bluuebunny/crossref_metadata_2025 huggingface dataset:
Lopinavir/ritonavir for the treatment of COVID-19: A living systematic review protocol
Authors: Verdugo-Paiva Francisca , Izcovich Ariel , Ragusa Martín , Rada Gabriel
Published: April 2020

Objective

To assess the efficacy and safety of lopinavir/ritonavir for the treatment of patients with COVID-19.

Design

This is the protocol of a living systematic review.

Data sources

We will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature and in a centralised repository in L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it covers and customised to group all COVID-19 evidence in one place. The search will cover the period until the day before submission to a journal.

Eligibility criteria for selecting studies and methods

We adapted an already published common protocol for multiple parallel systematic reviews to the specificities of this question.

We will include randomised trials evaluating the effect of lopinavir/ritonavir— as monotherapy or in combination with other drugs — versus placebo or no treatment in patients with COVID-19. Randomised trials evaluating lopinavir/ritonavir in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomised studies in COVID-19 will be searched in case no direct evidence from randomised trials is found, or if the direct evidence provides low- or very low-certainty for critical outcomes.

Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias. We will perform random-effects meta-analyses and use GRADE to assess the certainty of the evidence for each outcome.

A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it if the conclusions change or there are substantial updates.

Ethics and dissemination

No ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media.

PROSPERO Registration

Submitted to PROSPERO (awaiting ID allocation).
Prevalence and Predictors of Depression among Training Physicians in China: A Comparison to the United States
Authors: Chen Lihong , Zhao Zhuo , Wang Zhen , Zhou Ying , Zhou Xin , Pan Hui , Shen Fengtao , Zeng Suhua , Shao Xinhua , Sen Srijan , Li Weidong , Burmeister Margit
Published: April 2020

Resident physician training is associated with a substantial increase in depression in the United States, with rates increasing from about 4% before internship to 35% at least once during the first year of residency1.

Here, we sought to assess whether the rate of depression among residents in China are similar to their US counterparts and identify the common and differential predictors of depression in the two training systems. We assessed 1006 residents across three cohorts (2016-2019) at 16 affiliated hospitals of Shanghai Jiao Tong University and Peking Union Medical College. In parallel, we assessed three cohorts of 7028 residents at 100+ US institutions.

At the Chinese institutions, similarly, the proportion of participants who met depression criteria increased from 9% prior to residency to 35% at least once during the first year of residency (P<0.0001), an increase similar in magnitude to residents during internship in US institutions. Among factors assessed before residency, prior history of depression and depressive symptom score at baseline were common factors associated with depression during residency in both China and the US. In contrast, neuroticism and early family environment were strongly associated with depression risk in the US but not in China. Young age was a predictor of depression in China but not in the US sample. Among residency training factors, long duty hours and reduced sleep duration emerged as predictors of depression in both China and the US.

To gain insight into whether differences in personal predictors between the residents in China compared to the US residents were driven more by differences between cohorts, or by training system differences, we compared US residents of East Asian descent to other US and Chinese residents. We found that for most predictors (age, Neuroticism, early family environment), US residents of East Asian descent were more similar to other US residents than to the residents training in China.

Overall, the magnitude of depression increase and work-related drivers of depression were similar between China and the US, suggesting a need for system reforms, and that the types of effective reforms may be similar across the two systems.
A Simple Method to Estimate Flow Restriction for Dual Ventilation of Dissimilar Patients: The BathRC Model
Authors: Plummer Andrew , du Bois Jonathan L. , Flynn Joseph , Roesner Jens , Lee Siu Man , Magee Patrick , Thornton Malcolm , Padkin Andrew , Gill Harinderjit S.
Published: April 2020

Objectives

With large numbers of COVID-19 patients requiring mechanical ventilation and ventilators possibly being in short supply, in extremis two patients may have to share one ventilator. Careful matching of patient ventilation requirements is necessary. However, good matching is difficult to achieve as lung characteristics can have a wide range and may vary over time. Adding flow restriction to the flow path between ventilator and patient gives the opportunity to control the airway pressure and hence flow and volume individually for each patient. This study aimed to create and validate a simple model for calculating required flow restriction.

Design/Setting

Experimental/Secondary Care

Methods

We created a simple linear resistance-compliance model, termed the BathRC model, of the ventilator tubing system and lung allowing direct calculation of the relationships between pressures, volumes, and required flow restriction. Experimental measurements were made for parameter determination and validation using a clinical ventilator connected to two test lungs. For validation, differing amounts of restriction were introduced into the ventilator circuit.

Results

The BathRC model was able to predict tidal lung volumes with a mean error of 4% (min:1.2%, max:9.3%).

Conclusion

We present a simple model validated model that can be used to estimate required flow restriction for dual patient ventilation. The BathRC model is freely available; this tool is provided to demonstrate that flow restriction can be readily estimated.

