bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-cohort analysis of host immune response identifies conserved protective and detrimental modules associated with severity irrespective of virus
Authors: Zheng Hong , Rao Aditya M , Dermadi Denis , Toh Jiaying , Jones Lara Murphy , Donato Michele , Liu Yiran , Su Yapeng , Karagiannis Minas , Marantos Theodoros , Hasin-Brumshtein Yehudit , He Yudong D , Giamarellos-Bourboulis Evangelos J , Heath Jim , Khatri Purvesh
Published: October 2020

SARS-CoV-2 pandemic, the fourth pandemic of the decade, has underscored gaps in global pandemic preparedness and the need for generalizable tests to avert overwhelming healthcare systems worldwide, irrespective of a virus. We integrated 4,780 blood transcriptome profiles from patients infected with one of 16 viruses across 34 independent cohorts from 18 countries, and 71 scRNA-seq profiles of 264,224 immune cells across three independent cohorts. We found a myeloid cell-dominated conserved host response associated with severity. It showed increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells with increased severity. We identified four gene modules that delineate distinct trajectories associated with mild and severe outcomes, and show the interferon response was decoupled from protective host response during severe viral infection. These modules distinguished non-severe from severe viral infection with clinically useful accuracy. Together, our findings provide insights into immune response dynamics during viral infection, and identify factors that may influence patient outcomes.
PVP1–The People’s Ventilator Project: A fully open, low-cost, pressure-controlled ventilator
Authors: LaChance Julienne , Zajdel Tom J. , Schottdorf Manuel , Saunders Jonny L. , Dvali Sophie , Marshall Chase , Seirup Lorenzo , Notterman Daniel A. , Cohen Daniel J.
Published: October 2020

We present a fully open ventilator platform–The People’s Ventilator: PVP1– with complete documentation and detailed build instructions, and a DIY cost of $1,300 USD. Here, we validate PVP1 against key performance criteria specified in the U.S. Food and Drug Administration’s Emergency Use Authorization for Ventilators. Notably, PVP1 performs well over a wide range of test conditions and has been demonstrated to perform stably for a minimum of 72,000 breath cycles over three days with a mechanical test lung. As an open project, PVP1 can enable both future educational, academic, and clinical developments in the ventilator space.
Vulnerability and burden of all-cause mortality associated with particulate air pollution increased during COVID-19 pandemic: a nationwide observed study in Italy
Authors: Ye Tingting , Xu Rongbin , Yu Wenhua , Chen Zhaoyue , Guo Yuming , Li Shanshan
Published: October 2020

Background

Limited evidence is available on the health effects of particulate matter (i.e. PM2.5, particulate matter with an aerodynamic diameter < 2.5μm; PM10, < 10μm; PM2.5-10, 2.5-10μm) during the pandemic of COVID-19 in Italy.

Objectives

To examine the associations between all-cause mortality and daily PM2.5, PM2.5-10, and PM10in the pandemic period, and compare them to the normal periods (2015-2019) in Italy.

Methods

We collected daily data regarding all-cause (stratified by age and gender), and PM2.5, PM2.5-10, and PM10for 107 Italian provinces from 1, January 2015 to 31, May 2020. A time-stratified case-cross design with the distributed lag non-linear model was used to examine the association between PM and all-cause mortality during the first three months of the COVID-19 outbreak (March to May in 2020) and the same months in 2015-2019. We also compared the counts and fractions of death attributable to PM in two periods.

Results

Overall, Italy saw an increase in daily death counts while slight decreases in PM concentrations in 2020 pandemic period compared to same months of 2015-2019. Mortality effects were significant in lag 0-3 days for PM2.5, lag 0-2 for PM10, and lag 0-1 for PM2.5-10. Each 10 µg/m3increase in PM was associated much higher increase in daily all-cause mortality during 2020 pandemic period compared to the same months during 2015-2019 [increased mortality rate: 7.24 % (95%CI: 4.84%, 9.70%) versus 1.69% (95%CI: 1.12%, 2.25%) for PM2.5; 3.45 % (95%C: 2.58%, 4.34%) versus 1.11% (95%CI: 0.79%, 1.42%) for PM10, 4.25% (95%CI: 2.99%, 5.52%) versus 1.76% (95%CI: 1.14%, 2.38%) for PM2.5-10]. The counts and fractions of deaths attributable to PM were higher in 2020 than the normal periods for PM2.5(attributable death counts: 20,062 in 2020 versus 3,927 per year in 2015-2019; attributable fractions: 10.2% versus 2.4%), PM10(15,112 versus 3,999; 7.7% versus 2.5%), and PM2.5-10(7,193 versus 2303; 3.7% versus 1.4%).

