bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular response to small molecules that selectively stall protein synthesis by the ribosome
Authors: Liaud Nadège , Horlbeck Max A. , Gilbert Luke A. , Gjoni Ketrin , Weissman Jonathan S. , Cate Jamie H. D. 
Published: November 2018

ABSTRACTIdentifying small molecules that inhibit protein synthesis by selectively stalling the ribosome constitutes a new strategy for therapeutic development. Compounds that inhibit the translation of PCSK9, a major regulator of low-density lipoprotein cholesterol, have been identified that reduce LDL cholesterol in preclinical models and that affect the translation of only a few off-target proteins. Although some of these compounds hold potential for future therapeutic development, it is not known how they impact the physiology of cells or ribosome quality control pathways. Here we used a genome-wide CRISPRi screen to identify proteins and pathways that modulate cell growth in the presence of high doses of a selective PCSK9 translational inhibitor, PF-06378503 (PF8503). The two most potent genetic modifiers of cell fitness in the presence of PF8503, the ubiquitin binding protein ASCC2 and helicase ASCC3, bind to the ribosome and protect cells from toxic effects of high concentrations of the compound. Surprisingly, translation quality control proteins Pelota (PELO) and HBS1L sensitize cells to PF8503 treatment. In genetic interaction experiments, ASCC3 acts together with ASCC2, and functions downstream of HBS1L. Taken together, these results identify new connections between ribosome quality control pathways, and provide new insights into the selectivity of compounds that stall human translation that will aid the development of next-generation selective translation stalling compounds to treat disease.
Locating ligand binding sites in G-protein coupled receptors using combined information from docking and sequence conservation
Authors: Vidad Ashley R. , Macaspac Stephen , Ng Ho-Leung 
Published: November 2018

AbstractG-protein coupled receptors (GPCRs) are the largest protein family of drug targets. Detailed mechanisms of binding are unknown for many important GPCR-ligand pairs due to the difficulties of GPCR recombinant expression, biochemistry, and crystallography. We describe our new method, ConDock, for predicting ligand binding sites in GPCRs using combined information from surface conservation and docking starting from crystal structures or homology models. We demonstrate the effectiveness of ConDock on well-characterized GPCRs such as the β2 adrenergic and A2A adenosine receptors. We also demonstrate that ConDock successfully predicts ligand binding sites from high-quality homology models. Finally, we apply ConDock to predict ligand binding sites on a structurally uncharacterized GPCR, GPER. GPER is the G-protein coupled estrogen receptor, with four known ligands: estradiol, G1, G15, and tamoxifen. ConDock predicts that all four ligands bind to the same location on GPER, centered on L119, H307, and N310; this site is deeper in the receptor cleft than predicted by previous studies. We compare the sites predicted by ConDock and traditional methods that utilize information from surface geometry, surface conservation, and ligand chemical interactions. Incorporating sequence conservation information in ConDock overcomes errors introduced from physics-based scoring functions and homology modeling.
A thermodynamic chemical reaction network drove autocatalytic prebiotic peptides formation
Authors: Bao Peng , He Yu-Qin , Li Guo-Xiang , Zhang Hui-En , Xiao Ke-Qing 
Published: November 2018

SUMMARYThe chemical reaction networks (CRNs), which led to the transition on early Earth from geochemistry to biochemistry remain unknown. We show that under mild hydrothermal circumstances, a thermodynamic chemical reaction network including sulfite/sulfate coupled with anaerobic ammonium oxidation (Sammox), might have driven prebiotic peptides synthesis. Peptides comprise 14 proteinogenic amino acids, endowed Sammox-driven CRNs with autocatalysis. The peptides exhibit both forward and reverse catalysis, with the opposite catalytic impact in sulfite- and sulfate-fueled Sammox-driven CRNs, respectively, at both a variable temperature range and a fixed temperature, resulting in seesaw-like catalytic properties. The ratio of sulfite to sulfate switches the catalytic orientation of peptides, resulting in Sammox-driven CRNs that has both anabolic and catabolic reactions at all times. Furthermore, peptides produced from sulfite-fueled Sammox-driven CRNs could catalyze both sulfite-fueled Sammox and Anammox (nitrite reduction coupled with anaerobic ammonium oxidation) reactions. We propose that Sammox-driven CRNs were critical in the creation of life and that Anammox microorganisms that have both Sammox functions are direct descendants of Sammox-driven CRNs.
The Brain-Derived Neurotrophic Factor Val66Met Genotype Does Not Influence the Grey or White Matter Structures Underlying Recognition Memory
Authors: McKay Nicole S. , Moreau David. , Henare Dion T. , Kirk Ian J. 
Published: November 2018

