bluuebunny/crossref_metadata_2025 huggingface dataset:
Allele-specific variation atAPOEincreases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer’s disease and myocardial infarction
Authors: Palmer Nicholette D , Kahali Bratati , Kuppa Annapurna , Chen Yanhua , Du Xiaomeng , Feitosa Mary F , Bielak Lawrence F , O’Connell Jeffrey R , Musani Solomon K , Guo Xiuqing , Smith Albert V , Ryan Kathleen A , Eirksdottir Gudny , Allison Matthew A , Bowden Donald W , Budoff Matthew J , Carr J Jeffrey , Chen Yii-Der I , Taylor Kent D , Correa Adolfo , Crudup Breland F , Halligan Brian , Yang Jian , Kardia Sharon L R , Launer Lenore J , Fu Yi-Ping , Mosley Thomas H , Norris Jill M , Terry James G , O’Donnell Christopher J , Rotter Jerome I , Wagenknecht Lynne E , Gudnason Vilmundur , Province Michael A , Peyser Patricia A , Speliotes Elizabeth K
Published: April 2021

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10−7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer’s disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.
Epigenetic regulation of mRNA N6-methyladenosine modifications in mammalian gametogenesis
Authors: Fang Fang , Wang Xiao , Li Zili , Ni Ke , Xiong Chengliang
Published: April 2021

N6-methyladenosine (m6A) is the most prevalent epigenetic modification of mRNAs and broadly influences various biological processes by regulating post-transcriptional gene expression in eukaryotes. The reversible m6A modification is catalyzed by methyltransferases, METTL3 and METTL14 (writers), removed by the demethylases FTO and ALKBH5 (erasers) and recognized by m6A-binding proteins, namely the YTH domain-containing family of proteins (readers). Both m6A modification and the related enzymes are involved in the regulation of normal gametogenesis and embryonic development in many species. Recent studies showed that loss of m6A compromises gamete maturation, sex hormone synthesis, fertility and early embryonic development. In this review, we have summarized the most recent findings on the role of mRNA m6A modification in mammalian gametogenesis to emphasize the epigenetic regulation of mRNA in the reproductive system.
High-fat diet promotes hypothalamic inflammation in animal models: a systematic review
Authors: Santos Lucimeire S , Cordeiro Gabriele S , Matos Rhowena J B , Perez Gabriela S , Silva Rafael T , Boaventura Gilson T , Barreto-Medeiros Jairza M
Published: April 2021

Context

Hypothalamic inflammation and dysfunction may be induced by high-fat diets. However, the mechanisms involved in this process have not been fully elucidated.

Objective

To evidence, in animal models, of how a high-fat diet influence the mechanisms involved in hypothalamic inflammation.

Data sources

Scopus, PubMed/Medline, Web of Science, Science Direct, and Embase databases were searched.

Data extraction

The exclusion criteria were human studies, studies with medicinal products or other substances not related to food, paper reviews, studies that used a surgical intervention or an intervention with food to reverse hypothalamic inflammation, and studies with genetically modified animals. The identified studies were evaluated according to the following inclusion criteria: animal studies, studies in which a control group was included in the experimental design, and studies in which markers of inflammation in the hypothalamus were evaluated.

Data analysis

A total of 322 studies were found, of which 9 met the inclusion criteria for a systematic review, conducted in accordance with the PRISMA guidelines, and were included in this review.

Conclusion

The exposure of rodents to high-fat diets promoted an increase in levels of several pro-inflammatory cytokines and other proteins involved in the inflammatory process in the hypothalamus. This process was associated with increased glial cell activity.
Correcting parentage relationships in the endangered California Condor: Improving mean kinship estimates for conservation management
Authors: Moran Brigid M , Thomas Steven M , Judson Jessica M , Navarro Asako , Davis Heidi , Sidak-Loftis Lindsay , Korody Marisa , Mace Michael , Ralls Katherine , Callicrate Taylor , Ryder Oliver A , Chemnick Leona G , Steiner Cynthia C
Published: April 2021

Maintaining the existing biodiversity of endangered species is a goal of conservation management programs, and a major component of many collaborative efforts undertaken by zoos, field biologists, and conservation scientists. Over the past 3 decades, the San Diego Zoo has performed long-term genetic studies in support of the recovery program for the critically endangered California Condor (Gymnogyps californianus). This work has included sex determination of hatchlings and parentage confirmation using microsatellite genotyping. This paper describes the genetic work associated with the California Condor recovery program, which aims to provide a highly accurate pedigree for making informed captive pairing and release recommendations. Initial genotyping began after reintroduced California Condors started reproducing, and the focus was on birds hatched from their wild-laid eggs. However, genetic analysis showed discrepancies relative to behavioral observations of wild birds and led to the species-wide testing of all available samples. This genetic study has resolved instances of individual misidentifications and parental misassignments, verified the first cases of extra-pair paternity in this species, identified parentage where chicks were observed being raised by trios, and found 2 apparent de novo mutations in the captive condor population. Correcting the California Condor pedigree according to genetic parental analysis has produced more accurate estimates of mean kinship values among living birds, ranking potential breeders according to their actual breeding value and helping managers to make informed decisions about captive pairing and release of condors in the wild.
An Examination of Officer Job Satisfaction and Workgroup Cultural Fit
Authors: Ingram Jason R , Rockwell Alexis R , Guerra Chris , Paoline III Eugene A
Published: April 2021