Conclusions

COVID-19 pandemic increased the vulnerability and excess cases of all-cause mortality associated with short-term exposure to PM2.5, PM2.5-10and PM10in Italy, despite a decline in air pollution level. This suggests using historical PM-mortality association to calculate health benefits associated with reduction in PMs has big uncertainties.
Paracoracoid versus Costoclavicular Approach to Infraclavicular Block: A Prospective, Two Arm, Parallel design, Single-centre Randomized Controlled Trial
Authors: Brown Brigid , Magsaysay Pauline , Bureau Yves , Yu Janice , Dhir Shalini
Published: October 2020

Introduction

Paracoracoid approach to the brachial plexus block is the conventional infraclavicular technique for upper limb surgeries. In this approach, the ultrasound transducer is placed in the parasagittal plane below the clavicle, medial to the coracoid process. In this view, three cords are separated from each other and are rarely visualized in a single ultrasound window. In the costoclavicular approach, the ultrasound transducer is placed parallel to and below the clavicle. In this view, the cords are clustered together, at a more superficial level. We conducted a randomized controlled trial to compare these two infraclavicular brachial plexus approaches.

Methods

Seventy patients were randomized to receive either a paracoracoid or costoclavicular infraclavicular block. Both groups received 35 ml of 0.5% ropivacaine under ultrasound guidance. The primary outcome was sensory block onset time while secondary outcomes included performance times, complications during block insertion (paresthesia, vascular puncture, pleural puncture), block failure, patient satisfaction, and postoperative complications. Telephone follow-up was done 24 h and 7 days later.

Results

Sensory block onset time was significantly shorter in the paracoracoid group 18.7 (4.4) min versus 22.2 (6.2) min (p=0.045). Block success at 30 minutes was the same between both groups. There was no difference in any secondary outcomes.

Conclusions

This randomized controlled trial demonstrated that the novel costoclavicular approach to the infraclavicular brachial plexus block had similar procedure time, block success and similar complication rates for upper limb surgery when compared to the traditional paracoracoid technique. However, it resulted in longer sensory block onset time.
Sars-Cov-2 in Argentina: Lockdown, Mobility, and Contagion
Authors: Larrosa Juan M.C.
Published: October 2020

There is a debate in Argentina about the effectiveness of mandatory lockdown measures in containing COVID-19 that lasts five months making it one of the longest in the World. The population effort to comply the lockdown has been decreasing over time given the economic and social costs that it entails. We contributes by analyzing the Argentinian case through information of mobility and contagion given answers to recurrent questions on these topics. This paper aims to fill the gap in the literature by assessing the effects of lockdown measures and the regional relaxation on the numbers of rate of new infections. We also respond to issues of internal political discussion on regional contagion and the effect of marches and unexpected crowd events. We use pool, fixed and random effects panel data modeling and Granger causality tests identifying relations between mobility and contagion. Our results show that lockdown in Argentina has been effective in reducing the mobility but not in way that reduces the rate of contagion. Strict lockdown seems to be effective in short periods of time and by extend it without complementary measures loss effectiveness. Contagion rate seems to be discretely displaced in time and resurging amidst slowly increasing in mobility.
SARS-CoV-2 Prevalence and Seroprevalence among Healthcare Workers in Belgian Hospitals: Baseline Results of a Prospective Cohort Study
Authors: Mortgat Laure , Barbezange Cyril , Fischer Natalie , Heyndrickx Leo , Hutse Veronik , Thomas Isabelle , Vuylsteke Bea , Arien Kevin , Desombere Isabelle , Duysburgh Els
Published: October 2020

Background

Given the current SARS-CoV-2 pandemic and the occurrence of a second wave, assessing the burden of disease among health care workers (HCWs) is crucial. We aim to document the prevalence of SARS-CoV-2 and the seroprevalence of anti-SARS-CoV-2 IgG among HCWs in Belgian hospitals, and to study potential risk factors for the infection in order to guide infection prevention and control (IPC) measures in healthcare institutions.

