bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying common pharmacotherapies associated with reduced COVID-19 morbidity using electronic health records
Authors: Castro Victor M , Ross Rachel A , McBride Sean M , Perlis Roy H
Published: April 2020

Objective

Absent a vaccine or any established treatments for the novel and highly infectious coronavirus-19 (COVID-19), rapid efforts to identify potential therapeutics are required. We sought to identify commonly prescribed medications that may be associated with lesser risk of morbidity with COVID-19 across 6 Eastern Massachusetts hospitals.

Design

In silico cohort using electronic health records from individuals evaluated in the emergency department between March 4, 2020 and July 12, 2020.

Setting

Emergency department and inpatient settings from 2 academic medical centers and 4 community hospitals.

Participants

All individuals presenting to an emergency department and undergoing COVID-19 testing.

Main Outcome or Measure

Inpatient hospitalization; documented requirement for mechanical ventilation.

Results

Among 7,360 individuals with COVID-19 positive test results by PCR, 3,693 (50.2%) were hospitalized in one of 6 hospitals. In models adjusted for sociodemographic features and overall burden of medical illness, medications significantly associated with diminished risk for hospitalization included ibuprofen and sumatriptan. Among individuals who were hospitalized, 962(26.0%) were admitted to the intensive care unit and 608 (16.5%) died; ibuprofen and naproxen were also more commonly prescribed among individuals not requiring intensive care.

Conclusions

These preliminary findings suggest that electronic health records may be applied to identify medications associated with lower risk of morbidity with COVID-19, but larger cohorts will be required to address the substantial problem of confounding by indication, such that extreme caution is warranted in interpreting nonrandomized results.

Trial Registration

None

Summary Boxes

Section 1: What is already known on this topic

Absent a vaccine or any established treatments for the novel and highly infectious coronavirus-19 (COVID-19), rapid efforts to identify potential therapeutics are required.

Section 2: What this study adds

This cohort study across 6 hospitals identified medications enriched among individuals positive for COVID-19 who are less likely to experience adverse outcomes including hospitalization, intensive care, or death.
Prediction of the time evolution of the COVID-19 disease in Guadeloupe with a stochastic evolutionary model
Authors: Allali Meriem , Portecop Patrick , Carlès Michel , Gibert Dominique
Published: April 2020

Predictions on the time-evolution of the number of severe and critical cases of COVID-19 patients in Guadeloupe are presented. A stochastic model is purposely developed to explicitly account for the entire population (≃400000 inhabitants) of Guadeloupe. The available data for Guadeloupe are analysed and combined with general characteristics of the COVID-19 to constrain the parameters of the model. The time-evolution of the number of cases follows the well-known exponential-like model observed at the very beginning of a pandemic outbreak. The exponential growth of the number of infected individuals is controlled by the so-called basic reproductive number,R0, defined as the likely number of additional cases generated by a single infectious case during its infectious periodTI. Because of the rather long duration of infectious period (≃14 days) a high rate of contamination is sustained during several weeks after the beginning of the containment period. This may constitute a source of discouragement for people restrained to respect strict containment rules. It is then unlikely that, during the containment period,R0falls to zero. Fortunately, our models shows that the containment effects are not much sensitive to the exact value ofR0provided we haveR0<0.6. For such conditions, we show that the number of severe and critical cases is highly tempered about 4 to 6 weeks after the beginning of the containment. Also, the maximum number of critical cases (i.e. the cases that may exceed the hospital’s intensive care capacity) remains near 30 whenR0<0.6. For a largerR0= 0.8 a slower decrease of the number of critical cases occurs, leading to a larger number of deceased patients. This last example illustrates the great importance to maintain an as low as possibleR0during and after the containment period. The rather long delay between the beginning of the containment and the appearance of the slowing-down of the rate of contamination puts a particular strength on the communication and sanitary education of people. To be mostly efficient, this communication must be done by a locally recognised medical staff. We believe that this point is a crucial matter of success. Appendix Posterior model assessment with data acquired after April 11, 2020 added in a second version of the paper compares the model predictions with the data acquired from April 12 to May 25 2020, after the construction of the model discussed in the present study. The remarkable agreement between the model predictions and the data may be explained by the good quality of first-hand data used to constrain the model, the ability of the stochastic approach to integrate new information and stability of the sanitary situation due to the respect of the recommendations emitted by medical and administrative authorities by the guadeloupean population.
Impact of population mask wearing on Covid-19 post lockdown
Authors: Javid Babak , Balaban Nathalie Q.
Published: April 2020

COVID-19, caused by SARS-CoV2 is a rapidly spreading global pandemic. Although precise transmission routes and dynamics are unknown, SARS-CoV2 is thought primarily to spread via contagious respiratory droplets. Unlike with SARS-CoV, maximal viral shedding occurs in the early phase of illness, and this is supported by models that suggest 40-80% of transmission events occur from pre- and asymptomatic individuals. One widely-discussed strategy to limit transmission of SARS-CoV2, particularly from presymptomatic individuals, has been population-level wearing of masks. Modelling for pandemic influenza suggests some benefit in reducing total numbers infected with even 50% mask-use. COVID-19 has a higher hospitalization and mortality rate than influenza, and the impacts on these parameters, and critically, at what point in the pandemic trajectory mask-use might exert maximal benefit are completely unknown. We derived a simplified SIR model to investigate the effects of near-universal mask-use on COVID-19 assuming 8 or 16% mask efficacy. We decided to model, in particular, the impact of masks on numbers of critically-ill patients and cumulative mortality, since these are parameters that are likely to have the most severe consequences in the COVID-19 pandemic. Whereas mask use had a relatively minor benefit on critical-care and mortality rates when transmissibility (Reff) was high, the reduction on deaths was dramatic as the effective R approached 1, as might be expected after aggressive social-distancing measures such as wide-spread lockdowns. One major concern with COVID-19 is its potential to overwhelm healthcare infrastructures, even in resource-rich settings, with one third of hospitalized patients requiring critical-care. We incorporated this into our model, increasing death rates for when critical-care resources have been exhausted. Our simple model shows that modest efficacy of masks could avert substantial mortality in this scenario. Importantly, the effects on mortality became hyper-sensitive to mask-wearing as the effective R approaches 1, i.e. near the tipping point of when the infection trajectory is expected to revert to exponential growth, as would be expected after effective lockdown. Our model suggests that mask-wearing might exert maximal benefit as nations plan their post-lockdown strategies and suggests that mask-wearing should be included in further more sophisticated models of the current pandemic.
Estimated regional white matter hyperintensity burden, resting state functional connectivity, and cognitive functions in older adults
Authors: Jaywant Abhishek , Dunlop Katharine , Victoria Lindsay W. , Oberlin Lauren , Lynch Charles J. , Respino Matteo , Kuceyeski Amy , Scult Matthew , Hoptman Matthew , Liston Conor , O’Dell Michael W. , Alexopoulos George S. , Perlis Roy H. , Gunning Faith M.
Published: April 2020

Objective

White matter hyperintensities (WMH) are linked to deficits in cognitive functioning, including cognitive control and memory; however, the structural and functional mechanisms are largely unknown. We investigated the relationship between estimated regional disruptions to white matter fiber tracts from WMH, resting state functional connectivity (RSFC), and cognitive functions in older adults.

Design

Cross-sectional study.

Setting

Community.

Participants

Fifty-eight cognitively-healthy older adults.

Measurements

Tasks of cognitive control and memory, structural MRI, and resting state fMRI. We estimated the disruption to white matter fiber tracts from WMH and its impact on gray matter regions in the cortical and subcortical frontoparietal network, default mode network, and ventral attention network by overlaying each subject’s WMH mask on a normative tractogram dataset. We calculated RSFC between nodes in those same networks.

Results

The interaction of estimated regional WMH burden and RSFC in cortico-striatal regions of the default mode network and frontoparietal network was associated with memory retrieval. Models predicting working memory, cognitive inhibition, and set-shifting were not significant.

Conclusions

Findings highlight the role of circuit-level alterations at the structural and functional levels in resting state networks that are related to WMH and impact memory retrieval in older adults.
Residual-matching: An efficient alternative to random sampling in human subjects research recruitment
Authors: Hooyman Andrew , Huentelman Matthew J. , Schaefer Sydney Y.
Published: April 2020

Given the time- and resource-intense nature of human subjects research, we have developed a more intelligent approach to participant recruitment above and beyond random sampling that leverages pilot or preliminary results to reduce the overall number of participants needed for recruitment from an existing electronic cohort or database. Using open-access data from the General Social Survey (GSS) of the National Opinion Research Center, we generated pilot and validation datasets through a simulation to establish moderate and weak relationships based on linear regression. We then compared the performance of our residual-matching method against random sampling in their probabilities of achieving a given level of statistical power as well as their prediction accuracies. Results showed that the residual-matching method was superior to random sampling, yielding smaller sample sizes with equivalent mean square error. We therefore advocate the use of residual matching when scaling up pilot studies to conserve time and resources in larger follow-up studies.
Mapping the human praxis network: an investigation of white matter disconnection in apraxia
Authors: Rosenzopf Hannah , Wiesen Daniel , Basilakos Alexandra , Yourganov Grigori , Bonilha Leonardo , Rorden Christopher , Fridriksson Julius , Karnath Hans-Otto , Sperber Christoph
Published: April 2020

Left hemispheric cerebral stroke can cause apraxia, a motor-cognitive disorder characterised by deficits of higher-order motor skills such as the failure to accurately produce meaningful gestures. This disorder provides unique insights into the anatomical and cognitive architecture of the human praxis system. The present study aimed to map the structural brain network that is damaged in apraxia. We assessed the ability to perform meaningful gestures with the hand in 101 patients with chronic left hemisphere stroke. Structural white matter fibre damage was directly assessed by diffusion tensor imaging and fractional anisotropy mapping. We used multivariate topographical inference on tract-based fractional anisotropy topographies to identify white matter disconnection associated with apraxia. We found relevant pathological white matter alterations in a densely connected fronto-temporo-parietal network of short and long association fibres. Hence, the findings suggest that heterogeneous topographical results in previous lesion mapping studies might not only result from differences in study design, but also from the general methodological limitations of univariate topographical mapping in uncovering the structural praxis network. A striking role of middle and superior temporal lobe disconnection, including temporo-temporal short association fibres, was found, suggesting strong involvement of the temporal lobe in the praxis network. Further, the results stressed the importance of subcortical disconnections for the emergence of apractic symptoms. Our study provides a fine-grain view into the structural connectivity of the human praxis network and suggests a potential value of disconnection measures in the clinical prediction of behavioural post-stroke outcome.
Glycosaminoglycan binding motif at S1/S2 proteolytic cleavage site on spike glycoprotein may facilitate novel coronavirus (SARS-CoV-2) host cell entry
Authors: Kim So Young , Jin Weihua , Sood Amika , Montgomery David W. , Grant Oliver C. , Fuster Mark M. , Fu Li , Dordick Jonathan S. , Woods Robert J. , Zhang Fuming , Linhardt Robert J.
Published: April 2020

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has resulted in a pandemic and continues to spread around the globe at an unprecedented rate. To date, no effective therapeutic is available to fight its associated disease, COVID-19. Our discovery of a novel insertion of glycosaminoglycan (GAG)-binding motif at S1/S2 proteolytic cleavage site (681-686 (PRRARS)) and two other GAG-binding-like motifs within SARS-CoV-2 spike glycoprotein (SGP) led us to hypothesize that host cell surface GAGs might be involved in host cell entry of SARS-CoV-2. Using a surface plasmon resonance direct binding assay, we found that both monomeric and trimeric SARS-CoV-2 spike more tightly bind to immobilized heparin (KD= 40 pM and 73 pM, respectively) than the SARS-CoV and MERS-CoV SGPs (500 nM and 1 nM, respectively). In competitive binding studies, the IC50of heparin, tri-sulfated non-anticoagulant heparan sulfate, and non-anticoagulant low molecular weight heparin against SARS-CoV-2 SGP binding to immobilized heparin were 0.056 μM, 0.12 μM, and 26.4 μM, respectively. Finally, unbiased computational ligand docking indicates that heparan sulfate interacts with the GAG-binding motif at the S1/S2 site on each monomer interface in the trimeric SARS-CoV-2 SGP, and at another site (453-459 (YRLFRKS)) when the receptor-binding domain is in an open conformation. Our study augments our knowledge in SARS-CoV-2 pathogenesis and advances carbohydrate-based COVID-19 therapeutic development.
Hype versus hope: Deep learning encodes more predictive and robust brain imaging representations than standard machine learning
Authors: Abrol Anees , Fu Zening , Salman Mustafa , Silva Rogers , Du Yuhui , Plis Sergey , Calhoun Vince
Published: April 2020

Previous successes of deep learning (DL) approaches on several complex tasks have hugely inflated expectations of their power to learn subtle properties of complex brain imaging data, and scale to large datasets. Perhaps as a reaction to this inflation, recent critical commentaries unfavorably compare DL with standard machine learning (SML) approaches for the analysis of brain imaging data. Yet, their conclusions are based on pre-engineered features which deprives DL of its main advantage: representation learning. Here we evaluate this and show the importance of representation learning for DL performance on brain imaging data. We report our findings from a large-scale systematic comparison of SML approaches versus DL profiled in a ten-way age and gender-based classification task on 12,314 structural MRI images. Results show that DL methods, if implemented and trained following the prevalent DL practices, have the potential to substantially improve compared to SML approaches. We also show that DL approaches scale particularly well presenting a lower asymptotic complexity in relative computational time, despite being more complex. Our analysis reveals that the performance improvement saturates as the training sample size grows, but shows significantly higher performance throughout. We also show evidence that the superior performance of DL is primarily due to the excellent representation learning capabilities and that SML methods can perform equally well when operating on representations produced by the trained DL models. Finally, we demonstrate that DL embeddings span a comprehensible projection spectrum and that DL consistently localizes discriminative brain biomarkers, providing an example of the robustness of prediction relevance estimates. Our findings highlight the presence of non-linearities in brain imaging data that DL frameworks can exploit to generate superior predictive representations for characterizing the human brain, even with currently available data sizes.
Pervasive cooperative mutational effects on multiple catalytic enzyme traits emerge via long-range conformational dynamics
Authors: Acevedo-Rocha Carlos G. , Li Aitao , D’Amore Lorenzo , Hoebenreich Sabrina , Sanchis Joaquin , Lubrano Paul , Ferla Matteo P. , Garcia-Borràs Marc , Osuna Sílvia , Reetz Manfred T.
Published: April 2020

Multidimensional fitness landscapes provide insights into the molecular basis of laboratory and natural evolution. Yet such efforts are rare and focus only on limited protein families and a single enzyme trait, with little concern about the relationship between protein epistasis and conformational dynamics. Here, we report the first multiparametric fitness landscape for a cytochrome P450 monooxygenase that was engineered for the regio- and stereoselective hydroxylation of a steroid. We developed a computational program to automatically quantify non-additive effects among all possible mutational pathways, finding pervasive cooperative sign and magnitude epistasis on multiple catalytic traits. By using quantum mechanics and molecular dynamics simulations, we show that these effects are modulated by long-range interactions in loops, helices and beta-strands that gate the substrate access channel allowing for optimal catalysis. Our work highlights the importance of conformational dynamics on epistasis in an enzyme involved in secondary metabolism and offers lessons for engineering P450s.
PD-1 Specific ‘Blocking’ Antibodies That Deplete PD-1+ T Cells Present An Inconvenient Variable In Pre-clinical Immunotherapy Experiments
Authors: Polesso Fanny , Munks Michael W. , Rott Katherine H. , Smart Savannah , Hill Ann B. , Moran Amy E.
Published: April 2020

