bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disability-adjusted life years (DALYs) due to the direct health impact of COVID-19 in India, 2020
Authors: Singh Balbir B , Devleesschauwer Brecht , Khatkar Mehar S , Lowerison Mark , Singh Baljit , Dhand Navneet K , Barkema Herman W 
Published: August 2021

AbstractCOVID-19 has affected all countries. Its containment represents a unique challenge for India due to a large population (>1.38 billion) across a wide range of population densities. Assessment of the COVID-19 disease burden is required to put the disease impact into context and support future pandemic policy development. Here, we present the national-level burden of COVID-19 in India in 2020 that accounts for differences across urban and rural regions and across age groups. Disability-adjusted life years (DALY) due to COVID-19 were estimated in the Indian population in 2020, comprised of years of life lost (YLL) and years lived with disability (YLD). Scenario analyses were conducted to account for excess deaths not recorded in the official data and for reported COVID-19 deaths. The direct impact of COVID-19 in 2020 in India was responsible for 14,106,060 (95% uncertainty interval [UI] 14,030,129–14,213,231) DALYs, consisting of 99.2% (95% UI 98.47–99.64%) YLLs and 0.80% (95% UI 0.36–1.53) YLDs. DALYs were higher in urban (56%; 95% UI 56–57%) than rural areas (44%; 95% UI 43.4–43.6) and in males (64%) than females (36%). In absolute terms, the highest DALYs occurred in the 51–60-year-old age group (28%) but the highest DALYs per 100,000 persons were estimated for the 71-80 year old age group (5,481; 95% UI 5,464–5,500 years). There were 4,823,791 (95% UI 4,760,908–4,924,307) DALYs after considering reported COVID-19 deaths only. The DALY estimations have direct and immediate implications not only for public policy in India, but also internationally given that India represents one sixth of the world’s population.
COVID-19 patient serum less potently inhibits ACE2-RBD binding for various SARS-CoV-2 RBD mutants
Authors: Junker Daniel , Dulovic Alex , Becker Matthias , Wagner Teresa R. , Kaiser Philipp D. , Traenkle Bjoern , Kienzle Katharina , Bunk Stefanie , Struemper Carlotta , Haeberle Helene , Schmauder Kristina , Ruetalo Natalia , Malek Nisar , Althaus Karina , Koeppen Michael , Rothbauer Ulrich , Walz Juliane S. , Schindler Michael , Bitzer Michael , Göpel Siri , Schneiderhan-Marra Nicole 
Published: August 2021

AbstractAs global vaccination campaigns against SARS-CoV-2 proceed, there is particular interest in the longevity of immune protection, especially with regard to increasingly infectious virus variants. Neutralizing antibodies (Nabs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are promising correlates of protective immunity and have been successfully used for prevention and therapy. As SARS-CoV-2 variants of concern (VOCs) are known to affect binding to the ACE2 receptor and by extension neutralizing activity, we developed a bead-based multiplex ACE2-RBD inhibition assay (RBDCoV-ACE2) as a highly scalable, time-, cost-, and material-saving alternative to infectious live-virus neutralization tests. By mimicking the interaction between ACE2 and the RBD, this serological multiplex assay allows the simultaneous analysis of ACE2 binding inhibition to the RBDs of all SARS-CoV-2 VOCs and variants of interest (VOIs) in a single well. Following validation against a classical virus neutralization test and comparison of performance against a commercially available assay, we analyzed 266 serum samples from 168 COVID-19 patients of varying severity. ACE2 binding inhibition was reduced for ten out of eleven variants examined compared to wild-type, especially for those displaying the E484K mutation such as VOCs beta and gamma. ACE2 binding inhibition, while highly individualistic, positively correlated with IgG levels. ACE2 binding inhibition also correlated with disease severity up to WHO grade 7, after which it reduced.
A composite endpoint for acceptability evaluation of oral drug formulations in the pediatric population
Authors: Wargenau Manfred , Reidemeister Sibylle , Klingmann Ingrid , Klingmann Viviane 
Published: August 2021