Research has found officer job satisfaction to be correlated with aspects of their work environment. Police culture serves as a coping mechanism for work environment stressors. Despite the connections, research has yet to investigate the impact of a broad range of cultural norms as well as the influence of cultural fit and strength on job satisfaction. The current study examines how officers alignments with traditional police culture norms, relative to their workgroup peers (i.e. cultural fit), relate to job satisfaction. Results indicated that officers who adhered to traditional norms, in general, were more satisfied; however, officers who subscribed substantially less to traditional cultural norms relative to their workgroup peers (i.e. con-culture misfits) were significantly less satisfied. Being a con-culture misfit was associated with perceptions of danger and role clarity. Collectively, the findings provide practical insights for departments concerned with their officers satisfaction by addressing cultural features of their work environments.
A Small Cysteine-Rich Phytotoxic Protein of Phytophthora capsici Functions as Both Plant Defense Elicitor and Virulence Factor
Authors: Zhang Zi-Hui , Jin Jing-Hao , Sheng Gui-Lin , Xing Yu-Ping , Liu Wang , Zhou Xue , Liu Yi-Qing , Chen Xiao-Ren
Published: April 2021

Small cysteine-rich (SCR) proteins, including fungal avirulence proteins, play important roles in pathogen–plant interactions. SCR protein-encoding genes have been discovered in the genomes of Phytophthora pathogens but their functions during pathogenesis remain obscure. Here, we report the characterization of one Phytophthora capsici SCR protein (namely, SCR82) with similarity to Phytophthora cactorum phytotoxic protein PcF. The scr82 gene has 10 allelic sequences in the P. capsici population. Homologs of SCR82 were not identified in fungi or other organisms but in Phytophthora relative species. Initially, scr82 was weakly expressed during the mycelium, sporangium, and zoospore stages but quickly upregulated when the infection initiated. Both ectopic expression of SCR82 and recombinant yeast-expressed protein (rSCR82) caused cell death on tomato leaves. Upon treatment, rSCR82 induced plant defense responses, including the induction of defense gene expression, reactive oxygen species burst, and callose deposition. Knockout of scr82 in P. capsici by CRISPR/Cas9 severely impaired its virulence on host plants and significantly reduced its resistance against oxidative stress. Inversely, its overexpression increased the pathogen’s virulence and tolerance to oxidative stress. Our results collectively demonstrate that SCR82 functions as both an important virulence factor and plant defense elicitor, which is conserved across Phytophthora spp.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Pregnancy Has No Clinically Significant Effect on the Pharmacokinetics of Bupropion or Its Metabolites
Authors: Fay Emily E. , Czuba Lindsay C. , Sager Jennifer E. , Shum Sara , Stephenson-Famy Alyssa , Isoherranen Nina
Published: April 2021

Background:

Bupropion (BUP) is a chiral antidepressant and smoking cessation aide with benefits and side effects correlated with parent and active metabolite concentrations. BUP is metabolized by CYP2B6, CYP2C19, and CYP3A4 to hydroxy-BUP (OH-BUP) as well as by 11β-hydroxysteroid dehydrogenase-1 and aldo-keto reductases to threohydrobupropion (Threo) and erythrohydrobupropion (Erythro), respectively. As pregnancy alters the activity of drug-metabolizing enzymes, the authors hypothesized that BUP metabolism and BUP metabolite concentrations would be altered during pregnancy, potentially affecting the efficacy and safety of BUP in pregnant women.

Methods:

Pregnant women (n = 8) taking BUP chronically were enrolled, and steady-state plasma samples and dosing interval urine samples were collected during pregnancy and postpartum. Maternal and umbilical cord venous blood samples were collected at delivery from 3 subjects, and cord blood/maternal plasma concentration ratios were calculated. The concentrations of BUP stereoisomers and their metabolites were measured. Paired t tests were used to compare pharmacokinetic parameters during pregnancy and postpartum.

Results:

No significant changes were observed in the steady-state plasma concentrations, metabolite to parent ratios, formation clearances, or renal clearance of any of the compounds during pregnancy when compared with postpartum. The umbilical cord venous plasma concentrations of BUP and its metabolites were 30%–60% lower than maternal plasma concentrations.

Conclusions:

This study showed that there are no clinically meaningful differences in the stereoselective disposition of BUP or its metabolites during pregnancy, indicating that dose adjustment during pregnancy may not be necessary. The results also showed that the placenta provides a partial barrier for bupropion and its metabolite distribution to the fetus, with possible placental efflux transport of bupropion and its metabolites.
Representation of Black patients in heart failure clinical trials
Authors: Azam Tariq U. , Colvin Monica M.
Published: April 2021

Purpose of review

Black patients with heart failure in the United States are underrepresented in clinical trials relative to their overrepresentation in the heart failure population and in adverse heart failure outcomes. We aim to evaluate historical trends in this space and highlight recent developments.

