bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceived stress by students of the medical sciences in Cuba toward the COVID-19 pandemic: results of an online survey
Authors: Hernández-García Frank , Gómez Onelis Góngora , González-Velázquez Victor Ernesto , Pedraza-Rodríguez Elys María , Zamora-Fung Rolando , Lazo Herrera Luis Alberto
Published: October 2021

Introduction

The aims of this study were to determine the usefulness of the Modified (10-items) Scale of Perceived Stress related to COVID-19 (EEP-10-C by its acronym in Spanish) and to identify the levels of stress perceived by students of the medical sciences in Cuba toward the COVID-19 pandemic.

Methods

A cross-sectional study was conducted, with self-reported data of students from fourteen Cuban Universities of Medical Sciences (n = 200), through an online survey. The EEP-10-C was used as an instrument to identify stress. Its validity was determined through a confirmatory factor analysis and its internal consistency and reliability was measured by the Cronbach’ alph. A cluster analysis was performed to establish as cut-off point the center of the cluster with the highest values of stress perceived by the scale.

Results

The average age of the sample was 23.30 ± 1.91 years, with observed scores of the EEP-10-C between 0 and 29 points (13.25 ± 5,404). When applying the cut-off point ≥25, only two students had high rates of stress perceived. The confirmatory factor analysis supported the validity of the instrument; with a Cronbach’s alpha of 0.755. The cutoff point ≥20 was proposed as a reference of high stress perceived for the study population, when applying this one, 14% of students presented high rates of stress.

Discussion

In Cuba, students of the medical sciences have participated in research and supporting health care, despite which they have presented low levels of stress. The main contribution of the research was the validation of the EEP-10-C for its use in assessing levels of stress in Cuban medical students, proposing the cut-off point ≥20 as a reference of high stress perceived.
Structural Variants Are a Major Component of the Missing Heritability of Autism Spectrum Disorder
Authors: Kainer David , Templeton Alan , Prates Erica T. , Allan Euan , Climer Sharlee , Jacobson Daniel A. , Garvin Michael R.
Published: October 2021

The heritability of autism spectrum disorder (ASD), based on 680,000 families and five countries, is estimated to be nearly 80%, yet we lack genetic markers that adequately explain it. It is increasingly clear that genomic structural variants (SVs) are a major component of the “missing heritability” for many complex phenotypes. Here we use a novel method to identify SVs based on non-Mendelian inheritance patterns in pedigrees using parent-child genotypes from ASD families and demonstrate that the genes that the ASD-specific SVs overlap recapitulate the known molecular biology of ASD including dendritic spinogenesis, axon guidance, and chromatin modification. We further define fine-grained biological pathways that strongly implicate aberrant early development of the cerebellum. Importantly, using these previously excluded variants, we identify theACMSDgene in the kynurenine pathway as significantly associated with non-verbal cases of ASD and we then use an explainable artificial intelligence approach to define subgroups for future diagnosis and deployment of personalized medicine.
Genome Recombination between Delta and Alpha Variants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Authors: Sekizuka Tsuyoshi , Itokawa Kentaro , Saito Masumichi , Shimatani Michitsugu , Matsuyama Shutoku , Hasegawa Hideki , Saito Tomoya , Kuroda Makoto ,   COVID-19 Genomic Surveillance Network in Japan (COG-JP)
Published: October 2021

Prominent genomic recombination has been observed between the Delta and Alpha variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolated from clinical specimens in Japan. It is necessary to intensively study such marked genetic variations and characterize the emerging variants after careful verification of their lineage and clade assignment.
Preserved T cell responses to SARS-CoV-2 in anti-CD20 treated multiple sclerosis
Authors: Schwarz Tatjana , Otto Carolin , Jones Terry C. , Pache Florence , Schindler Patrick , Niederschweiberer Moritz , Schmidt Felix A. , Drosten Christian , Corman Victor M. , Ruprecht Klemens
Published: October 2021

Objective

To analyze humoral and cellular immune responses to SARS-CoV-2 vaccinations and infections in anti-CD20 treated patients with multiple sclerosis (pwMS).

Methods

181 pwMS on anti-CD20 therapy and 41 pwMS who began anti-CD20 therapy were included in a prospective, observational, single-center cohort study between March 2020 and August 2021. 51 pwMS under anti-CD20 treatment, 14 anti-CD20 therapy-naïve pwMS and 19 healthy controls (HC) were vaccinated twice against SARS-CoV-2. We measured SARS-CoV-2 spike protein (full-length, S1 domain and receptor binding domain) immunoglobulin (Ig)G and S1 IgA and virus neutralizing capacity and avidity of SARS-CoV-2 antibodies. SARS-CoV-2 specific T cells were determined by interferon-γ release assays.