Therapeutic antibodies blocking PD-1-/PD-L1 interaction have achieved remarkable clinical success in cancer. In addition to blocking a target molecule, some isotypes of antibodies can activate complement, NK cells or phagocytes, resulting in death of the cell expressing the antibody’s target. Human anti-PD-1 therapeutics use antibody isotypes designed to minimize such antibody-dependent lysis. In contrast, anti-PD-1 reagents used in mice are derived from multiple species, with different isotypes, and are not engineered to reduce target cell death: few studies analyze or discuss how antibody species and isotype may impact data interpretation. We demonstrate here that anti-PD-1 therapy to promote activation and proliferation of PD-1-expressing CD8 T cells sometimes led instead to a loss of antigen specific cells. This phenomenon was seen in two tumor models and a model of virus infection, and was varied with the clone of anti-PD-1 antibody. Additionally, we compared competition among anti-PD-1 clones to find a combination that allows detection of PD-1-expressing cells despite the presence of blocking anti-PD1 antibodiesin vivo.These data bring attention to the possibility of unintended target cell depletion with some commonly used anti-mouse PD-1 clones, and should provide a valuable resource for the design and interpretation of anti-PD-1 studies in mice. (200)
The evolution of sex-biased gene expression in theDrosophilabrain
Authors: Khodursky Samuel , Svetec Nicolas , Durkin Sylvia , Zhao Li
Published: April 2020

Genes with sex-biased expression inDrosophilaare thought to underlie sexually dimorphic phenotypes and have been shown to possess important evolutionary properties. However, the forces and constraints governing the evolution of sex-biased genes in the somatic tissues ofDrosophilaare largely unknown. Using population-scale RNA sequencing data we show that sex-biased genes in theDrosophilabrain are highly enriched on the X Chromosome and that most are biased in a species-specific manner. We show that X-linked male-biased genes, and to a lesser extent female-biased genes, are enriched for signatures of directional selection at the gene expression level. By examining the evolutionary properties of gene flanking regions on the X Chromosome, we find evidence that adaptive cis-regulatory changes are more likely to drive the expression evolution of X-linked male-biased genes than other X-linked genes. Finally, we examine whether constraint due to broad expression across multiple tissues and genetic constraint due to the largely shared male and female genomes could be responsible for the observed patterns of gene expression evolution. We find that expression breadth does not constrain the directional evolution of gene expression in the brain. Additionally, we find that the shared genome between males and females imposes a substantial constraint on the expression evolution of sex-biased genes. Overall, these results significantly advance our understanding of the patterns and forces shaping the evolution of sexual dimorphism in theDrosophilabrain.
Comprehensive genome analyses ofSellimonas intestinalis, a potential biomarker of homeostasis gut recovery
Authors: Muñoz Marina , Guerrero-Araya Enzo , Cortés-Tapia Catalina , Plaza-Garrido Ángela , Lawley Trevor D. , Paredes-Sabja Daniel
Published: April 2020

Sellimonas intestinalisis a Gram positive and anaerobic bacterial species previously considered as uncultivable. Although little is known about this Lachnospiraceae family member, its increased abundance has been reported in patients who recovered intestinal homeostasis after dysbiosis events. In this context, the aim of this work was taken advantage of a culturomics protocol that allowed the recovery species extremely oxygen-sensitive from faecal samples, which led to the establishment of an S. intestinalis isolate. Whole genome sequencing and taxonomic allocation confirmation were the base to develop comparative analyses including 11 public genomes closely related. Phylogeographic analysis revealed the existence of three lineages (linage-I including isolates from Chile and France, linage-II from South Korea and Finland, and linage-III from China and one isolate from USA). Pangenome analysis on the established dataset revealed that although S. intestinalis seems to have a highly conserved genome (with 50.1% of its coding potential being part of the coregenome), some recombination signals were evidenced. The identification of cluster of orthologous groups revealed a high number of genes involved in metabolism, including amino acid and carbohydrate transport as well as energy production and conversion, which matches with the metabolic profile previously reported for healthy microbiota. Additionally, virulence factors and antimicrobial resistance genes were found (mainly in linage-III), which could favour their survival during antibiotic-induced dysbiosis. These findings provide the basis of knowledge about this species with potential as a bioindicator of intestinal homeostasis recovery and contribute to advance in the characterization of gut microbiota members with beneficial potential.
De novo 3D models of SARS-CoV-2 RNA elements and small-molecule-binding RNAs to aid drug discovery
Authors: Rangan Ramya , Watkins Andrew M. , Chacon Jose , Kladwang Wipapat , Zheludev Ivan N. , Townley Jill , Rynge Mats , Thain Gregory , Das Rhiju
Published: April 2020