Methods

We performed a cross-sectional analysis of the baseline results (April 22 - April 26) of an ongoing cohort study. All staff who were present in the hospital during the sampling period and whose profession involved contact with patients were eligible. Fourteen hospitals across Belgium and 50 HCW per hospital were randomly selected. RT-qPCR was performed to detect SARS-CoV-2 RNA on nasopharyngeal swabs, and a semi-quantitative IgG ELISA was used to detect anti-SARS-CoV-2 antibodies in sera. Individual characteristics likely to be associated with seropositivity were collected using an online questionnaire.

Findings

698 participants completed the questionnaire; 80.8% were women, median age was 39.5, and 58.5% were nurses. Samples were collected on all 699 participants. The weighted anti-SARS-CoV-2 IgG seroprevalence was 7.7% (95%CI, 4.7%-12.2%), while 1.1% (95%CI, 0.4%-3.0%) of PCR results were positive. Unprotected contact with a confirmed case was the only factor associated with seropositivity (PR 2.16, 95% CI, 1.4-3.2).

Interpretation

Most Belgian HCW did not show evidence of SARS-CoV-2 infection by late April 2020, and unprotected contact was the most important risk factor. This confirms the importance of widespread availability of protective equipment and use of adequate IPC measures in hospital settings.
Characteristics and outcomes of hospitalized adults with COVID-19 in Nepal: a multicenter, prospective cohort study
Authors: Chaudhary Ashok , Singh Uday Narayan , Paudel Pramod , Thapa Niresh , Khadka Kamal , Sah Prameshwar Kumar , Kamar Sher Bahadur , Joshi Jagadish , Ansari Kamar Hasan , Tiwari Shree Ram , Sharma Sarbesh , Jaiswal Sanjay Kumar , Joshi Ramesh , Baskota Samikchya , Tiwari Arjun Prasad , Pandey Hem Raj
Published: October 2020

Introduction

There is limited data on clinical course and outcomes of hospitalized adults with COVID-19 in Nepal. Thus, it is imperative to characterize the features of this disease in the domestic context.

Methodology

We identified all adult patients with laboratory-confirmed COVID-19 admitted to five different hospitals in Nepal from June 15 to July 15, 2020. We collected epidemiological, socio-cultural and clinicopathologic data, and stratified the patients based on their symptom status.

Results

The study included 220 patients with an overall median age of 31.5 (25-37) years, and 181 (82.3%) were males. 159 (72.3%) were asymptomatic, and 163 (74.1%) were imported cases. Of 217 patients with the available data, 110 (50.7%) reported their annual household income less than 2000 US dollars, and 122 (56.2%) practiced Pranayama (yogic rhythmic breathing techniques) regularly. Eight patients (3.6%) required supplemental oxygen and two patients (0.9%) died. None of the patients who practiced Pranayama regularly required supplemental oxygen. Compared to asymptomatic patients, symptomatic patients had greater proportion of females (31.1% vs. 12.6%, p=0.001), imported cases (85.2% vs. 69.8%, p=0.02), illiterates (26.8% vs. 12.1%, p=0.01), alcohol users (43.3% vs. 24.5%, p=0.01), patients feeling stigmatized by society (45.8% vs. 22.6%, p=0.001), and had higher platelet count (253× 109/L vs. 185×109/L, p=0.02).

Conclusions

Most cases were imported, asymptomatic young males, with very few deaths. Pranayama practice was associated with protection against severe COVID-19, but more data is needed to substantiate this. The association of platelets count with symptom status in the Nepalese population needs further exploration.
Detecting and Monitoring Brain Disorders Using Smartphones and Machine Learning
Authors: Colbaugh Rich , Glass Kristin , Global Volv
Published: October 2020

The ubiquity of smartphones in modern life suggests the possibility to use them to continuously monitor patients, for instance to detect undiagnosed diseases or track treatment progress. Such data collection and analysis may be especially beneficial to patients with i.) mental disorders, as these individuals can experience intermittent symptoms and impaired decision-making, which may impede diagnosis and care-seeking, and ii.) progressive neurological diseases, as real-time monitoring could facilitate earlier diagnosis and more effective treatment. This paper presents a new method of leveraging passively-collected smartphone data and machine learning to detect and monitor brain disorders such as depression and Parkinson’s disease. Crucially, the algorithm is able learn accurate, interpretable models from small numbers of labeled examples (i.e., smartphone users for whom sensor data has been gathered and disease status has been determined). Predictive modeling is achieved by learning from both real patient data and ‘synthetic’ patients constructed via adversarial learning. The proposed approach is shown to outperform state-of-the-art techniques in experiments involving disparate brain disorders and multiple patient datasets.
Temporal Analysis of COVID-19 Convalescent Plasma Donations Reveals Significant Decrease in Neutralizing Capacity Over Time
Authors: Girardin Roxie C. , Dupuis Alan P. , Payne Anne F. , Sullivan Timothy J. , Strauss Donna , Parker Monica M. , McDonough Kathleen A.
Published: October 2020