Results

Following two SARS-CoV-2 vaccinations, levels of IgG and IgA antibodies to SARS-CoV-2 spike protein as well as neutralizing capacity and avidity of SARS-CoV-2 IgG were lower in anti-CD20 treated pwMS than in anti-CD20 therapy-naïve pwMS and in HC (p<0.003 for all pairwise comparisons). However, in all anti-CD20 treated pwMS vaccinated twice (n=26) or infected with SARS-CoV-2 (n=2), in whom SARS-CoV-2 specific T cells could be measured, SARS-CoV-2 specific T cells were detectable, at levels similar to those of twice-vaccinated anti-CD20 therapy-naïve pwMS (n=7) and HC (n=19). SARS-CoV-2 S1 IgG levels (r=0.42, p=0.002), antibody avidity (r=0.7, p<0.001) and neutralizing capacity (r=0.44, p=0.03) increased with time between anti-CD20 infusion and second vaccination. Based on detection of SARS-CoV-2 antibodies, SARS-CoV-2 infections occurred in 4/175 (2.3%) anti-CD20 treated pwMS, all of whom recovered fully.

Interpretation

These findings should inform treatment decisions and SARS-CoV-2 vaccination management in pwMS.
Transmission of SARS-CoV-2 associated with cruise ship travel: protocol for a systematic review (Version 1)
Authors: Rosca Elena C , Heneghan Carl , Spencer Elizabeth A , Brassey Jon , Plüddemann Annette , Onakpoya Igho J , Evans David H , Conly John M , Jefferson Tom
Published: October 2021

Background

Maritime and river travel, including cruise ships, have been implicated with spreading viruses through infected passengers and crew. Given the novelty of the SARS-CoV-2 infection, early cruise ship travel transmission models of spread are based on what is known of the dynamics of other respiratory viral infections. Our objective is to provide a rapid summary and evaluation of relevant data on SARS-CoV-2 transmission aboard cruise ships, report policy implications, and highlight research gaps requiring attention.

Methods

We will search LitCovid, medRxiv, Google Scholar, and the WHO Covid-19 database using COVID-19, SARS-CoV-2, transmission, and cruise ship appropriate synonyms. We will also search the reference lists of included studies for additional relevant studies. We will include studies reporting onboard SARS-CoV-2 transmission from passengers and/or crew to passengers and/or crew. We will consider any potential transmission mode. We will assess study quality based on five criteria and report important findings. The outcome will consist of the onboard cruise ships’ transmission of SARS-CoV-2. We will provide a narrative summary of the data and report the outcomes, including quantitative estimates where feasible and relevant. Where possible, compatible datasets may be pooled for meta-analysis.

Expected results

We will present the evidence in three distinct packages: study description, methodological quality assessment and data extracted. We will summarize the evidence and will draw conclusions as to the quality of the evidence.
Young women’s knowledge and attitudes towards cervical cancer screening at a selected higher education institution in Lesotho
Authors: Nyangu Isabel , Moteane Tanki
Published: October 2021

Background

In Lesotho, cervical cancer is the most common female cancer and leading cause of death amongst women. In 2019, the annual number of new cancer cases was 477 and 346 women died from cancer related complications in Lesotho.

Aim

The aim of this study was to assess the knowledge and attitudes of young women towards cervical cancer screening at a selected higher education institution in Lesotho.

Methods

A quantitative cross-sectional research design was used to collect data using an interviewer administered semi-structured questionnaire from 80 young women who were randomly selected. Permission to conduct the study was sought and granted from relevant authorities. Informed consent was sought from the respondents who were identified using codes and participated voluntarily.

Results

Fifty percent (n=40) of the women did not know cervical cancer screening tests, 70% (n=56) did not know about the frequency of screening, whilst 75% (n=60) knew that human papilloma virus (HPV) vaccine is be used to prevent cervical cancer. Additionally, 95% (n=76) had not screened for cervical cancer, 65% (n=52) perceived cervical cancer screening as painful, and 95% (n=76) needed more information on cervical cancer screening.

Conclusions

The practice of cervical cancer screening is low and there is a high need for health education and incorporating regular cervical cancer screening in health care services to increase the uptake amongst young women. Many participants were hesitant to screen as they perceived the procedure to be painful and this suggests the need for reassurance and counselling on cervical cancer screening techniques.
Urine extracellular vesicles capture kidney transcriptome and hyperglycemia linked mRNA signatures for type 1 diabetic kidney disease
Authors: Dwivedi Om Prakash , Barreiro Karina , Käräjämäki Annemari , Valo Erkka , Prasad Rashmi B , Holthöfer Harry , Groop Per-Henrik , Tuomi Tiinamaija , Forsblom Carol , Groop Leif , Puhka Maija
Published: October 2021

Diabetic kidney disease (DKD) is a severe complication of type 1 diabetes (T1D), which lacks non-invasive early biomarkers. Although less explored, mRNAs in urinary extracellular vesicles (uEV) could reflect changes in the kidney transcriptome during DKD development. We performed genome-wide mRNA sequencing of >100 uEV samples from two T1D cohorts with 24-hour and overnight urine collections. Our uEV pipeline allowed reproducible detection of >10,000 mRNAs bearing overall similarity to kidney transcriptome. uEV from T1D DKD groups showed significant upregulation of 13 genes, prevalently expressed by proximal tubular cells within the kidney. Strikingly, six genes involved in cellular stress responses including protection against oxidative stress (GPX3, NOX4, MSRB, MSRA, HRSP12andCRYAB) correlated with hyperglycemia and long-term changes in kidney function independent of albuminuria status. The study identified genes associated with glycemic stress in T1D DKD and confirmed the utility of uEV in capturing pathological gene expression signatures from kidney.
Molecular phenotypes associated with antipsychotic drugs in the human caudate nucleus
Authors: Perzel Mandell Kira A. , Eagles Nicholas J. , Deep-Soboslay Amy , Tao Ran , Han Shizhong , Wilton Richard , Szalay Alexander S. , Hyde Thomas M. , Kleinman Joel E. , Jaffe Andrew E. , Weinberger Daniel R.
Published: October 2021