The rapid spread of COVID-19 is motivating development of antivirals targeting conserved SARS-CoV-2 molecular machinery. The SARS-CoV-2 genome includes conserved RNA elements that offer potential small-molecule drug targets, but most of their 3D structures have not been experimentally characterized. Here, we provide a compilation of chemical mapping data from our and other labs, secondary structure models, and 3D model ensembles based on Rosetta’s FARFAR2 algorithm for SARS-CoV-2 RNA regions including the individual stems SL1-8 in the extended 5’ UTR; the reverse complement of the 5’ UTR SL1-4; the frameshift stimulating element (FSE); and the extended pseudoknot, hypervariable region, and s2m of the 3’ UTR. For eleven of these elements (the stems in SL1-8, reverse complement of SL1-4, FSE, s2m, and 3’ UTR pseudoknot), modeling convergence supports the accuracy of predicted low energy states; subsequent cryo-EM characterization of the FSE confirms modeling accuracy. To aid efforts to discover small molecule RNA binders guided by computational models, we provide a second set of similarly prepared models for RNA riboswitches that bind small molecules. Both datasets (‘FARFAR2-SARS-CoV-2’, https://github.com/DasLab/FARFAR2-SARS-CoV-2; and ‘FARFAR2-Apo-Riboswitch’, at https://github.com/DasLab/FARFAR2-Apo-Riboswitch’) include up to 400 models for each RNA element, which may facilitate drug discovery approaches targeting dynamic ensembles of RNA molecules.
A transcription regulatory network within the ACE2 locus may promote a pro-viral environment for SARS-CoV-2 by modulating expression of host factors
Authors: Fadason Tayaza , Gokuladhas Sreemol , Golovina Evgeniia , Ho Daniel , Farrow Sophie , Nyaga Denis , Pan Hong , Karnani Neerja , Wong Conroy , Cooper Antony , Schierding William , O’Sullivan Justin M.
Published: April 2020

Introduction

A novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was recently identified as the pathogen responsible for the COVID-19 outbreak. SARS-CoV-2 triggers severe pneumonia, which leads to acute respiratory distress syndrome and death in severe cases. As reported, SARS-CoV-2 is 80% genetically identical to the 2003 SARS-CoV virus. Angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for entry of both SARS-CoV and SARS-CoV-2 into human cells. ACE2 is normally expressed in cardiovascular and lung type II alveolar epithelial cells, where it positively modulates the RAS system that regulates blood flow, pressure, and fluid homeostasis. Thus, virus-induced reduction of ACE2 gene expression is considered to make a significant contribution to severe acute respiratory failure. Chromatin remodeling plays a significant role in the regulation of ACE2 gene expression and the activity of regulatory elements within the genome.

Methods

Here, we integrated data on physical chromatin interactions within the genome organization (captured by Hi-C) with tissue-specific gene expression data to identify spatial expression quantitative trait loci (eQTLs) and thus regulatory elements located within the ACE2 gene.

Results

We identified regulatory elements withinACE2that control the expression of PIR, CA5B, and VPS13C in the lung. The gene products of these genes are involved in inflammatory responses,de novopyrimidine and polyamine synthesis, and the endoplasmic reticulum, respectively.

Conclusion

Our study, although limited by the fact that the identification of the regulatory interactions is putative until proven by targeted experiments, supports the hypothesis that viral silencing ofACE2alters the activity of gene regulatory regions and promotes an intra-cellular environment suitable for viral replication.
Structures of metabotropic GABABreceptor
Authors: Papasergi-Scott Makaía M. , Robertson Michael J. , Seven Alpay B. , Panova Ouliana , Mathiesen Jesper M. , Skiniotis Georgios
Published: April 2020

GABA (γ-aminobutyric acid) stimulation of the metabotropic GABABreceptor results in prolonged inhibition of neurotransmission that is central to brain physiology. GABABbelongs to the Family C of G protein-coupled receptors (GPCRs), which operate as dimers to relay synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins. GABAB, however, is unique in its function as an obligate heterodimer in which agonist binding and G protein activation take place on distinct subunits. Here we show structures of heterodimeric and homodimeric full-length GABABreceptors. Complemented by cellular signaling assays and atomistic simulations, the structures reveal an essential role for the GABABextracellular loop 2 (ECL2) in relaying structural transitions by ordering the linker connecting the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of both GABABsubunits caps and interacts with the hydrophilic head of a phospholipid occupying the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G protein. These results provide a starting framework to decipher mechanistic modes of signal transduction mediated by GABABdimers and have important implications for rational drug design targeting these receptors.
Designing a multi-epitope peptide-based vaccine against SARS-CoV-2
Authors: Singh Abhishek , Thakur Mukesh , Sharma Lalit Kumar , Chandra Kailash
Published: April 2020

