBA was found to be a partial agonist. [(3)H]Nicotine competition-binding experiments confirmed that 4OH-DMXBA has higher affinity than DMXBA for the agonist sites, and that DMXBA is also a competitive antagonist. 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine is a partial agonist for human fetal muscle nAChRs, whereas DMXBA only has competitive and NCA activities. The NCA-binding site for BAs overlaps both the phencyclidine- and dizocilpine-binding sites in the desensitized Torpedo nAChR ion channel. The desensitizing property of BAs suggests another possible mode of non-competitive inhibition in addition to direct channel-blocking mechanisms.},
  chemicals       = {Benzylidene Compounds, Nicotinic Agonists, Receptors, Nicotinic, anabaseine, Anabasine},
  citation-subset = {IM},
  completed       = {2009-08-14},
  country         = {England},
  issn-linking    = {0007-1188},
  keywords        = {Allosteric Site; Anabasine, analogs & derivatives, pharmacology; Animals; Benzylidene Compounds, pharmacology; Cells, Cultured; Humans; Muscles, metabolism; Nicotinic Agonists, pharmacology; Radioligand Assay; Receptors, Nicotinic, metabolism; Torpedo},
  nlm-id          = {7502536},
  owner           = {NLM},
  pii             = {BPH156},
  pmc             = {PMC2697798},
  pmid            = {19338581},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{timofeeva2011,
  author          = {Timofeeva, O A and Levin, E D},
  title           = {Glutamate and nicotinic receptor interactions in working memory: importance for the cognitive impairment of schizophrenia.},
  journal         = {Neuroscience},
  year            = {2011},
  volume          = {195},
  month           = nov,
  pages           = {21--36},
  issn            = {1873-7544},
  doi             = {10.1016/j.neuroscience.2011.08.038},
  abstract        = {This article reaches across disciplines to correlate results in molecular, cellular, behavioral, and clinical research to develop a more complete picture of how working memory (WM) functions. It identifies a new idea that deserves further investigation. NMDA glutamate receptors (NMDAR) are critical for memory function. NMDAR inhibition effectively reproduces principal manifestations of schizophrenia (SP), such as WM impairment and GABAergic deficit (mainly reduction of glutamic acid decarboxylase 67 (GAD67) and parvalbumin (PV) content). Nicotine and selective α7 nicotinic acetylcholine receptor (nAChR) agonists reduce WM impairments in patients with SP and reverse WM deficits in animals treated with NMDAR antagonists. The mechanism of this effect is unknown. Importantly, WM recovery occurs even before restoration of NMDAR blockade-induced molecular alterations, including reduced GAD67 in interneurons. Our insight into the cognitive-enhancing effect of α7 nAChR agonists, particularly in the animal models of SP, combines reviews of recent findings on glutamate and nicotinic receptor expression in the neuronal circuits involved in WM, the properties of these receptors, their implication in WM regulation, generation of rhythmic neuronal activity, resulting in a proposed hypothesis for further investigations. We suggest that (1) cortical/hippocampal interneurons, particularly PV positive, play a crucial role in WM and that impairment of these cells in SP could be behind the WM deficit; (2) activation of α7 nAChRs could restore calcium signaling and intrinsic properties of these interneurons, and associated with these events, computational capacity, gamma rhythmic activity, and WM would also be restored.},
  chemicals       = {Receptors, Glutamate, Receptors, Nicotinic},
  citation-subset = {IM},
  completed       = {2012-02-06},
  country         = {United States},
  issn-linking    = {0306-4522},
  keywords        = {Animals; Brain, metabolism; Cognition Disorders, etiology, metabolism; Humans; Memory, Short-Term, physiology; Receptors, Glutamate, metabolism; Receptors, Nicotinic, metabolism; Schizophrenia, complications, metabolism},
  nlm-id          = {7605074},
  owner           = {NLM},
  pii             = {S0306-4522(11)00980-8},
  pmid            = {21884762},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2011-10-07},
}

@Article{ween2010,
  author          = {Ween, Hilde and Thorin-Hagene, Kirsten and Andersen, Elisabeth and Grønlien, Jens Halvard and Lee, Chih-Hung and Gopalakrishnan, Murali and Malysz, John},
  title           = {Alpha3* and alpha 7 nAChR-mediated Ca2+ transient generation in IMR-32 neuroblastoma cells.},
  journal         = {Neurochem . Int.},
  year            = {2010},
  volume          = {57},
  issue           = {3},
  month           = oct,
  pages           = {269--277},
  issn            = {1872-9754},
  doi             = {10.1016/j.neuint.2010.06.005},
  abstract        = {Alpha3-containing (alpha 3*) and alpha 7 nicotinic acetylcholine receptors (nAChRs) are expressed in human IMR-32 neuroblastoma cells and implicated in Ca(2+) signaling. In this study, we investigated the intracellular Ca(2+) transient generation evoked by selective activation of alpha 3* (agonist potency rank order: epibatidine>varenicline>nicotine approximately cytisine) and alpha 7 (rank order in the presence of alpha 7 positive allosteric modulator or PAM: A-795723>NS6784 approximately PNU-282987) using, respectively, varenicline and NS6784 (+alpha 7 PAM) by Ca(2+) imaging. Effects of inhibitors of nAChRs (MLA and mecamylamine), ER Ca(2+) ATPase pump (CPA and thapsigargin), Ca(2+)-induced Ca(2+) release (ryanodine and dantrolene), Ca(2+) channels (nitrendipine, diltiazem, and Cd(2+)), and removal of extracellular Ca(2+) were examined. alpha 7 PAMs, when tested in the presence of NS6784, were more active when added first, followed by the agonist, than in the reverse order. Removal of extracellular Ca(2+) - but not CPA, thapsigargin, ryanodine, dantrolene, nitrendipine, diltiazem, or Cd(2+) - diminished the alpha 7 agonist-evoked Ca(2+) transients. In contrast, only diltiazem and nitrendipine and removal of extracellular Ca(2+) inhibited the alpha 3*-mediated Ca(2+) transients. The differential effect of diltiazem and nitrendipine versus Cd(2+) was due to direct inhibition of alpha 3* nAChRs as revealed by Ca(2+) imaging in HEK-293 cells expressing human alpha 3 beta 4 nAChRs and patch clamp in IMR-32 cells. In summary, this study provides evidence that alpha 3* and alpha 7 nAChR agonist-evoked global Ca(2+) transient generation in IMR-32 cells does not primarily involve voltage-dependent Ca(2+) channels, intracellular Ca(2+) stores, or Ca(2+)-induced Ca(2+) release. These mechanisms may, however, be still involved in other forms of nAChR-mediated Ca(2+) signaling.},
  chemicals       = {4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide, Benzamides, Bridged Bicyclo Compounds, Calcium Channel Blockers, Chrna7 protein, human, Nicotinic Agonists, PNU-282987, Pyrroles, Receptors, Nicotinic, Sulfonamides, alpha7 Nicotinic Acetylcholine Receptor, nicotinic receptor subunit alpha3, Nitrendipine, Calcium-Transporting ATPases, Diltiazem},
  citation-subset = {IM},
  completed       = {2010-11-04},
  country         = {England},
  issn-linking    = {0197-0186},
  keywords        = {Benzamides, pharmacology; Brain Neoplasms, metabolism; Bridged Bicyclo Compounds, pharmacology; Calcium Channel Blockers, pharmacology; Calcium Signaling, physiology; Calcium-Transporting ATPases, metabolism; Cell Line, Tumor; Data Interpretation, Statistical; Diltiazem, pharmacology; Electrophysiology; Endoplasmic Reticulum, metabolism; Humans; Neuroblastoma, metabolism; Nicotinic Agonists, pharmacology; Nitrendipine, pharmacology; Patch-Clamp Techniques; Pyrroles, pharmacology; Receptors, Nicotinic, drug effects, metabolism; Sulfonamides, pharmacology; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {8006959},
  owner           = {NLM},
  pii             = {S0197-0186(10)00189-0},
  pmid            = {20558224},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-11-25},
}

@Article{adams2000,
  author          = {Adams, C E and Stevens, K E and Kem, W R and Freedman, R},
  title           = {Inhibition of nitric oxide synthase prevents alpha 7 nicotinic receptor-mediated restoration of inhibitory auditory gating in rat hippocampus.},
  journal         = {Brain res.},
  year            = {2000},
  volume          = {877},
  issue           = {2},
  month           = sep,
  pages           = {235--244},
  issn            = {0006-8993},
  abstract        = {The hippocampus rapidly inhibits its response to repetitive auditory stimulation, an example of an auditory sensory gating mechanism involved in human psychopathology. The neuronal basis of this inhibitory gating mechanism has been investigated in rats. Activation of the alpha 7 nicotinic receptor is required. alpha 7 nicotinic receptor activation also releases nitric oxide in the hippocampus and blockade of nitric oxide synthase reduces inhibitory gating of auditory response. There has not been a direct demonstration that blockade of nitric oxide synthase specifically prevents alpha 7 nicotinic receptor activation of the inhibition of auditory response. Therefore, the goal of the present study was to determine whether this functional effect of alpha 7 receptor activation requires release of nitric oxide. Lesions of the fimbria-fornix disrupt auditory gating by preventing cholinergic stimulation of the hippocampus. Following recovery from this surgery, rats were administered 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A; 10 mg/kg, sc), an agonist at the alpha 7 receptor. DMXB-A restored auditory gating in the fimbria-fornix-lesioned rats, indicating that activation of the alpha 7 nicotinic receptor alone is sufficient to restore auditory gating following lesions of the fimbria-fornix. However, intracerebroventricular infusion of N(omega)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, blocked the DMXB-A-mediated restoration of auditory gating; infusion of the inactive D-enantiomer did not. Restoration of auditory gating by DMXB-A in the fimbria-fornix-lesioned rats was blocked by intracerebroventricular infusion of alpha-bungarotoxin, but not by mecamylamine or dihydro-beta-erythroidine. Together, these data support the hypothesis that nitric oxide mediates alpha 7 nicotinic receptor activation of gating of auditory response in rat hippocampus.},
  chemicals       = {Benzylidene Compounds, Chrna7 protein, human, Chrna7 protein, rat, Nicotinic Agonists, Nicotinic Antagonists, Pyridines, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor, Nitric Oxide, 3-(2,4-dimethoxybenzylidene)anabaseine, Nitric Oxide Synthase, NG-Nitroarginine Methyl Ester},
  citation-subset = {IM},
  completed       = {2000-12-14},
  country         = {Netherlands},
  issn-linking    = {0006-8993},
  keywords        = {Acoustic Stimulation; Animals; Auditory Perception, drug effects, physiology; Benzylidene Compounds, pharmacology; Denervation, adverse effects; Evoked Potentials, Auditory, drug effects, physiology; Fornix, Brain, physiology, surgery; Hippocampus, cytology, drug effects, metabolism; Male; NG-Nitroarginine Methyl Ester, pharmacology; Neural Inhibition, drug effects, physiology; Neurons, cytology, drug effects, metabolism; Nicotinic Agonists, pharmacology; Nicotinic Antagonists, pharmacology; Nitric Oxide, biosynthesis; Nitric Oxide Synthase, drug effects, metabolism; Pyridines, pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic, drug effects, metabolism; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {0045503},
  owner           = {NLM},
  pii             = {S0006-8993(00)02677-9},
  pmid            = {10986337},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@Article{summers2003,
  author          = {Summers, Andrea E and Whelan, Clifford J and Parsons, Mike E},
  title           = {Nicotinic acetylcholine receptor subunits and receptor activity in the epithelial cell line HT29.},
  journal         = {Life sciences},
  year            = {2003},
  volume          = {72},
  issue           = {18-19},
  month           = mar,
  pages           = {2091--2094},
  issn            = {0024-3205},
  abstract        = {In the present study we have used RT-PCR to investigate nicotinic acetylcholine receptor (nAChR) subunit expression, and studied the effect of nicotine on TNFalpha-induced cytokine (IL-8) release in the epithelial cell line HT29. RNA was extracted using a commercial kit and amplified by RT-PCR. RT-PCR products were separated by electrophoresis and visualised using ethidium bromide. IL-8 release was measured by ELISA from cells activated for 6 h with TNFalpha (50 ng ml(-1)) in the absence and presence of nicotine (10(-11)-10(-6) M). HT29 cells contained mRNA for beta1, alpha4, alpha5, and alpha7 nAChR subunits. Activation of HT29 cells increased IL-8 release from undetectable amounts to 3.92 +/- 0.51 ng ml(-1) (n = 5). Nicotine significantly inhibited TNFalpha-induced IL-8 release in a concentration related manner with peak inhibition occurring at 10(-7) M (2.39 +/- 0.78 ng ml(-1), n = 5). Our data suggests that, while HT29 cells express mRNA for nAChR subunits, the only nAChR subunits that could form functional receptors and inhibit IL-8 release are alpha7.},
  chemicals       = {Interleukin-8, Nicotinic Agonists, Receptors, Nicotinic, Tumor Necrosis Factor-alpha, Nicotine},
  citation-subset = {IM},
  completed       = {2003-04-04},
  country         = {Netherlands},
  issn-linking    = {0024-3205},
  keywords        = {Colitis, Ulcerative, metabolism; Enzyme-Linked Immunosorbent Assay; Epithelial Cells, metabolism; HT29 Cells; Humans; Interleukin-8, metabolism; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Receptors, Nicotinic, biosynthesis, drug effects, metabolism; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha, metabolism},
  nlm-id          = {0375521},
  owner           = {NLM},
  pii             = {S0024320503000894},
  pmid            = {12628462},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{dunckley2006,
  author          = {Dunckley, Travis and Lukas, Ronald J},
  title           = {Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells.},
  journal         = {Brain res.},
  year            = {2006},
  volume          = {1116},
  issue           = {1},
  month           = oct,
  pages           = {39--49},
  issn            = {0006-8993},
  doi             = {10.1016/j.brainres.2006.07.111},
  abstract        = {Exposure to nicotine has a broad range of physiological and psychological effects that can be long lasting and contribute to nicotine dependence. On a time course longer than that needed to activate nicotinic acetylcholine receptor (nAChR) function, nicotine exposure induces functional inactivation of nAChR, upregulation of nAChR radioligand binding sites, and other alterations of cellular functions. To identify possible mechanisms underlying nicotine-induced changes in nAChR numbers and function, we defined changes in gene expression in neuron-like, SH-SY5Y human neuroblastoma cells following 24 h of continuous exposure to 1 mM nicotine. This treatment condition produces both functional inactivation and upregulation of nAChR. Repeat and cross-controlled microarray ( approximately 5000 genes queried) analyses revealed 163 genes whose expression was consistently altered at the p<0.01 level following nicotine treatment. Quantitative, real-time, reverse transcription-polymerase chain reaction analyses confirmed altered expression of thirteen out of fourteen of these genes chosen for further study, including contactin 1, myozenin 2, and ubiquitin-conjugating enzymes E2C and E2S. Inhibition or reversal of these effects by the general nAChR antagonist, d-tubocurarine, indicated that gene expression changes are dependent on nAChR activation. Studies using other nAChR subtype-selective antagonists identified gene expression changes that required activation of both alpha7- and alpha3*-nAChR, alpha7-nAChR alone, or either alpha7- or alpha3beta4*-nAChR, suggesting some convergent and some divergent pathways of gene activation coupled to these nAChR subtypes. These results suggest that longer-term physiological and psychological effects of nicotine exposure and changes in nAChR expression may be due in part to effects on gene expression initiated by interactions with nAChR.},
  chemicals       = {DNA, Complementary, DNA, Neoplasm, Nicotinic Agonists, Nicotinic Antagonists, Receptors, Nicotinic, Nicotine},
  citation-subset = {IM},
  completed       = {2006-12-12},
  country         = {Netherlands},
  issn-linking    = {0006-8993},
  keywords        = {Brain Neoplasms, genetics, metabolism; Cell Line, Tumor; DNA, Complementary, biosynthesis, genetics; DNA, Neoplasm, biosynthesis; Gene Expression Regulation, Neoplastic, physiology; Humans; In Situ Hybridization; Neuroblastoma, genetics, metabolism; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Nicotinic Antagonists, pharmacology; Oligonucleotide Array Sequence Analysis; Radioligand Assay; Receptors, Nicotinic, biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Transcriptional Activation; Up-Regulation, drug effects},
  nlm-id          = {0045503},
  owner           = {NLM},
  pii             = {S0006-8993(06)02297-9},
  pmid            = {16949557},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{abdrakhmanova2008,
  author          = {Abdrakhmanova, Galya R and Carroll, F Ivy and Damaj, M I and Martin, Billy R},
  title           = {3'-Fluoro substitution in the pyridine ring of epibatidine improves selectivity and efficacy for alpha4beta2 versus alpha3beta4 nAChRs.},
  journal         = {Neuropharm.},
  year            = {2008},
  volume          = {55},
  issue           = {8},
  month           = dec,
  pages           = {1287--1292},
  issn            = {0028-3908},
  doi             = {10.1016/j.neuropharm.2008.08.007},
  abstract        = {The analog of epibatidine having a fluoro substituent at the 3' position of the pyridine ring has been recently developed and shown to possess binding affinity in the pM range to alpha4beta2 nAChRs and in the nM range to alpha7 nAChRs and to exhibit potent agonist activity in nicotine-induced analgesia tests. Here we used patch-clamp technique in a whole-cell configuration to compare functional activity of 3'-fluoroepibatidine to that of epibatidine by itself on recombinant alpha4beta2, alpha7 and alpha3beta4 neuronal nAChRs. The agonist effect of (+/-)-epibatidine was partial and yielded comparable EC50s of 0.012 microM (72% efficacy) and 0.027 microM (81% efficacy) at alpha4beta2 and alpha3beta4 nAChRs, respectively, but was full at alpha7 nAChRs with an EC50 of 4.8 muM. Testing of the analog at different concentrations revealed that it acts as a full agonist with an EC50 of 0.36 microM at alpha4beta2 nAChRs and induces partial agonist effect (66% efficacy) at alpha7 nAChRs with an EC50 of 9.8 microM and an IC50 corresponding to 225 microM. In contrast, the analog caused only 24% maximal activation at the range of concentrations from 0.1 to 100 microM and, in addition, induced an inhibition of alpha3beta4 nAChR function with an IC50 of 8.3 microM. Our functional data, which are in agreement with previous binding and behavioral findings, demonstrate that 3'-fluoro substitution in the pyridine ring of epibatidine results in an improved pharmacological profile as observed by an increased efficacy and selectivity for alpha4beta2 versus alpha3beta4 nAChRs.},
  chemicals       = {Bridged Bicyclo Compounds, Heterocyclic, Nicotinic Agonists, Pyridines, Receptors, Nicotinic, nicotinic receptor alpha3beta4, nicotinic receptor alpha4beta2, Dihydro-beta-Erythroidine, epibatidine, Acetylcholine, pyridine},
  citation-subset = {IM},
  completed       = {2009-04-15},
  country         = {England},
  issn-linking    = {0028-3908},
  keywords        = {Acetylcholine, pharmacology; Binding, Competitive, drug effects; Bridged Bicyclo Compounds, Heterocyclic, chemistry, pharmacology; Cell Line, Transformed; Dihydro-beta-Erythroidine, pharmacology; Dose-Response Relationship, Drug; Humans; Membrane Potentials, drug effects, genetics; Nicotinic Agonists, chemistry, pharmacology; Patch-Clamp Techniques, methods; Pyridines, chemistry, metabolism, pharmacology; Receptors, Nicotinic, drug effects, metabolism; Structure-Activity Relationship; Transfection},
  mid             = {NIHMS83574},
  nlm-id          = {0236217},
  owner           = {NLM},
  pii             = {S0028-3908(08)00361-4},
  pmc             = {PMC2669717},
  pmid            = {18775444},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{szendrei2012,
  author          = {Szendrei, Z. and Grafius, E. and Byrne, A. and Ziegler, A.},
  title           = "{Resistance to Neonicotinoid Insecticides in Field Populations of the Colorado Potato Beetle \textit{(Coleoptera: Chrysomelidae)}.}",
  journal         = {Pest Manag. Sci.},
  year            = {2012},
  volume          = {68},
  issue           = {6},
  month           = jun,
  pages           = {941--946},
  issn            = {1526-4998},
  doi             = {10.1002/ps.3258},
  abstract        = {Neonicotinoid insecticides were first used commercially for Colorado potato beetle [Leptinotarsa decemlineata (Say), Coleoptera: Chrysomelidae] control in the United States in 1995, and since then have been critical for management of this pest. Field populations from the northeastern and midwestern United States were tested from 1998 to 2010 for susceptibility to imidacloprid and thiamethoxam using standard topical dose assays with adults. From 1998 to 2001, imidacloprid resistance was present in only a few locations in the eastern United States. By 2003, imidacloprid resistance was common in the northeastern Unites States. In 2004, imidacloprid resistance in Colorado potato beetle was detected for the first time in the midwestern United States. In 2003, the first case of resistance to thiamethoxam was found in a population from Massachusetts. Neonicotinoid resistance in summer-generation adults was higher than in overwintered adults from the same locations. By 2009, 95% of the populations tested from the northeastern and midwestern United States had significantly higher LD(50) values for imidacloprid than the susceptible population. The increasing resistance to neonicotinoid insecticides raises concerns for the continued effective management of Colorado potato beetles in potatoes and highlights the need for more rigorous practice of integrated pest management methods.},
  chemicals       = {Imidazoles, Insecticides, Neonicotinoids, Nitro Compounds, Oxazines, Thiazoles, imidacloprid, Thiamethoxam},
  citation-subset = {IM},
  completed       = {2012-09-07},
  country         = {England},
  issn-linking    = {1526-498X},
  keywords        = {Animals; Coleoptera, physiology; Drug Resistance; Geography; Imidazoles; Insecticides; Lethal Dose 50; Neonicotinoids; Nitro Compounds; Oxazines; Seasons; Thiamethoxam; Thiazoles; Time Factors},
  nlm-id          = {100898744},
  owner           = {NLM},
  pmid            = {22345080},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-01},
}

@Article{horowitz2004,
  author          = {Horowitz, A. R. and Kontsedalov, S. and Ishaaya, I.},
  title           = {Dynamics of resistance to the neonicotinoids acetamiprid and thiamethoxam in Bemisia tabaci (Homoptera: Aleyrodidae).},
  journal         = {Journal of economic entomology},
  year            = {2004},
  volume          = {97},
  issue           = {6},
  month           = dec,
  pages           = {2051--2056},
  issn            = {0022-0493},
  abstract        = {The dynamics of resistance in the sweetpotato whitefly, Bemisia tabaci (Gennadius), to the neonicotinoids acetamiprid and thiamethoxam was studied extensively in cotton fields in Israel during the cotton-growing seasons 1999-2003. Whitefly strains were collected in early and late seasons mainly in three locations in northern, central, and southern Israel. The whiteflies were assayed under laboratory conditions for susceptibility to neonicotinoids, as part of the Israeli cotton insecticide resistance management strategy. Selections to both acetamiprid and thiamethoxam and cross-resistance between them also were conducted in the laboratory. Although no appreciable resistance to acetamiprid was observed up to 2001, a slight increase of approximately five-fold resistance was detected during 2002 and 2003. However, from 2001 to 2003 thiamethoxam resistance increased >100-fold in the Ayalon Valley and Carmel Coast cotton fields. In cross-resistance assays with both neonicotinoids, the strain that had been selected with thiamethoxam for 12 generations demonstrated almost no cross-resistance to acetamiprid, whereas the acetamiprid-selected strain exhibited high cross-resistance of >500-fold to thiamethoxam.},
  chemicals       = {Neonicotinoids, Nitro Compounds, Oxazines, Pyridines, Thiazoles, acetamiprid, Thiamethoxam},
  citation-subset = {IM},
  completed       = {2005-02-25},
  country         = {England},
  issn-linking    = {0022-0493},
  keywords        = {Animals; Gossypium, growth & development; Hemiptera; Insecticide Resistance; Israel; Neonicotinoids; Nitro Compounds; Oxazines; Pyridines; Thiamethoxam; Thiazoles},
  nlm-id          = {2985127R},
  owner           = {NLM},
  pmid            = {15666764},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-12-01},
}

@Article{eng2017,
  author  = {Eng, M. L. and Stutchbury, J. M. and Morrissey, C. A.},
  title   = {Imidacloprid and chlorpyrifos insecticides impair migratory ability in a seed-eating songbird},
  journal = {Sci. Rep.},
  year    = {2017},
  volume  = {7},
  number  = {15176},
}

@Article{baylay2012,
  author          = {Baylay, A. .J and Spurgeon, D. J. and Svendsen, C. and Griffin, J. L. and Swain, S. C. and Sturzenbaum, S. R. and Jones, O. A. H.},
  title           = "{A Metabolomics Based Test of Independent Action and Concentration Addition Using the Earthworm \textit{Lumbricus rubellus}.}",
  journal         = {Ecotoxicol.},
  year            = {2012},
  volume          = {21},
  issue           = {5},
  month           = jul,
  pages           = {1436--1447},
  issn            = {1573-3017},
  doi             = {10.1007/s10646-012-0897-0},
  abstract        = {A major challenge in Ecotoxicol. is to understand the effects of multiple toxicants on organisms. Here we assess the effects on survival, weight change, cocoon production and metabolism caused by exposure to two similarly acting (imidacloprid/thiacloprid) and two dissimilarly acting (chlorpyrifos/Nickel) chemicals on the earthworm Lumbricus rubellus. We assessed the standard models of concentration addition (CA) and independent action (IA), in conjunction with a metabolomics based approach to elucidate mechanisms of effect. For imidacloprid and thiacloprid the reproductive effects indicated probable additivity. Although this suggests joint effects through a similar mechanism, metabolite changes for each pesticide actually indicated distinct effects. Further, earthworms exposed to a 0.5 toxic unit equitoxic mixture demonstrated metabolic effects intermediate between those for each pesticide, indicating a non-interactive, independent joint effect. For higher effect level mixtures (1 and 1.5 toxic units), metabolite changes associated with thiacloprid exposure began to dominate. The metabolomic effects of the two dissimilarly acting chemicals were distinct, confirming separate modes of action and both proved more toxic than anticipated from previous studies. In the mixtures, phenotypic effects were in accordance with IA estimates, while metabolite changes were dominated by Ni effects, even though chlorpyrifos contributed most to reproductive toxicity. This could be attributed to the greater systematic effect of Ni when compared to the more specifically acting chlorpyrifos.},
  chemicals       = {Imidazoles, Neonicotinoids, Nitro Compounds, Pesticides, Pyridines, Soil Pollutants, Thiazines, imidacloprid, Nickel, thiacloprid, Chlorpyrifos},
  citation-subset = {IM},
  completed       = {2012-11-08},
  country         = {United States},
  issn-linking    = {0963-9292},
  keywords        = {Animals; Chlorpyrifos, toxicity; Dose-Response Relationship, Drug; Ecotoxicol., methods; Imidazoles, toxicity; Magnetic Resonance Spectroscopy, methods; Metabolomics, methods; Neonicotinoids; Nickel, toxicity; Nitro Compounds, toxicity; Oligochaeta, drug effects, metabolism; Pesticides, toxicity; Pyridines, toxicity; Reproduction, drug effects; Soil Pollutants, toxicity; Thiazines, toxicity},
  nlm-id          = {9885956},
  owner           = {NLM},
  pmid            = {22476697},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{alves2013,
  author          = {Alves, P. R. L. and Cardoso, E. J. B. and Martines, A. M. and Sousa, J. P. and Pasini, A.},
  title           = {Earthworm ecotoxicological assessments of pesticides used to treat seeds under tropical conditions.},
  journal         = {Chemosphere},
  year            = {2013},
  volume          = {90},
  issue           = {11},
  month           = mar,
  pages           = {2674--2682},
  issn            = {1879-1298},
  doi             = {10.1016/j.chemosphere.2012.11.046},
  abstract        = {Ecotoxicological laboratory tests (lower-tier tests) are fundamental tools for assessing the toxicity of pesticides to soil organisms. In this study, using these tests under tropical conditions, we quantified the impact of the insecticides imidacloprid, fipronil, and thiametoxam, and the fungicides captan and carboxin+thiram, all of which are used in the chemical treatment of crop seeds, on the survival, reproduction, and behavior of Eisenia andrei (Oligochaeta). With the exception of imidacloprid, none of the pesticides tested caused mortality in E. andrei in artificial soils. The LC(50) of imidacloprid was estimated as 25.53 mg active ingredient kg(-1) of dry soil. Earthworm reproduction rates were reduced by imidacloprid (EC(50)=4.07 mgkg(-1)), fipronil (EC(20)=23.16 mgkg(-1)), carboxin+thiram (EC(50)=56.38 mgkg(-1)), captan (EC(50)=334.84 mgkg(-1)), and thiametoxam (EC(50)=791.99 mgkg(-1)). Avoidance behavior was observed in the presence of imidacloprid (AC(50)=0.11 mgkg(-1)), captan (AC(50)=33.54 mgkg(-1)), carboxin+thiram (AC(50)=60.32 mgkg(-1)), and thiametoxam (AC(50)=>20 mgkg(-1)). Earthworms showed a preference for soils with the insecticide fipronil. Imidacloprid was the most toxic of the substances tested for E. andrei. The avoidance test was the most sensitive test for most pesticides studied, but results varied between pesticides. These results offer new insights on the toxicity of pesticides used to treat seeds in tropical regions. However, they should be complemented with higher-tier tests in order to reduce the uncertainties in risk assessment.},
  chemicals       = {Pesticides, Soil Pollutants},
  citation-subset = {IM},
  completed       = {2013-06-19},
  country         = {England},
  issn-linking    = {0045-6535},
  keywords        = {Agriculture; Animals; Environmental Monitoring; Oligochaeta; Pesticides, toxicity; Risk Assessment; Seeds; Soil Pollutants, toxicity; Tropical Climate},
  nlm-id          = {0320657},
  owner           = {NLM},
  pii             = {S0045-6535(12)01451-8},
  pmid            = {23261124},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-02-11},
}

@Article{kreutzweiser2008,
  author          = {Kreutzweiser, D. P. and Good, K. P. and Chartrand, D. T. and Scarr, T. A. and Holmes, S. B. and Thompson, D. G.},
  title           = {Effects on litter-dwelling earthworms and microbial decomposition of soil-applied imidacloprid for control of wood-boring insects.},
  journal         = {Pest Manag. Sci.},
  year            = {2008},
  volume          = {64},
  issue           = {2},
  month           = feb,
  pages           = {112--118},
  issn            = {1526-498X},
  doi             = {10.1002/ps.1478},
  abstract        = {Imidacloprid is an effective, systemic insecticide for the control of wood-boring insect pests in trees. Systemic applications to trees are often made by soil injections or drenches, and the resulting imidacloprid concentrations in soil or litter may pose a risk of harm to natural decomposer organisms. The authors tested effects of imidacloprid on survival and weight gain or loss of the earthworms Eisenia fetida (Savigny) and Dendrobaena octaedra (Savigny), on leaf consumption rates and cocoon production by D. octaedra and on microbial decomposition activity in laboratory microcosms containing natural forest litter. Dendrobaena octaedra was the most sensitive of the two earthworm species, with an LC(50) of 5.7 mg kg(-1), an LC(10) of about 2 mg kg(-1) and significant weight losses among survivors at 3 mg kg(-1). Weight losses resulted from a physiological effect rather than from feeding inhibition. There were no effects on cocoon production among survivors at 3 mg kg(-1). The LC(50) for E. fetida was 25 mg kg(-1), with significant weight losses at 14 mg kg(-1). There were no significant effects on microbial decomposition of leaf material at the maximum test concentration of 1400 mg kg(-1). The results indicate that, when imidacloprid is applied as a systemic insecticide to the soil around trees, it is likely to cause adverse effects on litter-dwelling earthworms if concentrations in the litter reach or exceed about 3 mg kg(-1).},
  chemicals       = {Imidazoles, Insecticides, Neonicotinoids, Nitro Compounds, imidacloprid},
  citation-subset = {IM},
  completed       = {2008-03-27},
  country         = {England},
  issn-linking    = {1526-498X},
  keywords        = {Animals; Dose-Response Relationship, Drug; Imidazoles, pharmacology; Insecta, drug effects; Insecticides, pharmacology; Neonicotinoids; Nitro Compounds, pharmacology; Oligochaeta, drug effects; Soil Microbiology; Time Factors; Wood, parasitology},
  nlm-id          = {100898744},
  owner           = {NLM},
  pmid            = {18069649},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@Article{dittbrenner2011,
  author  = {Dittbrenner, N. and Moser, I. and Triebskorna, R. and Capowiez, Y.},
  title   = "{Assessment of Short and Long-Term Effects of Imidacloprid on the Burrowing Behaviour of two Earthworm Species (\textit{Aporrectodea caliginosa} and \textit{Lumbricus terrestris}) by Using 2D and 3D Post-Exposure Techniques}",
  journal = {Chemosphere},
  year    = {2011},
  volume  = {84},
  issue   = {10},
  pages   = {1349--1355},
}

@Article{jones2014,
  author          = {Jones, A. and Harrington, P. and Turnbull, G.},
  title           = {Neonicotinoid concentrations in arable soils after seed treatment applications in preceding years.},
  journal         = {Pest Manag. Sci.},
  year            = {2014},
  volume          = {70},
  issue           = {12},
  month           = dec,
  pages           = {1780--1784},
  issn            = {1526-4998},
  doi             = {10.1002/ps.3836},
  abstract        = {Concentrations of the neonicotinoid insecticides clothianidin, thiamethoxam and imidacloprid were determined in arable soils from a variety of locations in England. In soil samples taken from the central area of fields, concentrations of clothianidin ranged from 0.02 to 13.6 µg kg(-1) . Thiamethoxam concentrations were between <0.02 and 1.50 µg kg(-1) , and imidacloprid concentrations between <0.09 and 10.7 µg kg(-1) . Concentrations of clothianidin and thiamethoxam were lower in soil samples taken from the edges of fields than from the centres of fields, but this difference was less pronounced for imidacloprid. This work gives a clear indication of the levels of neonicotinoids in arable soils after typical use of these compounds as seed dressings in the United Kingdom. There was evidence that imidacloprid was more persistent in the soils studied than clothianidin and thiamethoxam. As clothianidin and thiamethoxam have largely superseded imidacloprid in the United Kingdom, neonicotinoid levels were lower than suggested by predictions based on imidacloprid alone.},
  chemicals       = {Guanidines, Imidazoles, Insecticides, Neonicotinoids, Nitro Compounds, Oxazines, Pesticide Residues, Soil Pollutants, Thiazoles, clothianidin, imidacloprid, Thiamethoxam},
  citation-subset = {IM},
  completed       = {2015-07-22},
  country         = {England},
  issn-linking    = {1526-498X},
  keywords        = {England; Guanidines, analysis; Imidazoles, analysis; Insecticides, analysis; Neonicotinoids; Nitro Compounds, analysis; Oxazines, analysis; Pesticide Residues, analysis; Soil Pollutants, analysis; Thiamethoxam; Thiazoles, analysis; Apis mellifera; bumblebee; clothianidin; honey bee; imidacloprid; neonicotinoids; pollinator; soil; thiamethoxam},
  nlm-id          = {100898744},
  owner           = {NLM},
  pmid            = {24888990},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-02},
}

@Article{perre2015,
  author          = {de Perre, C. and Murphy, T. M. and Lydy, M. J.},
  title           = {Fate and effects of clothianidin in fields using conservation practices.},
  journal         = {Environ toxicol chemi},
  year            = {2015},
  volume          = {34},
  issue           = {2},
  month           = feb,
  pages           = {258--265},
  issn            = {1552-8618},
  doi             = {10.1002/etc.2800},
  abstract        = {Despite the extensive use of the neonicotinoid insecticide clothianidin, and its known toxicity to beneficial insects such as pollinators, little attention has been given to its fate under agricultural field conditions. The present study investigated the fate and toxicity of clothianidin applied every other year as a corn seed-coating at 2 different rates, 0.25 mg/seed and 0.50 mg/seed, in an agricultural field undergoing a corn-soybean annual rotation, and conservation tillage. Concentrations were measured in soil, surface runoff, infiltration, and groundwater from 2011 to 2013. Clothianidin was detected at low concentrations in soil and water throughout the 2-yr corn and soybean rotation. Low and no-tillage had little or no effect on clothianidin concentrations. Laboratory toxicity bioassays were performed on nontarget species, including Daphnia magna, Hyalella azteca, Chironomus dilutus, Pimephales promelas and Eisenia fetida. Risk quotients were calculated from clothianidin concentrations measured in the field and compared with the laboratory toxicity bioassay results to assess the environmental risk of the insecticide. The risk quotient was found to be lower than the level of concern for C. dilutus, which was the most sensitive species tested; therefore, no short-term environmental risk was expected for the species investigated in the present study.},
  chemicals       = {Guanidines, Insecticides, Neonicotinoids, Soil, Soil Pollutants, Thiazoles, Water Pollutants, Chemical, clothianidin},
  citation-subset = {IM},
  completed       = {2015-05-29},
  country         = {United States},
  issn-linking    = {0730-7268},
  keywords        = {Agriculture; Amphipoda, drug effects; Animals; Biological Assay; Chironomidae, drug effects; Conservation of Natural Resources; Daphnia, drug effects; Groundwater, chemistry; Guanidines, analysis, toxicity; Insecticides, analysis, toxicity; Neonicotinoids; Oligochaeta, drug effects; Seeds, chemistry; Soil, chemistry; Soil Pollutants, analysis, toxicity; Thiazoles, analysis, toxicity; Toxicity Tests; Water Pollutants, Chemical, analysis, toxicity; Zea mays, chemistry; Ecotoxicol.; Environmental risk; Neonicotinoids; Tillage; Water},
  nlm-id          = {8308958},
  owner           = {NLM},
  pmid            = {25376402},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-02},
}

@Article{botias2015,
  author          = {Botías, C. and David, A. and Horwood, J. and Abdul-Sada, A. and Nicholls, E. and Hill, E. and Goulson, D.},
  title           = {Neonicotinoid Residues in Wildflowers, a Potential Route of Chronic Exposure for Bees.},
  journal         = {Environ. Sci, Technol.},
  year            = {2015},
  volume          = {49},
  issue           = {21},
  month           = nov,
  pages           = {12731--12740},
  issn            = {1520-5851},
  doi             = {10.1021/acs.est.5b03459},
  abstract        = {In recent years, an intense debate about the environmental risks posed by neonicotinoids, a group of widely used, neurotoxic insecticides, has been joined. When these systemic compounds are applied to seeds, low concentrations are subsequently found in the nectar and pollen of the crop, which are then collected and consumed by bees. Here we demonstrate that the current focus on exposure to pesticides via the crop overlooks an important factor: throughout spring and summer, mixtures of neonicotinoids are also found in the pollen and nectar of wildflowers growing in arable field margins, at concentrations that are sometimes even higher than those found in the crop. Indeed, the large majority (97%) of neonicotinoids brought back in pollen to honey bee hives in arable landscapes was from wildflowers, not crops. Both previous and ongoing field studies have been based on the premise that exposure to neonicotinoids would occur only during the blooming period of flowering crops and that it may be diluted by bees also foraging on untreated wildflowers. Here, we show that exposure is likely to be higher and more prolonged than currently recognized because of widespread contamination of wild plants growing near treated crops. },
  chemicals       = {Insecticides, Plant Nectar, Soil, Anabasine},
  citation-subset = {IM},
  completed       = {2016-06-06},
  country         = {United States},
  issn-linking    = {0013-936X},
  keywords        = {Anabasine, toxicity; Animals; Bees, metabolism; Brassica rapa, chemistry; Crops, Agricultural, chemistry; Environmental Exposure, analysis; Flowers, chemistry; Hordeum, chemistry; Insecticides, analysis; Plant Nectar, chemistry; Pollen, chemistry; Seeds, chemistry; Soil, chemistry; Triticum, chemistry},
  nlm-id          = {0213155},
  owner           = {NLM},
  pmid            = {26439915},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-02},
}

@Article{schaafsma2016,
  author          = {Schaafsma, A. and Limay-Rios, V. and Xue, Y. and Smith, J. and Baute, T.},
  title           = {Field-scale examination of neonicotinoid insecticide persistence in soil as a result of seed treatment use in commercial maize (corn) fields in southwestern Ontario.},
  journal         = {Environ toxicol chemi},
  year            = {2016},
  volume          = {35},
  issue           = {2},
  month           = feb,
  pages           = {295--302},
  issn            = {1552-8618},
  doi             = {10.1002/etc.3231},
  abstract        = {Neonicotinoid insecticides, especially as seed treatments, have raised concerns about environmental loading and impacts on pollinators, biodiversity, and ecosystems. The authors measured concentrations of neonicotinoid residues in the top 5 cm of soil before planting of maize (corn) in 18 commercial fields with a history of neonicotinoid seed treatment use in southwestern Ontario in 2013 and 2014 using liquid chromatography-tandem mass spectrometry with electrospray ionization. A simple calculator based on first-order kinetics, incorporating crop rotation, planting date, and seed treatment history from the subject fields, was used to estimate dissipation rate from the seed zone. The estimated half-life (the time taken for 50% of the insecticide to have dissipated by all mechanisms) based on 8 yr of crop history was 0.64 (range, 0.25-1.59) yr and 0.57 (range, 0.24-2.12) yr for 2013 and 2014, respectively. In fields where neonicotinoid residues were measured in both years, the estimated mean half-life between 2013 and 2014 was 0.4 (range, 0.27-0.6) yr. If clothianidin and thiamethoxam were used annually as a seed treatment in a typical crop rotation of maize, soybean, and winter wheat over several years, residues would plateau rather than continue to accumulate. Residues of neonicotinoid insecticides after 3 yr to 4 yr of repeated annual use tend to plateau to a mean concentration of less than 6 ng/g in agricultural soils in southwestern Ontario.},
  chemicals       = {Cholinergic Agents, Guanidines, Insecticides, Neonicotinoids, Nitro Compounds, Oxazines, Pesticide Residues, Soil Pollutants, Thiazoles, clothianidin, Thiamethoxam},
  citation-subset = {IM},
  completed       = {2016-09-26},
  country         = {United States},
  issn-linking    = {0730-7268},
  keywords        = {Agriculture; Cholinergic Agents, analysis; Ecosystem; Guanidines, analysis; Half-Life; Insecticides, analysis; Neonicotinoids; Nitro Compounds, analysis; Ontario; Oxazines, analysis; Pesticide Residues, analysis; Seeds, chemistry; Soil Pollutants, analysis; Thiamethoxam; Thiazoles, analysis; Zea mays, chemistry; Clothianidin; Dissipation; Half-life; Pesticide; Thiamethoxam},
  nlm-id          = {8308958},
  owner           = {NLM},
  pmid            = {26332416},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-02},
}

@Article{xu2016,
  author          = {Xu, T. and Dyer, D. G. and McConnell, L. L. and Bondarenko, S. and Allen, R. and Heinemann, O.},
  title           = {Clothianidin in agricultural soils and uptake into corn pollen and canola nectar after multiyear seed treatment applications.},
  journal         = {Environ toxicol chemi},
  year            = {2016},
  volume          = {35},
  issue           = {2},
  month           = feb,
  pages           = {311--321},
  issn            = {1552-8618},
  doi             = {10.1002/etc.3281},
  abstract        = {Limited data are available on the fate of clothianidin under realistic agricultural production conditions. The present study is the first large-scale assessment of clothianidin residues in soil and bee-relevant matrices from corn and canola fields after multiple years of seed-treatment use. The average soil concentration from 50 Midwest US corn fields with 2 yr to 11 yr of planting clothianidin-treated seeds was 7.0 ng/g, similar to predicted concentrations from a single planting of Poncho 250-treated corn seeds (6.3 ng/g). The water-extractable (i.e., plant-bioavailable) clothianidin residues in soil were only 10% of total residues. Clothianidin concentrations in soil reached a plateau concentration (amount applied equals amount dissipated) in fields with 4 or more application years. Concentrations in corn pollen from these fields were low (mean: 1.8 ng/g) with no correlation to total years of use or soil concentrations. For canola, soil concentrations from 27 Canadian fields with 2 yr to 4 yr of seed treatment use (mean = 5.7 ng/g) were not correlated with use history, and plant bioavailability was 6% of clothianidin soil residues. Average canola nectar concentrations were 0.6 ng/g and not correlated to use history or soil concentrations. Under typical cropping practices, therefore, clothianidin residues are not accumulating significantly in soil, plant bioavailability of residues in soil is limited, and exposure to pollinators will not increase over time in fields receiving multiple applications of clothianidin.},
  chemicals       = {Guanidines, Insecticides, Neonicotinoids, Pesticide Residues, Plant Nectar, Soil, Soil Pollutants, Thiazoles, clothianidin},
  citation-subset = {IM},
  completed       = {2016-09-26},
  country         = {United States},
  issn-linking    = {0730-7268},
  keywords        = {Adsorption; Agriculture; Animals; Bees, drug effects; Brassica rapa, chemistry; Canada; Europe; Guanidines, analysis, pharmacokinetics; Insecticides, analysis, pharmacokinetics; Midwestern United States; Neonicotinoids; Pesticide Residues, analysis; Plant Nectar, chemistry; Pollen, chemistry; Soil, chemistry; Soil Pollutants, analysis; Thiazoles, analysis, pharmacokinetics; Zea mays, chemistry; Adsorption; Bioavailability; Clothianidin; Fate and transport; Neonicotinoid; Pollen},
  nlm-id          = {8308958},
  owner           = {NLM},
  pmc             = {PMC4736462},
  pmid            = {26467536},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-02},
}

@Article{goulson2014,
  author          = {Goulson, D.},
  title           = {Pesticides linked to bird declines.},
  journal         = {Nature},
  year            = {2014},
  volume          = {511},
  issue           = {7509},
  month           = jul,
  pages           = {295--296},
  issn            = {1476-4687},
  doi             = {10.1038/nature13642},
  chemicals       = {Imidazoles, Insecticides, Neonicotinoids, Nitro Compounds, imidacloprid},
  citation-subset = {IM},
  completed       = {2014-08-19},
  country         = {England},
  issn-linking    = {0028-0836},
  keywords        = {Animals; Birds, physiology; Diet, veterinary; Environmental Monitoring; Food Chain; Imidazoles, adverse effects; Insecta; Insecticides, adverse effects; Neonicotinoids; Nitro Compounds, adverse effects},
  nlm-id          = {0410462},
  owner           = {NLM},
  pii             = {nature13642},
  pmid            = {25030159},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-02},
}

@Article{bennett2012,
  author          = {Bennett, Hayley M and Lees, Kristin and Harper, Kate M and Jones, Andrew K and Sattelle, David B and Wonnacott, Susan and Wolstenholme, Adrian J},
  title           = {Xenopus laevis RIC-3 enhances the functional expression of the C. elegans homomeric nicotinic receptor, ACR-16, in Xenopus oocytes.},
  journal         = {J. Neurochem.},
  year            = {2012},
  volume          = {123},
  issue           = {6},
  month           = dec,
  pages           = {911--918},
  issn            = {1471-4159},
  doi             = {10.1111/jnc.12013},
  abstract        = {RIC-3 enhances the functional expression of certain nicotinic acetylcholine receptors (nAChRs) in vertebrates and invertebrates and increases the availability of functional receptors in cultured cells and Xenopus laevis oocytes. Maximal activity of RIC-3 may be cell-type dependent, so neither mammalian nor invertebrate proteins is optimal in amphibian oocytes. We cloned the X. laevis ric-3 cDNA and tested the frog protein in oocyte expression studies. X. laevis RIC-3 shares 52% amino acid identity with human RIC-3 and only 17% with that of Caenorhabditis elegans. We used the C. elegans nicotinic receptor, ACR-16, to compare the ability of RIC-3 from three species to enhance receptor expression. In the absence of RIC-3, the proportion of oocytes expressing detectable nAChRs was greatly reduced. Varying the ratio of acr-16 to X. laevis ric-3 cRNAs injected into oocytes had little impact on the total cell current. When X. laevis, human or C. elegans ric-3 cRNAs were co-injected with acr-16 cRNA (1 : 1 ratio), 100 μM acetylcholine induced larger currents in oocytes expressing X. laevis RIC-3 compared with its orthologues. This provides further evidence for a species-specific component of RIC-3 activity, and suggests that X. laevis RIC-3 is useful for enhancing the expression of invertebrate nAChRs in X. laevis oocytes.},
  chemicals       = {Caenorhabditis elegans Proteins, Chrna7 protein, human, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Molecular Chaperones, RIC-3 protein, Xenopus, Receptors, Nicotinic, Xenopus Proteins, acr-16 protein, C elegans, alpha7 Nicotinic Acetylcholine Receptor, ric-3 protein, C elegans},
  citation-subset = {IM},
  completed       = {2013-02-14},
  country         = {England},
  issn-linking    = {0022-3042},
  keywords        = {Amino Acid Sequence; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins, biosynthesis, genetics, physiology; Gene Expression Regulation, Developmental, genetics; Humans; Intracellular Signaling Peptides and Proteins, biosynthesis, genetics, physiology; Membrane Proteins, physiology; Molecular Chaperones, physiology; Molecular Sequence Data; Oocytes, metabolism, physiology; Receptors, Nicotinic, biosynthesis, genetics, physiology; Up-Regulation, genetics; Xenopus Proteins, physiology; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {2985190R},
  owner           = {NLM},
  pmc             = {PMC3549563},
  pmid            = {22970690},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{lansdell2005,
  author          = {Lansdell, S. J. and Gee, V. J. and Harkness, P. C. and Doward, A. I. and Baker, E. R. and Environ. Health Perspect., A. J. and Millar, N. S.},
  title           = {RIC-3 enhances functional expression of multiple nicotinic acetylcholine receptor subtypes in mammalian cells.},
  journal         = {Molecular pharmacology},
  year            = {2005},
  volume          = {68},
  issue           = {5},
  month           = nov,
  pages           = {1431--1438},
  issn            = {0026-895X},
  doi             = {10.1124/mol.105.017459},
  abstract        = {Recent studies have shown that RIC-3, originally identified in Caenorhabditis elegans as the protein encoded by the gene resistance to inhibitors of cholinesterase (ric-3), can enhance functional expression of alpha7 nicotinic acetylcholine receptors (nAChRs). In the present study, the influence of C. elegans and human RIC-3 upon multiple homomeric (alpha7, alpha8, and alpha9) and heteromeric (alpha3beta2, alpha3beta4, alpha4beta2, alpha4beta4, and alpha9alpha10) nAChR subtypes has been examined in transfected mammalian cells by radioligand binding and functional characterization. Coexpression of RIC-3 facilitates a dramatic enhancement of the ability of alpha7 (and the closely related alpha8 subunit) to generate functional nAChRs in otherwise nonpermissive mammalian cells. In contrast, coexpression of RIC-3 did not facilitate functional expression of either homomeric alpha9 or heteromeric alpha9alpha10 nAChRs in mammalian cell lines. It is noteworthy that whereas RIC-3 has been reported to cause a marked functional inhibition of heteromeric nAChRs such as alpha3beta4 and alpha4beta2 expressed in Xenopus laevis oocytes, RIC-3 significantly enhances levels of functional expression of these and other (alpha3beta2 and alpha4beta4) heteromeric nAChRs when expressed in mammalian cell lines. In addition, the interaction of multiple nAChR subunits (alpha3, alpha4, alpha7, beta2, and beta4) with RIC-3 has been demonstrated by coimmunoprecipitation from metabolically labeled transfected cells. It is significant that coimmunoprecipitation experiments have provided evidence that RIC-3 associates with unassembled nAChR subunits, a finding that is consistent with previous suggestions that RIC-3 may act by enhancing the maturation (subunit folding and assembly) of nAChRs. We conclude that RIC-3 is an nAChR-associated protein that can enhance functional expression of multiple nAChR subtypes in transfected mammalian cells.},
  chemicals       = {CHRNA9 protein, human, Chrna7 protein, human, Chrna7 protein, rat, Intracellular Signaling Peptides and Proteins, Proteins, RIC3 protein, human, Receptors, Nicotinic, alpha7 Nicotinic Acetylcholine Receptor},
  citation-subset = {IM},
  completed       = {2005-11-28},
  country         = {United States},
  issn-linking    = {0026-895X},
  keywords        = {Animals; Cell Line; Humans; Immunoprecipitation; Intracellular Signaling Peptides and Proteins; Proteins, analysis, physiology; Rats; Receptors, Nicotinic, analysis, chemistry, classification, physiology; alpha7 Nicotinic Acetylcholine Receptor},
  nlm-id          = {0035623},
  owner           = {NLM},
  pii             = {mol.105.017459},
  pmid            = {16120769},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{claudio1987,
  author          = {Claudio, T. and Green, W. N. and Hartman, D. S. and Hayden, D. and Paulson, H. L. and Sigworth, F. .J and Sine, .S M. and Swedlund, A.},
  title           = {Genetic reconstitution of functional acetylcholine receptor channels in mouse fibroblasts.},
  journal         = {Science},
  year            = {1987},
  volume          = {238},
  issue           = {4834},
  month           = dec,
  pages           = {1688--1694},
  issn            = {0036-8075},
  abstract        = {Foreign genes can be stably integrated into the genome of a cell by means of DNA-mediated gene transfer techniques, and large quantities of homogenous cells that continuously express these gene products can then be isolated. Such an expression system can be used to study the functional consequences of introducing specific mutations into genes and to study the expressed protein in the absence of cellular components with which it is normally in contact. All four Torpedo acetylcholine receptor (AChR) subunit complementary DNA's were introduced into the genome of a mouse fibroblast cell by DNA-mediated gene transfer. A clonal cell line that stably produced high concentrations of correctly assembled cell surface AChR's and formed proper ligand-gated ion channels was isolated. With this new expression system, recombinant DNA, biochemical, pharmacological, and electrophysiological techniques were combined to study Torpedo AChR's in a single intact system. The physiological and pharmacological profiles of Torpedo AChR's expressed in mouse fibroblast cells differ in some details from those described earlier, and may provide a more accurate reflection of the properties of this receptor in its natural environment.},
  chemicals       = {Receptors, Cholinergic},
  citation-subset = {IM},
  completed       = {1988-01-21},
  country         = {United States},
  issn-linking    = {0036-8075},
  keywords        = {Animals; Cell Line; Cell Membrane, physiology; Fibroblasts, metabolism; Genes; Kinetics; Mice; Receptors, Cholinergic, genetics, metabolism; Torpedo; Transfection},
  nlm-id          = {0404511},
  owner           = {NLM},
  pmid            = {3686008},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2007-11-14},
}

@Article{mishina1984,
  author          = {Mishina, M. and Kurosaki, T. and Tobimatsu, T. and Morimoto, Y. and Noda, M. and Yamamoto, T. and Terao, M. and Lindstrom, J. and Takahashi, T. and Kuno, M.},
  title           = {Expression of functional acetylcholine receptor from cloned cDNAs.},
  journal         = {Nature},
  year            = {1984},
  volume          = {307},
  issue           = {5952},
  pages           = {604--608},
  issn            = {0028-0836},
  abstract        = {The cloned cDNAs encoding the four subunits of the Torpedo californica acetylcholine receptor, each carried by a simian virus 40 vector, direct the synthesis of the functional receptor in a combined expression system consisting of COS monkey cells and Xenopus oocytes. Our results suggest that all four subunits are required to elicit a normal nicotinic response to acetylcholine, whereas only the alpha-subunit is indispensable for alpha-bungarotoxin binding activity.},
  chemicals       = {Macromolecular Substances, Receptors, Cholinergic, DNA},
  citation-subset = {IM},
  completed       = {1984-03-23},
  country         = {England},
  issn-linking    = {0028-0836},
  keywords        = {Animals; Cloning, Molecular; DNA, genetics; Female; Gene Expression Regulation; Genetic Vectors; Macromolecular Substances; Oocytes, physiology; Receptors, Cholinergic, genetics; Structure-Activity Relationship; Torpedo; Xenopus laevis},
  nlm-id          = {0410462},
  owner           = {NLM},
  pmid            = {6320016},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2006-11-15},
}

@Article{kenny2000,
  author          = {Kenny, P. J. and File, S. E. and Neal, M. J.},
  title           = {Evidence for a complex influence of nicotinic acetylcholine receptors on hippocampal serotonin release.},
  journal         = {J. Neurochem.},
  year            = {2000},
  volume          = {75},
  issue           = {6},
  month           = dec,
  pages           = {2409--2414},
  issn            = {0022-3042},
  abstract        = {The effects of nicotine on 5-hydroxytryptamine (5-HT) release from serotonergic nerve endings in rat dorsal hippocampal slices were studied. Nicotine (50-500 microM:) caused a concentration-dependent increase in 5-HT release. This effect was antagonised by mecamylamine (0.5 microM:), indicating an action at nicotinic receptors. Nicotine-evoked 5-HT release was not affected by tetrodotoxin (3 microM:), cadmium chloride (0.1 mM:), or the absence of Ca(2+) or Na(+) in the superfusion medium. Unexpectedly, higher concentrations of mecamylamine alone (1-50 microM:) increased 5-HT release. This suggested the presence of inhibitory input to 5-HT neurones and that these inhibitory neurones possess tonically active nicotinic receptors. The effect of mecamylamine (50 microM:) on 5-HT release was reduced by the muscarinic M(1) receptor agonist, McN-A-343 (100 microM:), but pirenzepine (0.005-1 microM:), which blocks M(1) receptors, alone increased 5-HT release. Hippocampal serotonergic neurones are known to possess both excitatory nicotinic receptors and inhibitory M(1) receptors. Although there may be several explanations for our results, one possible explanation is that nicotine stimulates 5-HT release by activating nicotinic heteroreceptors on 5-HT terminals. Mecamylamine (0.5 microM:) antagonises this effect, but higher concentrations increase 5-HT release indirectly by blocking the action of endogenous acetylcholine on nicotinic receptors situated on cholinergic neurones that provide muscarinic inhibitory input to 5-HT neurones.},
  chemicals       = {Calcium Channel Blockers, Carrier Proteins, Membrane Glycoproteins, Membrane Transport Proteins, Nerve Tissue Proteins, Nicotinic Agonists, Nicotinic Antagonists, Receptor, Muscarinic M1, Receptors, GABA-A, Receptors, Glutamate, Receptors, Muscarinic, Receptors, Nicotinic, Serotonin Plasma Membrane Transport Proteins, Serotonin Uptake Inhibitors, Slc6a4 protein, rat, Serotonin, Paroxetine, Tetrodotoxin, Mecamylamine, Nicotine, Calcium},
  citation-subset = {IM},
  completed       = {2000-12-28},
  country         = {England},
  issn-linking    = {0022-3042},
  keywords        = {Animals; Calcium, metabolism; Calcium Channel Blockers, pharmacology; Carrier Proteins, antagonists & inhibitors, metabolism; Dose-Response Relationship, Drug; Hippocampus, drug effects, metabolism; In Vitro Techniques; Male; Mecamylamine, pharmacology; Membrane Glycoproteins, antagonists & inhibitors, metabolism; Membrane Transport Proteins; Nerve Tissue Proteins; Nicotine, pharmacology; Nicotinic Agonists, pharmacology; Nicotinic Antagonists, pharmacology; Paroxetine, pharmacology; Rats; Rats, Inbred Strains; Receptor, Muscarinic M1; Receptors, GABA-A, metabolism; Receptors, Glutamate, metabolism; Receptors, Muscarinic, metabolism; Receptors, Nicotinic, drug effects, metabolism; Serotonin, metabolism; Serotonin Plasma Membrane Transport Proteins; Serotonin Uptake Inhibitors, pharmacology; Tetrodotoxin, pharmacology},
  nlm-id          = {2985190R},
  owner           = {NLM},
  pmid            = {11080192},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-30},
}

@Article{araujo1988,
  author    = {Araujo, D. M. and Lapchak, P. A. and Collier, B. and Quirion, R.},
  title     = {Characterization of N-[3H] methylcarbamylcholine binding sites and effect of N-methylcarbamylcholine on acetylcholine release in rat brain},
  journal   = {J. Neurochem.},
  year      = {1988},
  volume    = {51},
  number    = {1},
  pages     = {292--299},
  publisher = {Wiley Online Library},
}

@Article{fabian-fine2001,
  author    = {Fabian-Fine, R. and Skehel, P. and Errington, M. L. and Davies, H. A. and Sher, E. and Stewart, M. G. and Fine, A.},
  title     = {Ultrastructural distribution of the $\alpha$7 nicotinic acetylcholine receptor subunit in rat hippocampus},
  journal   = {J. Neurosci.},
  year      = {2001},
  volume    = {21},
  number    = {20},
  pages     = {7993--8003},
  publisher = {Soc Neuroscience},
}

@Article{cooper1991,
  author    = {Cooper, E. and Couturier, S. and Ballivet, M.},
  title     = {Pentameric structure and subunit stoichiometry of a neuronal nicotinic acetylcholine receptor},
  journal   = {Nature},
  year      = {1991},
  volume    = {350},
  number    = {6315},
  pages     = {235},
  publisher = {Nature Publishing Group},
}

@Article{boorman2000,
  author    = {Boorman, J. P. B. and Groot-Kormelink, P. J. and Sivilotti, L. G.},
  title     = {Stoichiometry of human recombinant neuronal nicotinic receptors containing the $\beta$3 subunit expressed in Xenopus oocytes},
  journal   = { J. Physiol.},
  year      = {2000},
  volume    = {529},
  number    = {3},
  pages     = {565--577},
  publisher = {Wiley Online Library},
}

@Article{nelson2003,
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  title     = {Alternate stoichiometries of $\alpha$4$\beta$2 nicotinic acetylcholine receptors},
  journal   = {Molecular pharmacology},
  year      = {2003},
  volume    = {63},
  number    = {2},
  pages     = {332--341},
  publisher = {ASPET},
}

@Article{couturier1990,
  author    = {Couturier, S. and Bertrand, D. and Matter, J-M. and Hernandez, M-C. and Bertrand, S. and Millar, N. and Valera, S. and Barkas, T. and Ballivet, M.},
  title     = {A neuronal nicotinic acetylcholine receptor subunit ($\alpha$7) is developmentally regulated and forms a homo-oligomeric channel blocked by $\alpha$-BTX},
  journal   = {Neuron},
  year      = {1990},
  volume    = {5},
  number    = {6},
  pages     = {847--856},
  publisher = {Elsevier},
}

@Article{keyser1993,
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  title     = {Three subtypes of alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors are expressed in chick retina},
  journal   = {J. Neurosci.},
  year      = {1993},
  volume    = {13},
  number    = {2},
  pages     = {442--454},
  publisher = {Soc Neuroscience},
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@Article{chen1997,
  author    = {Chen, D.. and Patrick, J. W.},
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  year      = {1997},
  volume    = {272},
  number    = {38},
  pages     = {24024--24029},
  publisher = {ASBMB},
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@Article{drisdel2000,
  author    = {Drisdel, R. C and Green, W. N.},
  title     = {Neuronal $\alpha$-bungarotoxin receptors are $\alpha$7 subunit homomers},
  journal   = {J. Neurosci.},
  year      = {2000},
  volume    = {20},
  number    = {1},
  pages     = {133--139},
  publisher = {Soc Neuroscience},
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@Article{khiroug2002,
  author    = {Khiroug, S. S. and Harkness, P. C. and Lamb, P. W. and Sudweeks, S. N. and Khiroug, L. and Millar, N. S. and Yakel, J. L.},
  title     = {Rat nicotinic ACh receptor $\alpha$7 and $\beta$2 subunits co-assemble to form functional heteromeric nicotinic receptor channels},
  journal   = { J. Physiol.},
  year      = {2002},
  volume    = {540},
  number    = {2},
  pages     = {425--434},
  publisher = {Wiley Online Library},
}

@Article{palma1999,
  author    = {Palma, E. and Maggi, L. and Barabino, B. and Eusebi, F. and Ballivet, M.},
  title     = {Nicotinic acetylcholine receptors assembled from the $\alpha$7 and $\beta$3 subunits},
  journal   = {J. Biol. Chem.},
  year      = {1999},
  volume    = {274},
  number    = {26},
  pages     = {18335--18340},
  publisher = {ASBMB},
}

@Article{chavez-noriega1997,
  author    = {Chavez-Noriega, L. E. and Crona, J. H. and Washburn, M. S. and Urrutia, A. and Elliott, K. J. and Johnson, E. C.},
  title     = "{Pharmacological Characterization of Recombinant Human Neuronal Nicotinic Acetylcholine Receptors h$\alpha$2$\beta$2, h$\alpha$2$\beta$4, h$\alpha$3$\beta$2, h$\alpha$3$\beta$4, h$\alpha$4$\beta$2, h$\alpha$4$\beta$4 and h$\alpha$7 Expressed in \textit{Xenopus} oocytes}",
  journal   = {J. Pharmacol. Exp. Ther.},
  year      = {1997},
  volume    = {280},
  number    = {1},
  pages     = {346--356},
  publisher = {ASPET},
}

@Article{oleskevich1999,
  author    = {Oleskevich, S.},
  title     = {Cholinergic synaptic transmission in insect mushroom bodies in vitro},
  journal   = {J. Neurophys.},
  year      = {1999},
  volume    = {82},
  number    = {2},
  pages     = {1091--1096},
  publisher = {American Physiological Society Bethesda, MD},
}

@Article{mobbs1982,
  author    = {Mobbs, P. G.},
  title     = {The brain of the honeybee Apis mellifera. I. The connections and spatial organization of the mushroom bodies},
  journal   = {Philosophical Transactions of the Royal Society of London. B, Biological Sciences},
  year      = {1982},
  volume    = {298},
  number    = {1091},
  pages     = {309--354},
  publisher = {The Royal Society London},
}

@Article{gu2006,
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  year      = {2006},
  volume    = {26},
  number    = {1},
  pages     = {265--272},
  publisher = {Soc Neuroscience},
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@Article{kreissl1989,
  author    = {Kreissl, S. and Bicker, G.},
  title     = {Histochemistry of acetylcholinesterase and immunocytochemistry of an acetylcholine receptor-like antigen in the brain of the honeybee},
  journal   = {J. Comp. Neurol.},
  year      = {1989},
  volume    = {286},
  number    = {1},
  pages     = {71--84},
  publisher = {Wiley Online Library},
}

@Article{bai1992,
  author    = {Bai, D. and Erdbrugger, H. and Breer, H. and Sattelle, D. B.},
  title     = "{Acetylcholine Receptors of Thoracic Dorsal Midline Neurones in the Cockroach, \textit{Periplaneta americana}}",
  journal   = {Archives of insect biochemistry and physiology},
  year      = {1992},
  volume    = {21},
  number    = {4},
  pages     = {289--301},
  publisher = {Wiley Online Library},
}

@Article{sinakevitch1996,
  author    = {Sinakevitch, I. G. and Geffard, M. and Pelhate, M. and Lapied, B.},
  title     = {Anatomy and targets of dorsal unpaired median neurones in the terminal abdominal ganglion of the male cockroach Periplaneta americana L.},
  journal   = {J. Comp. Neurol.},
  year      = {1996},
  volume    = {367},
  number    = {1},
  pages     = {147--163},
  publisher = {Wiley Online Library},
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@Article{jensen2012,
  author    = {Jensen, M. and Hoerndli, F. J. and Brockie, P. J. and Wang, R. and Johnson, E. and Maxfield, D. and Francis, M. M. and Madsen, D. M. and Maricq, A. V.},
  title     = {Wnt signaling regulates acetylcholine receptor translocation and synaptic plasticity in the adult nervous system},
  journal   = {Cell},
  year      = {2012},
  volume    = {149},
  number    = {1},
  pages     = {173--187},
  publisher = {Elsevier},
}

@Article{barnard1971,
  author    = {Barnard, E. A. and Wieckowski, J. and Chiu, T. H.},
  title     = {Cholinergic receptor molecules and cholinesterase molecules at mouse skeletal muscle junctions},
  journal   = {Nature},
  year      = {1971},
  volume    = {234},
  number    = {5326},
  pages     = {207},
  publisher = {Nature Publishing Group},
}

@Article{millar2009a,
  author    = {Millar, Neil S},
  title     = {A review of experimental techniques used for the heterologous expression of nicotinic acetylcholine receptors},
  journal   = {Biochem. Pharmacol.},
  year      = {2009},
  volume    = {78},
  number    = {7},
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@Article{salom2012,
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  journal   = {The FASEB Journal},
  year      = {2012},
  volume    = {26},
  number    = {2},
  pages     = {492--502},
  publisher = {Federation of American Societies for Experimental Biology Bethesda, MD, USA},
}

@Article{yabe2005,
  author    = {Yabe, Tomoko and Suzuki, Norio and Furukawa, Tatsuhiko and Ishihara, Takeshi and Katsura, Isao},
  title     = {Multidrug resistance-associated protein MRP-1 regulates dauer diapause by its export activity in Caenorhabditis elegans},
  journal   = {Development},
  year      = {2005},
  volume    = {132},
  number    = {14},
  pages     = {3197--3207},
  publisher = {The Company of Biologists Ltd},
}

@Article{clarke1985,
  author    = {Clarke, P. B. and Schwartz, R. D. and Paul, S. M. and Pert, C. B. and Pert, A.},
  title     = {Nicotinic binding in rat brain: autoradiographic comparison of [3H]-acetylcholine,[3H]-nicotine, and [125I]-alpha-bungarotoxin},
  journal   = {J. Neurosci.},
  year      = {1985},
  volume    = {5},
  number    = {5},
  pages     = {1307--1315},
  publisher = {Soc Neuroscience},
}

@Article{carbonetto1979,
  author    = {Carbonetto, S. and Fambrough, D. M.},
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  year      = {1979},
  volume    = {81},
  number    = {3},
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@Article{corrie2011,
  author    = {Corrie, J. B. and Free, .C R. and Corradi, J. and Bouzat, C. and Sine, S. M.},
  title     = {Single-channel and structural foundations of neuronal $\alpha$7 acetylcholine receptor potentiation},
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  year      = {2011},
  volume    = {31},
  number    = {39},
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@Article{baez-pagan2015,
  author    = {B{\'a}ez-Pag{\'a}n, C. A. and Delgado-V{\'e}lez, M. and Lasalde-Dominicci, J. A.},
  title     = {Activation of the macrophage $\alpha$7 nicotinic acetylcholine receptor and control of inflammation},
  journal   = {Journal of Neuroimmune Pharmacology},
  year      = {2015},
  volume    = {10},
  number    = {3},
  pages     = {468--476},
  publisher = {Springer},
}

@Article{Lasala2019,
  author    = {Lasala, Mat{\'\i}as and Fabiani, Camila and Corradi, Jeremias and Antollini, Silvia and Bouzat, Cecilia},
  title     = {Molecular Modulation of Human $\alpha$7 Nicotinic Receptor by Amyloid-$\beta$ Peptides},
  journal   = {Frontiers in cellular neuroscience},
  year      = {2019},
  volume    = {13},
  publisher = {Frontiers Media SA},
}

@Article{Nielsen2018,
  author    = {Nielsen, Beatriz E and Minguez, Teresa and Bermudez, Isabel and Bouzat, Cecilia},
  title     = {Molecular function of the novel $\alpha$7$\beta$2 nicotinic receptor},
  journal   = {Cellular and molecular life sciences},
  year      = {2018},
  volume    = {75},
  number    = {13},
  pages     = {2457--2471},
  publisher = {Springer},
}

@Article{Lasala2018,
  author    = {Lasala, Mat{\'\i}as and Corradi, Jerem{\'\i}as and Bruzzone, Ariana and del Carmen Esandi, Mar{\'\i}a and Bouzat, Cecilia},
  title     = {A human-specific, truncated $\alpha$7 nicotinic receptor subunit assembles with full-length $\alpha$7 and forms functional receptors with different stoichiometries},
  journal   = {J. Biol. Chem.},
  year      = {2018},
  volume    = {293},
  number    = {27},
  pages     = {10707--10717},
  publisher = {ASBMB},
}

@Article{papke2006,
  author    = {Papke, R. L.},
  title     = {Estimation of both the potency and efficacy of $\alpha$7 nAChR agonists from single-concentration responses},
  journal   = {Life sciences},
  year      = {2006},
  volume    = {78},
  number    = {24},
  pages     = {2812--2819},
  publisher = {Elsevier},
}

@Article{mike2000,
  author    = {Mike, A. and Castro, N. G. and Albuquerque, E. X.},
  title     = {Choline and acetylcholine have similar kinetic properties of activation and desensitization on the $\alpha$7 nicotinic receptors in rat hippocampal neurons},
  journal   = {Brain res.},
  year      = {2000},
  volume    = {882},
  number    = {1-2},
  pages     = {155--168},
  publisher = {Elsevier},
}

@Article{Jones1997,
  author    = {Jones, Susan and Yakel, Jerrel L},
  title     = {Functional nicotinic ACh receptors on interneurones in the rat hippocampus},
  journal   = { J. Physiol.},
  year      = {1997},
  volume    = {504},
  number    = {3},
  pages     = {603--610},
  publisher = {Wiley Online Library},
}

@Article{Coppola2016,
  author    = {Coppola, Jennifer J and Ward, Nicholas J and Jadi, Monika P and Disney, Anita A},
  title     = {Modulatory compartments in cortex and local regulation of cholinergic tone},
  journal   = {Journal of Physiology-Paris},
  year      = {2016},
  volume    = {110},
  number    = {1-2},
  pages     = {3--9},
  publisher = {Elsevier},
}

@Article{Choueiry2019,
  author    = {Choueiry, Joelle and Blais, Crystal M and Shah, Dhrasti and Smith, Dylan and Fisher, Derek and Labelle, Alain and Knott, Verner},
  title     = {Combining CDP-choline and galantamine, an optimized $\alpha$7 nicotinic strategy, to ameliorate sensory gating to speech stimuli in schizophrenia},
  journal   = {International Journal of Psychophysiology},
  year      = {2019},
  publisher = {Elsevier},
}

@Article{anderson1974,
  author    = {Anderson, M. J. and Cohen, M. W.},
  title     = {Fluorescent staining of acetylcholine receptors in vertebrate skeletal muscle},
  journal   = { J. Physiol.},
  year      = {1974},
  volume    = {237},
  number    = {2},
  pages     = {385--400},
  publisher = {Wiley Online Library},
}

@Article{huang2013,
  author    = {Huang, S. and Li, S. and Bren, N. and Cheng, K. and Gomoto, R. and Chen, L. and Sine, S. M.},
  title     = {Complex between $\alpha$-bungarotoxin and an $\alpha$7 nicotinic receptor ligand-binding domain chimaera},
  journal   = {Biochemical Journal},
  year      = {2013},
  volume    = {454},
  number    = {2},
  pages     = {303--310},
  publisher = {Portland Press Limited},
}

@Article{orr-urtreger1997,
  author    = {Orr-Urtreger, A. and G{\"o}ldner, F. M. and Saeki, M. and Lorenzo, I. and Goldberg, L. and De Biasi, M. and Dani, J. A. and Patrick, J. W. and Beaudet, A. L.},
  title     = {Mice deficient in the $\alpha$7 neuronal nicotinic acetylcholine receptor lack $\alpha$-bungarotoxin binding sites and hippocampal fast nicotinic currents},
  journal   = {J. Neurosci.},
  year      = {1997},
  volume    = {17},
  number    = {23},
  pages     = {9165--9171},
  publisher = {Soc Neuroscience},
}

@Article{alkondon1991,
  author    = {Alkondon, M. and Albuquerque, E. X.},
  title     = {Initial characterization of the nicotinic acetylcholine receptors in rat hippocampal neurons},
  journal   = {J. Recept. Res.},
  year      = {1991},
  volume    = {11},
  number    = {6},
  pages     = {1001--1021},
  publisher = {Taylor \& Francis},
}

@Article{schoepfer1990,
  author    = {Schoepfer, R. and Conroy, W. G. and Whiting, P. and Gore, M. and Lindstrom, J.},
  title     = {Brain $\alpha$-bungarotoxin binding protein cDNAs and MAbs reveal subtypes of this branch of the ligand-gated ion channel gene superfamily},
  journal   = {Neuron},
  year      = {1990},
  volume    = {5},
  number    = {1},
  pages     = {35--48},
  publisher = {Elsevier},
}

@Article{toro1994,
  author    = {del Toro, E. D. and Juiz, J. M. and Peng, X. and Lindstrom, J. and Criado, M.},
  title     = {Immunocytochemical localization of the $\alpha$7 subunit of the nicotinic acetylcholine receptor in the rat central nervous system},
  journal   = {J. Comp. Neurol.},
  year      = {1994},
  volume    = {349},
  number    = {3},
  pages     = {325--342},
  publisher = {Wiley Online Library},
}

@Article{McFadden2014,
  author    = {McFadden, Kristina L and Cornier, Marc-Andre and Tregellas, Jason R},
  title     = {The role of alpha-7 nicotinic receptors in food intake behaviors},
  journal   = {Frontiers in psychology},
  year      = {2014},
  volume    = {5},
  pages     = {553},
  publisher = {Frontiers},
}

@Article{Rothermel2014,
  author    = {Rothermel, Markus and Wachowiak, Matt},
  title     = {Functional imaging of cortical feedback projections to the olfactory bulb},
  journal   = {Frontiers in neural circuits},
  year      = {2014},
  volume    = {8},
  pages     = {73},
  publisher = {Frontiers},
}

@Article{Toro1994a,
  author  = {Toro, E. D. and Juiz, J. M. and Peng, X. and Lindstrom, J. and Criado, M.},
  title   = {Immunocytochemical localization of the $\alpha$7 subunit of nicotinic acetylcholine receptor in rat central nervous system},
  journal = {J Comp. Neurol},
  year    = {1994},
  volume  = {349},
  pages   = {325--342},
}

@Article{Liu2012,
  author    = {Liu, Qiang and Huang, Yao and Shen, Jianxin and Steffensen, Scott and Wu, Jie},
  title     = {Functional $\alpha$7$\beta$2 nicotinic acetylcholine receptors expressed in hippocampal interneurons exhibit high sensitivity to pathological level of amyloid $\beta$ peptides},
  journal   = {BMC neuroscience},
  year      = {2012},
  volume    = {13},
  number    = {1},
  pages     = {155},
  publisher = {BioMed Central},
}

@Article{Proulx2014,
  author    = {Proulx, Eliane and Piva, Matthew and Tian, Michael K and Bailey, Craig DC and Lambe, Evelyn K},
  title     = {Nicotinic acetylcholine receptors in attention circuitry: the role of layer VI neurons of prefrontal cortex},
  journal   = {Cellular and molecular life sciences},
  year      = {2014},
  volume    = {71},
  number    = {7},
  pages     = {1225--1244},
  publisher = {Springer},
}

@Article{Happ2018,
  author    = {Happ, Denise F and Tasker, R Andrew},
  title     = {Effects of $\alpha$7 nicotinic receptor activation on cell survival in rat organotypic hippocampal slice cultures},
  journal   = {Neurotoxicity research},
  year      = {2018},
  volume    = {33},
  number    = {4},
  pages     = {887--895},
  publisher = {Springer},
}

@Article{Messi2018,
  author    = {Messi, Elio and Pimpinelli, Federica and Andr{\`e}, Valentina and Rigobello, Chiara and Gotti, Cecilia and Maggi, Roberto},
  title     = {The alpha-7 nicotinic acetylcholine receptor is involved in a direct inhibitory effect of nicotine on GnRH release: In vitro studies},
  journal   = {Molecular and cellular endocrinology},
  year      = {2018},
  volume    = {460},
  pages     = {209--218},
  publisher = {Elsevier},
}

@Article{segal1978,
  author    = {Segal, M. and Dudai, Y. and Amsterdam, A.},
  title     = {Distribution of an $\alpha$-bungarotoxin-binding cholinergic nicotinic receptor in rat brain},
  journal   = {Brain res.},
  year      = {1978},
  volume    = {148},
  number    = {1},
  pages     = {105--119},
  publisher = {Elsevier},
}

@Article{matta2017,
  author    = {Matta, J. A. and Gu, S. and Davini, W. B. and Lord, B. and Siuda, E. R. and Harrington, A. W. and Bredt, D. S.},
  title     = {N{ACHO} mediates nicotinic acetylcholine receptor function throughout the brain},
  journal   = {Cell reports},
  year      = {2017},
  volume    = {19},
  number    = {4},
  pages     = {688--696},
  publisher = {Elsevier},
}

@Article{crespi2018,
  author    = {Crespi, A. and Colombo, S. F. and Gotti, C.},
  title     = {Proteins and chemical chaperones involved in neuronal nicotinic receptor expression and function: an update},
  journal   = {Br. J. Pharmacol.},
  year      = {2018},
  volume    = {175},
  number    = {11},
  pages     = {1869--1879},
  publisher = {Wiley Online Library},
}

@InProceedings{roncarati2006,
  author    = {Roncarati, R. and Seredenina, T. and Kremer, A. and Caricasole, A. and Terstappen, G. C.},
  title     = {Expression and subcellular localization of R{IC}-3, a putative alpha7-nAChR chaperone},
  booktitle = {FENS Abstr},
  year      = {2006},
  volume    = {3},
  pages     = {A044},
}

@Article{kuryatov2013,
  author    = {Kuryatov, A. and Mukherjee, J. and Lindstrom, J.},
  title     = {Chemical chaperones exceed the chaperone effects of RIC-3 in promoting assembly of functional $\alpha$7 AChRs},
  journal   = {PloS one},
  year      = {2013},
  volume    = {8},
  number    = {4},
  pages     = {e62246},
  publisher = {Public Library of Science},
}

@Article{mulcahy2015,
  author    = {Mulcahy, M. J. and Blattman, S. B. and Barrantes, F. J. and Lukas, R. J. and Hawrot, E.},
  title     = "{Resistance to Inhibitors of Cholinesterase 3 (RIC-3) Expression Promotes Selective Protein Associations with the Human $\alpha$7-Nicotinic Acetylcholine Receptor Interactome}",
  journal   = {PloS one},
  year      = {2015},
  volume    = {10},
  number    = {8},
  pages     = {e0134409},
  publisher = {Public Library of Science},
}

@Article{mulcahy2018,
  author    = {Mulcahy, Matthew J and Paulo, Joao A and Hawrot, Edward},
  title     = {Proteomic Investigation of Murine Neuronal $\alpha$7-Nicotinic Acetylcholine Receptor Interacting Proteins},
  journal   = {Journal of proteome research},
  year      = {2018},
  volume    = {17},
  number    = {11},
  pages     = {3959--3975},
  publisher = {ACS Publications},
}

@Article{halevi2003,
  author    = {Halevi, S. and Yassin, L. and Eshel, M. and Sala, F. and Sala, S. and Criado, M. and Treinin, M.},
  title     = "{Conservation Within the RIC-3 Gene Family Effectors of Mammalian Nicotinic Acetylcholine Receptor Expression}",
  journal   = {J. Biol. Chem.},
  year      = {2003},
  volume    = {278},
  number    = {36},
  pages     = {34411--34417},
  publisher = {ASBMB},
}

@Article{wang2009,
  author    = {Wang, Y. and Yao, Y. and Tang, X. and Wang, Z.},
  title     = "{Mouse RIC-3, an Endoplasmic Reticulum Chaperone, Promotes Assembly of the $\alpha$7 Acetylcholine Receptor Through a Cytoplasmic Coiled-Coil Domain}",
  journal   = {J. Neurosci.},
  year      = {2009},
  volume    = {29},
  number    = {40},
  pages     = {12625--12635},
  publisher = {Soc Neuroscience},
}

@Article{alexander2010,
  author          = {Alexander, J. K. and Sagher, D. and Krivoshein, A. V. and Criado, M. and Jefford, G. and Green, W. N},
  title           = {Ric-3 promotes alpha7 nicotinic receptor assembly and trafficking through the {ER} subcompartment of dendrites.},
  journal         = {The J. Neurosci. : the official journal of the Society for Neuroscience},
  year            = {2010},
  volume          = {30},
  issue           = {30},
  month           = jul,
  pages           = {10112--10126},
  issn            = {1529-2401},
  doi             = {10.1523/JNEUROSCI.6344-09.2010},
  abstract        = {The function of Ric-3, which is required for nicotinic acetylcholine receptor (nAChR) expression in C. elegans, is unclear. Here we found that Ric-3 can promote or inhibit cell-surface delivery of alpha-bungarotoxin-binding nAChRs (BgtRs) composed of alpha7 subunits. At low levels, Ric-3 promoted BgtR assembly, endoplasmic reticulum (ER) release, and cell-surface delivery without trafficking from the ER. At high Ric-3 levels, Ric-3 suppressed BgtR surface delivery, but not its assembly, and BgtRs were retained in the ER or in Ric-3-containing aggregates. In PC12 cells, native BgtRs trafficked to the cell surface from the ER where low levels of endogenous Ric-3 were observed. In cultured neurons, native Ric-3 levels were higher than in PC12 cells, and Ric-3 and alpha7 subunits were found in somata and dendrites, but not axons, of inhibitory interneurons. Ric-3 trafficked with alpha7 subunits in rapidly moving vesicles to dendrites, where it was restricted to the ER subcompartment. We conclude that Ric-3 has two potential functions. At low levels, Ric-3 interactions are short-lived and promote BgtR assembly and ER release. At higher levels, Ric-3 interactions are longer-lived and mediate ER retention. In neurons, Ric-3 ER retention appears to promote transport within the dendritic ER subcompartment, thereby restricting alpha7 trafficking to dendrites and preventing axonal transport.},
  chemicals       = {Autoantigens, Bungarotoxins, Cholinergic Agents, Chrna7 protein, human, Chrna7 protein, mouse, Chrna7 protein, rat, Cyan Fluorescent Protein, Golgin subfamily A member 2, Iodine Isotopes, Membrane Proteins, Molecular Chaperones, Receptors, Nicotinic, Ric-3 protein, mouse, alpha7 Nicotinic Acetylcholine Receptor, Green Fluorescent Proteins, Glutamate Decarboxylase, Protein Disulfide-Isomerases, Acetylcholine},
  citation-subset = {IM},
  completed       = {2010-08-20},
  country         = {United States},
  issn-linking    = {0270-6474},
  keywords        = {Acetylcholine, pharmacology; Animals; Autoantigens, metabolism; Bungarotoxins, metabolism, pharmacology; Cell Line, cytology; Cells, Cultured; Chickens; Cholinergic Agents, pharmacology; Dendrites, drug effects, ultrastructure; Endoplasmic Reticulum, drug effects, metabolism; Flow Cytometry, methods; Glutamate Decarboxylase, metabolism; Green Fluorescent Proteins, genetics; Hippocampus, cytology; Humans; Iodine Isotopes, metabolism; Membrane Potentials, drug effects, genetics; Membrane Proteins, genetics, metabolism; Mice; Models, Biological; Molecular Chaperones, genetics; Patch-Clamp Techniques, methods; Protein Binding, drug effects, genetics; Protein Disulfide-Isomerases, metabolism; Protein Transport, genetics; Rats; Receptors, Nicotinic, metabolism; Tissue Distribution, drug effects; Transfection, methods; alpha7 Nicotinic Acetylcholine Receptor},
  mid             = {NIHMS224990},
  nlm-id          = {8102140},
  owner           = {NLM},
  pii             = {30/30/10112},
  pmc             = {PMC2945888},
  pmid            = {20668195},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{neher1995,
  author          = {Neher, E.},
  title           = {The use of fura-2 for estimating {C}a buffers and {C}a fluxes.},
  journal         = {Neuropharm.},
  year            = {1995},
  volume          = {34},
  issue           = {11},
  pages           = {1423--1442},
  issn            = {0028-3908},
  abstract        = {The compound fura-2 (Grynkiewicz et al., J. Biol. Chem. 260, 3440-3450, 1985) is generally known as an indicator dye for measuring the concentration of free calcium ([Ca2+]) inside living cells. It should be appreciated, however, that this is not what it actually is. More accurately, it is a divalent metal ion chelator which changes its fluorescence properties upon complexation. Thus, [Ca2+] has to be inferred indirectly by means of the law of mass action. As a chelator, fura-2 may influence the quantity of interest, the Ca signal. On the other hand, the chelator action may be used for a number of other purposes, some of them more directly related to its molecular properties: as a chelator, competing with endogenous Ca buffers, it can be used to estimate endogenous buffers and their properties. When present at sufficiently high concentration, such that it outcompetes endogenous buffers, fura-2 reports total Ca changes and is a probe for Ca fluxes across the membrane. Here, theory and methodological considerations of such applications of fura-2 will be summarized and results on Ca buffer and Ca flux measurements derived from various methods will be compared.},
  chemicals       = {Buffers, Chelating Agents, Fluorescent Dyes, Calcium, Fura-2},
  citation-subset = {IM},
  completed       = {1996-05-20},
  country         = {England},
  issn-linking    = {0028-3908},
  keywords        = {Animals; Buffers; Calcium, analysis, metabolism; Cell Physiological Phenomena; Chelating Agents; Fluorescent Dyes; Fura-2; Mathematics; Spectrometry, Fluorescence, methods},
  nlm-id          = {0236217},
  owner           = {NLM},
  pii             = {002839089500144U},
  pmid            = {8606791},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{fucile2000,
  author          = {Fucile, S. and Palma, E. and Mileo, A. M. and Miledi, R. and Eusebi, F.},
  title           = {Human neuronal threonine-for-leucine-248 alpha7 mutant nicotinic acetylcholine receptors are highly Ca2+ permeable.},
  journal         = { Proc. Natl. Acad. Sci. USA of the United States of America},
  year            = {2000},
  volume          = {97},
  issue           = {7},
  month           = mar,
  pages           = {3643--3648},
  issn            = {0027-8424},
  doi             = {10.1073/pnas.050582497},
  abstract        = {A cDNA coding for the human neuronal nicotinic alpha7 receptor subunit with Leu-248 mutated to threonine was expressed in Xenopus oocytes. When activated by acetylcholine (AcCho), the receptors expressed generated currents that had low desensitization, linear current-voltage relation, and high apparent affinity for both AcCho and nicotine. These characteristics are similar to those already described for the chick threonine-for-leucine-247 alpha7 nicotinic AcCho receptor (nAcChoR) mutant (L247Talpha7). These properties were all substantially maintained when the human L248Talpha7 mutant was transiently expressed in human Bosc 23 cells. Simultaneous whole-cell clamp and fluorescence measurements with the Ca(2+) indicator dye Fura-2 showed that nicotine induced a Ca(2+) influx in standard 2 mM Ca(2+) solution. The average fractional Ca(2+) current flowing through L248Talpha7 nAcChoRs was 6.7%, which is larger than that flowing through muscle alpha(beta)epsilon(delta) nAcChoRs (4.1%). The relative Ca(2+) permeability, determined in oocytes in the absence of Cl(-), was measured from the shift in reversal potential caused by increasing the external Ca(2+) concentration from 1 to 10 mM. The human wild-type alpha7 nAcChoR was found to be more permeable than the L248Talpha7 mutant to Ca(2+). Our findings indicate that the Ca(2+) permeability of the homomeric alpha7 nAcChoR is larger than that of the heteromeric neuronal nicotinic receptors studied to date and is possibly similar to that of the N-methyl-D-aspartate subtype of brain glutamate receptors.},
  chemicals       = {DNA Primers, Nicotinic Agonists, Nicotinic Antagonists, Receptors, Nicotinic, Threonine, Leucine, Calcium},
  citation-subset = {IM},
  completed       = {2000-04-24},
  country         = {United States},
  issn-linking    = {0027-8424},
  keywords        = {Base Sequence; Calcium, metabolism; Cell Line; DNA Primers; Humans; Ion Transport; Leucine, genetics; Mutagenesis, Site-Directed; Neurons, metabolism; Nicotinic Agonists, pharmacology; Nicotinic Antagonists, pharmacology; Receptors, Nicotinic, chemistry, genetics, metabolism; Spectrometry, Fluorescence; Threonine, genetics},
  nlm-id          = {7505876},
  owner           = {NLM},
  pii             = {050582497},
  pmc             = {PMC16293},
  pmid            = {10716716},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{weltzin2019,
  author       = {Weltzin, M. M. and George, A. A. and Lukas, R. J. and Whiteaker, P.},
  title        = {Distinctive single-channel properties of α4β2-nicotinic acetylcholine receptor isoforms.},
  journal      = {PloS one},
  year         = {2019},
  volume       = {14},
  issue        = {3},
  pages        = {e0213143},
  issn         = {1932-6203},
  doi          = {10.1371/journal.pone.0213143},
  abstract     = {Central nervous system nicotinic acetylcholine receptors (nAChR) are predominantly of the α4β2 subtype. Two isoforms exist, with high or low agonist sensitivity (HS-(α4β2)2β2- and LS-(α4β2)2α4-nAChR). Both isoforms exhibit similar macroscopic potency and efficacy values at low acetylcholine (ACh) concentrations, mediated by a common pair of high-affinity α4(+)/(-)β2 subunit binding interfaces. However LS-(α4β2)2α4-nAChR also respond to higher concentrations of ACh, acting at a third α4(+)/(-)α4 subunit interface. To probe isoform functional differences further, HS- and LS-α4β2-nAChR were expressed in Xenopus laevis oocytes and single-channel responses were assessed using cell-attached patch-clamp. In the presence of a low ACh concentration, both isoforms produce low-bursting function. HS-(α4β2)2β2-nAChR exhibit a single conductance state, whereas LS-(α4β2)2α4-nAChR display two distinctive conductance states. A higher ACh concentration did not preferentially recruit either conductance state, but did result in increased LS-(α4β2)2α4-nAChR bursting and reduced closed times. Introduction of an α4(+)/(-)α4-interface loss-of-function α4W182A mutation abolished these changes, confirming this site's role in mediating LS-(α4β2)2α4-nAChR responses. Small or large amplitude openings are highly-correlated within individual LS-(α4β2)2α4-nAChR bursts, suggesting that they arise from distinct intermediate states, each of which is stabilized by α4(+)/(-)α4 site ACh binding. These findings are consistent with α4(+)/(-)α4 subunit interface occupation resulting in allosteric potentiation of agonist actions at α4(+)/(-)β2 subunit interfaces, rather than independent induction of high conductance channel openings.},
  country      = {United States},
  issn-linking = {1932-6203},
  nlm-id       = {101285081},
  owner        = {NLM},
  pii          = {PONE-D-18-26985},
  pmc          = {PMC6405073},
  pmid         = {30845161},
  pubmodel     = {Electronic-eCollection},
  pubstatus    = {epublish},
  revised      = {2019-05-08},
}

@Article{fenster1997,
  author          = {Fenster, C. P. and Rains, M. F. and Noerager, B. and Quick, M. W. and Lester, R. A.},
  title           = {Influence of subunit composition on desensitization of neuronal acetylcholine receptors at low concentrations of nicotine.},
  journal         = {The J. Neurosci. : the official journal of the Society for Neuroscience},
  year            = {1997},
  volume          = {17},
  issue           = {15},
  month           = aug,
  pages           = {5747--5759},
  issn            = {0270-6474},
  abstract        = {The influence of alpha and beta subunits on the properties of nicotine-induced activation and desensitization of neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes was examined. Receptors containing alpha4 subunits were more sensitive to activation by nicotine than alpha3-containing receptors. At low concentrations of nicotine, nAChRs containing beta2 subunits reached near-maximal desensitization more rapidly than beta4-containing receptors. The concentration of nicotine producing half-maximal desensitization was influenced by the particular alpha subunit expressed; similar to results for activation, alpha4-containing receptors were more sensitive to desensitizing levels of nicotine than alpha3-containing receptors. The alpha subunit also influenced the rate of recovery from desensitization; this rate was approximately inversely proportional to the apparent nicotine affinity for the desensitized state. The homomeric alpha7 receptor showed the lowest sensitivity to nicotine for both activation and desensitization; alpha7 nAChRs also demonstrated the fastest desensitization kinetics. These subunit-dependent properties remained in the presence of external calcium, although subtle, receptor subtype-specific effects on both the apparent affinities for activation and desensitization and the desensitization kinetics were noted. These data imply that the subunit composition of various nAChRs determines the degree to which receptors are desensitized and/or activated by tobacco-related levels of nicotine. The subtype-specific balance between receptor activation and desensitization should be considered important when the cellular and behavioral actions of nicotine are interpreted.},
  chemicals       = {Receptors, Cholinergic, Nicotine},
  citation-subset = {IM},
  completed       = {1997-10-03},
  country         = {United States},
  issn-linking    = {0270-6474},
  keywords        = {Animals; Dose-Response Relationship, Drug; Nicotine, pharmacology; Oocytes, drug effects; Receptors, Cholinergic, drug effects; Xenopus},
  nlm-id          = {8102140},
  owner           = {NLM},
  pmid            = {9221773},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2015-11-19},
}

@Article{miller2014,
  author          = {Miller, P. S. and Aricescu, A. R.},
  title           = {Crystal structure of a human G{ABA}a receptor.},
  journal         = {Nature},
  year            = {2014},
  volume          = {512},
  issue           = {7514},
  month           = aug,
  pages           = {270--275},
  issn            = {1476-4687},
  doi             = {10.1038/nature13293},
  abstract        = {Type-A γ-aminobutyric acid receptors (GABAARs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signalling triggers hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here we present the first three-dimensional structure of a GABAAR, the human β3 homopentamer, at 3 Å resolution. This structure reveals architectural elements unique to eukaryotic Cys-loop receptors, explains the mechanistic consequences of multiple human disease mutations and shows an unexpected structural role for a conserved N-linked glycan. The receptor was crystallized bound to a previously unknown agonist, benzamidine, opening a new avenue for the rational design of GABAAR modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitized state. These results offer new insights into the signalling mechanisms of pentameric ligand-gated ion channels and enhance current understanding of GABAergic neurotransmission. },
  chemicals       = {Benzamidines, GABA-A Receptor Agonists, Polysaccharides, Protein Subunits, Receptors, GABA-A, benzamidine},
  citation-subset = {IM},
  completed       = {2014-09-15},
  country         = {England},
  issn-linking    = {0028-0836},
  keywords        = {Benzamidines, chemistry, metabolism, pharmacology; Binding Sites; Cell Membrane, chemistry, metabolism; Conserved Sequence; Crystallography, X-Ray; Drug Design; GABA-A Receptor Agonists, chemistry, metabolism, pharmacology; Genetic Predisposition to Disease; Glycosylation; Humans; Models, Molecular; Mutation, genetics; Polysaccharides, chemistry, metabolism; Protein Structure, Quaternary; Protein Structure, Tertiary; Protein Subunits; Receptors, GABA-A, chemistry, genetics; Synaptic Transmission},
  mid             = {EMS57867},
  nlm             = {EMS57867},
  nlm-id          = {0410462},
  owner           = {NLM},
  pii             = {nature13293},
  pmc             = {PMC4167603},
  pmid            = {24909990},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{huang2015,
  author          = {Huang, X. and Chen, H. and Michelsen, K. and Schneider, S. and Shaffer, P. L.},
  title           = {Crystal structure of human glycine receptor-α3 bound to antagonist strychnine.},
  journal         = {Nature},
  year            = {2015},
  volume          = {526},
  issue           = {7572},
  month           = oct,
  pages           = {277--280},
  issn            = {1476-4687},
  doi             = {10.1038/nature14972},
  abstract        = {Neurotransmitter-gated ion channels of the Cys-loop receptor family are essential mediators of fast neurotransmission throughout the nervous system and are implicated in many neurological disorders. Available X-ray structures of prokaryotic and eukaryotic Cys-loop receptors provide tremendous insights into the binding of agonists, the subsequent opening of the ion channel, and the mechanism of channel activation. Yet the mechanism of inactivation by antagonists remains unknown. Here we present a 3.0 Å X-ray structure of the human glycine receptor-α3 homopentamer in complex with a high affinity, high-specificity antagonist, strychnine. Our structure allows us to explore in detail the molecular recognition of antagonists. Comparisons with previous structures reveal a mechanism for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric binding site in the extracellular domain that is coupled to closure of the ion pore in the transmembrane domain. },
  chemicals       = {Receptors, Glycine, glycine receptor alpha3 subunit, Strychnine},
  citation-subset = {IM},
  completed       = {2016-03-30},
  country         = {England},
  issn-linking    = {0028-0836},
  keywords        = {Binding Sites; Crystallography, X-Ray; Humans; Ion Channel Gating, drug effects; Models, Molecular; Protein Multimerization, drug effects; Protein Structure, Tertiary, drug effects; Receptors, Glycine, antagonists & inhibitors, chemistry, metabolism; Strychnine, chemistry, metabolism, pharmacology; Substrate Specificity},
  nlm-id          = {0410462},
  owner           = {NLM},
  pii             = {nature14972},
  pmid            = {26416729},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{peternel2011,
  author          = {Peternel, S. and Komel, R.},
  title           = "{Active Protein Aggregates Produced in \textit{Escherichia coli}.}",
  journal         = {International journal of molecular sciences},
  year            = {2011},
  volume          = {12},
  issue           = {11},
  pages           = {8275--8287},
  doi             = {10.3390/ijms12118275},
  abstract        = {Since recombinant proteins are widely used in industry and in research, the need for their low-cost production is increasing. Escherichia coli is one of the best known and most often used host organisms for economical protein production. However, upon over-expression, protein aggregates called inclusion bodies (IBs) are often formed. Until recently IBs formation represented a bottleneck in protein production as they were considered as deposits of inactive proteins. However, recent studies show that by choosing the appropriate host strain and designing an optimal production process, IBs composed from properly folded and biologically active recombinant proteins can be prepared. Such active protein particles can be further used for the isolation of pure proteins or as whole active protein particles in various biomedical and other applications. Therefore interest in understanding the mechanisms of their formation as well as their properties is increasing.},
  chemicals       = {Protein Aggregates, Recombinant Proteins},
  citation-subset = {IM},
  completed       = {2014-12-30},
  country         = {Switzerland},
  issn-linking    = {1422-0067},
  keywords        = {Escherichia coli, metabolism; Hydrogen-Ion Concentration; Inclusion Bodies, metabolism; Protein Aggregates; Recombinant Proteins, biosynthesis; E. coli; IBs; active protein aggregates; inclusion bodies},
  nlm-id          = {101092791},
  owner           = {NLM},
  pii             = {ijms-12-08275},
  pmc             = {PMC3233469},
  pmid            = {22174663},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{haugstetter2005,
  author          = {Haugstetter, J. and Blicher, T. and Ellgaard, L.},
  title           = {Identification and characterization of a novel thioredoxin-related transmembrane protein of the endoplasmic reticulum.},
  journal         = {J. Biol. Chem.},
  year            = {2005},
  volume          = {280},
  issue           = {9},
  month           = mar,
  pages           = {8371--8380},
  issn            = {0021-9258},
  doi             = {10.1074/jbc.M413924200},
  abstract        = {The endoplasmic reticulum (ER) contains a number of thiol-disulfide oxidoreductases of the protein-disulfide isomerase (PDI) family that catalyze the formation of disulfide bonds in newly synthesized proteins. Here we describe the identification and characterization of a novel member of the human PDI family, TMX3 (thioredoxin-related transmembrane protein 3). The TMX3 gene encodes a protein of 454 amino acid residues that contains a predicted N-terminal signal sequence, a single domain with sequence similarity to thioredoxin and a CGHC active site sequence, a potential transmembrane domain, and a C-terminal KKKD tetrapeptide sequence that matches the classical KKXX-type consensus sequence for ER retrieval of type I transmembrane proteins. Endogenous TMX3 contains endoglycosidase H-sensitive glycans, localizes to the ER by immunofluorescence microscopy, and is present in the membrane fraction after alkaline extraction of the ER luminal content. The TMX3 transcript is found in a variety of tissues and is not up-regulated by the unfolded protein response. Circular dichroism spectroscopy of the recombinantly expressed luminal domain of TMX3 showed features typical of a properly folded protein of the alpha/beta type. The redox potential of recombinant luminal TMX3 was determined to -0.157 V, similar to the values previously found for PDI and ERp57. Interestingly, TMX3 showed oxidase activity, and in human tissue-culture cells the protein was found partially in the oxidized form, potentially suggesting a function of the protein as a dithiol oxidase.},
  chemicals       = {Peptides, RNA, Messenger, Recombinant Proteins, Thioredoxins, Oxidoreductases, Glycoside Hydrolases, Protein Disulfide-Isomerases, TMX3 protein, human, Glutathione, Oxygen},
  citation-subset = {IM},
  completed       = {2005-04-07},
  country         = {United States},
  issn-linking    = {0021-9258},
  keywords        = {Amino Acid Sequence; Animals; Binding Sites; Blotting, Northern; Blotting, Western; Catalysis; Cell Line; Cell Membrane, metabolism; Cells, Cultured; Cercopithecus aethiops; Circular Dichroism; Dose-Response Relationship, Drug; Endoplasmic Reticulum, metabolism; Exons; Genetic Vectors; Glutathione, chemistry; Glycoside Hydrolases, chemistry, metabolism; HeLa Cells; Humans; Introns; Kinetics; Microscopy, Fluorescence; Molecular Sequence Data; Oxidation-Reduction; Oxidoreductases, chemistry, metabolism; Oxygen, metabolism; Peptides, chemistry; Plasmids, metabolism; Protein Denaturation; Protein Disulfide-Isomerases, biosynthesis, chemistry; Protein Folding; Protein Structure, Tertiary; RNA, Messenger, metabolism; Recombinant Proteins, chemistry; Sequence Homology, Amino Acid; Spectrometry, Fluorescence; Spectrophotometry; Subcellular Fractions; Thioredoxins, chemistry; Time Factors; Tissue Distribution; Transcription, Genetic; Ultraviolet Rays; Up-Regulation; Vero Cells},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pii             = {M413924200},
  pmid            = {15623505},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{miller1996,
  author          = {Miller, K. G. and Alfonso, A. and Nguyen, M. and Crowell, J. A. and Johnson, C. D. and Rand, J. B.},
  title           = "{A Genetic Selection for \textit{Caenorhabditis elegans} Synaptic Transmission Mutants.}",
  journal         = { Proc. Natl. Acad. Sci. USA of the United States of America},
  year            = {1996},
  volume          = {93},
  issue           = {22},
  month           = oct,
  pages           = {12593--12598},
  issn            = {0027-8424},
  doi             = {10.1073/pnas.93.22.12593},
  abstract        = {We have isolated 165 Caenorhabditis elegans mutants, representing 21 genes, that are resistant to inhibitors of cholinesterase (Ric mutants). Since mutations in 20 of the genes appear not to affect acetylcholine reception, we suggest that reduced acetylcholine release contributes to the Ric phenotype of most Ric mutants. Mutations in 15 of the genes lead to defects in a gamma-aminobutyric acid-dependent behavior; these genes are likely to encode proteins with general, rather than cholinergic-specific, roles in synaptic transmission. Ten of the genes have been cloned. Seven encode homologs of proteins that function in the synaptic vesicle cycle: two encode cholinergic-specific proteins, while five encode general presynaptic proteins. Two other Ric genes encode homologs of G-protein signaling molecules. Our assessment of synaptic function in Ric mutants, combined with the homologies of some Ric mutants to presynaptic proteins, suggests that the analysis of Ric genes will continue to yield insights into the regulation and functioning of synapses.},
  chemicals       = {Cholinesterase Inhibitors, Helminth Proteins, Receptors, Cholinergic, Levamisole, gamma-Aminobutyric Acid, Aldicarb, Acetylcholine},
  citation-subset = {IM},
  completed       = {1996-12-24},
  country         = {United States},
  issn-linking    = {0027-8424},
  keywords        = {Acetylcholine, metabolism; Aldicarb, pharmacology; Animals; Caenorhabditis elegans, drug effects, genetics; Cholinesterase Inhibitors, pharmacology; Helminth Proteins, genetics; Levamisole, pharmacology; Mutagenesis; Phenotype; Receptors, Cholinergic, metabolism; Signal Transduction; Synaptic Transmission, drug effects, genetics; gamma-Aminobutyric Acid, metabolism},
  nlm-id          = {7505876},
  owner           = {NLM},
  pmc             = {PMC38037},
  pmid            = {8901627},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2019-05-01},
}

@Article{lewis1980,
  author    = {Lewis, J. A. and Wu, C. H. and Berg, H. and Levine, J. H.},
  title     = "{The Genetics of Levamisole Resistance in the Nematode \textit{Caenorhabditis elegans}.}",
  journal   = {Genetics},
  year      = {1980},
  volume    = {95},
  number    = {4},
  pages     = {905--928},
  publisher = {Genetics Soc America},
}

@Article{abiusi2017,
  author          = {Abiusi, E. and D'Alessandro, M. and Dieterich, K. and Quevarec, L. and Turczynski, S. and Valfort, A.-C. and Mezin, P. and Jouk, P. S. and Gut, M. and Gut, I. and Bessereau, J. L. and Melki, J.},
  title           = {Biallelic mutation of UNC50, encoding a protein involved in AChR trafficking, is responsible for arthrogryposis.},
  journal         = {Hum. Mo. Genet.},
  year            = {2017},
  volume          = {26},
  issue           = {20},
  month           = oct,
  pages           = {3989--3994},
  issn            = {1460-2083},
  doi             = {10.1093/hmg/ddx288},
  abstract        = {Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Homozygosity mapping of disease loci combined with whole exome sequencing in a consanguineous family presenting with lethal AMC allowed the identification of a homozygous frameshift deletion in UNC50 gene (c.750_751del:p.Cys251Phefs*4) in the index case. To assess the effect of the mutation, an equivalent mutation in the Caenorhabditis elegans orthologous gene was created using CRISPR/Cas9. We demonstrated that unc-50(kr331) modification caused the loss of acetylcholine receptor (AChR) expression in C. elegans muscle. unc-50(kr331) animals were as resistant to the cholinergic agonist levamisole as unc-50 null mutants suggesting that AChRs were no longer expressed in this animal model. This was confirmed by using a knock-in strain in which a red fluorescent protein was inserted into the AChR locus: no signal was detected in unc-50(kr331) background, suggesting that UNC-50, a protein known to be involved in AChR trafficking, was no longer functional. These data indicate that biallelic mutation in the UNC50 gene underlies AMC through a probable loss of AChR expression at the neuromuscular junction which is essential for the cholinergic transmission during human muscle development.},
  chemicals       = {Caenorhabditis elegans Proteins, Membrane Proteins, RNA-Binding Proteins, Receptors, Cholinergic, UNC50 protein, human},
  citation-subset = {IM},
  completed       = {2018-03-05},
  country         = {England},
  issn-linking    = {0964-6906},
  keywords        = {Alleles; Amino Acid Sequence; Animals; Arthrogryposis, genetics, metabolism; Caenorhabditis elegans; Caenorhabditis elegans Proteins, genetics; Disease Models, Animal; Female; Frameshift Mutation; Humans; Male; Membrane Proteins, genetics, metabolism; Neuromuscular Junction, genetics, metabolism; Pedigree; Protein Transport; RNA-Binding Proteins, genetics, metabolism; Receptors, Cholinergic, genetics, metabolism; Stillbirth, genetics},
  nlm-id          = {9208958},
  owner           = {NLM},
  pii             = {3980257},
  pmid            = {29016857},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-03-05},
}

@Article{dalessandro2018,
  author          = {D'Alessandro, M. and Richard, M. and Stigloher, C. and Gache, V. and Boulin, T. and Richmond, J. E. and Bessereau, J-L.},
  title           = {CRELD1 is an evolutionarily-conserved maturational enhancer of ionotropic acetylcholine receptors.},
  journal         = {eLife},
  year            = {2018},
  volume          = {7},
  issn            = {2050-084X},
  doi             = {10.7554/eLife.39649},
  abstract        = {The assembly of neurotransmitter receptors in the endoplasmic reticulum limits the number of receptors delivered to the plasma membrane, ultimately controlling neurotransmitter sensitivity and synaptic transfer function. In a forward genetic screen conducted in the nematode  , we identified   as a gene required for the synaptic expression of ionotropic acetylcholine receptors (AChR). We demonstrated that the CRLD-1A isoform is a membrane-associated ER-resident protein disulfide isomerase (PDI). It physically interacts with AChRs and promotes the assembly of AChR subunits in the ER. Mutations of   the human ortholog of   are responsible for developmental cardiac defects. We showed that   knockdown in mouse muscle cells decreased surface expression of AChRs and that expression of mouse   in   rescued   mutant phenotypes. Altogether these results identify a novel and evolutionarily-conserved maturational enhancer of AChR biogenesis, which controls the abundance of functional receptors at the cell surface.},
  chemicals       = {CRELD1 protein, mouse, Caenorhabditis elegans Proteins, Cell Adhesion Molecules, Extracellular Matrix Proteins, Receptors, Cholinergic, Crld1 protein, C elegans, Protein Disulfide-Isomerases},
  citation-subset = {IM},
  completed       = {2019-03-12},
  country         = {England},
  issn-linking    = {2050-084X},
  keywords        = {Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins, genetics, metabolism; Cell Adhesion Molecules, genetics, metabolism; Cell Line; Extracellular Matrix Proteins, genetics, metabolism; Gene Knockdown Techniques; Genetic Complementation Test; Heart Defects, Congenital; Mice; Muscle Cells; Protein Binding; Protein Disulfide-Isomerases, genetics, metabolism; Protein Multimerization; Receptors, Cholinergic, metabolism; Synapses, metabolism; C. elegans; Cys-loop receptor; acetylcholine receptor (AChR); cell biology; endoplasmic reticulum (ER); mouse; neuromuscular junction (NMJ); neuroscience; protein disulphide isomerase (PDI)},
  nlm-id          = {101579614},
  owner           = {NLM},
  pii             = {e39649},
  pmc             = {PMC6245729},
  pmid            = {30407909},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2019-05-22},
}

@Article{almedom2009,
  author          = {Almedom, R. B. and Liewald, J. F. and Hernando, G. and Schultheis, C. and Rayes, D. and Pan, J. and Schedletzky, T. and Hutter, H. and Bouzat, C. and Gottschalk, A.},
  title           = {An {ER-resident} membrane protein complex regulates nicotinic acetylcholine receptor subunit composition at the synapse.},
  journal         = {The EMBO journal},
  year            = {2009},
  volume          = {28},
  issue           = {17},
  month           = sep,
  pages           = {2636--2649},
  issn            = {1460-2075},
  doi             = {10.1038/emboj.2009.204},
  abstract        = {Nicotinic acetylcholine receptors (nAChRs) are homo- or heteropentameric ligand-gated ion channels mediating excitatory neurotransmission and muscle activation. Regulation of nAChR subunit assembly and transfer of correctly assembled pentamers to the cell surface is only partially understood. Here, we characterize an ER transmembrane (TM) protein complex that influences nAChR cell-surface expression and functional properties in Caenorhabditis elegans muscle. Loss of either type I TM protein, NRA-2 or NRA-4 (nicotinic receptor associated), affects two different types of muscle nAChRs and causes in vivo resistance to cholinergic agonists. Sensitivity to subtype-specific agonists of these nAChRs is altered differently, as demonstrated by whole-cell voltage-clamp of dissected adult muscle, when applying exogenous agonists or after photo-evoked, channelrhodopsin-2 (ChR2) mediated acetylcholine (ACh) release, as well as in single-channel recordings in cultured embryonic muscle. These data suggest that nAChRs desensitize faster in nra-2 mutants. Cell-surface expression of different subunits of the 'levamisole-sensitive' nAChR (L-AChR) is differentially affected in the absence of NRA-2 or NRA-4, suggesting that they control nAChR subunit composition or allow only certain receptor assemblies to leave the ER.},
  chemicals       = {Caenorhabditis elegans Proteins, Membrane Proteins, Protein Subunits, Receptors, Nicotinic},
  citation-subset = {IM},
  completed       = {2009-10-22},
  country         = {England},
  issn-linking    = {0261-4189},
  keywords        = {Action Potentials; Animals; Animals, Genetically Modified; Caenorhabditis elegans, metabolism; Caenorhabditis elegans Proteins, genetics, metabolism; Electrophysiology; Endoplasmic Reticulum, metabolism; Humans; Membrane Proteins, metabolism; Protein Subunits, metabolism; Receptors, Nicotinic, genetics, metabolism; Synapses, metabolism},
  nlm-id          = {8208664},
  owner           = {NLM},
  pii             = {emboj2009204},
  pmc             = {PMC2738700},
  pmid            = {19609303},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{richard2013,
  author          = {Richard, M. and Boulin, T. and Robert, V. J. .P and Richmond, J. E. and Bessereau, J-L.},
  title           = {Biosynthesis of ionotropic acetylcholine receptors requires the evolutionarily conserved E{R} membrane complex.},
  journal         = { Proc. Natl. Acad. Sci. USA of the United States of America},
  year            = {2013},
  volume          = {110},
  issue           = {11},
  pages           = {E1055--E1063},
  issn            = {1091-6490},
  doi             = {10.1073/pnas.1216154110},
  abstract        = {The number of nicotinic acetylcholine receptors (AChRs) present in the plasma membrane of muscle and neuronal cells is limited by the assembly of individual subunits into mature pentameric receptors. This process is usually inefficient, and a large number of the synthesized subunits are degraded by endoplasmic reticulum (ER)-associated degradation. To identify cellular factors required for the synthesis of AChRs, we performed a genetic screen in the nematode Caenorhabditis elegans for mutants with decreased sensitivity to the cholinergic agonist levamisole. We isolated a partial loss-of-function allele of ER membrane protein complex-6 (emc-6), a previously uncharacterized gene in C. elegans. emc-6 encodes an evolutionarily conserved 111-aa protein with two predicted transmembrane domains. EMC-6 is ubiquitously expressed and localizes to the ER. Partial inhibition of EMC-6 caused decreased expression of heteromeric levamisole-sensitive AChRs by destabilizing unassembled subunits in the ER. Inhibition of emc-6 also reduced the expression of homomeric nicotine-sensitive AChRs and GABAA receptors in C. elegans muscle cells. emc-6 is orthologous to the yeast and human EMC6 genes that code for a component of the recently identified ER membrane complex (EMC). Our data suggest this complex is required for protein folding and is connected to ER-associated degradation. We demonstrated that inactivation of additional EMC members in C. elegans also impaired AChR synthesis and induced the unfolded protein response. These results suggest that the EMC is a component of the ER folding machinery. AChRs might provide a valuable proxy to decipher the function of the EMC further.},
  chemicals       = {Caenorhabditis elegans Proteins, Multiprotein Complexes, Receptors, Cholinergic, Receptors, GABA-A},
  citation-subset = {IM},
  completed       = {2013-05-23},
  country         = {United States},
  issn-linking    = {0027-8424},
  keywords        = {Animals; Caenorhabditis elegans, cytology, genetics, metabolism; Caenorhabditis elegans Proteins, genetics, metabolism; Endoplasmic Reticulum, genetics, metabolism; Humans; Intracellular Membranes, metabolism; Multiprotein Complexes, genetics, metabolism; Protein Folding; Receptors, Cholinergic, genetics, metabolism; Receptors, GABA-A, genetics, metabolism},
  nlm-id          = {7505876},
  owner           = {NLM},
  pii             = {1216154110},
  pmc             = {PMC3600456},
  pmid            = {23431131},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{miller1980,
  author          = {Miller, M. J.},
  title           = {Use of levamisole in parasitic infections.},
  journal         = {Drugs},
  year            = {1980},
  volume          = {20},
  issue           = {2},
  month           = aug,
  pages           = {122--130},
  issn            = {0012-6667},
  doi             = {10.2165/00003495-198020020-00005},
  abstract        = {Levamisole is a drug of choice for treatment of ascariasis. With recommended dosages, it is virtually free of side effects. Single doses of 50 to 150mg will eliminate all parasites in 90 to 100% of ascariasis patients irrespective of worm burden. Activity against hookworms has been demonstrated for levamisole but the most effective treatment regimen has not been determined. Further drug trials are needed for better assessment of efficacy. Levamisole has little or no curative action on infections with whipworms and pinworms. It may have some activity against strongyloides but confirmatory studies are needed. It has been shown that levamisole has significant activity against microfilariae of Wuchereria bancrofti and Brugia malayi. It is not, however, as effective as diethylcarbamazine ('Hetrazan'), and side reactions are greater. In tolerated doses, levamisole does not have significant action on adult forms or microfilariae of Onchoceea volvulus. The drug applied topically, however, may find a place in treatment of ocular onchocerciasis. Limited trials with levamisole for toxoplasmosis and chronic cutaneous leishmaniasis have given promising results, and further studies are indicated.},
  chemicals       = {Levamisole},
  citation-subset = {IM},
  completed       = {1980-10-27},
  country         = {New Zealand},
  issn-linking    = {0012-6667},
  keywords        = {Ascariasis, drug therapy; Filariasis, drug therapy; Hookworm Infections, drug therapy; Humans; Intestinal Diseases, Parasitic, drug therapy; Levamisole, administration & dosage, therapeutic use; Nematode Infections, drug therapy; Onchocerciasis, drug therapy; Parasitic Diseases, drug therapy; Protozoan Infections, drug therapy},
  nlm-id          = {7600076},
  owner           = {NLM},
  pmid            = {6995094},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {30},
  revised         = {2018-11-13},
}

@Article{matsuda2005,
  author          = {Matsuda, K. and Shimomura, M. and Ihara, M. and Akamatsu, M. and Sattelle, D. B.},
  title           = {Neonicotinoids show selective and diverse actions on their nicotinic receptor targets: electrophysiology, molecular biology, and receptor modeling studies.},
  journal         = {Bioscience, biotechnology, and biochemistry},
  year            = {2005},
  volume          = {69},
  issue           = {8},
  month           = aug,
  pages           = {1442--1452},
  issn            = {0916-8451},
  doi             = {10.1271/bbb.69.1442},
  abstract        = {Neonicotinoid insecticides, which act selectively on insect nicotinic acetylcholine receptors (nAChRs), are used worldwide for insect pest management. Studies that span chemistry, biochemistry, molecular biology, and electrophysiology have contributed to our current understanding of the important physicochemical and structural properties essential for neonicotinoid actions as well as key receptor residues contributing to the high affinity of neonicotinoids for insect nAChRs. Research to date suggests that electrostatic interactions and possibly hydrogen bond formation between neonicotinoids and nAChRs contribute to the selectivity of these chemicals. A rich diversity of neonicotinoid-nAChR interactions has been demonstrated using voltage-clamp electrophysiology. Computational modeling of nAChR-imidacloprid interaction has assisted in the interpretation of these results.},
  chemicals       = {Receptors, Nicotinic, Anabasine},
  citation-subset = {IM},
  completed       = {2005-12-01},
  country         = {England},
  issn-linking    = {0916-8451},
  keywords        = {Amino Acid Motifs; Anabasine, chemistry, pharmacology; Animals; Insecta; Membrane Potentials, drug effects; Models, Molecular; Receptors, Nicotinic, drug effects},
  nlm-id          = {9205717},
  owner           = {NLM},
  pii             = {JST.JSTAGE/bbb/69.1442},
  pmid            = {16116270},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {77},
  revised         = {2017-11-16},
}

@Article{Holden-Dye2014,
  author          = {Holden-Dye, L. and Walker, R. J.},
  title           = {Anthelmintic drugs and nematicides: studies in Caenorhabditis elegans.},
  journal         = {WormBook : the online review of C. elegans biology},
  year            = {2014},
  month           = dec,
  pages           = {1--29},
  issn            = {1551-8507},
  doi             = {10.1895/wormbook.1.143.2},
  abstract        = {Parasitic nematodes infect many species of animals throughout the phyla, including humans. Moreover, nematodes that parasitise plants are a global problem for agriculture. As such, these nematodes place a major burden on human health, on livestock production, on the welfare of companion animals and on crop production. In the 21st century there are two major challenges posed by the wide-spread prevalence of parasitic nematodes. First, many anthelmintic drugs are losing their effectiveness because nematode strains with resistance are emerging. Second, serious concerns regarding the environmental impact of the nematicides used for Crop Prot. have prompted legislation to remove them from use, leaving agriculture at increased risk from nematode pests. There is clearly a need for a concerted effort to address these challenges. Over the last few decades the free-living nematode Caenorhabditis elegans has provided the opportunity to use molecular genetic techniques for mode of action studies for anthelmintics and nematicides. These approaches continue to be of considerable value. Less fruitful so far, but nonetheless potentially very useful, has been the direct use of C. elegans for anthelmintic and nematicide discovery programmes. Here we provide an introduction to the use of C. elegans as a 'model' parasitic nematode, briefly review the study of nematode control using C. elegans and highlight approaches that have been of particular value with a view to facilitating wider-use of C. elegans as a platform for anthelmintic and nematicide discovery and development. },
  chemicals       = {Anthelmintics, Antinematodal Agents},
  citation-subset = {IM},
  completed       = {2015-12-04},
  country         = {United States},
  issn-linking    = {1551-8507},
  keywords        = {Animals; Anthelmintics, classification, pharmacology; Antinematodal Agents, classification, pharmacology; Caenorhabditis elegans, drug effects; Drug Evaluation, Preclinical; Helminthiasis, drug therapy; Humans; Models, Biological},
  nlm-id          = {101303985},
  owner           = {NLM},
  pmc             = {PMC5402214},
  pmid            = {25517625},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2017-04-25},
}

@Article{martin1991,
  author          = {Martin, R. J. and Pennington, A. J. and Duittoz, A. H. and Robertson, S. and Kusel, J. R.},
  title           = {The physiology and pharmacology of neuromuscular transmission in the nematode parasite, Ascaris suum.},
  journal         = {Parasitology},
  year            = {1991},
  volume          = {102 Suppl},
  pages           = {S41--S58},
  issn            = {0031-1820},
  abstract        = {The organization of Ascaris motoneurones and nervous system is summarized. There is an anterior nerve ring and associated ganglia, main dorsal and ventral nerve cords which run longitudinally, and a small set of posterior ganglia. Cell bodies of motoneurones are found in the ventral nerve cord and occur in 5 repeating 'segments'; each contains 11 motoneurones. Seven morphological types of excitatory or inhibitory motoneurone are recognized. Each Ascaris somatic muscle cell is composed of the contractile spindle; the bag region, containing the nucleus; the arm; and the syncytial region, the location of neuromuscular junctions. The resting membrane potential of muscle is approximately -30 mV and shows regular depolarizing, Ca-dependent 'spike potentials' superimposed on smaller Na(+)- and Ca2(+)-dependent 'slow waves' and even slower 'modulation waves'. The membrane shows high Cl- permeability. Adjacent cells are electrically coupled so that electrical activity in the cells is synchronized. Acetylcholine (ACh) and gamma-aminobutyric acid (GABA) affect the electrical activity. Bath-applied ACh increases membrane cation conductance, depolarizes the cells, alters the frequency and amplitude of spike potentials and produces contraction. Bath-applied GABA increases Cl- conductance, decreases spike activity and causes hyperpolarization and muscle relaxation. The extra-synaptic ACh receptors on the bag region of Ascaris muscle can be regarded as a separate subtype of nicotinic receptor. ACh and anthelmintic agonists (pyrantel, morantel, levamisole) produce a dose-dependent increase in cation conductance and membrane depolarization which is blocked by tubocurarine, mecamylamine but not by hexamethonium. The potency of GABA agonists, with the exception of sulphonic acid derivatives, correlates with the vertebrate GABAa receptor. The potency of antagonists does not. Thus, bicuculline, securinine, pitrazepine, SR95531 and RU5135 are potent vertebrate GABAa antagonists but have little effect on GABA receptors. The potency order of the arylaminopyridazine GABA antagonists: SR95103, SR95132, SR42666, SR95133, SR95531, SR42627 and SR42640 at the Ascaris GABA receptors contrasts with that at vertebrate GABAa receptors. It has been suggested that the receptor is referred to as a GABAn receptor. Patch-clamp studies show that ACh activates a non-selective cation channel which has a main conductance of 40-50pS and apparent mean open time of 1.3 ms; a smaller channel of 20-30 pS with a similar open-time is also activated. Pyrantel and levamisole also produce openings with similar conductances and open-times.(ABSTRACT TRUNCATED AT 400 WORDS)},
  chemicals       = {Anthelmintics, GABA Antagonists, Parasympatholytics, Parasympathomimetics, Receptors, Cholinergic, Receptors, GABA-A, gamma-Aminobutyric Acid, Acetylcholine},
  citation-subset = {IM},
  completed       = {1991-07-29},
  country         = {England},
  issn-linking    = {0031-1820},
  keywords        = {Acetylcholine, antagonists & inhibitors, physiology; Animals; Anthelmintics, pharmacology; Ascaris, anatomy & histology, drug effects, physiology; Electrophysiology; Female; GABA Antagonists; Ion Channel Gating, drug effects; Locomotion; Male; Motor Neurons, physiology; Muscle Contraction, drug effects, physiology; Neuromuscular Junction, drug effects, physiology; Parasympatholytics, pharmacology; Parasympathomimetics, pharmacology; Receptors, Cholinergic, drug effects, physiology; Receptors, GABA-A, drug effects, physiology; Structure-Activity Relationship; Synaptic Transmission, drug effects; gamma-Aminobutyric Acid, physiology},
  nlm-id          = {0401121},
  owner           = {NLM},
  pmid            = {1647516},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  references      = {99},
  revised         = {2013-11-21},
}

