bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insights into the secondary structural ensembles of the full SARS-CoV-2 RNA genome in infected cells
Authors: Lan Tammy C. T. , Allan Matthew F. , Malsick Lauren E. , Khandwala Stuti , Nyeo Sherry S. Y. , Sun Yu , Guo Junjie U. , Bathe Mark , Griffiths Anthony , Rouskin Silvi 
Published: July 2020

SummarySARS-CoV-2 is a betacoronavirus with a single-stranded, positive-sense, 30-kilobase RNA genome responsible for the ongoing COVID-19 pandemic. Currently, there are no antiviral drugs with proven efficacy, and development of these treatments are hampered by our limited understanding of the molecular and structural biology of the virus. Like many other RNA viruses, RNA structures in coronaviruses regulate gene expression and are crucial for viral replication. Although genome and transcriptome data were recently reported, there is to date little experimental data on native RNA structures in SARS-CoV-2 and most putative regulatory sequences are functionally uncharacterized. Here we report secondary structure ensembles of the entire SARS-CoV-2 genome in infected cells at single nucleotide resolution using dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) and the algorithm ‘detection of RNA folding ensembles using expectation–maximization’ clustering (DREEM). Our results reveal previously undescribed alternative RNA conformations across the genome, including structures of the frameshift stimulating element (FSE), a major drug target, that are drastically different from prevailingin vitropopulation average models. Importantly, we find that this structural ensemble promotes frameshifting rates (~40%) similar toin vivoribosome profiling studies and much higher than the canonical minimal FSE (~20%). Overall, our result highlight the value of studying RNA folding in its native, dynamic and cellular context. The genomic structures detailed here lays the groundwork for coronavirus RNA biology and will guide the design of SARS-CoV-2 RNA-based therapeutics.
Integrated glycoproteomics identifies a role ofN-glycosylation and galectin-1 on myogenesis and muscle development
Authors: Blazev Ronnie , Ashwood Christopher , Abrahams Jodie L. , Chung Long H. , Francis Deanne , Yang Pengyi , Watt Kevin I. , Qian Hongwei , Quaife-Ryan Gregory A. , Hudson James E. , Gregorevic Paul , Thaysen-Andersen Morten , Parker Benjamin L. 
Published: July 2020

ABSTRACTMany cell surface and secreted proteins are modified by the covalent addition of glycans that play an important role in the development of multicellular organisms. These glycan modifications enable communication between cells and the extracellular matrix via interactions with specific glycan-binding lectins and the regulation of receptor-mediated signaling. Aberrant protein glycosylation has been associated with the development of several muscular diseases suggesting essential glycan- and lectin-mediated functions in myogenesis and muscle development but our molecular understanding of the precise glycans, catalytic enzymes and lectins involved remain only partially understood. Here, we quantified dynamic remodeling of the membrane-associated proteome during a time-course of myogenesis in cell culture. We observed wide-spread changes in the abundance of several important lectins and enzymes facilitating glycan biosynthesis. Glycomics-based quantification of releasedN-linked glycans confirmed remodeling of the glycome consistent with the regulation of glycosyltransferases and glycosidases responsible for their formation including a previously unknown di-galactose-to-sialic acid switch supporting a functional role of these glycoepitopes in myogenesis. Furthermore, dynamic quantitative glycoproteomic analysis with multiplexed stable isotope labelling and analysis of enriched glycopeptides with multiple fragmentation approaches identified glycoproteins modified by these regulated glycans including several integrins and growth factor receptors. Myogenesis was also associated with the regulation of several lectins most notably the up-regulation of galectin-1 (LGALS1). CRISPR/Cas9-mediated deletion ofLgals1inhibited differentiation and myotube formation suggesting an early functional role of galectin-1 in the myogenic program. Importantly, similar changes inN-glycosylation and the up-regulation of galectin-1 during postnatal skeletal muscle development were observed in mice. Treatment of new-born mice with recombinant adeno-associated viruses to overexpress galectin-1 in the musculature resulted in enhanced muscle mass. Our data form a valuable resource to further understand the glycobiology of myogenesis and will aid the development of intervention strategies to promote healthy muscle development or regeneration.
Discovery of Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 In Vitro
Authors: Bobrowski Tesia , Chen Lu , Eastman Richard T. , Itkin Zina , Shinn Paul , Chen Catherine , Guo Hui , Zheng Wei , Michael Sam , Simeonov Anton , Hall Matthew D. , Zakharov Alexey V. , Muratov Eugene N. 
Published: July 2020

AbstractCOVID-19 is undoubtedly the most impactful viral disease of the current century, afflicting millions worldwide. As yet, there is not an approved vaccine, as well as limited options from existing drugs for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2. Usingin silicoapproaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested themin vitro. Overall, we identified 16 synergistic and 8 antagonistic combinations, 4 of which were both synergistic and antagonistic in a dose-dependent manner. Among the 16 synergistic cases, combinations of nitazoxanide with three other compounds (remdesivir, amodiaquine and umifenovir) were the most notable, all exhibiting significant synergy against SARS-CoV-2. The combination of nitazoxanide, an FDA-approved drug, and remdesivir, FDA emergency use authorization for the treatment of COVID-19, demonstrate a strong synergistic interaction. Notably, the combination of remdesivir and hydroxychloroquine demonstrated strong antagonism. Overall, our results emphasize the importance of both drug repurposing and preclinical testing of drug combinations for potential therapeutic use against SARS-CoV-2 infections.
Membrane pore energetics and the pathways to membrane rupture
Authors: An Dong , Thiyagarajan Sathish , Antipov Egor , Alcott Brett , O’Shaughnessy Ben 
Published: July 2020

AbstractBiological membranes owe their strength and low permeability to the phospholipid bilayers at their core. Membrane strength is determined by the energetics and dynamics of membrane pores, whose tension-dependent nucleation and growth leads to rupture. Creation of nanoscale membrane pores is central to exocytosis, trafficking and other processes fundamental to life that require breaching of secure plasma or organelle membranes, and is the basis for biotechnologies using drug delivery, delivery of genetic material for gene editing and antimicrobial peptides. A prevailing view from seminal electroporation and membrane rupture studies is that pore growth and bilayer rupture are controlled by macroscopically long-lived metastable defect states that precede fully developed pores. It was argued that defect nucleation becomes rate-limiting at high tensions, explaining the exponential tension-dependence of rupture times [E. Evans et al.,Biophys. J.85, 2342-2350 (2003)]. Here we measured membrane pore free energies and bilayer rupture using highly coarse-grained simulations that probe very long time scales. We find no evidence of metastable pore states. At lower tensions, small hydrophobic pores mature into large hydrophilic pores on the pathway to rupture, with classical tension dependence of rupture times. Above a critical tension membranes rupture directly from a small hydrophobic pore, and rupture times depend exponentially on tension. Thus, we recover the experimentally reported regimes, but the origin of the high tension exponential regime is unrelated to macroscopically long-lived pre-pore defects. It arises because hydrophilic pores cannot exist above a critical tension, leading to radically altered pore dynamics and rupture kinetics.
A simple, safe and sensitive method for SARS-CoV-2 inactivation and RNA extraction for RT-qPCR
Authors: Kalnina Lelde , Mateu-Regué Àngels , Oerum Stephanie , Hald Annemette , Gerstoft Jan , Oerum Henrik , Nielsen Finn Cilius , Iversen Astrid K.N. 
Published: July 2020

ABSTRACTThe SARS-CoV-2 pandemic has created an urgent need for large amounts of diagnostic tests to detect viral RNA, which commercial suppliers are increasingly unable to deliver. In addition to the lack of availability, the current methods do not always fully inactivate the virus. Together, this calls for the development of safer methods for extraction and detection of viral RNA from patient samples that utilise readily available reagents and equipment present in most standard laboratories. We present a rapid and straightforward RNA extraction protocol for inactivating the SARS-CoV-2 virus that uses standard lab reagents. This protocol expands analysis capacity as the inactivated samples can be used in RT-qPCR detection tests at laboratories not otherwise classified for viral work. The method circumvents the need for commercial RNA purification kits, takes about 30 minutes from swab to PCR-ready viral RNA, and enables downstream detection of SARS-CoV-2 by RT-qPCR with very high sensitivity (~4 viral RNA copies per RT-qPCR). In summary, we present a rapid, safe and sensitive method for high-throughput detection of SARS-CoV-2, that can be conducted in any laboratory equipped with a qPCR machine.
Pseudo-Likelihood Based Logistic Regression for Estimating COVID-19 Infection and Case Fatality Rates by Gender, Race, and Age in California
Authors: Xiong Di , Zhang Lu , Watson Gregory L. , Sundin Phillip , Bufford Teresa , Zoller Joseph A. , Shamshoian John , Suchard Marc A. , Ramirez Christina M. 
Published: July 2020

