bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-state transitions and collective cell movement generate an endoderm-like region in gastruloids
Authors: Hashmi Ali , Tlili Sham , Perrin Pierre , Martinez-Arias Alfonso , Lenne Pierre-François
Published: May 2020

Shaping the animal body plan is a complex process that involves the spatial organization and patterning of the different germ layers. Recent advances in live imaging have started to unravel the cellular choreography underlying this process in mammals, however, the sequence of events transforming an unpatterned cell ensemble into structured territories is largely unknown. Here, using gastruloids −3D aggregates of mouse embryonic stem cells-we study the formation of one of the three germ layers, the endoderm. We show that the endoderm is generated from an epiblast-like homogeneous state by a three-step mechanism: (i) a loss of E-cadherin mediated contacts in parts of the aggregate leading to the appearance of islands of E-cadherin expressing cells surrounded by cells devoid of E-cadherin, (ii) a separation of these two populations with islands of E-cadherin expressing cells flowing toward the aggregate tip, and (iii) their differentiation into an endoderm population. During the flow, the islands of E-cadherin expressing cells are surrounded by cells expressing T-Brachyury, reminiscent of the process occurring at the primitive streak. Consistent with recent in vivo observations, the endoderm formation in the gastruloids does not require an epithelial-to-mesenchymal transition, but rather a maintenance of an epithelial state for a subset of cells coupled with fragmentation of E-cadherin contacts in the vicinity, and a sorting process. Our data emphasize the role of signaling and tissue flows in the establishment of the body plan.
Optogenetic inhibition of colon epithelium reduces hypersensitivity in a mouse model of inflammatory bowel disease
Authors: Najjar Sarah A. , Ejoh Lindsay L. , Loeza-Alcocer Emanuel , Edwards Brian S. , Smith-Edwards Kristen M. , Epouhe Ariel Y. , Gold Michael S. , Davis Brian M. , Albers Kathryn M.
Published: May 2020

Visceral pain is a prevalent symptom of inflammatory bowel disease (IBD) that can be difficult to treat. Pain and hypersensitivity are mediated by extrinsic primary afferent neurons (ExPANs) that innervate the colon. Recent studies indicate that the colon epithelium contributes to initiating ExPAN firing and nociceptive responses. Based on these findings we hypothesized that the epithelium contributes to inflammation-induced hypersensitivity. A key prediction of this hypothesis is that inhibition of the epithelium would attenuate nociceptive signaling and inflammatory hypersensitivity. To test this hypothesis, the inhibitory yellow light activated protein archaerhodopsin was targeted to the intestinal epithelium (villin-Arch) or the ExPANs (TRPV1-Arch) that innervate the colon. Visceral sensitivity was assessed by measuring the visceromotor response (VMR) to colorectal distension (CRD), with and without yellow light illumination of the colon lumen. Inhibition of the colon epithelium in healthy villin-Arch mice significantly diminished the CRD-induced VMR. Direct inhibition of ExPANs during CRD using TRPV1-Arch mice showed that ExPAN and epithelial inhibition were similarly effective in reducing the VMR to CRD. We then investigated the effect of epithelial and ExPAN inhibition in the dextran sulfate sodium (DSS) model of inflammatory bowel disease (IBD). Inhibition of the colon epithelium significantly decreased DSS-induced hypersensitivity and was comparable to inhibition of ExPANS. Together these results reveal the potential of targeting the colon epithelium for treatment of pain.
Cold-induced hyperphagia requires AgRP neuron activation in mice
Authors: Deem Jennifer D. , Faber Chelsea L. , Pedersen Christian , Phan Bao Anh , Larsen Sarah A. , Ogimoto Kayoko , Nelson Jarrell T. , Damian Vincent , Tran Megan A. , Palmiter Richard D. , Kaiyala Karl J. , Scarlett Jarrad M. , Bruchas Michael R. , Schwartz Michael W. , Morton Gregory J.
Published: May 2020

To maintain energy homeostasis during cold exposure, the increased energy demands of thermogenesis must be counterbalanced by increased energy intake. To investigate the neurobiological mechanisms underlying this cold-induced hyperphagia, we asked whether agouti-related peptide (AgRP) neurons are activated when animals are placed in a cold environment and, if so, whether this response is required for the associated hyperphagia. We report that AgRP-neuron activation occurs rapidly upon acute cold exposure, as do increases of both energy expenditure and energy intake, suggesting the mere perception of cold is sufficient to engage each of these responses. We further report that silencing of AgRP neurons selectively blocks the effect of cold exposure to increase food intake. Together, these findings establish a physiologically important role for AgRP neurons in the hyperphagic response to cold exposure.
Proliferation is a requirement for differentiation of oligodendrocyte progenitor cells during CNS remyelination
Authors: Foerster Sarah , Neumann Björn , McClain Crystal , Di Canio Ludovica , Chen Civia Z , Reich Daniel S , Simons Benjamin D , Franklin Robin JM
Published: May 2020