@Article{lewis1980b,
  author          = {Lewis, J. A. and Wu, C. H. and Levine, J. H. and Berg, H.},
  title           = "{Levamisole-Resistant Mutants of the Nematode \textit{Caenorhabditis elegans} Appear to Lack Pharmacological Acetylcholine Receptors.}",
  journal         = {Neuroscience},
  year            = {1980},
  volume          = {5},
  issue           = {6},
  pages           = {967--989},
  issn            = {0306-4522},
  doi             = {10.1016/0306-4522(80)90180-3},
  chemicals       = {Cholinesterase Inhibitors, Receptors, Cholinergic, Levamisole, Acetylcholine},
  citation-subset = {IM},
  completed       = {1980-10-24},
  country         = {United States},
  issn-linking    = {0306-4522},
  keywords        = {Acetylcholine, metabolism; Animals; Caenorhabditis, drug effects, genetics, metabolism; Cholinesterase Inhibitors, pharmacology; Drug Resistance; Levamisole, pharmacology; Mutation; Receptors, Cholinergic, drug effects, metabolism; Species Specificity},
  nlm-id          = {7605074},
  owner           = {NLM},
  pii             = {0306-4522(80)90180-3},
  pmid            = {7402460},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2019-07-12},
}

@Article{qian2006,
  author          = {Qian, H. and Martin, R. J. and Robertson, A. P.},
  title           = {Pharmacology of N-, L-, and B-subtypes of nematode nAChR resolved at the single-channel level in Ascaris suum.},
  journal         = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
  year            = {2006},
  volume          = {20},
  issue           = {14},
  month           = dec,
  pages           = {2606--2608},
  issn            = {1530-6860},
  doi             = {10.1096/fj.06-6264fje},
  abstract        = {Pharmacological experiments on Ascaris suum have demonstrated the presence of three (N-, L-, and B-) subtypes of cholinergic receptor mediating contraction of body wall muscle in parasitic nematodes. In the present study, these ionotropic acetylcholine (ACh) receptors (nAChRs) were activated by levamisole and bephenium under patch-clamp conditions and competitively antagonized by paraherquamide and 2-desoxoparaherquamide. A number of recordings exhibited three separate current amplitude levels, indicating the presence of small, intermediate, and large conductance subtypes of receptor. The mean conductance of the small conductance subtype, G25, was 22 +/- 1 pS; the intermediate conductance channel, G35, was 33 +/- 1 pS; and the large conductance channel, G45, was 45 +/- 1 pS. The small channel was not antagonized significantly by paraherquamide and was identified as the N-subtype. The intermediate channel was preferentially activated by levamisole rather than bephenium and antagonized by paraherquamide: the intermediate channel was identified as the L-subtype. The large conductance channel was preferentially activated by bephenium, antagonized more by 2-desoxoparaherquamde than by paraherquamide and was identified as the B-subtype. These observations reveal that the three channel subtypes have different selectivity for cholinergic anthelmintics. The different selectivity of these compounds should be considered when dealing with drug resistant infections.},
  chemicals       = {2-desoxoparaherquamide A, Anthelmintics, Bephenium Compounds, Indolizines, Pyridines, Receptors, Cholinergic, Spiro Compounds, methyridine, Levamisole, paraherquamide},
  citation-subset = {IM},
  completed       = {2007-01-01},
  country         = {United States},
  issn-linking    = {0892-6638},
  keywords        = {Animals; Anthelmintics, metabolism, pharmacology; Ascaris suum, drug effects, metabolism; Bephenium Compounds, pharmacology; Dose-Response Relationship, Drug; Indolizines, pharmacology; Levamisole, pharmacology; Pyridines, pharmacology; Receptors, Cholinergic, classification, metabolism; Spiro Compounds, pharmacology},
  nlm-id          = {8804484},
  owner           = {NLM},
  pii             = {fj.06-6264fje},
  pmid            = {17056760},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

@Article{fleming1997,
  author          = {Fleming, J. T. and Squire, M. D. and Barnes, T. M. and Tornoe, C. and Matsuda, K .and Ahnn, J. and Fire, A. and Sulston, J. E. and Barnard, E. A. and Sattelle, D. B. and Lewis, J. A.},
  title           = "{\textit{Caenorhabditis elegans} Levamisole Resistance Genes lev-1, unc-29, and unc-38 Encode Functional Nicotinic Acetylcholine Receptor Subunits.}",
  journal         = {The J. Neurosci. : the official journal of the Society for Neuroscience},
  year            = {1997},
  volume          = {17},
  issue           = {15},
  month           = aug,
  pages           = {5843--5857},
  issn            = {0270-6474},
  abstract        = {We show that three of the eleven genes of the nematode Caenorhabditis elegans that mediate resistance to the nematocide levamisole and to other cholinergic agonists encode nicotinic acetylcholine receptor (nAChR) subunits. unc-38 encodes an alpha subunit while lev-1 and unc-29 encode non-alpha subunits. The nematode nAChR subunits show conservation of many mammalian nAChR sequence features, implying an ancient evolutionary origin of nAChR proteins. Expression in Xenopus oocytes of combinations of these subunits that include the unc-38 alpha subunit results in levamisole-induced currents that are suppressed by the nAChR antagonists mecamylamine, neosurugatoxin, and d-tubocurarine but not alpha-bungarotoxin. The mutant phenotypes reveal that unc-38 and unc-29 subunits are necessary for nAChR function, whereas the lev-1 subunit is not. An UNC-29-GFP fusion shows that UNC-29 is expressed in body and head muscles. Two dominant mutations of lev-1 result in a single amino acid substitution or addition in or near transmembrane domain 2, a region important to ion channel conductance and desensitization. The identification of viable nAChR mutants in C. elegans provides an advantageous system in which receptor expression and synaptic targeting can be manipulated and studied in vivo.},
  chemicals       = {Receptors, Nicotinic},
  citation-subset = {IM},
  completed       = {1997-10-03},
  country         = {United States},
  issn-linking    = {0270-6474},
  keywords        = {Amino Acid Sequence; Animals; Cloning, Molecular; Genes, genetics; Molecular Sequence Data; Mutation, genetics; Phenotype; Receptors, Nicotinic, genetics; Xenopus},
  nlm-id          = {8102140},
  owner           = {NLM},
  pmid            = {9221782},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2016-10-19},
}

@Article{pellegrino2011,
  author          = {Pellegrino, M. and Steinbach, N. and Stensmyr, M. C. and Hansson, B. S. and Vosshall, L. B.},
  title           = {A natural polymorphism alters odour and DEET sensitivity in an insect odorant receptor.},
  journal         = {Nature},
  year            = {2011},
  volume          = {478},
  issue           = {7370},
  month           = sep,
  pages           = {511--514},
  issn            = {1476-4687},
  doi             = {10.1038/nature10438},
  abstract        = {Blood-feeding insects such as mosquitoes are efficient vectors of human infectious diseases because they are strongly attracted by body heat, carbon dioxide and odours produced by their vertebrate hosts. Insect repellents containing DEET (N,N-diethyl-meta-toluamide) are highly effective, but the mechanism by which this chemical wards off biting insects remains controversial despite decades of investigation. DEET seems to act both at close range as a contact chemorepellent, by affecting insect gustatory receptors, and at long range, by affecting the olfactory system. Two opposing mechanisms for the observed behavioural effects of DEET in the gas phase have been proposed: that DEET interferes with the olfactory system to block host odour recognition and that DEET actively repels insects by activating olfactory neurons that elicit avoidance behaviour. Here we show that DEET functions as a modulator of the odour-gated ion channel formed by the insect odorant receptor complex. The functional insect odorant receptor complex consists of a common co-receptor, ORCO (ref. 15) (formerly called OR83B; ref. 16), and one or more variable odorant receptor subunits that confer odour selectivity. DEET acts on this complex to potentiate or inhibit odour-evoked activity or to inhibit odour-evoked suppression of spontaneous activity. This modulation depends on the specific odorant receptor and the concentration and identity of the odour ligand. We identify a single amino-acid polymorphism in the second transmembrane domain of receptor OR59B in a Drosophila melanogaster strain from Brazil that renders OR59B insensitive to inhibition by the odour ligand and modulation by DEET. Our data indicate that natural variation can modify the sensitivity of an odour-specific insect odorant receptor to odour ligands and DEET. Furthermore, they support the hypothesis that DEET acts as a molecular 'confusant' that scrambles the insect odour code, and provide a compelling explanation for the broad-spectrum efficacy of DEET against multiple insect species.},
  chemicals       = {Drosophila Proteins, Insect Repellents, Ligands, OR59B protein, Drosophila, Receptors, Odorant, DEET},
  citation-subset = {IM},
  completed       = {2012-01-26},
  country         = {England},
  issn-linking    = {0028-0836},
  keywords        = {Animals; Avoidance Learning, drug effects; Brazil; DEET, pharmacology; Drosophila Proteins; Drosophila melanogaster, classification, genetics, metabolism; Insect Repellents, pharmacology; Ligands; Odorants; Olfactory Receptor Neurons, drug effects; Polymorphism, Genetic, genetics; Protein Structure, Tertiary; Receptors, Odorant, chemistry, genetics, metabolism; Species Specificity; Substrate Specificity},
  mid             = {NIHMS317226},
  nlm-id          = {0410462},
  owner           = {NLM},
  pii             = {nature10438},
  pmc             = {PMC3203342},
  pmid            = {21937991},
  pubmodel        = {Electronic},
  pubstatus       = {epublish},
  revised         = {2018-11-13},
}

@Article{hunt2017,
  author          = {Hunt, P. R.},
  title           = "{The \textit{C. elegans} model in Toxicity Testing.}",
  journal         = {Journal of applied toxicology},
  year            = {2017},
  volume          = {37},
  issue           = {1},
  pages           = {50--59},
  issn            = {1099-1263},
  doi             = {10.1002/jat.3357},
  abstract        = {Caenorhabditis elegans is a small nematode that can be maintained at low cost and handled using standard in vitro techniques. Unlike toxicity testing using cell cultures, C. elegans toxicity assays provide data from a whole animal with intact and metabolically active digestive, reproductive, endocrine, sensory and neuromuscular systems. Toxicity ranking screens in C. elegans have repeatedly been shown to be as predictive of rat LD  ranking as mouse LD  ranking. Additionally, many instances of conservation of mode of toxic action have been noted between C. elegans and mammals. These consistent correlations make the case for inclusion of C. elegans assays in early safety testing and as one component in tiered or integrated toxicity testing strategies, but do not indicate that nematodes alone can replace data from mammals for hazard evaluation. As with cell cultures, good C. elegans culture practice (GCeCP) is essential for reliable results. This article reviews C. elegans use in various toxicity assays, the C. elegans model's strengths and limitations for use in predictive toxicology, and GCeCP. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Journal of Applied Toxicology published by John Wiley & Sons Ltd.},
  citation-subset = {IM},
  completed       = {2017-12-04},
  country         = {England},
  issn-linking    = {0260-437X},
  keywords        = {Animal Use Alternatives; Animals; Caenorhabditis elegans, drug effects, genetics, growth & development; Lethal Dose 50; Toxicity Tests, methods; alternative model; good C. elegans culture practice; predictive toxicology; screening; toxin ranking},
  nlm-id          = {8109495},
  owner           = {NLM},
  pmc             = {PMC5132335},
  pmid            = {27443595},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2019-01-15},
}

@Article{boyd2010,
  author          = {Boyd, W. A. and McBride, S. J. and Rice, J. R. and Snyder, D. W .. and Freedman, J. H.},
  title           = "{A High-Throughput Method for Assessing Chemical Toxicity Using a \textit{Caenorhabditis elegans} reproduction assay.}",
  journal         = {Toxicol. Appl. Pharm.},
  year            = {2010},
  volume          = {245},
  issue           = {2},
  month           = jun,
  pages           = {153--159},
  issn            = {1096-0333},
  doi             = {10.1016/j.taap.2010.02.014},
  abstract        = {The National Research Council has outlined the need for non-mammalian toxicological models to test the potential health effects of a large number of chemicals while also reducing the use of traditional animal models. The nematode Caenorhabditis elegans is an attractive alternative model because of its well-characterized and evolutionarily conserved biology, low cost, and ability to be used in high-throughput screening. A high-throughput method is described for quantifying the reproductive capacity of C. elegans exposed to chemicals for 48 h from the last larval stage (L4) to adulthood using a COPAS Biosort. Initially, the effects of exposure conditions that could influence reproduction were defined. Concentrations of DMSO vehicle <or=1% did not affect reproduction. Previous studies indicated that C. elegans may be influenced by exposure to low pH conditions. At pHs greater than 4.5, C. elegans reproduction was not affected; however below this pH there was a significant decrease in the number of offspring. Cadmium chloride was chosen as a model toxicant to verify that automated measurements were comparable to those of traditional observational studies. EC(50) values for cadmium for automated measurements (176-192 microM) were comparable to those previously reported for a 72-h exposure using manual counting (151 microM). The toxicity of seven test toxicants on C. elegans reproduction was highly correlative with rodent lethality suggesting that this assay may be useful in predicting the potential toxicity of chemicals in other organisms.},
  citation-subset = {IM},
  completed       = {2010-06-11},
  country         = {United States},
  issn-linking    = {0041-008X},
  keywords        = {Animals; Caenorhabditis elegans, drug effects; Dose-Response Relationship, Drug; High-Throughput Screening Assays, methods; Hydrogen-Ion Concentration; Lethal Dose 50; Reproduction, drug effects; Toxicity Tests, methods},
  mid             = {NIHMS186306},
  nlm-id          = {0416575},
  owner           = {NLM},
  pii             = {S0041-008X(10)00073-6},
  pmc             = {PMC2871981},
  pmid            = {20206647},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{Allard2013,
  author          = {Allard, Patrick and Kleinstreuer, Nicole C and Knudsen, Thomas B and Colaiácovo, Monica P},
  title           = {A C. elegans screening platform for the rapid assessment of chemical disruption of germline function.},
  journal         = {Environmental health perspectives},
  year            = {2013},
  volume          = {121},
  issue           = {6},
  month           = jun,
  pages           = {717--724},
  issn            = {1552-9924},
  doi             = {10.1289/ehp.1206301},
  abstract        = {Despite the developmental impact of chromosome segregation errors, we lack the tools to assess environmental effects on the integrity of the germline in animals. We developed an assay in Caenorhabditis elegans that fluorescently marks aneuploid embryos after chemical exposure. We qualified the predictive value of the assay against chemotherapeutic agents as well as environmental compounds from the ToxCast Phase I library by comparing results from the C. elegans assay with the comprehensive mammalian in vivo end point data from the ToxRef database. The assay was highly predictive of mammalian reproductive toxicities, with a 69% maximum balanced accuracy. We confirmed the effect of select compounds on germline integrity by monitoring germline apoptosis and meiotic progression. This C. elegans assay provides a comprehensive strategy for assessing environmental effects on germline function.},
  chemicals       = {Aneugens, Environmental Pollutants},
  citation-subset = {IM},
  completed       = {2013-11-19},
  country         = {United States},
  issn-linking    = {0091-6765},
  keywords        = {Aneugens, toxicity; Animals; Caenorhabditis elegans, drug effects, genetics; Chromosome Segregation, drug effects; Environmental Pollutants, toxicity; Germ Cells, drug effects; High-Throughput Screening Assays; Meiosis, drug effects; Reproduction, drug effects},
  nlm-id          = {0330411},
  owner           = {NLM},
  pmc             = {PMC3672921},
  pmid            = {23603051},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{reeder2001,
  author          = {Reeder, N. L. and Ganz, P. J. and Carlson, J. R. and Saunders, C. W.},
  title           = {Isolation of a deet-insensitive mutant of Drosophila melanogaster (Diptera: Drosophilidae).},
  journal         = {Journal of economic entomology},
  year            = {2001},
  volume          = {94},
  issue           = {6},
  month           = dec,
  pages           = {1584--1588},
  issn            = {0022-0493},
  doi             = {10.1603/0022-0493-94.6.1584},
  abstract        = {Despite the widespread use of N,N,-diethyl-3-methylbenzamide (deet) in insect repellent products, nothing is known about the molecular basis for the repellency of deet, we initiated a molecular genetics program to elucidate the molecular mechanism of deet repellency in Drosophila melanogaster (Meigen). Deet repellency was apparently due to airborne vapors, as wild type flies were repelled by a deet-treated surface in the absence of physical contact and in the dark. A mutant was isolated using chemical mutagenesis and at choice assay. In a choice assay, mutant flies entered 82 +/- 1% of deet-containing tubes, whereas wild type flies entered only 6 +/- 2% of deet-containing tubes. The mutant was repelled by other repellents, benzaldehyde and citronellal. The mutation was recessive and located on the X chromosome.},
  chemicals       = {Insect Repellents, DEET},
  citation-subset = {IM},
  completed       = {2002-01-23},
  country         = {England},
  issn-linking    = {0022-0493},
  keywords        = {Animals; DEET, pharmacology; Drosophila melanogaster, drug effects, genetics; Insect Repellents, pharmacology; Insecticide Resistance, genetics; Mutation; Vision, Ocular},
  nlm-id          = {2985127R},
  owner           = {NLM},
  pmid            = {11777068},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2019-05-13},
}

@Article{klun2004,
  author          = {Klun, J. A. and Strickman, D. and Rowton, E. and Williams, J. and Kramer, M. and Roberts, D. and Debboun, M.},
  title           = {Comparative resistance of Anopheles albimanus and Aedes aegypti to N,N-diethyl-3-methylbenzamide (Deet) and 2-methylpiperidinyl-3-cyclohexen-1-carboxamide (AI3-37220) in laboratory human-volunteer repellent assays.},
  journal         = {Journal of medical entomology},
  year            = {2004},
  volume          = {41},
  issue           = {3},
  month           = may,
  pages           = {418--422},
  issn            = {0022-2585},
  doi             = {10.1603/0022-2585-41.3.418},
  abstract        = {The insect repellents N,N-diethyl-3-methylbenzamide (Deet) and the racemate and 1S,2'S stereoisomer of 2-methylpiperidinyl-3-cyclohexene-1-carboxamide (AI3-37220) were tested against Anopheles albimanus Wiedemann and Aedes aegypti (L.) in laboratory human-volunteer assays. Estimated skin doses of Deet or racemic AI3-37220 required to reduce biting by 95% in Ae. aegypti were 2.3 and 3.5 x 10(-2) micromol/cm2 skin, respectively, whereas estimated doses for 95% bite reduction of An. albimanus in an approximately 40-yr-old laboratory colony established from El Salvador were 5 times higher at 12 x 10(-2) micromol Deet/cm2 skin and >20 x 10(-2) micromol/cm2 skin for AI3-37220. In tests with the 1S,2'S stereoisomer of AI3-37220, a newly established colony of An. albimanus from Belize bit less aggressively than El Salvador An. albimanus. However, the Belize-derived mosquitoes were as resistant as the old El Salvador colony to repellent effects of 1S,2'S stereoisomer of 2-methylpiperidinyl-3-cyclohexene-1-carboxamide. Earlier workers surmised that usual skin doses of Deet would offer only limited protection against An. albimanus in the field. Our findings support this speculation, but they also indicate that doses of Deet higher than those needed for protection against Ae. aegypti might offer reasonable protection against An. albimanus. Results indicate that neither racemate nor 1S,2'S stereoisomer of 2-methylpiperidinyl-3-cyclohexene-1-carboxamide offer as much protection as Deet against An. Albimanus, despite being highly effective against Ae. aegypti.},
  chemicals       = {Piperidines, DEET, 1-(3-cyclohexen-1-ylcarbonyl)-2-methylpiperidine},
  citation-subset = {IM},
  completed       = {2004-06-29},
  country         = {England},
  issn-linking    = {0022-2585},
  keywords        = {Aedes; Animals; Animals, Laboratory; Anopheles, classification; DEET, toxicity; Dose-Response Relationship, Drug; Female; Humans; Insect Bites and Stings; Insecticide Resistance; Male; Piperidines, toxicity; Species Specificity},
  nlm-id          = {0375400},
  owner           = {NLM},
  pmid            = {15185944},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2019-05-13},
}

@Online{peryea1998,
  author = {Peryea, F. J.},
  title  = {Historical use of lead arsenate insecticides, resulting soil contamination and implications for soil remediation. Proceedings of the 16th World Congress of Soil Sci., 25th, Montpellier, France},
  year   = {1998},
  url    = {http://natres.psu.ac.th/Link/SoilCongress/en/symt25.htm },
}

@Article{hood2006,
  author          = {Hood, Ernie},
  title           = {The apple bites back: claiming old orchards for residential development.},
  journal         = {Environmental health perspectives},
  year            = {2006},
  volume          = {114},
  issue           = {8},
  month           = aug,
  pages           = {A470--A476},
  issn            = {0091-6765},
  doi             = {10.1289/ehp.114-a470},
  chemicals       = {Arsenates, Pesticide Residues, Pesticides, Soil Pollutants, Lead, lead arsenate},
  citation-subset = {IM},
  completed       = {2006-11-30},
  country         = {United States},
  issn-linking    = {0091-6765},
  keywords        = {Agriculture; Arsenates, analysis; Environmental Restoration and Remediation; History, 19th Century; Housing; Lead, analysis; Malus; Pesticide Residues, analysis; Pesticides, adverse effects, analysis, history; Risk Assessment; Soil Pollutants, analysis; United States; United States Environmental Protection Agency},
  nlm-id          = {0330411},
  owner           = {NLM},
  pmc             = {PMC1551991},
  pmid            = {16882511},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-08-31},
}

@Book{cullen2008,
  author    = {Cullen, W. R.},
  title     = {Is Arsenic an Aphrodisiac?: The Sociochemistry of an Element},
  year      = {2008},
  publisher = {RSC Publishing},
}

@Online{nobel2019,
  author = "{NobelPrize.org}",
  title  = {Paul Müller-Facts. Nobel Media AB 2020},
  year   = {2019},
  url    = {https://www.nobelprize.org/prizes/medicine/1948/muller/facts/},
}

@Report{phsa2002,
  author      = "{U.S. Department of Health and Human Services}",
  title       = {Toxicological profile for D{DT}, D{DE}, and D{DD}},
  institution = {U.S. Department of Health and Human Services. Public Health Service Agency for Toxic Substances and Disease Registry},
  year        = {2002},
}

@Article{king2015,
  author          = {King, A. M. and Aaron, C. K.},
  title           = {Organophosphate and carbamate poisoning.},
  journal         = {Emergency medicine clinics of North America},
  year            = {2015},
  volume          = {33},
  issue           = {1},
  month           = feb,
  pages           = {133--151},
  issn            = {1558-0539},
  doi             = {10.1016/j.emc.2014.09.010},
  abstract        = {Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of disease-carrying vectors. Some OP and carbamates have therapeutic indications such as physostigmine. Certain organophosphorus compounds, known as nerve agents, have been employed in chemical warfare and terrorism incidents. Both classes inhibit acetylcholinesterase (AChE) enzymes, leading to excess acetylcholine accumulation at nerve terminals. In the setting of toxicity from either agent class, clinical syndromes result from excessive nicotinic and muscarinic neurostimulation. The toxic effects from OPs and carbamates differ with respect to reversibility, subacute, and chronic effects. Decontamination, meticulous supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management. },
  chemicals       = {Antidotes, Carbamates, Muscarinic Antagonists, Oximes},
  citation-subset = {IM},
  completed       = {2015-01-26},
  country         = {United States},
  issn-linking    = {0733-8627},
  keywords        = {Antidotes, therapeutic use; Carbamates, poisoning; Disease Management; Environmental Exposure, adverse effects; Humans; Muscarinic Antagonists, therapeutic use; Organophosphate Poisoning; Oximes, therapeutic use; Poisoning, therapy; Atropine; Carbamate; Chemical warfare; Insecticides; Nerve agents; Organophosphate; Oxime; Pesticides},
  nlm-id          = {8219565},
  owner           = {NLM},
  pii             = {S0733-8627(14)00080-7},
  pmid            = {25455666},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2014-12-03},
}