ARTICLE SUMMARY

Strengths and limitations of this study

Data collected on a clinical system

Simple model, easy to implement

Validation performed

Limited to 2 types of restrictors tested

Data from only one ventilator type
Basic reproduction number of 2019 Novel Coronavirus Disease in Major Endemic Areas of China: A latent profile analysis
Authors: Xu Honglv , Yuan Min , Ma Liya , Liu Meng , Zhang Yi , Liu Wenwen , Gan Hong , Tao Fangbiao
Published: April 2020

Objective

The aim of the study is to analyze the latent class of basic reproduction number (R0) trend of 2019 novel coronavirus disease (COVID-19) in major endemic areas of China.

Methods

The provinces that reported more than 500 cases of COVID-19 till February 18, 2020 were selected as the major endemic area. The Verhulst model was used to fit the growth rate of cumulative confirmed cases. The R0 of COVID-19 was calculated using the parameters of severe acute respiratory syndrome (SARS) and COVID-19, respectively. The latent class of R0 was analyzed using a latent profile analysis model.

Results

The median R0 calculated from SARS and COVID-19 parameters were 1.84 - 3.18 and 1.74 - 2.91, respectively. The R0 calculated from the SARS parameters was greater than that of calculated from the COVID-19 parameters (Z = −4.782 - −4.623, P < 0.01). Both R0 can be divided into three latent classes. The initial value of R0 in class 1 (Shandong Province, Sichuan Province and Chongqing Municipality) was relatively low and decreases slowly. The initial value of R0 in class 2 (Anhui Province, Hunan Province, Jiangxi Province, Henan Province, Zhejiang Province, Guangdong Province and Jiangsu Province) was relatively high and decreases rapidly. Moreover, the initial value of R0 of class 3 (Hubei Province) was between that of class 1 and class 2, but the higher level of R0 lasts longer and decreases slowly.

Conclusion

The results indicated that overall trend of R0 has been falling with the strengthening of China’s comprehensive prevention and control measures for COVID-19, however, presents regional differences.
Bayesian spatial modelling of Ebola outbreaks in Democratic Republic of Congo through the INLA-SPDE approach
Authors: Gayawan Ezra , Adegboye Oyelola A. , James Adewale , Adegboye Adedayo M. , Elfaki Faiz
Published: April 2020

Ebola virus (EBV) disease is globally acknowledged public health emergence, which is endemic in the West and equatorial Africa. To understand the epidemiology especially the dynamic pattern of EBV disease, we analyse the EBV case notification data for confirmed cases and reported deaths of the ongoing outbreak in Democratic Republic of Congo (DRC) between 2018 and 2019, and examined the impart of reported violence of the spread of the virus. Using fully Bayesian geo-statistical analysis through stochastic partial differential equations (SPDE) that allows us to quantify the spatial patterns at every point of the spatial domain. Parameter estimation based on the integrated nested Laplace approximation (INLA). Our findings reveal strong association between violent events in the affected areas and the reported EBV cases and deaths, and the presence of clusters for both cases and deaths both of which spread to neighbouring locations in similar manners. Findings from the study are therefore useful for hotspot identification, location-specific disease surveillance and intervention.

Impacts

In 2018, the Democratic Republic of Congo (DRC) confirmed their tenth Ebola epidemic in 40 years. The outbreak is the country’s largest Ebola outbreak and the second largest ever recorded after the West African epidemic of 2014-2016.

The current outbreak is reported to be occurring in a longstanding conflict zone, this study focused investigating the spatial distribution of Ebola incidence in DRC and the role of violent events.

Violent events in the affected areas was found to be significantly associated with reported Ebola cases, which is highly relevant for hotspot identification and location-specific disease surveillance and intervention.
A Genetic Profile of Refractory Individuals with Major Depressive Disorder and Their Responsiveness to Transcranial Magnetic Stimulation
Authors: Souza-Silva Nathália G. , Nicolau Eduardo S. , Hoy Kate , Hawi Ziarih , Bellgrove Mark A. , Miranda Débora M. , Romano-Silva Marco A. , Fitzgerald Paul B.
Published: April 2020

Background

Major depressive disorder (MDD) is a debilitating illness characterized by the persistence of negative thoughts and emotions. Although antidepressant medications are effective, less than half of patients achieve complete remission despite multiple treatment trials. Repetitive transcranial magnetic stimulation (rTMS) has proven effective in the treatment of depression, especially for patients resistant to antidepressant medications. Remission rates when using rTMS for treatment-resistant depression (TRD) patients are between 30% and 40%. The responsiveness to pharmacotherapy and rTMS therapy may be influenced by genetic factors.

Objective

Here we aim to characterize the genetic profile of refractory individuals with MDD and their rTMS responsiveness.

Methods

We used an extreme-phenotype design (rTMS responders vs. non-responders) and conducted a genome wide association study on 48 participants and 593,260 SNPs.

Results

We identified 53 significant SNP associations. Gene-set enrichment analysis showed that significantly associated genes loaded onto synaptic plasticity regulation pathways. Among the genes found differentially expressed in rTMS responders compared to non-responders were APP, GRID2 and SPPL2A genes.

