Готові списки джерел за темами / Class A GPCR

Добірка наукової літератури з теми "Class A GPCR"

Автор: Grafiati

Опубліковано: 14 березня 2023

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Статті в журналах з теми "Class A GPCR"

Vidad, Ashley Ryan, Stephen Macaspac, and Ho Leung Ng. "Locating ligand binding sites in G-protein coupled receptors using combined information from docking and sequence conservation." PeerJ 9 (September 24, 2021): e12219. http://dx.doi.org/10.7717/peerj.12219.

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GPCRs (G-protein coupled receptors) are the largest family of drug targets and share a conserved structure. Binding sites are unknown for many important GPCR ligands due to the difficulties of GPCR recombinant expression, biochemistry, and crystallography. We describe our approach, ConDockSite, for predicting ligand binding sites in class A GPCRs using combined information from surface conservation and docking, starting from crystal structures or homology models. We demonstrate the effectiveness of ConDockSite on crystallized class A GPCRs such as the beta2 adrenergic and A2A adenosine receptors. We also demonstrate that ConDockSite successfully predicts ligand binding sites from high-quality homology models. Finally, we apply ConDockSite to predict the ligand binding sites on a structurally uncharacterized GPCR, GPER, the G-protein coupled estrogen receptor. Most of the sites predicted by ConDockSite match those found in other independent modeling studies. ConDockSite predicts that four ligands bind to a common location on GPER at a site deep in the receptor cleft. Incorporating sequence conservation information in ConDockSite overcomes errors introduced from physics-based scoring functions and homology modeling.

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Hou, Tianling, Yuemin Bian, Terence McGuire, and Xiang-Qun Xie. "Integrated Multi-Class Classification and Prediction of GPCR Allosteric Modulators by Machine Learning Intelligence." Biomolecules 11, no. 6 (June 11, 2021): 870. http://dx.doi.org/10.3390/biom11060870.

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G-protein-coupled receptors (GPCRs) are the largest and most diverse group of cell surface receptors that respond to various extracellular signals. The allosteric modulation of GPCRs has emerged in recent years as a promising approach for developing target-selective therapies. Moreover, the discovery of new GPCR allosteric modulators can greatly benefit the further understanding of GPCR cell signaling mechanisms. It is critical but also challenging to make an accurate distinction of modulators for different GPCR groups in an efficient and effective manner. In this study, we focus on an 11-class classification task with 10 GPCR subtype classes and a random compounds class. We used a dataset containing 34,434 compounds with allosteric modulators collected from classical GPCR families A, B, and C, as well as random drug-like compounds. Six types of machine learning models, including support vector machine, naïve Bayes, decision tree, random forest, logistic regression, and multilayer perceptron, were trained using different combinations of features including molecular descriptors, Atom-pair fingerprints, MACCS fingerprints, and ECFP6 fingerprints. The performances of trained machine learning models with different feature combinations were closely investigated and discussed. To the best of our knowledge, this is the first work on the multi-class classification of GPCR allosteric modulators. We believe that the classification models developed in this study can be used as simple and accurate tools for the discovery and development of GPCR allosteric modulators.

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Sato. "Conserved 2nd Residue of Helix 8 of GPCR May Confer the Subclass-Characteristic and Distinct Roles through a Rapid Initial Interaction with Specific G Proteins." International Journal of Molecular Sciences 20, no. 7 (April 9, 2019): 1752. http://dx.doi.org/10.3390/ijms20071752.

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To obtain a systematic view of the helix-8-second residue responsible for G protein-coupled receptor (GPCR)–G protein initial specific interactions, 786 human GPCRs were subclassified based on the pairs of agonist groups and target G proteins and compared with their conserved second residue of helix 8. Of 314 non-olfactory and deorphanized GPCRs, 273 (87%) conserved single amino acids in the subclasses, while 93 (58%) of the 160 subclasses possessed only a single GPCR member. Class B, C, Frizzled, and trace amine-associated GPCRs demonstrated 100% conservation, whereas class Ⅰ and Ⅱ olfactory and vomeronasal 1 receptors demonstrated much lower rates of conservation (20–47%). These conserved residues are characteristic of GPCR classes and G protein subtypes and confer their functionally-distinct roles.

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Vohra, Shabana, Bruck Taddese, Alex C. Conner, David R. Poyner, Debbie L. Hay, James Barwell, Philip J. Reeves, Graham J. G. Upton, and Christopher A. Reynolds. "Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies." Journal of The Royal Society Interface 10, no. 79 (February 6, 2013): 20120846. http://dx.doi.org/10.1098/rsif.2012.0846.

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Modelling class B G-protein-coupled receptors (GPCRs) using class A GPCR structural templates is difficult due to lack of homology. The plant GPCR, GCR1, has homology to both class A and class B GPCRs. We have used this to generate a class A–class B alignment, and by incorporating maximum lagged correlation of entropy and hydrophobicity into a consensus score, we have been able to align receptor transmembrane regions. We have applied this analysis to generate active and inactive homology models of the class B calcitonin gene-related peptide (CGRP) receptor, and have supported it with site-directed mutagenesis data using 122 CGRP receptor residues and 144 published mutagenesis results on other class B GPCRs. The variation of sequence variability with structure, the analysis of polarity violations, the alignment of group-conserved residues and the mutagenesis results at 27 key positions were particularly informative in distinguishing between the proposed and plausible alternative alignments. Furthermore, we have been able to associate the key molecular features of the class B GPCR signalling machinery with their class A counterparts for the first time. These include the [K/R]KLH motif in intracellular loop 1, [I/L]xxxL and KxxK at the intracellular end of TM5 and TM6, the NPXXY/VAVLY motif on TM7 and small group-conserved residues in TM1, TM2, TM3 and TM7. The equivalent of the class A DRY motif is proposed to involve Arg 2.39 , His 2.43 and Glu 3.46 , which makes a polar lock with T 6.37 . These alignments and models provide useful tools for understanding class B GPCR function.

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Pellissier, Lucie P., Gaël Barthet, Florence Gaven, Elisabeth Cassier, Eric Trinquet, Jean-Philippe Pin, Philippe Marin, et al. "G Protein Activation by Serotonin Type 4 Receptor Dimers." Journal of Biological Chemistry 286, no. 12 (January 19, 2011): 9985–97. http://dx.doi.org/10.1074/jbc.m110.201939.

