bluuebunny/crossref_metadata_2025_split huggingface dataset:
Are Our COVID Warriors Cared-for Enough? A Nationwide Survey on Stress Among Doctors During the COVID-19 Pandemic
Authors: Nair Amritha , Menon Jagadeesh , Rammohan Ashwin , Hakeem Abdul R , Cherukuri Sathya D , Shanmugam Naresh , Rajakumar Akila , Reddy Mettu S , Kaliamoorthy Ilankumaran , Rela Mohamed 
Published: July 2020

AbstractLimited and uneven accessibility to healthcare is a major impediment in the fight against the COVID-19 pandemic which continues on inexorably, across various parts of the globe. We conducted a nationwide survey of a large sample of Indian doctors to measure levels of perceived stress, identify risk factors for severe stress and assess their response to current issues related to safety and well-being of the HCP community. The survey found severely stressed doctors to be younger (<45years), of female gender working in the ICU setting and insecure regarding their finances. Concern regarding PPE shortages and ethical dilemmas of rationing care are factors inducing severe stress amongst doctors working in ICU settings. This is the first such survey done in the context of the COVID-19 pandemic from the Indian sub-continent. The findings have important implications on the International healthcare community, especially across Africa, Asia & South America where the contagion continues to wreak havoc. The survey has identified factors which adversely impact the mental health of doctors during this Pandemic. This can act as a valuable guide for governmental authorities, professional organisations and hospital managements to establish support systems at multiple levels for these “COVID Warriors”.
Oxygen and mortality in COVID-19 pneumonia: a comparative analysis of supplemental oxygen policies and health outcomes across 26 countries
Authors: Goyal Daniel K , Donnelly Harry , Kussner Albrecht , Neil James , Bhatti Sohail , Mansab Fatma 
Published: July 2020

ABSTRACTIntroductionHypoxia is the main cause of morbidity and mortality in COVID-19. During the COVID-19 pandemic some countries have reduced access to supplemental oxygen (e.g. oxygen rationing), whereas other nations have maintained and even improved access to supplemental oxygen. We examined whether such variation in the access to supplemental oxygen had any bearing on mortality in COVID-19.MethodsThree independent investigators searched for, identified and extracted the nationally recommended target oxygen levels for the commencement of oxygen in COVID-19 pneumonia from the 29 worst affected countries. Mortality estimates were calculated from three independent sources. We then applied linear regression analysis to examine for potential association between national targets for the commencement of oxygen and case fatality rates.ResultsOf the 26 nations included, 15 had employed conservative oxygen strategies to manage COVID-19 pneumonia. Of them, Belgium, France, USA, Canada, China, Germany, Mexico, Spain, Sweden and the UK guidelines advised commencing oxygen when oxygen saturations (SpO2) fell to 91% or less. Target SpO2 ranged from 92% to 95% in the other 16 nations. Linear regression analysis demonstrated a strong inverse correlation between the national target for the commencement of oxygen and national case fatality rates (Spearman’s Rho = −0.622, p < 0.001).ConclusionOur study highlights the disparity in oxygen provision for COVID-19 patients between the nations analysed, and indicates such disparity in access to supplemental oxygen may represent a modifiable factor associated with mortality during the pandemic.Key MessagesWhat is already known?There were no prospective clinical trials we could identify relating to COVID-19 and supplemental oxygen, nor any published studies examining access to supplemental oxygen and mortality in COVID-19.There are a number of studies identifying an association with low oxygen saturations at presentation and mortality in COVID-19 pneumonia.There is good quality evidence that a delay in the correction of hypoxia in pneumonia increases mortality.What are the new findings?This study highlights the different thresholds for commencing supplemental oxygen in patients with COVID-19 across 26 nations.Those countries that provide better access to supplemental oxygen have a statistically significant lower mortality rate.Our results support the consensus view that improving access to supplemental oxygen in COVID-19 pneumonia is likely to reduce mortality.
Sub-epidemic model forecasts for COVID-19 pandemic spread in the USA and European hotspots, February-May 2020
Authors: Chowell Gerardo , Rothenberg Richard , Roosa Kimberlyn , Tariq Amna , Hyman James M. , Luo Ruiyan 
Published: July 2020