Oligodendrocytes that generate new myelin sheaths around demyelinated axons in the regenerative process of remyelination are generally derived from oligodendrocyte progenitor cells (OPCs). During this process, OPCs become activated, populate the area of myelin loss, and finally differentiate. Although much is known about the individual stages of remyelination, the exact sequence of events and whether a dependency of each individual stage on each other exists is unknown. Understanding the biology behind these questions is important for the development of remyelination therapies to overcome the age-related decline in remyelination efficiency observed in the chronic phase of multiple sclerosis (MS). Here we show that, following toxin-induced demyelination, all re-populating OPCs first migrate into the site of damage, undergo relatively few rounds of division and eventually differentiate. We further show that OPC proliferation is a requirement for differentiation. Together, our results reveal an unexpected link between OPC proliferation and differentiation, and opens up the possibility of novel regenerative strategies in MS focussing on stimulating OPC proliferation.
Whole genome analysis of four Bangladeshi individuals
Authors: Khan Salim , Akter Shahina , Goswami Barna , Habib Ahashan , Banu Tanjina Akhtar , Barton Carl , Osman Eshrar , Samir Samiruzzaman , Arjuman Farida , Hasan Saam , Hossain Maqsud
Published: May 2020

Whole-genome sequencing (WGS) is a comprehensive method for analysing entire genomes and this has been instrumental in characterizing the single nucleotide polymorphisms associated with different diseases including cancer, diabetes, cardiovascular diseases and many others. In this paper we undertake a pilot study for sequencing four Bangladeshi individuals and profiling their single nucleotide variants. Our findings shed possible light on specific biological pathways effected by such variants in this population.
Development of a genetic evaluation for hair shedding in American Angus cattle to improve thermotolerance
Authors: Durbin Harly J. , Lu Duc , Yampara-Iquise Helen , Miller Stephen P. , Decker Jared E.
Published: May 2020

Background

Heat stress and fescue toxicosis caused by ingesting tall fescue infected with the endophytic fungus Epichloë coenophiala represent two of the most prevalent stressors to beef cattle in the United States, costing the beef industry millions of dollars each year. The rate at which a beef cow sheds her winter coat early in the summer is an indicator of adaptation to heat and an economically relevant trait in many parts of the U.S. Further, research suggests that early-summer hair shedding may be reflective of tolerance to fescue toxicosis, as vasoconstriction induced by fescue toxicosis limits the ability of an animal to shed its winter coat. Here, we developed parameters for routine genetic evaluation of hair shedding score in American Angus cattle and identified genomic loci associated with variation in hair shedding score via genome-wide association analysis (GWAA).

Results

Hair shedding score was found to be moderately heritable (h2 = 0.34 to 0.40), with differing repeatability estimates between cattle grazing versus not grazing endophyte-infected tall fescue. Our results suggest modestly negative genetic and phenotypic correlations between a dam’s hair shedding score (lower score is earlier shedding) and the weaning weight of her calf, one metric of performance. Together, these results indicate that economic gains can be made via the use of hair shedding score breeding values to select for heat tolerant cattle. GWAA identified 176 variants significant at FDR < 0.05. Functional enrichment analyses using genes within 50 Kb of these variants identified pathways involved in keratin formation, prolactin signaling, host-virus interaction, and other biological processes.

Conclusions

This work contributes to a continuing trend in the development of genetic evaluations for environmental adaptation. The results of this work will aid beef cattle producers in selecting more sustainable and climate-adapted cattle, as well as enable the development of similar routine genetic evaluations in other breeds.
Performance and impact of disposable and reusable respirators for healthcare workers during pandemic respiratory disease: a rapid evidence review
Authors: Burton Chris , Coles Briana , Adisesh Anil , Smith Simon , Toomey Elaine , Chan Xin Hui , Ross Lawrence , Greenhalgh Trisha
Published: May 2020

Objectives

In the context of the Covid-19 pandemic, to identify the range of filtering respirators that can be used in patient care and synthesise evidence to guide the selection and use of different respirator types.

Design

Comparative analysis of international standards for filtering respirators and rapid review of their performance and impact in healthcare.

Data sources

Websites of international standards organisations, Medline and EMBASE (final search 11thMay 2020), with hand-searching of references and citations.

Study selection

Guided by the SPIDER tool, we included studies whose sample was healthcare workers (including students). The phenomenon of interest was respirators, including disposable and reusable types. Study designs including cross-sectional, observational cohort, simulation, interview and focus group. Evaluation approaches included test of respirator performance, test of clinician performance or adherence, self-reported comfort and impact, and perceptions of use. Research types included quantitative, qualitative and mixed methods. We excluded studies comparing the effectiveness of respirators with other forms of protective equipment.

Data extraction, analysis and synthesis

Two reviewers extracted data using a template. Suitability for inclusion in the analysis was judged by two reviewers. We synthesised standards by tabulating data according to key criteria. For the empirical studies, we coded data thematically followed by narrative synthesis.

Results

We included relevant standards from 8 authorities across Europe, North and South America, Asia and Australasia. 39 research studies met our inclusion criteria. There were no instances of comparable publications suitable for quantitative comparison. There were four main findings. First, international standards for respirators apply across workplace settings and are broadly comparable across jurisdictions. Second, effective and safe respirator use depends on proper fitting and fit-testing. Third, all respirator types carry a burden to the user of discomfort and interference with communication which may limit their safe use over long periods; studies suggest that they have little impact on specific clinical skills in the short term but there is limited evidence on the impact of prolonged wearing. Finally, some clinical activities, particularly chest compressions, reduce the performance of filtering facepiece respirators.

Conclusion

A wide range of respirator types and models is available for use in patient care during respiratory pandemics. Careful consideration of performance and impact of respirators is needed to maximise protection of healthcare workers and minimise disruption to the delivery of care.
Risk Factors for COVID-19 versus non-COVID-19 related in-hospital and community deaths by Local Authority District in Great Britain
Authors: Leighton Samuel Paul , Leighton Danielle Jane , Herron James , Upthegrove Rachel , Cavanagh Jonathan , Gkoutos Georgios , Cullen Breda , Mallikarjun Pavan K
Published: May 2020

Objectives:
To undertake a preliminary hypothesis-generating analysis exploring putative risk factors for coronavirus diseae 2019 (COVID-19) population-adjusted deaths, compared with non-COVID-19 related deaths, at a local authority district (LAD) level in hospital, care homes and at home.
Design:
Ecological retrospective cohort study
Setting
Local authority districts (LADs) in England, Scotland and Wales (Great Britain (GB)).
Participants
All LAD deaths registered by week 16 of 2020.
Main Outcome Measures
Death registration where COVID-19 is mentioned as a contributing factor per 100,000 people in all settings, and in i) cares homes, ii) hospitals or iii) home only, in comparison to non-COVID-19 related deaths.
Results
Across GB by week 16 of 2020, 20,684 deaths had been registered mentioning COVID-19, equivalent to 25.6 per 100,000 people. Significant risk factors for LAD COVID-19 death in comparison to non-COVID-19 related death were air pollution and proportion of the population who were female. Significant protective factors were higher air temperature and proportion of the population who were ex-smokers. Conversely, for all COVID-19 unrelated deaths in comparison to COVID-19 deaths, higher rates of communal living, higher population rates of chronic kidney disease, chronic obstructive pulmonary disease, cerebrovascular disease deaths under 75 and dementia were predictive of death, whereas, higher rates of flight passengers was protective. Looking at individual setttings, the most notable findings in care homes was Scotland being a significant risk factor for COVID-19 related deaths compared to England. For hospital setting, the proportion of the population who were from black and Asian minority ethnic (BAME) groups significantly predicted COVID-19 related death.
Conclusions
This is the first study within GB to assess COVID-19 related deaths in comparison to COVID-19 unrelated deaths across hospital, care homes and home combined. As an ecological study, the results cannot be directly extrapolated to individuals. However, the analysis may be informative for public health policy and protective measures. From our hypothesis-generating analysis, we propose that air pollution is a significant risk factor and high temperature a significant protective factor for COVID-19 related deaths. These factors cannot readily be modelled at an individual level. Scottish local authorities and local authorities with a higher proportion of individuals of BAME origin are potential risk factors for COVID-19 related deaths in care homes and in hospitals, respectively. Altogether, this analysis shows the benefits of access to high quality open data for public information, public health policy and further research.
Comparison of renin–angiotensin–aldosterone system inhibitors with other antihypertensives in association with coronavirus disease-19 clinical outcomes: systematic review and meta-analysis
Authors: Bezabih Yihienew M. , Bezabih Alemayehu , Aalamneh Endalkachew , Peterson Gregory M. , Bezabhe Woldesellassie M.
Published: May 2020

Introduction

The effects of renin–angiotensin–aldosterone system (RAAS) inhibitors on the clinical outcomes of coronavirus disease-19 (COVID-19) have been conflicting in different studies. This meta-analysis was undertaken to provide more conclusive evidence.

Methods

A systematic search for published articles was performed in PubMed and EMBASE from January 5 2020 till May 5 2020. Studies that reported the clinical outcomes of patients with COVID-19, stratified by the class of concomitant antihypertensive drug therapy, were included. The Mantel-Haenszel random effects model was used to estimate pooled odds ratio (OR).

Results

A total of 6,997 patients with COVID-19 were included, and all of them had hypertension. The overall risk of poor patient outcomes (severe COVID-19 or death) was lower in patients taking RAAS inhibitors (OR=0.84, 95% CI: [0.73, 0.96]; P=0.017) compared with those receiving non-RAAS inhibitor antihypertensives. Patients taking angiotensin-I-converting enzyme inhibitors (ACEIs) were less likely to experience poor clinical outcomes (OR=0.73, 95% CI: [0.58-0.92]; P=0.01) compared with those receiving angiotensin-II receptor blockers (ARBs). In addition, comparison of ACEIs to the rest of non-ACEI antihypertensives gave a consistently decreased risk of poor COVID-19 outcome (OR=0.77, 95% CI: [0.63-0.93]; P=0.002). However, ARBs did not decrease the risk of poor COVID-19 outcomes compared to all other non-ARB antihypertensives (OR=1.13, 95% CI: [0.95-1.35]).

Conclusion

The risk of developing severe illness or death from COVID-19 was lower in patients who received RAAS inhibitors compared with those who took non-RAAS inhibitors. ACEIs might be better in decreasing the severity and mortality of COVID-19 than ARBs.
SARS-CoV-2 infection in London, England: Impact of lockdown on community point-prevalence, March-May 2020
Authors: Edelstein Michael , Obi Chinelo , Chand Meera , Hopkins Susan , Brown Kevin , Ramsay Mary
Published: May 2020

