Dynamic chromatin accessibility and transcriptome changes following PDGF-BB treatment of bone-marrow derived mesenchymal stem cells.

Background: Mesenchymal stem cells (MSCs) are multipotent stem cells that are under investigation for use in clinical trials because they are capable of self-renewal and differentiating into different cell types under defined conditions. Nonetheless, the therapeutic effects of MSCs have been constrained by low engraftment rates, cell fusion, and cell survival. Various strategies have been explored to improve the therapeutic efficacy of MSCs, with platelet-derived growth factor (PDGF)-BB emerging as a promising candidate.

Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder.

Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. We found that a significant portion of the alcohol-induced changes in gene expression occurred through altered chromatin accessibility.

Functional 3'-UTR Variants Identify Regulatory Mechanisms Impacting Alcohol Use Disorder and Related Traits.

Although genome-wide association studies (GWAS) have identified loci associated with alcohol consumption and alcohol use disorder (AUD), they do not identify which variants are functional. To approach this, we evaluated the impact of variants in 3' untranslated regions (3'-UTRs) of genes in loci associated with substance use and neurological disorders using a massively parallel reporter assay (MPRA) in neuroblastoma and microglia cells. Functionally impactful variants explained a higher proportion of heritability of alcohol traits than non-functional variants.

Gene Expression Alterations in Peripheral Blood Following Sport-Related Concussion in a Prospective Cohort of Collegiate Athletes: A Concussion Assessment, Research and Education (CARE) Consortium Study.

Background: Molecular-based approaches to understanding concussion pathophysiology provide complex biological information that can advance concussion research and identify potential diagnostic and/or prognostic biomarkers of injury.

Objective: The aim of this study was to identify gene expression changes in peripheral blood that are initiated following concussion and are relevant to concussion response and recovery.

Methods: We analyzed whole blood transcriptomes in a large cohort of concussed and control collegiate athletes who were participating in the multicenter prospective cohort Concussion Assessment, Research, and Education (CARE) Consortium study.

Osteogenic Differentiation Potential of Mesenchymal Stem Cells Using Single Cell Multiomic Analysis.

Mesenchymal stem cells (MSC) are multipotent stem cells that can differentiate into multiple cell types, including osteoblasts, chondrocytes, and adipocytes. Osteoblast differentiation is reduced during osteoporosis development, resulting in reduced bone formation. Further, MSC isolated from different donors possess distinct osteogenic capacity.

Genetic Regulation of Human isomiR Biogenesis.

MicroRNAs play a critical role in regulating gene expression post-transcriptionally. Variations in mature microRNA sequences, known as isomiRs, arise from imprecise cleavage and nucleotide substitution or addition. These isomiRs can target different mRNAs or compete with their canonical counterparts, thereby expanding the scope of miRNA post-transcriptional regulation.

Glyphosate exposure in early pregnancy and reduced fetal growth: a prospective observational study of high-risk pregnancies.

Background: Prenatal glyphosate (GLY) exposure is associated with adverse reproductive outcomes in animal studies. Little is known about the effects of GLY exposure during pregnancy in the human population. This study aims to establish baseline urine GLY levels in a high-risk and racially diverse pregnancy cohort and to assess the relationship between prenatal GLY exposure and fetal development and birth outcomes.

Bioinformatics detection of modulators controlling splicing factor-dependent intron retention in the human brain.

Alternative RNA splicing is an important means of genetic control and transcriptome diversity. However, when alternative splicing events are studied independently, coordinated splicing modulated by common factors is often not recognized. As a result, the molecular mechanisms of how splicing regulators promote or repress splice site recognition in a context-dependent manner are not well understood.

Intron-Retention Neoantigen Load Predicts Favorable Prognosis in Pancreatic Cancer.

