bluuebunny/crossref_metadata_2025_split huggingface dataset:
Screening and Identification of Lujo Virus Entry Inhibitors from an FDA-Approved Drugs Library
Authors: Cao Junyuan , Liu Yang , Dong Siqi , Zhou Minmin , Guo Jiao , Jia Xiaoying , Zhang Yueli , Hou Yuxiao , Xiao Gengfu , Wang Wei 
Published: September 2021

ABSTRACTThe Lujo virus (LUJV) belongs to the Old World (OW) genus Mammarenavirus (family Arenaviridae); it is categorized as a biosafety level (BSL) 4 agent. Currently, there are no U.S. Food and Drug Administration (FDA)-approved drugs or vaccines specifically for LUJV or other pathogenic OW mammarenaviruses. Here, a high-throughput screening of an FDA-approved drug library was conducted using pseudotype viruses bearing LUJV envelope glycoprotein (GPC) to identify inhibitors of LUJV entry. Three hit compounds, trametinib, manidipine, and lercanidipine, were identified as LUJV entry inhibitors in the micromolar range. Mechanistic studies revealed that trametinib inhibited LUJV GPC-mediated membrane fusion by targeting C410 (located in the transmembrane (TM) domain), while manidipine and lercanidipine inhibited LUJV entry by acting as calcium channel blockers. Meanwhile, all three hits extended their antiviral spectra to the entry of other pathogenic mammarenaviruses. Furthermore, all three could inhibit the authentic prototype mammarenavirus, lymphocytic choriomeningitis virus (LCMV), and could prevent infection at the micromolar level. This study shows that trametinib, manidipine, and lercanidipine are candidates for LUJV therapy, and highlights the critical role of calcium in LUJV infection. The presented findings reinforce the notion that the key residue(s) located in the TM domain of GPC provide an entry-targeted platform for designing mammarenavirus inhibitors.IMPORTANCETo date, only one LUJV outbreak has been recorded; it occurred in 2008 and resulted in a fatality rate of 80% (4/5 cases). Pathogenesis studies and therapeutic strategies are therefore urgently needed. Repurposing approved drugs can accelerate the development of drug design and facilitate the understanding of infectious mechanisms. Here, three compounds, trametinib, manidipine, and lercanidipine, were identified as entry inhibitors against LUJV. Studying the underling mechanisms revealed that a key residue (C410) in LUJV GPC modulates its sensitivity/resistance to trametinib and demonstrated the critical role of calcium in LUJV infection.
Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19
Authors: Kousathanas Athanasios , Pairo-Castineira Erola , Rawlik Konrad , Stuckey Alex , Odhams Christopher A , Walker Susan , Russell Clark D , Malinauskas Tomas , Millar Jonathan , Elliott Katherine S , Griffiths Fiona , Oosthuyzen Wilna , Morrice Kirstie , Keating Sean , Wang Bo , Rhodes Daniel , Klaric Lucija , Zechner Marie , Parkinson Nick , Bretherick Andrew D. , Siddiq Afshan , Goddard Peter , Donovan Sally , Maslove David , Nichol Alistair , Semple Malcolm G , Zainy Tala , Maleady-Crowe Fiona , Todd Linda , Salehi Shahla , Knight Julian , Elgar Greg , Chan Georgia , Arumugam Prabhu , Fowler Tom A , Rendon Augusto , Shankar-Hari Manu , Summers Charlotte , Hinds Charles , Horby Peter , McAuley Danny , Montgomery Hugh , Openshaw Peter J.M. , Wu Yang , Yang Jian , Elliott Paul , Walsh Timothy ,   GenOMICC Investigators,   23andMe,   Covid-19 Human Genetics Initiative, Fawkes Angie , Murphy Lee , Rowan Kathy , Ponting Chris P , Vitart Veronique , Wilson James F , Scott Richard H , Clohisey Sara , Moutsianas Loukas , Law Andy , Caulfield Mark J , Baillie J. Kenneth 
Published: September 2021

AbstractCritical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1or hospitalisation2;3;4following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms.Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease.We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.
Schema formation in a neural population subspace underlies learning-to-learn in flexible sensorimotor problem-solving
Authors: Goudar Vishwa , Peysakhovich Barbara , Freedman David J. , Buffalo Elizabeth A. , Wang Xiao-Jing 
Published: September 2021

