bluuebunny/crossref_metadata_2025 huggingface dataset:
Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder
Authors: Melland Holly , Bumbak Fabian , Kolesnik-Taylor Anna , Ng-Cordell Elise , John Abinayah , Constantinou Panayiotis , Joss Shelagh , Larsen Martin , Fagerberg Christina , Thies Jenny , Emslie Frances , Willemsen Marjolein , Kleefstra Tjitske , Pfundt Rolf , Barrick Rebekah , Chang Richard , Loong Lucy , Alfadhel Majid , van der Smagt Jasper , Nizon Mathilde , Kurian Manju , Scott Daniel J , Ziarek Joshua J , Gordon Sarah , Baker Kate
Published: July 2021

Purpose

Synaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioural disturbance and EEG abnormalities. Here, we expand the genotypes and phenotypes and identify discriminating features of this disorder.

Methods

We describe 22 individuals with 15 de novo missense SYT1 variants. Evidence for pathogenicity is discussed, including ACMG criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioural data for 14 cases are compared to other monogenic neurodevelopmental disorders.

Results

Four variants lie in the C2A domain with the remainder in the C2B. We classify 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes include delayed developmental milestones, ophthalmic problems, abnormal EEG, movement disorders and sleep disturbance. Discriminating behavioural characteristics were severity of motor and communication impairment, presence of motor stereotypies and mood instability.

Conclusion

SYT1 variants associated with neurodevelopmental disorder extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severity than initially reported. This work guides diagnosis and molecular understanding of this rare neurodevelopmental disorder, and highlights a key role for SYT1 function in emotional regulation, motor control and emergent cognitive function.
The effect of transcranial direct current stimulation (tDCS) combined with cognitive training on EEG spectral power in adolescent boys with ADHD: a double-blind, randomised, sham-controlled trial
Authors: Westwood Samuel J. , Bozhilova Natali , Criaud Marion , Lam Sheut-Ling , Lukito Steve , Wallace-Hanlon Sophie , Kowalczyk Olivia S. , Kostara Afroditi , Mathew Joseph , Wexler Bruce E. , Kadosh Roi Cohen , Asherson Philip , Rubia Katya
Published: July 2021

Transcranial direct current stimulation (tDCS) is a possible neurotherapeutic alternative to psychostimulants in Attention-Deficit/Hyperactivity Disorder (ADHD). However, very little is known regarding the mechanisms of action of tDCS in children and adolescents with ADHD. We conducted the first multi-session, sham-controlled study of anodal tDCS over right inferior frontal cortex (rIFC), a consistently under-functioning region in ADHD, combined with cognitive training (CT) in 50 children/adolescents with ADHD. This study investigated the underlying mechanisms of action on resting and Go/No-Go Task-based QEEG measures in a subgroup of 23 participants with ADHD (n, sham=10; anodal tDCS=13). We found no significant sham versus anodal tDCS group differences in QEEG spectral power during rest and Go/No-Go Task performance, no correlation between the QEEG and Go/No-Go Task performance, and no effect on clinical and cognitive outcome measures. These findings extend the null clinical or cognitive effects in our whole sample of 50 children/adolescents with ADHD. Our findings do not indicate multi-session anodal tDCS with CT over rIFC as a treatment for children/adolescents with ADHD. Larger RCTs should explore different protocols titrated to the individual and using comprehensive measures to assess cognitive, clinical, and neural effects of tDCS and its underlying mechanisms of action in ADHD.
Widespread germline genetic heterogeneity of human ribosomal RNA genes
Authors: Fan Wenjun , Eklund Eetu , Sherman Rachel M. , Liu Hester , Pitts Stephanie , Ford Brittany , Rajeshkumar NV , Laiho Marikki
Published: July 2021

Polymorphism drives survival under stress and provides adaptability. Genetic polymorphism of ribosomal RNA (rRNA) genes derives from internal repeat variation of this multicopy gene, and from interindividual variation. A considerable amount of rRNA sequence heterogeneity has been proposed but has been challenging to estimate given the scarcity of accurate reference sequences. We identified four rDNA copies on chromosome 21 (GRCh38) with 99% similarity to recently introduced reference sequence KY962518.1. Pairwise alignment of the rRNA coding sequences of these copies showed differences in sequence and length. We customized a GATK bioinformatics pipeline using the four rDNA loci, spanning a total 145 kb, for variant calling. We employed whole genome sequencing (WGS) data from the 1000 Genomes Project phase 3 and analyzed variants in 2,504 individuals from 26 populations. Using the pipeline, we identified a total of 3,790 variant positions. The variants positioned non-randomly on the rRNA gene. Invariant regions included the promoter, early 5’ ETS, 5.8S, ITS1 and certain regions of the 28S rRNA, and large areas of the intragenic spacer. 18S rRNA coding region had very few variants, while a total of 470 variant positions were observed on 28S rRNA. The majority of the 28S rRNA variants located on highly flexible human-expanded rRNA helical folds ES7L and ES27L, suggesting that these represent positions of diversity and are potentially under continuous evolution. These findings provide a genetic view for rRNA heterogeneity and raise the need to functional assess how the 28S rRNA variants affect ribosome functions.
Proton pump inhibitor use is not associated with severe COVID-19 related outcomes: A propensity score weighted analysis of a national veteran cohort
Authors: Shah Shailja C. , Halvorson Alese E. , McBay Brandon , Dorn Chad , Wilson Otis , Denton Jason , Tuteja Sony , Chang Kyong-Mi , Cho Kelly , Hauger Richard L. , Suzuki Ayako , Hunt Christine M. , Siew Edward , Matheny Michael E. , Hung Adriana , Greevy Robert A. , Roumie Christianne L.
Published: July 2021

Background and Aims

Low pH deactivates most pathogens, including coronaviruses. Proton pump inhibitors (PPIs) are potent gastric acid suppressing medications. Whether PPI use vs non-use is associated with severe Coronavirus disease-2019 (COVID-19) outcomes remains uncertain. We aimed to compare severe COVID-19 outcomes between current outpatient PPI users and non-users.