COVID-19 pandemic has resulted so far 14,395,16 confirmed cases with 85,711 deaths from the 212 countries, or territories. Due to multifacet issues and challenges in implementation of the safety & preventive measures, inconsistent coordination between societies-governments and most importanly lack of specific vaccine to SARS-CoV-2, the spread of Wuhan originated virus is still uprising after taking a heavy toll on human life. In the present study, we mapped several immunogenic epitopes (B-cell, T-cell, and IFN-gamma) over the entire structural proteins of SARS-CoV-2 and by applying various computational and immunoinformatics approaches, we designed a multi-epitope peptide based vaccine that predicted high immunogenic response in the largest proportion of world’s human population. To ensure high expression of the recombinant vaccine inE. coli, codon optimization and in-silico cloning were also carried out. The designed vaccine with high molecular affinity to TLR3 and TLR4, was found capable to initiate effective innate and adaptive immune response. The immune simulation also suggested uprising high levels of both B-cell and T-cell mediated immunity which on subsequent exposure cleared antigen from the system. The proposed vaccine found promising by yielding desired results and hence, should be tested by practical experimentations for its functioning and efficacy to neutralize SARS-CoV-2.
Comparison of motility of H. pylori in broth and mucin reveals the interplay of effect of acid on bacterium and the rheology of the medium it swims in
Authors: Su C. , Bieniek K. , Liao W. , Constantino M. A. , Decker S. M. , Turner B. S. , Bansil R.
Published: April 2020

To colonize on the gastric epitheliumHelicobacter pyloribacteria have to swim across a gradient of pH from 2-7 in the mucus layer. Previous studies ofH. pylorimotility have shown that at pH below 4 do not swim in porcine gastric mucin (PGM) gels. To separately assess the influence of gelation of PGM and that of pH on motors and pH sensitive receptors ofH. pylori, we used phase contrast microscopy to compare the translational and rotational motion ofH. pyloriin PGMversusBrucella broth (BB10) at different pHs. We observed that decreasing pH leads to decreased fraction of motile swimmers with a decrease in the contribution of fast swimmers to the distributions of swimming speeds and length of trajectories. At all pH’s the bacteria swam faster with longer net displacement over the trajectory in BB10 as compared to PGM. While bacteria are stuck in PGM gels at low pH, they swim at low pH in broth,albeitwith reduced speed. The body rotation rate and estimated cell body torque are weakly dependent on pH in BB10, whereas in PGM the torque increases with increasing viscosity and bacteria stuck in the low pH gel rotate faster than the motile bacteria. Our results show thatH. pylorihas optimal swimming under slightly acidic conditions, and exhibits mechanosensing when stuck in low pH mucin gels.
Smelling sensations: olfactory crossmodal correspondences
Authors: Ward Ryan Joseph , Wuerger Sophie , Marshall Alan
Published: April 2020

Crossmodal correspondences are the associations between apparently distinct stimuli in different sensory modalities . These associations, albeit surprising, are generally shared in most of the population. Olfaction is ingrained in the fabric of our daily life and constitutes an integral part of our perceptual reality, with olfaction being more commonly used in the entertainment and analytical domains, it is crucial to uncover the robust correspondences underlying common aromatic compounds. Towards this end, we investigated an aggregate of crossmodal correspondences between ten olfactory stimuli and other modalities ( angularity of shapes, smoothness of texture, pleasantness, pitch, colours, musical genres and emotional dimensions ) using a large sample of 68 observers. We uncover the correspondences between these modalities and extent of these associations with respect to the explicit knowledge of the respective aromatic compound. The results revealed the robustness of prior studies, as well as, contributions towards olfactory integration between an aggregate of other dimensions. The knowledge of an odour's identity coupled with the multisensory perception of the odours indicates that these associations, for the most part, are relatively robust and do not rely on explicit knowledge of the odour. Through principal component analysis of the perceptual ratings, new cross-model mediations have been uncovered between odours and their intercorrelated sensory dimensions. Our results demonstrate a collective of associations between olfaction and other dimensions, potential cross modal mediations via exploratory factor analysis and the robustness of these correspondence with respect to the explicit knowledge of an odour. We anticipate the findings reported in this paper could be used as a psychophysical framework aiding in a collective of applications ranging from olfaction enhanced multimedia to marketing.
Elemental analysis of Moringa oleifera seeds by Laser Induced Breakdown Spectroscopy (LIBS) and its anti-cancer and anti-microbial studies
Authors: Gondal Mohammed A
Published: April 2020

Moringa oleifera plant contains a numerous antioxidants, antibiotics and nutrients (vitamins and minerals) which makes it prospective for diverse biomedical applications. This report investigated the anti-cancerous and anti-microbial potential of the Moringa oleifera seeds (MOSs) due to the bioactive components a detail elemental analysis. MOSs in the form of pellets were used in elemental analysis. Alcoholic extraction of were utilized in anti-cancerous and anti-microbial activity.To clarify the anti-cancerous and anti-microbial potential of the (MOSs) because of the bioactive components. An elemental analysis was conducted using Laser Induced Breakdown Spectroscopy (LIBS) . The GC-MS used for the validation of the LIBS outcome. Additionally, the anti-cancerous and anti-microbial activity of the MOSs was evaluated. Herein, the human colorectal carcinoma cells (HCT-116) were treated with the seeds aqueous extracts for 48 h and the cell viability plus the DNA nuclear morphology were measured via the MTT assay and DAPI staining. The cell viability of the normal human embryonic stem cells (HEK-293) was also examined after the treatment. Percentage of cell viability and inhibitory concentration (IC 50 ) of both normal and treated cells were determined.The recorded LIBS signal of the MOSs revealed the existence of elements like Ca, K, Mg, P, S, Fe, Mn, Zn, Na and Se (vital for human health). The results of the MTT assay revealed a profound inhibitory action of the MOSs extracts against the HCT-116 cells growth. On top, such extracts did not affect the HEK-293 cells growth, indicating the specificity of the proposed extracts towards cancer cells escalation hindrance. The anti-microbial activity of the ethanolic MOSs extracts was tested on the S. aureus and E. coli bacteria using the Agar well diffusion assay. The observed anti-cancerous and the anti-microbial activities of the MOSs extracts can be attributed to the charisma of various bioactive compounds including the oleic acid, palmitic acid, hexadecenoic acid ethyl ester and D-allose. Conclusion: Current observations may contribute towards the development of the MOSs-based biomedicine (organic without any side effects, cheap, plentiful, pure and sustainable) effective for the cancer and bacterial infection cure.
Socio-Ecological Network Structures from Process Graphs
Authors: Lao Angelyn , Cabezas Heriberto , Orosz Ákos , Friedler Ferenc , Tan Raymond
Published: April 2020