Antipsychotic drugs are the current first-line of treatment for schizophrenia and other psychotic conditions. However, their molecular effects on the human brain are poorly studied, due to difficulty of tissue access and confounders associated with disease status. Here we examine differences in gene expression and DNA methylation associated with positive antipsychotic drug toxicology status in the human caudate nucleus. We find no genome-wide significant differences in DNA methylation, but abundant differences in gene expression. These gene expression differences are overall quite similar to gene expression differences between schizophrenia cases and controls. Interestingly, gene expression differences based on antipsychotic toxicology are different between brain regions, potentially due to affected cell type differences. We finally assess similarities with effects in a mouse model, which finds some overlapping effects but many differences as well. As a first look at the molecular effects of antipsychotics in the human brain, the lack of epigenetic effects is unexpected, possibly because long term treatment effects may be relatively stable for extended periods.
Vaccine-induced, high magnitude HIV Env-specific antibodies with Fc-mediated effector functions are insufficient to protect infant rhesus macaques against oral SHIV infection
Authors: Curtis Alan D. , Saha Pooja T. , Dennis Maria , Berendam Stella J. , Alam S. Munir , Ferrari Guido , Kozlowski Pamela A. , Fouda Genevieve , Hudgens Michael , Van Rompay Koen KA , Pollara Justin , Permar Sallie R. , De Paris Kristina
Published: October 2021

Improved access to antiretroviral therapy and antenatal care have significantly reduced in-utero and peri-partum mother-to-child HIV transmission. However, as breastmilk transmission of HIV still occurs at an unacceptable rate there remains a need to develop an effective vaccine for the pediatric population.

Previously, we compared different HIV vaccine strategies, intervals, and adjuvants in infant rhesus macaques to optimize the induction of HIV envelope (Env)-specific antibodies with Fc-mediated effector function. Here, we tested the efficacy of an optimized vaccine regimen against oral SHIV acquisition in infant macaques. One group of 12 animals was immunized with 1086.c gp120 protein adjuvanted with 3M-052 in stable emulsion and Modified Vaccinia Ankara (MVA) virus vector expressing 1086.c HIV Env, while the control group (n=12) was immunized only with empty MVA. The first vaccine dose was given within 10 days of birth and booster doses were administered at weeks 6 and 12.

The vaccine regimen induced Env-specific plasma IgG antibodies capable of antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Beginning at week 15, infants were exposed orally to escalating doses of heterologous SHIV-1157(QNE)Y173H once a week until infected. Despite the induction of strong Fc-mediated antibody responses, the vaccine regimen did not reduce the risk of infection, time to acquisition, or peak viremia compared to controls. Our results suggest that the non-neutralizing Env-specific antibodies with Fc effector function elicited by this vaccine regimen were insufficient for protection against heterologous oral SHIV infection shortly after the final immunization.

IMPORTANCE

Women of childbearing age are three times more likely to contract HIV infection than their male counterparts. Poor HIV testing rates coupled with low adherence to antiretroviral therapy (ART) result in a high risk of mother-to-infant HIV transmission, especially during the breastfeeding period. A preventative vaccine could curb pediatric HIV infections, reduce potential health sequalae, and prevent the need for lifelong ART in this population. The results of the current study imply that the HIV Env-specific IgG antibodies elicited by this candidate vaccine regimen, despite high magnitude of Fc-mediated effector function, but lack of neutralizing antibodies and polyfunctional T cell responses, were insufficient to protect infant rhesus macaques against oral virus acquisition.
Neuroanatomical correlates of working memory performance in Neurofibromatosis 1
Authors: Sawyer Cameron , Green Jonathan , Lim Ben , Pobric Gorana , Jung JeYoung , Vassallo Grace , Evans D. Gareth , Stagg Charlotte J , Parkes Laura M , Stivaros Stavros , Muhlert Nils , Garg Shruti
Published: October 2021

Background

Neurofibromatosis 1 (NF1) is a single-gene neurodevelopmental disorder associated with cognitive and behavioural impairments, particularly with deficits in working memory. This study investigates the cerebral volumetric differences in adolescents with NF1 as compared to typically developing controls and how working memory task performance is associated with these differences.

Methods

31 adolescents aged 11-17 years were compared to age and sex-matched controls. NF1 subjects were assessed using detailed measurement of working memory at baseline followed by a 3T MR scan. A voxel-based morphometry approach was used to estimate the total and regional gray matter volumetric differences between the NF1 and control groups. The working memory metrics were subjected to a principal component analysis (PCA) approach. Finally, we examined how the components derived from PCA correlated with the changes in gray matter volume in the NF1 group, after adjusting for age, sex and total intracranial volume.