Recent findings

Multiple landmark heart failure trials published since 2019 have underrepresented Black patients, though several discussed this lack of representation as limitations. A review of large heart failure clinical trials from 2001 to 2016 found persistent underrepresentation of Black patients without significant change over time. Trials enrolling from North America exclusively had more proportional representation, enrolling an average of 31.6% Black participants.

There is a shrinking proportion of Black patients in pivotal heart failure trials despite a higher prevalence of disease and associated adverse outcomes. There is increasing awareness of these disparities within the heart failure community, potentially leading to improved representation in future studies.
Can Use of Default Dispensing Quantities in Electronic Medical Record Lower Opioid Prescribing?
Authors: Chua Wee-Jhong , Groenewald Cornelius B. , Varakitsomboon Shing , Harris Jacob , Faino Anna V. , Quan Linda , Walco Gary A. , Sousa Ted C.
Published: April 2021

Objectives

Leftover opioids can contribute to misuse and abuse. Recommended dosing quantities in the electronic medical record can guide prescribing patterns. We hypothesized that decreasing the default from 30 doses to 12 doses would decrease the overall number of opioids prescribed without increasing second opioid prescriptions or additional health utilization.

Methods

We performed a single-center retrospective study of children with forearm and elbow fractures who presented to the emergency department for evaluation and subsequent orthopedic follow-up between January 15, and September 19, 2017. The default dispensing quantity was decreased on June 1, 2016 from 30 doses to 12 doses. Patients were categorized to preintervention and postintervention groups. We compared the number of opioids prescribed, second opioid prescriptions, emergency department visits, and pain-related telephone calls and orthopedic visits with χ2 and logistic regression analyses.

Results

There were 1107 patients included. Rates of opioid prescribing were similar preintervention and postintervention (61% vs 56%, P = 0.13). After the change to the default quantity, the median number of doses decreased from 18 to 12 doses, with opioid prescriptions of 30 or more doses dropping from 35% to 11%. No significant association was found between preintervention versus postintervention, opioid prescription at discharge, and having 1 or more pain-related or unexpected follow-up visits.

Conclusions

Lowering the default dispensing quantity of opioids in the electronic medical record decreases the number of opioids prescribed without increasing second prescriptions or additional health care utilization. These findings suggest that a further reduction in the number of opioids prescribed for upper-extremity fractures may be possible.
Determining the cutoff points of the 5C scale for assessment of COVID-19 vaccines psychological antecedents among the Arab population: A multinational study
Authors: Ghazy Ramy Mohamed , ElHafeez Samar Abd , Shaaban Ramy , Elbarazi Iffat , Kheirallah Khalid A. , Abdou Marwa Shawky , Ramadan Ahmed
Published: April 2021

Background

One of the newly faced challenges during the COVID-19 is vaccine hesitancy (VH). The validated 5C scale, that assesses five psychological antecedents of vaccination, could be effective in exploring COVID-19 VH. This study aimed to determine a statistically valid cutoff points for the 5C sub-scales among the Arab population.

Methods

A cross-sectional study was conducted among 446 subjects from three Arab countries (Egypt, United Arab Emirates UAE, and Jordan). Information regarding sociodemographics, clinical history, COVID-19 infection and vaccination history, and 5C scale were collected online. The 5C scores were analyzed to define the cutoff points using the receiver operating characteristic curve (ROC) and to verify the capability of the questionnaire to differentiate whether responders are hesitant or non-hesitant to accept vaccination. ROC curve analysis was conducted setting for previous vaccine administration as a response, with the predictors being the main five domains of the 5C questionnaire. The mean score of each sub-scale was compared with COVID-19 vaccine intake

Results

The mean age of the studied population was 37±11, 42.9% were males, 44.8% from Egypt, 21.1% from Jordan, and 33.6% from UAE. Statistically significant differences between vaccinated and unvaccinated participants, respectively, weredetetd in the median score of confidence [6.0(1.3) versus 4.7(2.0)], complacency [(2.7(2.0) versus 3.0(2.0), constraints [1.7(1.7) versus 3.7(2.3)], and collective responsibility [6.7(1.7) versus 5.7(1.7)]. The area under the curve of the five scales was 0.72, 0.60, 0.76, 0.66, 0.66 for confidence, complacency, constraints, calculation, and collective responsibility at cutoff values of 5.7, 4.7, 6.0, 6.3, and 6.2, respectively.