AbstractMathematical models have been widely used to understand the dynamics of the ongoing coronavirus disease 2019 (COVID-19) pandemic as well as to predict future trends and assess intervention strategies. The asynchronicity of infection patterns during this pandemic illustrates the need for models that can capture dynamics beyond a single-peak trajectory to forecast the worldwide spread and for the spread within nations and within other sub-regions at various geographic scales. Here, we demonstrate a five-parameter sub-epidemic wave modeling framework that provides a simple characterization of unfolding trajectories of COVID-19 epidemics that are progressing across the world at different spatial scales. We calibrate the model to daily reported COVID-19 incidence data to generate six sequential weekly forecasts for five European countries and five hotspot states within the United States. The sub-epidemic approach captures the rise to an initial peak followed by a wide range of post-peak behavior, ranging from a typical decline to a steady incidence level to repeated small waves for sub-epidemic outbreaks. We show that the sub-epidemic model outperforms a three-parameter Richards model, in terms of calibration and forecasting performance, and yields excellent short- and intermediate-term forecasts that are not attainable with other single-peak transmission models of similar complexity. Overall, this approach predicts that a relaxation of social distancing measures would result in continuing sub-epidemics and ongoing endemic transmission. We illustrate how this view of the epidemic could help data scientists and policymakers better understand and predict the underlying transmission dynamics of COVID-19, as early detection of potential sub-epidemics can inform model-based decisions for tighter distancing controls.
Serial interval, basic reproduction number and prediction of COVID-19 epidemic size in Jodhpur, India
Authors: Saurabh Suman , Verma Mahendra Kumar , Gautam Vaishali , Goel Akhil , Gupta Manoj Kumar , Bhardwaj Pankaj , Misra Sanjeev 
Published: July 2020

ABSTRACTBackgroundUnderstanding the epidemiology of COVID-19 is important for design of effective control measures at local level. We aimed to estimate the serial interval and basic reproduction number for Jodhpur, India and to use it for prediction of epidemic size for next one month.MethodsContact tracing of SARS-CoV-2 infected individuals was done to obtain the serial intervals. Aggregate and instantaneousR0 values were derived and epidemic projection was done using R software v4.0.0.ResultsFrom among 79 infector-infectee pairs, the estimated median and 95 percentile values of serial interval were 5.98 days (95% CI 5.39 – 6.65) and 13.17 days (95% CI 11.27 – 15.57), respectively. The overallR0 value in the first 30 days of outbreak was 1.64 (95% CI 1.12 – 2.25) which subsequently decreased to 1.07 (95% CI 1.06 – 1.09). The instantaneousR0 value over 14 days window ranged from a peak of 3.71 (95% CI 1.85 -2.08) to 0.88 (95% CI 0.81 – 0.96) as on 24 June 2020. The projected COVID-19 case-load over next one month was 1881 individuals. Reduction ofR0 from 1.17 to 1.085 could result in 23% reduction in projected epidemic size over the next one month.ConclusionAggressive testing, contact-tracing and isolation of infected individuals in Jodhpur district resulted in reduction ofR0. Further strengthening of control measures could lead to substantial reduction of COVID-19 epidemic size. A data-driven strategy was found useful in surge capacity planning and guiding the public health strategy at local level.
Publicly available hiPSC lines with extreme polygenic risk scores for modeling schizophrenia
Authors: Rehbach Kristina , Zhang Hanwen , Das Debamitra , Abdollahi Sara , Prorok Tim , Ghosh Sulagna , Weintraub Sarah , Genovese Giulio , Powell Samuel , Lund Anina , Akbarian Schahram , Eggan Kevin , McCarroll Steven , Duan Jubao , Avramopoulos Dimitrios , Brennand Kristen J. 
Published: July 2020

ABSTRACTSchizophrenia (SZ) is a common and debilitating psychiatric disorder with limited effective treatment options. Although highly heritable, risk for this polygenic disorder depends on the complex interplay of hundreds of common and rare variants. Translating the growing list of genetic loci significantly associated with disease into medically actionable information remains an important challenge. Thus, establishing platforms with which to validate the impact of risk variants in cell-type-specific and donor-dependent contexts is critical. Towards this, we selected and characterize a collection of twelve human induced pluripotent stem cell (hiPSC) lines derived from control donors with extremely low and high SZ polygenic risk scores (PRS). These hiPSC lines are publicly available at the California Institute for Regenerative Medicine (CIRM). The suitability of these extreme PRS hiPSCs for CRISPR-based isogenic comparisons of neurons and glia was evaluated across three independent laboratories, identifying 9 out of 12 meeting our criteria. We report a standardized resource of publicly available hiPSCs, with which we collectively commit to conducting future CRISPR-engineering, in order to facilitate comparison and integration of functional validation studies across the field of psychiatric genetics.
Deviation from baseline mutation burden provides powerful and robust rare-variants association test for complex diseases
Authors: Jiang Lin , Jiang Hui , Dai Sheng , Chen Ying , Song Youqiang , Tang Clara Sze-Man , Wang Binbin , Garcia-Barcelo Maria-Mercedes , Tam Paul , Cherny Stacey S. , Sham Pak Chung , Li Miaoxin 
Published: July 2020

AbstractThe identification of rare variants that contribute to complex diseases is challenging due to low statistical power. Here we propose a novel and powerful rare variants association test based on the deviation of the observed mutational burden in a genomic region from a baseline mutation burden predicted by weighted recursive truncated negative-binomial regression (RUNNER) on genomic features available from public data. Simulation studies show that RUNNER is substantially more powerful than state-of-the-art rare variant association methods (including SKAT, CMC and KBAC), while maintaining correct type 1 error rates under population stratification and in small samples. Applied to real data, RUNNER “rediscovered” known genes of Hirschsprung disease missed by current methods, and detected promising new candidate genes, includingNXPE4for Hirschsprung disease andCXCL16for Alzheimer’s disease. The proposed approach provides a powerful and robust method to identify rare risk variants for complex diseases.
Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening
Authors: Kang Po Wei , Westerlund Annie M. , Shi Jingyi , White Kelli McFarland , Dou Alex K. , Cui Amy H. , Silva Jonathan R. , Delemotte Lucie , Cui Jianmin 
Published: July 2020

AbstractCalmodulin (CaM) and PIP2are potent regulators of the voltage-gated potassium channel KCNQ1 (KV7.1), which conducts the IKscurrent important for repolarization of cardiac action potentials. Although cryo-EM structures revealed intricate interactions between the KCNQ1 voltage-sensing domain (VSD), CaM, and PIP2, the functional consequences of these interactions remain unknown. Here, we show that CaM-VSD interactions act as a state-dependent switch to control KCNQ1 pore opening. Combined electrophysiology and molecular dynamics network analysis suggest that VSD transition into the fully-activated state allows PIP2to compete with CaM for binding to VSD, leading to the conformational change that alters the VSD-pore coupling. We identify a motif in the KCNQ1 cytosolic domain which works downstream of CaM-VSD interactions to facilitate the conformational change. Our findings suggest a gating mechanism that integrates PIP2and CaM in KCNQ1 voltage-dependent activation, yielding insights into how KCNQ1 gains the phenotypes critical for its function in the heart.
Evolution of DNA Replication Origin Specification and Gene Silencing Mechanisms
Authors: Hu Y. , Tareen A. , Sheu Y-J. , Ireland W. T. , Speck C. , Li H. , Joshua-Tor L. , Kinney J. B. , Stillman B. 
Published: July 2020

AbstractDNA replication in eukaryotic cells initiates from chromosomal locations, called replication origins, that bind the Origin Recognition Complex (ORC) prior to S phase. Origin establishment is guided by well-defined DNA sequence motifs in Saccharomyces cerevisiae and some other budding yeasts, but most eukaryotes lack sequence-specific origins. At present, the mechanistic and evolutionary reasons for this difference are unclear. A 3.9 Å structure of S. cerevisiae ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) bound to origin DNA revealed, among other things, that a loop within Orc2 inserts into a DNA minor groove and an α-helix within Orc4 inserts into a DNA major groove1. We show that this Orc4 α-helix mediates the sequence-specificity of origins in S. cerevisiae. Specifically, mutations were identified within this α-helix that alter the sequence-dependent activity of individual origins as well as change global genomic origin firing patterns. This was accomplished using a massively parallel origin selection assay analyzed using a custom mutual-information-based modeling approach and a separate analysis of whole-genome replication profiling and statistics. Interestingly, the sequence specificity of DNA replication initiation, as mediated by the Orc4 α-helix, has evolved in close conjunction with the gain of ORC-Sir4-mediated gene silencing and the loss of RNA interference.
New GFAP splice isoform (GFAPμ) differentially expressed in glioma translates into 21 kDa N-terminal GFAP protein
Authors: van Bodegraven Emma J. , Sluijs Jacqueline A. , Tan A. Katherine , Robe Pierre A.J.T. , Hol Elly M. 
Published: July 2020