Methods

We conducted a retrospective propensity score-weighted analysis of a national cohort of US veterans with established care who tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) through January 9, 2021, and who had 60 days of follow-up. The positive test date was the index date. Current outpatient PPI use up to and including the index date (primary exposure) was compared to non-use, defined as no PPI prescription fill in the 365 days prior to the index date. The primary outcome was a composite of use of mechanical ventilation or death within 60 days. Weighted logistic regression models evaluated severe COVID-19 outcomes between current PPI users vs non-users.

Results

Of 97,674 Veterans with SARS-CoV-2 testing, 14,958 tested positive (6262 [41.9%] current PPI users, 8696 [58.1%] non-users) and comprised the analytic cohort. After weighting, all covariates were well-balanced. In the weighted cohort, there was no difference in the primary composite outcome (8.2% vs 8.0%; OR 1.03, 95% CI 0.91-1.16), secondary composite outcome, nor individual component outcomes between current PPI users and non-users. There was no significant interaction between age and PPI use on outcomes.

Conclusion

Among patients with SARS-CoV-2 infection, current PPI use vs non-use is not associated with severe COVID-19 outcomes.
Identification and functional characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease
Authors: Grove Jane I. , Kiu Lo Peggy Cho , Shrine Nick , Barwell Julian , Wain Louise V. , Tobin Martin D. , Salter Andrew M. , Bennett Neil , John Catherine , Ntalla Ioanna , Jones Gabriela E. , Neal Christopher P. , Thomas Mervyn G. , Kuht Helen , Gupta Pankaj , Vemala Vishwaraj M. , Grant Allister , Adewoye Adeolu B. , Shenoy Kotacherry T. , Balakumaran Leena K. , Hollox Edward J. , Hannan Nicholas R.F. , Aithal Guruprasad P.
Published: July 2021

Background and aims

Non-alcoholic fatty liver disease (NAFLD) is a complex trait that has a global prevalence estimated as 25%. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes.

Methods

Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison to healthy non-carriers and wild type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human induced pluripotent stem cells generated from homozygous donor skin fibroblasts. The phenotype was assessed using imaging, targeted RNA analysis and molecular expression arrays.

Results

We identified a rare causal variant in MTTP, c.1691T>C p.I564T (rs745447480) encoding microsomal triglyceride transfer protein (MTP) associated with progressive non-alcoholic fatty liver disease, unrelated to metabolic syndrome. Although other described mutations in MTTP cause abetalipoproteinemia, neither homozygotes nor heterozygotes exhibited characteristic manifestations of this severe disease. HLCs derived from a homozygote donor had lower lipoprotein ApoB secretion, compared to wild type cells. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators and production of reactive oxygen species.

Conclusion

We have identified and characterized a rare causal variant in MTTP and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinemia.
Willingness to receive vaccination against COVID-19: results from a large nationally representative Australian population survey
Authors: Davis Sharon R , Ampon Rosario D , Poulos Leanne M , Marks Guy B , Toelle Brett G , Reddel Helen K
Published: July 2021

We surveyed 10,024 Australians regarding COVID-19 vaccine willingness. Overall, 59.9% indicated yes, 13.9% no and 26.3% unsure/don’t know. Vaccine willingness was higher in males, and increased with increasing education and socioeconomic advantage. Results contrast with earlier, smaller Australian surveys regarding vaccination willingness and confirm the need for targeted vaccination information.
An ergonomic assessment tool for evaluating the effect of back exoskeletons on injury risk
Authors: Zelik Karl E. , Nurse Cameron A. , Schall Mark C. , Sesek Richard F. , Marino Matthew C. , Gallagher Sean
Published: July 2021

Low back disorders (LBDs) are a leading injury in the workplace. Back exoskeletons (exos) are wearable assist devices that complement traditional ergonomic controls and reduce LBD risks by alleviating musculoskeletal overexertion. However, there are currently no ergonomic assessment tools to evaluate risk for workers wearing back exos. Exo-LiFFT, an extension of the Lifting Fatigue Failure Tool, is introduced as a means to unify the etiology of LBDs with the biomechanical function of exos. We present multiple examples demonstrating how Exo-LiFFT can assess or predict the effect of exos on LBD risk without costly, time-consuming electromyography studies. For instance, using simulated and real-world material handling data we show an exo providing a 30 Nm lumbar moment is projected to reduce cumulative back damage by ∼70% and LBD risk by ∼20%. Exo-LiFFT provides a practical, efficient ergonomic assessment tool to assist safety professionals exploring back exos as part of a comprehensive occupational health program.

