Ultrastructural studies in APP/PS1 mice expressing human ApoE isoforms: implications for Alzheimer’s disease

Alzheimer’s disease is characterized in part by extracellular aggregation of the amyloid-β peptide in the form of diffuse and fibrillar plaques in the brain. Electron microscopy (EM) has made an important contribution in understanding of the structure of amyloid plaques in humans. Classical EM studies have revealed the architecture of the fibrillar core, characterized the progression of neuritic changes, and have identified the neurofibrillary tangles formed by paired helical filaments (PHF) in degenerating neurons. Clinical data has strongly correlated cognitive impairment in AD with the substantial synapse loss observed in these early ultrastructural studies. Animal models of AD-type brain amyloidosis have provided excellent opportunities to study amyloid and neuritic pathology in detail and establish the role of neurons and glia in plaque formation. Transgenic mice overexpressing mutant amyloid precursor protein (APP) alone with or without mutant presenilin 1 (PS1), have shown that brain amyloid plaque development and structure grossly recapitulate classical findings in humans. Transgenic APP/PS1 mice expressing human apolioprotein E isoforms also develop amyloid plaque deposition. However no ultrastructural data has been reported for these animals. Here we show results from detailed EM analysis of amyloid plaques in APP/PS1 mice expressing human isoforms of ApoE and compare these findings with EM data in other transgenic models and in human AD. Our results show that similar to other transgenic animals, APP/PS1 mice expressing human ApoE isoforms share all major cellular and subcellular degenerative features and highlight the identity of the cellular elements involved in Aβ deposition and neuronal degeneration

Evaluation of Recruitment Strategies on Inclusiveness of Populations at Risk for Health Disparities in the Statewide Remote Online COVIDsmart Registry

Background The COVID-19 pandemic affected health research practices. The large-scale impacts of COVID-19 and restrictions on face-to-face interaction led to increased use of remote online data collection methods. However, it is unclear if such efforts led to the representation of populations at risk for health disparities. We evaluated whether multiple recruitment strategies would capture a representative sample of individuals at risk for health disparities. Methods The COVIDsmart registry collected clinical, social, economic, and behavioral data in the state of Virginia from March to November, 2021. Seven hundred eighty-two adult participants were enrolled. We compared the representation of COVIDsmart participants at risk for health disparities against state data with two-tailed Z tests. Monte-Carlo estimates evaluated the association between recruitment strategies utilized and health disparity risk status. Results The majority of participants were non-Hispanic White (81.5%), female (78.6%), non-rural (98%), had a Masters’ degree or higher (62.6%), and an income of $100,000 or higher (51%). The recruitment strategy that brought participants into the study did not differ significantly based on racial/ethnic minority status (p\u3e.05), but did differ for low SES versus high SES groups, p=.03. Low SES and ethnic/racial minority representation proportions were significantly lower for COVIDsmart participants than state data, (p\u3e.05). Conclusions Participants at risk for health disparities were not well represented in this registry despite multiple recruitment strategies. The use of targeted emails, social media, and community collaboration may improve the participation of populations at risk for health disparities in remote online research studies

Extraterrestrial nucleobases in the Murchison meteorite

Carbon-rich meteorites, carbonaceous chondrites, contain many biologically relevant organic molecules and delivered prebiotic material to the young Earth. We present compound-specific carbon isotope data indicating that measured purine and pyrimidine compounds are indigenous components of the Murchison meteorite. Carbon isotope ratios for uracil and xanthine of delta13C=+44.5per mil and +37.7per mil, respectively, indicate a non-terrestrial origin for these compounds. These new results demonstrate that organic compounds, which are components of the genetic code in modern biochemistry, were already present in the early solar system and may have played a key role in life's origin.Comment: 31 pages, 4 figures, 3 table

Debating Technology for Dialogical Argument:Sensemaking, Engagement and Analytics

Debating technologies, a newly emerging strand of research into computational technologies to support human debating, offer a powerful way of providing naturalistic, dialogue-based interaction with complex information spaces. The full potential of debating technologies for dialogical argument can, however, only be realized once key technical and engineering challenges are overcome, namely data structure, data availability, and interoperability between components. Our aim in this article is to show that the Argument Web, a vision for integrated, reusable, semantically rich resources connecting views, opinions, arguments, and debates online, offers a solution to these challenges. Through the use of a running example taken from the domain of citizen dialogue, we demonstrate for the first time that different Argument Web components focusing on sensemaking, engagement, and analytics can work in concert as a suite of debating technologies for rich, complex, dialogical argument

Dynamics of the Multiplicity of Cellular Infection in a Plant Virus

Recombination, complementation and competition profoundly influence virus evolution and epidemiology. Since viruses are intracellular parasites, the basic parameter determining the potential for such interactions is the multiplicity of cellular infection (cellular MOI), i.e. the number of viral genome units that effectively infect a cell. The cellular MOI values that prevail in host organisms have rarely been investigated, and whether they remain constant or change widely during host invasion is totally unknown. Here, we fill this experimental gap by presenting the first detailed analysis of the dynamics of the cellular MOI during colonization of a host plant by a virus. Our results reveal ample variations between different leaf levels during the course of infection, with values starting close to 2 and increasing up to 13 before decreasing to initial levels in the latest infection stages. By revealing wide dynamic changes throughout a single infection, we here illustrate the existence of complex scenarios where the opportunity for recombination, complementation and competition among viral genomes changes greatly at different infection phases and at different locations within a multi-cellular host

The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury

10.1371/journal.pone.0075483PLoS ONE810-POLN

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

An Integrated Transcriptomic and Meta-Analysis of Hepatoma Cells Reveals Factors That Influence Susceptibility to HCV Infection

Hepatitis C virus (HCV) is a global problem. To better understand HCV infection researchers employ in vitro HCV cell-culture (HCVcc) systems that use Huh-7 derived hepatoma cells that are particularly permissive to HCV infection. A variety of hyper-permissive cells have been subcloned for this purpose. In addition, subclones of Huh-7 which have evolved resistance to HCV are available. However, the mechanisms of susceptibility or resistance to infection among these cells have not been fully determined. In order to elucidate mechanisms by which hepatoma cells are susceptible or resistant to HCV infection we performed genome-wide expression analyses of six Huh-7 derived cell cultures that have different levels of permissiveness to infection. A great number of genes, representing a wide spectrum of functions are differentially expressed between cells. To focus our investigation, we identify host proteins from HCV replicase complexes, perform gene expression analysis of three HCV infected cells and conduct a detailed analysis of differentially expressed host factors by integrating a variety of data sources. Our results demonstrate that changes relating to susceptibility to HCV infection in hepatoma cells are linked to the innate immune response, secreted signal peptides and host factors that have a role in virus entry and replication. This work identifies both known and novel host factors that may influence HCV infection. Our findings build upon current knowledge of the complex interplay between HCV and the host cell, which could aid development of new antiviral strategies

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe