bluuebunny/crossref_metadata_2025_split huggingface dataset:
High and increasing prevalence of SARS-CoV-2 swab positivity in England during end September beginning October 2020: REACT-1 round 5 updated report
Authors: Riley Steven , Ainslie Kylie E. C. , Eales Oliver , Walters Caroline E. , Wang Haowei , Atchison Christina , Fronterre Claudio , Diggle Peter J. , Ashby Deborah , Donnelly Christl A. , Cooke Graham , Barclay Wendy , Ward Helen , Darzi Ara , Elliott Paul 
Published: October 2020

AbstractBackgroundREACT-1 is quantifying prevalence of SARS-CoV-2 infection among random samples of the population in England based on PCR testing of self-administered nose and throat swabs. Here we report results from the fifth round of observations for swabs collected from the 18th September to 5th October 2020. This report updates and should be read alongside our round 5 interim report.MethodsRepresentative samples of the population aged 5 years and over in England with sample size ranging from 120,000 to 175,000 people at each round. Prevalence of PCR-confirmed SARS-CoV-2 infection, estimation of reproduction number (R) and time trends between and within rounds using exponential growth or decay models.Results175,000 volunteers tested across England between 18th September and 5th October. Findings show a national prevalence of 0.60% (95% confidence interval 0.55%, 0.71%) and doubling of the virus every 29 (17, 84) days in England corresponding to an estimated national R of 1.16 (1.05, 1.27). These results correspond to 1 in 170 people currently swab-positive for the virus and approximately 45,000 new infections each day. At regional level, the highest prevalence is in the North West, Yorkshire and The Humber and the North East with strongest regional growth in North West, Yorkshire and The Humber and West Midlands.ConclusionRapid growth has led to high prevalence of SARS-CoV-2 virus in England, with highest rates in the North of England. Prevalence has increased in all age groups, including those at highest risk. Improved compliance with existing policy and, as necessary, additional interventions are required to control the spread of SARS-CoV-2 in the community and limit the numbers of hospital admissions and deaths from COVID-19.
Network Graph Representation of COVID-19 Scientific Publications to Aid Knowledge Discovery
Authors: Cernile George , Heritage Trevor , Sebire Neil J , Gordon Ben , Schwering Taralyn , Kazemlou Shana , Borecki Yulia 
Published: October 2020

AbstractIntroductionNumerous scientific journal articles have been rapidly published related to COVID-19 making navigation and understanding of relationships difficult.MethodsA graph network was constructed from the publicly available CORD-19 database of COVID-19-related publications using an engine leveraging medical knowledgebases to identify discrete medical concepts and an open source tool (Gephi) used to visualise the network.ResultsThe network shows connections between disease, medication and procedures identified from title and abstracts of 195,958 COVID-19 related publications (CORD-19 Dataset). Connections between terms with few publications, those unconnected to the main network and those irrelevant were not displayed. Nodes were coloured by knowledgebase and node size related to the number of publications containing the term. The dataset and visualisations made publicly accessible via a webtool.ConclusionKnowledge management approaches (text mining and graph networks) can effectively allow rapid navigation and exploration of entity interrelationships to improve understanding of diseases such as COVID-19.
Homeostatic depression shows heightened sensitivity to synaptic calcium
Authors: Yeates Catherine J. , Frank C. Andrew 
Published: October 2020