COVID-19 point prevalence PCR community testing allows disease burden estimation. In a sample of London residents, point prevalence decreased from 2.2% (95%CI 1.4;3.5) in early April (reflecting infection around lockdown implementation) to 0.2% (95%CI 0.03-1.6) in early May (reflecting infection 3-5 weeks into lockdown). Extrapolation from reports of confirmed cases suggest that 5-7.6% of total infections were confirmed by testing during this period. These data complement seroprevalence surveys improving the understanding of transmission in London.
Standardization of enzyme-linked immunosorbent assays for serosurveys of the SARS-CoV-2 pandemic using clinical and at-home blood sampling
Authors: Klumpp-Thomas Carleen , Kalish Heather , Drew Matthew , Hunsberger Sally , Snead Kelly , Fay Michael P , Mehalko Jennifer , Shunmugavel Anandakumar , Wall Vanessa , Frank Peter , Denson John-Paul , Hong Min , Gulten Gulcin , Messing Simon , Hicks Jennifer , Michael Sam , Gillette William , Hall Matthew D , Memoli Matthew , Esposito Dominic , Sadtler Kaitlyn
Published: May 2020

The extent of SARS-CoV-2 infection throughout the United States population is currently unknown. High quality serology is a key tool to understanding the spread of infection, immunity against the virus, and correlates of protection. Limited validation and testing of serology assays used for serosurveys can lead to unreliable or misleading data, and clinical testing using such unvalidated assays can lead to medically costly diagnostic errors and improperly informed public health decisions. Estimating prevalence and clinical decision making is highly dependent on specificity. Here, we present an optimized ELISA-based serology protocol from antigen production to data analysis. This protocol defines thresholds for IgG and IgM for determination of seropositivity with estimated specificity well above 99%. Validation was performed using both traditionally collected serum and dried blood on mail-in blood sampling kits, using archival (pre-2019) negative controls and known PCR-diagnosed positive patient controls. Minimal cross-reactivity was observed for the spike proteins of MERS, SARS1, OC43 and HKU1 viruses and no cross reactivity was observed with anti-influenza A H1N1 HAI titer during validation. This strategy is highly specific and is designed to provide good estimates of seroprevalence of SARS-CoV-2 seropositivity in a population, providing specific and reliable data from serosurveys and clinical testing which can be used to better evaluate and understand SARS-CoV-2 immunity and correlates of protection.
P0: Progress to zero: A simple metric to measure COVID-19 progress by country/region
Authors: Lavista Ferres Juan M , Etzioni Ruth B , Weeks William B.
Published: May 2020

The current COVID-19 pandemic is having a devastating impact on the world. As of May 8th, 2020, more than half of the world is in lockdown, 3.6 million people have been infected, and over 250,000 of them have died. This is the first pandemic in human history that has been tracked on a daily basis across the world. Currently, progress is being tracked by a series of metrics, including new cases, deaths, and the effective reproduction number over time (R(t)), which epidemiologists have emphasized. While it is an important measure, R(t) is not observable and is dependent on the absolute number of active cases; therefore, two geographies could have a similar R(t) but be having very different experiences. Here, we propose a metric to monitor progress on addressing the COVID pandemic that we name "progress to zero" or P0. P0 corresponds to the percentage decline from a previously recorded peak level. The metric ranges from 0% (representing a geography that has not yet peaked) to 100% (representing a geography wherein 0 cases have been recorded for at least seven days). Our metric helps leaders focus on progress to a desired goal, easily can be tracked over time, can quickly identify retreat from progress, and is comparable across geographies regardless of their size.
Data driven inference of the reproduction number (R0) for COVID-19 before and after interventions for 51 European countries
Authors: Karnakov Petr , Arampatzis Georgios , Kičić Ivica , Wermelinger Fabian , Wälchli Daniel , Papadimitriou Costas , Koumoutsakos Petros
Published: May 2020

The reproduction number (R0) is broadly considered as a key indicator for the spreading of the COVID-19 pandemic. The estimation of its value with respect to the key threshold of 1.0 is a measure of the need, and eventually effectiveness, of interventions imposed in various countries. Here we present an online tool for the data driven inference and quantification of uncertainties for R0 as well as the time points of interventions for 51 European countries. The study relies on the Bayesian calibration of the simple and well established SIR model with data from reported daily infections. The model is able to fit the data for most countries without individual tuning of parameters. We deploy an open source Bayesian inference framework and efficient sampling algorithms to present a publicly available GUI (https://www.cse-lab.ethz.ch/coronavirus/) that allows the user to assess custom data and compare predictions for pairs of European countries. The results provide a ranking based on the rate of the disease's spread suggesting a metric for the effectiveness of social distancing measures. They also serve to demonstrate how geographic proximity and related times of interventions can lead to similarities in the progression of the epidemic.
COVID-19 Confirmed Case Incidence Age Shift to Young Persons Age 0-19 and 20-39 Years Over Time: Washington State March - April 2020
Authors: Malmgren Judith , Guo Boya , Kaplan Henry G.
Published: May 2020

Background

As the coronavirus (COVID-19) epidemic passes the peak infection rate in some states and counties a phased re-opening with changes of stay-at-home restrictions and social distancing recommendations may lead to an increase of nonessential work, social activities and gathering, especially among younger persons.

Methods

A longitudinal cohort analysis of Washington State Department of Health COVID-19 confirmed case age distribution March 1-April 19 2020 for proportional change over time using chi square tests for significance (N = 13,934).

