bluuebunny/crossref_metadata_2025_split huggingface dataset:
The relative effects of non-pharmaceutical interventions on early Covid-19 mortality: natural experiment in 130 countries
Authors: Stokes Jonathan , Turner Alex James , Anselmi Laura , Morciano Marcello , Hone Thomas 
Published: October 2020

AbstractBackgroundConcurrent non-pharmaceutical interventions have been implemented around the world to control Covid-19 transmission. Their general effect on reducing virus transmission is proven, but they can also be negative to mental health and economies, and transmission behaviours can also change in absence of mandated policies. Their relative impact on Covid-19 attributed mortality rates, enabling policy selection for maximal benefit with minimal disruption, is not well established.MethodsWe exploited variations in nine non-pharmaceutical interventions implemented in 130 countries (3250 observations) in two periods chosen to limit reverse causality: i) prior to first Covid-19 death (when policymakers could not possibly be reacting to deaths in their own country); and, ii) 14-days-post first Covid-19 death (when deaths were still low, on average). We examined associations with daily deaths per million in each subsequent 24-day period (the time between virus transmission and mortality) which could only be affected by the policy period. A mean score of strictness and timeliness was coded for each intervention. Days in each country were indexed in time by first reported Covid-19 death to proxy for virus transmission rate. Multivariable linear regression models of Covid-19 mortality rates on all concurrent interventions were adjusted for seasonality, potential confounders, and potential cross-country differences in their mortality definitions. Robustness was checked by removing countries with known data reporting issues and with non-linear, negative binomial, models.ResultsAfter adjusting for multiple concurrent interventions and confounders, and accounting for both timing and strictness of interventions, earlier and stricter school (−1.23 daily deaths per million, 95% CI -2.20 -0.27) and workplace closures (−0.26, 95% CI -0.46 -0.05) were associated with lower Covid-19 mortality rates. Only controlling for strictness international travel controls, and only controlling for timing later restrictions on gatherings, were also associated with lower Covid-19 mortality. Other interventions, such as stay-at-home orders or restrictions on public transport, were not significantly associated with differences in mortality rates across countries. Findings were robust across multiple statistical approaches.ConclusionsFocusing on ‘compulsory’, particularly school closing, not ‘voluntary’ reduction of social interactions with mandated policies appears to have been the most effective strategy to mitigate early Covid-19 mortality.
A Bayesian approach for estimating typhoid fever incidence from large-scale facility-based passive surveillance data
Authors: Phillips Maile T. , Meiring James E. , Voysey Merryn , Warren Joshua L. , Baker Stephen , Basnyat Buddha , Clemens John D. , Dolecek Christiane , Dunstan Sarah J. , Dougan Gordon , Gordon Melita A. , Heyderman Robert S. , Holt Kathryn E. , Qadri Firdausi , Pollard Andrew J. , Pitzer Virginia E. ,   the STRATAA Study Group
Published: October 2020

AbstractDecisions about typhoid fever prevention and control are based on estimates of typhoid incidence and their uncertainty. Lack of specific clinical diagnostic criteria, poorly sensitive diagnostic tests, and scarcity of accurate and complete datasets contribute to difficulties in calculating age-specific population-level typhoid incidence. Using data from the Strategic Alliance across Africa & Asia (STRATAA) programme, we integrated demographic censuses, healthcare utilization surveys, facility-based surveillance, and serological surveillance from Malawi, Nepal, and Bangladesh to account for under-detection of cases. We developed a Bayesian approach that adjusts the count of reported blood-culture-positive cases for blood culture detection, blood culture collection, and healthcare seeking—and how these factors vary by age—while combining information from prior published studies. We validated the model using simulated data. The ratio of observed to adjusted incidence rates was 7.7 (95% credible interval (CrI): 6.0-12.4) in Malawi, 14.4 (95% CrI: 9.3-24.9) in Nepal, and 7.0 (95% CrI: 5.6-9.2) in Bangladesh. The probability of blood culture collection led to the largest adjustment in Malawi, while the probability of seeking healthcare contributed the most in Nepal and Bangladesh; adjustment factors varied by age. Adjusted incidence rates were within the seroincidence rate limits of typhoid infection. Estimates of blood-culture-confirmed typhoid fever without these adjustments results in considerable underestimation of the true incidence of typhoid fever. Our approach allows each phase of the reporting process to be synthesized to estimate the adjusted incidence of typhoid fever while correctly characterizing uncertainty, which can inform decision-making for typhoid prevention and control.
Hypercholesterolemia Impairs Clearance of Extracellular DNA and Promotes Inflammation and Atherosclerotic Plaque Progression
Authors: Dhawan Umesh Kumar , Bhattacharya Purbasha , Narayanan Sriram , Manickam Vijayprakash , Aggarwal Ayush , Subramanian Manikandan 
Published: October 2020

