bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intellectual disability-associated disruption of O-GlcNAcylation impairs neuronal development and cognitive function in Drosophila
Authors: Fenckova Michaela , Muha Villo , Mariappa Daniel , Catinozzi Marica , Czajewski Ignacy , Blok Laura E.R. , Ferenbach Andrew T. , Storkebaum Erik , Schenck Annette , van Aalten Daan M.F. 
Published: January 2022

AbstractO-GlcNAcylation is a reversible co-/post-translational modification involved in a multitude of cellular processes. The addition and removal of O-GlcNAc modification is controlled by two conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA). Mutations in OGT have recently been discovered to cause a novel Congenital Disorder of Glycosylation (OGT-CDG) that is characterized by intellectual disability. The mechanisms by which OGT-CDG mutations affect cognition remain unclear. We manipulated O-GlcNAc transferase and O-GlcNAc hydrolase activity in Drosophila and demonstrate an important role of O-GlcNAcylation in habituation learning and synaptic development at the larval neuromuscular junction. Introduction of patient-specific missense mutations into Drosophila O-GlcNAc transferase using CRISPR/Cas9 gene editing, leads to deficits in locomotor function and habituation learning. The habituation deficit can be corrected by blocking O-GlcNAc hydrolysis, indicating that OGT-CDG mutations affect cognitive function via reduced protein O-GlcNAcylation. This study establishes a critical role for O-GlcNAc cycling and disrupted O-GlcNAc transferase activity in cognitive dysfunction. These findings suggest that blocking O-GlcNAc hydrolysis is a potential treatment strategy for OGT-CDG.Author summaryAttachment of single N-acetylglucosamine (GlcNAc) sugars to intracellular proteins has recently been linked to neurodevelopment and cognition. This link has been strengthened by discovery of O-GlcNAc transferase (OGT) missense mutations in intellectual disability. Most of these mutations lie outside the catalytic O-GlcNAc transferase domain and it is unclear how they affect cognitive function. Using the fruit fly Drosophila melanogaster as a model organism, we found that a balance in O-GlcNAc cycling is required for learning and neuronal development. Habituation, a fundamental form of learning, is affected in flies that carry patient-specific OGT mutations, and increasing O-GlcNAcylation genetically corrects the habituation deficit. Our work establishes a critical role for O-GlcNAc cycling in a cognition-relevant process, identifies defective O-GlcNAc transferase activity as a cause of intellectual disability, and proposes underlying mechanisms that can be further explored as treatment targets.
Cell type-specific aging clocks to quantify aging and rejuvenation in regenerative regions of the brain
Authors: Buckley Matthew T. , Sun Eric , George Benson M. , Liu Ling , Schaum Nicholas , Xu Lucy , Reyes Jaime M. , Goodell Margaret A. , Weissman Irving L. , Wyss-Coray Tony , Rando Thomas A. , Brunet Anne 
Published: January 2022

AbstractAging manifests as progressive dysfunction culminating in death. The diversity of cell types is a challenge to the precise quantification of aging and its reversal. Here we develop a suite of ‘aging clocks’ based on single cell transcriptomic data to characterize cell type-specific aging and rejuvenation strategies. The subventricular zone (SVZ) neurogenic region contains many cell types and provides an excellent system to study cell-level tissue aging and regeneration. We generated 21,458 single-cell transcriptomes from the neurogenic regions of 28 mice, tiling ages from young to old. With these data, we trained a suite of single cell-based regression models (aging clocks) to predict both chronological age (passage of time) and biological age (fitness, in this case the proliferative capacity of the neurogenic region). Both types of clocks perform well on independent cohorts of mice. Genes underlying the single cell-based aging clocks are mostly cell-type specific, but also include a few shared genes in the interferon and lipid metabolism pathways. We used these single cell-based aging clocks to measure transcriptomic rejuvenation, by generating single cell RNA-seq datasets of SVZ neurogenic regions for two interventions – heterochronic parabiosis (young blood) and exercise. Interestingly, the use of aging clocks reveals that both heterochronic parabiosis and exercise reverse transcriptomic aging in the niche, but in different ways across cell types and genes. This study represents the first development of high-resolution aging clocks from single cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.
A novel structure-based approach for identification of vertebrate susceptibility to SARS-CoV-2: implications for future surveillance programmes
Authors: Kaushik Rahul , Kumar Naveen , Zhang Kam Y. J. , Srivastava Pratiksha , Bhatia Sandeep , Malik Yashpal Singh 
Published: January 2022