Results

From March 1st to April 19, 2020 age distribution shifted with a 10% decline in cases age 60 years and older and a 20% increase in age 0-19/20-39 years (chi-square = 223.10, p <.001). Number of cases over the eight-week analysis period were 0-19 years n = 515, 20-39 years n = 4078, 40-59 years n =4788, 60-79 years n = 3221, 80+ years n = 1332. New cases increased steadily among 0-19 and 20-39-year olds. After the peak (March 22, 2020), there was no decline among age 0-19 and a lesser decline among age 20-39 than older groups. As incidence declined in older age groups, the combined percentage of cases age 0-19 and 20-39 increased from 20% to 40% of total cases.

Conclusions

Increased COVID-19 infection among children and young adults is not without serious morbidity and mortality risk to them and others they may come in contact with, indicating a targeted approach for awareness and safety measures is advisable to reduce incidence among the supposedly less vulnerable but more mobile young population age 0-19 and 20-39 years.
Longitudinal laboratory testing tied to PCR diagnostics in COVID-19 patients reveals temporal evolution of distinctive coagulopathy signatures
Authors: Pawlowski Colin , Wagner Tyler , Puranik Arjun , Murugadoss Karthik , Loscalzo Liam , Venkatakrishnan AJ , Pruthi Rajiv K , Houghton Damon E , O'Horo John C , Morice William G , Halamka John , Badley Andrew D , Barnathan Elliot S , Makimura Hideo , Khan Najat , Soundararajan Venky
Published: May 2020

Temporal inference from laboratory testing results and their triangulation with clinical outcomes as described in the associated unstructured text from the provider notes in the Electronic Health Record (EHR) is integral to advancing precision medicine. Here, we studied 181 COVIDpos and 7,775 COVIDneg patients subjected to 1.3 million laboratory tests across 194 assays during a two-month observation period centered around their SARS-CoV-2 PCR testing dates. We found that compared to COVIDneg at the time of clinical presentation and diagnostic testing, COVIDpos patients tended to have higher plasma fibrinogen levels and similarly low platelet counts, with approximately 25% of patients in both cohorts showing outright thrombocytopenia. However, these measures show opposite longitudinal trends as the infection evolves, with declining fibrinogen and increasing platelet counts to levels that are lower and higher compared to the COVIDneg cohort, respectively. Our EHR augmented curation efforts suggest a minority of patients develop thromboembolic events after the PCR testing date, including rare cases with disseminated intravascular coagulopathy (DIC), with most patients lacking the platelet reductions typically observed in consumptive coagulopathies. These temporal trends present, for the first time, fine-grained resolution of COVID-19 associated coagulopathy (CAC), via a digital framework that synthesizes longitudinal lab measurements with structured medication data and neural network-powered extraction of outcomes from the unstructured EHR. This study demonstrates how a precision medicine platform can help contextualize each patients specific coagulation profile over time, towards the goal of informing better personalization of thromboprophylaxis regimen.
Modeling the COVID-19 outbreak in Ecuador: Is it the right time to lift social distancing containment measures?
Authors: Reina Ortiz Miguel , Sharma Vinita
Published: May 2020

Objective. Model the effect of partial and full reversal of containment measures on COVID-19 morbidity and mortality in Ecuador.
Methods. Susceptible, Infected, Recovered (SIR) models were used to simulate the transmission dynamics of COVID-19 before and after the implementation (and reversal) of containment measures. A Healthcare Compartmental Epidemic Model (HeCEM), which accounts for Hospital and Intensive Care Unit admission rates, was developed to also simulate the effect of reversing social distancing containment measures. Reported COVID-19 cases between February 29th and April 23rd, 2020 were obtained from the Servicio Nacional de Gestión de Riesgos y Emergencia, the national emergency management office of Ecuador. An ARIMA model was used to forecast reported number of cases based on the reported number of cases. SIR, HeCEM, and ARIMA model prediction errors were estimated.
Results. SIR and HeCEM models predict that, at the moment, hospital and ICU bed needs for COVID-19 patients exceed the capacity in Ecuador. Partial or full reversal of containment measures before reaching the point where hospital and ICU beds are enough to meet the expected demand will result in secondary waves that delay reaching this equilibrium, resulting in thousands of excess deaths. Forecasts predict over 50,000 reported COVID-19 cases by July 25th, 2020.
Conclusion. Partial reversal of containment measures should occur only after enough hospital and beds are available to meet the demand.
Decreased miR-24-3p potentiates DNA damage responses and increases susceptibility to COPD
Authors: Nouws Jessica , Wan Feng , Finnemore Eric , Roque Willy , Kim Sojin , Bazan Isabel , Li Chuan-xing , Magnus Skold C. , Yan Xiting , Neumeister Veronique , Britto Clemente J. , Sweasy Joann , Bindra Ranjit , Wheelock Åsa M. , Gomez-Villalobos Jose , Kaminski Naftali , Lee Patty J. , Sauler Maor
Published: May 2020

Activation of the DNA damage response (DDR) due to chronic exposure to cigarette smoke (CS) is implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). However, not all smokers develop COPD and the pathologic consequences of CS exposure are heterogenous. Cellular mechanisms that regulate the DDR and contribute to disease progression in susceptible individuals are poorly understood. Because microRNAs are well known regulators of the DDR, we evaluated microRNA expression arrays performed on lung samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA best correlated with radiographic emphysema (ρ=-0.353, P=1.3e-04) and validated this finding in multiple cohorts. In a CS-exposure mouse model, miR-24-3p inhibition increased emphysema severity. In human airway epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue and inversely correlated with miR-24-3p expression. We concluded that decreased miR-24-3p expression increases COPD susceptibility and potentiates the DDR through BIM and BRCA1.
Spatiotemporal structure of sensory-evoked and spontaneous activity revealed by mesoscale imaging in anesthetized and awake mice
Authors: Afrashteh Navvab , Inayat Samsoon , Contreras Edgar Bermudez , Luczak Artur , McNaughton Bruce L. , Mohajerani Majid H.
Published: May 2020