Results

The NF1 cohort showed increased gray matter volumes in the thalamus, globus pallidus, caudate, putamen, dorsal midbrain and cerebellum bilaterally as compared to controls. The PCA yielded three independent behavioural components reflecting high memory load, low memory load and auditory working memory. Correlation analyses revealed that increased volume of the inferior lateral parietal cortex was associated with poorer performance on the high working memory load tasks. Increased volume of posterior cingulate cortex, a key component of the default mode network (DMN) was significantly associated with poorer performance on low working memory load tasks.

Discussion

This is the first study to examine the neuroanatomical correlates of working memory in NF1 adolescents. Consistent with prior literature we show larger subcortical brain volumes in in the NF1 cohort. The strong association between posterior cingulate cortex volume and performance on low memory load conditions supports previously suggested hypotheses of deficient DMN structural development, which in turn may contribute to the cognitive impairments in NF1.
Maternal postnatal depression and offspring emotional and behavioural development at age 7 years in a UK-birth cohort: the role of paternal involvement
Authors: Culpin Iryna , Hammerton Gemma , Stein Alan , Bornstein Marc H , Tiemeier Henning , Cadman Tim , Fredriksen Eivor , Evans Jonathan , Miller Tina , Dermott Esther , Heron Jon , Sallis Hannah M , Pearson Rebecca M
Published: October 2021

Background

There is considerable variability in emotional and behavioural outcomes of children whose mothers experience depression. Few longitudinal studies have examined potential contributions of dimensions of paternal involvement in the association between maternal postnatal depression (PND) and offspring development.

Methods

We examined pathways from maternal PND at 8 weeks postnatally (assessed using the Edinburgh Postnatal Depression Scale) to offspring emotional and behavioural development at 7 years (assessed using the Strengths and Difficulties Questionnaire) through behavioural, affective and cognitive child-focused and mother-influenced dimensions of paternal involvement in 3,434 members of the UK-based birth cohort, the Avon Longitudinal Study of Parents and Children. Analyses were adjusted for a range of baseline confounders and paternal postnatal depression (PND) as an intermediate confounder.

Results

Maternal PND was associated with higher levels of some aspects of child-focused and mother-influenced paternal involvement in models accounting for paternal PND, however these pathways were not associated with offspring emotional and behavioural development at age 7 years. There was strong evidence of direct effect from maternal PND to offspring development, but no evidence of mediation through the combination of all indirect pathways through child-focused and mother-influenced paternal involvement. However, higher levels of father-child conflict were associated with increased risk of offspring emotional and behavioural difficulties, and this pathway mediated a proportion of the maternal PND to offspring risk. Additionally, maternal PND was associated with paternal PND, which, in turn, was associated with lower levels of child-focused and mother-influenced paternal involvement.

Conclusions

The positive associations between maternal PND and some aspects of paternal involvement suggest that non-depressed fathers may engage in ‘compensatory’ parenting strategies in response to maternal PND, which although important may not be sufficient in reducing the adverse impact of maternal PND on offspring emotional and behavioural development. Conflictual father-child relationships emerged as a risk factor for adverse offspring development and as an explanatory mechanism in the association between maternal PND and offspring development. These results suggest that interventions that reduce father-child conflict may reduce the risk of emotional and behavioural difficulties in offspring of depressed mothers.
Effects of Side-Effect Risk Framing Strategies on COVID-19 Vaccine Intentions: A Randomized Controlled Trial
Authors: Sudharsanan Nikkil , Favaretti Caterina , Hachaturyan Violetta , Bärnighausen Till , Vandormael Alain
Published: October 2021

Fear over side-effects is one of the main drivers of COVID-19 vaccine hesitancy. We conducted a pre-registered randomized controlled trial among 8998 individuals to examine the effects of different ways of framing and presenting vaccine side-effects on individuals’ willingness to get vaccinated. We found that adding a descriptive risk label (“very low risk”) next to the numerical side-effect and providing a comparison to motor vehicle mortality increased participants’ willingness to take the COVID-19 vaccine by 3.0 percentage points (p = 0.003) and 2.4 percentage points (p = 0.049), respectively. These effects were independent and additive and combining both framing strategies increased willingness to receive the vaccine by 6.1 percentage points (p < 0.001). Mechanistically, we find evidence that these framing effects operate by increasing individuals’ perceptions of how safe the vaccine is. Our results reveal that low-cost side-effect framing strategies can meaningfully affect vaccine intentions at a population level.
The impact of heating, ventilation, and air conditioning design features on the transmission of viruses, including the 2019 novel coronavirus: a systematic review of ultraviolet radiation
Authors: Thornton Gail M. , Fleck Brian A. , Fleck Natalie , Kroeker Emily , Dandnayak Dhyey , Zhong Lexuan , Hartling Lisa
Published: October 2021

Respiratory viruses are capable of transmitting via an aerosol route. Emerging evidence suggests that SARS-CoV-2 which causes COVID-19 can be spread through airborne transmission, particularly in indoor environments with poor ventilation. Heating, ventilation, and air conditioning (HVAC) systems can play a role in mitigating airborne virus transmission. We conducted a systematic review of the scientific literature examining the effectiveness of HVAC design features in reducing virus transmission—here we report results for ultraviolet (UV) radiation. Following international standards for systematic reviews, we conducted a comprehensive search and synthesized findings from 32 relevant studies published between 1936 and 2020. Research demonstrates that: viruses and bacteriophages are inactivated by UV radiation; increasing UV dose is associated with decreasing survival fraction of viruses and bacteriophages; increasing relative humidity is associated with decreasing susceptibility to UV radiation; UV dose and corresponding survival fraction are affected by airflow pattern, air changes per hour, and UV device location; and UV radiation is associated with decreased transmission in both animal and human studies. This comprehensive synthesis of the scientific evidence examining the impact of UV radiation on virus transmission can be used to guide implementation of systems to mitigate airborne spread and identify priorities for future research.

