bluuebunny/crossref_metadata_2025_split huggingface dataset:
DFT Modelling of the Electronic Structure and Stabilities of (Sb2O5.nH2O) Clusters towards Cysteine, Glucose and Trypanothione Complexation
Authors: Rabaa Hassan , Garfov Andriy , Sundholm Dage 
Published: June 2020

AbstractA large series of dipeptides containing sulfur groups and antimony SbVwere modeled to understand their inhibitor activity against Leishmaniasis. The trypanothione reductase (TR), which acts as a reducing agent in several vital processes, is responsible for maintaining the parasite’s cellular thiol redox balance. The antimonic SbVacid (Sb2O5·nH2O) is being evaluated as a drug with inhibitory activity against Leishmaniasis. In the present work, we investigated the inhibitory effect of antimony oxide on (TR) activity modeled as a substrate by probing two model clusters in gas phase and continuum water medium:A[(Sb2O10H8)]−2coordinated to cysteine, andB[Sb7O28H21] coordinated to trypanothione, including glucose adduct. We report here density functional theory (DFT and DFT-D3) using (B3LYP/LANL2DZ and (TPSS/def2TZVP) results on the binding energy of cysteine and trypanthione complexed to these clusters as possible sites promoting the inhibition process. Upon viewing the results of the computational studies of cluster models and theoretical thermochemistry data for receptor-substrate interactions, identification of ligand-cluster interactions helps to unravel the mechanism of inhibition. The acidity of (Sb2O5,nH2O) leads to great cluster-dipeptide passivation. The electrostatic forces between cluster interface and dipeptide interaction present relevant inhibition effects through proton transfer or mobility from the different amine and ketone groups. The reactivity differences come from the unoccupied lone pairs 5pSbwhich lie at higher energy but remain available to make a good interaction with the lowest orbital p nitrogen in NH2, and in the CO groups substrate fragment in the zone HOMO-LUMO. Further cluster stability comparisons show a lower Gibbs free energy inB3(B/trypanthione/glucose) (18 – 30 kcal/mol) at both used level in this study and gives good accurate intramolecular interactions, confirmed by the use of the dispersion-corrected density functional (DFT-D3). Given the dipeptide H-mobility and the (Sb2O5,nH2O) cluster acidity, (donor-acceptor duality), the system is predicted to be potent cluster of the inhibitors by endothermic and spontaneous reaction requiring 3.10 kcal/mol in aqueous medium.
What it takes to be at the top: The interrelationship between chronic social stress and social dominance
Authors: Šabanović Merima , Liu He , Mlambo Vongai , Aqel Hala , Chaudhury Dipesh 
Published: June 2020

AbstractDominance hierarchies of social animal groups are influenced by complex factors such as stress. Stress experienced by an animal prior to social interactions with a conspecific may be a determinant of their future social dynamics. Additionally, long-term occupancy of a specific hierarchical rank can have psychophysiological effects, leading to vulnerability to future stress.The current study aimed to delineate differential effects of stress acting before or after hierarchy formation. Using the chronic social defeat stress (CSDS) paradigm we performed behavioural investigations to determine whether exposure to CSDS before hierarchy formation predicted the new dominance status. Moreover, in another study we investigated whether social rank predicted stress vulnerability.We found that CSDS did not impede the establishment of dominance in new hierarchies as both stress-susceptible (socially avoidant) and –resilient (social) mice were able to attain dominant ranks. In contrast, within newly established hierarchies of stress-naïve mice, the subordinate, but not dominant, mice exhibit significantly greater avoidance of novel social targets. However, following exposure to CSDS, both lowest- and highest-ranked mice exhibit strong susceptibility to stress as measured by decreased interactions with a novel social target.These results suggest that the response to chronic social stress did not determine social rank in new cohorts, but low-status mice in newly established groups exhibited lower sociability to novel social targets. Interestingly, exposure of a hierarchical social group to chronic social stress led to stress-susceptibility in both high- and low-status mice as measured by social interaction.HighlightsStress susceptibility to chronic social defeat did not impede the establishment of dominance in new hierarchies.Subordinate mice exhibit reduced social preference after hierarchy formation.Following chronic social defeat stress, both subordinate and dominant mice exhibit susceptible-like reduction in social interaction, but dominant mice exhibit the greater decrease in social preference as compared to baseline.
Otx2 and Oc1 directly regulate the transcriptional program of cone photoreceptor development
Authors: Lonfat Nicolas , Wang Su , Lee ChangHee , Choi Jiho , Park Peter J. , Cepko Connie 
Published: June 2020