AbstractUnderstanding the origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a highly debatable and unsolved challenge for the scientific communities across the world. A key to dissect the susceptibility profiles of animal species to SARS-CoV-2 is to understand how virus enters into the cells. The interaction of SARS-CoV-2 ligands (RBD on spike protein) with its host cell receptor, angiotensin-converting enzyme 2 (ACE2), is a critical determinant of host range and cross-species transmission. In this study, we developed and implemented a rigorous computational approach for predicting binding affinity between 299 ACE2 orthologs from diverse vertebrate species and the SARS-CoV-2 spike protein. The findings show that the spike protein of SARS-CoV-2 can bind to many vertebrate species carrying evolutionary divergent ACE2, implying a broad host range at the virus entry level, which may contribute to cross-species transmission and further viral evolution. Additionally, the present study facilitated the identification of genetic determinants that may differentiate susceptible from the resistant host species based on the conservation of ACE2-spike protein interacting residues in vertebrate host species known to facilitate SARS-CoV-2 infection; however, these genetic determinants warrant in vivo experimental confirmation. The molecular interactions associated with varied binding affinity of distinct ACE2 isoforms in a specific bat species were identified using protein structure analysis, implying the existence of diversified susceptibility of bat species to SARS-CoV-2. The findings from current study highlight the importance of intensive surveillance programs aimed at identifying susceptible hosts, particularly those with the potential to transmit zoonotic pathogens, in order to prevent future outbreaks.
SARS-CoV-2 Point Mutation and Deletion Spectra, and Their Association with Different Disease Outcome
Authors: Martínez-González Brenda , Soria María Eugenia , Vázquez-Sirvent Lucía , Ferrer-Orta Cristina , Lobo-Vega Rebeca , Mínguez Pablo , de la Fuente Lorena , Llorens Carlos , Soriano Beatriz , Ramos Ricardo , Cortón Marta , López-Rodríguez Rosario , García-Crespo Carlos , Gallego Isabel , de Ávila Ana Isabel , Gómez Jordi , Enjuanes Luis , Salar-Vidal Llanos , Esteban Jaime , Fernandez-Roblas Ricardo , Gadea Ignacio , Ayuso Carmen , Ruíz-Hornillos Javier , Verdaguer Nuria , Domingo Esteban , Perales Celia 
Published: January 2022

ABSTRACTMutant spectra of RNA viruses are important to understand viral pathogenesis, and response to selective pressures. There is a need to characterize the complexity of mutant spectra in coronaviruses sampled from infected patients. In particular, the possible relationship between SARS-CoV-2 mutant spectrum complexity and disease associations has not been established. In the present study, we report an ultra-deep sequencing (UDS) analysis of the mutant spectrum of amplicons from the nsp12 (polymerase)- and spike (S)-coding regions of thirty nasopharyngeal isolates (diagnostic samples) of SARS-CoV-2 of the first COVID-19 pandemic wave (Madrid, Spain, April 2020) classified according to the severity of ensuing COVID-19. Low frequency mutations and deletions, counted relative to the consensus sequence of the corresponding isolate, were overwhelmingly abundant. We show that the average number of different point mutations, mutations per haplotype and several diversity indices was significantly higher in SARS-CoV-2 isolated from patients who developed mild disease than in those associated with moderate or severe disease (exitus). No such bias was observed with RNA deletions. Location of amino acid substitutions in the three dimensional structures of nsp12 (polymerase) and S suggest significant structural or functional effects. Thus, patients who develop mild symptoms may be a richer source of genetic variants of SARS-CoV-2 than patients with moderate or severe COVID-19.IMPORTANCEThe study shows that mutant spectra of SARS-CoV-2 from diagnostic samples differ in point mutation abundance and complexity, and that significantly larger values were observed in virus from patients who developed mild COVID-19 symptoms. Mutant spectrum complexity is not a uniform trait among isolates. The nature and location of low frequency amino acid substitutions present in mutant spectra anticipate great potential for phenotypic diversification of SARS-CoV-2.
Efficient inactivation of African swine fever virus by a highly complexed iodine combined with compound organic acids
Authors: Qi Mengnan , Pan Li , Gao Ying , Li Miao , Wang Yanjin , Li Lian-Feng , Ji Chen , Sun Yuan , Qiu Hua-Ji 
Published: January 2022

