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Cognative bias

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https://www.readbyqxmd.com/read/29751745/randomized-dna-libraries-construction-tool-a-new-3-bp-frequent-cutter-tthhb27i-sinefungin-endonuclease-with-chemically-induced-specificity
#1
Daria Krefft, Aliaksei Papkov, Maciej Prusinowski, Agnieszka Zylicz-Stachula, Piotr M Skowron
BACKGROUND: Acoustic or hydrodynamic shearing, sonication and enzymatic digestion are used to fragment DNA. However, these methods have several disadvantages, such as DNA damage, difficulties in fragmentation control, irreproducibility and under-representation of some DNA segments. The DNA fragmentation tool would be a gentle enzymatic method, offering cleavage frequency high enough to eliminate DNA fragments distribution bias and allow for easy control of partial digests. Only three such frequently cleaving natural restriction endonucleases (REases) were discovered: CviJI, SetI and FaiI...
May 11, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29626658/immunization-with-the-outer-membrane-proteins-ompk17-and-ompk36-elicits-protection-against-klebsiella-pneumoniae-in-the-murine-infection-model
#2
Kawther E Hussein, Mohammed Bahey-El-Din, Salah A Sheweita
Klebsiella pneumoniae is a Gram-negative bacterium that is increasingly reported as a serious nosocomial and community-acquired pathogen. In the current study, two K. pneumoniae antigens, OmpK17 and OmpK36, as well as their fusion protein cognate F36/17 were investigated as potential vaccine candidates in a murine infection model. Three immunoadjuvants, namely the Gram-positive Enhancer Matrix (GEM) adjuvant, synthetic hemozoin (Hz) adjuvant and incomplete Freund's adjuvant (IFA) were evaluated. Genes of OmpK17 and OmpK36 antigens as well as their fusion protein were cloned in Escherichia coli for recombinant expression...
April 4, 2018: Microbial Pathogenesis
https://www.readbyqxmd.com/read/29621569/alignment-based-and-alignment-free-methods-converge-with-experimental-data-on-amino-acids-coded-by-stop-codons-at-split-between-nuclear-and-mitochondrial-genetic-codes
#3
Hervé Seligmann
Genetic codes mainly evolve by reassigning punctuation codons, starts and stops. Previous analyses assuming that undefined amino acids translate stops showed greater divergence between nuclear and mitochondrial genetic codes. Here, three independent methods converge on which amino acids translated stops at split between nuclear and mitochondrial genetic codes: (a) alignment-free genetic code comparisons inserting different amino acids at stops; (b) alignment-based blast analyses of hypothetical peptides translated from non-coding mitochondrial sequences, inserting different amino acids at stops; (c) biases in amino acid insertions at stops in proteomic data...
April 2, 2018: Bio Systems
https://www.readbyqxmd.com/read/29523687/mini-g-protein-probes-for-active-g-protein-coupled-receptors-gpcrs-in-live-cells
#4
Qingwen Wan, Najeah Okashah, Asuka Inoue, Rony Nehmé, Byron Carpenter, Christopher G Tate, Nevin A Lambert
G protein-coupled receptors (GPCRs) are key signaling proteins that regulate nearly every aspect of cell function. Studies of GPCRs have benefited greatly from the development of molecular tools to monitor receptor activation and downstream signaling. Here, we show that mini G proteins are robust probes that can be used in a variety of assay formats to report GPCR activity in living cells. Mini G (mG) proteins are engineered GTPase domains of Gα subunits that were developed for structural studies of active-state GPCRs...
May 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29477072/family-wide-analysis-of-aminoacyl-sulfamoyl-3-deazaadenosine-analogues-as-inhibitors-of-aminoacyl-trna-synthetases
#5
Baole Zhang, Steff De Graef, Manesh Nautiyal, Luping Pang, Bharat Gadakh, Matheus Froeyen, Lieve Van Mellaert, Sergei V Strelkov, Stephen D Weeks, Arthur Van Aerschot
Aminoacyl-tRNA synthetases (aaRSs) are enzymes that precisely attach an amino acid to its cognate tRNA. This process, which is essential for protein translation, is considered a viable target for the development of novel antimicrobial agents, provided species selective inhibitors can be identified. Aminoacyl-sulfamoyl adenosines (aaSAs) are potent orthologue specific aaRS inhibitors that demonstrate nanomolar affinities in vitro but have limited uptake. Following up on our previous work on substitution of the base moiety, we evaluated the effect of the N3 -position of the adenine by synthesizing the corresponding 3-deazaadenosine analogues (aaS3DAs)...
March 25, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28977683/phosphoinositide-diversity-distribution-and-effector-function-stepping-out-of-the-box
#6
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...
December 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
#7
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...
January 2018: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28842645/population-mechanics-a-mathematical-framework-to-study-t-cell-homeostasis
#8
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
#9
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
#10
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
#11
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
#12
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...
October 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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