AbstractLearning-to-learn, a progressive speedup of learning while solving a series of similar problems, represents a core process of knowledge acquisition that draws attention in both neuroscience and artificial intelligence. To investigate its underlying brain mechanism, we trained a recurrent neural network model on arbitrary sensorimotor mappings known to depend on the prefrontal cortex. The network displayed an exponential time course of accelerated learning. The neural substrate of a schema emerges within a low-dimensional subspace of population activity; its reuse in new problems facilitates learning by limiting connection weight changes. Our work highlights the weight-driven modifications of the vector field, which determines the population trajectory of a recurrent network and behavior. Such plasticity is especially important for preserving and reusing the learnt schema in spite of undesirable changes of the vector field due to the transition to learning a new problem; the accumulated changes across problems account for the learning-to-learn dynamics.
Ether Lipid Biosynthesis Promotes Lifespan Extension and Enables Diverse Prolongevity Paradigms in Caenorhabditis elegans
Authors: Cedillo Lucydalila , Li Sainan , Ahsan Fasih M. , Stuhr Nicole L. , Zhou Yifei , Zhang Yuyao , Adedoja Adebanjo , Murphy Luke M. , Yerevanian Armen , Emans Sinclair , Dao Khoi , Li Zhaozhi , Peterson Nicholas D. , Watrous Jeramie , Jain Mohit , Das Sudeshna , Pukkila-Worley Read , Curran Sean P. , Soukas Alexander A. 
Published: September 2021

AbstractBiguanides, including the world’s most commonly prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. In spite of this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in C. elegans, we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor Nrf2/skn-1. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, fard-1/FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.
Exploring bycatch diversity of organisms in whole genome sequencing of Erebidae moths (Lepidoptera)
Authors: Ghanavi Hamid Reza , Twort Victoria , Duplouy Anne 
Published: September 2021

AbstractModels estimate that up to 80% of all butterfly and moth species host vertically transmitted endosymbiotic microorganisms, which can affect the host fitness, metabolism, reproduction, population dynamics, and genetic diversity, among others. The supporting empirical data are however currently highly biased towards the generally more colourful butterflies, and include less information about moths. Additionally, studies of symbiotic partners of Lepidoptera predominantly focus on the common bacterium Wolbachia pipientis, while infections by other inherited microbial partners have more rarely been investigated. Here, we mine the whole genome sequence data of 47 species of Erebidae moths, with the aims to both inform on the diversity of symbionts potentially associated with this Lepidoptera group, and discuss the potential of metagenomic approaches to inform on their associated microbiome diversity. Based on the result of Kraken2 and MetaPhlAn2 analyses, we found clear evidence of the presence of Wolbachia in four species. Our result also suggests the presence of three other bacterial symbionts (Burkholderia spp., Sodalis spp. and Arsenophonus spp.), in three other moth species. Additionally, we recovered genomic material from bracovirus in about half of our samples. The detection of the latter, usually found in mutualistic association to braconid parasitoid wasps, may inform on host-parasite interactions that take place in the natural habitat of the Erebidae moths, suggesting either contamination with material from species of the host community network, or horizontal transfer of members of the microbiome between interacting species.
Neurodevelopmental clustering of gene expression identifies lipid metabolism genes associated with neuroprotection and neurodegeneration
Authors: Kohane Akiva A. , Wood Tim R. 
Published: September 2021

AbstractAPOE variants present the strongest association with sporadic Alzheimer’s Disease. APOE is also highly expressed during neurodevelopment in the Central Nervous System (CNS) and has been shown to be neuroprotective in infancy and gestation. We explored other lipid metabolism genes to determine whether they show a similar neurodevelopmental expression trajectory and are associated with neurodegeneration. APOE was by far the most highly expressed of the lipid metabolism genes in the CNS. Two other genes, Apolipoprotein C1 (APOC1) Glutamate-Ammonia Ligase (GLUL—also known as glutamine synthetase), co-clustered with Apolipoprotein E (APOE) in its developmental trajectory in late gestation through early childhood. These three genes highlight brain structures and developmental time-windows distinct from other lipid metabolism genes. In the CNS they are primarily expressed in astrocytes and are implicated in neuroprotection and neurodegeneration.
Alignment of multiple metabolomics LC-MS datasets from disparate diseases to reveal fever-associated metabolites
Authors: Năstase Ana-Maria , Barrett Michael P. , Cárdenas Washington B. , Cordeiro Fernanda Bertuccez , Zambrano Mildred , Andrade Joyce , Chang Juan , Regato Mary , Carrillo Eugenia , Botana Laura , Moreno Javier , Milne Kathryn , Spence Philip J. , Rowe J. Alexandra , Rogers Simon 
Published: September 2021