AbstractDefects in clearance of extracellular DNA due to sub-optimal activity of DNase results in exacerbated inflammation and contributes to the pathophysiology of atherosclerosis and other inflammatory diseases. However, the physiological mechanisms that regulate systemic DNase levels and the basis of its functional impairment during disease are poorly understood. Using a mouse model of experimental increase in systemic extracellular DNA levels, we identify the existence of a physiologic DNA-induced DNase response. Importantly, hypercholesterolemia in mice impairs this critical DNA-induced DNase response through an endoplasmic reticulum stress-mediated mechanism with consequences in advanced atherosclerotic plaque progression including increased extracellular DNA accumulation, exacerbated inflammation, and development of pathological features of necrotic rupture-prone vulnerable plaques. From a translational standpoint in humans, we demonstrate that individuals with hypercholesterolemia have elevated systemic extracellular DNA levels and decreased plasma DNase activity. These data suggest that the restoration of DNA-induced DNase response could be a potential therapeutic strategy to promote inflammation resolution during hypercholesterolemia.
Pan-Cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology
Authors: Fort Rafael Sebastián , Duhagon María Ana 
Published: October 2020

AbstractThe vault RNAs (vtRNAs) are a class of 84-141 nt eukaryotic non-coding RNAs transcribed by RNA polymerase III, named for their association with the conserved vault particle, a riboprotein complex whose function remains poorly understood. Of the 4 human vtRNA genes, the three clustered at locus 1, i.e. vtRNA1-1, vtRNA1-2 and vtRNA1-3, are integral components of the vault particle, while vtRNA2-1 is a more divergent homologue located in a second locus. Gene expression studies of vtRNAs in large cancer cohorts have been hindered by the failure of vtRNA sequencing using conventional transcriptomic approaches. However, since the vtRNAs transcription is regulated by DNA methylation, the analysis of the chromatin status of their promoters is a suitable surrogate approach to study their expression. Here we infer the landscape of vtRNA expression in cancer from the genome-wide DNA methylation (Illumina Infinium Human Methylation 450 K BeadChip) and chromatin accessibility (ATAC-seq) data of The Cancer Genome Atlas (TCGA). On average, vtRNA1-1 has the most accessible chromatin, followed by vtRNA1-2, vtRNA2-1 and vtRNA1-3. The correlation of the chromatin status of the vtRNA promoters and the binding sites of a common core of transcription factors stands for their transcriptional co-regulation by factors related to viral infection. Yet, vtRNA2-1 is the most independently regulated vtRNA homologue across tissue types. VtRNA1-1 and vtRNA1-3 chromatin status does not significantly change in cancer, though vtRNA1-3 promoter has repressive chromatin marks in a few cancer types. However, vtRNA2-1 and vtRNA1-2 expression are widely deregulated in neoplastic tissues and is compatible with a broad oncogenic role of vtRNA1-2, and both tumor suppressor and oncogenic functions of vtRNA2-1 depending of tissue contexts. Yet, vtRNA1-1, vtRNA1-2 and vtRNA2-1 promoter DNA methylation predicts a shorter patient overall survival cancer-wide. In addition, gene ontology analyses of co-regulated genes identifies a chromosome 5 regulatory domain controlling vtRNA1-1 and neighboring genes, and epithelial differentiation, immune and thyroid cancer gene sets for vtRNA1-2, vtRNA2-1 and vtRNA1-3 respectively. Furthermore, vtRNA expression patterns are associated with cancer immune subtypes. Finally, vtRNA1-2 expression is positively associated with cell proliferation and wound healing, in agreement with its oncogenic expression profile. Overall, our study presents the landscape of vtRNA expression cancer-wide, identifying co-regulated gene networks and ontological pathways associated with the different vtRNA genes that may account for their diverse roles in cancer.
Coding variants identified in diabetic patients alter PICK1 BAR domain function in insulin granule biogenesis
Authors: Andersen Rita C. , Lycas Matthew D. , Schmidt Jan H. , Christensen Nikolaj R. , Lund Viktor K. , Rombach Joscha , Stoklund Mikkel , Stapleton Donnie S. , Noes-Holt Gith , Keller Mark P. , Jansen Anna M. , Herlo Rasmus , Kjærulff Ole , Holst Birgitte , Attie Alan D. , Gether Ulrik , Madsen Kenneth L. 
Published: October 2020

