bluuebunny/crossref_metadata_2025 huggingface dataset:
Innate immunity plays a key role in controlling viral load in COVID-19: mechanistic insights from a whole-body infection dynamics model
Authors: Dogra Prashant , Ruiz-Ramírez Javier , Sinha Kavya , Butner Joseph D. , Peláez Maria J , Rawat Manmeet , Yellepeddi Venkata K. , Pasqualini Renata , Arap Wadih , Sostman H. Dirk , Cristini Vittorio , Wang Zhihui
Published: November 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. To develop disease management strategies, a better understanding of SARS-CoV-2 pathogenesis and population susceptibility to infection are needed. To this end, physiologically-relevant mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency for infection) of the virus, and by incorporating cellular-scale viral dynamics and innate and adaptive immune responses, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body (respiratory tract, gut, liver, spleen, heart, kidneys, and brain). Following calibration with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, we conducted global sensitivity analysis of model parameters and ranked them for their significance in governing clearance of viral load to understand the effects of physiological factors and underlying conditions on viral load dynamics. Antiviral drug therapy, interferon therapy, and their combination was simulated to study the effects on viral load kinetics of SARS-CoV-2. The model revealed the dominant role of innate immunity (specifically interferons and resident macrophages) in controlling viral load, and the impotance of timing when initiating therapy following infection.

Graphical Abstract
Trends in known and undiagnosed diabetes, HbA1c levels, cardio-metabolic risk factors and diabetes treatment target achievement in repeated cross-sectional surveys – The Tromsø Study 1994-2016
Authors: Langholz Petja Lyn , Wilsgaard Tom , Njølstad Inger , Jorde Rolf , Hopstock Laila Arnesdatter
Published: November 2020

Objectives

The aim of this study was to investigate time trends in known and undiagnosed diabetes, HbA1c levels, and other cardio-metabolic risk factors in the general population as well as treatment target achievement among those with diabetes.

Design and setting

Repeated cross-sectional surveys in the population-based Tromsø Study.

Methods

We used age-adjusted generalized estimating equation models to study trends in self-reported and undiagnosed (HbA1c ≥6.5%) diabetes, cardio-metabolic risk factors and the metabolic syndrome in 27281 women and men aged 40-84 years examined in up to four surveys of the Tromsø Study between 1994 and 2016. Further, we analyzed trends in diabetes treatment target achievement.

Results

During 1994-2016 diabetes prevalence increased in women (2.3% to 3.9%) and men (2.4% to 5.3%) and in all age-groups, while the proportion of undiagnosed diabetes in women (33% to 20%) and men (37% to 27%) decreased. Blood pressure and total cholesterol decreased, while waist circumference increased in participants with and without diabetes, leading to a relatively stable prevalence of the metabolic syndrome throughout the study period. There was a marginal increase in HbA1c levels among participants without diabetes. Only half of those with diabetes achieved the treatment target of HbA1c ≤7.0%.

Conclusion

In the last two decades diabetes prevalence increased, while the proportion of undiagnosed diabetes declined. The prevalence of the metabolic syndrome remained stable throughout, driven by opposing trends with an increase in obesity and a decrease in other cardio-metabolic risk factors. HbA1c treatment target achievement did not improve.
Epigenome-wide association studies of three social determinants of health and implications for lung functions among survivors of childhood cancer
Authors: Song Nan , Sim Jin-ah , Dong Qian , Zheng Yinan , Hou Lifang , Li Zhenghong , Hsu Chia-Wei , Pan Haitao , Mulder Heather , Easton John , Walker Emily , Neale Geoffrey , Wilson Carmen L. , Ness Kirsten K. , Krull Kevin R. , Srivastava Deo Kumar , Yasui Yutaka , Zhang Jinghui , Hudson Melissa M. , Robison Leslie L. , Huang I-Chan , Wang Zhaoming
Published: November 2020

Background

Emerging evidence suggests that social determinants of health (SDOH) may influence health and wellness through an epigenetic mechanism in the general population. However, the social epigenomic approach has not yet been applied to survivors of childhood cancer, a vulnerable population with elevated risk for chronic health conditions (CHCs).

Methods

Study participants were drawn from the St Jude Lifetime Cohort, a hospital-based retrospective cohort with prospective follow up. DNA methylation (DNAm) profiling was generated based on blood derived DNA collected during follow-up visit. SDOH included educational attainment, personal income, and area deprivation index (ADI) based on baseline or follow-up questionnaires and geocoding. CHCs were clinically assessed with severity grade.