HIGHLIGHTS

Back exos are wearable assist devices that complement ergonomic controls for reducing low back disorder (LBD) risks

However, no ergonomic assessment tools exist to evaluate LBD risks for workers wearing back exos

We introduce Exo-LiFFT, an ergonomic assessment tool adapted from the Lifting Fatigue Failure Tool

Exo-LiFFT is a practical tool that unifies the etiology of LBDs and biomechanical function of exos

Exo-LiFFT can be used to assess or predict the effect of exos on LBD risk without EMG testing
A spatio-temporal study of state-wide case-fatality risks during the first wave of the COVID-19 pandemic in Mexico
Authors: Ramírez-Aldana Ricardo , Gomez-Verjan Juan Carlos , Bello-Chavolla Omar Yaxmehen , Naranjo Lizbeth
Published: July 2021

We study case-fatality risks (risks of dying in sick individuals) corresponding to the first wave of the COVID-19 pandemic in Mexico. Spatio-temporal analysis by state were performed, mainly from April to September 2020, including descriptive analyses through mapping and time series representations, and the fit of linear mixed models and time series clustering to analyze trends by state. The association of comorbidities and other variables with the risks were studied by fitting a spatial panel data linear model (splm). As results, we observed that on average the greatest risks were reached by July, and that highest risks were observed in some states, Baja California Norte, Chiapas, and Sonora; interestingly, some densely populated states, as Mexico City, had lower values. Different trends by state were observed, and a four-order polynomial, including fixed and random effects, was necessary to model them. The most general structure is one in which the risks increase and then decrease and was observed in states belonging to two clusters; however, there is a cluster corresponding to states with a retarded increase, and another in which increasing risks through time were observed. A cyclic behavior in terms of states having a second increasing trend was observed. Finally, according to the splm, percentage of men, being in the group of 50 years and over, chronic kidney disease failure, cardiovascular disease, asthma, and hypertension were positively associated with the case-fatality risks. This analysis may provide valuable insight into COVID-19 dynamics in future outbreaks, as well as the determinants of these trends at a state level; and, by combining spatial and temporal information, provide a better understanding of COVID-19 case-fatality.
A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia
Authors: Kechin Andrey , Boyarskikh Ulyana , Barinov Alexey , Tanas Alexander , Kazakova Svetlana , Zhevlova Anastasia , Khrapov Evgeniy , Subbotin Sergey , Mishukova Olga , Kekeeva Tatiana , Demidova Irina , Filipenko Maxim
Published: July 2021

Pathogenic mutations in BRCA1 and BRCA2 genes are essential biomarkers of an increased breast and ovarian cancer risk and tumor sensitivity to poly ADP ribose (PARP) inhibitors. In many countries, their detection includes patient prescreening with quantitative PCR (qPCR) identifying several founder mutations. In Russia, eight mutations are included in such tests, among which c.5266dup (5382insC) is the most frequently identified one. Here, we showed the distribution of 1406 pathogenic or likely pathogenic mutations in BRCA1/2 genes identified in ovarian cancer patients recruited into the study from 72 Russian regions in 2015-2021. The most of mutations were detected with qPCR, for qPCR mutation negative samples, targeted next-generation sequencing (NGS) covering whole coding sequences of the genes was applied. As expected, the most abundant mutations were c.5266dupC (41.0%), c.4035delA (7.0%), c.1961delA (6.3%), c.181T>G (5.2%), c.3756_3759delGTCT (1.8%), c.3700_3704delGTAAA (1.5%), and c.68_69delAG (1.5%). However, we identified several mutations which were more frequent than the founder c.5946delT mutation (also known as 6174delT, 0.5% of participants): c.5152+1G>T (1.2%), c.1687C>T (1.0%), c.4689C>G (0.9%), c.1510delC (0.6%), c.2285_2286delGA (0.6%) in the BRCA1 gene; and c.5286T>G (1.2%), c.2808_2811delACAA (0.8%), c.658_659delGT (0.7%), c.7879A>T (0.6%), c.3847_3848delGT (0.6%) in the BRCA2 gene. Having developed an NGS-targeted panel on SNPs flanking BRCA2 c.5286T>G, we showed the founder effect for this mutation and suggested that it arose about 700 years ago that is twice later that it is thought for the c.5266dupC. The total occurrence of mutations identified in at least 10 participants (13 mutations) was only 70%. To our knowledge, eighty-nine mutations (identified in 8% of participants) have not been described previously. Thus, this study may help in improving prescreening qPCR tests and extend our knowledge about the BRCA1 and BRCA2 genes variability in ovarian cancer patients.
Mental Health of HBCU College Students during the COVID-19 Pandemic
Authors: Wang Sharron Xuanren , Goodman Jarid
Published: July 2021

Objective

This study investigated rates and predictors of mental health issues (e.g., depression and anxiety) in a sample of college students currently attending a historically Black college/university (HBCU) during the COVID-19 pandemic.

Participants/Methods

98 undergraduate students (81 female and 17 male) completed an online survey containing questions about demographics, socioeconomic status, academic characteristics, and pandemic-related concerns. The survey also included PHQ-9 and GAD-7 questionnaires to evaluate depression and anxiety, respectively.

Results

49% of students met the clinical cutoff for depression, 39% for anxiety, and 52% for depression and/or anxiety. Significant predictors of meeting the cutoffs included parental job loss/hour reduction, being a senior, and feeling that the pandemic negatively impacted daily life, among other factors. Demographic variables (age, gender, etc.) had no effect.