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The discovery that class C G protein-coupled receptors (GPCRs) function as obligatory dimeric entities has generated major interest in GPCR oligomerization. Oligomerization now appears to be a common feature among all GPCR classes. However, the functional significance of this process remains unclear because, in vitro, some monomeric GPCRs, such as rhodopsin and β2-adrenergic receptors, activate G proteins. By using wild type and mutant serotonin type 4 receptors (5-HT4Rs) (including a 5-HT4-RASSL) expressed in COS-7 cells as models of class A GPCRs, we show that activation of one protomer in a dimer was sufficient to stimulate G proteins. However, coupling efficiency was 2 times higher when both protomers were activated. Expression of combinations of 5-HT4, in which both protomers were able to bind to agonists but only one could couple to G proteins, suggested that upon agonist occupancy, protomers did not independently couple to G proteins but rather that only one G protein was activated. Coupling of a single heterotrimeric Gs protein to a receptor dimer was further confirmed in vitro, using the purified recombinant WT RASSL 5-HT4R obligatory heterodimer. These results, together with previous findings, demonstrate that, differently from class C GPCR dimers, class A GPCR dimers have pleiotropic activation mechanisms.

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Chattopadhyay, Amitabha. "GPCRs: Lipid-Dependent Membrane Receptors That Act as Drug Targets." Advances in Biology 2014 (October 2, 2014): 1–12. http://dx.doi.org/10.1155/2014/143023.

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G protein-coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across cell membranes and represent major targets in the development of novel drug candidates in all clinical areas. Although there have been some recent leads, structural information on GPCRs is relatively rare due to the difficulty associated with crystallization. A specific reason for this is the intrinsic flexibility displayed by GPCRs, which is necessary for their functional diversity. Since GPCRs are integral membrane proteins, interaction of membrane lipids with them constitutes an important area of research in GPCR biology. In particular, membrane cholesterol has been reported to have a modulatory role in the function of a number of GPCRs. The role of membrane cholesterol in GPCR function is discussed with specific example of the serotonin1A receptor. Recent results show that GPCRs are characterized with structural motifs that preferentially associate with cholesterol. An emerging and important concept is oligomerization of GPCRs and its role in GPCR function and signaling. The role of membrane cholesterol in GPCR oligomerization is highlighted. Future research in GPCR biology would offer novel insight in basic biology and provide new avenues for drug discovery.

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Ellisdon, Andrew M., and Michelle L. Halls. "Compartmentalization of GPCR signalling controls unique cellular responses." Biochemical Society Transactions 44, no. 2 (April 11, 2016): 562–67. http://dx.doi.org/10.1042/bst20150236.

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With >800 members, G protein-coupled receptors (GPCRs) are the largest class of cell-surface signalling proteins, and their activation mediates diverse physiological processes. GPCRs are ubiquitously distributed across all cell types, involved in many diseases and are major drug targets. However, GPCR drug discovery is still characterized by very high attrition rates. New avenues for GPCR drug discovery may be provided by a recent shift away from the traditional view of signal transduction as a simple chain of events initiated from the plasma membrane. It is now apparent that GPCR signalling is restricted to highly organized compartments within the cell, and that GPCRs activate distinct signalling pathways once internalized. A high-resolution understanding of how compartmentalized signalling is controlled will probably provide unique opportunities to selectively and therapeutically target GPCRs.

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Guo, Yan-Zhi, Meng-Long Li, Ke-Long Wang, Zhi-Ning Wen, Min-Chun Lu, Li-Xia Liu, and Lin Jiang. "Fast Fourier Transform-based Support Vector Machine for Prediction of G-protein Coupled Receptor Subfamilies." Acta Biochimica et Biophysica Sinica 37, no. 11 (November 1, 2005): 759–66. http://dx.doi.org/10.1111/j.1745-7270.2005.00110.x.

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Abstract Although the sequence information on G-protein coupled receptors (GPCRs) continues to grow, many GPCRs remain orphaned (i.e. ligand specificity unknown) or poorly characterized with little structural information available, so an automated and reliable method is badly needed to facilitate the identification of novel receptors. In this study, a method of fast Fourier transform-based support vector machine has been developed for predicting GPCR subfamilies according to protein's hydrophobicity. In classifying Class B, C, D and F subfamilies, the method achieved an overall Matthew's correlation coefficient and accuracy of 0.95 and 93.3%, respectively, when evaluated using the jackknife test. The method achieved an accuracy of 100% on the Class B independent dataset. The results show that this method can classify GPCR subfamilies as well as their functional classification with high accuracy. A web server implementing the prediction is available at http://chem.scu.edu.cn/blast/Pred-GPCR.

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Fu, Zhe, Linjie Zhang, Sijin Hang, Shiyi Wang, Na Li, Xiaojing Sun, Zian Wang, et al. "Synthesis of Coumarin Derivatives: A New Class of Coumarin-Based G Protein-Coupled Receptor Activators and Inhibitors." Polymers 14, no. 10 (May 15, 2022): 2021. http://dx.doi.org/10.3390/polym14102021.

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To expand the range of daphnetin-based inhibitors/activators used for targeting G protein-coupled receptors (GPCRs) in disease treatment, twenty-five coumarin derivatives 1–25, including 7,8-dihydroxycoumarin and 7-hydroxycoumarin derivatives with various substitution patterns/groups at C3-/4- positions, were synthesized via mild Pechmann condensation and hydroxyl modification. The structures were characterized by 1H NMR, 13C NMR and ESI-MS. Their inhibition or activation activities relative to GPCRs were evaluated by double-antibody sandwich ELISA (DAS–ELISA) in vitro. The results showed that most of the coumarin derivatives possessed a moderate GPCR activation or inhibitory potency. Among them, derivatives 14, 17, 18, and 21 showed a remarkable GPCR activation potency, with EC50 values of 0.03, 0.03, 0.03, and 0.02 nM, respectively. Meanwhile, derivatives 4, 7, and 23 had significant GPCR inhibitory potencies against GPCRs with IC50 values of 0.15, 0.02, and 0.76 nM, respectively. Notably, the acylation of hydroxyl groups at the C-7 and C-8 positions of 7,8-dihydroxycoumarin skeleton or the etherification of the hydroxyl group at the C-7 position of the 7-hydroxycoumarin skeleton could successfully change GPCRs activators into inhibitors. This work demonstrated a simple and efficient approach to developing coumarin derivatives as remarkable GPCRs activators and inhibitors via molecular diversity-based synthesis.