Conclusion

the Arabic validated version of the 5C scale has a good discriminatory power to predict COVID-19 vaccines antecedent.
Tobacco Smoking and Associated Factors among In-school Adolescents in Vietnam in 2013, 2019
Authors: Van Minh Hoang , Long Khuong Quynh , Van Vuong Do , Hung Nguyen Manh , Park Kidong , Takeuchi Momoe , Kashiwabara Mina , Lam Nguyen Tuan , Quynh Nga Pham Thi , Anh Le Phuong , Van Tuan Le , Bao Tran Quoc , Minh Anh Le Duong , Tuyet Hanh Tran Thi
Published: April 2021

Tobacco smoking is one of the most dangerous risk behaviors, leading to many adverse human health consequences. The aims of this study is to estimate the prevalence of tobacco smoking and related factor among adolescents aged 13–17 years in Vietnam. The data were from two rounds of the Vietnam Global School-based Student Health Survey (GSHS) that is the nationally representative survey conducted in 2013 and 2019. The logistic regressions were carried out to identify factors associated with tobacco smoking among study participants. We found the prevalence of current smoking (water pipe and cigarettes) reduced significantly from 5.4% (95% CI: 4.0–7.2) in 2013 to 2.8% (95% CI: 2.2–3.6) in 2019. In 2019, 2.6% of students used electronic cigarette products in the last 30 days. Factors associated with higher odds of current smoking status included study year, gender, parental monitoring, loneliness, suicide attempt, sexual intercourse, truancy, alcohol drinking. Similar patterns were found in e-cigarette use. Smoking among adolescents in Vietnam reduced between 2013 and 2019. Further follow-up studies are needed to confirm the causal factors of the reduction and e-cigarettes use.
Clinical Evidence for Improved Outcomes with Histamine Antagonists and Aspirin in 22,560 COVID-19 Patients
Authors: Mura Cameron , Preissner Saskia , Nahles Susanne , Heiland Max , Bourne Philip E. , Preissner Robert
Published: April 2021

COVID-19 has spurred much interest in the therapeutic potential of repurposed drugs. A family of acid-reducing drugs, known as histamine H2receptor antagonists (H2RA), competitively bind the H2R and block its stimulation by histamine; examples of such drugs are famotidine (e.g., Pepcid) and ranitidine (e.g., Zantac). A dense web of functionalities between histamine and H2RAs, on the one hand, and downstream cellular pathways, on the other hand, links disparate physiological pathways in gastrointestinal contexts (e.g., acid reduction) to the dysregulated inflammatory cas-cades (cytokine storm) underlying the pathophysiology of COVID-19. Is famotidine beneficial in treating COVID-19? This question remains unresolved, though not for lack of effort: over 10 studies have examined the potential therapeutic value of famotidine in COVID-19, but have found conflicting results (pro-famotidine, anti-famotidine, and neutral). Given the contradictory reports, we have undertaken the new analysis reported herein. Notably, studies published thus far rest upon substantially smaller datasets than drawn upon in the present work. We analyzed a cohort of 22,560 COVID-19 patients taking H1/H2receptor antagonists, focusing on 1,379 severe cases requiring respiratory support. We analyzed outcomes for treatment with the H1RAs loratadine (e.g., Claritin) and cetirizine (e.g., Zyrtec), the H2RA famotidine, aspirin, and a famotidine & aspirin combination. For cases that reached the point of respiratory support, we found a significantly reduced fatality risk for famotidine treatment. We did not detect a benefit from dual-histamine receptor blockade (concurrently targeting H1and H2receptors). Notably, famotidine combined with aspirin did exhibit a significant synergistic survival benefit (odds ratio of 0.55). The relative risk for death decreased by 32.5%--an immense benefit, given the more than 2.6 million COVID-19-related deaths thus far. We found lower levels of serum markers for severe disease (e.g., C-reactive protein) in famotidine users, consistent with prior findings by others and with a role for famotidine in attenuating cytokine release. The large, international, multi-center retrospective study reported here, sampling over 250,000 COVID-19 cases, hopefully helps clarify the possible value of clinically-approved histamine antagonists such as famotidine. Given these findings, alongside the cost-effectiveness and mild side-effects of popular drugs like famotidine and aspirin, we suggest that further prospective clinical trials, perhaps utilizing the aspirin combination reported here, are advisable.
Multiverse to inform neurological research: an example using recovery outcome of neglect
Authors: Moore Margaret J , Demeyere Nele
Published: April 2021

Objective

Multiverse analysis provides an ideal tool for understanding how inherent, yet ultimately arbitrary methodological choices impact the conclusions of individual studies. With this investigation we aimed to demonstrate the utility of multiverse analysis for evaluating generalisability and identifying potential sources of bias within studies employing neurological populations.

Method

Multiverse analysis was used to evaluate the robustness of the relationship between post-stroke visuospatial neglect and poor long term recovery outcome within a sample of 1113 (age =72.5, 45.1% female) stroke survivors. A total of 25,600 t-test comparisons were run across 400 different patient groups defined using various combinations of valid inclusion criteria based on lesion location, stroke type, assessment time, neglect impairment definition, and scoring criteria across 16 standardised outcome measures.