COVID-19 convalescent plasma (CCP) received approval for use under an Emergency Use Authorization by the FDA for treatment of seriously ill patients. Use of CCP units with a signal-to-cutoff ratio of ≥12 using the Ortho VITROS SARS-CoV-2 IgG test (OVSARS2IgG) is authorized. Little is known about the relationship between this ratio and the neutralizing capacity of plasma/sera against genuine SARS-CoV-2 virus. We measured the neutralizing capacity of 981 samples from 196 CCP donors 7-119 days post initial donation (DPID). Neutralizing capacity was assessed for 50% (PRNT50) and 90% (PRNT90) reduction of infectious virus using the gold standard plaque reduction neutralization test (PRNT). Importantly, while 32.7%/79.5% (PRNT90/PRNT50) of donations met the FDA minimum titer of 1:80 initially, only 14.0%/48.8% (PRNT90/PRNT50) met this cut-off ≥85 DPID. A subset of 91 donations were evaluated using the OVSARS2IgG and compared to PRNT titers for diagnostic accuracy. The correlation of OVSARS2IgG results to neutralizing capacity allowed extrapolation to CCP therapy efficacy results. CCP with OVSARS2IgG ratios in the therapeutically beneficial group had neutralizing titers of ≥1:640 (PRNT50) and/or ≥1:80 (PRNT90). This information provides a new basis for refining the recommended properties of CCP that is used to treat severe COVID-19.
Deep Homology-Based Protein Contact-Map Prediction
Authors: Ronen Omer , Zuk Or
Published: October 2020

Prediction of Proteins’ three dimensional structure and their contact maps from their amino-acid sequences is a fundamental problem in structural computational biology. The structure and contacts shed light on protein function, enhance our basic understanding of their molecular biology and may potentially aid in drug design. In recent years we have seen significant progress in protein contact map prediction from Multiple Sequence Alignments (MSA) of the target protein and its homologous, using signals of co-evolution and applying deep learning methods.

Homology modelling is a popular and successful approach, where the structure of a protein is determined using information from known template structures of similar proteins, and has been shown to improve prediction even in cases of low sequence identity. Motivated by these observations, we developedPeriscope, a method for homology-assisted contact map prediction using a deep convolutional network. Our method automatically integrates the co-evolutionary information from the MSA, and the physical contact information from the template structures.

We apply our method to families of CAMEO and membrane proteins, and show improved prediction accuracy compared to the MSA-only based method RaptorX. Finally, we use our method to improve the subsequent task of predicting the proteins’ three dimensional structure based on the (improved) predicted contact map, and show initial promising results in this task too - our overall accuracy is comparable to the template-based Modeller software, yet the two methods are complementary and succeed on different targets.
Proteolytic activation of SARS-CoV-2 spike at the S1/S2 boundary: potential role of proteases beyond furin
Authors: Tang Tiffany , Jaimes Javier A. , Bidon Miya K. , Straus Marco R. , Daniel Susan , Whittaker Gary R.
Published: October 2020