Results

We included 258 childhood cancer survivors of African ancestry (AA) (median time from diagnosis=25.2 years, interquartile range [IQR]=19.9-32.1 years) and 1,618 survivors of European ancestry (EA) (median time from diagnosis=27.3, IQR=21.1-33.7 years). Through epigenome-wide association studies, we identified 130 SDOH-CpG associations including educational attainment (N=88), personal income (N=23), and ADI (N=19) at epigenome-wide significance level (P<9×10−8). There were 13 CpGs, commonly associated with all three SDOH factors, with attenuated remaining effect sizes (36.8-48.3%) after additionally adjusting body mass index and smoking, mapped to smoking-related genes including GPR55, CLDND1, CPOX, GPR15, AHRR, PRRC2B, and ELMSAN1. Among 130 SDOH-related CpGs, three independent CpGs (cg04180924, cg1120500, and cg27470486) had a significant combined mediation effect for educational attainment (%mediation=48.9%), and a single mediator cg08064403 was found with significant mediation effect for personal income (25.9%) and ADI (24.1%) on pulmonary diffusion deficit, which showed higher incidence in AA than in EA survivors implying racial disparity which is possibly due to more disadvantageous SDOH factors in AA than in EA.

Conclusions

We demonstrated striking DNAm signatures associated with multiple SDOH factors (educational attainment, personal income, and ADI) and many epigenome-wide significant CpG sites resembling the effect of smoking exposure. We also identified an exemplified racial health disparity in pulmonary diffusion deficit between AA and EA survivors and illuminated DNAm as potential mechanistic mediators for SDOH factors using a social epigenomic approach.
ROLE OF LUNG ULTRASOUND FOR THE ETIOLOGICAL DIAGNOSIS OF COMMUNITY- ACQUIRED PNEUMONIA IN CHILDREN: A PROSPECTIVE STUDY
Authors: Buonsenso Danilo , Musolino Annamaria , Ferro Valentina , De Rose Cristina , Morello Rosa , Ventola Chiara , Liotti Flora Marzia , Chiaretti Antonio , Biasucci Daniele Guerino , Spanu Teresa , Sanguinetti Maurizio , Valentini Piero
Published: November 2020

Objective and design

Our prospective study is one of the largest prospective study assessing the role of detailed lung ultrasound features to discriminate the etiological diagnosis of Community acquired pneumonia (CAP) in children.

Methodology

We prospectively analysed patients aged from 1 month to 17 years admitted between March 2018 and April 2020 who were hospitalized for CAP. For all patients included in the study, history, clinical parameters, microbiological data, and lung ultrasound data were collected.

Patients were stratified into three main groups (“bacterial”, “viral”, “atypical”) according to the presumed microbial aetiology and lung ultrasound findings evaluated according to the aetiological group.

Results

We found that some ultrasound findings as size, number and distribution of consolidations, the position and motion of air bronchograms, pleural effusions and distribution of vertical artifacts significantly differ (p < 0.05) in children with bacterial, viral and atypical CAP. Conversely, clinical parameters and laboratory were not able to significantly distinguish between these groups. Chest x-ray, despite being still widely used, was the less useful tool in this discrimination.

Conclusion

Our study provides a detailed analysis of LUS features able to predict the etiology CAP in children. These findings may help the physicians to better manage a child with CAP and to offer personalized approach, from diagnosis to treatment and follow-up.
Size matters: large copy number losses reveal novel Hirschsprung disease genes
Authors: Kuil Laura , MacKenzie Katherine C. , Tang Clara S , Windster Jonathan D. , Le Thuy Linh , Karim Anwarul , de Graaf Bianca M. , van der Helm Robert , van Bever Yolande , Sloots Cornelius E.J. , Meeussen Conny , Tibboel Dick , de Klein Annelies , Wijnen René M. H. , Amiel Jeanne , Lyonnet Stanislas , Garcia-Barcelo Maria-Mercè , Tam Paul K.H. , Alves Maria M. , Brooks Alice , Hofstra Robert M.W. , Brosens Erwin
Published: November 2020

Background

Hirschsprung disease (HSCR) is characterized by absence of ganglia in the intestine. Approximately 18% of patients have additional anatomical malformations or neurological symptoms (HSCR-AAM). HSCR is a complex genetic disease in which the loss of enteric ganglia stems from a combination of genetic alterations: rare coding variants, predisposing haplotypes and Copy Number Variation (CNV). Pinpointing the responsible culprits within a large CNV is challenging as often many genes are affected. We investigated if we could find deleterious CNVs and if we could identify the genes responsible for the aganglionosis.

Results

Deleterious CNVs were detected in three groups of patients: HSCR-AAM, HSCR patients with a confirmed causal genetic variant and HSCR-isolated patients without a known causal variant and controls. Predisposing haplotypes were determined, confirming that every HSCR subgroup had increased contributions of predisposing haplotypes, but their contribution was highest in isolated HSCR patients withoutRETcoding variants. CNV profiling proved that HSCR-AAM patients had larger copy number losses. Gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics were used to determine plausible candidate genes in Copy Number Losses. Validation in zebrafish using CRISPR/Cas9 targeting confirmed the contribution ofUFD1L, TBX2, SLC8A1andMAPK8to ENS development. In addition, we revealed epistasis between reduced Ret and Gnl1 expressionin vivo.

