bluuebunny/crossref_metadata_2025_split huggingface dataset:
COVID-19 Test & Trace Success Determinants: Modeling On A Network
Authors: Reich Ofir 
Published: August 2020

AbstractWhat determines the success of a COVID-19 Test & Trace policy? We use an SEIR agent-based model on a graph, with realistic epidemiological parameters. Simulating variations in certain parameters of Testing & Tracing, we find that important determinants of successful containment are: (i) the time from symptom onset until a patient is self-isolated and tested, and (ii) the share of contacts of a positive patient who are successfully traced. Comparatively less important is (iii) the time of test analysis and contact tracing. When the share of contacts successfully traced is higher, the Test & Trace Time rises somewhat in importance. These results are robust to a wide range of values for how infectious presymptomatic patients are, to the amount of asymptomatic patients, to the network degree distribution and to base epidemic growth rate. We also provide mathematical arguments for why these simulation results hold in more general settings. Since real world Test & Trace systems and policies could affect all three parameters, Symptom Onset to Test Time should be considered, alongside test turnaround time and contact tracing coverage, as a key determinant of Test & Trace success.
Inflammasome activation in COVID-19 patients
Authors: Rodrigues Tamara S. , de Sá Keyla S.G. , Ishimoto Adriene Y. , Becerra Amanda , Oliveira Samuel , Almeida Leticia , Gonçalves Augusto V. , Perucello Debora B. , Andrade Warrison A. , Castro Ricardo , Veras Flavio P. , Toller-Kawahisa Juliana E. , Nascimento Daniele C. , de Lima Mikhael H.F. , Silva Camila M. S. , Caetite Diego B. , Martins Ronaldo B. , Castro Italo A. , Pontelli Marjorie C. , de Barros Fabio C. , do Amaral Natália B. , Giannini Marcela C. , Bonjorno Letícia P. , Lopes Maria Isabel F. , Benatti Maíra N. , Santana Rodrigo C. , Vilar Fernando C. , Auxiliadora-Martins Maria , Luppino-Assad Rodrigo , de Almeida Sergio C.L. , de Oliveira Fabiola R. , Batah Sabrina S. , Siyuan Li , Benatti Maira N. , Cunha Thiago M. , Alves-Filho José C. , Cunha Fernando Q. , Cunha Larissa D. , Frantz Fabiani G. , Kohlsdorf Tiana , Fabro Alexandre T. , Arruda Eurico , de Oliveira Renê D.R. , Louzada-Junior Paulo , Zamboni Dario S. 
Published: August 2020

AbstractSevere cases of COVID-19 are characterized by a strong inflammatory process that may ultimately lead to organ failure and patient death. The NLRP3 inflammasome is a molecular platform that promotes inflammation via cleavage and activation of key inflammatory molecules including active caspase-1 (Casp1p20), IL-1β and IL-18. Although the participation of the inflammasome in COVID-19 has been highly speculated, the inflammasome activation and participation in the outcome of the disease is unknown. Here we demonstrate that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and it is active in COVID-19, influencing the clinical outcome of the disease. Studying moderate and severe COVID-19 patients, we found active NLRP3 inflammasome in PBMCs and tissues of post-mortem patients upon autopsy. Inflammasome-derived products such as Casp1p20 and IL-18 in the sera correlated with the markers of COVID-19 severity, including IL-6 and LDH. Moreover, higher levels of IL-18 and Casp1p20 are associated with disease severity and poor clinical outcome. Our results suggest that the inflammasome is key in the pathophysiology of the disease, indicating this platform as a marker of disease severity and a potential therapeutic target for COVID-19.
Unique monocyte transcriptomic profiles are associated with preclinical atherosclerosis in women with systemic lupus erythematosus (SLE)
Authors: Woodridge Laurel , Chocano Elvira C , Ashford Paul , Robinson George , Waddington Kirsty , Rahman Anisur , Orengo Christine , Jury Elizabeth C , Torra Inés Pineda 
Published: August 2020