Practical Implications

In-duct ultraviolet germicidal irradiation (UVGI) addresses virus transmission throughout the heating, ventilation, and air conditioning (HVAC) system of a building as a whole; whereas, upper-room UVGI addresses virus transmission in one room of that building. The susceptibility of a virus is often determined from the relationship between UV dose and survival fraction of the virus, and can be affected by relative humidity. Modelling studies revealed that practical implementation of UVGI in HVAC systems should consider airflow patterns, air changes per hour, and UV device location. Future field studies of UVGI systems could address an existing research gap and provide important information on system performance in real-world situations.
Soluble angiotensin-converting enzyme 2 as a prognostic biomarker for disease progression in patients infected with SARS-CoV-2
Authors: Troyano Noelia Diaz , Medina Pablo Gabriel , Weber Stephen , Klammer Martin , Barquin-DelPino Raquel , Castillo-Ribelles Laura , Esteban Angels , Hernández-González Manuel , Ferrer-Costa Roser , Pumarola Tomas , Frias Francisco Rodriguez
Published: October 2021

Background

There is a need for better prediction of disease severity in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble angiotensin-converting enzyme 2 (sACE2) arises from shedding of membrane ACE2 (mACE2) that is known to be a receptor for the spike protein of SARS-CoV-2; however, its value as a biomarker for disease severity is unknown. This study evaluated the predictive value of sACE2 in the context of other known biomarkers of inflammation and tissue damage (C-reactive protein [CRP], growth/differentiation factor-15 [GDF-15], interleukin-6 [IL-6], and soluble fms-like tyrosine kinase-1 [sFlt-1]) in patients with and without SARS-CoV-2 with different clinical outcomes.

Methods

For univariate analyses, median differences between biomarker levels were calculated for the following patient groups classified according to clinical outcome: reverse transcription polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 positive (Groups 1–4); RT-PCR-confirmed SARS-CoV-2 negative following previous SARS-CoV-2 infection (Groups 5 and 6); and RT-PCR-confirmed SARS-CoV-2 negative controls (Group 7).

Results

Median levels of CRP, GDF-15, IL-6, and sFlt-1 were significantly higher in patients with SARS-CoV-2 who were admitted to hospital compared with patients who were discharged (all p<0.001), whereas levels of sACE2 were significantly lower (p<0.001). Receiver operating characteristic curve analysis of sACE2 provided cut-offs for the prediction of hospital admission of ≤0.05 ng/mL (positive predictive value: 89.1%) and ≥0.42 ng/mL (negative predictive value: 84.0%).

Conclusion

These findings support further investigation of sACE2, either as a single biomarker or as part of a panel, to predict hospitalisation risk and disease severity in patients infected with SARS-CoV-2.

HIGHLIGHTS

Noelia Diaz Troyano: Noy-Lee-ah Dee-az Tro-yah-no

Better prediction of disease severity in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed. We measured soluble angiotensin-converting enzyme 2 (soluble ACE2) and other biomarkers of inflammation and tissue damage in patients recruited from Vall d’Hebron University Hospital, with and without SARS-CoV-2 and with different clinical outcomes. Levels of soluble ACE2 were significantly lower in patients with SARS-CoV-2 who had the most severe clinical outcome in all comparisons. These findings support a protective role for soluble ACE2 in SARS-CoV-2 infection and warrant further investigation of soluble ACE2 as a biomarker for disease severity in patients with SARS-CoV-2.
Nasopharyngeal Dysbiosis Precedes the Development of Lower Respiratory Tract Infections in Young Infants, a Longitudinal Infant Cohort Study
Authors: Lapidot Rotem , Faits Tyler , Ismail Arshad , Allam Mushal , Khumalo Zamantungwak T.H , MacLeod William , Kwenda Geoffrey , Mupila Zacharia , Nakazwe Ruth , Segrè Daniel , Johnson W. Evan , Thea Donald M , Mwananyanda Lawrence , Gill Christopher J
Published: October 2021

Background

Infants suffering from lower respiratory tract infections (LRTIs) have distinct nasopharyngeal (NP) microbiome profiles that correlate with severity of disease. Whether these profiles precede the infection or a consequence of it, is unknown. In order to answer this question, longitudinal studies are needed.

Methods

We conducted an analysis of a longitudinal prospective cohort study of 1,981 Zambian mother-infant pairs who underwent NP sampling from 1-week through 14-weeks of age at 2-3-week intervals. Ten of the infants in the cohort developed LRTI and were matched 3:1 with healthy comparators. We completed 16S rRNA gene sequencing on the samples each of these infants contributed, as well as from baseline samples of the infants’ mothers, and characterized the normal maturation of the healthy infant NP microbiome, compared to infants who developed LRTI.