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Wright, Shane C., Maria Consuelo Alonso Cañizal, Tobias Benkel, Katharina Simon, Christian Le Gouill, Pierre Matricon, Yoon Namkung та ін. "FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs". Science Signaling 11, № 559 (4 грудня 2018): eaar5536. http://dx.doi.org/10.1126/scisignal.aar5536.

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Frizzleds (FZDs) are a group of seven transmembrane–spanning (7TM) receptors that belong to class F of the G protein–coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD5) is one of the most studied class F GPCRs that promote the functional inactivation of the β-catenin destruction complex in response to WNTs. However, whether FZDs function as prototypical GPCRs has been heavily debated and, in particular, FZD5 has not been shown to activate heterotrimeric G proteins. Here, we show that FZD5 exhibited a conformational change after the addition of WNT-5A, which is reminiscent of class A and class B GPCR activation. In addition, we performed several live-cell imaging and spectrometric-based approaches, such as dual-color fluorescence recovery after photobleaching (dcFRAP) and resonance energy transfer (RET)–based assays that demonstrated that FZD5 activated Gαq and its downstream effectors upon stimulation with WNT-5A. Together, these findings suggest that FZD5 is a 7TM receptor with a bona fide GPCR activation profile and suggest novel targets for drug discovery in WNT-FZD signaling.

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Більше джерел

Дисертації з теми "Class A GPCR"

Zhang, Boyang. "Functional and Structural Insights into the First and Second Intracellular Domains for D1-Class Dopaminergic Receptors." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35932.

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Previous studies have shown that the subtype-specific pharmacological properties of D1-class receptors (D1R and D5R) can be attributed to their third intracellular domain and C-terminal tail. However, the importance of their first and second intracellular domains (IC1 and IC2) has yet to be explored. Using mutagenesis and bioinformatics, we examine the functional and structural roles of Ser/Thr spanning IC1 and IC2—most of which are conserved not only among D1-class receptors but also among other GPCRs. Mutant receptors of human D1-class receptors (hD1R and hD5R) were constructed whereby all Ser and Thr were mutated to the respective Ala and Val in the IC1 region (termed ST1 mutant receptors) and in the IC2 region (termed ST2 mutant receptors). We found that hD1-ST2 and hD5-ST2 exhibited contrasting properties of agonist affinity, constitutive activity, and dopamine potency. On the other hand, both ST2 mutants underwent internalization as wild-type but displayed weakened desensitization abilities. Homology models, which have been refined under membrane simulations, illustrate that the conserved Ser3.55 and Thr3.65 utilize their side chains to anchor the loop regions of IC2 to cytoplasmic helices. We also found multiple functional alterations in the hD1-ST1 and hD5-ST2, but in a subtype-similar manner. Mutating the conserved Thr2.39 recapitulated the ablated basal activity and drastic decrease in dopamine potency previously witnessed in the hD1-ST1. Based on the recurring theme observed in crystal structures, the side-chain of Thr2.39 may help to position IC2 to have proper contacts with the G protein. Mutating the conserved Ser2.45 was found to be solely responsible for the elevated Emax (maximal response) of the hD1-ST1. Using single point mutagenesis, we further found that breaking the potential molecular interactions of Ser2.45 in hD1R (i.e. with Asn3.42 and Trp4.50) mimicked its elevated Emax. This elevated Emax was not found to be caused by altered abilities to undergo agonist-induced desensitization or internalization relative to hD1R. Overall, our work highlights the important functional and structural roles of IC1 and IC2 that needs to be accounted for in our current canonical models of GPCR signalling. Given the conserved nature of these Ser/Thr, our work may also be pertinent towards understanding the roles of IC1 and IC2 for other GPCRs.

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Ellaithy, Amr. "Metabotropic Glutamate Receptor 2 Activation: Computational Predictions and Experimental Validation." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5319.

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G protein-coupled receptors (GPCRs) are the largest family of signaling proteins in animals and represent the largest family of druggable targets in the human genome. Therefore, it is of no surprise that the molecular mechanisms of GPCR activation and signal transduction have attracted close attention for the past few decades. Several stabilizing interactions within the GPCR transmembrane (TM) domain helices regulate receptor activation. An example is a salt bridge between 2 highly conserved amino acids at the bottom of TM3 and TM6 that has been characterized for a large number of GPCRs. Through structural modeling and molecular dynamics (MD) simulations, we predicted several electrostatic interactions to be involved in metabotropic glutamate receptor 2 (mGlu2R) activation. To experimentally test these predictions, we employed a charge reversal mutagenesis approach to disrupt predicted receptor electrostatic intramolecular interactions as well as intermolecular interactions between the receptor and G proteins. Using two electrode voltage clamp in Xenopus laevis oocytes expressing mutant receptors and G-proteins, we revealed novel electrostatic interactions, mostly located around intracellular loops 2 and 3 of mGlu2R, that are critical for both receptor and G-protein activation. These studies contribute to elucidating the molecular determinants of mGluRs activation and conformational coupling to G-proteins, and can likely be extended to include other classes of GPCRs.

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Song, Bo [Verfasser], Hauke [Akademischer Betreuer] Lilie, Harald [Akademischer Betreuer] Kolmar, and Marcus [Akademischer Betreuer] Fändrich. "Affilin binding proteins selected against a class B GPCR ectodomain / Bo Song. Betreuer: Hauke Lilie ; Harald Kolmar ; Marcus Fändrich." Halle, Saale : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2012. http://d-nb.info/1025302435/34.

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Hajj, Mariana. "Le récepteur orphelin GPR158 : fonction et partenaires protéiques." Thesis, Montpellier 1, 2012. http://www.theses.fr/2012MON1T009.