Conclusions

Based on these findings, we suggest that the identified genes may influence of rTMS responsiveness. Furthermore, the rTMS responsiveness may be associated with several pathways and not just to the influence of a single gene. To the best of our knowledge, this is the first report on the genetic profile of rTMS response using a GWAS approach. Nevertheless, further studies are necessary to enlight the molecular mechanism by which these genes affect response to rTMS treatment.
Accurate Prediction of COVID-19 using Chest X-Ray Images through Deep Feature Learning model with SMOTE and Machine Learning Classifiers
Authors: Kumar Rahul , Arora Ridhi , Bansal Vipul , Sahayasheela Vinodh J , Buckchash Himanshu , Imran Javed , Narayanan Narayanan , Pandian Ganesh N , Raman Balasubramanian
Published: April 2020

According to the World Health Organization (WHO), the coronavirus (COVID-19) pandemic is putting even the best healthcare systems across the world under tremendous pressure. The early detection of this type of virus will help in relieving the pressure of the healthcare systems. Chest X-rays has been playing a crucial role in the diagnosis of diseases like Pneumonia. As COVID-19 is a type of influenza, it is possible to diagnose using this imaging technique. With rapid development in the area of Machine Learning (ML) and Deep learning, there had been intelligent systems to classify between Pneumonia and Normal patients. This paper proposes the machine learning-based classification of the extracted deep feature using ResNet152 with COVID-19 and Pneumonia patients on chest X-ray images. SMOTE is used for balancing the imbalanced data points of COVID-19 and Normal patients. This non-invasive and early prediction of novel coronavirus (COVID-19) by analyzing chest X-rays can further be used to predict the spread of the virus in asymptomatic patients. The model is achieving an accuracy of 0.973 on Random Forest and 0.977 using XGBoost predictive classifiers. The establishment of such an approach will be useful to predict the outbreak early, which in turn can aid to control it effectively.
Estimating the Fraction of Unreported Infections in Epidemics with a Known Epicenter: an Application to COVID-19
Authors: Hortaçsu Ali , Liu Jiarui , Schwieg Timothy
Published: April 2020

We develop a simple analytical method to estimate the fraction of unreported infections in epidemics with a known epicenter and estimate the number of unreported COVID-19 infections in the US during the first half of March 2020. Our method utilizes the covariation in initial reported infections across US regions and the number of travelers to these regions from the epicenter, along with the results of a randomized testing study in Iceland. We estimate that 4-14% (1.5%-10%) of actual infections had been reported in US up to March 16, accounting for an assumed reporting lag of 8 (5) days.
The Effect of Stay-at-Home Orders on COVID-19 Cases and Fatalities in the United States
Authors: Fowler James H. , Hill Seth J. , Levin Remy , Obradovich Nick
Published: April 2020

Governments issue “stay at home” orders to reduce the spread of contagious diseases, but the magnitude of such orders’ effectiveness is uncertain. In the United States these orders were not coordinated at the national level during the coronavirus disease 2019 (COVID-19) pandemic, which creates an opportunity to use spatial and temporal variation to measure the policies’ effect with greater accuracy. Here, we combine data on the timing of stay-at-home orders with daily confirmed COVID-19 cases and fatalities at the county level in the United States. We estimate the effect of stay-at-home orders using a difference-in- differences design that accounts for unmeasured local variation in factors like health systems and demographics and for unmeasured temporal variation in factors like national mitigation actions and access to tests. Compared to counties that did not implement stay-at-home orders, the results show that the orders are associated with a 30.2 percent (11.0 to 45.2) reduction in weekly cases after one week, a 40.0 percent (23.4 to 53.0) reduction after two weeks, and a 48.6 percent (31.1 to 61.7) reduction after three weeks. Stay-at-home orders are also associated with a 59.8 percent (18.3 to 80.2) reduction in weekly fatalities after three weeks. These results suggest that stay-at-home orders reduced confirmed cases by 390,000 (170,000 to 680,000) and fatalities by 41,000 (27,000 to 59,000) within the first three weeks in localities where they were implemented.
Sequential data assimilation of the stochastic SEIR epidemic model for regional COVID-19 dynamics
Authors: Engbert Ralf , Rabe Maximilian M. , Kliegl Reinhold , Reich Sebastian
Published: April 2020

Abstract

Newly emerging pandemics like COVID-19 call for predictive models to implement precisely tuned responses to limit their deep impact on society. Standard epidemic models provide a theoretically well-founded dynamical description of disease incidence. For COVID-19 with infectiousness peaking before and at symptom onset, the SEIR model explains the hidden build-up of exposed individuals which creates challenges for containment strategies. However, spatial heterogeneity raises questions about the adequacy of modeling epidemic outbreaks on the level of a whole country. Here, we show that by applying sequential data assimilation to the stochastic SEIR epidemic model, we can capture the dynamic behavior of outbreaks on a regional level. Regional modeling, with relatively low numbers of infected and demographic noise, accounts for both spatial heterogeneity and stochasticity. Based on adapted models, short-term predictions can be achieved. Thus, with the help of these sequential data assimilation methods, more realistic epidemic models are within reach.
REGIONAL DETERMINANTS OF THE EXPANSION OF COVID-19 IN BRAZIL
Authors: Rodrigues Waldecy , Prata David Nadler , Camargo Wainesten
Published: April 2020

Objective

This study investigates the regional differences in the occurrence of COVID-19 in Brazil and its relationship with climatic and demographic factors by use data from February 26 to April 04, 2020. Methods: A Polynomial Regression Model with cubic adjustments of the number of days of contagion, demographic density, city population and climatic factors was designed and used to explain the spread of COVID-19 in Brazil.

