bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between lower limb isometric torque, isokinetic torque, and explosive force with phases of reactive stepping in young, healthy adults
Authors: Saumur Tyler M. , Nestico Jacqueline , Mochizuki George , Perry Stephen D. , Mansfield Avril , Mathur Sunita 
Published: January 2021

AbstractReactive stepping is one of the only strategies that can lead to successful stabilization following a large challenge to balance. Improving function of specific muscles associated with reactive stepping may improve features of reactive balance control. Accordingly, this study aimed to determine the relationship between lower limb muscle strength and explosive force with force plate-derived timing measures of reactive stepping. Nineteen young, healthy adults (27.6 ± 3.0 years of age; 10 women: 9 men) responded to 6 perturbations (~13-15% of body weight) using an anterior lean-and-release system (causing a forward fall), where they were instructed to recover balance in as few steps as possible. Foot-off, swing, and restabilization times were estimated from force plates. Peak isokinetic torque, isometric torque, and explosive force of the knee extensors/flexors and plantar/dorsiflexors were measured using isokinetic dynamometry. Correlations were run based ona priorihypotheses and corrected for the number of comparisons (Bonferroni) for each variable. Knee extensor explosive force was negatively correlated with swing time (r = −0.582, p = 0.009). Knee flexor peak isometric torque also showed a negative association with restabilization time (r = −0.459, p = 0.048), however this was not statistically significant after correcting for multiple comparisons. There was no significant relationship between foot-off time and knee or plantar flexor explosive force (p > 0.025). These findings suggest that there may be utility to identifying specific aspects of reactive step timing when studying the relationship between muscle strength and reactive balance control. Exercise training aimed at improving falls risk should consider targeting specific aspects of muscle strength depending on specific deficits in reactive stepping.
In-Pero: Exploiting deep learning embeddings of protein sequences to predict the localisation of peroxisomal proteins
Authors: Anteghini Marco , dos Santos Vitor AP Martins , Saccenti Edoardo 
Published: January 2021

AbstractPeroxisomes are ubiquitous membrane-bound organelles, and aberrant localisation of peroxisomal proteins contributes to the pathogenesis of several disorders. Many computational methods focus on assigning protein sequences to subcellular compartments, but there are no specific tools tailored for the sub-localisation (matrix vs membrane) of peroxisome proteins. We present here In-Pero, a new method for predicting protein sub-peroxisomal cellular localisation. In-Pero combines standard machine learning approaches with recently proposed multi-dimensional deep-learning representations of the protein amino-acid sequence. It showed a classification accuracy above 0.9 in predicting peroxisomal matrix and membrane proteins. The method is trained and tested using a double cross-validation approach on a curated data set comprising 160 peroxisomal proteins with experimental evidence for sub-peroxisomal localisation. We further show that the proposed approach can be easily adapted (In-Mito) to the prediction of mitochondrial protein localisation obtaining performances for certain classes of proteins (matrix and inner-membrane) superior to existing tools. All data sets and codes are available athttps://github.com/MarcoAnteghiniand atwww.systemsbiology.nl
Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir
Authors: Gautam Nagsen , McMillan JoEllyn M. , Kumar Devendra , Bade Aditya N. , Pan Qiaoyu , Kulkarni Tanmay A. , Li Wenkuan , Smith Nathan A , Dyavar Shetty Bhagya L. , Sillman Brady , Szlachetka Adam , Edagwa Benson J. , Gendelman Howard E. , Alnouti Yazen 
Published: January 2021

AbstractA single, once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one (HIV-1) transmission. Extending CAB dosing to a yearly injectable can advance efforts leading to the elimination of viral transmission. The current submission adds rigor, reproducibility and mechanistic insights for the extended apparent half-life of a yearlong antiretroviral injectable. Pharmacokinetic (PK) profiles of a nanoformulated fatty acid ester CAB prodrug (named NM2CAB) were affirmed at two academic and one contract research laboratory. PK profiles showed plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for up to one year after a single dose. Measures of drug biodistribution demonstrated sustained native drug at the muscle injection site and in lymphoid tissues (spleen and lymph nodes). The results paralleled NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals were stable in blood, tissue and liver homogenates. The long apparent drug half-life followed pH-dependent slow prodrug release in weeks from the nanocrystal. In contrast, solubilized prodrug was hydrolyzed in hours in plasma and tissues recorded from multiple mammalian species at basic pH. No measurable toxicities were recorded. These results, taken together, affirm the pharmacological mechanistic properties of a year-long nanoformulated CAB prodrug supporting the established protocol design for formulation safety, rigor and reproducibility.
Identifying neuron subtype-specific metabolic network changes in single cell transcriptomics of Alzheimer’s Disease using perturb-Met
Authors: Wang Yuliang 
Published: January 2021