AbstractThe vertebrate retina is a highly organized structure of approximately 110 cell types. Retinal progenitor cells (RPCs) produce these cell types in a temporal order that is highly conserved. While some RPCs produce many cell types, some terminally dividing RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). Here, we compared the transcriptomes and chromatin profiles of such a restricted cone/HC RPC with those of other RPCs. We identified many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. We then showed that Otx2 and Oc1 directly regulate the activity of multiple CRMs genome-wide, including near genes important for cone development, such as Rxrg and Neurod1. In addition, we found that Otx2 regulates itself. These results suggest that Otx2 and Oc1 have a broader role than previously appreciated, and deepen our understanding of retinal development, which may benefit therapies for retinal diseases.
DRAM for distilling microbial metabolism to automate the curation of microbiome function
Authors: Shaffer Michael , Borton Mikayla A. , McGivern Bridget B. , Zayed Ahmed A. , La Rosa Sabina L. , Solden Lindsey M. , Liu Pengfei , Narrowe Adrienne B. , Rodríguez-Ramos Josué , Bolduc Benjamin , Gazitua M. Consuelo , Daly Rebecca A. , Smith Garrett J. , Vik Dean R. , Pope Phil B. , Sullivan Matthew B. , Roux Simon , Wrighton Kelly C. 
Published: June 2020

ABSTRACTMicrobial and viral communities transform the chemistry of Earth’s ecosystems, yet the specific reactions catalyzed by these biological engines are hard to decode due to the absence of a scalable, metabolically resolved, annotation software. Here, we present DRAM (Distilled and Refined Annotation of Metabolism), a framework to translate the deluge of microbiome-based genomic information into a catalog of microbial traits. To demonstrate the applicability of DRAM across metabolically diverse genomes, we evaluated DRAM performance on a defined, in silico soil community and previously published human gut metagenomes. We show that DRAM accurately assigned microbial contributions to geochemical cycles, and automated the partitioning of gut microbial carbohydrate metabolism at substrate levels. DRAM-v, the viral mode of DRAM, established rules to identify virally-encoded auxiliary metabolic genes (AMGs), resulting in the metabolic categorization of thousands of putative AMGs from soils and guts. Together DRAM and DRAM-v provide critical metabolic profiling capabilities that decipher mechanisms underpinning microbiome function.
Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males
Authors: Walker Emily M. , Cha Jeeyeon , Tong Xin , Guo Min , Liu Jin-Hua , Yu Sophia , Iacovazzo Donato , Mauvais-Jarvis Franck , Flanagan Sarah E. , Korbonits Márta , Stafford John , Jacobson David , Stein Roland 
Published: June 2020

AbstractA heterozygous missense mutation producing a variant of the islet β-cell-enriched MAFA transcription factor (Ser(S)64Phe(F) MAFA) was identified in humans who developed adult-onset, β-cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes. This mutation engenders increased stability to the normally unstable MAFA protein. To obtain insight into how this variant impacts β cell function, we developed a mouse model expressing S64F MafA and found sex-dependent phenotypes, with heterozygous mutant males displaying impaired glucose tolerance while females were slightly hypoglycemic with improved blood glucose clearance. Only heterozygous males showed transiently higher MafA protein levels preceding the onset of glucose intolerance and sex-dependent, differential expression of genes involved in calcium signaling, DNA damage, aging, and senescence. Functional changes in islet calcium handling and signs of islet aging and senescence processes were uniquely observed in male animals. In addition, S64F MAFA expression in human, male EndoC-βH2 β cells accelerated cellular senescence and increased production of senescence-associated secretory proteins compared to cells expressing wild-type MAFA. Together, these results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in S64F MAFA carriers in a sex-dependent manner.
Alignment-free identification of COI DNA barcode data with the Python package Alfie
Authors: Nugent Cameron M. , Adamowicz Sarah J. 
Published: June 2020