AbstractIn emerging epidemics, early estimates of key epidemiological characteristics of the disease are critical for guiding public policy. In particular, identifying high risk population subgroups aids policymakers and health officials in combatting the epidemic. This has been challenging during the coronavirus disease 2019 (COVID-19) pandemic, because governmental agencies typically release aggregate COVID-19 data as marginal summary statistics of patient demographics. These data may identify disparities in COVID-19 outcomes between broad population subgroups, but do not provide comparisons between more granular population subgroups defined by combinations of multiple demographics.We introduce a method that overcomes the limitations of aggregated summary statistics and yields estimates of COVID-19 infection and case fatality rates — key quantities for guiding public policy related to the control and prevention of COVID-19 — for population subgroups across combinations of demographic characteristics. Our approach uses pseudo-likelihood based logistic regression to combine aggregate COVID-19 case and fatality data with population-level demographic survey data to estimate infection and case fatality rates for population subgroups across combinations of demographic characteristics.We illustrate our method on California COVID-19 data to estimate test-based infection and case fatality rates for population subgroups defined by gender, age, and race and ethnicity. Our analysis indicates that in California, males have higher test-based infection rates and test-based case fatality rates across age and race/ethnicity groups, with the gender gap widening with increasing age. Although elderly infected with COVID-19 are at an elevated risk of mortality, the test-based infection rates do not increase monotonically with age. LatinX and African Americans have higher test-based infection rates than other race/ethnicity groups. The subgroups with the highest 5 test-based case fatality rates are African American male, Multi-race male, Asian male, African American female, and American Indian or Alaska Native male, indicating that African Americans are an especially vulnerable California subpopulation.
Multimodal imaging improves brain age prediction and reveals distinct abnormalities in patients with psychiatric and neurological disorders
Authors: Rokicki Jaroslav , Wolfers Thomas , Nordhøy Wibeke , Tesli Natalia , Quintana Daniel S. , Alnæs Dag , Richard Genevieve , de Lange Ann-Marie G. , Lund Martina J. , Norbom Linn , Agartz Ingrid , Melle Ingrid , Nærland Terje , Selbæk Geir , Persson Karin , Nordvik Jan Egil , Schwarz Emanuel , Andreassen Ole A. , Kaufmann Tobias , Westlye Lars T. 
Published: July 2020

BackgroundThe deviation between chronological age and age predicted using brain MRI is a putative marker of brain health and disease-related deterioration. Age prediction based on structural MRI data shows high accuracy and sensitivity to common brain disorders. However, brain aging is complex and heterogenous, both in terms of individual differences and the biological processes involved. Here, we implemented a multimodal age prediction approach and tested the predictive value across patients with a range of disorders with distinct etiologies and clinical features.MethodsWe implemented a multimodal model to estimate brain age using different combinations of cortical area, thickness and sub-cortical volumes, cortical and subcortical T1/T2-weighted ratios, and cerebral blood flow (CBF) calculated from functional arterial spin labeling (ASL) data. For each of the 11 models we assessed the age prediction accuracy in HC n=761 and compared the resulting brain age gaps (BAGs) between each clinical group and age-matched subsets of HC in patients with Alzheimer’s disease (AD, n=54), mild cognitive impairment (MCI, n=88), subjective cognitive impairment (SCI, n=55), schizophrenia (SZ, n=156), bipolar disorder (BD, n=136), autism spectrum disorder (ASD, n=28).ResultsAmong the 11 models, we found highest age prediction accuracy in HC when integrating all modalities (mean absolute error=6.5 years). Beyond this global BAG, the area under the curve for the receiver-operating characteristics based on two-group case-control classifications showed strongest effects for AD and ASD in global T1-weighted BAG (T1w-BAG), while MCI, SCI, BD and SZ showed strongest effects in CBF-based BAGs.ConclusionsCombining multiple MRI modalities improves brain age prediction and reveals distinct deviations in patients with psychiatric and neurological disorders. The multimodal BAG was most accurate in predicting age in HC, while group differences between patients and controls were often larger for BAGs based on single modalities. These findings demonstrate that multidimensional phenotyping provides a mapping of overlapping and distinct pathophysiology in common disorders of the brain, and specifically suggest metabolic and neurovascular aberrations in SZ and at-risk and early stage dementia.
Droughts, cyclones, and intimate partner violence: A disastrous mix for Indian women
Authors: Rai Ayushi , Sharma Anupam Joya , Subramanyam Malavika A. 
Published: July 2020