AbstractMetabolic aberrations are a prominent feature of Alzheimer’s Disease (AD). Different neuronal subtypes have selective vulnerability in AD. Despite the recent advance of single cell and single nucleus RNA-seq of AD brains, genome-scale metabolic network changes in neuronal subtypes have not been systematically studied with detail. To bridge this knowledge gap, I developed a computational method called perturb-Met that can uncover transcriptional dysregulation centered at hundreds of metabolites in a metabolic network. perturb-Met successfully recapitulated known glycolysis, cholesterol, and other metabolic defects in APOE4-neurons and microglia, many of which are missed by current methods. Applying perturb-Met on AD snRNA-seq data, I revealed that the four neuronal subtypes in the entorhinal cortex shows subtype-specific metabolic changes, namely mitochondrial complex I metabolism, ganglioside metabolism, galactose and heparan sulfate metabolism, as well as glucose and lipid metabolism, respectively. perturb-Met also revealed significant changes in protein glycosylation in the neuron subtype specifically found in AD brains. These subtype-specific metabolic changes may potentially underlie their selective vulnerability in AD. perturb-Met is a valuable tool to discover potential metabolic network changes in many other single cell or bulk transcriptomic studies.
Resonance in physiologically structured population models
Authors: Gross Kevin , de Roos André M. 
Published: January 2021

AbstractEcologists have long sought to understand how the dynamics of natural populations are affected by the environmental variation those populations experience. A transfer function is a useful tool for this purpose, as it uses linearization theory to show how the frequency spectrum of the fluctuations in a population’s abundance relates to the frequency spectrum of environmental variation. Here, we show how to derive and to compute the transfer function for a continuous-time model of a population that is structured by a continuous individual-level state variable such as size. To illustrate, we derive, compute, and analyze the transfer function for a size-structured population model of stony corals with open recruitment, parameterized for a common Indo-Pacific coral species complex. This analysis identifies a sharp multi-decade resonance driven by space competition between existing coral colonies and incoming recruits. The resonant frequency is most strongly determined by the rate at which colonies grow, and the potential for resonant oscillations is greatest when colony growth is only weakly density-dependent. While these resonant oscillations are unlikely to be a predominant dynamical feature of degraded reefs, they suggest dynamical possibilities for marine invertebrates in more pristine waters. The size-structured model that we analyze is a leading example of a broader class of physiologically structured population models, and the methods we present should apply to a wide variety of models in this class.
Packing the Standard Genetic Code in its box: 3-dimensional late Crick wobble
Authors: Yarus Michael 
Published: January 2021

AbstractMinimally-evolved codes are constructed with randomly chosen Standard Genetic Code (SGC) triplets, and completed with completely random triplet assignments. Such “genetic codes” have not evolved, but retain SGC qualities. Retained qualities are inescapable, part of the logic of code evolution. For example, sensitivity of coding to arbitrary assignments, which must be <≈ 10%, is intrinsic. Such sensitivity comes from elementary combinatorial properties of coding, and constrains any SGC evolution hypothesis. Similarly, evolution of last-evolved functions is difficult, due to late kinetic phenomena, likely common across codes. Census of minimally-evolved code assignments shows that shape and size of wobble domains controls packing into a coding table, strongly shifting accuracy of codon assignments. Access to the SGC therefore requires a plausible pathway to limited randomness, avoiding difficult completion while packing a highly ordered, degenerate code into a fixed three-dimensional space. Late Crick wobble in a 3-dimensional genetic code assembled by lateral transfer satisfies these varied, simultaneous requirements. By allowing parallel evolution of SGC domains, it can yield shortened evolution to SGC-level order, and allow the code to arise in smaller populations. It effectively yields full codes. Less obviously, it unifies well-studied sources for order in amino acid coding, including a stereochemical minority of triplet-amino acid associations. Finally, fusion of its intermediates into the definitive SGC is credible, mirroring broadly-accepted later cellular evolution.
Spatial pattern analysis of line-segment data in ecology
Authors: Yates Luke A. , Brook Barry W. , Buettel Jessie C. 
Published: January 2021