AbstractAcute febrile illnesses are still a major cause of mortality and morbidity globally, particularly in low to middle income countries. The aim of this study was to determine any possible metabolic commonalities of patients infected with disparate pathogens that cause fever. Three liquid chromatography-mass spectrometry (LC-MS) datasets investigating the metabolic effects of malaria, leishmaniasis and Zika virus infection were used. The retention time (RT) drift between the datasets was determined using landmarks obtained from the standard reference mixtures generally used in the quality control of the LC-MS experiments. We used fitted Gaussian Process models (GPs) to perform a high level correction of the RT drift between the experiments, followed by standard peakset alignment between the samples with corrected RTs of the three LC-MS datasets. Statistical analysis, annotation and pathway analysis of the integrated peaksets were subsequently performed. Metabolic dysregulation patterns common across the datasets were identified, with kynurenine pathway being the most affected pathway between all three fever-associated datasets.
Freshwater dissolved oxygen dynamics: changes due to glyphosate, 2,4-D and their mixture, both under clear and turbid-organic conditions
Authors: Lozano V.L. , Miranda C.E. , Vinocur A.L. , Sabio y García C.A. , Vera M.S. , González C. , Wolansky M.J. , Pizarro H.N. 
Published: September 2021

AbstractWe performed two independent outdoor mesocosm experiments where we measured the variation of DO saturation (DO%) in freshwater after a single input of Roundup Max®(G) (glyphosate-based formulation), AsiMax 50®(2,4-D) (2,4-D-based formulation) and their mixture (M). Two concentration levels were tested; 0.3 mg/L G and 0.135 mg/L 2,4-D (Low; L) and 3 mg/L G and 1.35 mg/L 2,4-D (High; H). We assayed consolidated microbial communities coming from a system in organic turbid eutrophic status and a system in clear mesotrophic status during 21 and 23 days, respectively. A sample of phytoplankton (micro+nano, pico-eukaryotes, pico-cyanobacteria), mixotrophic algae and heterotrophic bacteria was collected to determine abundances at each of four sampling dates. The clear and turbid systems showed similar, but not synchronized, patterns of daily DO% changes in relation to the controls (DO%v), after exposure to both single and combined formulations. Under glyphosate scenarios (GL, GH, ML and MH), the two types of systems showed similar DO%vbut different microbial abundances, being associated to an increase in the micro+nano and pico-eukaryotic phytoplankton fractions for the clear system. In contrast, in the turbid system changes were associated with increased pico-cyanobacteria and decreased mixotrophic algae. Effects of 2,4-D were only observed in the turbid system, leading to decreased micro+nano phytoplankton abundances. Under the turbid scenario, the herbicide mixture at high concentration had a synergistic effect on DO%vand recovery was not detected by the end of the experiment. Our results revealed that herbicides inputs induced changes in phytoplankton abundances that leads to measurable DO variations.
Public human microbiome data dominated by highly developed countries
Authors: Abdill Richard J. , Adamowicz Elizabeth M. , Blekhman Ran 
Published: September 2021

AbstractThe importance of sampling from globally representative populations has been well established in human genomics. In human microbiome research, however, we lack a full understanding of the global distribution of sampling in research studies. This information is crucial to better understand global patterns of microbiome-associated diseases and to extend the health benefits of this research to all populations. Here, we analyze the country of origin of all 444,829 human microbiome samples that have been collected to date and are available from the world’s three largest genomic data repositories, including the Sequence Read Archive (SRA). We show that more than 71% of publicly available human microbiome samples with a known origin come from Europe, the United States, and Canada, including 46.8% from the United States alone, despite the country representing only 4.3% of the global population. We also find that central and southern Asia is the most underrepresented region: Countries such as India, Pakistan, and Bangladesh account for more than a quarter of the world population but make up only 1.8 percent of human microbiome samples. These results demonstrate a critical need to ensure more global representation of participants in microbiome studies.
Systematic and quantitative view of the antiviral arsenal of prokaryotes
Authors: Tesson Florian , Hervé Alexandre , Touchon Marie , d’Humières Camille , Cury Jean , Bernheim Aude 
Published: September 2021

AbstractFacing the abundance and diversity of phages, bacteria have developed multiple anti-phage mechanisms. In the past three years, the number of known anti-phage mechanisms has been expanded by at least 5-fold rendering our view of prokaryotic immunity obsolete. Most anti-phage systems have been studied as standalone mechanisms, however many examples demonstrate strains encode not one but several anti-viral mechanisms. How these different systems integrate into an anti-viral arsenal at the strain level remains to be elucidated. Much could be learned from establishing fundamental description of features such as the number and diversity of anti-phage systems encoded in a given genome. To address this question, we developed DefenseFinder, a tool that automatically detects known anti-phage systems in prokaryotic genomes. We applied DefenseFinder to >20 000 fully sequenced genomes, generating a systematic and quantitative view of the anti-viral arsenal of prokaryotes. We show prokaryotic genomes encode on average five anti-phage systems from three different families of systems. This number varies drastically from one strain to another and is influenced by the genome size and the number of prophages encoded. Distributions of different systems are also very heterogenous with some systems being enriched in prophages and in specific clades. Finally, we provide a detailed comparison of the anti-viral arsenal of 15 common bacterial species, revealing drastic differences in anti-viral strategies. Overall, our work provides a free and open-source software, available as a command line tool or, on a webserver. It allows the rapid detection of anti-phage systems, enables a comprehensive description of the anti-viral arsenal of prokaryotes and paves the way for large scale genomics study in the field of anti-phage defense.
Evaluation of rubber tree transcriptome and discovery of SNP and SSR from candidate genes involved in cellulose and lignin biosynthesis
Authors: Othman Ahmad Sofiman , Abu Bakar Mohd Fahmi 
Published: September 2021