Conclusion

HBCU students show high rates of depression and anxiety during the COVID-19 pandemic, which may be predicted based on the student’s academic, socioeconomic, and pandemic-related concerns.
Reduced dementia incidence following varicella zoster vaccination in Wales 2013–2020
Authors: Schnier Christian , Janbek Janet , Lathe Richard , Haas Jürgen
Published: July 2021

INTRODUCTION

Chronic infection with herpes viruses is a potential contributing factor to the development of dementia. The introduction of nationwide shingles (varicella zoster) vaccination in Wales might therefore be associated with reduced incident dementia.

METHODS

We analyzed the association of shingles vaccination with incident dementia in Wales between 2013 and 2020 using retrospectively collected national health data.

RESULTS

Vaccinated individuals were at reduced risk of dementia (adjusted hazard ratio: 0.72; 95% CI: 0.69 to 0.75). The association was not modified by a reduction in shingles diagnosis and was stronger for vascular dementia than for Alzheimer’s disease. Vaccination was also associated with a reduction in several other diseases and all-cause mortality.

DISCUSSION

Our study shows a clear association of shingles vaccination with reduced dementia, consistent with other observational cohort studies. The association may reflect selection bias with people choosing to be vaccinated having a higher healthy life expectancy.
Hypocalcemia and Acute Pulmonary Embolism Hospitalizations in the United States: Highlights from the propensity matched 2017 Nationwide Inpatient Sample
Authors: Murthi Mukunthan , Shaka Hafeez , El-amir Zain , Velagapudi Sujitha , Jamil Abdul , Wani Farah , Atluri Ramtej , Kumar Akshay , Kichloo Asim
Published: July 2021

Acute pulmonary embolism (PE) is a common cause for hospitalization associated with significant mortality and morbidity. Disorders of calcium metabolism are a frequently encountered medical problem. The effect of hypocalcemia is not well defined on the outcomes of patients with PE. We aimed to identify the prognostic value of hypocalcemia in hospitalized PE patients utilizing the 2017 Nationwide Inpatient Sample (NIS). In this retrospective study, we selected patients with a primary diagnosis of Acute PE using ICD 10 codes. They were further stratified based on the presence of hypocalcemia. We primarily aimed to compare in-hospital mortality for PE patients with and without hypocalcemia. In the 2017 NIS, 187,989 patients had a principal diagnosis of acute PE. Among the above study group, 1565(0.8%)had an additional diagnosis of hypocalcemia. 12.4% of PE patients with hypocalcemia died in the hospital in comparison to 2.95% without hypocalcemia. On multivariate regression analysis, PE and hypocalcemia patients had 4 times higher odds (aOR-4.03, 95% CI 2.78-5.84, p<0.001) of in-hospital mortality compared to those with only PE. We observed a similarly high odds of mortality(aOR=4.4) on 1:1 propensity-matched analysis. The incidence of acute kidney injury (aOR=2.62, CI 1.95-3.52, p<0.001), acute respiratory failure (a0R=1.84, CI 1.42-2.38, p<0.001), sepsis (aOR=4.99, CI 3.08-8.11, p<0.001) and arrhythmias (aOR=2.63, CI 1.99-3.48, p<0.001) were also higher for PE patients with hypocalcemia. Thus, PE patients with hypocalcemia have higher in-hospital complications and mortality than those without hypocalcemia.
Impact of SARS-CoV-2 variant on the severity of maternal infection and perinatal outcomes: Data from the UK Obstetric Surveillance System national cohort
Authors: Vousden Nicola , Ramakrishnan Rema , Bunch Kathryn , Morris Edward , Simpson Nigel , Gale Christopher , O’Brien Patrick , Quigley Maria , Brocklehurst Peter , Kurinczuk Jennifer J , Knight Marian
Published: July 2021

Background

In the UK, the Alpha variant of SARS-CoV-2 became dominant in late 2020, rapidly succeeded by the Delta variant in May 2021. The aim of this study was to compare the impact of these variants on severity of maternal infection and perinatal outcomes within the time-periods in which they predominated.

Methods

This national, prospective cohort study collated data on hospitalised pregnant women with symptoms of confirmed SARS-CoV-2 infection and compared the severity of infection and perinatal outcomes across the Wildtype (01/03/20-30/11/20), Alpha (01/12/20-15/05/21) and Delta dominant periods (16/05/21-11/07/21), using multivariable logistic regression.

Findings

Of 3371 pregnant women, the proportion that experienced moderate to severe infection significantly increased between Wildtype and Alpha periods (24.4% vs. 35.8%; aOR1.75 95%CI 1.48-2.06), and between Alpha and Delta periods (35.8% vs. 45.0%; aOR1.53, 95%CI 1.07-2.17). Compared to the Wildtype period, symptomatic women admitted in the Alpha period were more likely to require respiratory support (27.2% vs. 20.3%, aOR1.39, 95%CI 1.13-1.78), have pneumonia (27.5% vs. 19.1%, aOR1.65, 95%CI 1.38-1.98) and be admitted to intensive care (11.3% vs. 7.7%, aOR1.61, 95%CI 1.24-2.10). Women admitted during the Delta period had further increased risk of pneumonia (36.8% vs. 27.5%, aOR1.64 95%CI 1.14-2.35). No fully vaccinated pregnant women were admitted between 01/02/2021 when vaccination data collection commenced and 11/07/2021. The proportion of women receiving pharmacological therapies for SARS-CoV-2 management was low, even in those critically ill.