AbstractA single nucleotide polymorphism (SNP) in the gene coding for brain-derived neurotrophic factor (BDNF) has previously been associated with a reduction in recognition memory performance. While previous findings have highlighted that this SNP contributes to recognition memory, little is known about its influence on subprocesses of recognition, familiarity and recollection. Previous research has reported reduced hippocampal volume and decreased fractional anisotropy in carriers of the Met allele across a range of white matter tracts, including those networks that may support recognition memory. Here, in a sample of 61 healthy young adults, we used a source memory task to measure accuracy on each recognition subprocess, in order to determine whether the Val66Met SNP (rs6265) influences these equally. Additionally, we compared grey matter volume between these groups for structures that underpin familiarity and recollection separately. Finally, we used probabilistic tractography to reconstruct tracts that subserve each of these two recognition systems. Behaviourally, we found group differences on the familiarity measure, but not on recollection. However, we did not find any group difference on grey- or white-matter structures. Together, these results suggest a functional influence of the Val66Met SNP that is independent of coarse structural changes, and nuance previous research highlighting the relationship between BDNF, brain structure, and behaviour.
Destin: toolkit for single-cell analysis of chromatin accessibility
Authors: Urrutia Eugene , Chen Li , Zhou Haibo , Jiang Yuchao 
Published: November 2018

AbstractSummarySingle-cell assay of transposase-accessible chromatin followed by sequencing (scATAC-seq) is an emerging new technology for the study of gene regulation with single-cell resolution. The data from scATAC-seq are unique sparse, binary, and highly variable even within the same cell type. As such, neither methods developed for bulk ATAC-seq nor single-cell RNA-seq data are appropriate. Here, we present Destin, a bioinformatic and statistical framework for comprehensive scATAC-seq data analysis. Destin performs cell-type clustering via weighted principle component analysis, weighting accessible chromatin regions by existing genomic annotations and publicly available regulomic data sets. The weights and additional tuning parameters are determined via model-based likelihood. We evaluated the performance of Destin using downsampled bulk ATAC-seq data of purified samples and scATAC-seq data from seven diverse experiments. Compared to existing methods, Destin was shown to outperform across all data sets and platforms. For demonstration, we further applied Destin to 2,088 adult mouse forebrain cells and identified cell type-specific association of previously reported schizophrenia GWAS loci.AvailabilityDestin toolkit is freely available as an R package at https://github.com/urrutiag/destin.Contactyuchaoj@email.unc.edu.
On the adaptive behavior of head-fixed flies navigating in two-dimensional, visual virtual reality
Authors: Haberkern Hannah , Basnak Melanie A. , Ahanonu Biafra , Schauder David , Cohen Jeremy D. , Bolstad Mark , Bruns Christopher , Jayaraman Vivek 
Published: November 2018