AbstractSynapses and circuits rely on homeostatic forms of regulation in order to transmit meaningful information. TheDrosophila melanogasterneuromuscular junction (NMJ) is a well-studied synapse that shows robust homeostatic control of function. Most prior studies of homeostatic plasticity at the NMJ have centered on presynaptic homeostatic potentiation (PHP). PHP happens when postsynaptic muscle neurotransmitter receptors are impaired, triggering retrograde signaling that causes an increase in presynaptic neurotransmitter release. As a result, normal levels of evoked excitation are maintained. The counterpart to PHP at the NMJ is presynaptic homeostatic depression (PHD). Overexpression of the Drosophila vesicular glutamate transporter (VGlut) causes an increase in the amplitude of spontaneous events. PHD happens when the synapse responds to the challenge by decreasing quantal content during evoked neurotransmission – again, resulting in normal levels of postsynaptic excitation.We hypothesized that there may exist a class of molecules that affects both PHP and PHD. Impairment of any such molecule could hurt a synapse’s ability to respond to any significant homeostatic challenge. We conducted an electrophysiology-based screen for blocks of PHD. We did not observe a block of PHD in the genetic conditions screened, but we did find loss-of-function conditions that led to a substantial deficit in evoked amplitude when combined with VGlut overexpression. The conditions causing this phenotype included a double heterozygous loss-of-function condition for genes encoding the inositol trisphosphate receptor (IP3R –itpr) and ryanodine receptor (RyR). IP3Rs and RyRs gate calcium release from intracellular stores. Pharmacological agents targeting IP3R and RyR recapitulated the genetic losses of these factors, as did lowering calcium levels from other sources. Our data are consistent with the idea that the homeostatic signaling process underlying PHD is especially sensitive to levels of calcium at the presynapse.
Enzymatic analysis of yeast cell wall-resident GAPDH and its secretion
Authors: Cohen Michael J. , Philippe Brianne , Lipke Peter N. 
Published: October 2020

AbstractIn yeast, many proteins are found both in the cytoplasmic and extracellular compartments, and consequently it can be difficult to distinguish non-conventional secretion from cellular leakage. We therefore monitored extracellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity of intact cells as a specific marker for non-conventional secretion. Extracellular GAPDH activity was proportional to the number of cells assayed, increased with incubation time, and was dependent on added substrates. Preincubation of intact cells with 100μM dithiothreitol increased the reaction rate, consistent with increased access of the enzyme after reduction of cell wall disulfide crosslinks. Such treatment did not increase cell permeability to propidium iodide, in contrast to effects of higher concentrations of reducing agents. An amine-specific membrane-impermeant biotinylation reagent specifically inactivated extracellular GAPDH. The enzyme was secreted again after a 30-60-minute lag following the inactivation, and there was no concomitant increase in propidium iodide staining. There were about 4 × 104active GAPDH molecules per cell at steady state, and secretion studies showed replenishment to that level one hour after inactivation. These results establish conditions for specific quantitative assays of cell wall proteins in the absence of cytoplasmic leakage and for subsequent quantification of secretion rates in intact cells.ImportanceEukaryotic cells secrete many proteins, including many proteins that do not follow the classical secretion pathway. Among these, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is unexpectedly found in the walls of yeasts and other fungi, and in extracellular space in mammalian cell cultures. It is difficult to quantify extracellular GAPDH, because leakage of just a little of the very large amount of cytoplasmic enzyme can invalidate the determinations. We used enzymatic assays of intact cells, while also maintaining membrane integrity. The results lead to estimates of the amount of extracellular enzyme, and its rate of secretion to the wall in intact cells. Therefore, enzyme assays under controlled conditions can be used to investigate non-conventional secretion more generally.
Nonameric structures of the cytoplasmic domain of FlhA and SctV in the context of the full-length protein
Authors: Kuhlen Lucas , Johnson Steven , Cao Jerry , Deme Justin C. , Lea Susan M. 
Published: October 2020

AbstractType three secretion is the mechanism of protein secretion found in bacterial flagella and injectisomes. At its centre is the export apparatus (EA), a complex of five membrane proteins through which secretion substrates pass the inner membrane. While the complex formed by four of the EA proteins has been well characterised structurally, little is known about the structure of the membrane domain of the largest subunit, FlhA in flagella, SctV in injectisomes. Furthermore, the biologically relevant nonameric assembly of FlhA/SctV has been infrequently observed and differences in conformation of the cytoplasmic portion of FlhA/SctV between open and closed states have been suggested to reflect secretion system specific differences. FlhA has been shown to bind to chaperone-substrate complexes in an open state, but in previous assembled ring structures, SctV is in a closed state. Here, we identify FlhA and SctV homologues that can be recombinantly produced in the oligomeric state and study them using cryo-electron microscopy. The structures of the cytoplasmic domains from both FlhA and SctV are in the open state and we observe a conserved interaction between a short stretch of residues at the N-terminus of the cytoplasmic domain, known as FlhAL/SctVL, with a groove on the adjacent protomer’s cytoplasmic domain, which stabilises the nonameric ring assembly.
A delayed modulation of solar ultraviolet radiation on the COVID-19 transmission reflects an incubation period
Authors: He Maosheng , Fang Keyan , Zhou Feifei , Ou Tinghai , Chen Deliang 
Published: October 2020