AbstractIntroductionA medicine’s acceptability is likely to have significant impact on pediatric compliance. EMA and FDA guidance on this topic ask for investigation of acceptability. Although palatability and deglutition are denoted as elements of acceptability, the impact of both on acceptability remains unclear as an unambiguous definition of acceptability is lacking. Actually, globally applied standards for acceptability definition, testing methodology and assessment criteria do not exist. A definition of acceptability establishing a composite endpoint that combines deglutition and palatability in different age groups is presented here.MethodsThis composite acceptability endpoint is based on validated assessment methods for deglutition and palatability in children of different age groups with different galenic placebo formulations, in line with criteria EMA proposed for assessing acceptability in children from newborn to 18 years. Data from two studies investigating mini-tablets, oblong tablets, orodispersible films and syrup were used to investigate the validity, expediency and applicability of the suggested composite acceptability assessment tool.ResultsThe new composite endpoint is highly suitable and efficient to distinguish preferences of oral formulations: Mini-tablets and oblong tablets were significantly better accepted than syrup and orodispersible film.ConclusionSince the suggested acceptability criterion takes both deglutition and palatability into account as composite endpoint, it is highly sensitive to detect acceptability differences between oral formulations. It is a well-defined, valid approach, which particularly meets regulatory requirements in an appropriate and comprehensive manner and may in future serve as an easy, standardized method to assess and compare acceptability of pediatric formulations with active substances.
Predictors of Adolescent Engagement and Outcomes – a cross-sectional study using the Togetherall (formerly Big White Wall) digital mental health platform
Authors: Marinova Nushka , Rogers Tim , MacBeth Angus 
Published: August 2021

AbstractOnline mental health platforms can improve access to, and use of, mental health support for young people who may find it difficult to engage with face-to-face delivery.We modelled engagement and change in anxiety and depression symptoms in adolescent users of the Togetherall (formerly “Big White Wall”) anonymous digital mental health peer-support platform.A cross-sectional study assessed online activity data from members of Togetherall in UK adolescents referred from mental health services (N=606). Baseline demographics, depression, anxiety, and usage statistics were assessed. Symptom levels among participants who chose to take validated anxiety and depression measures were measured. And participant characteristics were used to predict engagement.Mean number of logins for adolescent members was higher for older adolescents, and for a longer duration than younger adolescents. Mean number of logins and usage time was higher in female adolescents than males. For the total sample, 47.9% of users accessed more than one course, and 27% accessed at least one self-help resource. Gender and age predicted number of joined courses. Greater accessed self-help materials predicted reduced anxiety symptoms. Members’ mean baseline symptom levels were: GAD-7 between 13.63 and 14.79; PHQ-9 between 16.8 and 18.58.Data were derived from a naturalistic design and modelling of multiple symptom scores should be interpreted with caution.Findings show that adolescents readily engage with an anonymous online platform for common mental disorder, with scope for tailored pathways for different symptom profiles. Members benefit from engagement with Togetherall materials and courses.
Effect of COVID-19 infection related experiences on outing behaviors when a state of emergency is declared: a cohort study
Authors: Mori Takahiro , Nagata Tomohisa , Ikegami Kazunori , Hino Ayako , Tateishi Seiichiro , Tsuji Mayumi , Matsuda Shinya , Fujino Yoshihisa , Mori Koji ,   the CORoNaWork project
Published: August 2021