Brain activity propagates across the cortex in diverse spatiotemporal patterns, both as a response to sensory stimulation and during spontaneous activity. Despite been extensively studied, the relationship between the characteristics of such patterns during spontaneous and evoked activity is not completely understood. To investigate this relationship, we compared visual, auditory, and tactile evoked activity patterns elicited with different stimulus strengths and spontaneous activity motifs in lightly anesthetized and awake mice using mesoscale wide-field voltage-sensitive dye and glutamate imaging respectively. The characteristics of cortical activity that we compared include amplitude, speed, direction, and complexity of propagation trajectories in spontaneous and evoked activity patterns. We found that the complexity of the propagation trajectories of spontaneous activity, quantified as their fractal dimension, is higher than the one from sensory evoked responses. Moreover, the speed and direction of propagation, are modulated by the amplitude during both, spontaneous and evoked activity. Finally, we found that spontaneous activity had similar amplitude and speed when compared to evoked activity elicited with low stimulus strengths. However, this similarity gradually decreased when the strength of stimuli eliciting evoked responses increased. Altogether, these findings are consistent with the fact that even primary sensory areas receive widespread inputs from other cortical regions, and that, during rest, the cortex tends to reactivate traces of complex, multi-sensory experiences that may have occurred in a range of different behavioural contexts.
Reevaluation of theToxoplasma gondiiandNeospora caninumgenomes reveals misassembly, karyotype differences and chromosomal rearrangements
Authors: Berna Luisa , Marquez Pablo , Cabrera Andrés , Greif Gonzalo , Francia María E. , Robello Carlos
Published: May 2020

Neospora caninumprimarily infects cattle causing abortions with an estimated impact of a billion dollars on worldwide economy, annually. However, the study of its biology has been unheeded by the established paradigm that it is virtually identical to its close relative, the widely studied human pathogen,Toxoplasma gondii. By revisiting the genome sequence, assembly and annotation using third generation sequencing technologies, here we show that theN. caninumgenome was originally incorrectly assembled under the presumption of synteny withT. gondii. We show that major chromosomal rearrangements have occurred between these species. Importantly, we show that chromosomes originally annotated as ChrVIIb and VIII are indeed fused, reducing the karyotype of bothN. caninumandT. gondiito 13 chromosomes. We reannotate theN. caninumgenome, revealing over 500 new genes. We sequence and annotate the non-photosynthetic plastid and mitochondrial genomes, and show that while apicoplast genomes are virtually identical, high levels of gene fragmentation and reshuffling exists between species and strains. Our results correct assembly artifacts that are currently widely distributed in the genome database ofN. caninumandT. gondii, but more importantly, highlight the mitochondria as a previously oversighted source of variability and pave the way for a change in the paradigm of synteny, encouraging rethinking the genome as basis of the comparative unique biology of these pathogens.
Inhibition of Osteoclast Differentiation and Activation by Leukotriene B4 Loaded in Microspheres
Authors: Lorencetti-Silva Francine , Manfrin Arnez Maya Fernanda , de Queiroz Thomé João Pedro , de Carvalho Fabrício Kitazono , Faccioli Lúcia Helena , Paula-Silva Francisco Wanderley Garcia
Published: May 2020

Abstract

Aim

Leukotriene B4(LTB4) is a labile inflammatory lipid mediator important for host defense. We hypothesised that sustained delivery of LTB4would be a therapeutic strategy to prevent osteoclast cell differentiation in bone resorption in inflammatory diseases. Therefore, the aim of this study was to investigate the role of LTB4in differentiation of monocytic lineage cells into osteoclasts after stimulation with LTB4loaded in microspheres (MS).

Design

LTB4-MS were prepared using an oil-in-water emulsion solvent extraction-evaporation process. Sterility, LPS contamination, characterization and efficiency of LTB4encapsulation were investigated. J774A.1 cells were cultured in the presence of monocyte colony stimulating factor (M-CSF) and ligand for receptor activator of nuclear factor kappa B (RANKL) and then stimulated with LTB4-MS. Cytotoxicity was determined by lactate dehydrogenase assay, osteoclast formation by means of the activity of tartrate-resistant acid phosphatase enzyme and gene expression was measured by quantitative reverse transcription polymerase chain reaction to investigate regulation ofAlox5, Alox5ap, Acp5, Mmp9, CalcrandCtsk.

Results

We found that 5-lipoxygenase pathway is involved in the osteoclastic differentiation hematopoietic lineage cells and that exogenous addition of LTB4-MS inhibited osteoclastogenesis induced by M-CSF and RANKL. The mechanism of LTB4-MS involved induction ofMmp9gene expression and inhibition ofCalcrandCtsk, without changingAcp5.