AbstractA navigating animal’s sensory experience is shaped not just by its surroundings, but by its movements within them, which in turn are influenced by its past experiences. Studying the intertwined roles of sensation, experience and directed action in navigation has been made easier by the development of virtual reality (VR) environments for head-fixed animals, which allow for quantitative measurements of behavior in well-controlled sensory conditions. VR has long featured in studies ofDrosophila melanogaster, but these experiments have typically relied on one-dimensional (1D) VR, effectively allowing the fly to change only its heading in a visual scene, and not its position. Here we explore how flies navigate in a two-dimensional (2D) visual VR environment that more closely resembles their experience during free behavior. We show that flies’ interaction with landmarks in 2D environments cannot be automatically derived from their behavior in simpler 1D environments. Using a novel paradigm, we then demonstrate that flies in 2D VR adapt their behavior in a visual environment in response to optogenetically delivered appetitive and aversive stimuli. Much like free-walking flies after encounters with food, head-fixed flies respond to optogenetic activation of sugar-sensing neurons by initiating a local search behavior. Finally, by pairing optogenetic activation of heat-sensing cells to the flies’ presence near visual landmarks of specific shapes, we elicit selective learned avoidance of landmarks associated with aversive “virtual heat”. These head-fixed paradigms set the stage for an interrogation of fly brain circuitry underlying flexible navigation in complex visual environments.
Stable and Reversible Functionalization of the Native Phosphate Groups on Live Cells
Authors: Majumder Joydeb , Chopra Gaurav 
Published: November 2018

AbstractSurface modification of live cells has important biomedical and therapeutic applications. Current methods to label cells require artificial cell surface engineering (via metabolic, docking or anchoring methods) before conjugative chemistries, which is not always trivial to accomplish and/or not appropriate for multiple cell types. A new method without the need of initial cell surface anchoring will greatly facilitate live cell surface labelling. Herein, we provide a general strategy for live cell functionalization that utilizes the native phosphate groups on every cell. We have designed a dual conjugation cargo molecule with a cationic side chain for non-covalent bonds with the negatively-charged cell surface and a phosphoric acid containing ligand for covalent bonding with the cell membrane phospholipid phosphate. Our dual conjugation strategy on live cell surfaces is non-toxic with enhanced stability to functionalize live cells. This provides a stable, reversible and reusable reagent with direct conjugation strategy to image live cell membranes.SignificanceThe ability to label live cell surfaces has many applications ranging fromin vivomonitoring of cell populations to diagnostics and use of cells as drugs. Thus far, most reported strategies to label cell surfaces are not broadly applicable or easy to use for any cell type as it has relied on engineering cells with artificial moieties or conjugations that may affect cellular function. We provide a general solution to this long-standing problem by developing two-sided functionalization of the phosphate moieties that are ubiquitous on all cells. We show one application of our chemical strategy as a general-purpose live-cell membrane imaging reagent with long-time stability. Our strategy is broadly applicable to imaging, sensing, drug delivery, bioengineering, diagnostics and cell therapy.
tartanunderlies the evolution of maleDrosophilagenital morphology
Authors: Hagen Joanna F. D. , Mendes Cláudia C. , Blogg Amber , Payne Alex , Tanaka Kentaro M. , Gaspar Pedro , Jimenez Javier Figueras , Kittelmann Maike , McGregor Alistair P. , Nunes Maria Daniela S. 
Published: November 2018