Interpretation

SARS-CoV-2 infection during Alpha and Delta dominant periods was associated with more severe infection and worse pregnancy outcomes compared to the Wildtype infection, which itself increased risk compared to women without SARS-CoV-2 infection.1 Clinicians need to be aware and implement COVID-specific therapies in keeping with national guidance. Urgent action to tackle vaccine misinformation and policy change to prioritise uptake in pregnancy is essential.

Funding

National Institute for Health Research HS&DR Programme (11/46/12).
The olfactory organ is a unique site for resident neutrophils in the brain
Authors: Palominos M. Fernanda , Candia Danissa , Paz Jorge Torres , Whitlock Kathleen E.
Published: July 2021

For decades we have known that the brain “drains” through the subarachnoid space following a route that crosses the cribriform plate to the nasal mucosa and cervical lymph nodes. Yet little is known about the potential role of the olfactory epithelia and associated lymphatic vasculature in the immune response. To better understand the immune response in the olfactory organs we used cell-specific fluorescent reporter lines in dissected, intact adult brains to visualize blood-lymphatic vasculature and neutrophils in the olfactory sensory system. Here we show that the extensive blood vasculature of the olfactory organs is associated with a lymphatic cell type resembling high endothelial venules (HEVs) of the lymph nodes in mammals and a second resembling Mural Lymphatic Endothelial Cells (muLECs) that extended from the brain to the peripheral olfactory epithelia. Surprisingly, the olfactory organs contained the only neutrophil populations observed in the brain. Damage to the olfactory epithelia resulted in a rapid increase of neutrophils within the olfactory organs as well as the appearance of neutrophils in the brain suggesting that neutrophils enter the brain in response to damage. Analysis of cell division during and after damage showed an increase in BrdU labeling in the olfactory epithelia and a subset of the neutrophils. Our results reveal a unique population of neutrophils in the olfactory organs that are associated with an extensive lymphatic vasculature suggesting a dual olfactory-immune function for this unique sensory system.

Highlights

The olfactory organ is the only region of the brain that contains resident neutrophils in the adult animal.

Damage to olfactory sensory neurons triggers a rapid mobilization of neutrophils within the olfactory organ and in the central nervous system.

Two types of lymphatic vasculature resembling Mural Lymphatic Endothelial Cells (muLEC) and High Endothelial Venules (HEV) are present in the olfactory sensory system.

Lymphatic vasculature resembling Mural Lymphatic Endothelial Cells (muLEC) wrap the olfactory bulbs and extend across the cribriform plate to olfactory epithelia.
Mechanisms of phosphatidylserine influence on viral production: a computational model of Ebola virus matrix protein assembly
Authors: Liu Xiao , Pappas Ethan J. , Husby Monica L. , Motsa Balindile B. , Stahelin Robert V. , Pienaar Elsje
Published: July 2021

Ebola virus (EBOV) infections continue to pose a global public health threat, with high mortality rates and sporadic outbreaks in Central and Western Africa. A quantitative understanding of the key processes driving EBOV assembly and budding could provide valuable insights to inform drug development. Here we used a computational model to evaluate EBOV matrix assembly. Our model focused on the assembly kinetics of VP40, the matrix protein in EBOV, and its interaction with phosphatidylserine (PS) in the host cell membrane. Human cells transfected with VP40-expressing plasmids are capable of producing virus-like particles (VLPs) that closely resemble EBOV virions. We used data from this in vitro VP40 system to calibrate our computational model. PS levels in the host cell membrane had been shown to affect VP40 dynamics as well as VLP production through recruiting VP40 dimers to plasma membrane inner leaflet. Our computational results indicated that PS may have direct influence on VP40 filament growth and affect multiple steps in the assembly and budding of VP40 VLPs. We also proposed that the assembly of VP40 filaments may follow the nucleation-elongation theory where initialization and oligomerization of VP40 are two separate and distinct steps in the assembly process. This work illustrated how computational and experimental approaches can be combined to allow for additional analysis and hypothesis generation. Our findings advanced understanding of the molecular process of EBOV assembly and budding processes and may help the development of new EBOV treatments targeting VP40 matrix assembly.
Intrinsic water use efficiency depends on stomatal aperture rather than stomatal density in C3 and C4 grasses grown at glacial CO2 and low light
Authors: Israel Walter Krystler , Watson-Lazowski Alexander , Chen Zhong-Hua , Ghannoum Oula
Published: July 2021

We investigated how stomatal morphology and physiology control intrinsic leaf water use efficiency (iWUE) in grasses. Two C3 and six C4 grasses were grown at ambient (400 µl L-1) or glacial CO2 (180 µl L-1) and high (1000 µmol m-2 s-1) or low light intensity (200 µmol m-2 s-1). C4 grasses tended to have higher iWUE and CO2 assimilation rates, and lower stomatal conductance (gs), operational stomatal aperture (aop) and guard cell K+ influx rate relative to C3 grasses, while stomatal size (SS) and stomatal density (SD) did not vary according to the photosynthetic type. Overall, iWUE and gs depended most on aop and density of open stomata. In turn, aop correlated with K+ influx, stomatal opening speed on transition to high light and SS. Species with higher SD had smaller and faster-opening stomata. Although C4 grasses operated with lower gs and aop at ambient CO2, they showed a greater potential to open stomata relative to maximal stomatal conductance (gmax), indicating heightened stomatal sensitivity and control. We uncover novel links between aop, gs, iWUE and K+ influx amongst grasses and differential K+ influx responses of C4 guard cells to low light, revealing molecular targets for breeding crops with high iWUE.