ABSTRACTAfrican swine fever (ASF) is a highly contagious disease with high morbidity and mortality caused by African swine fever virus (ASFV). Cleaning and disinfection remain one of the most effective biosecurity measures to prevent and control the spread of ASFV. In this study, we evaluated the inactivation effects of highly complexed iodine (HPCI) combined with compound organic acids (COAs) against ASFV under different conditions. The results showed that the inactivation rates of the disinfectants on the reporter ASFV increased in dose- and time-dependent manners, the best inactivation effects were obtained when the compatibility ratio of HPCI and COAs was 5:1 at 25°C. Furthermore, there were no significant differences by comparing the efficacy of HPCI combined with COAs (HPCI+COAs) in inactivating wild-type ASFV and the reporter ASFV (P > 0.05). ASFV of 104.0 TCID50/mL was completely inactivated by 0.13% HPCI (0.0065% effective iodine), 0.06% COAs or 0.13% HPCI+COAs (approximately 0.0054% effective iodine), respectively, while 106.0 TCID50/mL ASFV was completely inactivated by 1.00% HPCI (0.05% effective iodine), 0.50% COAs or 1.00% HPCI+COAs (0.042% effective iodine), respectively. Therefore, HPCI+COAs had synergistic effects to inactivate ASFV. This study demonstrated that HPCI+COAs could rapidly and efficiently inactivate ASFV and represent an effective compound disinfectant for the control of ASF.IMPORTANCEAfrican swine fever (ASF) is a highly contagious disease with high morbidity and mortality caused by African swine fever virus (ASFV). Due to the lack of commercial vaccines and treatment available for ASF, effective disinfectants and the proper use of them are extremely essential to inactivate ASFV. The significance of this research is in searching for an ideal disinfectant that not only has the advantages of low toxicity and non-pollution but also can inactivate ASFV rapidly and efficiently. In this study, we proved that HPCI+COAs not only exhibited low cytotoxicity, but also could completely inactivate ASFV within 5 min at 4°C, 25°C and 37°C. In addition, HPCI+COAs had synergistic effects on inactivated ASFV. Thus, HPCI +COAs could be used as an effective disinfectant for the control of ASF.
COVID-19 vaccination breakthrough infections in a real-world setting: Using community reporters to evaluate vaccine effectiveness
Authors: Reynolds Matthew W , Xie Yiqiong , Knuth Kendall B , Mack Christina D , Brinkley Emma , Toovey Stephen , Dreyer Nancy A 
Published: January 2022

AbstractBackgroundCOVID-19 has highlighted the need for new methods of pharmacovigilance. Here we use community volunteers to obtain systematic information on vaccine effectiveness and the nature and severity of breakthrough infections.MethodsBetween December 15, 2020 to September 16, 2021, 10,412 unpaid community-based participants reported the following information to an on-line registry: COVID-19 test results, vaccination (Pfizer, Moderna, or Johnson & Johnson), COVID-19 symptoms and perceived severity using a 4-point scale. COVID-19 infections were described for those who were 1) fully vaccinated, 2) partially vaccinated (received first of two dose vaccines or were <14 days post-final dose), or 3) unvaccinated.ResultsOf 8,554 who were vaccinated, COVID-19 infections were reported by 74 (1.0%) of those who were fully vaccinated and 198 (2.3%) of those who were partially vaccinated. Among the 74 participants who reported a breakthrough infection after full vaccination, the median time to reported positive test result was 104.5 days (Interquartile range: 77-135 days), with no difference among vaccine manufactures. One quarter (25.7%) of breakthrough infections in the fully vaccinated cases were asymptomatic. More than 97% of fully vaccinated participants reported no moderate/severe symptoms compared to 89.3% of the unvaccinated cases; and only 1.4% of fully vaccinated participants reported experiencing at least 3 moderate to severe symptoms compared to 7.8% in the unvaccinated.ConclusionPerson-generated health data, also referred to as patient-reported outcomes, is a useful resource for quantifying breakthrough infections and their severity, showing here that fully vaccinated participants report no or very mild COVID-19 symptoms.Trial registrationClinicaltrials.govNCT04368065, EU PAS Register EUPAS36240
How do growth and nutrition explain social inequalities in lung function in children with cystic fibrosis? A longitudinal mediation analysis using interventional disparity effects with time-varying mediators and intermediate confounders
Authors: Schlüter Daniela K. , Keogh Ruth H. , Daniel Rhian M. , Agbla Schadrac C. , Taylor-Robinson David 
Published: January 2022