Results

Overall, 33.9% of conducted comparisons yielded significant results. 99.9% of these significant results fell below the null specification curve, indicating a highly robust relationship between neglect and poor recovery outcome. However, the strength of this effect was not constant across all comparison groups. Comparisons which included <100 participants, pre-selected patients based on lesion type, or failed to account for allocentric neglect impairment were found to yield average effect sizes which differed substantially. Similarly, average effect sizes differed across various outcome measures with the strongest average effect in comparisons involving an activities of daily living measure and the weakest in comparisons employing a depression subscale.

Conclusions

This investigation demonstrates the utility of multiverse analysis techniques for evaluating effect robustness and identifying potential sources of bias within neurological research.
Clinical efficacy of Early Administration of Convalescent Plasma among COVID-19 Cases in Egypt
Authors: Asem Noha , Massoud Hossam Hosny , Serag Ihab , Hassany Mohamed , ElAssal Gehan , Abdelbary Akram , Mohsen Marwa , Baki Amin Abdel , Zaky Samy , Amin Wagdy , Kamal Ehab , Ibrahem Hamdy , Abdel Mohsen Ahmed Said , Ali Mohamed Ahmed , Elgendy Nancy , Elbadry Mohamed , Ahmed Salwa Hassan , shenouda Ahmed Naguib Nassif , Fathy Mohamed Abdelhamed , Zaid Hala
Published: April 2021

Importance

Early and effective treatment of COVID-19 is vital for control of SARS-CoV-2 infection

Objectives

The primary objective of the study was to assess the degree of clinical improvement in severe and critically ill COVID-19 patients, treated early with early CPT.

Designs

An interventional, single-arm, non-randomized clinical trial conducted in Egypt from April 15 to July 21, 2020.

Settings

This was a multi-centre study conducted in 3 hospitals in Egypt.

Participants

a total of 94 COVID-19 laboratory-confirmed patients using qRT-PCR were enrolled in the study.

Intervention

All patients were administered with two plasma units (each unit is 200cc). The volume of donated plasma was 800cc.

Main Outcome and Measures

Primary measure was the degree of clinical improvement among the COVID-19 patients who received CPT within seven days

Results

A total of 94 patients were enrolled who received CPT either within seven days or after seven days of hospitalization. 82 were severely ill, 12 were critically ill. The average age remained 58 years (±SD 15.1 years). Male were 69% and 49% patients got cured while 51% died with CFR 51%. 75% deaths were above 45years of age. The symptoms were dyspnoea (55%), fever (52%), cough (46%), and loss of taste and smell (21%), and cyanosis (15%). The most common co-morbidities among the <40 years remained Diabetes Mellitus (21%) and Asthma (14%). Among 40-60 years Hypertension (56%), Diabetes Mellitus (39%) and among >60 years age group Hypertension (57%) and Chronic Heart Disease (24%) were reported. CPT within seven days remained significant as compared with the CPT after seven days with the number of days to cure (p=0.007) and ICU stay (P=0.008) among severely ill cured cases.

Conclusion and Relevance

Among patients with COVID-19 and severe or critical illness, the use of CPT along with routine standard therapy resulted in a statistically significant improvement when administered within seven days of hospital admission. However, plasma transfusion, irrespective of days to transfusion may not help treat critically ill patients. The overall mean time to cure in severely ill patients was 15 days if CPT provided within seven days with 65% cure rate.

Trial Registration

Clinical Intervention identifier: MOHP_COVID-19_Ver1.1
A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex
Authors: Antaki D , Maihofer A , Klein M , Guevara J , Grove J , Carey Caitlin , Hong O , Arranz MJ , Hervas A , Corsello C , Muotri AR , Iakoucheva LM , Courchesne E , Pierce K , Gleeson JG , Robinson E , Nievergelt CM , Sebat J
Published: April 2021

The genetic etiology of autism spectrum disorder (ASD) is multifactorial with contributions from rare variants, polygenic risk, and sex. How combinations of factors determine risk for ASD is unclear. In 11,313 ASD families (N = 37,375 subjects), we investigated the effects rare and polygenic risk individually and in combination. We show that genetic liability for ASD differs by sex, with females having a greater polygenic load, and males having a lower liability threshold as evident by a negative correlation of rare and polygenic risk. Multiple genetic factors were associated with differing sets of behavioral traits with effects that differed by sex. Furthermore, the correlation of parental age with genetic risk for ASD was attributable tode novomutations and sex-biased effects of inherited risk in parents. Our results demonstrate that a phenotypic spectrum of ASD is attributable to the relative loadings and gene-by-sex effects of rare and common variation.
Visuomotor brain network activation and functional connectivity among individuals with autism spectrum disorder
Authors: Lepping Rebecca J. , McKinney Walker S. , Magnon Grant C. , Keedy Sarah K. , Wang Zheng , Coombes Stephen A. , Vaillancourt David E. , Sweeney John A. , Mosconi Matthew W.
Published: April 2021

Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and predictive of functional outcomes, though their neural underpinnings remain poorly understood. Using functional magnetic resonance imaging (fMRI), we examined both brain activation and functional connectivity during visuomotor behavior in 27 individuals with ASD and 30 typically developing (TD) controls (ages 9-35 years). Participants maintained a constant grip force while receiving visual feedback at three different visual gain levels. Relative to controls, ASD participants showed increased force variability, especially at high gain, and reduced entropy. Brain activation was greater in individuals with ASD than controls in supplementary motor area, bilateral superior parietal lobules, and left middle frontal gyrus at high gain. During motor action, functional connectivity was reduced between parietal-premotor and parietal-putamen in individuals with ASD compared to controls. Individuals with ASD also showed greater age-associated increases in functional connectivity between cerebellum and visual, motor, and prefrontal cortical areas relative to controls. These results indicate that visuomotor deficits in ASD are associated with atypical activation and functional connectivity of posterior parietal, premotor, and striatal circuits involved in translating sensory feedback information into precision motor behaviors, and that functional connectivity of cerebellar-cortical sensorimotor and non-sensorimotor networks show delayed maturation.

HIGHLIGHTS

Individuals with ASD show impaired precision manual force control, especially when visual feedback is magnified

Visuomotor deficits in ASD are associated with increased activity in frontal and parietal cortex and reduced parietal-frontal and parietal-putamen functional connectivity

Visuomotor-dependent functional connectivity of cerebellum with visual, motor, and prefrontal cortices shows atypical age-associated trajectories in ASD
SARS-CoV-2 Detection in the Nasopharyngeal Swabs and Saliva of College Students using RT-qPCR and RT-LAMP
Authors: Bikos D. A. , Hwang C. , Brileya K. A. , Parker A. , Loveday E. K. , Rodriguez M. , Thornton I. , LeFevre T. , Wilking J. N. , Dills M. , Walk S. T. , Adams A. K. , Plowright R. K. , Hoegh A. B. , Carter J. R. , Morrow J. , Taylor M. P. , Keil D. E. , Fields M. W. , Chang C. B.
Published: April 2021

Background

Diagnostic testing can identify outbreaks and inform preventive strategies for slowing the spread of SARS-CoV-2, the virus that causes Covid-19. The “gold standard” method for detection of SARS-CoV-2 is reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed on samples collected using nasopharyngeal (NP) swabs. While NP RT-qPCR achieves high sensitivity, it requires trained personnel to administer and suffers from lengthy time-to-result. Instead, rapid saliva-based reverse transcription loop-mediated amplification (RT-LAMP) screening methods may offer advantages in sample collection and speed.

Methods

Regardless of symptomatic presentation, a total of 233 individuals were tested for SARS-CoV-2 using NP RT-qPCR, alongside saliva-based RT-qPCR (SalivirDetect) and RT-LAMP (SLAMP), a simple and rapid fluorometric RT-LAMP assay performed directly on heat-inactivated saliva without any additional treatments or RNA extraction. SLAMP is conducted in triplicate and takes 45 min. Samples found negative using both saliva-based methods but positive under CDC NP RT-qPCR above the saliva method LoD were excluded from evaluation, suggesting significant differences in viral titer between sampling sites. Individuals who consumed potential inhibitors in the form of food, drink, and oral health products within 30 min of sampling were identified using a self-reported questionnaire.

Results

Of the 233 NP RT-qPCR tests, 58 were positive and 175 were negative. Comparatively, SLAMP resulted in 95% sensitivity and 98% specificity and SalivirDetect 97% sensitivity and 98% specificity. Prior consumption had no measurable effect on test outcomes, except for drinking, which lowered Ct values in saliva.

Conclusions

SLAMP requires less technician and instrument time than CDC-approved NP RT-qPCR and demonstrates that saliva-based RT-LAMP can enable frequent and rapid identification of pre-symptomatic and asymptomatic SARS-CoV-2 infections with high sensitivity and specificity.
Genomic epidemiology of SARS-CoV-2 transmission lineages in Ecuador
Authors: Gutierrez Bernardo , Márquez Sully , Prado-Vivar Belén , Becerra-Wong Mónica , Guadalupe Juan José , da Silva Candido Darlan , Fernandez-Cadena Juan Carlos , Morey-Leon Gabriel , Armas-Gonzalez Rubén , Andrade-Molina Derly Madeleiny , Bruno Alfredo , de Mora Domenica , Olmedo Maritza , Portugal Denisse , Gonzalez Manuel , Orlando Alberto , Drexler Jan Felix , Moreira-Soto Andres , Sander Anna-Lena , Brünink Sebastian , Kühne Arne , Patiño Leandro , Carrazco-Montalvo Andrés , Mestanza Orson , Zurita Jeannete , Sevillano Gabriela , du Plessis Louis , McCrone John T. , Coloma Josefina , Trueba Gabriel , Barragán Verónica , Rojas-Silva Patricio , Grunauer Michelle , Kraemer Moritz U.G. , Faria Nuno R. , Escalera-Zamudio Marina , Pybus Oliver G. , Cárdenas Paúl
Published: April 2021