AbstractCharacterization of biodiversity from environmental DNA samples and bulk metabarcoding data is hampered by off-target sequences that can confound conclusions about a taxonomic group of interest. Existing methods for isolation of target sequences rely on alignment to existing reference barcodes, but this can bias results against novel genetic variants. Effectively parsing targeted DNA barcode data from off-target noise improves the quality of biodiversity estimates and biological conclusions by limiting subsequent analyses to a relevant subset of available data. Here, we present Alfie, a Python package for the alignment-free classification of cytochrome c oxidase subunit I (COI) DNA barcode sequences to taxonomic kingdoms. The package determinesk-mer frequencies of DNA sequences, and the frequencies serve as input for a neural network classifier that was trained and tested using ~58,000 publicly available COI sequences. The classifier was designed and optimized through a series of tests that allowed for the optimal set of DNAk-mer features and optimal machine learning algorithm to be selected. The neural network classifier rapidly assigns COI sequences to kingdoms with greater than 99% accuracy and is shown to generalize effectively and make accurate predictions about data from previously unseen taxonomic classes. The package contains an application programming interface that allows the Alfie package’s functionality to be extended to different DNA sequence classification tasks to suit a user’s need, including classification of different genes and barcodes, and classification to different taxonomic levels. Alfie is free and publicly available through GitHub (https://github.com/CNuge/alfie) and the Python package index (https://pypi.org/project/alfie/).
TNFα-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells
Authors: Okoro Emmanuel Ugochukwu 
Published: June 2020

ABSTRACTExcess lipid droplets are frequently observed in arterial endothelial cells at sites of advanced atherosclerotic plaques. Here, the role of tumor necrosis factor alpha (TNFα) in modulating low density lipoprotein (LDL) content in confluent primary human aortic endothelial cells (pHAECs) was investigated. TNFα promoted up to 2 folds increase in cellular cholesterol, which was resistant to ACAT inhibition. The cholesterol increase was associated with increased125I-LDL surface binding. Using the non-hydrolysable label, Dil, TNFα could induce a massive increase in Dil-LDL by over 200 folds. The elevated intracellular Dil-LDL was blocked with excess unlabeled LDL and PCSK9, but not oxidized LDL (oxLDL), receptor associated protein (RAP), or apolipoprotein (apoE) depletion. Moreover, TNFα-induced increase of LDL-derived lipids was elevated through lysosome inhibition. Using specific LDLR antibody, the Dil-LDL accumulation was reduced by over 99%. Effects of TNFα included LDLR cell surface increase by 138%, and very large increases in ICAM-1 total and surface proteins, respectively. In contrast, that of scavenger receptor B1 (SR-B1) was reduced. Additionally, LDLR antibody bound rapidly in TNFα-treated cells by about 30 folds, inducing a migrating shift in the LDLR protein. The effect of TNFα on Dil-LDL accumulation was inhibited by the antioxidant tetramethythiourea (TMTU) dose-dependently, but not by inhibitors against NF-κB, stress kinases, ASK1, JNK, p38, or apoptosis caspases. Grown on transwell inserts, TNFα did not enhance apical to basolateral LDL cholesterol or Dil release. It is concluded that TNFα promotes LDLR functions through combined increase at the cell surface and SR-B1 downregulation.
GWAS reveals the genetic complexity of fructan accumulation patterns in barley grain
Authors: Matros Andrea , Houston Kelly , Tucker Matthew R. , Schreiber Miriam , Berger Bettina , Aubert Matthew K. , Wilkinson Laura G. , Witzel Katja , Waugh Robbie , Seiffert Udo , Burton Rachel A. 
Published: June 2020