AbstractBackgroundDeprivation is associated with poorer growth, worse lung function and shorter life expectancy in children with cystic fibrosis (CF). While early growth is associated with lung function when first measured at around age 6, it is unclear whether improving early growth in the most disadvantaged children would reduce inequalities in lung function.MethodsWe used data from children born 2000-2010 and followed up to 2016 in the UK CF Registry. To estimate the association between deprivation and lung function at around age six, and the causal contribution of early weight trajectories, we extended the mediation analysis approach based on interventional disparity effects to the setting of a longitudinally measured mediator. We adjusted for baseline confounding by sex, birthyear and genotype and accounted for time-varying intermediate confounding by lung infection.Results853 children were included in the study, including 165 and 172 children from the least and most deprived population quintiles, respectively. The average difference in lung function between the least and most deprived quintile of children, was 4.51 percent of predicted forced expiratory volume in one second (95% CI: 1.08 - 7.93). We estimated this would be reduced to 3.97 percentage points (95% CI: 0.57 – 7.38) if early weight trajectories in the most deprived children were shifted to the distribution observed in the least disadvantaged children.ConclusionSocio-economic conditions are strongly associated with lung function for children with CF which we estimated would only be marginally reduced if early weight trajectories could be improved for the most disadvantaged children.
Smoking in social housing among adults in England, 2015-2020: a nationally representative survey
Authors: Jackson Sarah E. , Cheeseman Hazel , Arnott Deborah , Titmarsh Robbie , Brown Jamie 
Published: January 2022

AbstractObjectivesTo analyse associations between living in social housing and smoking in England and evaluate progress toward reducing disparities in smoking prevalence among residents of social housing compared with other housing types.DesignNationally-representative, cross-sectional survey between January 2015 and February 2020.SettingEngland.Participants105,562 adults (≥16y).Primary and secondary outcome measuresLinear and logistic regression were used to analyse associations between living in social housing (vs. other housing types) and smoking status, cigarettes per day, time to first cigarette, exposure to smoking by others, motivation to stop smoking, quit attempts, and use of cessation support. Analyses adjusted for sex, age, social grade, region, and survey year.ResultsAdults living in social housing had twice the odds of being a smoker (ORadj=2.17, 95%CI 2.08- 2.27), and the decline in smoking prevalence between 2015 and 2020 was less pronounced in this high-risk group (−7%; ORadj=0.98, 95%CI 0.96-1.01) than among adults living in other housing types (− 24%; ORadj=0.95, 95%CI 0.94-0.96; housing tenure*survey year interaction p=0.020). Smokers living in social housing were more addicted than those in other housing (smoking within 30 minutes of waking: ORadj=1.50, 95%CI 1.39-1.61), but were no less motivated to stop smoking (ORadj=1.06, 95%CI 0.96-1.17) and had higher odds of having made a serious attempt to quit in the past year (ORadj=1.16, 95%CI 1.07-1.25). Among smokers who had tried to quit, those living in social housing had higher odds of using evidence-based cessation support (ORadj=1.22, 95%CI 1.07-1.39) but lower odds of remaining abstinent (ORadj=0.63, 95%CI 0.52-0.76).ConclusionsThere remain stark inequalities in smoking and quitting behaviour by housing tenure in England, with declines in prevalence stalling between 2015 and 2020 despite progress in the rest of the population. In the absence of targeted interventions to boost quitting among social housing residents, inequalities in health are likely to worsen.Strengths and limitations of this studyA major strength of this study was the large sample, which was representative of adults living in England.Another strength was the broad range of smoking outcomes assessed, offering a detailed view of smoking behaviour among people living in social housing compared with those living in other housing types.The main limitation was that all outcomes were self-reported, introducing scope for bias.
The incidence and mortality of COVID-19 related TB disease in Sub-Saharan Africa: A systematic review and meta-analysis
Authors: Tamuzi Jacques L , Lulendo Gomer , Mbuesse Patrick , Nyasulu Peter S. 
Published: January 2022