Conclusion

Rare large Copy Number losses - oftende novo- contribute to the disease in HSCR-AAM patients specifically. We proved the involvement of five genes in enteric nervous system development and Hirschsprung disease.
SARS-CoV-2 Testing Disparities in Massachusetts
Authors: Dryden-Peterson Scott , Velásquez Gustavo E. , Stopka Thomas J. , Davey Sonya , Lockman Shahin , Ojikutu Bisola
Published: November 2020

Objective

Early deficiencies in testing capacity contributed to poor control of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the context of marked improvement in SARS-CoV-2 testing infrastructure, we sought to examine the alignment of testing with epidemic intensity to mitigate subsequent waves of COVID-19 in Massachusetts.

Methods

We compiled publicly available weekly SARS-CoV-2 molecular testing data for period (May 27 to October 14, 2020) following the initial COVID-19 wave. We defined testing intensity as weekly SARS-CoV-2 tests performed per 100,000 population and used weekly test positivity (percent of tests positive) as a measure of epidemic intensity. We considered optimal alignment of testing resources to be matching community ranks of testing and positivity. In communities with a lower rank of testing than positivity in a given week, the testing gap was calculated as the additional tests required to achieve matching ranks. Multivariable Poisson modeling was utilized to assess for trends and association with community characteristics.

Results

During the observation period, 4,262,000 tests were reported in Massachusetts and the misalignment of testing with epidemic intensity increased. The weekly testing gap increased 9.0% per week (adjusted rate ratio [aRR]: 1.090, 95% confidence interval [CI]: 1.08-1.10). Increasing levels of community socioeconomic vulnerability (aRR: 1.35 per quartile increase, 95% CI: 1.23-1.50) and the highest quartile of minority and language vulnerability (aRR: 1.46, 95% CI 0.96-1.49) were associated with increased testing gaps, but the latter association was not statistically significant. Presence of large university student population (>10% of population) was associated with a marked decrease in testing gap (aRR 0.21, 95% CI: 0.12-0.38).

Conclusion

These analyses indicate that despite objectives to promote equity and enhance epidemic control in vulnerable communities, testing resources across Massachusetts have been disproportionally allocated to more affluent communities. Worsening structural inequities in access to SARS-CoV-2 testing increase the risk for another intense wave of COVID-19 in Massachusetts, particularly among vulnerable communities.
Altered Resting State Brain Networks and Cognition in Familial Adenomatous Polyposis
Authors: Cali Ryan J. , Nephew Benjamin C. , Moore Constance M. , Chumachenko Serhiy , Sala Ana Cecilia , Cintron Beatriz , Luciano Carlos , King Jean A. , Hooper Stephen R. , Giardiello Francis M. , Cruz-Correa Marcia
Published: November 2020

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.
Client-perpetrated gender-based violence among female sex workers in post-conflict Gulu district, Northern Uganda: a cross-sectional study
Authors: Ouma Simple , Ndejjo Rawlance , Abbo Catherine , Tumwesigye Nazarius Mbona
Published: November 2020

Background: Gender-based violence (GBV) among female sex workers (FSWs) negatively affects their mental wellbeing and sexual and reproductive health and rights. This study aimed to determine the prevalence and associated factors of client-perpetrated GBV among FSWs in post-conflict Gulu district, Northern Uganda.

Methods: A cross-sectional study was conducted among 300 FSWs aged 18+ years who were operating in Gulu district. Participants were selected using simple random sampling and interviewed between March and June 2020. Pre-tested semi-structured questionnaires were utilized to collect information on socio-demographic and sex-work-related characteristics, alcohol and illicit drug use, HIV status, and exposure to client-perpetrated GBV. Data were entered into EPI INFO 7 and analyzed using logistic regression with the aid of STATA 14.0.

Results: Sixty one percent (61.0%) of the participants reported client-perpetrated GBV. The most common forms of GBV in this population were economic (58.7%) and emotional (52.0%) violence. Meanwhile, sexual violence (21.0%) was the least common form of GBV among the study participants. At multivariate level; street-based sex work (aOR=9.66, 95%CI: 2.78-33.5), mobile sex work (aOR=3.21, 95%CI: 1.83-5.64), HIV-positive status (aOR=1.90, 95%CI: 1.09-3.31), and low monthly income below 50th percentile {<200,000 UGX}(aOR= 2.26, 95% CI: 1.18-4.30) remained independently associated with client-perpetrated GBV.

Conclusion: Our findings revealed a high prevalence of client-perpetrated GBV driven by street-based sex work, sex work-related mobility, HIV-positive status, and low income. Therefore, interventions to address client-perpetrated GBV should target FSWs who are street-based, HIV-positive, mobile, and with low income.
The duration, dynamics and determinants of SARS-CoV-2 antibody responses in individual healthcare workers
Authors: Lumley Sheila F , Wei Jia , O’Donnell Denise , Stoesser Nicole E , Matthews Philippa C , Howarth Alison , Hatch Stephanie B , Marsden Brian D , Cox Stuart , James Tim , Peck Liam , Ritter Thomas , de Toledo Zoe , Cornall Richard J , Jones E Yvonne , Stuart David I , Screaton Gavin , Ebner Daniel , Hoosdally Sarah , Crook Derrick W ,   Oxford University Hospitals Staff Testing Group, Conlon Christopher P , Pouwels Koen B , Walker A Sarah , Peto Tim EA , Walker Timothy M , Jeffery Katie , Eyre David W
Published: November 2020

Background

SARS-CoV-2 IgG antibody measurements can be used to estimate the proportion of a population exposed or infected and may be informative about the risk of future infection. Previous estimates of the duration of antibody responses vary.