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Les récepteurs couplés aux protéines G (RCPG) constituent l'une des plus grandes familles de gènes du génome des mammifères. Ils sont impliqués dans la plupart des processus physiologiques et physiopathologiques ce qui en a fait des cibles thérapeutiques de choix. GPR158 est un récepteur orphelin, dont on ne connaît pas de ligand, de la classe C des RCPG. Il partage 20% d'identité de séquence entre son domaine transmembranaire (TM) et celui du récepteur GABAB mais son domaine N-terminal est dépourvu du domaine Venus Flytrap (VFT), le domaine de liaison du ligand caractéristique des RCPG de la classe C, ce qui suggère que cette protéine a développé un autre mode de liaison de son ligand endogène (s'il existe). GPR158 est exprimé majoritairement au niveau du cerveau. De manière intéressante, son expression a été aussi décrite, dans des cribles à plus ou moins grande échelle, comme étant associée ou modifiée dans différentes conditions pathologiques dont 50% sont des maladies cancéreuses.À ce jour, on ne connait ni la fonction physiologique, ni les voies de signalisation de GPR158. Dans un premier temps, notre objectif était de comprendre la fonctionnalité de GPR158 en cherchant une activité constitutive de ce récepteur ou en essayant de générer des mutants, des récepteurs tronqués ou des récepteurs chimériques constitutivement actifs. Jusqu'à présent, nous n'avons pas réussi à avoir un récepteur actif, malgré les résidus des boucles intracellulaires et des domaines TM importants pour le couplage aux protéines G et pour l'activation des autres RCPG, qui sont conservés dans GPR158. Ce qui suggère que ce récepteur pourrait ne pas avoir une signalisation en lui même, et il régulerait ainsi l'activité d'autres RCPG. Dans le cas inverse, GPR158 aurait un mode de signalisation très original qui reste à découvrir. Puis nous avons cherché à comprendre le rôle physiologique lié aux trois motifs VCPWE, que nous avons identifiés au niveau du domaine C-terminal (C-ter), très long, de ce récepteur. Ces motifs sont bien conservés chez les différentes espèces et joueraient ainsi des rôles fonctionnels importants. À ce sujet, nous avons montré que le troisième motif s'associe spécifiquement avec la sous-unité Gαo, probablement activée, des protéines G. Et nous avons également identifié, un site d'interaction d'un régulateur de l'activité des protéines G, RGS7, au niveau du domaine C-ter de GPR158, en amont des motifs. Vu que Gαo est le substrat de RGS7, nous suggérons que Gαo lierait en même temps le domaine RGS de la protéine RGS7, et ils formeraient ainsi avec GPR158 un complexe de régulation de l'activité du récepteur orphelin ainsi que d'autres RCPG présents dans le nano-environnement de GPR158. Enfin, afin de mieux comprendre la fonction et les possibles voies de signalisation de GPR158, une analyse protéomique des complexes multi-protéiques bâtis autour du domaine C-ter de GPR158, a été menée. Après purification du récepteur orphelin et des protéines associées par immunoprécipitation, l'identification par spectrométrie de masse des protéines présentes a permis d'identifier 6 nouveaux partenaires potentiels. Parmi eux, quatre protéines, p53, PPM1G, Sgt1 et SIRT1, sont des régulateurs du facteur de transcription suppresseur de tumeur p53, et deux protéines, SIRT1 et TRIM58, sont impliquées dans le processus de vieillissement cellulaire. Par conséquent, une implication dans la transcription, la régulation du cycle cellulaire, la réparation de l'ADN, la prolifération, l'apoptose, la tumorigenèse et le vieillissement, du récepteur orphelin GPR158 peut être envisagée
G protein-coupled receptors (GPCR) are known to form the largest family of cell communication proteins, and to participate to all functions of the body, making them high potential therapeutic targets. However, lots of these proteins are still orphan receptors, for which no ligand, neither function have been described, although some could be of very high interest, like GPR158, a class C orphan GPCR. The seven transmembrane domain (7TM) of this orphan receptor was related to class C GPCR (GPR158 and GABAB share 20% sequence identity in the TM core region) but its N-terminal domain was not homologous to the typical Venus Flytrap (VFT) known to bind the ligands in most of class C receptors. Which suggests that GPR158 has developed different ligand binding mode. GPR158 is expressed mainly in the brain. Interestingly, the expression of this receptor has been found in many cells and tissues to be potentially regulated in pathological conditions, of which 50% are cancerous diseases. We thus intended to decipher its cellular function and partners, to understand its potential physiological and physiopathological roles. Initially, our goal was to determine the functionality of GPR158, and the possible signaling and cellular mechanisms it was involved in, by looking for some constitutive activity for this orphan GPCR, in the absensce of any ligand. Curiously, we could not detect any G protein coupling, like constitutive G protein stimulation by overexpression of wild type, mutated, truncated and chimeric receptors. This despite the residues of intracellular loops and TM domain, important for the G protein coupling and for the activation of other GPCR, which are conserved in GPR158. This suggests that GPR158 in itself might not have a signalization, and thus it would regulate the activity of other GPCR. Alternatively, GPR158 would have an original way of signaling to be discovered with more sophisticated techniques.Then, we tried to understand the role of three VCPWE specific motifs that we have identified at the long C-terminal (C-ter) domain of GPR158. These motifs are well conserved among different species and thus would play important functional roles. Therefore, we have shown that the third motif indeed binds G protein alpha o subunit, likely in active state. Interestingly, we have also shown that RGS7 that deactivated alpha o, interacts constitutively with the C-terminal domain of GPR158 upstream of VCPWE motifs. Thus, RGS7 would regulate the alpha subunit association with GPR158. Hence, GPR158 would act as a signaling regulatory platform, controlling G protein pathways by binding active alpha subunit and RGS7. This would be of great importance as a local signaling regulatory mechanism. Finally, to better understand the function and possible signaling pathways of GPR158, a proteomic analysis of multi-protein complexes built around the C-ter domain of GPR158, was conducted. After purification of the orphan receptor and its associated proteins by immunoprecipitation, the identification by mass spectrometry of GPR158 interacting proteins led to the identification of six potential new partners. Among them, four proteins, p53, PPM1G, SGT1 and SIRT1, are regulators of the p53 tumor suppressor protein widely known for its role as a transcription factor that regulates the expression of stress response genes, and two proteins, SIRT1 and TRIM58 are involved in cellular aging process. Therefore, GPR158 could be involved in transcription, cell cycle regulation, DNA repair, proliferation, apoptosis, tumorigenesis and cell aging

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Mohamedgamil, Sana Siddig Abdelrahman [Verfasser], and Davide [Gutachter] Calebiro. "Organization and dynamics of class C GPCR nanodomains in neurons visualized by single-molecule microscopy / Sana Siddig Abdelrahman Mohamedgamil ; Gutachter: Davide Calebiro." Würzburg : Universität Würzburg, 2020. http://d-nb.info/1207760897/34.