Results

The infant NP microbiome maturation was characterized by transitioning from Staphylococcus dominant to respiratory-genera dominant profiles during the first three months of life, similar to what is described in the literature. Interestingly, infants who developed LRTI had NP dysbiosis before infection, in most cases as early as the first week of life. Dysbiosis was characterized by the presence of Novosphingobium, Delftia, high relative abundance of Anaerobacillus, Bacillus, and low relative abundance of Dolosigranulum, compared to the healthy controls. Mothers of infants with LRTI also had low relative abundance of Dolosigranulum in their baseline samples compared to mothers of infants that did not develop an LRTI.

Conclusions

Our results suggest that NP microbiome dysbiosis precedes LRTI in young infants and may be present in their mothers as well. Early dysbiosis may play a role in the causal pathway leading to LRTI or could be a marker of other pathogenic forces that directly lead to LRTI.

Funding

This work was supported by The Southern Africa Mother Infant Pertussis Study – Nasopharyngeal Carriage (SAMIPS-NPC). PI Gill. Funder NIH/NIAID (1R01AI133080). WEJ and TF were supported by funds from the NIH, U01CA220413 and R01GM127430.
Breakthrough SARS-CoV-2 infections in 620,000 U.S. Veterans, February 1, 2021 to August 13, 2021
Authors: Cohn Barbara A. , Cirillo Piera M. , Murphy Caitlin C. , Krigbaum Nickilou Y. , Wallace Arthur W.
Published: October 2021

National data on COVID-19 vaccine breakthrough infections is inadequate but urgently needed to determine U.S. policy during the emergence of the Delta variant. We address this gap by comparing SARS CoV-2 infection by vaccination status from February 1, 2021 to August 13, 2021 in the Veterans Health Administration, covering 2.7% of the U.S. population. Vaccine protection declined by mid-August 2021, decreasing from 91.9% in March to 53.9% (p<0.01, n=619,755). Declines were greatest for the Janssen vaccine followed by Pfizer–BioNTech and Moderna. Patterns of breakthrough infection over time were consistent by age, despite rolling vaccine eligibility, implicating the Delta variant as the primary determinant of infection. Findings support continued efforts to increase vaccination and an immediate, national return to additional layers of protection against infection.
The adenosine analogue prodrug ATV006 is orally bioavailable and has potent preclinical efficacy against SARS-CoV-2 and its variants
Authors: Cao Liu , Li Yingjun , Yang Sidi , Li Guanguan , Zhou Qifan , Sun Jing , Xu Tiefeng , Yang Yujian , Zhu Tiaozhen , Huang Siyao , Ji Yanxi , Cong Feng , Luo Yinzhu , Zhu Yujun , Luan Hemi , Zhang Huan , Chen Jingdiao , Liu Xue , Wang Ping , Yu Yang , Xing Fan , Ke Bixia , Zheng Huanying , Deng Xiaoling , Zhang Wenyong , Li Chun-Mei , Zhang Yu , Zhao Jincun , Zhang Xumu , Guo Deyin
Published: October 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the COVID-19 pandemic, is rapidly evolving. Due to the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOC), including the currently most prevalent Delta variant, orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously we showed that adenosine analogue 69-0 (also known as GS-441524), possesses potent anti-SARS-CoV-2 activity. Herein, we report that esterification of the 5’-hydroxyl moieties of 69-0 markedly improved the antiviral potency. The 5’-hydroxyl-isobutyryl prodrug, ATV006, showed excellent oral bioavailability in rats and cynomolgus monkeys and potent antiviral efficacy against different VOCs of SARS-CoV-2 in cell culture and three mouse models. Oral administration of ATV006 significantly reduced viral loads, alleviated lung damage and rescued mice from death in the K18-hACE2 mouse model challenged with the Delta variant. Moreover, ATV006 showed broad antiviral efficacy against different mammal-infecting coronaviruses. These indicate that ATV006 represents a promising oral drug candidate against SARS-CoV-2 VOCs and other coronaviruses.
Genetic map of regional sulcal morphology in the human brain
Authors: Sun Benjamin B. , Loomis Stephanie J. , Pizzagalli Fabrizio , Shatokhina Natalia , Painter Jodie N. , Foley Christopher N. , Team Biogen Biobank , Jensen Megan E. , McLaren Donald G. , Chintapalli Sai Spandana , Zhu Alyssa H. , Dixon Daniel , Islam Tasfiya , Gari Iyad Ba , Runz Heiko , Medland Sarah E. , Thompson Paul M. , Jahanshad Neda , Whelan Christopher D.
Published: October 2021