Highlights

Across C3 and six C4 grasses, intrinsic water use efficiency was strongly associated with stomatal conductance, operational stomatal aperture, guard cell K+ influx and stomatal opening speed on transition to high light.
Antiviral metabolite 3’-Deoxy-3’,4’-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19
Authors: Mehta Ravi , Chekmeneva Elena , Jackson Heather , Sands Caroline , Mills Ewurabena , Arancon Dominique , Li Ho Kwong , Arkell Paul , Rawson Timothy M. , Hammond Robert , Amran Maisarah , Haber Anna , Cooke Graham , Noursadeghi Mahdad , Kaforou Myrsini , Lewis Matthew , Takats Zoltan , Sriskandan Shiranee
Published: July 2021

There is a critical need for improved infectious disease diagnostics to enable rapid case identification in a viral pandemic and support targeted antimicrobial prescribing. Here we use high-resolution liquid chromatography coupled with mass spectrometry to compare the admission serum metabolome of patients attending hospital with a range of viral infections, including SARS-CoV-2, to those with bacterial infections, non-infected inflammatory conditions and healthy controls. We demonstrate for the first time that 3’-Deoxy-3’,4’-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), is detectable in serum. ddhC acts as an accurate biomarker for viral infections, generating an area under the receiver operating characteristic curve of 0.954 (95% confidence interval 0.923-0.986) when comparing viral to non-viral cases. Gene expression of viperin, the enzyme responsible for ddhCTP synthesis, is highly correlated with ddhC, providing a biological mechanism for its increase during viral infection. These findings underline a key future diagnostic role of ddhC in the context of pandemic preparedness and antimicrobial stewardship.
A cross-sectional study of psychosocial factors and sickness presenteeism in Japanese workers during the COVID-19 pandemic
Authors: Masuda Masashi , Ishimaru Tomohiro , Hino Ayako , Ando Hajime , Tateishi Seiichiro , Nagata Tomohisa , Tsuji Mayumi , Matsuda Shinya , Fujino Yoshihisa
Published: July 2021

Background

We examined the association between socioeconomic and health status, and lifestyle and sickness presenteeism among Japanese workers during the COVID-19 epidemic.

Methods

A cross-sectional study using an Internet-monitor survey was conducted in December, 2020 in Japan. Of 33,302 survey participants, we analyzed 27,036 participants (13,814 men and 13,222 women) who reported experience with sickness presenteeism.

Results

The odds ratio (OR) of sickness presenteeism associated with unmarried versus married status was 1.15. Respective figures for other variables were 1.11 for manual laboring work compared to desk work; 1.79 and 2.29 for loss of employment at the time the pandemic began and continuation of unemployment compared to maintaining employment during the pandemic; and 3.34 for a feeling of financial instability compared to stability.

Conclusion

The issue of sickness presenteeism has become more prominent under the COVID-19 epidemic.
Prevention and Control of Acute Respiratory Viral Infections in Adult Population: A Systematic Review and Meta-Analysis on Ginseng-Based Clinical Trials
Authors: Adusei-Mensah Frank , Agjei Richard Osei , Awoniyi Luqman Oluwaseun , David Lekpa K. , Awoniyi Fatima Badmus , Adeyemi Oluwafikayo S. , Olawuni Adedayo , Adegbite Ayobami
Published: July 2021

Introduction

Acute respiratory infections are continuously emerging. Discovered in Wuhan city, China in 2019, COV-SARS-2 and most viral respiratory diseases presently do not have a definitive cure. This paper aims to evaluate the therapeutic effectiveness of ginseng for prevention and control of acute respiratory illness including SARS-COV-2 in adult population.

Method

We performed a systematic literature review using databases PubMed, Medline, Scopus, Google Scholar, Web of Science, and Cochrane library from 1st through the 27th of April 2020. All related articles that reported the use of Ginseng in COVID-19 patients were included in this analysis. Screening was done by 2-independent researchers. The meta-analysis was performed using comprehensive meta-analysis package.

Result

596 articles were retrieved for the time frame. After screening, 5 articles with RCTs outcomes relevant to the review were selected. Ginseng was found to be effective in the reduction of risk by 38 % and 3-days shorter duration of acute respiratory illness (ARI) in all trials than placebo.

Conclusion

As the world continues to race to find a cure, it is important to consider the use of ginseng which has been proven over the years to be effective in the treatment of acute respiratory illnesses. Further studies should however be conducted to determine the right dosage to improve efficacy and prevent adverse events.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Highlight

⍰

COVID-19 is very infectious ravaging the globe

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Millions have been infected and hundreds of thousands lost their lives to COVID-19

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Due to absence of vaccines, urgent search for vaccines and drugs is still underway

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Ginseng has been useful in similar respiratory viral infections in the past

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Current paper throws more light on the need to consider ginseng for COVID-19 control
Knowledge, attitude, and practices towards COVID-19 among the Rohingya refugees in Cox’s Bazar, Bangladesh
Authors: Jubayer Md. Fahad , Islam Limon Md. Tariqul , Rana Md. Masud , Kayshar Md. Shahidullah , Arifin Md. Shoaib , Uddin AHM Musleh , Rahman Mazumder Md. Anisur
Published: July 2021