Conclusion

LTB4-MS inhibited differentiation of macrophages into an osteoclastic phenotype and cell activation under M-CSF and RANKL stimulus shedding light on a potential therapeutic strategy to prevent osteoclast differentiation.
A conserved amino acid in the C-terminus of HPV E7 mediates binding to PTPN14 and repression of epithelial differentiation
Authors: Hatterschide Joshua , Brantly Alexis C. , Grace Miranda , Munger Karl , White Elizabeth A.
Published: May 2020

The human papillomavirus (HPV) E7 oncoprotein is a primary driver of HPV-mediated carcinogenesis. The E7 proteins from diverse HPV bind to the host cellular non-receptor protein tyrosine phosphatase type 14 (PTPN14) and direct it for degradation through the activity of the E7-associated host E3 ubiquitin ligase UBR4. Herein we show that a highly conserved arginine residue in the C-terminal domain of diverse HPV E7 mediates interaction with PTPN14. We found that disruption of PTPN14 binding through mutation of the C-terminal arginine did not impact the ability of several high-risk HPV E7 proteins to bind and degrade the retinoblastoma tumor suppressor or activate E2F target gene expression. HPVs infect human keratinocytes and we previously reported that both PTPN14 degradation by HPV16 E7 and PTPN14 CRISPR knockout repress keratinocyte differentiation-related genes. Now we have found that blocking PTPN14 binding through mutation of the conserved C-terminal arginine rendered both HPV16 and HPV18 E7 unable to repress differentiation-related gene expression. We then confirmed that the HPV18 E7 variant that could not bind PTPN14 was also impaired in repressing differentiation when expressed from the complete HPV18 genome. Finally, we found that the ability of HPV18 E7 to extend the lifespan of primary human keratinocytes required PTPN14 binding. CRISPR/Cas9 knockout of PTPN14 rescued keratinocyte lifespan extension in the presence of the PTPN14 binding-deficient HPV18 E7 variant. These results support the model that PTPN14 degradation by high-risk HPV E7 leads to repression of differentiation and contributes to its carcinogenic activity.

IMPORTANCE

Human papillomavirus (HPV)-positive carcinomas account for nearly 5% of the global human cancer burden. The E7 oncoprotein is a primary driver of HPV-mediated carcinogenesis. HPV E7 binds and degrades the putative tumor suppressor, PTPN14. However, the impact of PTPN14 binding by E7 on cellular processes is not well defined. Here, we show that PTPN14 binding is mediated by a conserved C-terminal arginine residue of HPV E7in vivo. Additionally, we found that PTPN14 binding contributes to the carcinogenic activity of HPV18 E7 (the second most abundant HPV type in cancers). Finally, we determined that PTPN14 binding by HPV16 E7 and HPV18 E7 represses keratinocyte differentiation. HPV-positive cancers are frequently poorly differentiated and the HPV life cycle is dependent upon the keratinocyte differentiation program. The finding that PTPN14 binding by HPV E7 impairs differentiation has significant implications for both HPV-mediated carcinogenesis and the HPV life cycle.
Association of country-wide coronavirus mortality with demographics, testing, lockdowns, and public wearing of masks (Update August 4, 2020)
Authors: Leffler Christopher T. , Ing Edsel , Lykins Joseph D. , Hogan Matthew C. , McKeown Craig A. , Grzybowski Andrzej
Published: May 2020

Purpose

To determine sources of variation between countries in per-capita mortality from COVID-19 (caused by the SARS-CoV-2 virus).

Methods

Potential predictors of per-capita coronavirus-related mortality in 200 countries by May 9, 2020 were examined, including age, sex, obesity prevalence, temperature, urbanization, smoking, duration of infection, lockdowns, viral testing, contact tracing policies, and public mask-wearing norms and policies. Multivariable linear regression analysis was performed.

Results

In univariate analyses, the prevalence of smoking, per-capita gross domestic product, urbanization, and colder average country temperature were positively associated with coronavirus-related mortality. In a multivariable analysis of 196 countries, the duration of infection in the country, and the proportion of the population 60 years of age or older were positively associated with per-capita mortality, while duration of mask-wearing by the public was negatively associated with mortality (all p<0.001). International travel restrictions and a lower prevalence of obesity were independently associated with mortality in a model which controlled for testing policy. Internal lockdown requirements and viral testing policies and levels were not associated with mortality. The association of contact tracing policy with mortality approached statistical significance (p=0.06). In countries with cultural norms or government policies supporting public mask-wearing, per-capita coronavirus mortality increased on average by just 15.8% each week, as compared with 62.1% each week in remaining countries.

Conclusions

Societal norms and government policies supporting the wearing of masks by the public, as well as international travel controls, are independently associated with lower per-capita mortality from COVID-19.
Performance and Thermal Perceptions of Runners Competing in the London Marathon: Impact of environmental conditions
Authors: Vernon Tim , Ruddock Alan D , Gregory Maxine
Published: May 2020

