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Cognative bias

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https://www.readbyqxmd.com/read/28977683/phosphoinositide-diversity-distribution-and-effector-function-stepping-out-of-the-box
#1
REVIEW
Christopher H Choy, Bong-Kwan Han, Roberto J Botelho
Phosphoinositides (PtdInsPs) modulate a plethora of functions including signal transduction and membrane trafficking. PtdInsPs are thought to consist of seven interconvertible species that localize to a specific organelle, to which they recruit a set of cognate effector proteins. Here, in reviewing the literature, we argue that this model needs revision. First, PtdInsPs can carry a variety of acyl chains, greatly boosting their molecular diversity. Second, PtdInsPs are more promiscuous in their localization than is usually acknowledged...
October 4, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28887659/ligand-biased-ensemble-receptor-docking-ligbend-a-hybrid-ligand-receptor-structure-based-approach
#2
Polo C-H Lam, Ruben Abagyan, Maxim Totrov
Ligand docking to flexible protein molecules can be efficiently carried out through ensemble docking to multiple protein conformations, either from experimental X-ray structures or from in silico simulations. The success of ensemble docking often requires the careful selection of complementary protein conformations, through docking and scoring of known co-crystallized ligands. False positives, in which a ligand in a wrong pose achieves a better docking score than that of native pose, arise as additional protein conformations are added...
September 8, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28842645/population-mechanics-a-mathematical-framework-to-study-t-cell-homeostasis
#3
Clemente F Arias, Miguel A Herrero, Francisco J Acosta, Cristina Fernandez-Arias
Unlike other cell types, T cells do not form spatially arranged tissues, but move independently throughout the body. Accordingly, the number of T cells in the organism does not depend on physical constraints imposed by the shape or size of specific organs. Instead, it is determined by competition for interleukins. From the perspective of classical population dynamics, competition for resources seems to be at odds with the observed high clone diversity, leading to the so-called diversity paradox. In this work we make use of population mechanics, a non-standard theoretical approach to T cell homeostasis that accounts for clone diversity as arising from competition for interleukins...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28819267/decoding-disease-causing-mechanisms-of-missense-mutations-from-supramolecular-structures
#4
Atsushi Hijikata, Toshiyuki Tsuji, Masafumi Shionyu, Tsuyoshi Shirai
The inheritance modes of pathogenic missense mutations are known to be highly associated with protein structures; recessive mutations are mainly observed in the buried region of protein structures, whereas dominant mutations are significantly enriched in the interfaces of molecular interactions. However, the differences in phenotypic impacts among various dominant mutations observed in individuals are not fully understood. In the present study, the functional effects of pathogenic missense mutations on three-dimensional macromolecular complex structures were explored in terms of dominant mutation types, namely, haploinsufficiency, dominant-negative, or toxic gain-of-function...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28696674/lasso-peptide-benenodin-1-is-a-thermally-actuated-1-rotaxane-switch
#5
Chuhan Zong, Michelle J Wu, Jason Z Qin, A James Link
Mechanically interlocked molecules that change their conformation in response to stimuli have been developed by synthetic chemists as building blocks for molecular machines. Here we describe a natural product, the lasso peptide benenodin-1, which exhibits conformational switching between two distinct threaded conformers upon actuation by heat. We have determined the structures of both conformers and have characterized the kinetics and energetics of the conformational switch. Single amino acid substitutions to benenodin-1 generate peptides that are biased to a single conformer, showing that the switching behavior is potentially an evolvable trait in these peptides...
August 2, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28679952/severe-asthma-in-humans-and-mouse-model-suggests-a-cxcl10-signature-underlies-corticosteroid-resistant-th1-bias
#6
Marc Gauthier, Krishnendu Chakraborty, Timothy B Oriss, Mahesh Raundhal, Sudipta Das, Jie Chen, Rachael Huff, Ayan Sinha, Merritt Fajt, Prabir Ray, Sally E Wenzel, Anuradha Ray
We previously showed that Th1/type 1 inflammation marked by increased IFN-γ levels in the airways can be appreciated in 50% of patients with severe asthma, despite high dose corticosteroid (CS) treatment. We hypothesized that a downstream target of IFN-γ, CXCL10, which recruits Th1 cells via the cognate receptor CXCR3, is an important contributor to Th1high asthma and CS unresponsiveness. We show high levels of CXCL10 mRNA closely associated with IFNG levels in the BAL cells of 50% of severe asthmatics and also in the airways of mice subjected to a severe asthma model, both in the context of high-dose CS treatment...