Main results

It was evidenced that temperature variation maintains a relationship with the reduction in the number of cases of COVID-19. A variation -3.4% in the number of COVID-19 cases was found for each increase of 1 ° C.

Conclusion

There are evidences that the temperature, has a relative effect in the variation in the number of COVID-19’s researched cases. For the reason, it recommends this relationship deserves to be investigated in other tests with more extended time series, wide and with especially non-linear data adjustments.
Quantifying population contact patterns in the United States during the COVID-19 pandemic
Authors: Feehan Dennis M. , Mahmud Ayesha S.
Published: April 2020

SARS-CoV-2 is transmitted primarily through close, person-to-person interactions. In the absence of a vaccine, interventions focused on physical distancing have been widely used to reduce community transmission. These physical distancing policies can only control the spread of SARS-CoV-2 if they are able to reduce the amount of close interpersonal contact in a population. To quantify the impact of these policies over the first months of the COVID-19 pandemic in the United States, we conducted three waves of contact surveys between March 22 and June 23, 2020. We find that rates of interpersonal contact have been dramatically reduced at all ages in the US, with an 82% (95% CI:80% - 83%) reduction in the average number of daily contacts observed during the first wave compared to pre-pandemic levels. We find that this decline reduced the reproduction number, R0, to below one in March and early April (0.66, 95% CI:0.35 - 0.88). However, with easing of physical distancing measures, we find increases in interpersonal contact rates over the subsequent two waves, pushing R0 above 1. We also find significant differences in numbers of reported contacts by age, gender, race and ethnicity. Certain demographic groups, including people under 45, males, and Black and Hispanic respondents, have significantly higher contact rates than the rest of the population. Tracking changes in interpersonal contact patterns can provide rapid assessments of the impact of physical distancing policies over the course of the pandemic and help identify at-risk populations.
Complete mitochondrial genomes do not distinguish phenotypically distinct lineages of AndeanCoeligenahummingbirds
Authors: Palacios Catalina , Campagna Leonardo , Parra Juan Luis , Cadena Carlos Daniel
Published: April 2020

Lack of divergence in mitochondrial DNA between species with clear phenotypic differences may be the result of low resolution of markers, incomplete lineage sorting, introgression, or the interplay of various evolutionary mechanisms acting on different traits and genomic regions through time. Previous work revealed that the Andean hummingbirdsCoeligena bonaparteiandC. helianthealack genetic divergence in the mitochondrialND2gene, which shows variation discordant with coloration phenotype but consistent with geography. We sequenced and analyzed complete mitochondrial genomes forC. b. bonapartei, C. b. consita, C. h. heliantheaandC. h. tamaito assess whether patterns revealed byND2analyses hold when considering the entire mitogenome, and to shed light into the evolutionary history of these hummingbirds. We found very low genetic differentiation in mitogenomes among the four lineages ofCoeligena, confirming patterns based onND2data. Estimates of genetic differentiation, phylogenies and haplotype network analyses of complete mitogenomes did not separate phenotypically distinct taxa, but were consistent with a previously described pattern of northern vs. southern divergence along the Cordillera Oriental of Colombia. Mitogenomes ofC. b. bonaparteiandC. h. heliantheaare indistinguishable, suggesting incomplete lineage sorting or strong introgression. Mitogenomes ofC. b. consitaandC. h. tamaiare slightly differentiated, but they are more similar to each other than either is to that of its respective nominate subspecies, a result also suggestive of mtDNA introgression despite distinct phenotypic differences. Our results indicate that various evolutionary mechanisms playing out over a complex biogeographic scenario in the Colombian Andes drove divergence in phenotypes and mitochondrial genomes ofCoeligenahummingbirds, and lead to alternative hypotheses to be tested with whole-genome analyses.
Astrocyte- and neuron-derived extracellular vesicles from Alzheimer’s disease patients effect complement-mediated neurotoxicity
Authors: Nogueras-Ortiz Carlos J , Mahairaki Vasiliki , Delgado-Peraza Francheska , Das Debamitra , Avgerinos Konstantinos , Hentschel Matthew , Goetzl Edward J , Mattson Mark P , Kapogiannis Dimitrios
Published: April 2020