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Charrette, Andrew. "The Role of the Central Region of the Third Intracellular Loop of D1-Class Receptors in Signalling." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23080.

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The D1-class receptors (D1R, D5R) each possess distinct signaling characteristics; however, pharmacological selectivity between them remains elusive. The third intracellular loops (IL3) of D1R and D5R harbour divergent residues that may contribute to their individual signalling phenotypes. Here we probe the function of central region of IL3 of D1R and D5R using deletion mutagenesis. Radioligand binding and whole cell cAMP assays suggest that the N-terminal and C-terminal moieties of the central IL3 oppositely contribute to the constitutive and agonist-dependant activity of D1-Class receptors. Whereas the N-terminal deletions ablated constitutive activity and decreased DA-induced activation, C-terminal deletions induced robust increases. These data, interpreted in concert with structural predictions generated from homology modeling implicate the central IL3 as playing an important role in the activation and subtype-specific characteristics of the D1-class receptors. This study may serve as a basis for the development of novel drugs targeting the central IL3 region.

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Chéron, Jean-Baptiste. "Modélisation moléculaire de la perception de la saveur sucrée : approches structurales et dynamiques." Thesis, Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4066/document.

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La consommation excessive et chronique de sucre est un facteur de risque pour l'apparition de pathologies telles que le diabète de type II ou l'obésité. Une des solutions pour répondre à cet enjeu majeur de santé publique, tout en conservant le plaisir de la saveur sucrée, consiste en l'utilisation d'édulcorants en substitution du sucre. Actuellement, un certain nombre d'édulcorants sur le marché présentent arrière-goût amer ou sont sujets à débat quant à leurs effets sur la santé. Un des objectifs de ces travaux de thèse consiste à proposer de nouveaux édulcorants grâce à des approches rationnelles in silico. Un modèle statistique a été établi sur la base des structures chimiques et a permis d'identifier de nouveaux édulcorants d'origine naturelle. Ensuite, la reconstruction par homologie du récepteur à la saveur sucrée et l'étude des sites de liaison apportent des indices, à l'échelle atomique, qui permettront d'identifier ou même de concevoir de nouveaux édulcorants. L'étude dynamique d'un récepteur de la même famille (Récepteur Couplé aux Protéines G (RCPG) de classe C) a permis d'émettre une hypothèse sur le mécanisme d'activation, phénomène important pour la compréhension de la conversion du signal chimique en signal électrique
Sugar overconsumption is a risk factor for pathologies such as type II diabetes or obesity. Sweeteners consumption is used to overcome this public health issue. Indeed, they have low caloric value but still preserve the pleasure of sweet taste. Currently, number of sweeteners are commercially available, but they present a bitter aftertaste or there is a debate about their safety. One aim of this work was to propose new intense sweeteners using computational modeling strategies. Through a statistical approach to predict the sweetness based on the chemical structure of already known sweeteners, new natural compounds have been identified. Furthermore, the structural study of the homology model of the sweet taste receptor provides some clues to design new sweeteners. The molecular dynamic study of a class C G-protein coupled receptor gives the first molecular hypothesis of the activation process

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Albaker, Awatif. "Mutational Analysis to Define the Functional Role of the Third Intracellular Loop of D1-Class Dopaminergic Receptors." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/35063.

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The third intracellular loop (IL3) and cytoplasmic tail (CT), which are the most divergent regions between human D1-class dopaminergic receptors (hD1R and hD5R), have been implicated in modulating their subtype-specific functional phenotypes. The importance of the IL3 for Guanine nucleotide-binding protein (G-protein) coupling and specificity has long been acknowledged in the G-protein-coupled receptor (GPCR) field. However, the exact role the central region of the IL3, notably the N- and C-terminal moieties, plays in GPCR receptor functionality remains unclear. Studies in our laboratory indicated that the IL3/N-terminal moiety of hD1-class receptors appears to be critical for facilitating agonist-independent and dependent activation of hD1R and hD5R. Furthermore, the IL3/C-terminal portion of hD1-class receptors constrains the receptor in the inactive state and reduces receptor affinity for agonists and G-protein coupling. I put forward the following hypothesis: 1. The functional properties of hD1-class receptors are regulated via a molecular micro-switch present within the IL3 central region modulating the functional properties of the receptor distinctly, 2. The functional differences between D1R and D5R require structural elements from both N- and C-terminal halves of the IL3 central region, and 3. The molecular interplay between the N- and C-terminal halves of the IL3 central region is dependent on the amino acid chain length and content. Herein, I have employed site-directed mutagenesis, and alanine replacement approaches to analyze comprehensively the structural determinants within the N- and C-terminal moieties of the IL3 central region that regulate ligand binding and G-protein coupling properties of hD1-class receptors. Moreover, my Ph.D. research aimed to pinpoint whether the IL3 length and/or structural motif(s) regulate ligand binding and activation properties of hD1R and hD5R. The results of my study highlight the importance of structural elements from both the proximal and distal segments of the IL3/central region of hD1-class receptors for the ligand binding and receptor activation status. Additionally, my results underline the significance of preserving the length of the IL3 regardless of the amino acid content. This study also shows the pivotal role played by a phenylalanine residue, F2646.27, in the signaling properties of hD1R. Notably, mutating F2646.27 leads to a mutant hD1R with characteristics resembling those of constitutively active mutant GPCRs. Unraveling the amino acid/amino acids constraining the receptor in the inactive state will perhaps provide an attractive target for drug design. Future work aims at developing drugs that particularly bind to the intracellular face of hD1R and improving selectivity towards hD1R may prove useful in limiting the side effects associated with the conventional therapy of brain disorders such as in the case of L-DOPA induced dyskinesia (LID) seen in individuals suffering from Parkinson’s disease.

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Seier, Kerstin [Verfasser], and Davide [Gutachter] Calebiro. "Investigation of dynamic processes of prototypical class A GPCRs by single-molecule microscopy / Kerstin Seier ; Gutachter: Davide Calebiro." Würzburg : Universität Würzburg, 2020. http://d-nb.info/1205259058/34.