July 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28455789/functional-and-structural-consequences-of-chemokine-c-x-c-motif-receptor-4-activation-with-cognate-and-non-cognate-agonists
#7
Jonathan M Eby, Hazem Abdelkarim, Lauren J Albee, Abhishek Tripathi, Xianlong Gao, Brian F Volkman, Vadim Gaponenko, Matthias Majetschak
Chemokine (C-X-C motif) receptor 4 (CXCR4) regulates cell trafficking and plays important roles in the immune system. Ubiquitin has recently been identified as an endogenous non-cognate agonist of CXCR4, which activates CXCR4 via interaction sites that are distinct from those of the cognate agonist C-X-C motif chemokine ligand 12 (CXCL12). As compared with CXCL12, chemotactic activities of ubiquitin in primary human cells are poorly characterized. Furthermore, evidence for functional selectivity of CXCR4 agonists is lacking, and structural consequences of ubiquitin binding to CXCR4 are unknown...
April 28, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28449947/barcoding-of-gpcr-trafficking-and-signaling-through-the-various-trafficking-roadmaps-by-compartmentalized-signaling-networks
#8
REVIEW
Suleiman W Bahouth, Mohammed M Nooh
Proper signaling by G protein coupled receptors (GPCR) is dependent on the specific repertoire of transducing, enzymatic and regulatory kinases and phosphatases that shape its signaling output. Activation and signaling of the GPCR through its cognate G protein is impacted by G protein-coupled receptor kinase (GRK)-imprinted "barcodes" that recruit β-arrestins to regulate subsequent desensitization, biased signaling and endocytosis of the GPCR. The outcome of agonist-internalized GPCR in endosomes is also regulated by sequence motifs or "barcodes" within the GPCR that mediate its recycling to the plasma membrane or retention and eventual degradation as well as its subsequent signaling in endosomes...
August 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28413950/a-critical-review-of-validation-blind-testing-and-real-world-use-of-alchemical-protein-ligand-binding-free-energy-calculations
#9
REVIEW
Robert Abel, Lingle Wang, David L Mobley, Richard A Friesner
Protein-ligand binding is among the most fundamental phenomena underlying all molecular biology, and a greater ability to more accurately and robustly predict the binding free energy of a small molecule ligand for its cognate protein is expected to have vast consequences for improving the efficiency of pharmaceutical drug discovery. We briefly reviewed a number of scientific and technical advances that have enabled alchemical free energy calculations to recently emerge as a preferred approach, and critically considered proper validation and effective use of these techniques...
2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28363772/characterization-of-signal-bias-at-the-glp-1-receptor-induced-by-backbone-modification-of-glp-1
#10
Marlies V Hager, Lachlan Clydesdale, Samuel H Gellman, Patrick M Sexton, Denise Wootten
The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that is a major therapeutic target for the treatment of type 2 diabetes. Activation of this receptor promotes insulin secretion and blood glucose regulation. The GLP-1R can initiate signaling through several intracellular pathways upon activation by GLP-1. GLP-1R ligands that preferentially stimulate subsets among the natural signaling pathways ("biased agonists") could be useful as tools for elucidating the consequences of specific pathways and might engender therapeutic agents with tailored effects...
