bluuebunny/crossref_metadata_2025_split huggingface dataset:
A cysteine protease inhibitor blocks SARS-CoV-2 infection of human and monkey cells
Authors: Mellott Drake M. , Tseng Chien-Te , Drelich Aleksandra , Fajtová Pavla , Chenna Bala C. , Kostomiris Demetrios H. , Hsu Jason , Zhu Jiyun , Taylor Zane W. , Tat Vivian , Katzfuss Ardala , Li Linfeng , Giardini Miriam A. , Skinner Danielle , Hirata Ken , Beck Sungjun , Carlin Aaron F. , Clark Alex E. , Beretta Laura , Maneval Daniel , Frueh Felix , Hurst Brett L. , Wang Hong , Kocurek Klaudia I. , Raushel Frank M. , O’Donoghue Anthony J. , de Siqueira-Neto Jair Lage , Meek Thomas D. , McKerrow James H. 
Published: October 2020

ABSTRACTK777 is a di-peptide analog that contains an electrophilic vinyl-sulfone moiety and is a potent, covalent inactivator of cathepsins. Vero E6, HeLa/ACE2, Caco-2, A549/ACE2, and Calu-3, cells were exposed to SARS-CoV-2, and then treated with K777. K777 reduced viral infectivity with EC50 values of inhibition of viral infection of: 74 nM for Vero E6, <80 nM for A549/ACE2, and 4 nM for HeLa/ACE2 cells. In contrast, Calu-3 and Caco-2 cells had EC50 values in the low micromolar range. No toxicity of K777 was observed for any of the host cells at 10-100 μM inhibitor. K777 did not inhibit activity of the papain-like cysteine protease and 3CL cysteine protease, encoded by SARS-CoV-2 at concentrations of ≤ 100 μM. These results suggested that K777 exerts its potent anti-viral activity by inactivation of mammalian cysteine proteases which are essential to viral infectivity. Using a propargyl derivative of K777 as an activity-based probe, K777 selectively targeted cathepsin B and cathepsin L in Vero E6 cells. However only cathepsin L cleaved the SARS-CoV-2 spike protein and K777 blocked this proteolysis. The site of spike protein cleavage by cathepsin L was in the S1 domain of SARS-CoV-2, differing from the cleavage site observed in the SARS CoV-1 spike protein. These data support the hypothesis that the antiviral activity of K777 is mediated through inhibition of the activity of host cathepsin L and subsequent loss of viral spike protein processing.SIGNIFICANCEThe virus causing COVID-19 is highly infectious and has resulted in a global pandemic. We confirm that a cysteine protease inhibitor, approved by the FDA as a clinical-stage compound, inhibits SARS-CoV-2 infection of several human and monkey cell lines with notable(nanomolar) efficacy. The mechanism of action of this inhibitor is identified as a specific inhibition of host cell cathepsin L. This in turn inhibits host cell processing of the coronaviral spike protein, a step required for cell entry. Neither of the coronaviral proteases are inhibited, and the cleavage site of spike protein processing is different from that reported in other coronaviruses. Hypotheses to explain the differential activity of the inhibitor with different cell types are discussed.
Alleloscope: Integrative single cell analysis of allele-specific copy number alterations and chromatin accessibility in cancer
Authors: Wu Chi-Yun , Lau Billy T. , Kim Heon Seok , Sathe Anuja , Grimes Susan M. , Ji Hanlee P. , Zhang Nancy R. 
Published: October 2020

AbstractCancer progression is driven by both somatic copy number aberrations (CNAs) and chromatin remodeling, yet little is known about the interplay between these two classes of events in shaping the clonal diversity of cancers. We present Alleloscope, a method for allele-specific copy number estimation that can be applied to single cell DNA and ATAC sequencing data, either separately or in combination. This approach allows for integrative multi-omic analysis of allele-specific copy number and chromatin accessibility on the same cell. On scDNA-seq data from gastric, colorectal, and breast cancer samples, with extensive validation using matched linked-read sequencing, Alleloscope finds pervasive occurrence of highly complex, multi-allelic copy number aberrations, where cells that carry varying allelic configurations adding to the same total copy number co-evolve within a tumor. The contributions of such allele-specific events to intratumor heterogeneity have been under-reported and under-studied due to the lack of methods for their detection. On scATAC-seq from two basal cell carcinoma samples and a gastric cancer cell line, Alleloscope detects multi-allelic copy number events and copy neutral loss-of-heterozygosity, enabling the dissection of the contributions of chromosomal instability and chromatin remodeling in tumor evolution.
Dynamical interactions reconfigure the gradient of cortical timescales
Authors: Sorrentino P , Rabuffo G , Baselice F , Troisi Lopez E , Liparoti M , Quarantelli M , Sorrentino G , Bernard C , Jirsa V 
Published: October 2020