Laboratory experiments have revealed the meteorological sensitivity of the coronavirus disease 2019 (COVID-19) virus. However, no consensus has been reached about how outdoor meteorological conditions modulate the virus transmission as it is also constrained by non-meteorological conditions. Here, we find that statistically, non-meteorological factors constrain the growth rate of cumulative confirmed cases least when the cases in a country arrive around 1300–3200. The least-constrained growth rate correlates with the ultraviolet flux and temperature significantly (correlation coefficientsr=-0.55±0.09 and -0.40±0.10 atp <0.01, respectively), but not with precipitation, humidity, and wind. The ultraviolet correlation exhibits a delay of about seven days, providing a meteorological measure of the incubation period. Our work reveals a seasonality of COVID-19 and a high risk of a pandemic resurgence in winter, implying a need for seasonal adaption in public policies.One-sentence summaryA delayed modulation of ultraviolet radiation on the COVID-19 transmission provides independent evidence for a 7-day incubation period and implies a strong seasonality
Countering the potential re-emergence of a deadly infectious disease - information warfare, identifying strategic threats, launching countermeasures
Authors: Ali Rex N. , Rubin Harvey , Sarkar Saswati 
Published: October 2020

AbstractEradicated infectious diseases like smallpox can re-emerge through accident or designs of bioterrorists, and perpetrate heavy casualties. Currently, only a small percentage of the populace is vaccinated, and their protection is likely to have waned. Most therefore are susceptible today. And when the disease re-emerges the susceptible individuals may be manipulated by disinformation on Social Media to refuse vaccines. Thus, a combination of countermeasures consisting of antiviral drugs and vaccines and a range of policies for their application need to be investigated. Opinions as to receptivity of vaccines evolve with time through social exchanges over networks that overlap with but are not identical to the disease propagation networks. These couple the spread of the biological and information contagion and necessitate a joint investigation of the two. Towards these, we develop a computationally tractable metapopulation epidemiological model that captures the joint spatio-temporal evolution of smallpox and opinion dynamics. The computations based on the model show that opinion dynamics has a substantial impact on the fatality count. Towards understanding how perpetrators are likely to seed the infection we identify a) the initial distribution of infected individuals that maximize the overall fatality count regardless of mobility patterns, and b) which habitation structures are more vulnerable to outbreaks. We assess the relative efficacy of different countermeasures and conclude that a combination of vaccines and drugs minimizes the fatalities, and by itself, for smallpox, drugs reduce fatalities more than the vaccine. Accordingly, we assess the efficacies of three separate policies for administering the drugs and identify the best among them for various parameter combinations. When the availability of the drug is finite, we show that increase in its supply substantially reduces the overall fatality. Our findings lead to policy recommendations for public health and urban design authorities towards thwarting smallpox and other infectious disease outbreaks.
A pilot study of discovery and validation of peritoneal endometriosis biomarkers in peritoneal fluid and serum
Authors: Loy See Ling , Zhou Jieliang , Cui Liang , Tan Tse Yeun , Ee Tat Xin , Min Chern Bernard Su , Yen Chan Jerry Kok , Lee Yie Hou 
Published: October 2020