AbstractIndia has reported a high prevalence of Intimate Partner Violence (IPV) against women over the years. Previous Western research have found an increased IPV risk among women in the aftermath of natural disasters, underscoring the need for such studies in India. We could not locate any study focusing on the impact of slow-onset versus rapid-onset disasters, which might have differing impacts on the vulnerable, especially on the incidence of IPV in India. Using data on ever-married women from the National Family Health Survey-4, we investigated the association of residing in districts exposed to a drought (N=31,045), and separately, to two cyclones (N=8469), with three forms of self-reported IPV against women (emotional, physical, and sexual). Survey-adjusted logistic regression models showed that exposure to cyclone was positively associated with emotional IPV (AOR: 1.59, CI: 1.20, 2.10) after adjusting for sociodemographic covariates. Although not statistically significant, exposure to cyclone was also positively associated with physical and sexual IPV, and drought with physical IPV. However, we did not find an association of drought with emotional and sexual violence. Notably, we corroborated previous findings that women from wealthier households, educated, and whose husbands had no history of alcohol consumption, were less likely to experience any form of IPV independent of the influence of other factors. These results highlight the potential increased risk of IPV following natural disasters. In a patriarchal society such as India vulnerable to climate-change, these sobering results highlight the need to prepare for the social disasters that might accompany natural disasters.
Social Distancing Causally Impacts the Spread of SARS-CoV-2: A U.S. Nationwide Event Study
Authors: Gagnon Louis , Gagnon Stephanie , Lloyd Jessica 
Published: July 2020

AbstractObjectivesTo assess the causal impact of a spontaneous relaxation of social distancing on the spread of SARS-CoV-2 in the United States (U.S.), while controlling for social mobility and state-imposed social distancing restrictions.DesignEvent study.SettingQuasi-experimental setting created by the U.S. nationwide protests precipitated by George Floyd’s tragic death on May 25, 2020.PopulationIndividuals in 3,142 U.S. counties from all 50 states and the District of Columbia.Main Outcome MeasuresThe number of daily confirmed COVID-19 cases in all U.S. counties between the period of January 22, 2020, and June 20, 2020, and the cumulative change in COVID-19 cases in protest counties relative to non-protest counties following the onset of the protests.ResultsWe document a country-wide increase of over 3·06 cases per day, per 100,000 population, following the onset of the protests (95%CI: 2·47–3·65), and a further increase of 1·73 cases per day, per 100,000 population, in the counties in which the protests took place (95%CI: 0·59–2·87). Relative to the week preceding the onset of the protests, this represents a 61·2% country-wide increase in COVID-19 cases, and a further 34·6% increase in the protest counties.ConclusionsOur study documents a significant increase in COVID-19 case counts in counties that experienced a protest, and we conclude that social distancing practices causally impact the spread of SARS-CoV-2. The observed effect cannot be explained by changes in social distancing restrictions and social mobility, and placebo tests rule out the possibility that this finding is attributable to chance. Our research informs policy makers and provides insights regarding the usefulness of social distancing as an intervention to minimize the spread of SARS-CoV-2.
Lungs contribute to solving the frog’s cocktail party problem by enhancing the spectral contrast of conspecific vocal signals
Authors: Lee N. , Christensen-Dalsgaard J. , White L. A. , Schrode K. M. , Bee M. A. 
Published: July 2020