Methods

We present 6 months of data from a longitudinal seroprevalence study of 3217 UK healthcare workers (HCWs). Serial measurements of IgG antibodies to SARS-CoV-2 nucleocapsid were obtained. Bayesian mixed linear models were used to investigate antibody waning and associations with age, gender, ethnicity, previous symptoms and PCR results.

Results

In this cohort of working age HCWs, antibody levels rose to a peak at 24 (95% credibility interval, CrI 19-31) days post-first positive PCR test, before beginning to fall. Considering 452 IgG seropositive HCWs over a median of 121 days (maximum 171 days) from their maximum positive IgG titre, the mean estimated antibody half-life was 85 (95%CrI, 81-90) days. The estimated mean time to loss of a positive antibody result was 137 (95%CrI 127-148) days. We observed variation between individuals; higher maximum observed IgG titres were associated with longer estimated antibody half-lives. Increasing age, Asian ethnicity and prior self-reported symptoms were independently associated with higher maximum antibody levels, and increasing age and a positive PCR test undertaken for symptoms with longer antibody half-lives.

Conclusion

IgG antibody levels to SARS-CoV-2 nucleocapsid wane within months, and faster in younger adults and those without symptoms. Ongoing longitudinal studies are required to track the long-term duration of antibody levels and their association with immunity to SARS-CoV-2 reinfection.

Serially measured SARS-CoV-2 anti-nucleocapsid IgG titres from 452 seropositive healthcare workers demonstrate levels fall by half in 85 days. From a peak result, detectable antibodies last a mean 137 days. Levels fall faster in younger adults and following asymptomatic infection.
Racial disparities in the prevalence of vaccine and non-vaccine HPV types and multiple HPV infection between Asia and Africa: A systematic review
Authors: Okoye Jude Ogechukwu , Okekpa Simon Imakwu , Chukwukelu Chiemeka Franklin , Onyekachi-Umeh Ifeoma Nora , Ngokere Anthony Ajuluchukwu
Published: November 2020

Background

Cervical Cancer is the 6th most common and 3rd most deadly cancer among women. Despite the fact that majority of the countries in Asia and Africa have similar economy and low life expectancy, the mean age standardized incidence rate (ASIR) of cervical cancer is substantially higher in Africa than Asia. Thus, this study aimed to identify the correlates of the higher ASIR rates in Africa relative to Asia.

Methods

Peer-reviewed articles published between 2004 and 2017 were selected using the PRISMA standard. Sources of articles include Google Scholar, Scopus, PubMed Central, and EMBASE. Search keywords included: HPV genotypes, cervical cancer, HPV vaccine, and multiple infection in Africa and Asia.

Result

A total of 29 and 17 full-length articles were selected from Africa and Asia respectively. Based on estimates in the general population, the incidence of high-risk HPV (hrHPV) types in Africa and Asia was 3.5 and 1.0 respectively. The prevalence of HPV infection was higher in Africa than in Asia (p< 0.001). The prevalence of HPV infection between 2004-2009 and 2010-2017 decreased in Africa but increased in Asia. More so, the prevalence of multiple HPV and non-vaccine HPV infection were higher in Africa than Asia (p< 0.001). The prevalent HPV types in Africa were HPV16, HPV18, and HPV52, while that of Asia were HPV16, HPV52, and HPV58, in descending order of prevalence. This study revealed that nonavalent HPV vaccine could prevent the development of 69.3% and 83.2% of HPV associated cervical abnormalities in Africa and Asia, respectively.

Conclusion

This study revealed higher prevalence of HPV infection and multiple HPV infection in Africa compared with Asia, which could be responsible for the higher ASIR in Africa. It suggests that nonavalent vaccination including cervical screening using Pap smear could prevent over 90% of the cervical abnormalities in Africa.
Immunopeptidomics for Dummies: Detailed Experimental Protocols and Rapid, User-Friendly Visualization of MHC I and II Ligand Datasets with MhcVizPipe
Authors: Kovalchik Kevin A. , Wessling Laura , Saab Frederic , Ma Qing , Despault Jérôme , Kubiniok Peter , Hamelin David , Faridi Pouya , Li Chen , Purcell Anthony , Tognetti Marco , Reiter Lukas , Bruderer Roland , Lanoix Joël , Bonneil Éric , Courcelles Mathieu , Thibault Pierre , Caron Etienne , Sirois Isabelle
Published: November 2020