AbstractA hierarchy of local timescales with a back (sensory)-to-front (prefrontal) gradient reflects brain region specialization. However, cognitive processes emerge from the coordinated activity across regions, and the corresponding timescales should refer to the interactions rather than to regional activity. Using edgewise connectivity on magnetoencephalography signals, we demonstrate a reverse front-to-back gradient when non-local interactions are prominent. Thus, the timescales are dynamic and reconfigure between back-to-front and front-to-back patterns.
Dysregulated gene expression of imprinted and X-linked genes: a link to poor development of bovine haploid androgenetic embryos
Authors: Aguila Luis , Therrien Jacinthe , Suzuki Joao , García Mónica , Trindade Amanda , Smith Lawrence C. 
Published: October 2020

AbstractMammalian uniparental embryos are efficient models for genome imprinting research and allow studies on the contribution of the paternal and maternal genome to early embryonic development. In this study, we analyzed different methodologies for production of bovine haploid androgenetic embryos (hAE) to elucidate the causes behind their poor developmental potential. The results showed that hAE can be efficiently generated by using intracytoplasmic sperm injection and oocyte enucleation at telophase II. Although haploidy does not disturb early development up to around the 3rdmitotic division, androgenetic development is disturbed after the time of zygote genome activation those that reach the morula stage are less capable to become a blastocyst. Analysis of gene expression indicated abnormal levels of methyltransferase 3B and key long non-coding RNAs involved in X-chromosome inactivation and genomic imprinting of the KCNQ1 locus, which is associated to the methylation status of imprinted control regions of XIST and KCNQ1OT1. Thus, our results seem to exclude micromanipulation consequences and chromosomal abnormalities as major factors in developmental restriction, suggesting that their early developmental constraint is regulated at an epigenetic level.
Insight into the origin of 5’UTR and source of CpG reduction in SARS-CoV-2 genome
Authors: Afrasiabi Ali , Alinejad-Rokny Hamid , Lovell Nigel , Xu Zhenming , Ebrahimi Diako 
Published: October 2020

AbstractSARS-CoV-2, the causative agent of COVID-19, has an RNA genome, which is, overall, closely related to the bat coronavirus sequence RaTG13. However, the ACE2-binding domain of this virus is more similar to a coronavirus isolated from a Guangdong pangolin. In addition to this unique feature, the genome of SARS-CoV-2 (and its closely related coronaviruses) has a low CpG content. This has been postulated to be the signature of an evolutionary pressure exerted by the host antiviral protein ZAP. Here, we analyzed the sequences of a wide range of viruses using both alignment-based and alignment free approaches to investigate the origin of SARS-CoV-2 genome. Our analyses revealed a high level of similarity between the 5’UTR of SARS-CoV-2 and that of the Guangdong pangolin coronavirus. This suggests bat and pangolin coronaviruses might have recombined at least twice (in the 5’UTR and ACE2 binding regions) to seed the formation of SARS-CoV-2. An alternative hypothesis is that the lineage preceding SARS-CoV-2 is a yet to be sampled bat coronavirus whose ACE2 binding domain and 5’UTR are distinct from other known bat coronaviruses. Additionally, we performed a detailed analysis of viral genome compositions as well as expression and RNA binding data of ZAP to show that the low CpG abundance in SARS-CoV-2 is not related to an evolutionary pressure from ZAP.
A two-hit adversity model in developing rats reveals sex-specific impacts on prefrontal cortex structure and behavior
Authors: Gildawie Kelsea R. , Ryll Lilly M. , Hexter Jessica C. , Peterzell Shayna , Valentine Alissa A. , Brenhouse Heather C. 
Published: October 2020