AbstractNoise impairs signal perception and is a major source of selection on animal communication. Identifying adaptations that enable receivers to cope with noise is critical to discovering how animal sensory and communication systems evolve. We integrated biophysical and bioacoustic measurements with physiological modeling to demonstrate that the lungs of frogs serve a heretofore unknown noise-control function in vocal communication. Lung resonance enhances the signal-to-noise ratio for communication by selectively reducing the tympanum’s sensitivity at critical frequencies where the tuning of two inner ear organs overlaps. Social network analysis of citizen-science data on frog calling behavior indicates the calls of other frog species in multi-species choruses are a prominent source of environmental noise attenuated by the lungs. These data reveal that an ancient adaptation for detecting sound via the lungs has been evolutionarily co-opted to create spectral contrast enhancement that contributes to solving a multi-species cocktail party problem.
Development of RNA-based assay for rapid detection of SARS-CoV-2 in clinical samples
Authors: Kumar Vinod , Mishra Suman , Sharma Rajni , Agarwal Jyotsana , Ghoshal Ujjala , Khanna Tripti , Sharma Lokendra K. , Verma Santosh Kumar , Mishra Prabhakar , Tiwari Swasti 
Published: July 2020

AbstractThe ongoing spread of pandemic coronavirus disease (COVID-19) is caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). In the lack of specific drugs or vaccines for SARS-CoV-2, demands rapid diagnosis and management are crucial for controlling the outbreak in the community. Here we report the development of the first rapid-colorimetric assay capable of detecting SARS-CoV-2 in the human nasopharyngeal RNA sample in less than 30 minutes. We utilized a nanomaterial-based optical sensing platform to detect RNA-dependent RNA polymerase (RdRp) gene of SARS-CoV-2, where the formation of oligo probe-target hybrid led to salt-induced aggregation and changes in gold-colloid color from pink to blue in visible range. Accordingly, we found a change in colloid color from pink to blue in assay containing nasopharyngeal RNA sample from the subject with clinically diagnosed COVID-19. The colloid retained pink color when the test includes samples from COVID-19 negative subjects or human papillomavirus (HPV) infected women. The results were validated using nasopharangeal RNA samples from suspected COVID-19 subjects (n=136). Using RT-PCR as gold standard, the assay was found to have 85.29% sensitivity and 94.12% specificity. The optimized method has detection limit as little as 0.5 ng of SARS-CoV-2 RNA. Overall, the developed assay rapidly detects SARS-CoV-2 RNA in clinical samples in a cost-effective manner and would be useful in pandemic management by facilitating mass screening.
Oxidative stress pathogenically remodels the cardiac myocyte cytoskeleton via structural alterations to the microtubule lattice
Authors: Goldblum Rebecca R. , McClellan Mark , Hou Cody , Thompson Brian R. , White Kyle , Vang Hluechy X. , Cohen Houda , Metzger Joseph M. , Gardner Melissa K. 
Published: July 2020

AbstractIn the failing heart, the cardiac myocyte microtubule network is remodeled, which increases cellular stiffness and disrupts contractility, contributing to heart failure and death. However, the origins of this deleterious cytoskeletal reorganization are unknown. We now find that oxidative stress, a condition characteristic of failing heart cells, leads to cysteine oxidation of microtubules. Further, our electron and fluorescence microscopy experiments revealed regions of structural damage within the oxidized microtubule lattice. These damaged regions led to the lengthening, realignment, and acetylation of dynamic microtubules within cardiac myocytes. Thus, we found that oxidative stress acts inside of cardiac myocytes to facilitate a dramatic, pathogenic shift from a dynamic, multifaceted microtubule network into a highly acetylated, longitudinally aligned, and static microtubule network. Our results demonstrate how a disease condition characterized by oxidative stress can trigger a molecular oxidation event, which propagates a toxic cellular-scale transformation of the cardiac myocyte microtubule network.