Biology subjects

Sansing, L. H.

Publications and source records attributed to Sansing, L. H..

4 recordsLinked to original sources

bioRxiv2026

Proteomic and Transcriptomic Differences in Ischemic Stroke Patients with Atrial Fibrillation Versus Carotid Atherosclerosis

BackgroundIschemic stroke occurring in the setting of atrial fibrillation (AF) or carotid atherosclerosis (CA) may reflect distinct underlying biological processes. We integrated proteomic, transcriptomic, and genetic data from different sources to identify circulating proteins and molecular pathways associated with ischemic stroke in patients with AF versus CA. MethodsWe conducted a nested proteomic study within the UK Biobank comparing plasma protein levels among ischemic stroke patients with AF (n=539) and CA (n=127). Linear regression models were used to evaluate 2,923 proteins measured using the Olink Explore platform (false discovery rate [FDR] <0.05). In a separate Yale cohort, we evaluated expression of genes encoding identified proteins in thrombectomy clot single-cell RNA sequencing data from ischemic stroke patients with AF (n=7) or CA (n=7), including cell type-specific expression patterns. We then used summary statistics to perform 2-sample Mendelian randomization analyses using cis-protein quantitative trait loci to evaluate associations between genetically predicted levels of proteins identified in prior analyses and ischemic stroke subtypes. Exploratory pathway enrichment analyses were also performed. ResultsTwelve circulating proteins differed significantly between ischemic stroke patients with AF versus CA. AF was associated with higher levels of NTproBNP, NPPB, and ACP5, and lower levels of APCS, ANGPT2, PAMR1, PRCP, PROS1, LARP1, F7, F10, and LEO1 (all FDR<0.05). Clot transcriptomic analyses showed corresponding differential expression of ACP5, PRCP, LARP1, ANGPT2, and LEO1 across AF versus CA patients. Pathway analyses suggested enrichment of coagulation-related pathways among proteins associated with CA and natriuretic peptide signaling pathways among proteins associated with AF. Mendelian randomization analyses demonstrated associations between genetically predicted protein levels and ischemic stroke subtypes (AF or CA), including cardioembolic stroke for NTproBNPand ischemic stroke for ANGPT2, ACP5, APCS, and PAMR1. ConclusionComplementary proteomic, transcriptomic, and genetic analyses identified differing molecular profiles among ischemic stroke patients with AF versus CA. These findings support established biomarkers, including NTproBNP and coagulation-related proteins, while identifying additional candidate pathways that may contribute to biological differences between these stroke-associated conditions. Further validation in clinically adjudicated and longitudinal cohorts is needed.

neuroscience↗

bioRxiv2024

Single-Cell Temporal Atlas of Myeloid Cells in the Live Haemorrhagic Brain

Innate immune cells contribute to both secondary brain injury and repair following intracerebral hemorrhage (ICH). However, the specific signaling pathways that govern initial inflammatory and subsequent reparative myeloid programs in living patients remain poorly understood. To better characterize mononuclear phagocyte cell changes over time, we generated a single-cell transcriptomic dataset of paired hematoma clot evacuates and peripheral blood samples from 10 patients following ICH (5 - 290 hours). We identified distinct populations of activated and TNF-low microglia, as well as a unique, highly activated population of CD14+ monocytes in the hematoma. Perturbation analysis identified TNF signaling as the primary driver of hematoma monocyte activation. Custom temporal trajectory analysis using single-cell foundation model embeddings found that this TNF response in monocytes was transient, peaking early after hemorrhage and decreasing over the following 48 hours as monocytes shifted to reparative transcriptional programs. Transiently activated microglia emerged as the likely acute source of TNF, signaling through monocyte TNFR2. Surprisingly, acute TNF signaling in CD14+ monocytes was also associated with better severity-adjusted neurological outcomes both in our cohort and an independent validation cohort. These findings suggest acute TNF signaling between activated microglia and hematoma-associated monocytes, particularly through TNFR2, may contribute to recovery following ICH. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/630187v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@ff4fa0org.highwire.dtl.DTLVardef@1c4cc5borg.highwire.dtl.DTLVardef@1449761org.highwire.dtl.DTLVardef@2e7ea6_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Single-nucleus RNA sequencing of human periventricular white matter in vascular dementia

Vascular dementia (VaD) refers to a variety of dementias driven by cerebrovascular disease and is the second leading cause of dementia globally. VaD may be caused by ischemic strokes, intracerebral hemorrhage, and/or cerebral small vessel disease, commonly identified as white matter hyperintensities on MRI. The mechanisms underlying these white matter lesions in the periventricular brain are poorly understood. In this study we perform an extensive transcriptomic analysis on human postmortem periventricular white matter lesions in patients with VaD with the goal of identifying molecular pathways in the disease. We find increased cellular stress responses in astrocytes, oligodendrocytes, and oligodendrocyte precursor cells as well as transcriptional and translational repression in microglia in our dataset. We show that several genes identified by GWAS as being associated with white matter disease are differentially expressed in cells in VaD. Finally, we compare our dataset to an independent snRNAseq dataset of PVWM in VaD and a scRNAseq dataset on human iPSC-derived microglia exposed to oxygen glucose deprivation (OGD). We identify the increase of the heat shock protein response as a conserved feature of VaD across celltypes and show that this increase is not linked to OGD exposure. Overall, our study is the first to show that increased heat shock protein responses are a common feature of lesioned PVWM in VaD and may represent a potential therapeutic target.

neuroscience↗

bioRxiv2020

Leukocyte dynamics after intracerebral hemorrhage in a living patient reveal rapid adaptations to tissue milieu

Intracerebral hemorrhage (ICH) is a devastating form of stroke with a high mortality rate and few treatment options. Discovery of therapeutic interventions has been slow given the challenges associated with studying acute injury, particularly over time, in the human brain. Inflammation induced by exposure of brain tissue to blood appears to be a major part of brain tissue injury. Here we longitudinally profiled blood and cerebral hematoma effluent from a patient enrolled in the Minimally Invasive Surgery with Thrombolysis in Intracerebral Haemorrhage Evacuation (MISTIEIII) trial, offering a rare window into the local and systemic immune responses to acute brain injury. Using single-cell RNA-sequencing, we characterized the local cellular response during ICH in the brain of a living patient at single-cell resolution for the first time. Our analysis revealed rapid shifts in the activation states of myeloid and T cells in the brain over time, suggesting that leukocyte responses are dynamically reshaped by the hematoma microenvironment. Interestingly, the patient had an asymptomatic re-bleed (second local exposure to blood) that our transcriptional data indicated occurred more than 30 hours prior to detection by CT scan. This case highlights the rapid immune dynamics in the brain after ICH and suggests that sensitive methods like scRNA-seq can inform our understanding of complex intracerebral events.

immunology↗