AbstractMale genital structures are among the most rapidly evolving morphological traits and are often the only features that can distinguish closely related species. This process is thought to be driven by sexual selection and may reinforce species separation. However, while the genetic basis of many phenotypic differences have been identified, we still lack knowledge about the genes underlying evolutionary differences in male genital organs and organ size more generally. The claspers (surstyli) are periphallic structures that play an important role in copulation in insects. Here we show that natural variation in clasper size and bristle number betweenDrosophila mauritianaandD. simulansis caused by evolutionary changes intartan (trn), which encodes a transmembrane leucine-rich repeat domain protein that mediates cell-cell interactions and affinity differences. There are no fixed amino acid differences intrnbetweenD. mauritianaandD. simulansbut differences in the expression of this gene in developing genitalia suggest cis-regulatory changes intrnunderlie the evolution of clasper morphology in these species. Finally, analysis of reciprocal hemizyotes that are genetically identical, except for which species the functional allele oftrnis from, determined that thetrnallele ofD. mauritianaspecifies larger claspers with more bristles than the allele ofD. simulans. Therefore we have identified the first gene underlying evolutionary change in the size of a male genital organ, which will help to better understand the rapid diversification of these structures and the regulation and evolution of organ size more broadly.Significance StatementThe morphology of male genital organs evolves rapidly driven by sexual selection. However, little is known about the genes underlying genitalia differences between species. Identifying these genes is key to understanding how sexual selection acts on development to produce rapid phenotypic change. We have found that the genetartanunderlies differences between maleDrosophila mauritianaandD. simulansin the size and bristle number of the claspers - genital projections that grasp the female during copulation. Moreover, sincetartanencodes a protein that is involved in cell affinity, this may represent a new developmental mechanism for morphological change. Therefore, our study provides new insights into genetic and developmental bases for the rapid evolution of male genitalia and organ size more generally.
Spectroscopic study on binding of cationic Pheophorbide-ato antiparallel quadruplex Tel22
Authors: Ryazanova Olga , Zozulya Victor , Voloshin Igor , Glamazda Alexander , Dubey Igor , Dubey Larysa , Karachevtsev Victor 
Published: November 2018

AbstractBinding of water-soluble cationic Pheophorbide-aderivative (CatPheo-a) to Na+–stabilized antiparallel quadruplex formed by 22-mer oligonucleotide d[AG3(T2AG3)3], a fragment of human telomeric DNA (Tel22, PDB ID: 143D), has been examined using experimental techniques of absorption and polarized fluorescent spectroscopy as well as absorption melting. The binding affinity of CatPheo-ato Tel22 was studied in titration experiments registering the dependence of the dye fluorescence intensity and polarization degree on molar phosphate-to-dye ratio (P/D). CatPheo-awas found to bind effectively to the quadruplex, and two competitive binding modes were detected. The first one predominates at the dye excess and results in the fluorescence quenching, whereas the second one is preferential at the biopolymer excess and results in the enhancement of pheophorbide emission. The effect of CatPheo-aon thermodynamic parameters of Tel22 quadruplex unfolding was estimated using a two-state model. It was found that CatPheo-adestabilizes the quadruplex structure of Tel22 slightly decreasing its 4→1 transition midpoint temperature, gives destabilizing increment into Gibbs standard free energy and 2-fold decrease in the equilibrium quadruplex folding constant at 37°C. In ethanol CatPheo-aexhibits 15% higher efficiency of singlet oxygen generation as compared to the parent Pheo-acompound that makes it a promising photosensitizer for photodynamic therapy.
A sequence-based approach for identifying protein fold switchers
Authors: Mishra Soumya , Looger Loren L. , Porter Lauren L. 
Published: November 2018

AbstractAlthough most proteins conform to the classical one-structure/one-function paradigm, an increasing number of proteins with dual structures and functions are emerging. These fold-switching proteins remodel their secondary structures in response to cellular stimuli, fostering multi-functionality and tight cellular control. Accurate predictions of fold-switching proteins could both suggest underlying mechanisms for uncharacterized biological processes and reveal potential drug targets. Previously, we developed a prediction method for fold-switching proteins based on secondary structure predictions and structure-based thermodynamic calculations. Given the large number of genomic sequences without homologous experimentally characterized structures, however, we sought to predict fold-switching proteins from their sequences alone. To do this, we leveraged state-of-the-art secondary structure predictions, which require only amino acid sequences but are not currently designed to identify structural duality in proteins. Thus, we hypothesized that incorrect and inconsistent secondary structure predictions could be good initial predictors of fold-switching proteins. We found that secondary structure predictions of fold-switching proteins with solved structures are indeed less accurate than secondary structure predictions of non-fold-switching proteins with solved structures. These inaccuracies result largely from the conformations of fold-switching proteins that are underrepresented in the Protein Data Bank (PDB), and, consequently, the training sets of secondary structure predictors. Given that secondary structure predictions are homology-based, we hypothesized that decontextualizing the inaccurately-predicted regions of fold-switching proteins could weaken the homology relationships between these regions and their overpopulated structural representatives. Thus, we reran secondary structure predictions on these regions in isolation and found that they were significantly more inconsistent than in regions of non-fold-switching proteins. Thus, inconsistent secondary structure predictions can serve as a preliminary marker of fold switching. These findings have implications for genomics and the future development of secondary structure predictors.
Iron deficiency affects early stages of embryonic hematopoiesis but not the endothelial to hematopoietic transition
Authors: Shvartsman Maya , Bilican Saygin , Lancrin Christophe 
Published: November 2018