We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurodegeneration, we assessed the neurotoxicity of immunocaptured AEVs (with anti-GLAST antibody), neuronal-origin NEVs (with anti-L1CAM antibody), and multicellular-origin (with anti-CD81 antibody) EVs from the plasma of AD, frontotemporal lobar degeneration (FTLD) and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons, membrane disruption, reduced neurite density, and decreased cell viability in rat cortical neurons and human IPSC-derived neurons. Neurodegenerative effects were not produced by multicellular-origin EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and suggest that neuronal MAC deposition is necessary for AEV/NEV-mediated neurodegeneration in AD.
Monitoring and predicting viral dynamics in SARS-CoV-2-infected Patients
Authors: Wen Shaoqing , Xiong Jianxue , Sun Chang , Young Barnaby Edward , Lye David Chien , Leo Yee Sin , Jin Li , Wang Yi
Published: April 2020

This study is based on the a simple but robust model we developed urgently to accurately monitor and predict viral dynamics for each SARS-CoV-2-infected patient, given the limited number of RT-PCR tests and the complexity of each individual’s physical health situation. We used the mathematical model to monitor and predict the changes of viral loads from different nasal and throat swab of clinical specimens collected from diagnosed patients. We also tested this real-time model by using the data from the SARS-CoV-2-infected patients with different severity. By using this model (http://58.87.113.187:8080/), we can predict the viral dynamics of patients, minimize false-negative test results, and screen the patients who are at risk of testing positive again after recovery. We sincerely thank those who are on the front lines battling SARS-CoV-2 virus. We hope this model will be useful for SARS-CoV-2-infected patients.
Automated and semi-automated contact tracing: Protocol for a rapid review of available evidence and current challenges to inform the control of COVID-19
Authors: Braithwaite Isobel , Callender Tom , Bullock Miriam , Aldridge Robert W
Published: April 2020

Introduction

Traditional approaches to case-finding, case isolation, and contact tracing methods have so far proved insufficient on their own to prevent the development of local epidemics of COVID-19 in many high-income countries despite relatively advanced public health systems. As a result, many governments have resorted to widespread social distancing measures and mass quarantines (‘lock-downs’) to reduce transmission and to prevent healthcare systems from being overwhelmed. However, such measures impose heavy human and societal costs. Automated or semi-automated digital contact tracing, in conjunction with scaled-up community testing, has been proposed as a key part of exit strategies from lockdowns. However, the effectiveness of these approaches to contact tracing is unclear, and to be effective, trusted, and widely adopted such technology must overcome several challenges.

Methods and analysis

We will perform a rapid systematic review to assess the effectiveness of automated and semi-automated digital tools for contact tracing, and identify key considerations for successful implementation, to inform the control of COVID-19. We will search PubMed, EMBASE, EBSCO Medical COVID information portal, OVID Global Health, Cochrane Library, medRxiv, BioRxiv, and arXiv for peer-reviewed and pre-print papers on automated or semi-automated digital tools for contact tracing of COVID-19, another respiratory disease with pandemic potential (limited to SARS, MERS, or pandemic influenza), or Ebola, in human populations. Studies will be eligible if published in English between 1 January 2000 and 14 April 2020. We will synthesise study findings narratively and will consider meta-analysis if ≥ 3 suitable studies with comparable interventions and outcomes are available.

Ethics and dissemination

Ethical approval is not required for this review. We plan to disseminate findings via pre-print, journal publication, through social media and web-based platforms and through direct stakeholder engagement.
Maternal Serum Concentrations of Selenium, Copper and Zinc during Pregnancy are associated with Risk of Spontaneous Preterm Birth: A case-control study from Malawi
Authors: Chiudzu Grace , Choko Augustine T. , Maluwa Alfred , Huber Sandra , Odland Jon
Published: April 2020

Preterm birth is delivery before 37 completed weeks. A study was conducted to evaluate the association of maternal serum concentrations of selenium, copper, and zinc, and preterm birth. There were 181 women in this nested case-control study, 90/181 (49.7%) term and 91/181 (50.3%) preterm pregnant women. The overall mean serum concentration of selenium was 77.0; SD 19.4µg/L, copper was 2.50; SD 0.52 mg/L and zinc was 0.77; SD 0.20 mg/L with reference values of 47-142µg/L, 0.76-1.59mg/L and 0.59-1.11 mg/L, respectively. For preterm birth, mean serum concentrations for selenium was 79.7; SD 21.6µg/L, copper was 2.61; SD 0.57 mg/L, and zinc was 0.81; SD 0.20 mg/L compared to that of term births: selenium (74.2; SD 16.5µg/L; p=0.058), copper (2.39; SD 0.43 mg/L; p = 0.004), and zinc (0.73; SD 0.19 mg/L; p = 0.006) respectively. In adjusted analysis, every unit increase in maternal selenium concentrations gave increased odds of being a case OR 1.01 (95% CI: 0.99; 1.03), p=0.234, copper OR 1.62 (95% CI: 0.80; 3.32); p = 0.184, zinc OR 6.88 (95% CI: 1.25; 43.67); p=0.032. Results show that there was no deficiency of selenium, and zinc; and high serum concentrations of copper in pregnancy. Preterm birth was associated with higher maternal serum concentrations of copper and zinc.
Sequestration of TDP-43216-414aggregates by cytoplasmic expression of the proSAAS chaperone
Authors: Peinado Juan R. , Chaplot Kriti , Jarvela Timothy S. , Barbieri Edward M. , Shorter James , Lindberg Iris
Published: April 2020