AbstractWe profiled the grain oligosaccharide content of 154 two-row spring barley genotypes and quantified 27 compounds, mainly fructans, that exhibited differential abundance. Clustering revealed two major profile groups where the ‘high’ set contained greater amounts of sugar monomers, sucrose and overall fructans, but lower fructosylraffinose. GWAS identified a significant association for the variability of two fructan types; neoseries-DP7 and inulin-DP9 which showed increased strength when a compound-ratio GWAS was applied. Gene models within this region included five fructan biosynthesis genes, of which three (fructan:fructan 1-fructosyltransferase, sucrose:sucrose 1-fructosyltransferase, and sucrose:fructan 6-fructosyltransferase)have already been described. The remaining two,6(G)-fructosyltransferaseandvacuolar invertase1have not previously been linked to fructan biosynthesis in barley and showed expression patterns distinct from those of the other three genes, including exclusive expression of6(G)-fructosyltransferasein outer grain tissues at the storage phase. From exome capture data several SNPs related to inulin- and neoseries-type fructan variability were identified infructan:fructan 1-fructosyltransferaseand6(G)-fructosyltransferasegenes Co-expression analyses uncovered potential regulators of fructan biosynthesis including transcription factors. Our results provide evidence for the distinct biosynthesis of neoseries-type fructans during barley grain maturation plus new gene candidates likely involved in the differential biosynthesis of the various fructan types.HighlightGrain fructan profiles in barley are more complex than previously expected and variations in a diversity panel relate to a genomic region where fructan biosynthesis genes cluster.
The diverging evolutionary history of opsin genes in Diptera
Authors: Feuda Roberto , Goulty Matthew , Zadra Nicola , Gasparetti Tiziana , Rosato Ezio , Segata Nicola , Rizzoli Annapaola , Pisani Davide , Ometto Lino , Stabelli Omar Rota 
Published: June 2020

AbstractOpsin receptors mediate the visual process in animals and their evolutionary history can provide precious hints on the ecological factors that underpin their diversification. Here we mined the genomes of more than 60 Dipteran species and reconstructed the evolution of their opsin genes in a phylogenetic framework. Our phylogenies indicate that dipterans possess an ancestral set of five core opsins which have undergone several lineage-specific events including an independent expansion of low wavelength opsins in flies and mosquitoes and numerous family specific duplications and losses. Molecular evolutionary studies indicate that gene turnover rate, overall mutation rate, and site-specific selective pressure are higher inAnophelesthan inDrosophila; we found signs of positive selection in both lineages, including events possibly associated with their peculiar behaviour. Our findings indicate an extremely variable pattern of opsin evolution in dipterans, showcasing how two similarly aged radiations -AnophelesandDrosophila- can be characterized by contrasting dynamics in the evolution of this gene family.
Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis
Authors: Ruiz-Ojeda Francisco Javier , Wang Jiefu , Bäcker Theresa , Krueger Martin , Zamani Samira , Rosowski Simon , Gruber Tim , Feuchtinger Annette , Schulz Tim J. , Fässler Reinhard , Müller Timo D. , García-Cáceres Cristina , Meier Matthias , Blüher Matthias , Ussar Siegfried 
Published: June 2020

AbstractReorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell-matrix interaction in adipocyte function and insulin sensitivity. Using adipose selective deletion of β1 integrin (Itgb1adipo-cre) and Kindlin-2 (Kind2adipo-cre), we demonstrate here that active β1 and β3 integrins directly interact with the insulin receptor to regulate white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in lipodystrophy and systemic insulin resistance. Conversely, we find that brown adipose tissue of Kind2adipo-creand Itgb1adipo-cremice is chronically hyperactivated, and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport. Thus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole body metabolism.
Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy
Authors: Srivastava Swayam Prakash , Zhou Han , Setia Ocean , Dardik Alan , Fernandez-Hernando Carlos , Goodwin Julie 
Published: June 2020

AbstractEndothelial cells play a key role in the regulation of disease and other developmental processes. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells by autocrine effects or of neighboring cell types by paracrine effects, and in both cases contribute to organ fibrosis. However, regulatory control of endothelial cell homeostasis, is not well studied. Diabetes induced renal fibrosis in endothelial GR knock out mice (GRfl/fl;Tie 1 Cre; GRECKO) but not in control mice (GRfl/fl); hypercholesterolemia further enhanced severe renal fibrosis in diabeticGRECKO;Apoe−/−(DKO) but not in diabetic littermates (GRfl/fl;Apoe−/−). The fibrogenic phenotype in the kidneys of diabetic GRECKOand diabetic DKO were associated with aberrant cytokine and chemokine reprogramming. Canonical Wnt signaling was identified as new target for the action of endothelial GR. Wnt inhibiton improved kidney fibrosis by mitigating endothelial-to-mesenchymal transition (EndMT) and epithelial-to-mesenchymal transitions (EMT). Similarly, activation of fatty acid oxidation also suppressed kidney fibrosis. Conditioned media from endothelial cells from diabetic GRECKOstimulated Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic core molecule in diabetes.
Angiotensin-(3–4) modulates angiotensin converting enzyme 2 (ACE2) downregulation in proximal tubule cells due to overweight and undernutrition: implications regarding the severity of renal lesions in Covid-19 infection
Authors: Luzes Rafael , Muzi-Filho Humberto , Pereira-Acácio Amaury , Crisóstomo Thuany , Vieyra Adalberto 
Published: June 2020