AbstractThe glial fibrillary acidic protein (GFAP) is a type III intermediate filament (IF) protein that is highly expressed in astrocytes, neural stem cells, and in gliomas. Gliomas are a heterogeneous group of primary brain tumors that arise from glia cells or neural stem cells and rely on accurate diagnosis for prognosis and treatment strategies. GFAP is differentially expressed between glioma subtypes and therefore often used as a diagnostic marker. However, GFAP is highly regulated by the process of alternative splicing; many different isoforms have been identified. Differential expression of GFAP isoforms between glioma subtypes suggests that GFAP isoform-specific analyses could benefit diagnostics. In this study we report on the differential expression of a new GFAP isoform between glioma subtypes, GFAPμ. A short GFAP transcript resulting from GFAP exon 2 skipping was detected by RNA sequencing of human glioma. We show that GFAPμ mRNA is expressed in healthy brain tissue, glioma cell lines, and primary glioma cells and that it translates into a~21 kDa GFAP protein. 21 kDa GFAP protein was detected in the IF protein fraction isolated from human spinal cord as well. We further show that induced GFAPμ expression disrupts the GFAP IF network. The characterization of this new GFAP isoform adds on to the numerous previously identified GFAP splice isoforms. It emphasizes the importance of studying the contribution of IF splice variants to specialized functions of the IF network and to glioma diagnostics.Summary statementRNA sequencing data of glioma patient material reveals the differential expression of a short GFAP splice isoform,GFAPμ, between glioma subtypes.GFAPμtranslates into a 21 kDa N-terminal GFAP protein which can disrupt the GFAP intermediate filament network.
Allostery through DNA drives phenotype switching
Authors: Rosenblum Gabriel , Elad Nadav , Rozenberg Haim , Wiggers Felix , Hofmann Hagen 
Published: July 2020

SummaryAllostery is a pervasive principle to regulate protein function. Here, we show that DNA also transmits allosteric signals over long distances to boost the binding cooperativity of transcription factors. Phenotype switching inBacillus subtilisrequires an all-or-none promoter binding of multiple ComK proteins. Using single-molecule FRET, we find that ComK-binding at one promoter site increases affinity at a distant site. Cryo-EM structures of the complex between ComK and its promoter demonstrate that this coupling is due to mechanical forces that alter DNA curvature. Modifications of the spacer between sites tune cooperativity and show how to control allostery, which paves new ways to design the dynamic properties of genetic circuits.
Large-scale curvature sensing by epithelial monolayers depends on active cell mechanics and nuclear mechanoadaptation
Authors: Luciano Marine , Xue Shi-Lei , De Vos Winnok H. , Morata Lorena Redondo , Surin Mathieu , Lafont Frank , Hannezo Edouard , Gabriele Sylvain 
Published: July 2020

AbstractWhile many tissues foldin vivoin a highly reproducible and robust way, epithelial folds remain difficult to reproducein vitro, so that the effects and underlying mechanisms of local curvature on the epithelial tissue remains unclear. Here, we photoreticulated polyacrylamide hydrogels though an optical photomask to create corrugated hydrogels with isotropic wavy patterns, allowed us to show that concave and convex curvatures affect cellular and nuclear shape. By culturing MDCK epithelial cells at confluency on corrugated hydrogels, we showed that the substrate curvature leads to thicker epithelial zones in the valleys and thinner ones on the crest, as well as corresponding density, which can be generically explained by a simple 2D vertex model, leading us to hypothesize that curvature sensing could arise from resulting density/thickness changes. Additionally, positive and negative local curvatures lead to significant modulations of the nuclear morphology and positioning, which can also be well-explained by an extension of vertex models taking into account membrane-nucleus interactions, where thickness/density modulation generically translate into the corresponding changes in nuclear aspect ratio and position, as seen in the data. Consequently, we find that the spatial distribution of Yes associated proteins (YAP), the main transcriptional effector of the Hippo signaling pathway, is modulated in folded epithelial tissues according to the resulting thickness modulation, an effect that disappears at high cell density. Finally, we showed that these deformations are also associated with changes of A-type and B-type lamin expression, significant chromatin condensation and to lower cell proliferation rate. These findings show that active cell mechanics and nuclear mechanoadaptation are key players of the mechanistic regulation of epithelial monolayers to substrate curvature, with potential application for a number ofin vivosituations.
The Evolution of Sex Chromosome Dosage Compensation in Animals
Authors: Chen Jiabi , Wang Menghan , He Xionglei , Yang Jian-Rong , Chen Xiaoshu 
Published: July 2020