Immunopeptidomics refers to the science of investigating the composition and dynamics of peptides presented by major histocompatibility complex (MHC) class I and class II molecules using mass spectrometry (MS). Here, we aim to provide a technical report to any non-expert in the field wishing to establish and/or optimize an immunopeptidomic workflow with relatively limited computational knowledge and resources. To this end, we thoroughly describe step-by-step instructions to isolate MHC class I and II-associated peptides from various biological sources, including mouse and human biospecimens. Most notably, we created MhcVizPipe (MVP) (https://github.com/CaronLab/MhcVizPipe), a new and easy-to-use open-source software tool to rapidly assess the quality and the specific enrichment of immunopeptidomic datasets upon the establishment of new workflows. In fact, MVP enables intuitive visualization of multiple immunopeptidomic datasets upon testing sample preparation protocols and new antibodies for the isolation of MHC class I and II peptides. In addition, MVP enables the identification of unexpected binding motifs and facilitates the analysis of non-canonical MHC peptides. We anticipate that the experimental and bioinformatic resources provided herein will represent a great starting point for any non-expert and will therefore foster the accessibility and expansion of the field to ultimately boost its maturity and impact.
Reaction-Diffusion Model of Cortical Atrophy Spread during Early Stages of Alzheimer’s Disease
Authors: Kulason Sue , Miller Michael I , Trouvé Alain ,   Alzheimer’s Disease Neuroimaging Initiative
Published: November 2020

1.

This study introduces a reaction-diffusion model of atrophy spread across the rhinal cortex during early stages of Alzheimer’s disease. Our finite elements model of atrophy spread is motivated by histological evidence of a spatio-temporally specific pattern of neurofibrillary tau accumulation, and evidence of grey matter atrophy correlating with sites of neurofibrillary tau accumulation. The goal is to estimate disease-related parameters such as the origin of atrophy, the speed at which atrophy spreads, and the stage of the disease. We solve a constrained optimization problem using the adjoint state method and gradient descent to match modeled cortical thickness to observed cortical thickness as calculated from 3T MRI scans. Simulation testing shows that disease-related parameters can be estimated accurately with as little as 2 years of annual observations, depending on the stage of the disease. Case studies of 3 subjects suggests that we can pinpoint the origin of atrophy to the anterior transentorhinal cortex, and that the speed of atrophy spread is less than 1 mm per year. In the future, this type of modeling could be useful to stage the progression of the disease prior to the onset of clinical symptoms.

2.

Author Summary

Misfolded tau proteins are associated with Alzheimer’s disease. They are known to accumulate and spread across the rhinal cortex, which is an area of the temporal lobe. Recent imaging studies suggest that we can detect grey matter thinning that occurs in pattern similar to tau spread. In this study, we introduce a model of disease spread to examine where thinning begins, how fast it spreads, and the stage of the disease. The results show that the origin of thinning corresponds with the earliest known location of tau accumulation, and spreads at a rate of less than 1 mm per year. Future work may focus on staging the progression of the disease using this type of model.
Potential Opportunity of Antisense Therapy of COVID-19 on an in Vitro Model
Authors: Goryachev A.N. , Kalantarov S.A. , Severova A.G. , Goryacheva A.S.
Published: November 2020

Data on potential effectiveness and prospects of treatment of new coronavirus infection of COVID-19 caused by virus SARS-CoV-2 with the help of antisense oligonucleotides acting against RNA of virus on an in vitro model are given. The ability of antisense oligonucleotides to suppress viral replication in diseases caused by coronaviruses using the example of SARS and MERS is shown. The identity of the initial regulatory section of RNA of various coronaviruses was found within 50 - 100 nucleotides from the 5’-end, which allows using antisense suppression of this RNA fragment. A new RNA fragment of the virus present in all samples of coronovirus SARS-CoV-2 has been identified, the suppression of which with the help of an antisense oligonucleotide can be effective in the treatment of COVID-19. The study of the synthesized antisense oligonucleotide 5’ - AGCCGAGTGACAGCC ACACAG, complementary to the selected virus RNA sequence, was carried out. The low toxicity of the preparations of this group in the cell culture study and the ability to reduce viral load at high doses according to real time-PCR data are shown. The cytopathogenic dose exceeds 2 mg / ml. At a dosage of 1 mg / ml, viral replication is reduced by 5-13 times. Conclusions are made about the prospects of this direction and the feasibility of using the inhalation way of drug administration into the body.
Metabolomics shows the Australian dingo has a unique plasma profile
Authors: Yadav Sonu , Pickford Russell , Zammit Robert A. , Ballard J. William O.
Published: November 2020

Dingoes have not been artificially selected in the past 3,500 years. They occupy a wide range of the Australian mainland and play a crucial role as an apex predator with a generalist omnivorous feeding behaviour. In contrast, humans have selected breed dogs for novel and desirable traits. First, we explore whether the distinct evolutionary histories of dingoes and domestic dogs can lead to plasma metabolomic differences. We study metabolite composition differences between dingoes (n=15) and two domestic dog breeds (Basenji n= 9 and German Shepherd Dog: GSD n=10). After accounting for within group variation, 62 significant metabolite differences were detected between dingoes and domestic dogs, with a greater number of differences in protein (n= 14) and lipid metabolites (n= 12). Most differences were observed between dingoes and domestic dogs and fewest between the domestic dog breeds. Second, we investigate variation between pure dingoes (n=10) and dingo-dog hybrids (n=10) as hybridisation is common. We detected no significant differences in metabolite levels between dingoes and dingo-dog hybrids after Bonferroni correction. However, power analyses reported that increasing the sample size to 15 could result in differences in uridine 5’-diphosphogalactose (UDPgal) levels related to galactose metabolism. We suggest this may be related to an increase inAmylase 2Bcopy number in hybrids. Our study illustrates that the dingo metabolome is significantly different from domestic dog breeds and hybridisation is likely to influence carbohydrate metabolism.
Descending and ascending signals that maintain rhythmic walking pattern in the cricket
Authors: Naniwa Keisuke , Aonuma Hitoshi
Published: November 2020