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses its spike (S) protein to mediate viral entry into host cells. Cleavage of the S protein at the S1/S2 and/or S2’ site(s) is associated with viral entry, which can occur at either the cell plasma membrane (early pathway) or the endosomal membrane (late pathway), depending on the cell type. Previous studies show that SARS-CoV-2 has a unique insert at the S1/S2 site that can be cleaved by furin, which appears to expand viral tropism to cells with suitable protease and receptor expression. Here, we utilize viral pseudoparticles and protease inhibitors to study the impact of the S1/S2 cleavage on infectivity. Our results demonstrate that S1/S2 pre-cleavage is essential for early pathway entry into Calu-3 cells, a model lung epithelial cell line, but not for late pathway entry into Vero E6 cells, a model cell line. The S1/S2 cleavage was found to be processed by other proteases beyond furin. Using bioinformatic tools, we also analyze the presence of a furin S1/S2 site in related CoVs and offer thoughts on the origin of the insertion of the furin-like cleavage site in SARS-CoV-2.
Novel inhibitors ofE. colilipoprotein diacylglyceryl transferase are insensitive to resistance caused bylppdeletion
Authors: Diao Jingyu , Komura Rie , Sano Tatsuya , Pantua Homer , Storek Kelly M. , Inaba Hiroko , Ogawa Haruhiko , Noland Cameron L. , Peng Yutian , Gloor Susan L. , Yan Donghong , Kang Jing , Katakam Anand Kumar , Nickerson Nicholas N. , Austin Cary D. , Murray Jeremy , Rutherford Steven T. , Reichelt Mike , Xu Yiming , Xu Min , Yanagida Hayato , Nishikawa Junichi , Reid Patrick C , Cunningham Christian N. , Kapadia Sharookh B.
Published: October 2020

Lipoprotein diacylglyceryl transferase (Lgt) catalyzes the first step in the biogenesis of Gram-negative bacterial lipoproteins which play crucial roles in bacterial growth and pathogenesis. We demonstrate that Lgt depletion in a clinical uropathogenicEscherichia colistrain leads to permeabilization of the outer membrane and increased sensitivity to serum killing and antibiotics. Importantly, we identify the first ever described Lgt inhibitors that potently inhibit Lgt biochemical activityin vitroand are bactericidal against wild-typeAcinetobacter baumanniiandE. colistrains. Unlike inhibition of other steps in lipoprotein biosynthesis, deletion of the major outer membrane lipoprotein,lpp, is not sufficient to rescue growth after Lgt depletion or provide resistance to Lgt inhibitors. Our data validate Lgt as a novel druggable antibacterial target and suggest that inhibition of Lgt may not be sensitive to one of the most common resistance mechanisms that invalidate inhibitors of downstream steps of bacterial lipoprotein biosynthesis and transport.
Motif Analysis in k-mer Networks: An Approach towards Understanding SARS-CoV-2 Geographical Shifts
Authors: Biswas Sourav , Saha Suparna , Bandyopadhyay Sanghamitra , Bhattacharyya Malay
Published: October 2020

With an increasing number of SARS-CoV-2 sequences available day by day, new genomic information is getting revealed to us. As SARS-CoV-2 sequences highlight wide changes across the samples, we aim to explore whether these changes reveal the geographical origin of the corresponding samples. Thek-mer distributions, denoting normalized frequency counts of all possible combinations of nucleotide of size uptok, are often helpful to explore sequence level patterns. Given the SARS-CoV-2 sequences are highly imbalanced by its geographical origin (relatively with a higher number samples collected from the USA), we observe that with proper under-samplingk-mer distributions in the SARS-CoV-2 sequences predict its geographical origin with more than 90% accuracy. The experiments are performed on the samples collected from six countries with maximum number of sequences available till July 07, 2020. This comprises SARS-CoV-2 sequences from Australia, USA, China, India, Greece and France. Moreover, we demonstrate that the changes of genomic sequences characterize the continents as a whole. We also highlight that the network motifs present in the sequence similarity networks have a significant difference across the said countries. This, as a whole, is capable of predicting the geographical shift of SARS-CoV-2.
Gait-symmetry-based human-in-the-loop optimization for unilateral transtibial amputees with robotic prostheses
Authors: Feng Yanggan , Mao Chengqiang , Wang Qining
Published: October 2020