AbstractBackgroundRestricting the movement of the public to gathering places and limiting close physical contact are effective measures against COVID-19 infection. In Japan, states of emergency have been declared in specific prefectures to reduce public movement and control COVID-19 transmission. We investigated how COVID-19 infection related experiences including people with a history of infection, people with a history of close contact, and people whose acquaintances have been infected, affected self-restraint related to outing behaviors during the second state of emergency in Japan.MethodsA prospective cohort study was conducted among workers aged 20–65 years using data from an internet survey. The baseline survey was conducted on December 22–25, 2020, and a follow-up survey was on February 18–19, 2021. There were 19,941 participants who completed both surveys and were included in the final analysis. We identified eight outing behaviors: (1) eating out (4 people or fewer); (2) eating out (5 people or more); (3) gathering with friends and colleagues; (4) day trip; (5) overnight trip (excluding visiting home); (6) visiting home; (7) shopping for daily necessities; and (8) shopping for other than daily necessities. We set self-restraint regarding each outing behavior after the second state of emergency was declared in January 2021 as the dependent variable, and COVID-19 infection related experiences as independent variables. Odds ratios were estimated using multilevel logistic regression analyses.ResultsSignificant differences by COVID-19 infection related experiences were identified: compared to people without COVID-19 related experiences, people with a history of COVID-19 were less likely self-restraint from most outing behaviors. People whose acquaintance had been diagnosed with COVID-19 were significantly more likely to refrain from most outing behaviors. There was no significant difference in any outing behaviors for people with a history of close contact only.ConclusionsTo maximize the effect of a state of emergency, health authorities should disseminate information for each person in the target population, taking into account potential differences related to the COVID-19 infection related experiences.
Predictors of bovineSchistosoma japonicuminfection in rural Sichuan, China
Authors: Grover Elise , Paull Sara , Kechris Katerina , Buchwald Andrea , James Katherine , Liu Yang , Carlton Elizabeth J. 
Published: August 2021

AbstractIn China, bovines are believed to be the most common animal source of human schistosomiasis infections, though little is known about what factors promote bovine infections. The current body of literature features inconsistent, and sometimes contradictory results, and to date, few studies have looked beyond physical characteristics to identify the broader environmental conditions that predict bovine schistosomiasis. Because schistosomiasis is a sanitation-related, water-borne disease transmitted by many animals, we hypothesized that several environmental factors − such as the lack of improved sanitation systems, or participation in agricultural production that is water-intensive − could promote schistosomiasis infection in bovines. Using data collected as a part of a repeat cross-sectional study conducted in rural villages in Sichuan, China from 2007 to 2016, we used a Random Forests, machine learning approach to identify the best physical and environmental predictors of bovineS. japonicuminfection. Candidate predictors included: 1) physical/biological characteristics of bovines, 2) human sources of environmental schistosomes, 3) socio-economic indicators, 4) animal reservoirs, and 5) agricultural practices. The density of bovines in a village and agricultural practices such as the area of rice and dry summer crops planted and the use of night soil as an agricultural fertilizer, were among the top predictors of bovineS. japonicuminfection in all collection years. Additionally, human infection prevalence, pig ownership and bovine age were found to be strong predictors of bovine infection in at least one year. Our findings highlight that presumptively treating bovines in villages with high bovine density or human infection prevalence may help to interrupt transmission. Furthermore, village-level predictors were stronger predictors of bovine infection than household-level predictors, suggesting future investigations may need to apply a broad ecological lens to identify potential underlying sources of persistent transmission.
Dynamics of gut microbiome – mediated bile acid metabolism in progression to islet autoimmunity
Authors: Lamichhane Santosh , Sen Partho , Dickens Alex M. , Alves Marina Amaral , Härkönen Taina , Honkanen Jarno , Vatanen Tommi , Xavier Ramnik J. , Hyötyläinen Tuulia , Knip Mikael , Orešič Matej 
Published: August 2021

AbstractPrevious studies suggest that the human gut microbiome is dysregulated in islet autoimmunity, preceding the clinical onset of type 1 diabetes (T1D). The microbiota of the gut plays an important role in the regulation of bile acid (BA) metabolism. However, not much is known about the regulation of BAs during progression to T1D. Here, we analyzed BAs in a longitudinal series of serum (n= 333) and stool (n= 304) samples, collected at 3, 6, 12, 18, 24 and 36 months of age, from children who developed a single islet autoantibody (P1Ab), multiple islet autoantibodies (P2Ab), and controls (CTRs) who remained autoantibody (AAb) negative during the follow-up. In addition, we analyzed the stool microbiome by shotgun metagenomics in a subgroup of these children (n=111). Factor analysis showed that age had the strongest impact on BA and microbiome profiles. We found that, at an early age, the systemic BA (including taurine and glycine conjugates) and microbial secondary BA pathways were altered in the P2Ab group as compared to the P1Ab or CTR groups. Our findings thus suggest that dysregulated BA metabolism in early life may contribute to the risk and pathogenesis of T1D.
Disruption ofBrachypodiumLichenase Alters Metabolism of Mixed-linkage Glucan and Starch
Authors: Fan Mingzhu , Jensen Jacob K. , Zemelis-Durfee Starla , Kim Sang-Jin , Chan Jia-Yi , Beaudry Claudia M. , Brandizzi Federica , Wilkerson Curtis G. 
Published: August 2021