The cricket is one of the model animals used to investigate the neuronal mechanisms underlying adaptive locomotion. An intact cricket walks with a tripod gait, similar to other insects. The motor control center of the leg movements is located in the thoracic ganglia. In this study, we investigated the walking gait patterns of crickets whose ventral nerve cords were surgically cut to gain an understanding of how the descending signals from the head ganglia and ascending signals from the abdominal nervous system into the thoracic ganglia mediate the initiation and coordination of the walking gait pattern. Crickets whose paired connectives between the brain and subesophageal ganglion (SEG) were cut exhibited a tripod gait pattern. However, when one side of the connectives between the brain and SEG was cut, the crickets continued to turn in the opposite direction to the connective cut. Crickets whose paired connectives between the SEG and prothoracic ganglion were cut did not walk, whereas the crickets exhibited an ordinal tripod gait pattern when one side of the connectives was intact. Crickets whose paired connectives between the metathoracic ganglion and abdominal ganglia were cut initiated walking, although the gait was not a coordinated tripod pattern, whereas the crickets exhibited a tripod gait when one side of the connectives was intact. These results suggest that the brain plays an inhibitory role in initiating leg movements, and that both the descending signals from the head ganglia and the ascending signals from the abdominal nervous system are both important in initiating and coordinating insect walking gait patterns.
A global indicator of utilised wildlife populations: regional trends and the impact of management
Authors: McRae Louise , Freeman Robin , Geldmann Jonas , Moss Grace B. , Kjær-Hansen Louise , Burgess Neil D.
Published: November 2020

The sustainable use of wildlife is a core aspiration of biodiversity conservation but is the subject of intense debate in the scientific literature as to how, and whether, species are best used and managed. While both positive and negative outcomes of sustainable use are known for specific taxa or local case studies, a global and regional picture of trends in wildlife populations in use is lacking. We use a global data set of over 11,000 time-series to derive indices of ‘utilised’ and ‘not utilised’ wildlife populations and assess global and regional changes, principally for mammals, birds and fishes. We also assess whether ‘management’ makes a measurable difference to wildlife population trends, especially for the utilised species populations. Our results show that wildlife population trends globally are negative, but with utilised populations tending to decline more rapidly, especially in Africa and the Americas. Crucially, where utilised populations are managed, using a variety of mechanisms, there is a positive impact on the trend. It is therefore true that use of species can both be a driver of negative population trends, or a driver of species recovery, with numerous species and population specific case examples making up these broader trends. This work is relevant to the evidence base for the IPBES Sustainable Use Assessment, and to the development of indicators of sustainable use of species under the post-2020 Global Biodiversity Framework being developed under the Convention on Biological Diversity.
Computational prediction of SARS-CoV-2 encoded miRNAs and their putative host targets
Authors: Verma Sonia , Dwivedy Abhisek , Kumar Neeraj , Biswal Bichitra K.
Published: November 2020

Over the past two decades, there has been a continued research on the role of small non-coding RNAs including microRNAs (miRNAs) in various diseases. Studies have shown that viruses modulate the host cellular machinery and hijack its metabolic and immune signalling pathways by miRNA mediated gene silencing. Given the immensity of coronavirus disease 19 (COVID-19) pandemic and the strong association of viral encoded miRNAs with their pathogenesis, it is important to study Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) miRNAs. To address this unexplored area, we identified 8 putative novel miRNAs from SARS-CoV-2 genome and explored their possible human gene targets. A significant proportion of these targets populated key immune and metabolic pathways such as MAPK signalling pathway, maturity-onset diabetes, Insulin signalling pathway, endocytosis, RNA transport, TGF-β signalling pathway, to name a few. The data from this work is backed up by recently reported high-throughput transcriptomics datasets obtains from SARS-CoV-2 infected samples. Analysis of these datasets reveal that a significant proportion of the target human genes were down-regulated upon SARS-CoV-2 infection. The current study brings to light probable host metabolic and immune pathways susceptible to viral miRNA mediated silencing in a SARS-CoV-2 infection, and discusses its effects on the host pathophysiology.
Rice rhizospheric microbes confer limited Arsenic protection under high Arsenic conditions
Authors: Gundlah-Mooney Victoria , Bais Harsh P.
Published: November 2020