SummaryBin/amphiphysin/Rvs (BAR) domains are positively charged crescent-shaped modules that shape negatively charged curved lipid membranes during membrane remodeling processes. The BAR domain proteins ICA69, PICK1 and arfaptins have recently been demonstrated to coordinate the budding and formation of immature secretory granules (ISGs) at thetrans-Golgi network. Here, we identify four coding variants in the PICK1 gene from a Danish whole-exome screening of diabetic patients, that all involve change of positively charged residues in the PICK1 BAR domain. All four coding variants failed to rescue the insulin content in INS-1E cells upon KD of endogenous PICK1. Moreover, two variants showed dominant negative properties. Interestingly,in vitroassays addressing the BAR domain function suggest that the coding variants compromised membrane binding capacity but increased capacity to cause fission of liposomes.Live confocal microscopy and super-resolution microscopy further revealed that PICK1 resides transiently on ISGs before egress via vesicular budding events. Interestingly, this egress of PICK1 was accelerated in the coding variants. We propose that PICK1 assists or complements the removal of excess membrane and generic membrane trafficking proteins, and possibly also insulin from ISGs during the maturation process and that the coding variants may cause premature budding possibly explaining their dominant negative function.
Development and pilot screen of novel high content assay for down regulators of expression of heterogenous nuclear ribonuclear protein H2
Authors: Diez Juan , Rajendrarao Sumitha , Baajour Shadi A. , Sripadhan Praathibha , Spicer Timothy P. , Scampavia Louis D. , Minond Dmitriy 
Published: October 2020

ABSTRACTDespite recent advances in melanoma drug discovery, the average overall survival of patients with late stage metastatic melanoma is approximately 3 years, suggesting a need for new approaches and melanoma therapeutic targets. Previously we identified heterogeneous nuclear ribonucleoprotein H2 as a potential target of anti-melanoma compound 2155-14 (Palrasuet al,Cell Physiol Biochem2019;53:656-86). In the present study, we endeavored to develop an assay to enable a high throughput screening campaign to identify drug-like molecules acting via down regulation of heterogeneous nuclear ribonucleoprotein H that can be used for melanoma therapy and research.ResultsWe established a cell-based platform using metastatic melanoma cell line WM266-4 expressing hnRNPH2 conjugated with green fluorescent protein to enable assay development and screening. High Content Screening assay was developed and validated in 384 well plate format, followed by miniaturization to 1,536 well plate format. All plate-based QC parameters were acceptable: %CV = 6.7±0.3, S/B = 21±2.1, Z’ = 0.75±0.04. Pilot screen of FDA-approved drug library (n=1,400 compounds) demonstrated hit rate of 0.5%. Two compounds demonstrated pharmacological response and were authenticated by western blot analysis.ConclusionsWe developed a highly robust HTS-amenable high content screening assay capable of monitoring down regulation of hnRNPH2. This assay is thus capable of identifying authentic down regulators of hnRNPH1 and 2 in a large compound collection and, therefore, is amenable to a large-scale screening effort.
Morphological study of embryonicChd8+/-mouse brains using light-sheet microscopy
Authors: Gómez Harold F. , Hodel Leonie , Michos Odyssé , Iber Dagmar 
Published: October 2020