The human brain is a complex organ underlying many cognitive and physiological processes, affected by a wide range of diseases. Genetic associations with macroscopic brain structure are emerging, providing insights into genetic sources of brain variability and risk for functional impairments and disease. However, specific associations with measures of local brain folding, associated with both brain development and decline, remain under-explored. Here we carried out detailed large-scale genome-wide associations of regional brain cortical sulcal measures derived from magnetic resonance imaging data of 40,169 individuals in the UK Biobank. Combining both genotyping and whole-exome sequencing data (∼12 million variants), we discovered 388 regional brain folding associations across 77 genetic loci at p<5×10−8, which replicated at p<0.05. We found genes in associated loci to be independently enriched for expression in the cerebral cortex, neuronal development processes and differential regulation in early brain development. We integrated coding associations and brain eQTLs to refine genes for various loci and demonstrated shared signal in the pleiotropic KCNK2 locus with a cortex-specific KCNK2 eQTL. Genetic correlations with neuropsychiatric conditions highlighted emerging patterns across distinct sulcal parameters and related phenotypes. We provide an interactive 3D visualisation of our summary associations, making complex association patterns easier to interpret, and emphasising the added resolution of regional brain analyses compared to global brain measures. Our results offer new insights into the genetic architecture underpinning brain folding and provide a resource to the wider scientific community for studies of pathways driving brain folding and their role in health and disease.
Dual polarity voltage imaging reveals subthreshold dynamics and concurrent spiking patterns of multiple neuron-types
Authors: Kannan Madhuvanthi , Vasan Ganesh , Haziza Simon , Huang Cheng , Chrapkiewicz Radek , Luo Junjie , Cardin Jessica A. , Schnitzer Mark J. , Pieribone Vincent A.
Published: October 2021

Genetically encoded fluorescent voltage indicators are ideally suited to reveal the millisecond-scale interactions among and between distinct, targeted cell populations. However, current indicator families lack the requisite sensitivity forin vivomultipopulation imaging. We describe high-performance green and red sensors, Ace-mNeon2 and VARNAM2, and their reverse response-polarity variants, pAce and pAceR. Our indicators enable 0.4-1 kHz voltage recordings from >50 neurons per field-of-view in awake mice and ∼30-min continuous imaging in flies. Using dual-polarity multiplexed imaging, we uncovered behavioral state-dependent interactions between distinct neocortical subclasses, as well as contributions to hippocampal field potentials from non-overlapping projection neuronal ensembles. By combining three mutually compatible indicators, we demonstrate concurrent triple-population voltage imaging. Our approach will empower investigations of the dynamic interplay between neuronal subclasses at single-spike resolution.

One Sentence Summary

A new suite of voltage sensors enables simultaneous cellular-resolution activity imaging from multiple, targeted neuron-types in awake animals.
Time-tagged ticker tapes for intracellular recordings
Authors: Lin Dingchang , Li Xiuyuan (Ted) , Park Pojeong , Tang Benjamin , Shen Hao , Grimm Jonathan B. , Falco Natalie , Baker David , Lavis Luke D. , Cohen Adam E.
Published: October 2021

A core taken in a tree today can reveal climate events from centuries past. Here we adapt this idea to record histories of neural activation. We engineered slowly growing intracellular protein fibers which can incorporate diverse fluorescent marks during growth to store linear ticker tape-like histories. An embedded HaloTag reporter incorporated user-supplied HaloTag-ligand dyes, leading to colored stripes whose boundaries mapped fiber growth to wall-clock time. A co-expressed eGFP tag driven by the cFos immediate early gene promoter recorded the history of neural activity. High-resolution multispectral imaging on fixed samples read the cellular histories. We demonstrated recordings of cFos activation in ensembles of cultured neurons with a single-cell absolute accuracy of approximately 39 min over a 12-hour interval. Protein-based ticker tapes have the potential to achieve massively parallel single-cell recordings of multiple physiological modalities.
A KARRIKIN INSENSITIVE2 paralog in lettuce mediates highly sensitive germination responses to karrikinolide
Authors: Martinez Stephanie E. , Conn Caitlin E. , Guercio Angelica M. , Sepulveda Claudia , Fiscus Christopher J. , Koenig Daniel , Shabek Nitzan , Nelson David C.
Published: October 2021

Karrikins (KARs) are chemicals in smoke that can enhance germination of many plants. Lactuca sativa cv. Grand Rapids (lettuce), germinates in the presence of nanomolar karrikinolide (KAR1). We found that lettuce is much less responsive to KAR2 or a mixture of synthetic strigolactone analogs, rac-GR24. We investigated the molecular basis of selective and sensitive KAR1 perception in lettuce. The lettuce genome contains two copies of KARRIKIN INSENSITIVE2 (KAI2), a receptor that is required for KAR responses in Arabidopsis thaliana. LsKAI2b is more highly expressed than LsKAI2a in dry achenes and during early stages of seed imbibition. Through cross-species complementation assays in Arabidopsis we found that LsKAI2b confers robust responses to KAR1, but LsKAI2a does not. Therefore, LsKAI2b likely mediates KAR1 responses in lettuce. We compared homology models of the ligand-binding pockets of KAI2 proteins from lettuce and a fire follower, Emmenanthe penduliflora. This identified pocket residues 96, 124, 139, and 161 as candidates that influence the ligand-specificity of KAI2. Further support for the significance of these residues was found through a broader comparison of pocket residue conservation among 324 asterid KAI2 proteins. We tested the effects of substitutions at these four positions in Arabidopsis thaliana KAI2 and found that a broad array of responses to KAR1, KAR2, and rac-GR24 could be achieved.
ALLOPURINOL BLOCKS AORTIC ANEURYSM IN A MOUSE MODEL OF MARFAN SYNDROME VIA REDUCING AORTIC OXIDATIVE STRESS
Authors: Rodríguez-Rovira Isaac , Arce Cristina , De Rycke Karo , Pérez Belén , Carretero Aitor , Arbonés Marc , Teixidò-Turà Gisela , Gómez-Cabrera Mari Carmen , Campuzano Victoria , Jiménez-Altayó Francesc , Egea Gustavo
Published: October 2021

Background

Increasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy.