Rice (Oryza sativa) is a staple food crop worldwide and plays a critical role in ensuring food security as the global population continues to expand exponentially. Groundwater contamination with Arsenite [As(III)], a naturally occurring inorganic form of arsenic (As), leads to uptake and accumulation within rice plants. As a result, grain yield is lowered, the overall plant health is diminished, and there is a risk of arsenic toxicity from grain consumption. It was previously shown that a novel bacterial strain from the rice rhizosphere may reduce As accumulation in rice plants exposed to low levels of environmental As. We hypothesized that different rice varieties may exhibit varying responses to high As levels, resulting in differences in As uptake and toxicity. Utilizing the natural rice rhizospheric microbes, we initiated a set of hydroponic experiments with two rice varieties, Nipponbare (As tolerant) and IR66 (As susceptible). Rice varieties exposed to high As(III) concentration (50 μM) showed changes in both aboveground and belowground traits. As-tolerant Nipponbare varieties show grain production at high As(III) concentrations compared to the As-susceptible IR66 variety. Supplementation of natural rice rhizospheric microbes as single inoculums showed varied responses in both As-tolerant and As-susceptible varieties. Three natural rice rhizospheric microbesPantoeasps (EA106),Pseudomonas corrugata(EA104), andArthrobacter oxydans(EA201) were selected based on previously reported high Iron (Fe)-siderophore activity and were used for the hydroponic experiments as well as a non-rice rhizospheric strain,Bacillus subtilisUD1022. Interestingly, treatment with two strains (EA104 and EA201) led to reduction in As(III) uptake in shoots, roots, and grains and the degree of reduction of As(III) was pronounced in As-susceptible IR66 varieties. Non-rice rhizospheric UD1022 showed subtle protection against high As toxicity. High As(III) treatment led to lack or delay of flowering and seed setting in the As-susceptible IR66 variety. The data presented here may further the understanding of how beneficial microbes in the rhizosphere may help rice plants cope with high concentrations of As in the soil or groundwater.
Alcohol dependence activates ventral tegmental area projections to central amygdala in male mice and rats
Authors: Avegno Elizabeth M , Kasten Chelsea R , Snyder William B , Kelley Leslie K , Lobell Thomas D , Templeton Taylor J , Constans Michael , Wills Tiffany A , Middleton Jason W , Gilpin Nicholas W
Published: November 2020

The neural adaptations that occur during the transition to alcohol dependence are not entirely understood, but may include a gradual recruitment of brain stress circuitry by mesolimbic reward circuitry that is activated during early stages of alcohol use. Here, we focused on dopaminergic and non-dopaminergic projections from the ventral tegmental area (VTA), important for mediating acute alcohol reinforcement, to the central nucleus of the amygdala (CeA), important for alcohol dependence-related negative affect and escalated alcohol drinking. The VTA projects directly to the CeA, but the functional relevance of this circuit is not fully established. Therefore, we combined retrograde and anterograde tracing, anatomical, and electrophysiological experiments in mice and rats to demonstrate that the CeA receives input from both dopaminergic and non-dopaminergic projection neurons primarily from the lateral VTA. We then used slice electrophysiology and fos immunohistochemistry to test the effects of alcohol dependence on activity and activation profiles of CeA-projecting neurons in the VTA. Our data indicate that alcohol dependence activates midbrain projections to the central amygdala, suggesting that VTA projections may trigger plasticity in the CeA during the transition to alcohol dependence and that this circuit may be involved in mediating behavioral dysregulation associated with alcohol dependence.
Assessing uncertainty in connective field estimations from resting state fMRI activity
Authors: Invernizzi Azzurra , Gravel Nicolas , Haak Koen V. , Renken Remco J. , Cornelissen Frans W.
Published: November 2020

Connective Field (CF) modeling estimates the local spatial integration between signals in distinct cortical visual field areas. As we have shown previously using 7T data, CF can reveal the visuotopic organization of visual cortical areas even when applied to BOLD activity recorded in the absence of external stimulation. This indicates that CF modeling can be used to evaluate cortical processing in participants in which the visual input may be compromised. Furthermore, by using Bayesian CF modelling it is possible to estimate the co-variability of the parameter estimates and therefore, apply CF modeling to single cases. However, no previous studies evaluated the (Bayesian) CF model using 3T resting-state fMRI data, although this is important since 3T scanners are much more abundant and more often used in clinical research than 7T ones. In this study, we investigate whether it is possible to obtain meaningful CF estimates from 3T resting state (RS) fMRI data. To do so, we applied the standard and Bayesian CF modeling approaches on two RS scans interleaved by the acquisition of visual stimulation in 12 healthy participants.

Our results show that both approaches reveal good agreement between RS- and visual field (VF)-based maps. Moreover, the 3T observations were similar to those previously reported at 7T. In addition, to quantify the uncertainty associated with each estimate in both RS and VF data, we applied our Bayesian CF framework to provide the underlying marginal distribution of the CF parameters. Finally, we show how an additional CF parameter,beta, can be used as a data-driven threshold on the RS data to further improve CF estimates. We conclude that Bayesian CF modeling can characterize local functional connectivity between visual cortical areas from RS data at 3T. In particular, we expect the ability to assess parameter uncertainty in individual participants will be important for future clinical studies.

Highlights

Local functional connectivity between visual cortical areas can be estimated from RS-fMRI data at 3T using both standard CF and Bayesian CF modelling.