AbstractObjectiveAutism spectrum disorder (ASD) encompasses a group of neurodevelopmental conditions that remain poorly understood due to their genetic complexity.CHD8is a risk allele strongly associated with ASD, and heterozygousChd8loss-of-function mice have been reported to exhibit macrocephaly in early postnatal stages. In this work, we sought to identify measurable brain alterations in early embryonic development.ResultsWe performed light-sheet fluorescence microscopy imaging of N-cadherin stained and optically clearedChd8+/-and wild-type mouse brains at embryonic day 12.5 (E12.5). We report a detailed morphometric characterization of embryonic brain shapes and cortical neuroepithelial apical architecture. WhileChd8+/-characteristic expansion of the forebrain and midbrain was not observed this early in embryogenesis, a tendency for a decreased lateral ventricular sphericity and an increased intraocular distance inChd8+/-brains was found compared to controls. This study advocates the use of high-resolution microscopy technologies and multi-scale morphometric analyses of target brain regions to explore the etiology and cellular basis ofChd8haploinsufficiency.
Single depolymerizing and transport kinesins stabilize microtubule ends
Authors: Ciorîtă Alexandra , Bugiel Michael , Sudhakar Swathi , Schäffer Erik , Jannasch Anita 
Published: October 2020

ABSTRACTMicrotubules are highly dynamic cellular filaments and many intracellular processes like cell division depend on an accurate control of their length. Among other factors, microtubule length is actively modulated by motors from the kinesin superfamily. For example, yeast kinesin-8, Kip3, depolymerizes microtubules in a collective manner by a force- and length-dependent mechanism. However, whether single motors depolymerize or stabilize microtubule ends is unclear. Here, using interference reflection microscopy, we measured the influence of single kinesin motors on the stability of microtubules in anin vitroassay. Surprisingly, using unlabeled, stabilized microtubules, we found that both single kinesin-8 and non-depolymerizing kinesin-1 transport motors stabilized microtubule ends further by reducing the spontaneous microtubule depolymerization rate. Since we observed this effect for two very different kinesins, it implies a more general stabilization mechanism. For Kip3, this behavior is contrary to the collective force-dependent depolymerization activity of multiple motors. The complex, concentration-dependent interaction with microtubule ends provides new insights into the molecular mechanism of kinesin-8 and its regulatory function of microtubule length.
RESCRIPt: Reproducible sequence taxonomy reference database management for the masses
Authors: Robeson Michael S. , O’Rourke Devon R. , Kaehler Benjamin D. , Ziemski Michal , Dillon Matthew R. , Foster Jeffrey T. , Bokulich Nicholas A. 
Published: October 2020

AbstractBackgroundNucleotide sequence and taxonomy reference databases are critical resources for widespread applications including marker-gene and metagenome sequencing for microbiome analysis, diet metabarcoding, and environmental DNA (eDNA) surveys. Reproducibly generating, managing, using, and evaluating nucleotide sequence and taxonomy reference databases creates a significant bottleneck for researchers aiming to generate custom sequence databases. Furthermore, database composition drastically influences results, and lack of standardizations limits cross-study comparisons. To address these challenges, we developed RESCRIPt, a software package for reproducible generation and management of reference sequence taxonomy databases, including dedicated functions that streamline creating databases from popular sources, and functions for evaluating, comparing, and interactively exploring qualitative and quantitative characteristics across reference databases.ResultsTo highlight the breadth and capabilities of RESCRIPt, we provide several examples for working with popular databases for microbiome profiling (SILVA, Greengenes, NCBI-RefSeq, GTDB), eDNA, and diet metabarcoding surveys (BOLD, GenBank), as well as for genome comparison. We show that bigger is not always better, and reference databases with standardized taxonomies and those that focus on type strains have quantitative advantages, though may not be appropriate for all use cases. Most databases appear to benefit from some curation (quality filtering), though sequence clustering appears detrimental to database quality. Finally, we demonstrate the breadth and extensibility of RESCRIPt for reproducible workflows with a comparison of global hepatitis genomes.ConclusionsRESCRIPt provides tools to democratize the process of reference database acquisition and management, enabling researchers to reproducibly and transparently create reference materials for diverse research applications. RESCRIPt is released under a permissive BSD-3 license athttps://github.com/bokulich-lab/RESCRIPt.
Development of attention networks from childhood to young adulthood: A study of performance, intraindividual variability and cortical thickness
Authors: Boen Rune , Ferschmann Lia , Vijayakumar Nandita , Overbye Knut , Fjell Anders M. , Espeseth Thomas , Tamnes Christian K. 
Published: October 2020