@Article{shi2011,
  author          = {Shi, X. and Jiang, L. and Wang, H. and Qiao, K. and Wang, D. and Wang, K.},
  title           = "{Toxicities and Sublethal Effects of Seven Neonicotinoid Insecticides on Survival, Growth and Reproduction of Imidacloprid-Resistant Cotton Aphid, \textit{Aphis gossypii}.}",
  journal         = {Pest Manag. Sci.},
  year            = {2011},
  volume          = {67},
  issue           = {12},
  pages           = {1528--1533},
}

@Article{zhu2011,
  author          = {Zhu, Y. and Loso, M. R. and Watson, G. B. and Sparks, T. C. and Rogers, R. B. and Huang, J. X. and Gerwick, B. C. and Babcock, J. M. and Kelley, D. and Hegde, V. B. and Nugent, B. and Renga, J. M. and Denholm, I. and Gorman, K. and DeBoer., G. J. and Hasler, J. and Meade, T. and Thomas, J. D.},
  title           = {Discovery and characterization of sulfoxaflor, a novel insecticide targeting sap-feeding pests.},
  journal         = {J Agr Food Chem},
  year            = {2011},
  volume          = {59},
  issue           = {7},
  pages           = {2950--2957},
  issn            = {1520-5118},
  doi             = {10.1021/jf102765x},
  abstract        = {The discovery of sulfoxaflor [N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ(4)-sulfanylidene] cyanamide] resulted from an investigation of the sulfoximine functional group as a novel bioactive scaffold for insecticidal activity and a subsequent extensive structure-activity relationship study. Sulfoxaflor, the first product from this new class (the sulfoximines) of insect control agents, exhibits broad-spectrum efficacy against many sap-feeding insect pests, including aphids, whiteflies, hoppers, and Lygus, with levels of activity that are comparable to those of other classes of insecticides targeting sap-feeding insects, including the neonicotinoids. However, no cross-resistance has been observed between sulfoxaflor and neonicotinoids such as imidacloprid, apparently the result of differences in susceptibility to oxidative metabolism. Available data are consistent with sulfoxaflor acting via the insect nicotinic receptor in a complex manner. These observations reflect the unique structure of the sulfoximines compared with neonicotinoids.},
  chemicals       = {Imidazoles, Insecticides, Neonicotinoids, Nitro Compounds, Pyridines, Receptors, Nicotinic, Sulfur Compounds, imidacloprid, sulfoxaflor},
  citation-subset = {IM},
  completed       = {2011-08-17},
  country         = {United States},
  issn-linking    = {0021-8561},
  keywords        = {Animals; Aphids; Hemiptera; Imidazoles; Insecta; Insecticide Resistance; Insecticides, chemistry; Neonicotinoids; Nitro Compounds; Pyridines, chemistry; Receptors, Nicotinic; Structure-Activity Relationship; Sulfur Compounds, chemistry},
  nlm-id          = {0374755},
  owner           = {NLM},
  pmid            = {21105655},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@Article{nauen2015,
  author          = {Nauen, R. and Jeschke, P. and Velten, R. and Beck, M. E. and Ebbinghaus-Kintscher, U. and Thielert, W. and Wölfel, K. and Haas, M. and Kunz, K. and Raupach, G.},
  title           = {Flupyradifurone: a brief profile of a new butenolide insecticide.},
  journal         = {Pest Manag. Sci.},
  year            = {2015},
  volume          = {71},
  issue           = {6},
  month           = jun,
  pages           = {850--862},
  issn            = {1526-4998},
  doi             = {10.1002/ps.3932},
  abstract        = {The development and commercialisation of new chemical classes of insecticides for efficient Crop Prot. measures against destructive invertebrate pests is of utmost importance to overcome resistance issues and to secure sustainable crop yields. Flupyradifurone introduced here is the first representative of the novel butenolide class of insecticides active against various sucking pests and showing an excellent safety profile. The discovery of flupyradifurone was inspired by the butenolide scaffold in naturally occurring stemofoline. Flupyradifurone acts reversibly as an agonist on insect nicotinic acetylcholine receptors but is structurally different from known agonists, as shown by chemical similarity analysis. It shows a fast action on a broad range of sucking pests, as demonstrated in laboratory bioassays, and exhibits excellent field efficacy on a number of crops with different application methods, including foliar, soil, seed treatment and drip irrigation. It is readily taken up by plants and translocated in the xylem, as demonstrated by phosphor imaging analysis. Flupyradifurone is active on resistant pests, including cotton whiteflies, and is not metabolised by recombinantly expressed CYP6CM1, a cytochrome P450 conferring metabolic resistance to neonicotinoids and pymetrozine. The novel butenolide insecticide flupyradifurone shows unique properties and will become a new tool for integrated pest management around the globe, as demonstrated by its insecticidal, ecotoxicological and safety profile.},
  chemicals       = {Insecticides, Nicotinic Agonists, Pyridines, flupyradifurone, 4-Butyrolactone},
  citation-subset = {IM},
  completed       = {2016-03-25},
  country         = {England},
  issn-linking    = {1526-498X},
  keywords        = {4-Butyrolactone, analogs & derivatives, chemistry, toxicity; Animals; Aphids; Crops, Agricultural; Hemiptera; Insecticide Resistance; Insecticides, chemistry, toxicity; Nicotinic Agonists, chemistry, toxicity; Pyridines, chemistry, toxicity; CYP6CM1; Sivanto®; butenolide; flupyradifurone; metabolic resistance; nicotinic acetylcholine receptor agonist; resistance management; sucking pests},
  nlm-id          = {100898744},
  owner           = {NLM},
  pmc             = {PMC4657471},
  pmid            = {25351824},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-20},
}

@Report{eu2015,
  author = "{The European  Commision}",
  title  = {Final Review report for the active substance sulfoxaflor},
  year   = {2015},
  number = {SANTE/10665/2015 rev 2},
}

@Online{eu2019a,
  author = "{The European Commission}",
  title  = {EU Pesticides database. Entry for Sulfoxaflor},
  year   = {Accessed 01 Sep 2019},
  date   = {2019},
  url    = {https://ec.europa.eu/food/plant/pesticides/eu-pesticides-database/public/?event=activesubstance.detail&language=EN&selectedID=2282},
}

@Online{eu2019b,
  author = "{The European Commision}",
  title  = {EU pesticides database. Entry for Flupyradifurone},
  year   = {Accessed 01 Sep 2019.},
  date   = {2019},
  url    = {https://ec.europa.eu/food/plant/pesticides/eu-pesticides-database/public/?event=activesubstance.detail&language=EN&selectedID=2314},
}

@Report{pan2019,
  author      = "{Pest Action Network Europe}",
  title       = {Sulfoxaflor and flupyradifurone: Neonicotinoids or not?},
  institution = {Brussels},
  year        = {2016},
}

@Article{shao2013,
  author          = {Shao, X. and Swenson, T. L. and Casida, J. E.},
  title           = {Cycloxaprid insecticide: nicotinic acetylcholine receptor binding site and metabolism.},
  journal         = {J Agr Food Chem},
  year            = {2013},
  volume          = {61},
  issue           = {33},
  pages           = {7883--7888},
  issn            = {1520-5118},
  doi             = {10.1021/jf4030695},
  abstract        = {Cycloxaprid (CYC) is a novel neonicotinoid prepared from the (nitromethylene)imidazole (NMI) analogue of imidacloprid. In this study we consider whether CYC is active per se or only as a proinsecticide for NMI. The IC50 values (nM) for displacing [(3)H]NMI binding are 43-49 for CYC and 2.3-3.2 for NMI in house fly and honeybee head membranes and 302 and 7.2, respectively, in mouse brain membranes, potency relationships interpreted as partial conversion of some CYC to NMI under the assay conditions. The 6-8-fold difference in toxicity of injected CYC and NMI to house flies is consistent with their relative potencies as in vivo nicotinic acetylcholine receptor (nAChR) inhibitors in brain measured with [(3)H]NMI binding assays. CYC metabolism in mice largely involves cytochrome P450 pathways without NMI as a major intermediate. Metabolites of CYC tentatively assigned are five monohydroxy derivatives and one each of dihydroxy, nitroso, and amino modifications. CYC appears be a proinsecticide, serving as a slow-release reservoir for NMI with selective activity for insect versus mammalian nAChRs. },
  chemicals       = {Heterocyclic Compounds, 3-Ring, Imidazoles, Insect Proteins, Insecticides, Neonicotinoids, Nicotinic Antagonists, Nitro Compounds, Pyridines, Receptors, Nicotinic, cycloxaprid, imidacloprid},
  citation-subset = {IM},
  completed       = {2014-01-31},
  country         = {United States},
  issn-linking    = {0021-8561},
  keywords        = {Animals; Bees; Binding Sites; Heterocyclic Compounds, 3-Ring, chemistry, metabolism; Houseflies; Imidazoles, chemistry, metabolism; Insect Proteins, chemistry, metabolism; Insecticides, chemistry; Kinetics; Male; Mice; Neonicotinoids; Nicotinic Antagonists, chemistry, metabolism; Nitro Compounds, chemistry, metabolism; Pyridines, chemistry, metabolism; Receptors, Nicotinic, chemistry, metabolism},
  nlm-id          = {0374755},
  owner           = {NLM},
  pmid            = {23889077},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-11-16},
}

@WWW{fera2019,
  author = "{The Food and Environment Research Agency. Department for Environment, Food and Rural Affairs}",
  title  = {Pesticide usage statistics.},
  year   = {2019},
}

@WWW{usgs2019,
  author = "{United States Geological Survey}",
  title  = {National Water-Quality Assessment (NAWQA) Project. Estimated Annual Agricultural Pesticide Use},
  year   = {2019},
  url    = {https://water.usgs.gov/nawqa/pnsp/usage/maps/compound_listing.php},
}

@Article{simon-delso2015,
  author          = {Simon-Delso, N. and Amaral-Rogers, V. and Belzunces, L. P. and Bonmatin, J. M. and Chagnon, M. and Downs, C. and Furlan, L. and Environ. Health Perspect.ons, D. W. and Giorio, C. and Girolami, V. and Goulson, D. and Kreutzweiser, D. P. and Krupke, C. H. and Liess, M. and Long, E. and McField, M. and Mineau, P. and Mitchell, E. A. D. and Morrissey, C. A. and Noome, D. A. and Pisa, L. and Settele, J. and Stark, J. D. and Tapparo, A. and Van Dyck, H. and Van Praagh, J. and Van der Sluijs, J. P. and Whitehorn, P. R. and Wiemers, M.},
  title           = {Systemic insecticides (neonicotinoids and fipronil): trends, uses, mode of action and metabolites.},
  journal         = {Environ Sci Pollut Res Int},
  year            = {2015},
  volume          = {22},
  issue           = {1},
  month           = jan,
  pages           = {5--34},
  issn            = {1614-7499},
  doi             = {10.1007/s11356-014-3470-y},
  abstract        = {Since their discovery in the late 1980s, neonicotinoid pesticides have become the most widely used class of insecticides worldwide, with large-scale applications ranging from plant protection (crops, vegetables, fruits), veterinary products, and biocides to invertebrate pest control in fish farming. In this review, we address the phenyl-pyrazole fipronil together with neonicotinoids because of similarities in their toxicity, physicochemical profiles, and presence in the environment. Neonicotinoids and fipronil currently account for approximately one third of the world insecticide market; the annual world production of the archetype neonicotinoid, imidacloprid, was estimated to be ca. 20,000 tonnes active substance in 2010. There were several reasons for the initial success of neonicotinoids and fipronil: (1) there was no known pesticide resistance in target pests, mainly because of their recent development, (2) their physicochemical properties included many advantages over previous generations of insecticides (i.e., organophosphates, carbamates, pyrethroids, etc.), and (3) they shared an assumed reduced operator and consumer risk. Due to their systemic nature, they are taken up by the roots or leaves and translocated to all parts of the plant, which, in turn, makes them effectively toxic to herbivorous insects. The toxicity persists for a variable period of time-depending on the plant, its growth stage, and the amount of pesticide applied. A wide variety of applications are available, including the most common prophylactic non-Good Agricultural Practices (GAP) application by seed coating. As a result of their extensive use and physicochemical properties, these substances can be found in all environmental compartments including soil, water, and air. Neonicotinoids and fipronil operate by disrupting neural transmission in the central nervous system of invertebrates. Neonicotinoids mimic the action of neurotransmitters, while fipronil inhibits neuronal receptors. In doing so, they continuously stimulate neurons leading ultimately to death of target invertebrates. Like virtually all insecticides, they can also have lethal and sublethal impacts on non-target organisms, including insect predators and vertebrates. Furthermore, a range of synergistic effects with other stressors have been documented. Here, we review extensively their metabolic pathways, showing how they form both compound-specific and common metabolites which can themselves be toxic. These may result in prolonged toxicity. Considering their wide commercial expansion, mode of action, the systemic properties in plants, persistence and environmental fate, coupled with limited information about the toxicity profiles of these compounds and their metabolites, neonicotinoids and fipronil may entail significant risks to the environment. A global evaluation of the potential collateral effects of their use is therefore timely. The present paper and subsequent chapters in this review of the global literature explore these risks and show a growing body of evidence that persistent, low concentrations of these insecticides pose serious risks of undesirable environmental impacts. },
  chemicals       = {Environmental Pollutants, Imidazoles, Insecticides, Neonicotinoids, Nitro Compounds, Pyrazoles, imidacloprid, fipronil},
  citation-subset = {IM},
  completed       = {2015-06-15},
  country         = {Germany},
  issn-linking    = {0944-1344},
  keywords        = {Agriculture, methods, trends; Animals; Crops, Agricultural, metabolism; Environmental Pollutants, metabolism, toxicity; Herbivory; Imidazoles, metabolism, toxicity; Insecta, drug effects; Insecticides, metabolism, toxicity; Neonicotinoids; Nitro Compounds, metabolism, toxicity; Pyrazoles, metabolism, toxicity; Seeds, metabolism},
  nlm-id          = {9441769},
  owner           = {NLM},
  pmc             = {PMC4284386},
  pmid            = {25233913},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-12-02},
}

@Article{bass2015,
  author          = {Bass, C. and Denholm, I. and Williamson, M. S. and Nauen, R.},
  title           = {The global status of insect resistance to neonicotinoid insecticides.},
  journal         = {Pestic. Biochem. Phys.},
  year            = {2015},
  volume          = {121},
  month           = jun,
  pages           = {78--87},
  issn            = {1095-9939},
  doi             = {10.1016/j.pestbp.2015.04.004},
  abstract        = {The first neonicotinoid insecticide, imidacloprid, was launched in 1991. Today this class of insecticides comprises at least seven major compounds with a market share of more than 25% of total global insecticide sales. Neonicotinoid insecticides are highly selective agonists of insect nicotinic acetylcholine receptors and provide farmers with invaluable, highly effective tools against some of the world's most destructive crop pests. These include sucking pests such as aphids, whiteflies, and planthoppers, and also some coleopteran, dipteran and lepidopteran species. Although many insect species are still successfully controlled by neonicotinoids, their popularity has imposed a mounting selection pressure for resistance, and in several species resistance has now reached levels that compromise the efficacy of these insecticides. Research to understand the molecular basis of neonicotinoid resistance has revealed both target-site and metabolic mechanisms conferring resistance. For target-site resistance, field-evolved mutations have only been characterized in two aphid species. Metabolic resistance appears much more common, with the enhanced expression of one or more cytochrome P450s frequently reported in resistant strains. Despite the current scale of resistance, neonicotinoids remain a major component of many pest control programmes, and resistance management strategies, based on mode of action rotation, are of crucial importance in preventing resistance becoming more widespread. In this review we summarize the current status of neonicotinoid resistance, the biochemical and molecular mechanisms involved, and the implications for resistance management. },
  chemicals       = {Insecticides, Nicotinic Agonists},
  citation-subset = {IM},
  completed       = {2016-03-09},
  country         = {United States},
  issn-linking    = {0048-3575},
  keywords        = {Animals; Insecticide Resistance; Insecticides, pharmacology; Nicotinic Agonists, pharmacology; Imidacloprid; Neonicotinoids; Nicotinic acetylcholine receptor; Resistance management; Resistance mechanisms; Sucking pests},
  nlm-id          = {1301573},
  owner           = {NLM},
  pii             = {S0048-3575(15)00082-6},
  pmid            = {26047114},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2015-06-06},
}

@Article{brown1936,
  author       = {Brown, G. L. and Dale, H. H. and Feldberg, W.},
  title        = {Reactions of the normal mammalian muscle to acetylcholine and to eserine.},
  journal      = { J. Physiol.},
  year         = {1936},
  volume       = {87},
  issue        = {4},
  month        = sep,
  pages        = {394--424},
  issn         = {0022-3751},
  doi          = {10.1113/jphysiol.1936.sp003414},
  completed    = {2007-02-05},
  country      = {England},
  issn-linking = {0022-3751},
  nlm-id       = {0266262},
  owner        = {NLM},
  pmc          = {PMC1395069},
  pmid         = {16994802},
  pubmodel     = {Print},
  pubstatus    = {ppublish},
  revised      = {2019-05-13},
}

@Article{bacq1937,
  author       = {Bacq, Z. M. and Brown, G. L.},
  title        = {Pharmacological experiments on mammalian voluntary muscle, in relation to the theory of chemical transmission.},
  journal      = {J. Physiol.},
  year         = {1937},
  volume       = {89},
  issue        = {1},
  month        = feb,
  pages        = {45--60},
  issn         = {0022-3751},
  doi          = {10.1113/jphysiol.1937.sp003461},
  completed    = {2007-02-05},
  country      = {England},
  issn-linking = {0022-3751},
  nlm-id       = {0266262},
  owner        = {NLM},
  pmc          = {PMC1395034},
  pmid         = {16994843},
  pubmodel     = {Print},
  pubstatus    = {ppublish},
  revised      = {2019-05-13},
}

@Article{thesleft1955,
  author          = {Thesleft, S.},
  title           = {The mode of neuromuscular block caused by acetylcholine, nicotine, decamethonium and succinylcholine.},
  journal         = {Acta physiologica Scandinavica},
  year            = {1955},
  volume          = {34},
  issue           = {2-3},
  month           = oct,
  pages           = {218--231},
  issn            = {0001-6772},
  doi             = {10.1111/j.1748-1716.1955.tb01242.x},
  chemicals       = {Decamethonium Compounds, Muscle Relaxants, Central, Nicotine, decamethonium, Succinylcholine, Acetylcholine},
  citation-subset = {OM},
  clml            = {5629:34914},
  completed       = {2003-05-01},
  country         = {England},
  issn-linking    = {0001-6772},
  keywords        = {Acetylcholine, pharmacology; Decamethonium Compounds; Humans; Muscle Relaxants, Central, pharmacology; Neuromuscular Blockade; Neuromuscular Diseases; Neuromuscular Junction, drug effects; Nicotine, pharmacology; Succinylcholine, pharmacology; ACETYLCHOLINE/effects; MUSCLE RELAXANTS/effects; MYONEURAL JUNCTION/effect of drugs on; NICOTINE/effects; SUCCINYLCHOLINE/effects},
  nlm-id          = {0370362},
  owner           = {NLM},
  pmid            = {13282730},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-12-01},
}

@Article{lee1967,
  author          = {Lee, C. Y. and Tseng, L. F. and Chiu, T. H.},
  title           = {Influence of denervation on localization of neurotoxins from clapid venoms in rat diaphragm.},
  journal         = {Nature},
  year            = {1967},
  volume          = {215},
  issue           = {5106},
  month           = sep,
  pages           = {1177--1178},
  issn            = {0028-0836},
  doi             = {10.1038/2151177a0},
  chemicals       = {Iodine Isotopes, Toxins, Biological, Venoms},
  citation-subset = {IM},
  completed       = {1968-01-22},
  country         = {England},
  issn-linking    = {0028-0836},
  keywords        = {Animals; Diaphragm; Iodine Isotopes; Muscle Denervation; Neuromuscular Junction, physiology; Phrenic Nerve, surgery; Rats; Snakes; Synaptic Transmission, drug effects; Toxins, Biological, pharmacology, physiology; Venoms, physiology},
  nlm-id          = {0410462},
  owner           = {NLM},
  pmid            = {4294063},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2019-06-17},
}

@Article{chang1963,
  author          = {Chang, C. C. and Lee, C. Y.},
  title           = "{Isolation of Neurotoxins from the Venom of \textit{Bungarus multicinctus} and Their Modes of Neuromuscular Blocking Action}",
  journal         = {Archives internationales de pharmacodynamie et de therapie},
  year            = {1963},
  volume          = {144},
  pages           = {241--257},
  issn            = {0003-9780},
  chemicals       = {Antitoxins, Neurotoxins, Toxins, Biological, Venoms, Isoflurophate, Neostigmine, Physostigmine, Cholinesterases, Acetylcholine},
  citation-subset = {OM},
  completed       = {1996-12-01},
  country         = {Belgium},
  issn-linking    = {0003-9780},
  keywords        = {Acetylcholine; Animals; Antitoxins; Bungarus; Cholinesterases; Diaphragm; Electrophoresis; Ileum; Isoflurophate; Mice; Neostigmine; Neuromuscular Junction; Neurotoxins; Phrenic Nerve; Physostigmine; Poultry; Research; Snakes; Toxicology; Toxins, Biological; Venoms; ACETYLCHOLINE; CHOLINESTERASE; DIAPHRAGM; ELECTROPHORESIS; EXPERIMENTAL LAB STUDY; ILEUM; ISOFLUROPHATE; MICE; NEOSTIGMINE; NEUROMUSCULAR JUNCTION; PHRENIC NERVE; PHYSOSTIGMINE; POULTRY; SNAKES; TOXICOLOGIC REPORT; TOXINS AND ANTITOXINS; VENOMS},
  nlm-id          = {0405353},
  owner           = {NLM},
  pmid            = {14043649},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-12-01},
}

@Article{schiebler1980,
  author       = {Schiebler, W. and Bandini, G. and Hucho, F.},
  title        = "{Quaternary Structure and Reconstitution of Acetylcholine Receptor from \textit{Torpedo Californica}.}",
  journal      = {Neurochem . Int.},
  year         = {1980},
  volume       = {2C},
  pages        = {281--290},
  issn         = {0197-0186},
  abstract     = {The nicotinic acetylcholine receptor (AChR) from Torpedo californica electric tissue is a protein complex of MW 270 000 consisting of a binding moiety (receptor) and an ion channel (effector). Reconstitution experiments present evidence that receptor and effector may be located on different subunits of the protein complex. The subunit composition of the membrane bound AChR complex is investigated by affinity labeling experiments and nearest neighbour analysis using cross-linking reagents. In addition to the four main polypeptides ?, ?, ?, ?, other minor components are present. Two ATP binding polypeptide chains (MW 45,000 and 55,000) and one chain reacting with an N(3)-derivative of cobra toxin (MW 55 000) were detected. Nearest neighbour analysis showed close proximity between two ? polypeptide chains and also between two ? chains. Furthermore the agonist and antagonist binding chain ? is located close to ?, ?, and ?, and ? is close to ? and ?.},
  completed    = {2012-10-02},
  country      = {England},
  issn-linking = {0197-0186},
  nlm-id       = {8006959},
  owner        = {NLM},
  pii          = {0197-0186(80)90035-2},
  pmid         = {20487794},
  pubmodel     = {Print},
  pubstatus    = {ppublish},
  revised      = {2010-05-21},
}

@Article{Wise1979,
  author          = {Wise, D S and Karlin, A and Schoenborn, B P},
  title           = {An analysis by low-angle neutron scattering of the structure of the acetylcholine receptor from Torpedo californica in detergent solution.},
  journal         = {Biophys. J.},
  year            = {1979},
  volume          = {28},
  issue           = {3},
  month           = dec,
  pages           = {473--496},
  issn            = {0006-3495},
  doi             = {10.1016/S0006-3495(79)85194-2},
  abstract        = {The acetylcholine receptor from the electric tissue of Torpedo californica is a large, integral membrane protein containing four different types of polypeptide chains. The structure of the purified receptor in detergent solution has previously been investigated by sedimentation analysis and gel filtration. Sedimentation analysis yielded a molecular weight of 250,000 for the protein moiety of the receptor monomer-detergent complex; hydrodynamic characteristics such as the Stokes radius, however, refer to the receptor-detergent complex. In this paper we report the results of our use of low-angle neutron scattering to investigate the shape of the receptor-detergent (Triton X-100 from Rohm & Haas Co., Philadelphia, Pa.) complex and separately of its protein and detergent moieties. By adjustment of the neutron-scattering density of the solvent with D2O to match that of one or the other of the moieties, its contribution to the scattering can be nearly, if not completely, eliminated. Neutron scattering from Triton X-100 micelles established that this detergent is contrast matched in approximately 18% D2O. Scattering measurements on the receptor-detergent complex in this solvent yielded a radius of gyration of the acetylcholine receptor monomer of 46 +/- 1A. The radius of gyration and molecular volume (305,000 A3) of the receptor are inconsistent with a compact spherical shape. These parameters are consistent with, for example, a prolate cylinder of dimensions (length x diameter) approximately 150 x approximately 50 A or an oblate cylinder, approximately 25 x approximately 130 A. More complex shapes are possible and in fact seem to be required to reconcile the present results with previous electron microscopic and x-ray analyses of receptor in membrane and with considerations of the function of the receptor in controlling ion permeability. The neutron-scattering data yield, in addition, an independent determination of the molecular weight of the receptor protein (240,000 +/- 40,000), the extent of Triton X-100 binding in the complex (approximately 0.4 g/g protein), and from the extended scattering curve, an approximation to the shape of the receptor-Triton X-100 complex, namely an oblate ellipsoid of axial ratio 1:4.},
  chemicals       = {Detergents, Membrane Proteins, Receptors, Cholinergic, Solutions, Polyethylene Glycols, Octoxynol},
  citation-subset = {IM},
  completed       = {1981-11-24},
  country         = {United States},
  issn-linking    = {0006-3495},
  keywords        = {Animals; Detergents; Electric Organ, analysis; Membrane Proteins, analysis; Models, Chemical; Molecular Weight; Neutrons; Octoxynol; Polyethylene Glycols; Receptors, Cholinergic, analysis; Scattering, Radiation; Solutions; Torpedo},
  nlm-id          = {0370626},
  owner           = {NLM},
  pii             = {S0006-3495(79)85194-2},
  pmc             = {PMC1328651},
  pmid            = {262562},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-30},
}