Characterisation of SARS-CoV-2 genetic diversity through space and time can reveal trends in virus importation and domestic circulation, and permit the exploration of questions regarding the early transmission dynamics. Here we present a detailed description of SARS-CoV-2 genomic epidemiology in Ecuador, one of the hardest hit countries during the early stages of the COVID-19 pandemic. We generate and analyse 160 whole genome sequences sampled from all provinces of Ecuador in 2020. Molecular clock and phylgeographic analysis of these sequences in the context of global SARS-CoV-2 diversity enable us to identify and characterise individual transmission lineages within Ecuador, explore their spatiotemporal distributions, and consider their introduction and domestic circulation. Our results reveal a pattern of multiple international importations across the country, with apparent differences between key provinces. Transmission lineages were mostly introduced before the implementation of non-pharmaceutical interventions (NPIs), with differential degrees of persistence and national dissemination.
Heterogeneity ofStaphylococcus epidermidisin prosthetic joint infections: Time to reevaluate microbiological criteria?
Authors: Widerström Micael , Stegger Marc , Johansson Anders , Gurram Bharat Kumar , Larsen Anders Rhod , Wallinder Lars , Edebro Helen , Monsen Tor
Published: April 2021

Prosthetic joint infection (PJI) is a feared complication after arthroplasty withStaphylococcus epidermidisas a major pathogen. One diagnostic criteria for PJI diagnosis is the finding of phenotypically identical organisms based on common laboratory tests in two or more periprosthetic microbial cultures. Because of phenotypical variation within a genetic clone, and clonal variation within a phenotype, the criteria may be ambiguous. Here, we investigate the extent of diversity among coagulase-negative staphylococci in PJI and characterize in detailS. epidermidisisolates from these infections.

We performed a retrospective cohort study of 62 consecutive patients with PJI caused by coagulase-negative staphylococci (CoNS) from two hospitals in Northern Sweden. From 16 of the patients, two to nineS. epidermidisisolates were available for whole-genome analyses. Hospital-adapted multidrug-resistant genetic clones ofS. epidermidiswere identified in 40/62 (65%) of the PJIs using a combination of analysis by pulsed-field gel electrophoresis and multiple-locus sequence typing. Whole genome sequencing showed presence of multiple sequence types (STs) in seven (7/16, 44%) PJIs. Among isolates of the same ST, within-patient phenotypical variation in antibiotic susceptibility and/or whole-genome antibiotic resistance gene content was frequent (11/16, 69%).

These results highlight the ambiguity of using phenotypical characterization ofS. epidermidisas diagnostic criteria in PJI. The results call for larger systematic studies to determine the frequency of CoNS diversity in PJIs, the implications of such diversity for microbiological diagnostics, and for the therapeutic outcome in patients.
Which traits predict elevated distress during the Covid-19 pandemic? Results from a large, longitudinal cohort study with psychiatric patients and healthy controls
Authors: Brosch Katharina , Meller Tina , Pfarr Julia-Katharina , Stein Frederike , Schmitt Simon , Ringwald Kai G. , Waltemate Lena , Lemke Hannah , Thiel Katharina , Schrammen Elisabeth , Hülsmann Carina , Meinert Susanne , Dohm Katharina , Leehr Elisabeth J. , Opel Nils , Krug Axel , Dannlowski Udo , Nenadić Igor , Kircher Tilo
Published: April 2021

Background

The Covid-19 pandemic resulted in repeated, prolonged restrictions in daily life. Social distancing policies as well as health anxiety are thought to lead to mental health impairment. However, there is lack of longitudinal data identifying at-risk populations particularly vulnerable for elevated Covid-19-related distress.

Methods

We collected data of N=1268 participants (n=622 healthy controls (HC), and n=646 patients with major depression, bipolar disorder, schizophrenia or schizoaffective disorder) at baseline (2014-2018) and during the first lockdown in Germany (April-May 2020). We obtained information on Covid-19 restrictions (number and subjective impact of Covid-19 events), and Covid-19-related distress (i.e., subjective fear and isolation). Using multiple linear regression models including trait variables and individual Covid-19 impact, we sought to predict Covid-19-related distress.

Results

HC and patients reported similar numbers of Covid-19-related events, and similar subjective impact rating. They did not differ in Covid-19-related subjective fear. Patients reported significantly higher subjective isolation. 30.5% of patients reported worsened self-rated symptoms since the pandemic. Subjective fear in all participants was predicted by four variables: trait anxiety (STAI-T), conscientiousness (NEO-FFI), Covid-19 impact, and sex. Subjective isolation in HC was predicted by social support (FSozu), Covid-19 impact, age, and sex; in patients, it was predicted by social support and Covid-19 impact.

