Biology subjects

Alekseyev, Y.

Publications and source records attributed to Alekseyev, Y..

3 recordsLinked to original sources

bioRxiv2025

Validation of bronchial airway gene expression associated with bronchiectasis in nasal epithelium

ObjectivesExamination of bronchial epithelium-derived gene expression signature of bronchiectasis (BE) in nasal epithelium. MethodsWe studied 220 participants from the Detection of Early Lung Cancer Among Military Personnel study with bulk RNA-seq of nasal epithelium brushings. Gene set enrichment analysis (GSEA) was used to examine whether genes previously identified as increased or decreased in the bronchial epithelium of individuals with radiologic BE are significantly enriched among the genes most significantly altered in the nasal epithelium. GSEA and cell-type specific gene expression signatures were used to examine changes in the cellular composition of nasal epithelium associated with radiologic BE. ResultsGenes previously found to have significantly altered expression in bronchial epithelium in radiologic BE are concordantly enriched among the genes most increased or decreased in nasal epithelium in radiologic BE in this validation set (p = 3x10-7, increased; p = 6x10-8, decreased). GSEA performed using cell-type signatures demonstrates that in nasal epithelium, BE is associated with increased multiciliated and deuterosomal cell-related gene expression and decreased expression of basal cell- related gene expression, consistent with our previous findings in bronchial epithelium. ConclusionOur work validates our bronchial signature of BE in an independent dataset and demonstrates that similar gene expression changes are associated with radiologic BE in the bronchial and nasal epithelium. These findings support considering nasal epithelium brushing as a less invasive tool for screening and monitoring BE. SummaryThis study validates a previously reported bronchial signature of bronchiectasis (BE) in nasal epithelium. Changes in gene expression and cell-type composition associated with radiologic BE are similar across both bronchial and nasal epithelium.

bioinformatics↗

bioRxiv2023

Single nucleus transcriptomics of human and monkey striatum implicates DNA damage, neuroinflammation, and neurodegeneration signaling in opioid use disorder

The striatum in the brain is involved in various behavioral functions, including reward, and disease processes, such as opioid use disorder (OUD). Further understanding of the role of striatal subregions in reward behaviors and their potential associations with OUD requires molecular identification of specific striatal cell types in human brain. The human striatum contains subregions based on different anatomical, functional, and physiological properties, with the dorsal striatum further divided into caudate and putamen. Both caudate and putamen are involved in altered reward processing, formation of habits, and development of negative affect states associated with OUD. Using single nuclei RNA-sequencing of human postmortem caudate and putamen, we identified canonical neuronal cell types in striatum (e.g., dopamine receptor 1 or 2 expressing neurons, D1 or D2) and less abundant subpopulations, including D1/D2-hybrid neurons and multiple classes of interneurons. By comparing unaffected subjects to subjects with OUD, we found neuronal-specific differences in pathways related to neurodegeneration, interferon response, and DNA damage. DNA damage markers were also elevated in striatal neurons of rhesus macaques following chronic opioid administration. We also identified sex-dependent differences in the expression of stress-induced transcripts among astrocytes and oligodendrocytes from female subjects with OUD. Thus, we describe striatal cell types and leverage these data to gain insights into molecular alterations in human striatum associated with opioid addiction.

neuroscience↗

bioRxiv2021

Competition between distinct ApoE alleles and mCRP for the endothelial receptor CD31 differentially regulates neurovascular inflammation and Alzheimer's disease pathology

BACKGROUNDC-reactive protein (CRP) in peripheral inflammation is associated with increased Alzheimers disease (AD) risk in Apolipoprotein E4 (ApoE4), but not ApoE3 or E2, humans. It remains unknown whether peripheral monomeric CRP (mCRP) induces AD pathogenesis through some receptor of blood-facing endothelia in the brain in an ApoE genotype dependent fashion. METHODSWe used human samples, ApoE knock-in and deficient mouse models, and primary brain endothelia. Different ApoE mice were intraperitoneally (i.p.) injected with mCRP. The characterizations by immunostaining, proximity ligation assay (PLA) and siRNA were conducted to identify the receptor for mCRP. Brain microvessel and endothelia were isolated for RNA sequencing to explore the molecular pathway. RESULTSWe demonstrate that CD31 (PECAM-1), a blood-facing endothelial receptor in brain, is a competitive target of both mCRP and ApoE protein. ApoE2 competes more strongly with mCRP for CD31 than ApoE4 does, and expressing ApoE4 or knocking out ApoE gene results in higher levels of mCRP-CD31 binding, leading to a decrease of CD31 expression but an increase in CD31 phosphorylation, along with greater cerebrovascular damage and AD pathology. This competitive binding mediates differential endothelial molecular responses depending on ApoE genotype, increasing cerebrovascular inflammation and mitochondria impairment in ApoE4 mice, while inducing vasculogenesis and protective changes in the presence of ApoE2. CONCLUSIONSOur study reveals a novel and dynamic endothelial ApoE-mCRP-CD31 pathway for AD pathogenesis during chronic inflammation and provides some insight into the opposing ApoE4-neurodegenerative and ApoE2-neuroprotective effects in AD. Clinical PerspectiveO_ST_ABSWHAT IS NEW?C_ST_ABSO_LICD31 is a competitive target of both mCRP and ApoE in brain endothelia in an ApoE-allele dependent pattern C_LIO_LImCRP increases CD31 phosphorylation in the brain endothelia and damages cerebrovasculature in ApoE4 carriers and AD brains C_LIO_LImCRP expression results in neuroprotective or neurodegenerative pathway activation in an ApoE-dependent manner C_LI WHAT ARE THE CLINICAL IMPLICATIONS?O_LIAlthough ApoE4 is a major genetic risk factor of AD, some ApoE4 carriers do not develop AD by the age of 90. C_LIO_LIElderly people often experience peripheral inflammatory attacks and develop chronic low-grade inflammation, which results in the formation and release of mCRP. Because CRP is routine clinical laboratory test, clinicians can use blood CRP level to predict AD risk in ApoE4 carriers. C_LIO_LIEvidence of Apoe4 genotype and chronic low-grade inflammation stages marked by elevated CRP levels should be targeted in personalized treatment and clinical trials for AD. C_LI

neuroscience↗