AbstractIron is an essential micronutrient for hematopoiesis and previous research suggested that iron deficiency in the pregnant female could cause anemia in the offspring. Since the development of all embryonic and adult blood cells begins in the embryo, we aimed to resolve the role of iron in embryonic hematopoiesis. For this purpose, we used an experimental system of mouse embryonic stem cells differentiation into embryonic hematopoietic progenitors. We modulated the iron status in cultures by adding either an iron chelator DFO for iron deficiency, or ferric ammonium citrate for iron excess, and followed the emergence of developing hematopoietic progenitors by flow cytometry. We found interestingly that iron deficiency by DFO did not block the endothelial to hematopoietic transition, the first step of hematopoiesis. However, it had a differential effect on the proliferation, survival and clonogenic capacity of hematopoietic progenitors. Surprisingly, iron deficiency affected erythro-myeloid Kitpos CD41+ progenitors significantly more than the primitive erythroid Kitneg CD41+. The Kitpos progenitors paradoxically died more, proliferated less and had more reduction in colony formation than Kitneg after 24 hours of DFO treatment. Kitpos progenitors expressed less transferrin-receptor on the cell surface and had less labile iron compared to Kitneg, which could reduce their capacity to compete for scarce iron and survive iron deficiency. We suggest that iron deficiency could disturb hematopoiesis already at an early embryonic stage by compromising survival, proliferation and differentiation of definitive hematopoietic progenitors.
Characterization of cefotaxime resistant Escherichia coli isolated from broiler farms in Ecuador
Authors: Vinueza-Burgos Christian , Ortega-Paredes David , Narváez Cristian , Zutter Lieven De , Zurita Jeannete 
Published: November 2018

AbstractAntimicrobial resistance (AR) is a worldwide concern. Up to a 160% increase in antibiotic usage in food animals is expected in Latin American countries. The poultry industry is an increasingly important segment of food production and contributor to AR. The objective of this study was to evaluate the prevalence, AR patterns and the characterization of relevant resistance genes in Extended Spectrum β-lactamases (ESBL) and AmpC E. coli from large poultry farms in Ecuador. Sampling was performed from June 2013 to July 2014 in 6 slaughterhouses that slaughter broilers from 115 farms totaling 384 flocks. Each sample of collected caeca was streaked onto TBX agar supplemented with cefotaxime (3 mg/l). In total, 176 isolates were analyzed for antimicrobial resistance patterns by the disk diffusion method and for blaCTX-M, blaTEM, blaCMY, blaSHV, blaKPC, and mcr-1 by PCR and sequencing. ESBL and AmpC E. coli were found in 362 flocks (94.3%) from 112 farms (97.4%). We found that 98.3% of the isolates were multi-resistant to antibiotics. Low resistance was observed for ertapenem and nitrofurantoin. The most prevalent ESBL genes were the blaCTX-M (90.9%) blaCTX-M-65, blaCTX-M-55 and blaCTX-M-3 alleles. Most of the AmpC strains presented the blaCMY-2 gene. Three isolates showed the mcr-1 gene. Poultry production systems represent a hotspot for antimicrobial resistance in Ecuador, possibly mediated by the extensive use of antibiotics. Monitoring this sector in national and regional plans of antimicrobial resistance surveillance should therefore be considered.