Conclusion

Our data shed light on differential effects of the pandemic in psychiatric patients and HC. They identify relevant, easy-to-obtain variables for risk profiles related to interindividual differences in Covid-19-related distress for direct translation into clinical practice.
Clinical implementation of RNA sequencing for Mendelian disease diagnostics
Authors: Yépez Vicente A. , Gusic Mirjana , Kopajtich Robert , Mertes Christian , Smith Nicholas H. , Alston Charlotte L. , Ban Rui , Beblo Skadi , Berutti Riccardo , Blessing Holger , Ciara Elżbieta , Distelmaier Felix , Freisinger Peter , Häberle Johannes , Hayflick Susan J. , Hempel Maja , Itkis Yulia S. , Kishita Yoshihito , Klopstock Thomas , Krylova Tatiana D. , Lamperti Costanza , Lenz Dominic , Makowski Christine C. , Mosegaard Signe , Müller Michaela F. , Muñoz-Pujol Gerard , Nadel Agnieszka , Ohtake Akira , Okazaki Yasushi , Procopio Elena , Schwarzmayr Thomas , Smet Joél , Staufner Christian , Stenton Sarah L. , Strom Tim M. , Terrile Caterina , Tort Frederic , Van Coster Rudy , Vanlander Arnaud , Wagner Matias , Xu Manting , Fang Fang , Ghezzi Daniele , Mayr Johannes A. , Piekutowska-Abramczuk Dorota , Ribes Antonia , Rötig Agnès , Taylor Robert W. , Wortmann Saskia B. , Murayama Kei , Meitinger Thomas , Gagneur Julien , Prokisch Holger
Published: April 2021

Background

Lack of functional evidence hampers variant interpretation, leaving a large proportion of cases with a suspected Mendelian disorder without genetic diagnosis after genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies, and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA-sequencing (RNA-seq) in routine diagnostics.

Methods

We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease which previously underwent WES.

Results

We detected on average 12,500 genes per sample including around 60% disease genes - a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than one week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions.

Conclusion

Together, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics.

One sentence summary

Implementation of RNA-seq as a complementary tool in standard diagnostics achieves a 16% in diagnosis rate over whole exome sequencing.
Chemotherapy-induced collagen IV drives cancer cell invasion through activation of Src/FAK signaling
Authors: Fatherree Jackson P. , Guarin Justinne R. , McGinn Rachel A. , Naber Stephen P. , Oudin Madeleine J.
Published: April 2021

Triple-negative breast cancer (TNBC) is the most aggressive and deadly subtype of breast cancer, accounting for 30,000 cases annually in the US. While there are several clinical trials ongoing to identify new agents to treat TNBC, the majority of TNBC patients are treated with anthracycline- or taxane-based chemotherapies in the neoadjuvant setting, followed by surgical resection and adjuvant chemotherapy. While many patients respond well to this approach, as many as 25% will suffer local or metastatic recurrence within five years. Understanding the mechanisms that drive recurrence after chemotherapy treatment is critical to improving survival for patients with TNBC. It is well-established that the extracellular matrix, which provides structure and support to tissues, is a major driver of tumor growth, local invasion and dissemination of cancer cells to distant metastatic sites. In the present study, we show that decellularized extracellular matrix (dECM) obtained from chemotherapy-treated mice increases invasion of treatment-naïve breast cancer cells compared to vehicle-treated dECM. Using tandem-mass-tag proteomics, we further demonstrate that anthracycline- and taxane-based chemotherapies induce drug-specific changes in tumor ECM composition. We identify the basement membrane protein collagen IV as significantly upregulated in the ECM of chemotherapy-treated mice and patients treated with neoadjuvant chemotherapy. We show that collagen IV drives invasion via Src/FAK signaling and that inhibiting collagen IV-driven signaling decreases invasion in chemotherapy-treated dECM. These studies provide a novel mechanism by which chemotherapy may induce metastasis via effects on ECM composition.

One Sentence Summary

Chemotherapy alters the extracellular matrix of breast tumors leading to increased invasion of residual cancer cells.
Physiological function of Flo11p domains and the particular role of amyloid core sequences of this adhesin inSaccharomyces cerevisiae
Authors: Bouyx Clara , Schiavone Marion , Teste Marie-Ange , Dague Etienne , Sieczkowski Nathalie , Julien Anne , Francois Jean Marie
Published: April 2021

Flocculins are a family of glycosylated proteins that provide yeast cells with several properties such as biofilm formation, flocculation, invasive growth or formation of velum. These proteins are similarly organised with a N-terminal (adhesion) domain, a stalk-like central B-domain with several repeats and a C-terminal sequence carrying a cell wall anchor site. They also contain amyloid β-aggregation-prone sequences whose functional role is still unclear. In this work, we show that Flo11p differs from other flocculins by the presence of unique amyloid-forming sequences, whose the number is critical in the formation of adhesion nanodomains under a physical shear force. Using a genome editing approach to identify the function of domains in Flo11p phenotypes, we show that the formation of cellular aggregates whose density increases with the number of amyloid sequences cannot be attributed to a specific domain of Flo11p. The same is true for plastic adhesion and surface hydrophobicity the intensity of which depends mainly on the abundance of Flo11p on the cell surface. In contrast, the N and C domains of Flo11p are essential for invasive growth in agar, whereas a reduction in the number of repeats of the B domain weakens this phenotype. However, expression ofFLO11alone is not sufficient to trigger this invasion phenotype. Finally, we show that this flocculin contributes to the integrity of the cell wall.