As neurons age, protein homeostasis becomes less efficient, resulting in misfolding and aggregation. Chaperone proteins perform vital functions in the maintenance of cellular proteostasis, and chaperone-based therapies that promote sequestration of toxic aggregates may prove useful in blocking the development of neurodegenerative disease. We previously demonstrated that proSAAS, a small secreted neuronal protein, exhibits potent chaperone activity against protein aggregationin vitro, and blocks the cytotoxic effects of amyloid and alpha synuclein oligomers in cell culture models. We now examine whether cytoplasmic expression of proSAAS results in interaction with protein aggregates in this cellular compartment. We used site-directed mutagenesis, confocal microscopy,in vitroaggregation assays, and functional assays to investigate the interaction of proSAAS with TDP-43 and other known aggregating proteins. We report that expression of proSAAS within the cytoplasm generates dense, membrane-less 2 μm proSAAS spheres which progressively fuse to form larger spheres, suggesting liquid droplet-like properties. ProSAAS spheres selectively accumulate a C-terminally truncated fluorescently-tagged form of TDP-43216-414, initiating its cellular redistribution by sequestration within the sphere core; these TDP-43216-414-containing spheres also exhibit dynamic fusion. Removal of either the predicted α-helix (37-70) composed of hydrophobic and charged amino acids or the stretch of amino acids encompassing the conserved hydrophobic region and the positively charged furin site (163-189) inhibits the ability of proSAAS both to form spheres and to encapsulate TDP-43 aggregates. As a functional output, we demonstrate that proSAAS expression results in cytoprotection against full-length TDP-43 toxicity in yeast. In summary, the normally secreted neuronal chaperone proSAAS, when expressed in the cytoplasm unexpectedly phase-separates to form spherical liquid-like condensates that undergo dynamic fusion. We conclude that cyto-proSAAS acts as a functional holdase for cytoplasmic TDP-43216-414molecules via this phase-separation property, representing a cytoprotectant whose unusual biochemical properties can potentially be exploited in the design of therapeutic molecules.
Inter-relationships between changes in stress, mindfulness, and dynamic functional connectivity in response to a social stressor
Authors: Teng James , Massar Stijn A.A. , Lim Julian
Published: April 2020

We conducted a study to understand how dynamic functional brain connectivity contributes to the moderating effect of trait mindfulness on the stress response. 40 participants provided subjective reports of stress, cortisol assays, and functional MRI before and after undergoing a social stressor. Self-reported trait mindfulness was also collected. Experiencing stress led to significant decreases in the prevalence of a connectivity state previously associated with mindfulness, but no changes in two connectivity states with prior links to arousal. Connectivity did not return to baseline 30 minutes after stress. Higher trait mindfulness was associated with attenuated affective and neuroendocrine stress response, and smaller decreases in the mindfulness-related connectivity state. In contrast, we found no association between affective response and functional connectivity. Taken together, these data allow us to construct a preliminary brain-behaviour model of how mindfulness dampens stress reactivity.
The macroecology and evolution of avian competence forBorrelia burgdorferi
Authors: Becker Daniel J. , Han Barbara A.
Published: April 2020

Aim

Predicting novel reservoirs of zoonotic pathogens would be improved by identifying inter-specific drivers of host competence, the ability to transmit pathogens to new hosts or vectors. Tick-borne pathogens can provide a useful model system, as larvae become infected only when feeding on a competent host during their first bloodmeal. For tick-borne diseases, competence has been best studied forBorrelia burgdorferisensu lato (Bbsl), which causes Lyme borreliosis. Major reservoirs include several small mammal species, but birds may play an underrecognized role in human risk given their ability to disperse infected ticks across large spatial scales. Here, we provide a global synthesis of the ecological and evolutionary factors that determine the ability of bird species to infect larval ticks withBbsl.

Location

Global

Time period

1983 to 2019

Major taxa studied

Birds

Methods

We compiled a dataset ofBbsl competence across 183 bird species and applied meta-analysis, phylogenetic factorization, and boosted regression trees to describe spatial and temporal patterns in competence, characterize its phylogenetic distribution across birds, reconstruct its evolution, and evaluate the trait profiles associated with competent avian species.

Results

Half of sampled bird species show evidence of competence forBbsl. Competence displays moderate phylogenetic signal, has evolved multiple times across bird species, and is pronounced in the genusTurdus. Trait-based analyses distinguished competent birds with 80% accuracy and show that such species have low baseline corticosterone, exist on both ends of the pace-of-life continuum, breed and winter at high latitudes, and have broad migratory movements into their breeding range. We use these trait profiles to predict various likely but unsampled competent species, including novel concentrations of avian reservoirs within the Neotropics.