The Rohingya refugee population in Bangladesh has become more vulnerable to COVID-19 because of their living and environmental conditions. The current study represents an assessment of the Rohingya people’s COVID-19-related knowledge, attitude, and practices (KAP) at eight refugee camps in Cox’s Bazar. This cross-sectional study was completed with a total of 400 responses between July and September of 2020. A questionnaire was created to assess demographic characteristics (5 items), knowledge (10 items), attitude (5 items), practices (5 items), and information sources (1 item). Aside from the total KAP scores, the scores are also presented based on demographic variables. The KAP of the respondents were not satisfactory, with scores of 5.8 ±1.8, 2.2 ± 1.0, and 0.9 ± 0.7, respectively. We found significant differences only in the knowledge scores based on education and gender. In conclusion, this study emphasizes the importance of COVID-19 training that focuses on behavioral changes for the Rohingya people in Bangladesh.
EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders
Authors: Lenassi Eva , Carvalho Ana , Thormann Anja , Fletcher Tracy , Hardcastle Claire , Hunt Sarah E , Sergouniotis Panagiotis I , Michaelides Michel , Webster Andrew R , Cunningham F , Ramsden Simon , FitzPatrick David R , Black Graeme CM , Ellingford Jamie M
Published: July 2021

Purpose

The widespread adoption of genomic testing for individuals with ophthalmic disorders has increased demand on diagnostic genomic services for these conditions. Moreover, the clinical utility of a molecular diagnosis for individuals with inherited ophthalmic disorders is increasingly placing pressure on the speed and accuracy of genomic testing.

Methods

We created EyeG2P, a publically available resource to assist diagnostic filtering of genomic datasets for ophthalmic conditions, utilising the Ensembl Variant Effect Predictor. We assessed the sensitivity of EyeG2P for 1234 individuals with a broad range of conditions, who had previously received a confirmed molecular diagnosis through routine genomic diagnostic approaches. For a prospective cohort of 83 individuals, we also assessed the precision of EyeG2P in comparision to routine genomic diagnostic approaches.

Results

We observed that EyeG2P had a 99.5% sensitivity for genomic variants previously identified as a molecular diagnosis for 1234 individuals. EyeG2P enabled a significant increase in precision in comparison to routine testing strategies (p<0.001), with an increased precision in variant analysis of 35% per individual, on average.

Conclusion

Automated filtering of genomic variants through EyeG2P can increase the efficiency of diagnostic testing for individuals with a broad range of inherited ophthalmic disorders.
Challenges to self-isolation among contacts of cases of COVID-19: a national telephone survey in Wales
Authors: Isherwood Kate R , Kyle Richard G , Gray Benjamin J , Davies Alisha R
Published: July 2021

Objectives

To identify the specific challenges of self-isolation experienced by population sub-groups to better target and tailor support.

Design

The Contact Adherence Behavioural Insights Study (CABINS) was a 15-minute telephone survey of confirmed contacts of cases of COVID-19 identified through the national NHS Wales Test Trace Protect (TTP) database.

Methods

Confirmed contacts of cases of COVID-19 reached by TTP completed a 15-minute telephone survey (N = 2,027). Binary logistic regression models adjusted for age, gender, living alone, survey round, deprivation quintile (defined by the Welsh Index of Multiple Deprivation) and income precarity (financial security) determined which population sub-groups were more likely to experience challenges during self-isolation.

Results

Younger people (aged 18-29 years) were 3 times more likely to report mental health concerns (Adjusted Odds Ratio [aOR]: 3.16, 95% Confidence Interval [CI]: 2.05-4.86) and 2 times more likely to report loneliness (aOR: 1.96, CI: 1.37-2.81) compared to people aged over 60 years. Women were 1.5 times more likely to experience mental health concerns (aOR: 1.51, 95% CI: 1.20-1.92) compared to men. People with high/very high levels of income precarity were 8 times more likely to report financial challenges (aOR: 7.73, CI: 5.10-11.74) and 3 times more likely to report mental health concerns than their more financially secure counterparts (aOR: 3.08, CI: 2.22-4.28).

Conclusions

Self-isolation is particularly challenging for those with younger people, women and precarious incomes. Providing enhanced emotional, financial and social support and signposting to these groups is required to minimise the harms of self-isolation.

What is already known on this subject?

Self-isolation after notification as a contact of a positive case of COVID-19 is essential to prevent the spread of the disease. However, self-isolation can be challenging and adherence is dependent upon a range of psychological, social and economic factors.

Emerging data suggests that the COVID-19 pandemic is having disproportionate impact on those on lower incomes and those of lower socio-economic status.

What does this study add?

The most common challenges faced to self-isolation were wanting to see family and friends, followed by a lack of exercise.

Individuals with some income precarity were more than 7 times more likely to report financial concerns and 3 times more likely to report mental health concerns as a challenge to self-isolation than those who were financially secure.