AbstractWomen with Systemic Lupus Erythematosus (SLE) show significantly increased cardiovascular risk compared to the general population. However, despite CVD being a major cause of morbidity and mortality for these women, this increased risk is not managed clinically and tools to dissect and predict their cardiovascular risk are lacking. Notably, this elevated CVD risk is not captured by traditional risk factors. To explore molecular programs underlying asymptomatic atherosclerosis in SLE we used a well-characterised cohort of CVD-free women with SLE, scanned for asymptomatic atherosclerotic plaques using non-invasive ultrasound imaging of the carotid and femoral arteries. We investigated the transcriptomic profiles of CD14+ circulating monocytes in women with SLE with or without preclinical atherosclerosis. We identified unique monocytic gene expression profiles that distinguished the presence of preclinical plaques in women with SLE. In addition, advanced bioinformatic analysis revealed functional pathways and interactions between the genes identified that could explain mechanistic differences in plaque formation. We propose that these molecular signatures could help understand why a subset of women with SLE are predisposed to develop atherosclerosis and at higher risk of developing clinical CVD. Collectively with other efforts, these molecular insights will help to better define atherosclerosis in the context of SLE which will be critical for future patient stratification and identification of anti-atherosclerotic therapies.
Physioxia stimulates extra-cellular matrix deposition and increases mechanical properties of human chondrocyte-derived tissue-engineered cartilage
Authors: Dennis J E , Whitney G A , Rai J , Fernandes R J , Kean T J 
Published: August 2020

AbstractCartilage tissue has been recalcitrant to tissue engineering approaches. In this study, human chondrocytes were formed into self-assembled cartilage sheets, cultured in physiologic (5%) and atmospheric (20%) oxygen conditions and underwent biochemical, histological and biomechanical analysis at one- and two-months. The results indicated that sheets formed at physiological oxygen tension were thicker, contained greater amounts of glycosaminoglycans (GAGs) and type II collagen, and had greater compressive and tensile properties than those cultured in atmospheric oxygen. In all cases, cartilage sheets stained throughout for extracellular matrix components. Type II-IX-XI collagen heteropolymer formed in the neo-cartilage and fibrils were stabilized by trivalent pyridinoline cross-links. Collagen cross-links were not significantly affected by oxygen tension but increased with time in culture. Physiological oxygen tension and longer culture periods both served to increase extracellular matrix components. The foremost correlation was found between compressive stiffness and the GAG to collagen ratio.SummaryTissue-engineered cartilage formed from human articular chondrocytes produces thicker, stiffer, more extracellular-matrix rich cartilage tissue when grown under physiological (5%) vs. atmospheric oxygen (20%) tension.
vCOMBAT: a Novel Tool to Create and Visualize a COmputational Model of Bacterial Antibiotic Target-binding
Authors: Tran Vi Ngoc-Nha , Shams Alireza , Ascioglu Sinan , Martinecz Antal , Liang Jingyi , Clarelli Fabrizio , Mostowy Rafal , Cohen Ted , zur Wiesch Pia Abel 
Published: August 2020

AbstractMotivationAs antibiotic resistance creates a significant global health threat, we need not only to accelerate the development of novel antibiotics but also to develop better treatment strategies using existing drugs to improve their efficacy and prevent the selection of further resistance. We require new tools to rationally design dosing regimens to from data collected in early phases of antibiotic and dosing development. Mathematical models such as mechanistic pharmacodynamic drug-target binding explain mechanistic details of how the given drug concentration affects its targeted bacteria. However, there are no available tools in the literature that allows non-quantitative scientists to develop computational models to simulate antibiotic-target binding and its effects on bacteria.ResultsIn this work, we have devised an extension of a mechanistic binding-kinetic model to incorporate clinical drug concentration data. Based on the extended model, we develop a novel and interactive web-based tool that allows non-quantitative scientists to create and visualize their own computational models of bacterial antibiotic target-binding based on their considered drugs and bacteria. We also demonstrate how Rifampicin affects bacterial populations of Tuberculosis (TB) bacteria using our vCOMBAT tool.AvailabilityvCOMBAT online tool is publicly available athttps://combat-bacteria.org/.
Estimating SNP heritability in presence of population substructure in biobank-scale datasets
Authors: Lin Zhaotong , Seal Souvik , Basu Saonli 
Published: August 2020