AbstractAdversity early in life substantially impacts prefrontal cortex (PFC) development and vulnerability to later-life psychopathology. Importantly, repeated adverse experiences throughout childhood increase the risk for PFC-mediated behavioral deficits more commonly in women. Evidence from animal models points to effects of adversity on later-life neural and behavioral dysfunction; however, few studies have investigated the neurobiological underpinnings of sex-specific, long term consequences of multiple developmental stressors. We modeled early life adversity in rats via maternal separation (postnatal day (P)2-20) and juvenile social isolation (P21-35). Adult (P85) male and female rats were assessed for differences in the presence and structural integrity of PFC perineuronal nets (PNNs) enwrapping parvalbumin (PV)-expressing interneurons. PNNs are extracellular matrix structures formed during critical periods in postnatal development that play a key role in the plasticity of PV cells. Females – but not males – exposed to multiple hits of adversity demonstrated a reduction in PFC PV cells in adulthood. We also observed a sex-specific, potentiated reduction in PV+ PNN structural integrity. Moreover, correlations between neural disruption and hyperactivity/risk-assessment behavior were altered by adversity differently in males and females. These findings suggest a sex-specific impact of repeated adversity on neurostructural development and implicate PNNs as a contributor to associated behavioral dysfunction.
High precision in microRNA prediction: a novel genome-wide approach based on convolutional deep residual networks
Authors: Yones C. , Raad J. , Bugnon L.A. , Milone D.H. , Stegmayer G. 
Published: October 2020

AbstractMotivationMicroRNAs (miRNAs) are small non-coding RNAs that have a key role in the regulation of gene expression. The importance of miRNAs is widely acknowledged by the community nowadays, and the precise prediction of novel candidates with computational methods is still very needed. This could be done by searching homologous with sequence alignment tools, but this will be restricted only to sequences very similar to the known miRNA precursors (pre-miRNAs). Further-more, other important properties of pre-miRNAs, such as the secondary structure, are not taken into account by these methods. Many machine learning approaches were proposed in the last years to fill this gap, but these methods were tested in very controlled conditions, which are not fulfilled, for example, when predicting in newly sequenced genomes, where no miRNAs are known. If these methods are used under real conditions, the precision achieved is far from the one published.ResultsThis work provides a novel approach for dealing with the computational prediction of pre-miRNAs: a convolutional deep residual neural network. The proposed model has been tested on several complete genomes of animals and plants, achieving a precision up to 5 times higher than other approaches at the same recall rates. Also, a novel validation methodology is used to ensure that the performance reported can be achieved when using the method on new unknown species.AvailabilityTo provide fast an easy access to mirDNN, a web demo is availablehere. It can process fasta files with multiple sequences to calculate the prediction scores, and can generate the nucleotide importance plots. The full source code of this project is availablehereandhere.Contactcyones@sinc.unl.edu.ar
Free-living psychrophilic bacteria of the genusPsychrobacterare descendants of pathobionts
Authors: Welter Daphne K. , Ruaud Albane , Henseler Zachariah M. , De Jong Hannah N. , van Coeverden de Groot Peter , Michaux Johan , Gormezano Linda , Waters Jillian L. , Youngblut Nicholas D. , Ley Ruth E. 
Published: October 2020