AbstractHuman cognitive development is manifold, with different functions developing at different speeds at different ages. Attention is an important domain of this cognitive development, and involves distinct developmental trajectories in separate functions, including conflict processing, selection of sensory input and alertness. In children, several studies using the Attention Network Test (ANT) have investigated the development of three attentional networks that carry out the functions of executive control, orienting and alerting. There is, however, a lack of studies on the development of these attentional components across adolescence, limiting our understanding of their protracted development. To fill this knowledge gap, we performed a mixed cross-sectional and longitudinal study using mixed methods to examine the development of the attentional components and their intraindividual variability from late childhood to young adulthood (n = 287, n observations = 408, age range = 8.5–26.7 years, mean follow up interval = 4.4 years). The results indicated that executive control stabilized during late adolescence, while orienting and alerting continued to develop into young adulthood. In addition, a continuous development into young adulthood was observed for the intraindividual variability measures of orienting and alerting. In a subsample with available magnetic resonance imaging (MRI) data (n =169, n observations = 281), higher alerting scores were associated with thicker cortices within a right prefrontal cortical region and greater age-related cortical thinning in left rolandic operculum, while higher orienting scores were associated with greater age-related cortical thinning in frontal and parietal regions. Finally, increased consistency of orienting performance was associated with thinner cortex in prefrontal regions and reduced age-related thinning in frontal regions.
Lysophosphatidic acid (LPA)-antibody (504B3) validation by free-solution assay and interferometry identifies off-target binding
Authors: Ray Manisha , Kihara Yasuyuki , Bornhop Darryl J. , Chun Jerold 
Published: October 2020

AbstractAntibody specificity and sensitivity is required in basic and clinical research for ensuring scientific rigor and reproducibility, while off-target cross-reactivity could generate erroneous conclusions. Lysophosphatidic acid (LPA) is a bioactive lipid being targeted clinically by antibody strategies. Here, we reexamined binding properties of a commercially available monoclonal antibody (504B3) reported as specific for LPA using a free-solution assay measured in a compensated interferometric reader. The antibody showed comparable binding affinities to LPA and non-LPA lipids including phosphatidic acid (PA) and lysophosphatidylcholine (LPC). These results may alter conclusions drawn from current and past basic and clinical studies employing anti-LPA antibodies.
Putamen volume predicts real-time fMRI neurofeedback learning success across paradigms and neurofeedback target regions
Authors: Zhao Zhiying , Yao Shuxia , Zweerings Jana , Zhou Xinqi , Zhou Feng , Chen Huafu , Kendrick Keith M , Mathiak Klaus , Becker Benjamin 
Published: October 2020

AbstractReal-time fMRI guided neurofeedback training has gained increasing interest as a non-invasive brain regulation technique with the potential to normalize functional brain alterations in therapeutic contexts. Individual variations in learning success and treatment response have been observed, yet the neural substrates underlying the learning of self-regulation remain unclear. Against this background, we explored potential brain structural predictors for learning success with pooled data from three real-time fMRI datasets. Our analysis revealed that gray matter volume of the right putamen could predict neurofeedback learning success across the three datasets (n = 66 in total). Importantly, the original studies employed different neurofeedback paradigms during which different brain regions were trained pointing to a general association with learning success independent of specific aspects of the experimental design. Given the role of the putamen in associative learning the finding may reflect an important role of instrumental learning processes and brain structural variations in associated brain regions for successful acquisition of fMRI neurofeedback-guided self-regulation.