AbstractThe spatial analysis of linear features (lines and curves) is a challenging and rarely attempted problem in ecology. Existing methods are typically expressed in abstract mathematical formalism, making it difficult to assess their relevance and transferability into an ecological setting. A set of concrete and accessible tools is needed.We develop a new method to analyse the spatial patterning of line-segment data. It is based on a generalisation of Ripley’sK-function and includes an analogue of the transformedL-function, together with estimators and theoretical expectation values. We introduce a class of line-segment processes, related to the Boolean model, which we use in conjunction with Monte-Carlo methods and information criteria to generate and compare candidate models. We demonstrate the utility of our method using fallen tree (dead log) data collected from two one-hectare Australian tall eucalypt forest plots.Comparing six line-segment models, we find for both plots that the distribution of fallen logs is best explained by plot-level spatial heterogeneity. The use of non-uniform distributions to model dead-log orientation on the forest floor improves model performance in one of the two sites. Our case study highlights the challenges of model comparison in spatial-pattern analysis, where Monte-Carlo approaches based on the discrepancy of simulated summary functions can generate a different ranking of models than that of information criteria.These methods are of a general nature and are applicable to any line-segment data. In the context of forest ecology, the integration of fallen logs as linear structural features in a landscape with the point locations of living trees, and a quantification of their interactions, will yield new insights into the functional and structural role of tree fall in forest communities and their enduring post-mortem ecological legacy as spatially distributed decomposing logs.
Modelling pooling strategies for SARS-CoV-2 testing in a university setting
Authors: Hemani Gibran , Thomas Amy C , Walker Josephine G. , Trickey Adam , Nixon Emily , Ellis David , Kwiatkowska Rachel , Relton Caroline , Danon Leon , Christensen Hannah , Brooks-Pollock Ellen 
Published: January 2021

AbstractPre-symptomatic and asymptomatic transmission of SARS-CoV-2 are important elements in the Covid-19 pandemic, and until vaccines are made widely available there remains a reliance on testing to manage the spread of the disease, alongside non-pharmaceutical interventions such as measures to reduce close social interactions. In the UK, many universities opened for blended learning for the 2020-2021 academic year, with a mixture of face to face and online teaching. In this study we present a simulation framework to evaluate the effectiveness of different asymptomatic testing strategies within a university setting, across a range of transmission scenarios. We show that when positive cases are clustered by known social structures, such as student households, the pooling of samples by these social structures can substantially reduce the total cost of conducting RT-qPCR tests. We also note that routine recording of quantitative RT-qPCR results would facilitate future modelling studies.
Clinical utility of Corona Virus Disease-19 serum IgG, IgM, and neutralizing antibodies and inflammatory markers
Authors: Schaefer Ernst J. , Comite Florence , Dulipsingh Latha , Lang Maxine , Jimison Jessica , Grajower Martin M. , Lebowitz Nathan E. , Geller Andrew S. , Diffenderfer Margaret R. , He Lihong , Breton Gary , Dansinger Michael L. , Saida Ben , Yuan Chong 
Published: January 2021