Main conclusion

Our results can generate new hypotheses for how birds contribute to the dynamics of tick-borne pathogens and help prioritize surveillance of likely but unsampled competent birds. Our findings further emphasize that birds display underrecognized variation in their contributions to enzootic cycles ofBbsl and the broader need to better consider competence in ecological and predictive studies of multi-host pathogens.
Turning the Stimulus On and Off Dynamically Changes the Direction of Alpha Traveling Waves
Authors: Pang Zhaoyang , Alamia Andrea , VanRullen Rufin
Published: April 2020

Traveling waves have been studied to characterize the complex spatiotemporal dynamics of the brain. Several studies have suggested that the propagation direction of alpha traveling waves can be task-dependent. For example, a recent EEG study from our group found that forward waves (i.e. occipital to frontal, FW waves) were observed during visual processing, whereas backward waves (i.e. frontal to occipital, BW waves) mostly occurred in the absence of sensory input. These EEG recordings, however, were obtained from different experimental sessions and different groups of subjects. To further examine how the waves’ direction changes between task conditions, 13 participants were tested on a target detection task while EEG signals were recorded simultaneously. We alternated visual stimulation (5 s display of visual luminance sequences) and resting state (5 s of black screen) within each single trial, allowing us to monitor the moment-to-moment progression of traveling waves. As expected, the direction of alpha waves was closely linked with task conditions. First, FW waves from occipital to frontal regions, absent during rest, emerged as a result of visual processing, while BW waves in the opposite direction dominated in the absence of visual inputs, and were reduced (but not eliminated) by external visual inputs. Second, during visual stimulation (but not rest), both waves coexisted on average, but were negatively correlated. In summary, we conclude that the functional role of alpha traveling waves is closely related with their propagating direction, with stimulus-evoked FW waves supporting visual processing and spontaneous BW waves involved more in top-down control.
Novel non-transposable-element regulation patterns of KZFP family reveal new drivers of its rapid evolution
Authors: Shen Pan , Zheng Qijian , Xu Aishi , Liu Junhua , Hou Yushan , Gao Chao , Tian Chunyan , He Fuchu , Yang Dong
Published: April 2020

One striking feature of the large KRAB-containing zinc finger protein (KZFP) family is its rapid expansion and divergence since its formation about 400 million years ago. However, the evolutionary characteristics of KRAB domains, C2H2 zinc fingers and the full protein of KZFPs have not been fully analyzed. As for the drivers of the rapid evolution, it’s partly due to their coevolution with transposable elements (TEs). But their diverse functions besides inhibiting TEs suggest other reasons exist. Here we address these two issues by the systematic analysis of the divergence time and diversification pattern of KZFPs at three aspects and the functional analysis of the potential target genes besides TEs. We found that old-zinc-finger-containing KZFPs tend to have varied and disordered KRAB domains, indicating there are two ways of the evolution of KZFPs, including the variation of KRAB domains and the diversification of zinc fingers. Among them, the divergence of zinc fingers mainly contributes to the rapid evolution of KZFPs. Thus, we mainly focused on the functional requirements of the evolution of zinc fingers. Different from the classical regulation pattern of this family, we found and experimentally confirmed that KZFPs tend to bind to non-TE regions and can positively regulate target genes. Although most young genes tend to be with a low expression level, young-zinc-finger-containing KZFPs tend to be highly expressed in early embryonic development or early mesoderm differentiation, indicating their particular evolutionarily novel functional roles in these two processes. We further validated a young KZFP, ZNF611, can bind to non-TE region of STK38 gene and positively regulates its expression in ESCs. The emergence of new sequence in STK38 promoter may drive the evolution of zinc fingers in ZNF611. Finally, we proposed a ‘two-way evolution model’ of KZFP family.
Aquaporin mediating stomatal closure is associated with water conservation under mild water deficit
Authors: Ding Lei , Chaumont François
Published: April 2020

Contradictory results indicate that aquaporins might facilitate the diffusion of both water and H2O2during abscisic acid (ABA) triggered stomatal closure. Here, we tested whether maize plasma membrane PIP2;5 aquaporin regulates stomatal closure under water deficit or ABA treatment in intact plants, detached leaves, and peeled epidermis.

Transpiration, stomatal conductance and aperture, as well as reactive oxygen species (ROS) in stomatal complexes were studied in maize lines deregulated inPIP2;5gene expression, under water deficit and/or ABA treatments.

In well-watered conditions, the PIP2;5 overexpressing (OE) plants transpired more than the wild-type plants (WT), while no significant difference in transpiration was observed betweenpip2;5KO and WT plants. Upon mild-water deficit or low ABA concentration treatment, the transpiration and stomatal conductance decreased more in PIP2;5 OE, and less inpip2;5KO lines, in comparison with WT plants. Using isolated epidermis, ABA treatment induced faster stomatal closing in PIP2;5 OE lines compared to the WT, whilepip2;5KO stomata were ABA insensitive. These phenotypes were associated with guard cell ROS accumulation.