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Shofstall, Lisa. "Class III / short line system inventory to determine 286,000 lb (129,844 kg) railcar operational status in Kansas and determination of ballast fouling using ground penetrating radar." Thesis, Kansas State University, 2017. http://hdl.handle.net/2097/35477.

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Master of Science
Department of Civil Engineering
Eric J. Fitzsimmons
The rail industry's recent shift towards larger and heavier railcars has influenced Class III / short line railroad operation and track maintenance costs. Class III railroads earn less than $38.1 million in in annual revenue and generally operate first and last leg shipping for their customers. In Kansas, Class III railroads operate approximately 40 percent of the roughly 2,800 miles (4,500 km) of rail; however, due to the current Class III track condition they move lighter railcars at lower speeds than Class I railroads. The State of Kansas statutorily allots $5 million to support rail improvement projects, primarily for Class III railroads. Therefore, the objective of this study was to conduct an inventory of Kansas’s Class III rail network to identify the track segments in need of this support that would be most beneficial to the rail system. Representatives of each railroad were contacted and received a survey requesting information regarding the operational and structural status of their systems. The data collected were organized and processed to determine the sections of track that can accommodate the heavier axle load cars that are currently being utilized by Class I railroads. This study identified that Class III railroads shipped over 155,000 carloads of freight in 2016 and 30 percent of Kansas’s Class III track can currently accommodate heavy axle cars. The increased load from the increased railcar size has also increased the risk of damage to railroad’s track structure. Railroad ballast is the free draining granular material that supports the track structure. As the track ages, small particles can fill the voids of the granular material which is a process known as fouling. Established methods for determining the fouling of a section of ballast are destructive tests that usually require the railroad to restrict or reroute traffic on its network. Ground Penetrating Radar (GPR) is a nondestructive geophysical surveying method that measures the time required for electromagnetic wave impulses to reflect off differing subsurface interfaces. Historically, GPR surveys of track structures primarily determine the depth of ballast and track geometry. The objective of this study was to determine the viability of utilizing the laboratory’s existing GPR equipment to develop a methodology of measuring ballast fouling nondestructively. A 48 x 48 x 48 in (1.2 x 1.2 x 1.2 m) test box was built. The test box was filled with 48 in (1.2 m) of clean and ballast. Tests were run on dry and partially saturated material, wetted using 6 gallons (22.7 L). GPR data were collected hourly for the first 6 hours, then at the multiples of 12 and 24 hour marks for one week. Sand was chosen as an absorbent geologic material for the second stage of testing since no fouled ballast could be acquired at the time of the study. A 27 x18 x 18 in (0.69 x 0.46 x 0.046 m) box was filled with sand and wetted with water in one gallon (7.5 L) increments. GPR scans and samples to determine the water content were collected after the addition of each gallon. The data collected were processed to determine soil properties. Preliminary results from this research indicate that the GPR set up utilized can effectively determine the dielectric constant of geologic materials including ballast, although the dielectric constant is highly dependent on the volumetric moisture content of the material.

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Частини книг з теми "Class A GPCR"

Grinde, Ellinor, and Katharine Herrick-Davis. "Class A GPCR: Serotonin Receptors." In G-Protein-Coupled Receptor Dimers, 129–72. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-60174-8_6.

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Gingell, Joseph J., Christopher S. Walker, and Debbie L. Hay. "Class B GPCR: Receptors and RAMPs." In G-Protein-Coupled Receptor Dimers, 289–305. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-60174-8_11.

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Fan, Qing R., William Y. Guo, Yong Geng, and Marisa G. Evelyn. "Class C GPCR: Obligatory Heterodimerization of GABAB Receptor." In G-Protein-Coupled Receptor Dimers, 307–25. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-60174-8_12.

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König, Caroline, René Alquézar, Alfredo Vellido, and Jesús Giraldo. "Topological Sequence Segments Discriminate Between Class C GPCR Subtypes." In Advances in Intelligent Systems and Computing, 164–72. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-60816-7_20.

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Harikumar, Kaleeckal G., and Laurence J. Miller. "Secretin Receptor Dimerization. Prototypic of Class B GPCR Behavior." In G-Protein-Coupled Receptor Dimers, 273–87. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-60174-8_10.

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Hanyaloglu, Aylin C., F. Fanelli, and K. C. Jonas. "Class A GPCR: Di/Oligomerization of Glycoprotein Hormone Receptors." In G-Protein-Coupled Receptor Dimers, 207–31. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-60174-8_8.

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Cárdenas, Martha I., Alfredo Vellido, and Jesús Giraldo. "Visual Exploratory Assessment of Class C GPCR Extracellular Domains Discrimination Capabilities." In Advances in Intelligent Systems and Computing, 31–39. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-40126-3_4.

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König, Caroline, René Alquézar, Alfredo Vellido, and Jesús Giraldo. "Finding Class C GPCR Subtype-Discriminating N-grams through Feature Selection." In Advances in Intelligent Systems and Computing, 89–96. Cham: Springer International Publishing, 2014. http://dx.doi.org/10.1007/978-3-319-07581-5_11.

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Jastrzebska, Beata. "Class A GPCR: Light Sensing G Protein-Coupled Receptor – Focus on Rhodopsin Dimer." In G-Protein-Coupled Receptor Dimers, 79–97. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-60174-8_4.

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Hlaváčková, Veronika, Laurent Prézeau, Jean-Philippe Pin, and Jaroslav Blahos. "Class C GPCRs: Metabotropic Glutamate Receptors." In G-Protein-Coupled Receptor Dimers, 327–56. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-60174-8_13.

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Тези доповідей конференцій з теми "Class A GPCR"

Brooks, Charles L. "De novo modeling of GPCR class A structures." In Distributed Processing (IPDPS). IEEE, 2009. http://dx.doi.org/10.1109/ipdps.2009.5160868.

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Ahmed, M. A., S. A. Wicher, C. M. Bartman, B. S. Patel, C. M. Pabelick, and Y. S. Prakash. "Class C GPCR Effects on Airway Smooth Muscle Mitochondria." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a5600.

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Roos, B., J. J. Teske, S. Varadharajan, S. A. Wicher, R. D. Britt, C. M. Pabelick, S. Venkatachalem, and Y. S. Prakash. "Class C Orphan GPCR GPRC5A in Human Airway Smooth Muscle." In American Thoracic Society 2021 International Conference, May 14-19, 2021 - San Diego, CA. American Thoracic Society, 2021. http://dx.doi.org/10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a4504.