AbstractBackgroundCoronavirus disease 2019 (COVID-19) is also associated with other co-morbidities in people who have previously or currently have pulmonary tuberculosis (PTB). PTB is a risk factor for COVID-19, both in terms of severity and mortality, regardless of HIV status. However, there is less information available on COVID-19 and PTB in terms of incidence and mortality rates in Sub-Saharan Africa (SSA), a high-burden TB region. This systematic review provided a data synthesis of available evidence on COVID-19/PTB incidence and case fatality rates, as well as mortality rates found in clinical and post-mortem COVID-19/PTB diagnostics in SSA.MethodsWe conducted an electronic search in the PubMed, Medline, Google Scholar, Medrxix, and COVID-19 Global literature on coronavirus disease databases for studies involving COVID-19 and PTB in Sub-Saharan Africa. The primary outcomes were the incidence proportion of people with COVID-19 who had current or previous PTB, as well as the case fatality rate associated with COVID-19/PTB. Based on methodological similarities in the included random effect model studies, the combination method was developed using Stata version 16 and Prometa 3 software. We also performed sensitivity analysis and meta-regression.ResultsFrom the 548 references extracted by the literature search, 25 studies were selected and included in the meta-analysis with a total of 191, 250 COVID-19 infected patients and 11, 480 COVID-19 deaths. The pooled COVID-19/PTB incidence was 3% [2%-5%] and a case fatality rate of 13% [4%-23%]. The pooled estimates for case fatality rate among COVID-19/PTB were 7% [1%-12%] for clinical PTB diagnostic and 25% [3%-47%] for post-mortem PTB diagnostic. Previous TB had the highest incidence and fatality rates with 46 [19-73] per 1, 000 population and 8% [3%-19%], respectively. Meta-regression model including the effect sizes and cumulative COVID-19 cases (P= 0.032), HIV prevalence (P= 0.041), and TB incidence (P= 0.002) to explain high heterogeneity between studies.ConclusionTo summarize, the incidence of TB associated with COVID-19 is higher in SSA, as are the case fatality rates, when compared to the rest of the world. However, because the post-mortem TB diagnostic was higher, COVID-19 associated with TB may have been underreported in studies conducted in SSA. To confirm COVID-19/TB incidence and case fatality rates in SSA, large-scale cohort studies that adequately clear tools on previous and/or current TB diagnostic tools are required.Review registrationPROSPERO (CRD42021233387)
Functional status, mood state, and physical activity among women with post-acute COVID-19 syndrome
Authors: Carter Stephen J. , Baranauskas Marissa N. , Raglin John S. , Pescosolido Bernice A. , Perry Brea L. 
Published: January 2022

ABSTRACTObjectivesWhile organ-specific pathophysiology has been well-described in SARS-CoV-2 infection, less is known about the attendant effects on functional status, mood state and leisure-time physical activity (PA) in post-acute COVID-19 syndrome.MethodsA case-control design was employed to recruit 32 women (n = 17 SARS-CoV-2; n = 15 controls) matched on age (54 ± 12 years), body mass index (27 ± 6 kg/m2), smoking status, and history of cardiopulmonary disease. Participants completed a series of assessments including the Modified Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ-M), Profile of Mood States (POMS), and Godin-Shephard Leisure-Time PA.ResultsSARS-CoV-2 participants exhibited poorer functional status (p = 0.008) and reduced leisure-time PA (p = 0.004) compared to controls. Significant between-group differences were also detected for the POMS total mood disturbance with sub-scale analyses revealing elevated tension, confusion, and lower vigor among SARS-CoV-2 participants (all p-values < 0.05). The number of SARS-CoV-2 symptoms (e.g., loss of taste / smell, muscle aches etc.) were associated (r = 0.620, p = 0.008) with confusion.ConclusionThe sequela of persistent SARS-CoV-2 symptoms elicit clear disturbances in functional status, mood state, and leisure-time PA among women with post-acute COVID-19 syndrome.