AbstractHost-adapted microbiota are generally thought to have evolved from free-living ancestors. This process is in principle reversible, but examples are few. The genusPsychrobacter(familyMoraxellaceae, phylumGamma-Proteobacteria) includes species inhabiting diverse and mostly polar environments, such as sea ice and marine animals. To probePsychrobacter’sevolutionary history, we analyzed 85Psychrobacterstrains by comparative genomics and phenotyping under 24 different growth conditions. Genome-based phylogeny showsPsychrobacterare derived fromMoraxella, which are warm-adapted pathobionts.Psychrobacterstrains form two ecotypes based on growth temperature: flexible (FE, growth at 4 - 37°C), and restricted (RE, 4 - 25°C). FE strains, which can be either phylogenetically basal or derived, have smaller genomes and higher transposon copy numbers. RE strains have larger genomes, and show genomic adaptations towards a psychrophilic lifestyle and are phylogenetically derived only. We then assessedPsychrobacterabundance in 86 mostly wild polar bear stools and tested persistence of select strains in germfree mice.Psychrobacter(both FE and RE) was enriched in stool of polar bears feeding on mammals, but only FE strains persisted in germfree mice. Together these results indicate growth at 37°C is ancestral inPsychrobacter, lost in many derived species, and likely necessary to colonize the mammalian gut.
A computational approach to evaluate the combined effect of SARS-CoV-2 RBD mutations and ACE2 receptor genetic variants on infectivity: The COVID-19 host-pathogen nexus
Authors: Ashoor Dana , Khalaf Noureddine Ben , Marzouq Maryam , Al Jarjanazi Hamdi , Chelif Sadok , Fathallah M. Dahmani 
Published: October 2020

AbstractSARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy (ΔΔG) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.
H3k27ac-HiChIP in prostate cell lines identifies risk genes for prostate cancer susceptibility
Authors: Giambartolomei Claudia , Seo Ji-Heui , Schwarz Tommer , Freund Malika Kumar , Johnson Ruth Dolly , Spisak Sandor , Baca Sylvan C. , Gusev Alexander , Mancuso Nicholas , Pasaniuc Bogdan , Freedman Matthew L. 
Published: October 2020

AbstractGenome-wide association studies (GWAS) have identified more than 140 prostate cancer (PrCa) risk regions which provide potential insights into causal mechanisms. Multiple lines of evidence show that a significant proportion of PrCa risk can be explained by germline causal variants that dysregulate nearby target genes in prostate-relevant tissues thus altering disease risk. The traditional approach to explore this hypothesis has been correlating GWAS variants with steady-state transcript levels, referred to as expression quantitative trait loci (eQTLs). In this work, we assess the utility of chromosome conformation capture (3C) coupled with immunoprecipitation (HiChIP) to identify target genes for PrCa GWAS risk loci. We find that interactome data confirms previously reported PrCa target genes identified through GWAS/eQTL overlap (e.g.,MLPH). Interestingly, HiChIP identified links between PrCa GWAS variants and genes well-known to play a role in prostate cancer biology (e.g.,AR) that are not detected by eQTL-based methods. We validate these findings through CRISPR interference (CRISPRi) perturbation of the variant-containing regulatory elements forNKX3-1andARin the LNCaP cell line. Our results demonstrate that looping data harbor additional information beyond eQTLs and expand the number of PrCa GWAS loci that can be linked to candidate susceptibility genes.
Behavioural responses to chemical cues of predators differ between fire salamander larvae from two different habitats
Authors: Hahn Luca G. , Oswald Pia , Caspers Barbara A. 
Published: October 2020

AbstractPredation is one of the strongest selection pressures, forcing prey organisms to detect predators and to display various antipredator behaviours, such as refuge-use or decreased activity. To recognise predators, chemosensory cues play a pivotal role, particularly in aquatic ecosystems. However, it is less known whether the ability to use these cues to respond with adequate antipredator behaviour varies between individuals occupying different habitats that are dissimilar in predation risk. Using field experiments, we examined antipredator behaviour of larval fire salamanders (Salamandra salamandra) from two different habitats, ponds and streams. Among other differences, ponds and streams are inhabited by habitat-specific predators, such as alpine newts (Ichthyosaura alpestris) occurring in ponds. We exposed larvae from both habitats to either chemical cues from alpine newts or a blank control (tap water) and investigated potential differences in their behavioural responses in two experiments. Pond larvae, but not stream larvae, became significantly less active when faced with chemical cues from newts compared to those faced with a control stimulus. Moreover, larvae from both habitats tested in water containing chemical cues spent significantly less time outside a shelter than those in control water. Our results demonstrate that larval fire salamanders recognise predatory newts through kairomones and alter their behaviour accordingly. However, experience with predatory newts may not be necessary to differentiate kairomones from control water, but may be beneficial for larvae to further develop their antipredator behaviour, thus representing conformance to a niche.
Assumptions about frequency-dependent architectures of complex traits bias measures of functional enrichment
Authors: Zabad Shadi , Ragsdale Aaron P. , Sun Rosie , Li Yue , Gravel Simon 
Published: October 2020