ABSTRACTThe evolution of sex chromosomes in the XY or ZW systems shall lead to gene expression dosage problems, as in at least one of the sexes, the sex-linked gene dose has been reduced by half. It has been proposed, most notably by Susumu Ohno for mammals, that the transcriptional output of the whole sex chromosome should be doubled for a complete dosage compensation. However, due to the variability of the existing methods to determine the transcriptional differences betweenSex chromosomes andAutosomes (S:A ratios) in different studies, whether clade-specific results are comparable and whether there is a more general model to explain dosage compensation states remain unanswered. In this study, we collected more than 500 public RNA-seq datasets from multiple tissues and species in major clades (including mammals, birds, fishes, insects, and worms) and proposed a unified computational framework for unbiased and comparable measurement of the S:A ratios of multiple species. We also tested the evolution of dosage compensation more directly by assessing changes in the expression levels of the current sex-linked genes relative to those of the ancestral sex-linked genes. We found that in mammals and birds, the S:A ratio is approximately 0.5, while in insects, fishes and flatworms, the S:A ratio is approximately 1. Further analysis showed that the fraction of dosage-sensitive housekeeping genes on the sex chromosome is significantly correlated with the S:A ratio. In addition, the degree of degradation of the Y chromosome may be responsible for the change in the S:A ratio in mammals without a dosage-compensation mechanism. Our observations offer unequivocal support for the sex chromosome insensitivity hypothesis in animals and suggest that the dosage sensitivity states of sex chromosomes is a major factor underlying different evolutionary strategies of dosage compensation.
Reward-specific satiety affects subjective value signals in orbitofrontal cortex during multi-component economic choice
Authors: Pastor-Bernier Alexandre , Stasiak Arkadiusz , Schultz Wolfram 
Published: July 2020

AbstractSensitivity to satiety constitutes a basic requirement for neuronal coding of subjective reward value. Satiety from natural on-going consumption affects reward functions in learning and approach behavior. More specifically, satiety reduces the subjective economic value of individual rewards during choice between options that typically contain multiple reward components. The unconfounded assessment of economic reward value requires tests at choice indifference between two options, which is difficult to achieve with sated rewards. By conceptualizing choices between options with multiple reward components (‘bundles’), Revealed Preference Theory may offer a solution. Despite satiety, choices against an unaltered reference bundle may remain indifferent when the reduced value of a sated bundle reward is compensated by larger amounts of an unsated reward of the same bundle; then the value loss of the sated reward is indicated by the amount of the added unsated reward. Here we show psychophysically titrated choice indifference in monkeys between bundles of differently sated rewards. Neuronal chosen value signals in orbitofrontal cortex (OFC) followed closely the subjective value change within recording periods of individual neurons. A neuronal classifier distinguishing the bundles and predicting choice substantiated the subjective value change. Choice between conventional single rewards confirmed the neuronal changes seen with two-reward bundles. Thus, reward-specific satiety reduces subjective reward value signals in OFC. With satiety being an important factor of subjective reward value, these results extend the notion of subjective economic reward value coding in OFC neurons.SignificanceOn-going consumption reduces the subjective value of rewards to different degrees depending on their individual properties, a phenomenon referred to as sensory-specific satiety. Such value change should be manifested in economic choices, and neuronal signals for subjective economic reward value should be sensitive to reward-specific satiety. We tested monkeys during choice between two options that each contained two different rewards (‘bundles’); the two rewards were prone to different degrees of satiety. On-going reward consumption affected choices in a way that indicated satiety-induced reward-specific change of subjective economic value. Neuronal responses in the monkey orbitofrontal cortex (OFC) followed the differential reduction of subjective economic value. These results satisfy a crucial requirement for subjective reward value coding in OFC neurons.