Purpose: High tumor mutation burden (TMB) in many cancer types is associated with the production of tumor-specific neoantigens, a favorable outcome and response to immune checkpoint blockade (ICB) therapy. Besides mutation-derived neoantigens, aberrant intron retention also produces tumor neopeptides that could trigger an immune response. The relationship between intron-retention-derived tumor neoantigens (IR-neoAg) and clinical outcomes in pancreatic cancer remains uncertain.

Intron retention-induced neoantigen load correlates with unfavorable prognosis in multiple myeloma.

Neoantigen peptides arising from genetic alterations may serve as targets for personalized cancer vaccines and as positive predictors of response to immune checkpoint therapy. Mutations in genes regulating RNA splicing are common in hematological malignancies leading to dysregulated splicing and intron retention (IR). In this study, we investigated IR as a potential source of tumor neoantigens in multiple myeloma (MM) patients and the relationship of IR-induced neoantigens (IR-neoAg) with clinical outcomes.

Cryopreservation Preserves Cell-Type Composition and Gene Expression Profiles in Bone Marrow Aspirates From Multiple Myeloma Patients.

Single-cell RNA sequencing reveals gene expression differences between individual cells and also identifies different cell populations that are present in the bulk starting material. To obtain an accurate assessment of patient samples, single-cell suspensions need to be generated as soon as possible once the tissue or sample has been collected. However, this requirement poses logistical challenges for experimental designs involving multiple samples from the same subject since these samples would ideally be processed at the same time to minimize technical variation in data analysis.

The Access Technology Program of the Indiana Clinical Translational Sciences Institute (CTSI): A model to facilitate access to cutting-edge technologies across a state.

Introduction: Access to cutting-edge technologies is essential for investigators to advance translational research. The Indiana Clinical and Translational Sciences Institute (CTSI) spans three major and preeminent universities, four large academic campuses across the state of Indiana, and is mandate to provide best practices to a whole state.

Methods: To address the need to facilitate the availability of innovative technologies to its investigators, the Indiana CTSI implemented the Access Technology Program (ATP).

Differential Splicing of Skipped Exons Predicts Drug Response in Cancer Cell Lines.

Alternative splicing of pre-mRNA transcripts is an important regulatory mechanism that increases the diversity of gene products in eukaryotes. Various studies have linked specific transcript isoforms to altered drug response in cancer; however, few algorithms have incorporated splicing information into drug response prediction. In this study, we evaluated whether basal-level splicing information could be used to predict drug sensitivity by constructing doxorubicin-sensitivity classification models with splicing and expression data.

Integrative analysis of histopathological images and chromatin accessibility data for estrogen receptor-positive breast cancer.

Background: Existing studies have demonstrated that the integrative analysis of histopathological images and genomic data can be used to better understand the onset and progression of many diseases, as well as identify new diagnostic and prognostic biomarkers. However, since the development of pathological phenotypes are influenced by a variety of complex biological processes, complete understanding of the underlying gene regulatory mechanisms for the cell and tissue morphology is still a challenge. In this study, we explored the relationship between the chromatin accessibility changes and the epithelial tissue proportion in histopathological images of estrogen receptor (ER) positive breast cancer.

regSNPs-ASB: A Computational Framework for Identifying Allele-Specific Transcription Factor Binding From ATAC-seq Data.

Expression quantitative trait loci (eQTL) analysis is useful for identifying genetic variants correlated with gene expression, however, it cannot distinguish between causal and nearby non-functional variants. Because the majority of disease-associated SNPs are located in regulatory regions, they can impact allele-specific binding (ASB) of transcription factors and result in differential expression of the target gene alleles. In this study, our aim was to identify functional single-nucleotide polymorphisms (SNPs) that alter transcriptional regulation and thus, potentially impact cellular function.

Epigenetic changes on rat chromosome 4 contribute to disparate alcohol drinking behavior in alcohol-preferring and -nonpreferring rats.

Background: Paternal alcohol abuse is a well-recognized risk factor for the development of an alcohol use disorder (AUD). In addition to genetic and environmental risk factors, heritable epigenetic factors also have been proposed to play a key role in the development of AUD. However, it is not clear whether epigenetic factors contribute to the genetic inheritance in families affected by AUD.