ABSTRACTMixed-linkage glucan (MLG), which is widely distributed in grasses, is a polysaccharide highly abundant in cell walls of grass endosperm and young vegetative tissues. Lichenases are enzymes that hydrolyze MLG first identified in MLG-rich lichens. In this study, we identify a gene encoding a lichenase we nameBrachypodium distachyon LICHENASE 1(BdLCH1), which is highly expressed in the endosperm of germinating seeds and coleoptiles and at lower amounts in mature shoots. RNA in situ hybridization showed thatBdLCH1is primarily expressed in chlorenchyma cells of mature leaves and internodes. Disruption of BdLCH1 resulted in an eight-fold increase in MLG content in senesced leaves. Consistent with the in situ hybridization data, immunolocalization results showed that MLG was not removed in chlorenchyma cells oflch1mutants as it was in wild type and implicate the BdLCH1 enzyme in removing MLG in chlorenchyma cells in mature vegetative tissues. We also show that MLG accumulation inlch1mutants was resistant to dark induced degradation, and eight-week-oldlch1plants showed a faster rate of starch breakdown than wild type in darkness. Our results suggest a role for BdLCH1 in modifying the cell wall to support highly metabolically active cells.
Genome-wide in vivo screen of circulating tumor cells identifies SLIT2 as a regulator of metastasis
Authors: Xia Fan , Ma Yuan , Chen Kangfu , Duong Bill , Ahmed Sharif , Atwal Randy , Philpott David , Ketela Troy , Pantea Jennifer , Lin Sichun , Angers Stephane , Kelley Shana O. 
Published: August 2021

AbstractCirculating tumor cells (CTCs) break free from primary tumors and travel through the bloodstream and lymphatic system to seed metastatic tumors, which are the major cause of death from cancer. The identification of the major genetic factors that enhance production and persistence of CTCs in the bloodstream at a whole genome level would enable more comprehensive molecular mechanisms of metastasis to be elucidated and the identification of novel therapeutic targets, but this remains a challenging task due to the heterogeneity and extreme rarity of CTCs. Here, we describe the firstin vivogenome-wide CRISPR KO screen using CTCs directly isolated from a mouse xenograft. This screen elucidatedSLIT2– a gene encoding a secreted protein acting as a cellular migration cue – as the most significantly represented gene knockout in the CTC population.SLIT2knockout cells are highly metastatic with hypermigratory and mesenchymal phenotype. Reduced expression ofSLIT2is observed in human tumors, indicating its role as a negative modulator of tumor progression and metastasis.
Habitat fragmentation induces rapid divergence of migratory and isolated sticklebacks
Authors: Ramesh A. , Groothuis A.G.G. , Weissing F.J. , Nicolaus M. 
Published: August 2021