Gait asymmetry due to the loss of unilateral limb increases the risk of injury or progressive joint degeneration. The development of wearable robotic devices paves a way to improve gait symmetry of unilateral amputees. Moreover, the state-of-the-art studies on human-in-the-loop optimization strategies through decreasing the metabolic cost as the optimization task, have met several challenges, e.g. too long period of optimization and the optimization feasibility for unilateral amputees who have the deficit of gait symmetry. Here, in this paper, we proposed gait-symmetry-based human-in-the-loop optimization method to decrease the risk of injury or progressive joint degeneration for unilateral transtibial amputees. The experimental results (N= 3 unilateral transtibial subjects) demonstrate that only average 9.0±4.1minof convergence was taken. Compared to gait symmetry while wearing prosthetics, after optimization, the gait symmetry indicator value of the subjects wearing the robotic prostheses was improved by 21.0% and meanwhile the net metabolic energy consumption value was reduced by 9.2%. Also, this paper explores the rationality of gait indicators and what kind of gait indicators are the optimization target. These results suggest that gait-symmetry-based human-in-the-loop strategy could pave a practical way to improve gait symmetry by accompanying the reduction of metabolic cost, and thus to decrease the risk of joint injury for the unilateral amputees.
Sleeve gastrectomy promotes sustained weight loss while increasing heat production in middle aged, obese female mice
Authors: Emiliano Ana BF , He Ying , Higuchi Sei , Nemr Rabih , Lopatinsky Natalie , Schwartz Gary J.
Published: October 2020

Background

Sleeve gastrectomy (SG) is currently the most frequently performed bariatric surgery in the United States. The majority of patients undergoing SG are middle aged women. Most preclinical models of bariatric surgery, however, utilize juvenile male mice. A long-term characterization of the response of mature wild type, obese female mice to SG has not been performed. Thus, we set out to characterize the response of middle aged obese female mice to SG.

Methods

Ten-month old C57bl/6J obese female mice were randomized to undergo SG, sham surgery without caloric restriction (SH) or sham surgery with caloric restriction to match body weight to the SG group (SWM). Body weight, body composition and glucose tolerance were matched at baseline. Mice were followed for 60 days following their respective surgeries.

Results

The SG group had a more pronounced percent weight loss than the SH and SWM control groups (p<0.05), while consuming more calories than the SWM group (p<0.05). The SG group had a significant improvement in glucose tolerance compared to the SH control group (p<0.05). Plasma leptin was significantly decreased in the SG and SWM group, compared to the SH group (p<0.01). Unexpectedly, FGF-21 was increased in the SH group compared to the SG and SWM groups (p<0.01), while there was no difference in plasma insulin among the three groups. Heat production was increased in the SG group compared to SWM and SH groups (p<0.001). SG also had a significantly increased mRNA expression of Uncoupling Protein 1 (UCP-1), Adiponectin and Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC1-alpha) in brown adipose tissue (BAT), compared to SWM and SH groups. Both SG and SWM groups had increased fecal lipid excretion (p<0.05), compared to the SH group.

Conclusions

SG in obese, middle aged female mice leads to sustained weight loss and blood glucose improvement. It appears that increased metabolism in BAT may be linked to these effects.
LTA4Hassociation with montelukast response in early and late-onset asthma
Authors: Maroteau Cyrielle , Espuela-Ortiz Antonio , Herrera-Luis Esther , Srinivasan Sundararajan , Carr Fiona , Tavendale Roger , Wilson Karen , Hernandez-Pacheco Natalia , Chalmers James D. , Turner Steve , Mukhopadhyay Somnath , Maitland-van der Zee Anke-Hilse , Burchard Esteban G. , Pino-Yanes Maria , Young Simon , Lassi Glenda , Platt Adam , Palmer Colin N. A. ,   on behalf of the PiCA consortium
Published: October 2020

Leukotrienes play a central pathophysiological role in both pediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. To test the role of theLTA4Hregulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations.

We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta-analysis.

While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset individuals from European ancestry demonstrated the risk of experiencing asthma exacerbations in the G allele carriers’ group (AG or GG), despite montelukast treatment, was increased (odds-ratio=3.27, 95%confidence interval: 0.98–10.93, I2=69%, p=0.05) compared to those in the AA group. When meta-analyzing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR=1.69, 95% CI: 0.56-5.09, I2=84.81%, p=0.35).

Our study demonstrates that genetic variation inLTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. Europeans individuals with early-onset (≤18y) carrying the rs2660845 G allele have increased risk of exacerbation under montelukast treatment, presumably due to the up-regulation ofLTA4Hactivity. These findings support a precision medicine approach for the treatment of asthma with montelukast.
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

Background

Concurrent 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.

Methods

We 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.

Results

After 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.

Conclusions

Focusing 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

Decisions 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

Defects 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

The 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

Bin/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

Despite 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.

Results

We 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.

Conclusions

We 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

Objective

Autism 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.

Results

We 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

Microtubules 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

Background

Nucleotide 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.

Results

To 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.

Conclusions

RESCRIPt 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

Human 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.