Together, these data indicate that maize PIP2;5 regulates early stomatal closure for water conservation upon a water deficit environment.
Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients
Authors: Haupt Luis Peter , Maus Andreas , Tiburcy Malte , Köhne Steffen , Maurer Wiebke , Tappu Rewati , Haas Jan , Li Yun , Sasse Andre , Santos Celio C. X. , Dressel Ralf , Wojnowski L. , Bunt Gertrude , Shah Ajay M. , Meder Benjamin , Sossalla Samuel , Wollnik Bernd , Hasenfuß Gerd , Streckfuß-Bömeke Katrin
Published: April 2020

Cancer therapies have been shown to induce cardiovascular complications. The aims of this study were to establish anin vitroinduced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of cancer.

ACT-iPSC-CM generated from individuals with CD20+B-cell lymphoma cancer who had received high doses of DOX and suffered cardiac dysfunction were observed to be persistently more susceptible to DOX toxicity compared to control-iPSC-CM. ACT-iPSC-CM exhibited increased DOX-dependent disorganized myofilament structure and cell death, as well as higher reactive oxygen species (ROS) compared to controls. Importantly, analysis of engineered heart muscle (EHM) from ACT-iPSC-CM showed an impaired DOX-dependent mechanical functionality. Transcriptome profiles of EHM are in line with a disturbed adjustment to DOX-dependent alteration of Ca2+homeostasis in ACT-iPSC-CM. Furthermore, genetic variants in different cardiac key regulators were uncovered.

In conclusion, we developed the first human iPSC-CM and EHM model of DOX-induced cardiac dysfunction in patients with B-cell lymphoma. Our results suggest that DOX-related stress resulted in decreased contractile activity and finally in heart failure in ACT patients.

Brief summary

Development of the first human iPSC-CM model of DOX-induced cardiac dysfunction in patients with aggressive B cell lymphoma and high-dose DOX treatment.
Pre-stimulus beta-band activity is a signature of statistical learning
Authors: Bogaerts Louisa , Richter Craig G. , Landau Ayelet N. , Frost Ram
Published: April 2020

Statistical learning (SL) is taken to be the main mechanism by which cognitive systems discover the underlying regularities of the environment. We document, in the context of a classical visual SL task, divergent rhythmic EEG activity during the anticipation of stimuli within patterns versus pattern transitions. Our findings reveal differential pre-stimulus oscillatory activity in the beta band (∼20 Hz) that indexes learning: it emerges with increased pattern repetitions, and importantly, it is highly correlated with behavioral learning outcomes. These findings hold the promise of converging on an online measure of learning regularities and provide important theoretical insights regarding the mechanisms of SL and prediction.

Significance Statement

SL has become a major theoretical construct in cognitive science, providing the primary means by which organisms learn about regularities in the environment. As such it is a critical building block for basic and higher-order cognitive functions.

Here we identify for the first time a spectral neural index in the time window prior to stimulus presentation, which evolves with increased pattern exposure, and is predictive of learning performance.

The manifestation of learning that is revealed not in stimulus processing but in anticipatory moments of the learning episode, makes a direct link between the fields of statistical learning and predictive processing, and suggests a possible mechanistic account of visual SL.
Complement receptor 3 forms a compact high affinity complex with iC3b
Authors: Jensen Rasmus K. , Bajic Goran , Sen Mehmet , Springer Timothy A. , Vorup-Jensen Thomas , Andersen Gregers R.
Published: April 2020

Complement receptor 3 (CR3, also known as Mac-1, integrin αMβ2, or CD11b/CD18) is expressed on a subset of myeloid and certain activated lymphoid cells. CR3 is essential for the phagocytosis of complement-opsonized particles such as pathogens and apoptotic or necrotic cells opsonized with the complement fragment iC3b and to a lesser extent C3dg. While the interaction between the iC3b thioester domain and the ligand binding CR3 αMI-domain is structurally and functionally well characterized, the nature of additional CR3-iC3b interactions required for phagocytosis of complement opsonized objects remain obscure. Here we analyzed the interaction between iC3b and the 150 kDa headpiece fragment of the CR3 ectodomain. Surface plasmon resonance experiments demonstrated a 30 nM affinity of CR3 for iC3b compared to 515 nM for the iC3b thioester domain. Small angle x-ray scattering analysis revealed that iC3b adopts an extended but preferred conformation in solution. Upon interaction with CR3, iC3b rearranges to form a compact receptor-ligand complex. Overall, the data suggest that the iC3b-CR3 interaction is of high affinity and relies on minor contacts formed between CR3 and regions outside the iC3b thioester domain. Our results rationalize the more efficient phagocytosis elicited by iC3b than by C3dg and pave the way for development of specific therapeutics for treatment of inflammatory and neurodegenerative diseases that do not interfere with recognition of non-complement CR3 ligands.