AbstractThe adaptive capacity of many organisms is seriously challenged by human-imposed environmental change, which currently happens at unprecedented rates and magnitudes. For migratory fish, habitat fragmentation is a major challenge that can compromise their survival and reproduction. Therefore, it is important to study if fish populations can adapt to such modifications of their habitat. Here, we study whether originally anadromous three-spined stickleback populations (Gasterosteus aculeatus;‘migrants’) changed in behavior and morphology in response to human-induced isolation. We made use of a natural field-experiment, where the construction of pumping stations and sluices in the 1970s unintendedly created replicates of land-locked stickleback populations (‘resident’) in the Netherlands. For two years, we systematically tested populations of residents and migrants for differences in morphology and behavioral traits (activity, aggressiveness, exploration, boldness and shoaling) in lab-based assays. We detected differences between migrant and resident populations in virtually all phenotypic traits studied: compared to the ancestral migrants, residents were smaller in size, had fewer and smaller plates and were significantly more active, aggressive, exploratory and bolder and shoaled less. Despite large ecological differences between 2018 and 2019, results were largely consistent across the two years. Our study shows that human-induced environmental change has led to the rapid and consistent morphological and behavioral divergence of stickleback populations in about 50 generations. Such changes may be adaptive but this remains to be tested.Lay summaryThe adaptive capacity of many organisms is seriously challenged by human-imposed environmental changes. For example, migratory fish encounter man-made barriers that impede their movements and force them to adopt a resident lifecycle. Here we study whether and how populations of three-spined sticklebacks diverged in response to human-induced isolation. We show that about 50 generations of isolation were sufficient to induce substantial morphological and behavioral differentiation between land-locked populations (‘residents’) and their migratory ancestors (‘migrants’).
brca2-mutant zebrafish exhibit context- and tissue-dependent alterations in cell phenotypes and response to injury
Authors: Kouprianov Vassili A. , Selmek Aubrie A. , Ferguson Jordan L. , Mo Xiaokui , Shive Heather R. 
Published: August 2021

AbstractCancer cells frequently co-opt molecular programs that are normally activated in specific contexts, such as embryonic development and the response to injury. Determining the impact of cancer-associated mutations on cellular phenotypes within these discrete contexts can provide new insight into how such mutations lead to dysregulated cell behaviors and subsequent cancer onset. Here we assess the impact of heritable BRCA2 mutation on embryonic development and the injury response using a zebrafish model (Danio rerio). Unlike most mouse models for BRCA2 mutation, brca2-mutant zebrafish are fully viable and thus provide a unique tool for assessing both embryonic and adult phenotypes. We find that maternally provided brca2 is critical for normal oocyte development and embryonic survival in zebrafish, suggesting that embryonic lethality associated with BRCA2 mutation is likely to reflect defects in both meiotic and embryonic developmental programs. On the other hand, we find that adult brca2-mutant zebrafish exhibit aberrant proliferation of several cell types under basal conditions and in response to injury in tissues at high risk for cancer development. These divergent effects exemplify the often-paradoxical outcomes that occur in embryos (embryonic lethality) versus adult animals (cancer predisposition) with mutations in cancer susceptibility genes such as BRCA2. The altered cell behaviors identified in brca2-mutant embryonic and adult tissues, particularly in adult tissues at high risk for cancer, indicate that the effects of BRCA2 mutation on cellular phenotypes are both context- and tissue-dependent.
Distinct neural codes in primate Hippocampus and Lateral Prefrontal Cortex during associative learning in virtual environments
Authors: Corrigan B. W. , Gulli R. A. , Doucet G. , Roussy M. , Luna R. , Sachs A.J. , Martinez-Trujillo J. C. 
Published: August 2021

AbstractThe hippocampus (HPC) and the lateral prefrontal cortex (LPFC) are two cortical areas of the primate brain deemed essential to cognition. Here we hypothesize that the codes mediating neuronal communication in HPC and LPFC microcircuits have distinctively evolved to serve plasticity and memory function at different spatiotemporal scales. We used a virtual reality task in which animals navigated through a maze using a joystick and selected one of two targets in the arms of the maze according to a learned context-color rule. We found that neurons and neuronal populations in both regions encode similar information about the task. Moreover, we demonstrate that many HPC neurons concentrate spikes into bursts, whereas most layer II/III LPFC neurons sparsely distribute spikes over time. As the animals learned the task HPC neurons, but not LPFC neurons, increased their burst rate as a function of performance. When integrating spike rates over short intervals, HPC neuronal ensembles reached maximum decoded information with fewer neurons than LPFC ensembles. Our results show that during associative learning HPC principal cells concentrate spikes in bursts enabling temporal summation and fast synaptic plasticity in small populations of neurons and ultimately facilitating rapid encoding of associative memories. On the other hand, layers II/III LPFC pyramidal cells fire spikes more sparsely distributed in time and over a larger number of neurons. The latter would facilitate broadcasting of signals loaded in short term memory across neuronal populations without necessarily triggering fast synaptic plasticity.