Methods and Results

In aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1C1041G/+), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, fibrotic collagen remodeling, nuclear translocation of pNRF2 and increased 3’-nitrotyrosine levels all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression.

Conclusions

Allopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients.

HIGHLIGHTS

Xanthine oxidoreductase (XOR) is upregulated in the aortic aneurysm of Marfan syndrome (MFS) both in patients and young mice.

Allopurinol halts the formation and progression of aortic aneurysm in MFS mice

Allopurinol reduces a variety of oxidative stress-associated molecular reactions.

Allopurinol prevents MFS endothelial-dependent vasodilator dysfunction.

The antioxidant action of allopurinol suggests its repositioning for pharmacological use in MFS aortopathy.

GRAPHICAL ABSTRACT
Weak representation of awake/sleep states by local field potentials in aged mice
Authors: Konno Daichi , Ikegaya Yuji , Sasaki Takuya
Published: October 2021

Senescence affects various aspects of sleep, and it remains unclear how sleep-related neuronal network activity is altered by senescence. Here, we recorded local field potential signals from multiple brain regions covering the forebrain in young (10-week-old) and aged (2-year-old) mice. Interregional LFP correlations across these brain regions showed smaller differences between awake and sleep states in aged mice. Multivariate analyses with machine learning algorithms with uniform manifold approximation and projection (UMAP) and robust continuous clustering (RCC) demonstrated that these LFP correlational patterns in aged mice less represented awake/sleep states than those in young mice. By housing aged mice in an enriched environment, the LFP patterns were restored to those observed in young mice. Our results demonstrate senescence-induced changes in neuronal activity at the network level and provide insight into the prevention of pathological symptoms associated with sleep disturbance in senescence.
Detecting Cd adaptation footprint in C. riparius with a multi-genomic approach
Authors: Doria Halina Binde , Hannapel Pauline , Pfenninger Markus
Published: October 2021

Evolutionary processes and acquired tolerance to toxicants are important factors governing how animals respond to chemical exposure. Evidence for increased tolerance to cadmium (Cd), a widely distributed toxic metal in aquatic environments, inChironomus ripariusis conflicting and still questioned if it happens through phenotypic plasticity or genetic adaptation. The present study considered the relevance of directional environmental changes by increasing contaminant concentration in a multigenerational selection experiment. Evaluation of measurable life-cycle traits, transcriptomic responses and quantitative genetics from an evolve and resequencing (E&R) experiment were integrated to assess the potential ofC. ripariusto adapt to Cd. Survival tests revealed some adaptation to Cd exposure. Genomic analyses showed a strong, genome-wide selective response in all replicates, emphasizing that even control laboratory conditions continually exert selective pressure. The integration of transcriptomic and genomic data could isolate the genes related to Cd acquired resistance. Those genes could be linked to an efflux of metals. Therefore, it is possible to conclude thatC. ripariuscan endure long-term Cd exposure also through genetic adaptation.
Inhibition of TRPV4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism
Authors: Tzanoulinou Stamatina , Musardo Stefano , Contestabile Alessandro , Bariselli Sebastiano , Casarotto Giulia , Magrinelli Elia , Jiang Yong-hui , Jabaudon Denis , Bellone Camilla
Published: October 2021

Autism spectrum disorder is a neurodevelopmental disease characterized by social deficits and repetitive behaviors. The high heterogeneity of the disease may be explained by gene and environmental interactions and potential risk factors include immune dysfunctions and immune-mediated co-morbidities. Mutations in the SHANK3 gene have been recognized as a genetic risk factor for ASD. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioural deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the NAc promotes D1R-MSN hyperexcitability and upregulates Trpv4 to impair social behaviour. Interestingly, genetically vulnerable Shank3+/- mice, when challenged with Lipopolysaccharide to induce inflammatory response, showed similar circuit and behavioural alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.
Disentangling choice value and choice conflict in sequential decisions under risk
Authors: Fontanesi Laura , Shenhav Amitai , Gluth Sebastian
Published: October 2021

Recent years have witnessed a surge of interest in understanding the neural and cognitive dynamics that drive sequential decision making in general and foraging behavior in particular. Due to the intrinsic properties of most sequential decision-making paradigms, however, previous research in this area has suffered from the difficulty to disentangle properties of the decision related to (a) the value of switching to a new patch versus (b) the conflict experienced between choosing to stay or leave. Here, we show how the same problems arise in studies of sequential decision-making under risk, and how they can be overcome, taking as a specific example recent research on the ‘pig’ dice game. In each round of the ‘pig’ dice game, people roll a die and accumulate rewards until they either decide to proceed to the next round or lose all rewards. By combining simulation-based dissections of the task structure with two experiments, we show how an extension of the standard paradigm, together with cognitive modeling of decision-making processes, disentangles value-from conflict-related choice properties. Our study elucidates the cognitive mechanisms of sequential decision making and underscores the importance of avoiding potential pitfalls of paradigms that are commonly used in this research area.