AbstractHevea brasiliensis (the rubber tree) is a well-known species with high economic value, and it is the primary source of natural rubber globally. Increasing demand for furniture and related industries has made rubberwood production as important as latex production. Molecular markers such as Single Nucleotide Polymorphisms (SNPs) and Simple Sequence Repeats (SSRs) are widely used for Marker Assisted Selection (MAS) which can be detected in large quantity by transcriptome sequencing. MAS is thought to be a useful method for the development of new rubberwood clones for its shorter breeding cycle compared to a conventional breeding procedure. In this study we performed RNA sequencing (RNA-seq) on four H. brasiliensis clones (RRIM 712, RRIM 2025, RRIM 3001 and PB 314) from three tissues including bark, latex and leaf samples to identify SSRs and SNPs associated with wood-formation related genes. The RNA sequencing using the Illumina NextSeq 500 v2 platform, generated 1,697,491,922 raw reads. A total of 101,269 transcripts over 400 bp in size were obtained and similarity search of the non-redundant (nr) protein database returned 83,748 (83%) positive BLASTx hits. The transcriptome analysis was annotated using the NCBI NR (National Center for Biotechnology Information Non-Redundant), UniProtKB/Swiss-Prot, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Differential expression analysis between later-timber rubber clone and non-later-timber rubber clone on wood-formation related genes, showed genes encoding phenylalanine ammonia-lyase (PAL), caffeic acid O-methyltransferase (COMT) and cinnamoyl-CoA reductase (CCR) were highly up-regulated in a latex-timber rubber clone. In total, about 3,210,629 SNPs and 14,956 SSRs were detected with 1,786 SNPs and 31 SSRs were found for wood-formation biosynthesis of H. brasilensis from 11 lignin and cellulose gene toolboxes. After filtering and primer selection, 103 SNPs and 18 SSR markers were successfully amplified and could be useful as molecular tool for marker assisted breeding to produce new timber rubber clones.
Assessment of genome packaging in AAVs using Orbitrap-based charge detection mass spectrometry
Authors: Wörner Tobias P. , Snijder Joost , Friese Olga , Powers Thomas , Heck Albert J. R. 
Published: September 2021

AbstractAdeno-associated viruses (AAV) represent important gene therapy vectors with several approved clinical applications and numerous more in clinical trials. Genome packaging is an essential step in the bioprocessing of AAVs and needs to be tightly monitored to ensure the proper delivery of transgenes and the production of effective drugs. Current methods to monitor genome packaging have limited sensitivity, a high demand on labour, and struggle to distinguish between packaging of the intended genome or unwanted side-products. Here we show that Orbitrap based charge detection mass spectrometry allows the ultra-sensitive quantification of all these different AAV bioprocessing products. A protocol is presented that allows the quantification of genome packed AAV preparations in under half an hour, requiring only micro-liter quantities of typical AAV preparations with ~1013 viral genome copies per millilitre. The method quickly assesses the integrity and amount of genome packed AAV particles to support AAV bioprocessing and characterization of this rapidly emerging class of advanced drug therapies.
Sigma Oscillations Protect or Reinstate Motor Memory Depending on their Temporal Coordination with Slow Waves
Authors: Nicolas Judith , King Bradley R. , Levesque David , Lazzouni Latifa , Coffey Emily , Swinnen Stephan , Doyon Julien , Carrier Julie , Albouy Geneviève 
Published: September 2021

AbstractTargeted memory reactivation (TMR) during post-learning sleep is known to enhance motor memory consolidation but the underlying neurophysiological processes remain unclear. Here, we confirm the beneficial effect of auditory TMR on motor performance. At the neural level, TMR enhanced slow wave (SW) characteristics. Additionally, greater TMR-related phase-amplitude coupling between slow (0.5-2 Hz) and sigma (12-16 Hz) oscillations after the SW peak was related to higher TMR effect on performance. Importantly, sounds that were not associated to learning strengthened SW-sigma coupling at the SW trough and the increase in sigma power nested in the trough of the potential evoked by these unassociated sounds was related to the TMR benefit. Altogether, our data suggest that, depending on their precise temporal coordination during post learning sleep, slow and sigma oscillations play a crucial role in either memory reinstatement or protection against irrelevant information; two processes that critically contribute to motor memory consolidation.