July 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28273509/the-factor-of-10-in-forensic-dna-match-probabilities
#11
Simone Gittelson, Tamyra R Moretti, Anthony J Onorato, Bruce Budowle, Bruce S Weir, John Buckleton
An update was performed of the classic experiments that led to the view that profile probability assignments are usually within a factor of 10 of each other. The data used in this study consist of 15 Identifiler loci collected from a wide range of forensic populations. Following Budowle et al. [1], the terms cognate and non-cognate are used. The cognate database is the database from which the profiles are simulated. The profile probability assignment was usually larger in the cognate database. In 44%-65% of the cases, the profile probability for 15 loci in the non-cognate database was within a factor of 10 of the profile probability in the cognate database...
May 2017: Forensic Science International. Genetics
https://www.readbyqxmd.com/read/27834374/trna-mediated-codon-biased-translation-in-mycobacterial-hypoxic-persistence
#12
Yok Hian Chionh, Megan McBee, I Ramesh Babu, Fabian Hia, Wenwei Lin, Wei Zhao, Jianshu Cao, Agnieszka Dziergowska, Andrzej Malkiewicz, Thomas J Begley, Sylvie Alonso, Peter C Dedon
Microbial pathogens adapt to the stress of infection by regulating transcription, translation and protein modification. We report that changes in gene expression in hypoxia-induced non-replicating persistence in mycobacteria-which models tuberculous granulomas-are partly determined by a mechanism of tRNA reprogramming and codon-biased translation. Mycobacterium bovis BCG responded to each stage of hypoxia and aerobic resuscitation by uniquely reprogramming 40 modified ribonucleosides in tRNA, which correlate with selective translation of mRNAs from families of codon-biased persistence genes...
November 11, 2016: Nature Communications
https://www.readbyqxmd.com/read/27702906/ataluren-stimulates-ribosomal-selection-of-near-cognate-trnas-to-promote-nonsense-suppression
#13
Bijoyita Roy, Westley J Friesen, Yuki Tomizawa, John D Leszyk, Jin Zhuo, Briana Johnson, Jumana Dakka, Christopher R Trotta, Xiaojiao Xue, Venkateshwar Mutyam, Kim M Keeling, James A Mobley, Steven M Rowe, David M Bedwell, Ellen M Welch, Allan Jacobson
A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense suppression and has been thought to mediate the insertion of near-cognate tRNAs at PTCs. However, direct evidence for this activity has been lacking. Here, we expressed multiple nonsense mutation reporters in human cells and yeast and identified the amino acids inserted when a PTC occupies the ribosomal A site in control, ataluren-treated, and aminoglycoside-treated cells...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27661128/b-lymphocytes-as-direct-antigen-presenting-cells-for-anti-tumor-dna-vaccines
#14
Viswa Teja Colluru, Douglas G McNeel
In spite of remarkable preclinical efficacy, DNA vaccination has demonstrated low immunogenicity in humans. While efforts have focused on increasing cross-presentation of DNA-encoded antigens, efforts to increase DNA vaccine immunogenicity by targeting direct presentation have remained mostly unexplored. In these studies, we compared the ability of different APCs to present antigen to T cells after simple co-culture with plasmid DNA. We found that human primary peripheral B lymphocytes, and not monocytes or in vitro derived dendritic cells (DCs), were able to efficiently encode antigen mRNA and expand cognate tumor antigen-specific CD8 T cells ex vivo...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27636113/human-dp-and-ep2-prostanoid-receptors-take-on-distinct-forms-depending-on-the-diverse-binding-of-different-ligands
#15
Akiko Suganami, Hiromichi Fujino, Iori Okura, Naoki Yanagisawa, Hajime Sugiyama, John W Regan, Yutaka Tamura, Toshihiko Murayama
Human D-type prostanoid (DP) and E-type prostanoid 2 (EP2) receptors are G protein-coupled receptors and are regarded as the most closely related receptors among prostanoid receptors because they are generated by tandem duplication. The DP receptor-cognate ligand, prostaglandin D2 (PGD2 ) has the ability to activate not only DP receptors but also EP2 receptors. Likewise, the EP2 receptor-cognate ligand, prostaglandin E2 (PGE2 ) has the ability to activate DP receptors in addition to EP receptors in order to stimulate cAMP formation...