ObjectiveTo identify potential serum biomarkers in women with peritoneal endometriosis (PE) by first looking at its source in the peritoneal fluid (PF).DesignCase-control pilot studies, comprising independent discovery and validation sets.SettingKK Women’s and Children’s Hospital, Singapore.Patient(s)Women with laparoscopically confirmed PE and absence of endometriosis (control).Intervention(s)None.Main Outcome Measure(s)In the discovery set, we used untargeted liquid chromatography-mass spectrometry (LC-MS/MS) metabolomics, multivariable and univariable analyses to generate global metabolomic profiles of PF for endometriosis and to identify potential metabolites that could distinguish PE (n=10) from controls (n=31). Using targeted metabolomics, we validated the identified metabolites in PF and sera of cases (n=16 PE) and controls (n=19). We performed the area under the receiver-operating characteristics curve (AUC) analysis to evaluate the diagnostic performance of PE metabolites.Result(s)In the discovery set, PF phosphatidylcholine (34:3) and phenylalanyl-isoleucine were significantly increased in PE than controls groups, with AUC 0.77 (95% confidence interval 0.61-0.92; p=0.018) and AUC 0.98 (0.95-1.02; p<0.001), respectively. In the validation set, phenylalanyl-isoleucine retained discriminatory performance to distinguish PE from controls in both PF (AUC 0.77; 0.61-0.92; p=0.006) and serum samples (AUC 0.81; 0.64-0.99; p=0.004).Conclusion(s)Our preliminary results propose phenylalanyl-isoleucine as a potential biomarker of PE, which may be used as a minimally-invasive diagnostic biomarker of PE.
Virus detection and identification in minutes using single-particle imaging and deep learning
Authors: Shiaelis Nicolas , Tometzki Alexander , Peto Leon , McMahon Andrew , Hepp Christof , Bickerton Erica , Favard Cyril , Muriaux Delphine , Andersson Monique , Oakley Sarah , Vaughan Alison , Matthews Philippa C. , Stoesser Nicole , Crook Derrick , Kapanidis Achillefs N. , Robb Nicole C. 
Published: October 2020

ABSTRACTThe increasing frequency and magnitude of viral outbreaks in recent decades, epitomized by the current COVID-19 pandemic, has resulted in an urgent need for rapid and sensitive diagnostic methods. Here, we present a methodology for virus detection and identification that uses a convolutional neural network to distinguish between microscopy images of single intact particles of different viruses. Our assay achieves labeling, imaging and virus identification in less than five minutes and does not require any lysis, purification or amplification steps. The trained neural network was able to differentiate SARS-CoV-2 from negative clinical samples, as well as from other common respiratory pathogens such as influenza and seasonal human coronaviruses. Additionally, we were able to differentiate closely related strains of influenza, as well as SARS-CoV-2 variants. Single-particle imaging combined with deep learning therefore offers a promising alternative to traditional viral diagnostic and genomic sequencing methods, and has the potential for significant impact.
Intra-operative Laxity Following Total Knee Arthroplasty is Highly Variable and Different Than Osteoarthritic and Normal Knees
Authors: Siston Robert A. , Hutter Erin E. , Ewing Joseph A. , Hall Rachel K. , Granger Jeffrey F. , Beal Matthew D. 
Published: October 2020

AbstractBackgroundAchieving a stable joint is an important yet challenging part of total knee arthroplasty (TKA). Neither manual manipulation of the knee nor instrumented sensors biomechanically characterize knee laxity or objectively characterize how TKA changes the laxity of an osteoarthritic (OA) knee. Therefore, the purposes of this study were: 1) objectively characterize changes in knee laxity due to TKA, 2) objectively determine whether TKA resulted in equal amounts of varus-valgus motion under a given load (i.e., balance) and 3) determine how TKA knee laxity and balance differ from values seen in non-osteoarthritic knees.MethodsTwo surgeons used a custom navigation system and intra-operative device to record varus-valgus motion under quantified loads in a cohort of 31 patients (34 knees) undergoing primary TKA. Similar data previously were collected from a cohort of 42 native cadaveric knees.ResultsPerforming a TKA resulted in a “looser knee” on average, but great variability existed within and between surgeons. Under the maximum applied moment, 20 knees were “looser” in the varus-valgus direction, while 14 were “tighter”. Surgeon 1 generally “loosened” knees (OA laxity 6.1°±2.3°, TKA laxity 10.1°±3.6°), while Surgeon 2 did not substantially alter knee laxity (OA laxity 8.2°±2.4°, TKA laxity 7.5°±3.3°). TKA resulted in balanced knees, and, while several differences in laxity were observed between OA, TKA, and cadaveric knees, balance was only different under the maximum load between OA and cadaveric knees.ConclusionsLarge variability exists within and between surgeons suggests in what is considered acceptable laxity and balance of the TKA knee when it is assessed by only manual manipulation of the leg. Knees were “balanced” yet displayed different amounts of motion under applied load.Clinical RelevanceOur results suggest that current assessments of knee laxity may leave different patients with biomechanically different knees. Objective intra-operative measurements should inform surgical technique to ensure consistency across different patients.Level of EvidenceLevel II prospective observational study
A 3D Structural Interactome to Explore the Impact of Evolutionary Divergence, Population Variation, and Small-molecule Drugs on SARS-CoV-2-Human Protein-Protein Interactions
Authors: Wierbowski Shayne D. , Liang Siqi , Chen You , Andre Nicole M. , Lipkin Steven M. , Whittaker Gary R. , Yu Haiyuan 
Published: October 2020