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Cardenas, Martha-Ivon, Alfredo Vellido, and Jesus Giraldo. "Visual interpretation of class C GPCR subtype overlapping from the nonlinear mapping of transformed primary sequences." In 2014 IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI). IEEE, 2014. http://dx.doi.org/10.1109/bhi.2014.6864476.

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Scherr, Maximilian, and Shigeru Chiba. "Almost first-class language embedding: taming staged embedded DSLs." In GPCE'15: Generative Programming: Concepts and Experiences. New York, NY, USA: ACM, 2015. http://dx.doi.org/10.1145/2814204.2814217.

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Zarembski, Allan M., Joseph W. Palese, and Mike Nguyen. "Forecasting Track Geometry Degradation Using GPR Based Ballast Condition." In 2022 Joint Rail Conference. American Society of Mechanical Engineers, 2022. http://dx.doi.org/10.1115/jrc2022-79586.

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Abstract The ability to predict track geometry degradation is of critical importance in planning of track maintenance operations. This paper presents results of an FRA sponsored study on the relationship between track geometry degradation and ballast condition as measured by Ground Penetrating Radar (GPR). The study examined six different sites on a major Class 1 freight Railroad, with a range of ballast conditions and tie types, and developed a relationship between the rate of degradation of key track geometry parameters, profile (surface), and cross-level, as a function of two GPR measured ballast parameters: Ballast Fouling Index and Fouling Depth Layer (depth of clean ballast layer). The study sites included both fouled and clean ballast conditions that were monitored for track geometry on a very frequent basis (every two to four weeks) and also experienced multiple GPR measurements during that same period. Data analytic techniques were applied to this large data set to develop a relationship between rate of geometry degradation and ballast fouling condition and depth of ballast. The results showed a statistically significant relationship between high rates of geometry degradation and poor subsurface conditions as defined by the GPR parameters. A predictive model was developed to project and forecast geometry degradation as a function of ballast conditions.

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Patel, B. S., J. J. Teske, B. Roos, C. M. Pabelick, and Y. S. Prakash. "Role of Class C GPCRs in Airway Smooth Muscle Cells." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a1257.

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He, Ziming, and Wenxing Zhou. "Machine Learning Tools to Predict the Burst Capacity of Pipelines Containing Dent-Gouges." In 2022 14th International Pipeline Conference. American Society of Mechanical Engineers, 2022. http://dx.doi.org/10.1115/ipc2022-87176.

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Abstract Dent-gouges as a result of the mechanical damage have serious implications for the burst capacity of oil and gas pipelines. The burst capacity of pipelines containing dent-gouges is lower than that of the same plain dented pipelines without gouges and that of the same gouged pipelines without dents. The well-known burst capacity prediction model adopted by the European Pipeline Research Group, i.e. the EPRG model, results in predictions of the burst capacity with high variability. In this study, a machine learning tool is employed to improve the predictive accuracy of the EPRG model for pipelines containing dent-gouges. To this end, a relatively large number of full-scale burst tests of pipe specimens containing dent-gouges are collected from the literature. The Gaussian process regression (GPR) technique, which is a class of non-parametric Bayesian model widely used in the machine learning, is employed to improve the EPRG model based on the collected full-scale burst test data. The full-scale burst tests are used to evaluate the hyper-parameters involved in the GPR analysis and validate the predictive accuracy of the improved EPRG model after the application of GPR. To facilitate the practical application of the improved EPRG model, a computer program with a graphic user interface (GUI) is further developed to compute the burst capacity of pipelines containing dent-gouges by inputting key parameters such as the pipe geometry and material properties as well as sizes of the dent and gouge through a GUI. This research will improve the fitness-for-service assessment of pipelines containing dent-gouges.

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Hou, Feifei, Wentai Lei, Shuai Li, and Jingchun Xi. "Underground multi-class objects identification using hybrid task cascade from GPR bridge data." In 18th International Conference on Ground Penetrating Radar, Golden, Colorado, 14–19 June 2020. Society of Exploration Geophysicists, 2020. http://dx.doi.org/10.1190/gpr2020-039.1.

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Wang, Yiqing, and Peiwei Sun. "Fault Diagnosis Based on KPCA and RUSboost for Nuclear Power Plants." In 2022 29th International Conference on Nuclear Engineering. American Society of Mechanical Engineers, 2022. http://dx.doi.org/10.1115/icone29-92163.

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Abstract Nonlinear relationships among different process variables are very common in nuclear reactors. When constructing a nonlinear model to for process monitoring, linear-based monitoring technique has been proved inefficient and problematic. Kernel principle component analysis (KPCA) combines the principle component analysis and kernel method to cope with fault diagnose in nonlinear system. Experiments are conducted using data samples from Generic Pressurized Water Reactor Simulator(GPWR) to simulate sensor fault and three types system faults. The nonlinear relationship among monitoring variables is analyzed. KPCA is used to capture the nonlinear relationships to distinguish the sensor fault and system fault, which shows the superiority of KPCA to detect a univariate fault. Subsequently, system faults are further analyzed as a classification problem. Samples imbalance is another common problem existing in diagnose domains. When training samples of one class outnumber than other class, traditional classification algorithm performance may deteriorate. Random under-sampling boosting (RUSboost), a hybrid sampling and boosting algorithm is used to alleviate the imbalance problem. The performances of classifiers by four metrics is evaluated. When compared to Adaboost (contains only boosting), tree variants (base model and ensemble bagged trees) and Gaussian SVM, RUS boosting shows significantly high accuracy and robust performance in dealing with different ratio of training samples, which shows that RUSboost is an excellent technique to cope with imbalanced data in fault diagnose for nuclear power plants.

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Звіти організацій з теми "Class A GPCR"

Rafaeli, Ada, and Russell Jurenka. Molecular Characterization of PBAN G-protein Coupled Receptors in Moth Pest Species: Design of Antagonists. United States Department of Agriculture, December 2012. http://dx.doi.org/10.32747/2012.7593390.bard.