RegSNPs-intron: a computational framework for predicting pathogenic impact of intronic single nucleotide variants.

Single nucleotide variants (SNVs) in intronic regions have yet to be systematically investigated for their disease-causing potential. Using known pathogenic and neutral intronic SNVs (iSNVs) as training data, we develop the RegSNPs-intron algorithm based on a random forest classifier that integrates RNA splicing, protein structure, and evolutionary conservation features. RegSNPs-intron showed excellent performance in evaluating the pathogenic impacts of iSNVs.

Comprehensive Cis-Regulation Analysis of Genetic Variants in Human Lymphoblastoid Cell Lines.

Genetic variants can influence the expression of mRNA and protein. Genetic regulatory loci such as expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) exist in several species. However, it remains unclear how human genetic variants regulate mRNA and protein expression.

Allele-specific expression and high-throughput reporter assay reveal functional genetic variants associated with alcohol use disorders.

Genome-wide association studies (GWAS) of complex traits, such as alcohol use disorders (AUD), usually identify variants in non-coding regions and cannot by themselves distinguish whether the associated variants are functional or in linkage disequilibrium with the functional variants. Transcriptome studies can identify genes whose expression differs between alcoholics and controls. To test which variants associated with AUD may cause expression differences, we integrated data from deep RNA-seq and GWAS of four postmortem brain regions from 30 subjects with AUD and 30 controls to analyze allele-specific expression (ASE).

Lipopolysaccharides Improve Mesenchymal Stem Cell-Mediated Cardioprotection by MyD88 and stat3 Signaling in a Mouse Model of Cardiac Ischemia/Reperfusion Injury.

Bone marrow-derived mesenchymal stem cells (MSCs) improve cardiac function after ischemia/reperfusion injury, in part, due to the release of cytoprotective paracrine factors. Toll-like receptor 4 (TLR4) is expressed in MSCs and regulates the expression of cytoprotective factors, cytokines, and chemokines. Lipopolysaccharide (LPS) stimulation of TLR4 activates two distinct signaling pathways that are either MyD88 dependent or MyD88 independent/TIR-domain-containing adapter-inducing interferon-β (TRIF) dependent.

Estrogen-Dependent Upregulation of Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4.

Humans show sex differences related to alcohol use disorders (AUD). Animal model research has the potential to provide important insight into how sex differences affect alcohol consumption, particularly because female animals frequently drink more than males. In previous work, inbred strains of the selectively bred alcohol-preferring (P) and non-preferring (NP) rat lines revealed a highly significant quantitative trait locus (QTL) on rat chromosome 4, with a logarithm of the odds score of 9.

Cytogenetic features of human trophoblast cell lines SWAN-71 and 3A-subE.

Immortalization of primary cells with telomerase is thought to maintain normal phenotypic properties and avoid chromosomal abnormalities and other cancer-associated changes that occur following simian virus 40 tumor antigen (SV40 Tag) induced immortalization. However, we report that the human telomerase reverse transcriptase (hTERT)-immortalized SWAN-71 trophoblast cell line has a near pentaploid 103∼119,XXXX[cp20] karyotype. Additionally, DNA typing analysis indicated that SWAN-71 cells have acquired microsatellite instability.

Insulin receptor-like ectodomain genes and splice variants are found in both arthropods and human brain cDNA.

Truncated receptor ectodomains have been described for several classes of cell surface receptors, including those that bind to growth factors, cytokines, immunoglobulins, and adhesion molecules. Soluble receptor isoforms are typically generated by proteolytic cleavage of the cell surface receptor or by alternative splicing of RNA transcripts arising from the same gene encoding the full-length receptor. Both the epidermal growth factor receptor (EGFR) and the insulin receptor (INSR) families produce soluble receptor splice variants in vertebrates and truncated forms of insulin receptor-like sequences have previously been described in .