Bayesian CF modelling quantifies the model uncertainty associated with each CF parameter on RS and VF data, important in particular for future studies on clinical populations.

3T observations were qualitatively similar to those previously reported at 7T.
The Hsc70 Disaggregation Machinery Removes Monomer Units Directly from α-Synuclein Fibril Ends
Authors: Schneider Matthias M. , Gautam Saurabh , Herling Therese W. , Andrzejewska Ewa , Krainer Georg , Miller Alyssa M. , Peter Quentin A. E. , Ruggeri Francesco Simone , Vendruscolo Michele , Bracher Andreas , Dobson Christopher M. , Hartl F. Ulrich , Knowles Tuomas P. J.
Published: November 2020

Molecular chaperones contribute to the maintenance of cellular protein homeostasis through a wide range of mechanisms, including the assistance ofde novoprotein folding, the rescue of misfolded proteins, and the prevention of amyloid formation. Chaperones of the Hsp70 family have a striking capability of disaggregating otherwise irreversible aggregate structures such as amyloid fibrils that accumulate during the development of neurodegenerative diseases. However, the mechanisms of this key emerging functionality remain largely unknown. Here, we bring together microfluidic measurements with kinetic analysis and show that that the Hsp70 protein heat chock complement Hsc70 together with its two co-chaperones DnaJB1 and the nucleotide exchange factor Apg2 is able to completely reverse the aggregation process of alpha-synuclein, associated with Parkinson’s disease, back to its soluble monomeric state. Moreover, we show that this reaction proceeds with first order kinetics in a process where monomer units are taken off directly from the fibril ends. Our results demonstrate that all components of the chaperone triad are essential for fibril disaggregation. Lastly, we quantify the interactions between the three chaperones as well as between the chaperones and the fibrils in solution, yielding both binding stoichiometries and dissociation constants. Crucially, we find that the stoichiometry of Hsc70 binding to fibrils suggests Hsc70 clustering at the fibril ends. Taken together, our results show that the mechanism of action of the Hsc70–DnaJB1–Apg2 chaperone system in disaggregating α-synuclein fibrils involves the removal of monomer units without any intermediate fragmentation steps. These findings are fundamental to our understanding of the suppression of amyloid proliferation early in life and the natural clearance mechanisms of fibrillar deposits in Parkinson’s disease, and inform on the possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies and related neurodegenerative diseases.
Zinc-embedded fabrics inactivate SARS-CoV-2 and influenza A virus
Authors: Gopal Vikram , Nilsson-Payant Benjamin E. , French Hollie , Siegers Jurre Y. , Yung Wai-shing , Hardwick Matthew , te Velthuis Aartjan J.W.
Published: November 2020

Infections with respiratory viruses can spread via liquid droplets and aerosols, and cause diseases such as influenza and COVID-19. Face masks and other personal protective equipment (PPE) can act as barriers that prevent the spread of respiratory droplets containing these viruses. However, influenza A viruses and coronaviruses are stable for hours on various materials, which makes frequent and correct disposal of these PPE important. Metal ions embedded into PPE may inactivate respiratory viruses, but confounding factors such as absorption of viruses make measuring and optimizing the inactivation characteristics difficult. Here we used polyamide 6.6 (PA66) fibers that had zinc ions embedded during the polymerisation process and systematically investigated if these fibers can absorb and inactivate pandemic SARS-CoV-2 and influenza A virus H1N1. We find that these viruses are readily absorbed by PA66 fabrics and inactivated by zinc ions embedded into this fabric. The inactivation rate (pfu·gram−1·min−1) exceeds the number of active virus particles expelled by a cough and supports a wide range of viral loads. Moreover, we found that the zinc content and the virus inactivating property of the fabric remain stable over 50 standardized washes. Overall, these results provide new insight into the development of “pathogen-free” PPE and better protection against RNA virus spread.
Elemental Mapping of Labeled Biological Specimens at Intermediate Energy Loss in an Energy-Filtered TEM acquired using a Direct Detection Device
Authors: Ramachandra Ranjan , Mackey Mason R. , Hu Junru , Peltier Steven T. , Xuong Nguyen-Huu , Ellisman Mark H. , Adams Stephen R.
Published: November 2020

The multi-color or single-color EM that was developed previously, by the pseudo-colored overlay of the core-loss or high-loss EFTEM elemental map/s of the lanthanide onto the conventional image, the lanthanide chelates conjugated to diaminobenzidine being sequentially deposited as a result of selective oxidization by orthogonal photosensitizers / peroxidases. The synthesis of the new second generation lanthanide DABs, which contains 4 times more lanthanide per DAB, gives significant signal amplification and enabling collection of elemental maps at much lower energy-loss regions more favorable. Under the same experimental conditions, acquiring EFTEM elemental maps for the lanthanides at the lower energy-loss of N4,5edge instead of the core-loss M4,5edge, provides ~4x increase in signal-to-noise and ~2x increase in resolution. The higher signal at the N4,5edge, also allows for more sophisticated technique of EFTEM spectrum Image for the acquisition of elemental maps with very high signal fidelity.