AbstractLinkage-Disequilibrium Score Regression (LDSC) is a popular framework for analyzing GWAS summary statistics that allows for estimating SNP heritability, confounding, and functional enrichment of genetic variants with different annotations. Recent work has highlighted the influence of implicit and explicit assumptions of the model on the biological interpretation of the results. In this work, we explored a formulation of LDSC that replaces ther2measure of LD with a recently-proposed unbiased estimator of theD2statistic. In addition to modest statistical difference across estimators, this derivation highlighted implicit and unrealistic assumptions about the relationship between allele frequency, effect size, and annotation status. We carry out a systematic comparison of alternative LDSC formulations by applying them to summary statistics from 47 GWAS traits. Our results show that commonly used models likely underestimate functional enrichment. These results highlight the importance of calibrating the LDSC model to achieve a more robust understanding of polygenic traits.
Responses of Neurons in the Medullary Lateral Tegmental Field and Nucleus Tractus Solitarius to Vestibular Stimuli in Conscious Felines
Authors: Bielanin John P. , Douglas Nerone O. , Shulgach Jonathan A. , McCall Andrew A. , Miller Derek M. , Amin Pooja R. , Murphey Charles P. , Barman Susan M. , Yates Bill J. 
Published: October 2020

AbstractConsiderable evidence shows that the vestibular system contributes to adjusting sympathetic nervous system activity to maintain adequate blood pressure during movement and changes in posture. However, only a few prior experiments entailed recordings in conscious animals from brainstem neurons presumed to convey baroreceptor and vestibular inputs to neurons in the rostral ventrolateral medulla (RVLM) that provide inputs to sympathetic preganglionic neurons in the spinal cord. In this study, recordings were made in conscious felines from neurons in the medullary lateral tegmental field (LTF) and nucleus tractus solitarius (NTS) identified as regulating sympathetic nervous system activity by exhibiting changes in firing rate related to the cardiac cycle, or cardiac-related activity (CRA). Approximately 38% of LTF and NTS neurons responded to static 40° head up tilts with a change in firing rate of~50%. However, few of these neurons responded to 10° sinusoidal rotations in the pitch plane, in contrast to prior findings in decerebrate animals that the firing rates of both NTS and LTF neurons are modulated by small-amplitude body rotations. Thus, as previously demonstrated for RVLM neurons, in conscious animals NTS and LTF neurons only respond to large rotations that lead to changes in sympathetic nervous system activity. The similar responses to head-up rotations of LTF and NTS neurons with those documented for RVLM neurons suggest that LTF and NTS neurons are components of the vestibulo-sympathetic reflex pathway. However, a difference between NTS/LTF neurons and RVLM was variability in CRA over time. This variability was significantly greater for RVLM neurons, raising the hypothesis that the responsiveness of these neurons to baroreceptor input is adjusted based on the animal’s vigilance and alertness.
Women show enhanced attractiveness ratings and neural processing of male faces associated with male chemosensory signals
Authors: Klinkenberg Isabelle A. G. , Dobel Christian , Bröckelmann Ann-Kathrin , Plessow Franziska , Kirschbaum Clemens , Zwitserlood Pienie , Junghöfer Markus 
Published: October 2020

AbstractThere is growing evidence that humans use olfactory chemosensory signals for social communication, but their role in affective associative learning is largely unknown. To examine this, women implicitly learned face-odor associations by pairing different neutral male faces with either a male chemosignal presumably involved in human mating behavior (dissolved Δ4,16-androstadien-3-one, “AND”), a pleasant smell (dissolved vanillin) or the neutral solvent alone. After learning, women rated faces previously paired with AND or vanillin as more attractive than faces paired with solvent, even though they were unable to identify the contingency of face-odor pairings above chance level. On a neurophysiological level, both AND- and vanillin-associated faces evoked stronger magnetoencephalographic correlates of enhanced emotional attention than solvent-associated faces at early (<120 ms) and mid-latency (140-270 ms) processing stages. This study stresses the role of AND as a human chemosignal in implicit social communication and demonstrates its effectiveness in modulating emotional learning.