AbstractSNP heritability of a trait is measured by the proportion of total variance explained by the additive effects of genome-wide single nucleotide polymorphisms (SNPs). Linear mixed models are routinely used to estimate SNP heritability for many complex traits. The basic concept behind this approach is to model genetic contribution as a random effect, where the variance of this genetic contribution attributes to the heritability of the trait. This linear mixed model approach requires estimation of ‘relatedness’ among individuals in the sample, which is usually captured by estimating a genetic relationship matrix (GRM). Heritability is estimated by the restricted maximum likelihood (REML) or method of moments (MOM) approaches, and this estimation relies heavily on the GRM computed from the genetic data on individuals. Presence of population substructure in the data could significantly impact the GRM estimation and may introduce bias in heritability estimation. The common practice of accounting for such population substructure is to adjust for the top few principal components of the GRM as covariates in the linear mixed model. Here we propose an alternative way of estimating heritability in multi-ethnic studies. Our proposed approach is a MOM estimator derived from the Haseman-Elston regression and gives an asymptotically unbiased estimate of heritability in presence of population stratification. It introduces adjustments for the population stratification in a second-order estimating equation and allows for the total phenotypic variance vary by ethnicity. We study the performance of different MOM and REML approaches in presence of population stratification through extensive simulation studies. We estimate the heritability of height, weight and other anthropometric traits in the UK Biobank cohort to investigate the impact of subtle population substructure on SNP heritability estimation.
Molecular details of protein condensates probed by microsecond-long atomistic simulations
Authors: Zheng Wenwei , Dignon Gregory L. , Xu Xichen , Regy Roshan M. , Fawzi Nicolas L. , Kim Young C. , Best Robert B. , Mittal Jeetain 
Published: August 2020

AbstractThe formation of membraneless organelles in cells commonly occurs via liquid-liquid phase separation (LLPS), and is in many cases driven by multivalent interactions between intrinsically disordered proteins (IDPs). Molecular simulations can reveal the specific amino acid interactions driving LLPS, which is hard to obtain from experiment. Coarse-grained simulations have been used to directly observe the sequence determinants of phase separation but have limited spatial resolution, while all-atom simulations have yet to be applied to LLPS due to the challenges of large system sizes and long time scales relevant to phase separation. We present a novel multiscale computational framework by obtaining initial molecular configurations of a condensed protein-rich phase from equilibrium coarse-grained simulations, and back mapping to an all-atom representation. Using the specialized Anton 2 supercomputer, we resolve microscopic structural and dynamical details of protein condensates through microsecond-scale all-atom explicit-solvent simulations. We have studied two IDPs which phase separatein vitro: the low complexity domain of FUS and the N-terminal disordered domain of LAF-1. Using this approach, we explain the partitioning of ions between phases with low and high protein density, demonstrate that the proteins are remarkably dynamic within the condensed phase, identify the key residue-residue interaction modes stabilizing the dense phase, all while showing good agreement with experimental observations. Our approach is generally applicable to all-atom studies of other single and multi-component systems of proteins and nucleic acids involved in the formation of membraneless organelles.
Spontaneous replication fork collapse regulates telomere length homeostasis in wild type cells
Authors: Paschini Margherita , Reyes Cynthia M. , Gillespie Abigail E. , Lewis Karen A. , Glustrom Leslie W. , Sharpee Tatyana O. , Wuttke Deborah S. , Lundblad Victoria 
Published: August 2020

AbstractTelomeres present unique challenges for genomes with linear chromosomes, including the inability of the semi-conservative DNA replication machinery to fully duplicate the ends of linear molecules. This is solved in virtually all eukaryotes by the enzyme telomerase, through the addition of telomeric repeats onto chromosome ends. It is widely assumed that the primary site of action for telomerase is the single-stranded G-rich overhang at the ends of chromosomes, formed after DNA replication is complete. We show here that the preferred substrate for telomerase in wild type yeast is instead a collapsed fork generated during replication of duplex telomeric DNA. Furthermore, newly collapsed forks are extensively elongated by telomerase by as much as ∼200 nucleotides in a single cell division, indicating that a major source of newly synthesized telomeric repeats in wild type cells occurs at collapsed forks. Fork collapse and the subsequent response by telomerase are coordinated by the dual activities of a telomere-dedicated RPA-like complex, which facilitates replication of duplex telomeric DNA and also recruits telomerase to the fork, thereby ensuring a high probability of re-elongation if DNA replication fails. We further show that the ability of telomerase to elongate newly collapsed forks is dependent on the Rad51 protein, indicating that telomerase activity in response to fork collapse proceeds through a regulatory pathway distinct from how telomerase engages fully replicated chromosome termini. We propose a new model in which spontaneous replication fork collapse and the subsequent response by telomerase is a major determinant of telomere length homeostasis.
Evolutionary dynamics of SARS-CoV-2 nucleocapsid protein (N protein) and its consequences
Authors: Rahman M. Shaminur , Islam M. Rafiul , Ul Alam A. S. M. Rubayet , Islam Israt , Hoque M. Nazmul , Akter Salma , Rahaman Md. Mizanur , Sultana Munawar , Hossain M. Anwar 
Published: August 2020

AbstractThe emerging novel coronavirus SARS-CoV-2 has created a global confusing pandemic health crisis that warrants an accurate and detailed characterization of the rapidly evolving viral genome for understanding its epidemiology, pathogenesis and containment. We explored 61,485 sequences of the Nucleocapsid (N) protein, a potent diagnostic and prophylactic target, for identifying the mutations to review their roles in RT-PCR based diagnosis and observe consequent impacts. Compared to the Wuhan reference strain, a total of 1034 unique nucleotide mutations were identified in the mutant strains (49.15%, n=30,221) globally. Of these mutations, 367 occupy primer binding sites including 3’-end mismatch to primer-pair of 11 well characterized primer sets. Noteworthy, CDC (USA) recommended N2 primer set contained lower mismatch than the other primer sets. Moreover, 684 amino acid (aa) substitutions located across 317 (75.66% of total aa) unique positions including 82, 21, and 83 of those in RNA binding N-terminal domain (NTD), SR-rich region, and C-terminal dimerization domain (CTD), respectively. Moreover, 11 in-frame deletions were revealed, mostly (n =10) within the highly flexible linker region, and the rest within the NTD region. Furthermore, we predicted the possible consequences of high-frequency mutations (≥ 20) and deletions on the tertiary structure of the N protein. Remarkably, we observed that high frequency (67.94% of mutated sequences) coevolving mutations (R203K and G204R) destabilized and decreased overall structural flexibility. Despite being proposed as the alternate target to spike protein for vaccine and therapeutics, ongoing nonsynonymous evolution of the N protein may challenge the endeavors, thus need further immunoinformatics analyses. Therefore, continuous monitoring is required for tracing the ongoing evolution of the SARS-CoV-2 N protein in prophylactic and diagnostic interventions.
Analysis of single nucleotide polymorphisms between 2019-nCoV genomes and its impact on codon usage
Authors: Gupta Suruchi , Singh Ravail , Paul Prosenjit 
Published: August 2020

AbstractThe spread of COVID-19 is a global concern that has taken a toll on entire human health. Researchers across the globe has been working in devising the strategies to combat this dreadful disease. Studies focused on genetic variability helps design effective drugs and vaccines. Considering this, the present study entails the information regarding the genome-wide mutations detected in the 108 SARS CoV-2 genomes worldwide. We identified a few hypervariable regions localized in orf1ab, spike, and nucleocapsid gene. These nucleotide polymorphisms demonstrated their effect on both codon usage as well as amino acid usage pattern. Altogether the present study provides valuable information that would be helpful to ongoing research on 2019-nCoV vaccine development.
Phasic oxygen dynamics underlies fast choline-sensitive biosensor signals in the brain of behaving rodents
Authors: Santos Ricardo M. , Sirota Anton 
Published: August 2020