November 2016: FEBS Journal
https://www.readbyqxmd.com/read/27630114/glucagon-like-peptide-1-and-its-class-b-g-protein-coupled-receptors-a-long-march-to-therapeutic-successes
#16
REVIEW
Chris de Graaf, Dan Donnelly, Denise Wootten, Jesper Lau, Patrick M Sexton, Laurence J Miller, Jung-Mo Ahn, Jiayu Liao, Madeleine M Fletcher, Dehua Yang, Alastair J H Brown, Caihong Zhou, Jiejie Deng, Ming-Wei Wang
The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity...
October 2016: Pharmacological Reviews
https://www.readbyqxmd.com/read/27600870/biased-%C3%AE-opioid-receptor-agonists-diversely-regulate-lateral-mobility-and-functional-coupling-of-the-receptor-to-its-cognate-g-proteins
#17
COMPARATIVE STUDY
Barbora Melkes, Lucie Hejnova, Jiri Novotny
There are some indications that biased μ-opioid ligands may diversely affect μ-opioid receptor (MOR) properties. Here, we used confocal fluorescence recovery after photobleaching (FRAP) to study the regulation by different MOR agonists of receptor movement within the plasma membrane of HEK293 cells stably expressing a functional yellow fluorescent protein (YFP)-tagged μ-opioid receptor (MOR-YFP). We found that the lateral mobility of MOR-YFP was increased by (D-Ala(2),N-MePhe(4),Gly(5)-ol)-enkephalin (DAMGO) and to a lesser extent also by morphine but decreased by endomorphin-2...
December 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27422784/use-of-crispr-cas9-engineered-ins-1-pancreatic-%C3%AE-cells-to-define-the-pharmacology-of-dual-gipr-glp-1r-agonists
#18
Jacqueline Naylor, Arthur T Suckow, Asha Seth, David J Baker, Isabelle Sermadiras, Peter Ravn, Rob Howes, Jianliang Li, Mike R Snaith, Matthew P Coghlan, David C Hornigold
Dual-agonist molecules combining glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) activity represent an exciting therapeutic strategy for diabetes treatment. Although challenging due to shared downstream signalling pathways, determining the relative activity of dual agonists at each receptor is essential when developing potential novel therapeutics. The challenge is exacerbated in physiologically relevant cell systems expressing both receptors. To this end, either GIP receptors (GIPR) or GLP-1 receptors (GLP-1R) were ablated via RNA-guided clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 endonucleases in the INS-1 pancreatic β-cell line...
September 15, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27378730/ube2d2-is-not-involved-in-murf1-dependent-muscle-wasting-during-hindlimb-suspension
#19
Cécile Polge, Nathalie Koulmann, Agnès Claustre, Marianne Jarzaguet, Bernard Serrurier, Lydie Combaret, Daniel Béchet, Xavier Bigard, Didier Attaix, Daniel Taillandier
The Ubiquitin Proteasome System (UPS) is mainly responsible for the increased protein breakdown observed in muscle wasting. The E3 ligase MuRF1 is so far the only enzyme known to direct the main contractile proteins for degradation (i.e. troponin I, myosin heavy chains and actin). However, MuRF1 does not possess any catalytic activity and thus depends on the presence of a dedicated E2 for catalyzing the covalent binding of polyubiquitin (polyUb) chains on the substrates. The E2 enzymes belonging to the UBE2D family are commonly used for in vitro ubiquitination assays but no experimental data suggesting their physiological role as bona fide MuRF1-interacting E2 enzymes are available...
October 2016: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27354349/the-yin-and-yang-of-codon-usage
#20
Anton A Komar
The genetic code is degenerate. With the exception of two amino acids (Met and Trp), all other amino acid residues are each encoded by multiple, so-called synonymous codons. Synonymous codons were initially presumed to have entirely equivalent functions, however, the finding that synonymous codons are not present at equal frequencies in genes/genomes suggested that codon choice might have functional implications beyond amino acid coding. The pattern of non-uniform codon use (known as codon usage bias) varies between organisms and represents a unique feature of an organism...
June 27, 2016: Human Molecular Genetics
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