AbstractThe renal lesions – including severe acute kidney injury – are severe outcomes in SARS-CoV-2 infections. There are no reports regarding the influence of the nutritional status on the severity and progress of these lesions. Ageing is also an important risk factor. In the present communication we compare the influence of overweight and undernutrition in the levels of renal angiotensin converting enzymes 1 and 2. Since the renin-angiotensin-aldosterone system (RAAS) has been implicated in the progress of kidney failure during Covid-19, we also investigated the influence of Angiotensin-(3–4) (Ang-(3–4)) the shortest angiotensin-derived peptide, which is considered the physiological antagonist of several angiotensin II effects. We found that both overweight and undernutrition downregulate the levels of angiotensin converting enzyme 2 (ACE2) without influence on the levels of ACE1 in kidney rats. Administration of Ang-(3–4) recovers the control levels of ACE2 in overweight but not in undernourished rats. We conclude that chronic and opposite nutritional conditions play a central role in the pathophysiology of renal Covid-19 lesions, and that the role of RAAS is also different in overweight and undernutrition.
The silencing factor Sir3 is a molecular bridge that sticks together distant loci
Authors: Ruault Myriam , Scolari Vittore F. , Lazar-Stefanita Luciana , Hocher Antoine , Loïodice Isabelle , Noûs Camille , Koszul Romain , Taddei Angela 
Published: June 2020

ABSTRACTPhysical contacts between distant loci contribute to regulate genome function. However, the molecular mechanisms responsible for settling and maintaining such interactions remain poorly understood. Here we investigate the well conserved interactions between heterochromatin loci. In budding yeast, the 32 telomeres cluster in 3-5 foci in exponentially growing cells. This clustering is functionally linked to the formation of heterochromatin in subtelomeric regions through the recruitment of the silencing complex SIR composed of Sir2/3/4. Combining microscopy and Hi-C on strains expressing different alleles ofSIR3, we show that the binding of Sir3 directly promotes long range contacts between distant regions, including the rDNA, telomeres, and internal Sir3 bound sites. Furthermore, we unveil a new property of Sir3 in promoting rDNA compaction. Finally, using a synthetic approach we demonstrate that Sir3 can bond loci belonging to different chromosomes together, when targeted to these loci, independently of its interaction with its known partners (Rap1, and Sir4), Sir2 activity or chromosome context. Altogether these data suggest that Sir3 represents an uncommon example of protein able to bridge directly distant loci.
Implementation of PAR-CLIP to characterize RNA-protein interactions in prokaryotes at nucleotide resolution
Authors: Ojha Sandeep , Jain Chaitanya 
Published: June 2020

AbstractThe identification of RNAs that are recognized by RNA-binding proteins (RNA-BPs) using techniques such as “Crosslinking and Immunoprecipitation” (CLIP) has revolutionized the genome-wide discovery of RNA-BP RNA targets. Among the different versions of CLIP that have been developed, the use of photoactivable nucleoside analogs incorporated into cellular RNA has resulted in high efficiency photoactivable ribonucleoside-enhanced CLIP (PAR-CLIP). Nonetheless, PAR-CLIP has not yet been applied in prokaryotes. To determine if PAR-CLIP can be used in prokaryotes, we determined suitable conditions for the incorporation of 4-thiouridine (4SU), a photoactivable nucleoside, intoE. coliRNA, and for the isolation of crosslinked RNA. Applying this technique to Hfq, a well-characterized regulator of small RNA (sRNA)-messenger RNA (mRNA) interactions, we showed that PAR-CLIP identified most of the known sRNA targets of Hfq, as well as functionally relevant sites of Hfq-mRNA interactions at nucleotide resolution. Based on our findings, PAR-CLIP represents an improved method to identify both the RNAs and the specific regulatory sites that are recognized by RNA-BPs in prokaryotes.