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The proposed research was directed at determining the activation/binding domains and gene regulation of the PBAN-R’s thereby providing information for the design and screening of potential PBAN-R-blockers and to indicate possible ways of preventing the process from proceeding to its completion. Our specific aims included: (1) The identification of the PBAN-R binding domain by a combination of: (a) in silico modeling studies for identifying specific amino-acid side chains that are likely to be involved in binding PBAN with the receptor and; (b) bioassays to verify the modeling studies using mutant receptors, cell lines and pheromone glands (at tissue and organism levels) against selected, designed compounds to confirm if compounds are agonists or antagonists. (2) The elucidation ofthemolecular regulationmechanisms of PBAN-R by:(a) age-dependence of gene expression; (b) the effect of hormones and; (c) PBAN-R characterization in male hair-pencil complexes. Background to the topic Insects have several closely related G protein-coupled receptors (GPCRs) belonging to the pyrokinin/PBAN family, one with the ligand pheromone biosynthesis activating neuropeptide or pyrokinin-2 and another with diapause hormone or pyrokinin-1 as a ligand. We were unable to identify the diapause hormone receptor from Helicoverpa zea despite considerable effort. A third, related receptor is activated by a product of the capa gene, periviscerokinins. The pyrokinin/PBAN family of GPCRs and their ligands has been identified in various insects, such as Drosophila, several moth species, mosquitoes, Triboliumcastaneum, Apis mellifera, Nasoniavitripennis, and Acyrthosiphon pisum. Physiological functions of pyrokinin peptides include muscle contraction, whereas PBAN regulates pheromone production in moths plus other functions indicating the pleiotropic nature of these ligands. Based on the alignment of annotated genomic sequences, the primary and secondary structures of the pyrokinin/PBAN family of receptors have similarity with the corresponding structures of the capa or periviscerokinin receptors of insects and the neuromedin U receptors found in vertebrates. Major conclusions, solutions, achievements Evolutionary trace analysisof receptor extracellular domains exhibited several class-specific amino acid residues, which could indicate putative domains for activation of these receptors by ligand recognition and binding. Through site-directed point mutations, the 3rd extracellular domain of PBAN-R was shown to be critical for ligand selection. We identified three receptors that belong to the PBAN family of GPCRs and a partial sequence for the periviscerokinin receptor from the European corn borer, Ostrinianubilalis. Functional expression studies confirmed that only the C-variant of the PBAN-R is active. We identified a non-peptide agonist that will activate the PBAN-receptor from H. zea. We determined that there is transcriptional control of the PBAN-R in two moth species during the development of the pupa to adult, and we demonstrated that this transcriptional regulation is independent of juvenile hormone biosynthesis. This transcriptional control also occurs in male hair-pencil gland complexes of both moth species indicating a regulatory role for PBAN in males. Ultimate confirmation for PBAN's function in the male tissue was revealed through knockdown of the PBAN-R using RNAi-mediated gene-silencing. Implications, both scientific and agricultural The identification of a non-peptide agonist can be exploited in the future for the design of additional compounds that will activate the receptor and to elucidate the binding properties of this receptor. The increase in expression levels of the PBAN-R transcript was delineated to occur at a critical period of 5 hours post-eclosion and its regulation can now be studied. The mysterious role of PBAN in the males was elucidated by using a combination of physiological, biochemical and molecular genetics techniques.

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Rafaeli, Ada, Russell Jurenka, and Chris Sander. Molecular characterisation of PBAN-receptors: a basis for the development and screening of antagonists against Pheromone biosynthesis in moth pest species. United States Department of Agriculture, January 2008. http://dx.doi.org/10.32747/2008.7695862.bard.

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The original objectives of the approved proposal included: (a) The determination of species- and tissue-specificity of the PBAN-R; (b) the elucidation of the role of juvenile hormone in gene regulation of the PBAN-R; (c) the identificationof the ligand binding domains in the PBAN-R and (d) the development of efficient screening assays in order to screen potential antagonists that will block the PBAN-R. Background to the topic: Moths constitute one of the major groups of pest insects in agriculture and their reproductive behavior is dependent on chemical communication. Sex-pheromone blends are utilised by a variety of moth species to attract conspecific mates. In most of the moth species sex-pheromone biosynthesis is under circadian control by the neurohormone, PBAN (pheromone-biosynthesis-activating neuropeptide). In order to devise ideal strategies for mating disruption/prevention, we proposed to study the interactions between PBAN and its membrane-bound receptor in order to devise potential antagonists. Major conclusions: Within the framework of the planned objectives we have confirmed the similarities between the two Helicoverpa species: armigera and zea. Receptor sequences of the two Helicoverpa spp. are 98% identical with most changes taking place in the C-terminal. Our findings indicate that PBAN or PBAN-like receptors are also present in the neural tissues and may represent a neurotransmitter-like function for PBAN-like peptides. Surprisingly the gene encoding the PBAN-receptor was also present in the male homologous tissue, but it is absent at the protein level. The presence of the receptor (at the gene- and protein-levels), and the subsequent pheromonotropic activity are age-dependent and up-regulated by Juvenile Hormone in pharate females but down-regulated by Juvenile Hormone in adult females. Lower levels of pheromonotropic activity were observed when challenged with pyrokinin-like peptides than with HezPBAN as ligand. A model of the 3D structure of the receptor was created using the X-ray structure of rhodopsin as a template after sequence alignment of the HezPBAN-R with several other GPCRs and computer simulated docking with the model predicted putative binding sites. Using in silico mutagenesis the predicted docking model was validated with experimental data obtained from expressed chimera receptors in Sf9 cells created by exchanging between the three extracellular loops of the HezPBAN-R and the Drosophila Pyrokinin-R (CG9918). The chimera receptors also indicated that the 3ʳᵈ extracellular loop is important for recognition of PBAN or Diapause hormone ligands. Implications: The project has successfully completed all the objectives and we are now in a position to be able to design and screen potential antagonists for pheromone production. The successful docking simulation-experiments encourage the use of in silico experiments for initial (high-throughput) screening of potential antagonists. However, the differential responses between the expressed receptor (Sf9 cells) and the endogenous receptor (pheromone glands) emphasize the importance of assaying lead compounds using several alternative bioassays (at the cellular, tissue and organism levels). The surprising discovery of the presence of the gene encoding the PBAN-R in the male homologous tissue, but its absence at the protein level, launches opportunities for studying molecular regulation pathways and the evolution of these GPCRs. Overall this research will advance research towards the goal of finding antagonists for this important class of receptors that might encompass a variety of essential insect functions.

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