We propose a process graph (P-graph) approach to develop ecosystem networks from knowledge of the properties of the component species. Originally developed as a process engineering tool for designing industrial plants, the P-graph framework has key advantages over conventional ecological network analysis (ENA) techniques. A P-graph is a bipartite graph consisting of two types of nodes, which we propose to represent components of an ecosystem. Compartments within ecosystems (e.g., organism species) are represented by one class of nodes, while the roles or functions that they play relative to other compartments are represented by a second class of nodes. This bipartite graph representation enables a powerful, unambiguous representation of relationships among ecosystem compartments, which can come in tangible (e.g., mass flow in predation) or intangible form (e.g., symbiosis). For example, within a P-graph, the distinct roles of bees as pollinators for some plants and as prey for some animals can be explicitly represented, which would not otherwise be possible using conventional ENA. After a discussion of the mapping of ecosystems into P-graph, we also discuss how this framework can be used to guide understanding of complex networks that exist in nature. Two component algorithms of P-graph, namely maximal structure generation (MSG) and solution structure generation (SSG), are shown to be particularly useful for ENA. This method can be used to determine the (a) effects of loss of specific ecosystem compartments due to extinction, (b) potential efficacy of ecosystem reconstruction efforts, and (c) maximum sustainable exploitation of human ecosystem services by humans. We illustrate the use of P-graph for the analysis of ecosystem compartment loss using a small-scale stylized case study, and further propose a new criticality index that can be easily derived from SSG results.
An Autophagy-Dependent Tubular Lysosomal Network Synchronizes Degradative Activity Required for Muscle Remodeling
Authors: Murakawa Tadayoshi , Kiger Amy A. , Sakamaki Yuriko , Fukuda Mitsunori , Fujita Naonobu
Published: April 2020

Previously, we reported that autophagy is critical for Drosophila muscle remodeling during metamorphosis (Fujita et al., 2017). However, little is known about how lysosomes meet increased degradative demand upon cellular remodeling. Here, we found an extensive tubular autolysosomal network in remodeling muscle. The tubular network transiently appeared and exhibited the capacity to degrade autophagic cargoes. The tubular autolysosomal network was uniquely marked by the autophagic SNARE protein, Syntaxin 17, and its formation depended on both autophagic flux and degradative function, with the exception of the Atg12 and Atg8 ubiquitin-like conjugation systems. AmongATG-deficient mutants, the efficiency of lysosomal tubulation correlated with the phenotypic severity in muscle remodeling. The lumen of the tubular network was continuous and homogeneous across a broad region of the remodeling muscle. Altogether, we revealed that the dynamic expansion of a tubular autolysosomal network synchronizes the abundant degradative activity required for developmentally regulated muscle remodeling.

Impact Statement

Analysis of developmentally-regulated Drosophila muscle remodeling revealed autophagy-dependent formation of an extensive, Syntaxin 17-marked, tubular network that synchronizes the abundant degradative activity across a broad region of the remodeling muscle
Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2
Authors: Williamson Brandi N. , Feldmann Friederike , Schwarz Benjamin , Meade-White Kimberly , Porter Danielle P. , Schulz Jonathan , Doremalen Neeltje van , Leighton Ian , Yinda Claude Kwe , Pérez-Pérez Lizzette , Okumura Atsushi , Lovaglio Jamie , Hanley Patrick W. , Saturday Greg , Bosio Catharine M. , Anzick Sarah , Barbian Kent , Cihlar Tomas , Martens Craig , Scott Dana P. , Munster Vincent J. , Wit Emmie de
Published: April 2020

Background

Effective therapeutics to treat COVID-19 are urgently needed. Remdesivir is a nucleotide prodrug with in vitro and in vivo efficacy against coronaviruses. Here, we tested the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection.

Methods

To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease. Two groups of six rhesus macaques were infected with SARS-CoV-2 and treated with intravenous remdesivir or an equal volume of vehicle solution once daily. Clinical, virological and histological parameters were assessed regularly during the study and at necropsy to determine treatment efficacy.

Results

In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. At necropsy on day 7 after inoculation, lung viral loads of remdesivir-treated animals were significantly lower and there was a clear reduction in damage to the lung tissue.