Interventions to support individuals to self-isolate needs to be targeted at groups most susceptible to experiencing challenges to self-isolation for infectious diseases. Our research suggests that the use of income precarity questions as a screening tool is important to direct financial and practical support through contact tracing systems.
An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro/adipogenic progenitors in fibrodysplasia ossificans progressiva mice
Authors: Lees-Shepard John B. , Stoessel Sean J. , Chandler Julian , Bouchard Keith , Bento Patricia , Apuzzo Lorraine N. , Devarakonda Parvathi M. , Hunter Jeffrey W. , Goldhamer David J.
Published: July 2021

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive and catastrophic heterotopic ossification (HO) of skeletal muscle and associated soft tissues. FOP is caused by dominantly acting mutations in the bone morphogenetic protein (BMP) type I receptor, ACVR1 (also known as ALK2), the most prevalent of which is an arginine to histidine substitution [ACVR1(R206H)] in the glycine-serine rich intracellular domain of the receptor. A fundamental pathological consequence of FOP-causing ACVR1 receptor mutations is to enable activin A to initiate canonical BMP signaling in responsive progenitors, which drives skeletogenic commitment and HO. With the clear targets of activin A and ACVR1 identified, development of antibody therapeutics to prevent ligand-receptor interactions is an interventional approach currently being explored. Here, we developed a monoclonal blocking antibody (JAB0505) to the extracellular domain of ACVR1 and tested its ability to inhibit HO in established FOP mouse models. JAB0505 inhibited BMP-dependent gene expression in wild-type and ACVR1(R206H)-overexpressing cell lines. Strikingly, however, JAB0505 treatment markedly exacerbated injury-induced HO in two independent FOP mouse models in which ACVR1(R206H) was either broadly expressed, or more selectively expressed in fibro/adipogenic progenitors (FAPs). JAB0505 drove HO even under conditions of activin A inhibition, indicating that JAB0505 has receptor agonist activity. JAB0505-treated mice exhibited multiple, distinct foci of heterotopic lesions, suggesting an atypically broad anatomical domain of FAP recruitment to endochondral ossification. In addition, skeletogenic differentiation was both delayed and prolonged, and this was accompanied by dysregulation of FAP population growth. Collectively, alterations in the growth and differentiative properties of FAPs and FAP-derived skeletal cells are implicated in the aggravated HO phenotype. These data raise serious safety and efficacy concerns for the use of anti-ACVR1 antibodies to treat FOP patients.
Spatial and temporal localization of cell wall associated pili in Enterococcus faecalis
Authors: Choo Pei Yi , Wang Charles Y. , VanNieuwenhze Michael S. , Kline Kimberly A.
Published: July 2021

Enterococcus faecalis relies upon a number of cell wall-associated proteins for virulence. One virulence factor is the sortase-assembled endocarditis and biofilm associated pilus (Ebp), an important factor for biofilm formation in vitro and in vivo. The current paradigm for sortase-assembled pilus biogenesis in Gram-positive bacteria is that the pilus sortase covalently links pilus monomers prior to recognition, while the housekeeping sortase cleaves at the LPXTG motif within the terminal pilin subunit, and subsequently attaches assembled pilus fiber to the growing cell wall at sites of new cell wall synthesis. While the cell wall anchoring mechanism and polymerization of Ebp is well characterized, less is known about the spatial and temporal deposition of this protein on the cell surface. We followed the distribution of Ebp and peptidoglycan (PG) throughout the E. faecalis cell cycle via immunofluorescence microscopy and fluorescent D-amino acids (FDAA) staining. Surprisingly, cell surface Ebp did not co-localize with newly synthesized PG. Instead, surface-anchored Ebp was localized to the cell hemisphere but never at the septum where new cell wall is deposited. In addition, the older hemisphere of the E. faecalis diplococcus were completely saturated with Ebp, while Ebp appeared as two foci directly adjacent to the nascent septum in the newer hemisphere. A similar localization pattern was observed for another cell wall anchored substrate by sortase A, aggregation substance (AS), suggesting that this may be a general rule for all SrtA substrates in E. faecalis. When cell wall synthesis was inhibited by ramoplanin, an antibiotic that binds and sequesters lipid II cell wall precursors, new Ebp deposition at the cell surface was not disrupted. These data suggest an alternative paradigm for sortase substrate deposition in E. faecalis, in which Ebp are anchored directly onto un-crosslinked cell wall, independent of new PG synthesis.
A protocol for good quality genomic DNA isolation from formalin-fixed paraffin-embedded tissues without using commercial kits
Authors: Talukdar Fazlur Rahman , Abramović Irena , Cuenin Cyrille , Carreira Christine , Gangane Nitin , Sincic Nino , Herceg Zdenko
Published: July 2021

DNA isolation from formalin-fixed paraffin-embedded (FFPE) tissues for molecular analysis has become a frequent procedure in cancer research. However, the yield or quality of the isolated DNA is often compromised, and commercial kits are used to overcome this to some extent. We developed a new protocol (IARCp) to improve better quality and yield of DNA from FFPE tissues without using any commercial kit. To evaluate the IARCp’s performance, we compared the quality and yield of DNA with two commercial kits, namely NucleoSpin® DNA FFPE XS (MN) and QIAamp DNA Micro (QG) isolation kit. Total DNA yield for QG ranged from 120.0 – 282.0 ng (mean 216.5 ng), for MN: 213.6 – 394.2 ng (mean 319.1 ng), and with IARCp the yield was much higher ranging from 775.5 – 1896.9 ng (mean 1517.8 ng). Moreover, IARCp has also performed well in qualitative assessments. Overall, IARCp represents a novel approach to DNA isolation from FFPE which results in good quality and significant amounts of DNA suitable for many downstream genome-wide and targeted molecular analyses. Our proposed protocol does not require the use of any commercial kits for isolating DNA from FFPE tissues, making it suitable to implement in low-resource settings such as low and middle-income countries (LMICs).