AbstractThe recent COVID-19 pandemic has sparked a global public health crisis. Vital to the development of informed treatments for this disease is a comprehensive understanding of the molecular interactions involved in disease pathology. One lens through which we can better understand this pathology is through the network of protein-protein interactions between its viral agent, SARS-CoV-2, and its human host. For instance, increased infectivity of SARS-CoV-2 compared to SARS-CoV can be explained by rapid evolution along the interface between the Spike protein and its human receptor (ACE2) leading to increased binding affinity. Sequence divergences that modulate other protein-protein interactions may further explain differences in transmission and virulence in this novel coronavirus. To facilitate these comparisons, we combined homology-based structural modeling with the ECLAIR pipeline for interface prediction at residue resolution, and molecular docking with PyRosetta. This enabled us to compile a novel 3D structural interactome meta-analysis for the published interactome network between SARS-CoV-2 and human. This resource includes docked structures for all interactions with protein structures, enrichment analysis of variation along interfaces, predicted ΔΔG between SARS-CoV and SARS-CoV-2 variants for each interaction, predicted impact of natural human population variation on binding affinity, and a further prioritized set of drug repurposing candidates predicted to overlap with protein interfaces†. All predictions are available online†for easy access and are continually updated when new interactions are published.† Some sections of this pre-print have been redacted to comply with current bioRxiv policy restricting the dissemination of purely in silico results predicting potential therapies for SARS-CoV-2 that have not undergone thorough peer-review. The results section titled “Prioritization of Candidate Inhibitors of SARS-CoV-2-Human Interactions Through Binding Site Comparison,” Figure 4, Supplemental Table 9, and all links to our web resource have been removed. Blank headers left in place to preserve structure and item numbering. Our full manuscript will be published in an appropriate journal following peer-review.
Global Constraints within the Developmental Program of theDrosophilaWing
Authors: Alba Vasyl , Carthew James E. , Carthew Richard W. , Mani Madhav 
Published: October 2020

ABSTRACTOrganismal development is a complex process, involving a vast number of molecular constituents interacting on multiple spatio-temporal scales in the formation of intricate body structures. Despite this complexity, development is remarkably reproducible and displays tolerance to both genetic and environmental perturbations. This robust-ness implies the existence of hidden simplicities in developmental programs. Here, using theDrosophilawing as a model system, we develop a new quantitative strategy that enables a robust description of biologically salient phenotypic variation. Analyzing natural phenotypic variation across a highly outbred population, and variation generated by weak perturbations in genetic and environmental conditions, we observe a highly constrained set of wing phenotypes. Remarkably, the phenotypic variants can be described by a single integrated mode that corresponds to a non-intuitive combination of structural variations across the wing. This work demonstrates the presence of constraints that funnel environmental inputs and genetic variation into phenotypes stretched along a single axis in morphological space. Our results provide quantitative insights into the nature of robustness in complex forms while yet accommodating the potential for evolutionary variations. Methodologically, we introduce a general strategy for finding such invariances in other developmental contexts.