@Article{reynolds1978,
  author          = {Reynolds, J. A. and Karlin, A.},
  title           = "{Molecular Weight in Detergent Solution of Acetylcholine Receptor from \textit{Torpedo californica}.}",
  journal         = {Biochem.},
  year            = {1978},
  volume          = {17},
  issue           = {11},
  month           = may,
  pages           = {2035--2038},
  issn            = {0006-2960},
  doi             = {10.1021/bi00604a001},
  abstract        = {Acetylcholine receptor extracted in detergent solution from the electric tissue of Torpedo californica and purified by affinity chromatography contains predominantly two molecular weight species. These have been separated by sedimentation in a sucrose density gradient, and their molecular properties have been determined by sedimentation equilibrium and sedimentation velocity measurements in the analytical ultracentrifuge. The molecular weights of these species have been determined, without prior determination of the extent of detergent bound to them, by the adjustment of solvent density with D2O so as to blank out the contribution of bound detergent to the sedimentation potential. The molecular weights of the protein moieties are 250 000 and 500 000. Since these species are identical in specific activity and polypeptide composition they are related as monomer and dimer. The hydrodynamic properties of the detergent complexes of monomer and dimer were derived from combined measurements of sedimentation equilibrium and sedimentation velocity. The S20,w'S are 8.6 S and 12.8 S and the Stokes radii are 7.3 nm and 9.5 nm. For both monomer and dimer, the ratio of the Stokes radius to the minimum possible radius for the protein-detergent complex falls outside the range of values for globular proteins.},
  chemicals       = {Macromolecular Substances, Receptors, Cholinergic, Acetylcholine},
  citation-subset = {IM},
  completed       = {1978-09-15},
  country         = {United States},
  issn-linking    = {0006-2960},
  keywords        = {Acetylcholine, metabolism; Animals; Electric Organ, metabolism; Fishes; Macromolecular Substances; Molecular Weight; Receptors, Cholinergic, isolation & purification, metabolism},
  nlm-id          = {0370623},
  owner           = {NLM},
  pmid            = {667008},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2019-06-13},
}

@Article{schroeder1984,
  author    = {Schroeder, M. E. and Flattum, R. F.},
  title     = {The mode of action and neurotoxic properties of the nitromethylene heterocycle insecticides},
  journal   = {Pestic. Biochem. Phys.},
  year      = {1984},
  volume    = {22},
  number    = {2},
  pages     = {148--160},
  publisher = {Elsevier},
}

@Article{fatt1951,
  author    = {Fatt, P. and Katz, B.},
  title     = {An analysis of the end-plate potential recorded with an intra-cellular electrode},
  journal   = { J. Physiol.},
  year      = {1951},
  volume    = {115},
  number    = {3},
  pages     = {320},
  publisher = {Wiley-Blackwell},
}

@Article{colquhoun1985,
  author    = {Colquhoun, D. and Sakmann, B.},
  title     = {Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate.},
  journal   = { J. Physiol.},
  year      = {1985},
  volume    = {369},
  number    = {1},
  pages     = {501--557},
  publisher = {Wiley Online Library},
}

@Article{colquhoun1981,
  author          = {Colquhoun, D. and Sakmann, B.},
  title           = {Fluctuations in the microsecond time range of the current through single acetylcholine receptor ion channels.},
  journal         = {Nature},
  year            = {1981},
  volume          = {294},
  issue           = {5840},
  month           = dec,
  pages           = {464--466},
  issn            = {0028-0836},
  doi             = {10.1038/294464a0},
  chemicals       = {Dicarboxylic Acids, Ion Channels, Receptors, Cholinergic, subecholine, Choline},
  citation-subset = {IM},
  completed       = {1982-02-25},
  country         = {England},
  issn-linking    = {0028-0836},
  keywords        = {Animals; Choline, analogs & derivatives, pharmacology; Dicarboxylic Acids, pharmacology; Electric Conductivity; Ion Channels, physiology; Kinetics; Membrane Potentials; Rana temporaria; Receptors, Cholinergic, drug effects, physiology},
  nlm-id          = {0410462},
  owner           = {NLM},
  pmid            = {6273743},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2019-06-17},
}

@Article{breer1987,
  author    = {Breer, H. and Sattelle, D. B.},
  title     = {Molecular properties and functions of insect acetylcholine receptors},
  journal   = {J. Insect Physiol.},
  year      = {1987},
  volume    = {33},
  number    = {11},
  pages     = {771--790},
  publisher = {Elsevier},
}

@InCollection{sattelle1981,
  author    = {Sattelle, D. B.},
  title     = "{Acetylcholine Receptors in the Central Nervous System of an Insect \textit{Periplaneta americana L.}}",
  booktitle = {Neurotransmitters in Invertebrates},
  year      = {1981},
  publisher = {Elsevier},
  pages     = {31--58},
}

@Article{heisenberg1998,
  author    = {Heisenberg, M.},
  title     = {What do the mushroom bodies do for the insect brain? An introduction},
  journal   = {Learning \& Memory},
  year      = {1998},
  volume    = {5},
  number    = {1},
  pages     = {1--10},
  publisher = {Cold Spring Harbor Lab},
}

@Article{smarandache-wellmann2016,
  author    = {Smarandache-Wellmann, C. R.},
  title     = {Arthropod neurons and nervous system},
  journal   = {Curr. Biol.},
  year      = {2016},
  volume    = {26},
  number    = {20},
  pages     = {R960--R965},
  publisher = {Elsevier},
}

@Article{mongeon2011,
  author          = {Mongeon, R. and Walogorsky, M. and Urban, J. and Mandel, G. and Ono, F. and Brehm, .P.},
  title           = {An acetylcholine receptor lacking both γ and ε subunits mediates transmission in zebrafish slow muscle synapses.},
  journal         = {The Journal of general physiology},
  year            = {2011},
  volume          = {138},
  issue           = {3},
  month           = sep,
  pages           = {353--366},
  issn            = {1540-7748},
  doi             = {10.1085/jgp.201110649},
  abstract        = {Fast and slow skeletal muscle types in larval zebrafish can be distinguished by a fivefold difference in the time course of their synaptic decay. Single-channel recordings indicate that this difference is conferred through kinetically distinct nicotinic acetylcholine receptor (AChR) isoforms. The underlying basis for this distinction was explored by cloning zebrafish muscle AChR subunit cDNAs and expressing them in Xenopus laevis oocytes. Measurements of single-channel conductance and mean open burst duration assigned α(2)βδε to fast muscle synaptic current. Contrary to expectations, receptors composed of only αβδ subunits (presumed to be α(2)βδ(2) receptors) recapitulated the kinetics and conductance of slow muscle single-channel currents. Additional evidence in support of γ/ε-less receptors as mediators of slow muscle synapses was reflected in the inward current rectification of heterologously expressed α(2)βδ(2) receptors, a property normally associated with neuronal-type nicotinic receptors. Similar rectification was reflected in both single-channel and synaptic currents in slow muscle, distinguishing them from fast muscle. The final evidence for α(2)βδ(2) receptors in slow muscle was provided by our ability to convert fast muscle synaptic currents to those of slow muscle by knocking down ε subunit expression in vivo. Thus, for the first time, muscle synaptic function can be ascribed to a receptor isoform that is composed of only three different subunits. The unique functional features offered by the α(2)βδ(2) receptor likely play a central role in mediating the persistent contractions characteristic to this muscle type.},
  chemicals       = {Protein Subunits, Receptors, Cholinergic, Zebrafish Proteins},
  citation-subset = {IM},
  completed       = {2012-03-27},
  country         = {United States},
  issn-linking    = {0022-1295},
  keywords        = {Amino Acid Sequence; Animals; Female; Kinetics; Molecular Sequence Data; Muscle, Skeletal, physiology; Oocytes, metabolism; Protein Subunits, genetics, metabolism; Rats; Receptors, Cholinergic, genetics, metabolism; Sequence Alignment; Synapses, physiology; Xenopus laevis; Zebrafish, physiology; Zebrafish Proteins, genetics, metabolism},
  nlm-id          = {2985110R},
  owner           = {NLM},
  pii             = {jgp.201110649},
  pmc             = {PMC3171075},
  pmid            = {21844221},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{zirger2003,
  author  = {Zirger, J. M. and Beattie, C. E. and McKay, D. B. and Boyd R. T.},
  title   = {Cloning and expression of zebrafish neuronal nicotinic acetylcholine receptors.},
  journal = {Gene Expr Patterns},
  year    = {2003},
  volume  = {3},
}

@Article{ackerman2009,
  author          = {Ackerman, K. M. and Nakkula, R. and Zirger, J. M. and Beattie, C. E. and Boyd, R. T.},
  title           = {Cloning and spatiotemporal expression of zebrafish neuronal nicotinic acetylcholine receptor alpha 6 and alpha 4 subunit RNAs.},
  journal         = {Developmental dynamics : an official publication of the American Association of Anatomists},
  year            = {2009},
  volume          = {238},
  issue           = {4},
  month           = apr,
  pages           = {980--992},
  issn            = {1058-8388},
  doi             = {10.1002/dvdy.21912},
  abstract        = {Acetylcholine plays an important role in regulation of nervous system development and function. We are developing zebrafish (Danio rerio) as a model system to study the role of specific neuronal nicotinic acetylcholine receptor (nAChR) subtypes in development and the effects of nicotine on the developing vertebrate nervous system. We previously characterized the expression of several zebrafish nAChR subunits. To further develop the zebrafish model, here we report a study on the molecular characterization of two additional nAChR subunit genes, designated chrna6 and chrna4. Both zebrafish nAChRs have a high degree of sequence identity to nAChRs expressed in a variety of mammalian species. Reverse transcription polymerase chain reaction was used to show that both nAChR subunit RNAs were expressed early in zebrafish development, with the chrna4 transcript present at 3 hours postfertilization (hpf) and the chrna6 RNA present at 10 hpf. In situ hybridization was used to localize chrna6 and chrna4 RNA expression in 24, 48, 72, and 96 hpf zebrafish. The chrna6 and chrna4 RNAs were each expressed in a unique pattern, which changed during development. At various ages, chrna6 was expressed in Rohon-Beard sensory neurons, trigeminal ganglion, retina, and the pineal gland. Most notably, chrna6 was expressed in catecholaminergic neurons in the midbrain, but was also present in noncatecholaminergic cells in both midbrain and hindbrain. The expression of chrna6 RNA in catecholaminergic cells supports the use of zebrafish as a valid model system to better understand the molecular basis of cholinergic regulation of dopaminergic signaling and the role of alpha6-containing nAChRs in Parkinson's disease. The most notable chrna4 expression was in neural crest cells at 24 hpf and reticulospinal neurons in hindbrain at 48 hpf. chrna4 RNA exhibited a widespread and robust expression pattern in the midbrain in 72 hpf and 96 hpf zebrafish.},
  chemicals       = {Protein Subunits, RNA, Messenger, Receptors, Nicotinic, nicotinic acetylcholine receptor alpha4 subunit, nicotinic receptor alpha6},
  citation-subset = {IM},
  completed       = {2009-06-04},
  country         = {United States},
  issn-linking    = {1058-8388},
  keywords        = {Amino Acid Sequence; Animals; Cloning, Molecular; Conserved Sequence; Gene Expression Regulation, Developmental, genetics; Humans; In Situ Hybridization; Molecular Sequence Data; Phylogeny; Protein Subunits, chemistry, genetics, metabolism; RNA, Messenger, genetics; Receptors, Nicotinic, chemistry, genetics, metabolism; Sequence Alignment; Zebrafish, embryology, genetics, metabolism},
  mid             = {NIHMS646912},
  nlm-id          = {9201927},
  owner           = {NLM},
  pmc             = {PMC4267763},
  pmid            = {19301390},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2018-11-13},
}

@Article{adams2000a,
  author          = {Adams, M. D. and Celniker, S. E. and Holt, R. A. and Evans, C. A. and Gocayne ..., J. D. and Venter, J. C.},
  title           = {The genome sequence of \textit{Drosophila melanogaster}.},
  journal         = {Science},
  year            = {2000},
  volume          = {287},
  issue           = {5461},
  month           = mar,
  pages           = {2185--2195},
  issn            = {0036-8075},
  doi             = {10.1126/science.287.5461.2185},
  abstract        = {The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans. We have determined the nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map. Efforts are under way to close the remaining gaps; however, the sequence is of sufficient accuracy and contiguity to be declared substantially complete and to support an initial analysis of genome structure and preliminary gene annotation and interpretation. The genome encodes approximately 13,600 genes, somewhat fewer than the smaller Caenorhabditis elegans genome, but with comparable functional diversity.},
  chemicals       = {Chromatin, Euchromatin, Heterochromatin, Insect Proteins, Nuclear Proteins, Cytochrome P-450 Enzyme System},
  citation-subset = {IM},
  completed       = {2000-03-30},
  country         = {United States},
  issn-linking    = {0036-8075},
  keywords        = {Animals; Biological Transport, genetics; Chromatin, genetics; Cloning, Molecular; Computational Biology; Contig Mapping; Cytochrome P-450 Enzyme System, genetics; DNA Repair, genetics; DNA Replication, genetics; Drosophila melanogaster, genetics, metabolism; Euchromatin; Gene Library; Genes, Insect; Genome; Heterochromatin, genetics; Insect Proteins, chemistry, genetics, physiology; Nuclear Proteins, genetics; Protein Biosynthesis; Sequence Analysis, DNA; Transcription, Genetic},
  nlm-id          = {0404511},
  owner           = {NLM},
  pii             = {8392},
  pmid            = {10731132},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2019-06-19},
}

@Article{consortium2006,
  author          = "{Honeybee Genome Sequencing Consortium}",
  title           = "{Insights into Social Insects from the Genome of the Honeybee \textit{Apis mellifera}}",
  journal         = {Nature},
  year            = {2006},
  volume          = {443},
  issue           = {7114},
  month           = oct,
  pages           = {931--949},
  issn            = {1476-4687},
  doi             = {10.1038/nature05260},
  abstract        = {Here we report the genome sequence of the honeybee Apis mellifera, a key model for social behaviour and essential to global ecology through pollination. Compared with other sequenced insect genomes, the A. mellifera genome has high A+T and CpG contents, lacks major transposon families, evolves more slowly, and is more similar to vertebrates for circadian rhythm, RNA interference and DNA methylation genes, among others. Furthermore, A. mellifera has fewer genes for innate immunity, detoxification enzymes, cuticle-forming proteins and gustatory receptors, more genes for odorant receptors, and novel genes for nectar and pollen utilization, consistent with its ecology and social organization. Compared to Drosophila, genes in early developmental pathways differ in Apis, whereas similarities exist for functions that differ markedly, such as sex determination, brain function and behaviour. Population genetics suggests a novel African origin for the species A. mellifera and insights into whether Africanized bees spread throughout the New World via hybridization or displacement.},
  chemicals       = {DNA Transposable Elements, Proteome},
  citation-subset = {IM},
  completed       = {2006-11-29},
  country         = {England},
  investigator    = {Weinstock, George M and Robinson, Gene E and Environ. Health Perspect.s, Richard A and Weinstock, George M and Robinson, Gene E and Worley, Kim C and Evans, Jay D and Maleszka, Ryszard and Robertson, Hugh M and Weaver, Daniel B and Beye, Martin and Bork, Peer and Elsik, Christine G and Evans, Jay D and Hartfelder, Klaus and Hunt, Greg J and Robertson, Hugh M and Robinson, Gene E and Maleszka, Ryszard and Weinstock, George M and Worley, Kim C and Zdobnov, Evgeny M and Hartfelder, Klaus and Amdam, Gro V and Bitondi, Márcia M G and Collins, Anita M and Cristino, Alexandre S and Evans, Jay D and Lattorff, Michael G and Lobo, Carlos H and Moritz, Robin F A and Nunes, Francis M F and Page, Robert E and Simões, Zilá L P and Wheeler, Diana and Carninci, Piero and Fukuda, Shiro and Hayashizaki, Yoshihide and Kai, Chikatoshi and Kawai, Jun and Sakazume, Naoko and Sasaki, Daisuke and Tagami, Michihira and Maleszka, Ryszard and Amdam, Gro V and Albert, Stefan and Baggerman, Geert and Beggs, Kyle T and Bloch, Guy and Cazzamali, Giuseppe and Cohen, Mira and Drapeau, Mark David and Eisenhardt, Dorothea and Emore, Christine and Ewing, Michael A and Fahrbach, Susan E and Forêt, Sylvain and Grimmelikhuijzen, Cornelis J P and Hauser, Frank and Hummon, Amanda B and Hunt, Greg J and Huybrechts, Jurgen and Jones, Andrew K and Kadowaki, Tatsuhiko and Kaplan, Noam and Kucharski, Robert and Leboulle, Gérard and Linial, Michal and Littleton, J Troy and Mercer, Alison R and Page, Robert E and Robertson, Hugh M and Robinson, Gene E and Richmond, Timothy A and Rodriguez-Zas, Sandra L and Rubin, Elad B and Sattelle, David B and Schlipalius, David and Schoofs, Liliane and Shemesh, Yair and Sweedler, Jonathan V and Velarde, Rodrigo and Verleyen, Peter and Vierstraete, Evy and Williamson, Michael R and Beye, Martin and Ament, Seth A and Brown, Susan J and Corona, Miguel and Dearden, Peter K and Dunn, W Augustine and Elekonich, Michelle M and Elsik, Christine G and Forêt, Sylvain and Fujiyuki, Tomoko and Gattermeier, Eriko and Gempe, Tanja and Hasselmann, Martin and Kadowaki, Tatsuhiko and Kage, Eriko and Kamikouchi, Azusa and Kubo, Takeo and Kucharski, Robert and Kunieda, Takekazu and Lorenzen, Marcé and Maleszka, Ryszard and Milshina, Natalia V and Morioka, Mizue and Ohashi, Kazuaki and Overbeek, Ross and Page, Robert E and Robertson, Hugh M and Robinson, Gene E and Ross, Christian A and Schioett, Morten and Shippy, Teresa and Takeuchi, Hideaki and Toth, Amy L and Willis, Judith H and Wilson, Megan J and Robertson, Hugh M and Zdobnov, Evgeny M and Bork, Peer and Elsik, Christine G and Gordon, Karl H J and Letunic, Ivica and Hackett, Kevin and Peterson, Jane and Felsenfeld, Adam and Guyer, Mark and Solignac, Michel and Agarwala, Richa and Cornuet, Jean Marie and Elsik, Christine G and Emore, Christine and Hunt, Greg J and Monnerot, Monique and Mougel, Florence and Reese, Justin T and Schlipalius, David and Vautrin, Dominique and Weaver, Daniel B and Gillespie, Joseph J and Cannone, Jamie J and Gutell, Robin R and Johnston, J Spencer and Elsik, Christine G and Cazzamali, Giuseppe and Eisen, Michael B and Grimmelikhuijzen, Cornelis J P and Hauser, Frank and Hummon, Amanda B and Iyer, Venky N and Iyer, Vivek and Kosarev, Peter and Mackey, Aaron J and Maleszka, Ryszard and Reese, Justin T and Richmond, Timothy A and Robertson, Hugh M and Solovyev, Victor and Souvorov, Alexandre and Sweedler, Jonathan V and Weinstock, George M and Willliamson, Michael R and Zdobnov, Evgeny M and Evans, Jay D and Aronstein, Katherine A and Bilikova, Katarina and Chen, Yan Ping and Clark, Andrew G and Decanini, Laura I and Gelbart, William M and Hetru, Charles and Hultmark, Dan and Imler, Jean-Luc and Jiang, Haobo and Kanost, Michael and Kimura, Kiyoshi and Lazzaro, Brian P and Lopez, Dawn L and Simuth, Jozef and Thompson, Graham J and Zou, Zhen and De Jong, Pieter and Sodergren, Erica and Csûrös, Miklós and Milosavljevic, Aleksandar and Johnston, J Spencer and Osoegawa, Kazutoyo and Richards, Stephen and Shu, Chung-Li and Weinstock, George M and Elsik, Christine G and Duret, Laurent and Elhaik, Eran and Graur, Dan and Reese, Justin T and Robertson, Hugh M and Robertson, Hugh M and Elsik, Christine G and Maleszka, Ryszard and Weaver, Daniel B and Amdam, Gro V and Anzola, Juan M and Campbell, Kathryn S and Childs, Kevin L and Collinge, Derek and Crosby, Madeline A and Dickens, C Michael and Elsik, Christine G and Gordon, Karl H J and Grametes, L Sian and Grozinger, Christina M and Jones, Peter L and Jorda, Mireia and Ling, Xu and Matthews, Beverly B and Miller, Jonathan and Milshina, Natalia V and Mizzen, Craig and Peinado, Miguel A and Reese, Justin T and Reid, Jeffrey G and Robertson, Hugh M and Robinson, Gene E and Russo, Susan M and Schroeder, Andrew J and St Pierre, Susan E and Wang, Ying and Zhou, Pinglei and Robertson, Hugh M and Agarwala, Richa and Elsik, Christine G and Milshina, Natalia V and Reese, Justin T and Weaver, Daniel B and Worley, Kim C and Childs, Kevin L and Dickens, C Michael and Elsik, Christine G and Gelbart, William M and Jiang, Huaiyang and Kitts, Paul and Milshina, Natalia V and Reese, Justin T and Ruef, Barbara and Russo, Susan M and Venkatraman, Anad and Weinstock, George M and Zhang, Lan and Zhou, Pinglei and Johnston, J Spencer and Aquino-Perez, Gildardo and Cornuet, Jean Marie and Monnerot, Monique and Solignac, Michel and Vautrin, Dominique and Whitfield, Charles W and Behura, Susanta and Berlocher, Stewart H and Clark, Andrew G and Environ. Health Perspect.s, Richard A and Johnston, J Spencer and Sheppard, Walter S and Smith, Deborah R and Suarez, Andrew V and Tsutsui, Neil D and Weaver, Daniel B and Wei, Xuehong and Wheeler, David and Weinstock, George M and Worley, Kim C and Havlak, Paul and Li, Bingshan and Liu, Yue and Sodergren, Erica and Zhang, Lan and Beye, Martin and Hasselmann, Martin and Jolivet, Angela and Lee, Sandra and Nazareth, Lynne V and Pu, Ling-Ling and Thorn, Rachel and Weinstock, George M and Stolc, Viktor and Robinson, Gene E and Maleszka, Ryszard and Newman, Thomas and Samanta, Manoj and Tongprasit, Waraporn A and Aronstein, Katherine A and Claudianos, Charles and Berenbaum, May R and Biswas, Sunita and de Graaf, Dirk C and Feyereisen, Rene and Johnson, Reed M and Oakeshott, John G and Ranson, Hilary and Schuler, Mary A and Muzny, Donna and Environ. Health Perspect.s, Richard A and Weinstock, George M and Chacko, Joseph and Davis, Clay and Dinh, Huyen and Gill, Rachel and Hernandez, Judith and Hines, Sandra and Hume, Jennifer and Jackson, LaRonda and Kovar, Christie and Lewis, Lora and Miner, George and Morgan, Margaret and Nazareth, Lynne V and Nguyen, Ngoc and Okwuonu, Geoffrey and Paul, Heidi and Richards, Stephen and Santibanez, Jireh and Savery, Glenford and Sodergren, Erica and Svatek, Amanda and Villasana, Donna and Wright, Rita},
  issn-linking    = {0028-0836},
  keywords        = {Animals; Base Composition; Bees, genetics, growth & development, physiology; Behavior, Animal; DNA Transposable Elements, genetics; Evolution, Molecular; Female; Gene Expression Regulation, genetics; Genes, Insect, genetics; Genome, Insect, genetics; Genomics; Immunity, genetics; Male; Molecular Sequence Data; Phylogeny; Physical Chromosome Mapping; Proteome, genetics; Reproduction, genetics; Signal Transduction, genetics; Social Behavior; Telomere, genetics},
  mid             = {NIHMS30641},
  nlm-id          = {0410462},
  owner           = {NLM},
  pmc             = {PMC2048586},
  pmid            = {17073008},
  pubmodel        = {Print},
  pubstatus       = {ppublish},
  revised         = {2019-06-27},
}

@Article{consortium2008,
  author          = "{\textit{Tribolium} Genome Sequencing Consortium}",
  title           = "{The Genome of the Model Beetle and Pest \textit{Tribolium castaneum}}",
  journal         = {Nature},
  year            = {2008},
  volume          = {452},
  issue           = {7190},
  month           = apr,
  pages           = {949--955},
  issn            = {1476-4687},
  doi             = {10.1038/nature06784},
  abstract        = {Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some