Conclusions

Therapeutic remdesivir treatment initiated early during infection has a clear clinical benefit in SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.
Human SLC46A2 is the dominant cGAMP importer in extracellular cGAMP-sensing macrophages and monocytes
Authors: Cordova Anthony F. , Ritchie Christopher , Böhnert Volker , Li Lingyin
Published: April 2020

Administration of exogenous CDNs to activate the cGAMP-STING pathway is a promising therapeutic strategy to unleash the full potential of cancer immunotherapy. This strategy mirrors the role of endogenous extracellular cGAMP, an immunotransmitter that is transferred from cancer cells to cGAMP-sensing cells in the host, promoting immunity. However, the CDN import mechanisms used by host cells within tumors remain unknown. Here we identified the protein SLC46A2 as the dominant cGAMP importer in primary human monocytes. Furthermore, we discovered that monocytes and M1-polarized macrophages directly sense tumor-derived extracellular cGAMP in murine tumors. Finally, we demonstrated that SLC46A2 is the dominant cGAMP importer in monocyte-derived macrophages. Together, we provide the first cellular and molecular mechanisms of cGAMP as an immunotransmitter, paving the way for effective STING pathway therapeutics.
A multivalent fuzzy interface drives reversible COPII coat assembly
Authors: Stancheva Viktoriya G. , Hutchings Joshua , Li Xiao-Han , Santhanam Balaji , Babu M. Madan , Zanetti Giulia , Miller Elizabeth A.
Published: April 2020

Protein secretion is initiated at the endoplasmic reticulum by the COPII coat, which self-assembles to form vesicles. Here, we examine the mechanisms by which the outer scaffolding layer of the coat drives local assembly of a structure rigid enough to enforce membrane curvature, yet able to readily disassemble at the Golgi. An intrinsically disordered region in the outer coat protein, Sec31, drives binding with an inner coat layer via multiple distinct interfaces. Interactions are individually dispensable but combinatorially reinforce each other, suggesting coat oligomerization is driven by the cumulative effects of multivalent interactions. Such a multimodal assembly platform could be readily reversed at the Golgi via perturbation of each individual interface. These design principles provide an explanation for how cells build a powerful yet transient scaffold to direct vesicle traffic.
Complexity of the eukaryotic dolichol-linked oligosaccharide scramblase suggested by activity correlation profiling mass spectrometry
Authors: Verchère Alice , Cowton Andrew , Jenni Aurelio , Rauch Monika , Häner Robert , Graumann Johannes , Bütikofer Peter , Menon Anant K.
Published: April 2020

The canonical pathway ofN-linked protein glycosylation in yeast and humans involves transfer of the oligosaccharide moiety from the glycolipid Glc3Man9GlcNAc2-PP-dolichol to select asparagine residues in proteins that have been translocated into the lumen of the endoplasmic reticulum (ER). Synthesis of Glc3Man9GlcNAc2-PP-dolichol occurs in two stages, producing first the key intermediate Man5GlcNAc2-PP-dolichol (M5-DLO) on the cytoplasmic face of the ER, followed by translocation of M5-DLO across the ER membrane to the luminal leaflet where the remaining glycosyltransfer reactions occur to complete the structure. Despite its critical importance forN-glycosylation, the scramblase protein that mediates the translocation of M5-DLO across the ER membrane has not been identified. Building on our ability to recapitulate scramblase activity in large unilamellar proteoliposomes reconstituted with a crude mixture of ER membrane proteins, we developed a mass spectrometry-based ‘activity correlation profiling’ approach to identify scramblase candidates in the yeastSaccharomyces cerevisiae. Curation of the activity correlation profiling data prioritized six polytopic ER membrane proteins as scramblase candidates, but reconstitution-based assays and gene disruption in the protistTrypanosoma bruceirevealed, unexpectedly, that none of these proteins were necessary for M5-DLO scramblase activity. Our results instead suggest the possibility that the M5-DLO scramblase may be a protein, or protein complex, whose activity is regulated at the level of quaternary structure. This key insight will aid future attempts to identify the scramblase.
Analysis ofTreponema pallidumstrains from China using improved methods for whole-genome sequencing from primary syphilis chancres
Authors: Chen Wentao , Smajs David , Hu Yongfei , Ke Wujian , Pospíšilová Petra , Hawley Kelly L. , Caimano Melissa J. , Radolf Justin D. , Sena Arlene , Tucker Joseph D. , Yang Bin , Juliano Jonathan J. , Zheng Heping , Parr Jonathan B.
Published: April 2020

Whole-genome sequencing (WGS) ofTreponema pallidumsubsp.pallidum(TPA) has been constrained by the lack ofin vitrocultivation methods for isolating spirochetes from patient samples. We built upon recently developed enrichment methods to sequence TPA directly from primary syphilis chancre swabs collected in Guangzhou, China. By combining parallel, pooled whole-genome amplification (ppWGA) with hybrid selection, we generated high quality genomes from four of eight chancre-swab samples and two of two rabbit-passaged isolates, all subjected to challenging storage conditions. This approach enabled the first WGS of Chinese samples without rabbit passage and provided insights into TPA genetic diversity in China.