bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractDiabetic 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

AbstractAntipsychotic 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

ABSTRACTImproved 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.IMPORTANCEWomen 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

ABSTRACTBackgroundNeurofibromatosis 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.Methods31 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.ResultsThe 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.DiscussionThis 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

AbstractBackgroundThere 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.MethodsWe 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.ResultsMaternal 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.ConclusionsThe 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

AbstractFear 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

AbstractRespiratory 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 ImplicationsIn-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

ABSTRACTBackgroundThere 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.MethodsFor 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).ResultsMedian 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%).ConclusionThese 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.HIGHLIGHTSNoelia Diaz Troyano: Noy-Lee-ah Dee-az Tro-yah-noBetter 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

AbstractBackgroundInfants 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.MethodsWe 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.ResultsThe 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.ConclusionsOur 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.FundingThis 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

AbstractNational 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

AbstractSevere 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.