Objectives: The 2018 Virgin Money London Marathon (2018VMLM) was the hottest in the race's 37 year history, the major aims of this research were to 1) survey novice-mass participation marathoners to examine the thermal demands of the extreme weather event; and 3) investigate the effect of the air temperature on finish times. Methods: A mixed methods design involving the collection of survey data (n = 364; male = 63, female = 294) and secondary analysis of environmental and marathon performance (676,456 finishers) between 2009 and 2018 was used. Results: The 2018VMLM was hotter than the mean of all other marathons (P < 0.05); mean finishing time was slower than the mean of all other London Marathons (P < 0.05); there were positive correlations between maximum race-day temperature and finish time for mass-start participants and championship runners, and the difference in maximum race day temperature and mean maximum daily temperature for the 60 days prior to the London Marathon (P < 0.05). 23% of surveyed participants classified their thermal sensation and comfort as 'warm', 'hot' or 'very hot', with 68% 'comfortable' during training compared with a peak of 95% feeling 'warm', 'hot' or 'very hot' and 77% 'uncomfortable' or 'very uncomfortable' during 2018VMLM. Conclusion: Organisers should use temperature forecasting and plan countermeasures such as adjusting the start time of the event to avoid high-temperatures; help runners predict finish time and adjust pacing strategies accordingly and provide safety recommendations for participants at high risk time-points as well as cooling strategies.
Importations of COVID-19 into African countries and risk of onward spread
Authors: Sun Haoyang , Dickens Borame L , Cook Alex R , Clapham Hannah E
Published: May 2020

Background

The emergence of a novel coronavirus (SARS-CoV-2) in Wuhan, China, at the end of 2019 has caused widespread transmission around the world. As new epicentres in Europe and America have arisen, of particular concern is the increased number of imported coronavirus disease 2019 (COVID-19) cases in Africa, where the impact of the pandemic could be more severe. We aim to estimate the number of COVID-19 cases imported from 12 major epicentres in Europe and America to each African country, as well as the probability of reaching 10,000 infections in total by the end of March, April, and May following viral introduction.

Methods

We used the reported number of cases imported from the 12 major epicentres in Europe and America to Singapore, as well as flight data, to estimate the number of imported cases in each African country. Under the assumption that Singapore has detected all the imported cases, the estimates for Africa were thus conservative. We then propagated the uncertainty in the imported case count estimates to simulate the onward spread of the virus, until 10,000 infections are reached or the end of May, whichever is earlier. Specifically, 1,000 simulations were run separately under two scenarios, where the reproduction number under the stay-at-home order was assumed to be 1.5 and 1.0 respectively.

Findings

We estimated Morocco, Algeria, South Africa, Egypt, Tunisia, and Nigeria as having the largest number of COVID-19 cases imported from the 12 major epicentres. Based on our 1,000 simulation runs, Morocco and Algeria’s estimated probability of reaching 10,000 infections by end of March was close to 100% under both scenarios. In particular, we identified countries with less than 100 cases in total reported by end of April whilst the estimated probability of reaching 10,000 infections by then was higher than 50% even under the more optimistic scenario.

Conclusion

Our study highlights particular countries that are likely to reach (or have reached) 10,000 infections far earlier than the reported data suggest, calling for the prioritization of resources to mitigate the further spread of the epidemic.
Why are most COVID-19 infection curves linear?
Authors: Thurner Stefan , Klimek Peter , Hanel Rudolf
Published: May 2020

Many countries have passed their first COVID-19 epidemic peak. Traditional epidemiological models describe this as a result of non-pharmaceutical interventions that pushed the growth rate below the recovery rate. In this new phase of the pandemic many countries show an almost linear growth of confirmed cases for extended time-periods. This new containment regime is hard to explain by traditional models where infection numbers either grow explosively until herd immunity is reached, or the epidemic is completely suppressed (zero new cases). Here we offer an explanation of this puzzling observation based on the structure of contact networks. We show that for any given transmission rate there exists a critical number of social contacts,Dc, below which linear growth and low infection prevalence must occur. AboveDctraditional epidemiological dynamics takes place, as e.g. in SIR-type models. When calibrating our corresponding model to empirical estimates of the transmission rate and the number of days being contagious, we findDc~ 7.2. Assuming realistic contact networks with a degree of about 5, and assuming that lockdown measures would reduce that to household-size (about 2.5), we reproduce actual infection curves with a remarkable precision, without fitting or fine-tuning of parameters. In particular we compare the US and Austria, as examples for one country that initially did not impose measures and one that responded with a severe lockdown early on. Our findings question the applicability of standard compartmental models to describe the COVID-19 containment phase. The probability to observe linear growth in these is practically zero.
Outcomes from COVID-19 across the range of frailty: excess mortality in fitter older people
Authors: Miles Amy , Webb Thomas E , Mcloughlin Benjamin C , Mannan Imran , Rather Arshad , Knopp Paul , Davis Daniel
Published: May 2020

Purpose

Our aim was to quantify the mortality from COVID-19 and identify any interactions with frailty and other demographic factors.

Methods

Hospitalised patients aged ≥70 were included, comparing COVID-19 cases with non-COVID-19 controls admitted over the same period. Frailty was prospectively measured and mortality ascertained through linkage with national and local statutory reports.

Results

In 217 COVID-19 cases and 160 controls, older age and South Asian ethnicity, though not socioeconomic position, were associated with higher mortality. For frailty, differences in effect size were evident between cases (HR 1.02, 95%CI 0.93-1.12) and controls (HR 1.99, 95%CI 1.46-2.72), with an interaction term (HR 0.51, 95%CI 0.37-0.71) in multivariable models.

Conclusions

Our findings suggest that (i) frailty is not a good discriminator of prognosis in COVID-19 and (ii) pathways to mortality may differ in fitter compared with frailer older patients.

Key summary points

Aim

To describe associations between frailty, ethnicity, socioeconomic position and mortality in a cohort of older patients presenting to hospital with COVID-19.