AbstractFast time-scale modulation of synaptic and cellular physiology by acetylcholine is critical for many cognitive functions, but direct local measurement of neuromodulator dynamics in freely-moving behaving animals is technically challenging. Recentin vivobrain measurements using choline oxidase (ChOx)-based electrochemical biosensors have reported surprising fast cholinergic transients associated with reward-related behavioral events. However,in vivorecordings with conventional ChOx biosensors could be biased by phasic local field potential and O2-evoked enzymatic responses. Here, we have developed a Tetrode-based Amperometric ChOx (TACO) sensor enabling minimally invasive artifact-free simultaneous measurement of cholinergic activity and O2. Strikingly, the TACO sensor revealed highly-correlated O2and ChOx transients following spontaneous locomotion and sharp-wave/ripples fluctuations in the hippocampus of behaving rodents. Quantitative analysis of spontaneous activity,in vivoandin vitroexogenous O2perturbations revealed a directional effect of O2on ChOx phasic signals. Mathematical modeling of biosensors identified O2-evoked non-steadystate ChOx kinetics as a mechanism underlying artifactual biosensor phasic transients. This phasic O2-dependence of ChOx-based biosensor measurements confounds phasic cholinergic dynamics readoutin vivo,challenging previously proposed ACh role in reward-related learning. The discovered mechanism and quantitative modeling is generalizable to any oxidase-based biosensor, entailing rigorous controls and new biosensor designs.
Correlative Light Electron Ion Microscopy revealin vivolocalisation of bedaquiline inMycobacterium tuberculosisinfected lungs
Authors: Fearns Antony , Greenwood Daniel J. , Rodgers Angela , Jiang Haibo , Gutierrez Maximiliano G. 
Published: August 2020

AbstractCorrelative light, electron and ion microscopy (CLEIM) offers huge potential to track the intracellular fate of antibiotics, with organelle-level resolution. However, a correlative approach that enables subcellular antibiotic visualisation in pathogen-infected tissue is lacking. Here, we developed CLEIM in tissue (CLEIMiT), and used it to identify the cell-type specific accumulation of an antibiotic in lung lesions of mice infected withMycobacterium tuberculosis.Using CLEIMiT, we found that the anti-TB drug bedaquiline is localised not only in foamy macrophages in the lungs during infection but also accumulate in polymorphonuclear (PMN) cells.
Frontoparietal dynamics and value accumulation in intertemporal choice
Authors: Liu Qingfang , Yi Woojong , Rodriguez Christian A. , McClure Samuel M. , Turner Brandon M. 
Published: August 2020

AbstractIntertemporal choice requires choosing between a smaller reward available after a shorter time delay and a larger reward available after a longer time delay. Previous studies suggest that intertemporal preferences are formed by generating a subjective value of the monetary rewards that depends on reward amount and the associated time delay. Neuroimaging results indicate that this subjective value is tracked by ventral medial prefrontal cortex (vmPFC) and ventral striatum. Subsequently, an accumulation process, subserved by a network including dorsal medial frontal cortex (dmFC), dorsal lateral prefrontal cortex (dlPFC) and posterior parietal cortex (pPC), selects a choice based on the subjective values. The mechanisms of how value accumulation interacts with subjective valuation to make a choice, and how brain regions communicate during decision making are undetermined. We developed and performed an EEG experiment that parametrically manipulated the probability of preferring delayed larger rewards. A computational model equipped with time and reward information transformation, selective attention, and stochastic value accumulation mechanisms was constructed and fit to choice and response time data using a hierarchical Bayesian approach.Phase-based functional connectivity between putative dmFC and pPC was found to be associated with stimulus processing and to resemble the reconstructed accumulation dynamics from the best performing computational model across experimental conditions. By combining computational modeling and phase-based functional connectivity, our results suggest an association between value accumulation, choice competition, and frontoparietal connectivity in intertemporal choice.Author summaryIntertemporal choice is a prominent experimental assay for impulsivity. Behavior in the task involves several cognitive functions including valuation, action selection and self-control. It is unknown how these different functions are temporally implemented during the course of decision making. In the current study, we combined formal computational models of intertemporal choice with a phase-based EEG measure of activity across brain regions to show that functional connectivity between dmFC and pPC reflects cognitive mechanisms of both visual stimulus processing and choice value accumulation. The result supports the notion that dynamic interaction between frontopatietal regions instantiates the critical value accumulation process in intertemporal choice.