AbstractMost deaths from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection occur in older subjects. We assessed age effects and clinical utility of serum SARS-CoV-2 immunoglobulin G (IgG), immunoglobulin M (IgM), and neutralizing antibodies and serum inflammatory markers. Serum IgG, IgM, and neutralizing antibody levels were measured using chemiluminescence assays from Diazyme (Poway, CA), while serum interleukin-6 (IL-6), C reactive protein (CRP), and ferritin were measured with immunoassays obtained from Roche (Indianapolis, IN). In 79,005 subjects, IgG and IgM levels were positive (≥1.0 arbitrary units [AU]/mL) in 5.29% and 3.25% of subjects, respectively. In antibody positive subjects, median IgG levels were 3.93 AU/mL if <45 years of age, 10.18 AU/mL if 45-64 years of age, and 10.85 AU/mL if ≥65 years of age (p<0.0001). In SARS-CoV-2 RNA positive cases, family members and exposed subjects (n=1,111), antibody testing was found to be valuable for case finding, and persistent IgM levels were associated with chronic symptoms. In non-hospitalized and hospitalized subjects assessed for SARS-CoV-2 RNA (n=278), median IgG levels in AU/mL were 0.05 in negative subjects (n=100), 14.83 in positive outpatients (n=129), and 30.61 in positive hospitalized patients (n=49, p<0.0001). Neutralizing antibody levels correlated significantly with IgG (r=0.875; p<0.0001). Two or more of the criteria of IL-6 ≥10 pg/mL, CRP ≥10 mg/L, and/or IgM >1.0 AU/mL occurred in 97.7% of inpatients versus 1.8% of outpatients (>50-fold relative risk, C statistic 0.986, p<0.0001). Our data indicate that: 1) IgG levels are significantly higher in positive older subjects, possibly to compensate for decreased cellular immunity with aging; 2) IgG levels are important for case finding in family clusters; 3) IgG levels are significantly correlated with neutralizing antibody levels; 4) persistently elevated IgM levels are associated with chronic disease; and 5) markedly elevated IL-6, hs-CRP, and/or positive IgM accurately identify SARS-CoV-2 RNA positive subjects requiring hospitalization.
SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies
Authors: Collier Dami A. , De Marco Anna , Ferreira Isabella A.T.M. , Meng Bo , Datir Rawlings , Walls Alexandra C. , Kemp S Steven A. , Bassi Jessica , Pinto Dora , Fregni Chiara Silacci , Bianchi Siro , Tortorici M. Alejandra , Bowen John , Culap Katja , Jaconi Stefano , Cameroni Elisabetta , Snell Gyorgy , Pizzuto Matteo S. , Pellanda Alessandra Franzetti , Garzoni Christian , Riva Agostino ,   The CITIID-NIHR BioResource COVID-19 Collaboration, Elmer Anne , Kingston Nathalie , Graves Barbara , McCoy Laura E , Smith Kenneth GC , Bradley John R. , Temperton Nigel , Ceron-Gutierrez L Lourdes , Barcenas-Morales Gabriela ,   The COVID-19 Genomics UK (COG-UK) consortium, Harvey William , Virgin Herbert W. , Lanzavecchia Antonio , Piccoli Luca , Doffinger Rainer , Wills Mark , Veesler David , Corti Davide , Gupta Ravindra K. 
Published: January 2021

AbstractSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.
Systematic Review and Meta-analysis of Immunomodulator and Biologic Therapies for Treatment of Chronic Pouchitis
Authors: Khoo Emi , Lee Andrew , Neeman Teresa , An Yoon-Kyo , Begun Jakob 
Published: January 2021

SummaryBackgroundPouchitis is a common complication after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). Although antibiotics are the primary therapy for acute pouchitis, a proportion of patients developed chronic antibiotic-dependent pouchitis (CADP) or antibiotic-refractory pouchitis (CARP). The efficacy of second line immunomodulator and biologic therapies for chronic pouchitis remain undefined. We performed a systematic review and metanalysis of published studies to assess their efficacy.MethodThe online EMBASE database was searched for full-text articles describing the treatment of chronic pouchitis meeting our criteria. Post-induction clinical and endoscopic response and remission rates were extracted and combined for meta-analyses. The rate of treatment discontinuation and safety profiles were also assessed.ResultsA total of 21 full-text articles were included in this meta-analysis representing 491 patients. The overall clinical response rate was 49% with clinical remission rate of 34%. The overall endoscopic response and remission rates were 53% and 36% respectively. The safety profile of individual agents was reassuring, but vedolizumab appears to have a more favorable safety profile.ConclusionThis review and meta-analysis identified the effectiveness of vedolizumab and ustekinumab in achieving clinical and endoscopic response in chronic pouchitis, with a reassuring safety profile. There is limited data regarding use of immunomodulators and no conclusion can be drawn. Further studies are required to define the comparative effectiveness of available treatments of CADP or CARP.
Estimating dates of origin and end of COVID-19 epidemics
Authors: Beneteau Thomas , Elie Baptiste , Sofonea Mircea T. , Alizon Samuel 
Published: January 2021

AbstractEstimating the date at which an epidemic started in a country and the date at which it can end depending on interventions intensity are important to guide public health responses. Both are potentially shaped by similar factors including stochasticity (due to small population sizes), superspreading events, and ‘memory effects’ (the fact that the occurrence of some events, e.g. recovering from an infection, depend on the past, e.g. the number of days since the infection). Focusing on COVID-19 epidemics, we develop and analyse mathematical models to explore how these three factors may affect early and final epidemic dynamics. Regarding the date of origin, we find limited effects on the mean estimates, but strong effects on their variances. Regarding the date of extinction following lockdown onset, mean values decrease with stochasticity or with the presence of superspreading events. These results underline the importance of accounting for heterogeneity in infection history and transmission patterns to accurately capture early and late epidemic dynamics.