Biology subjects

Finkel, N.

Publications and source records attributed to Finkel, N..

5 recordsLinked to original sources

bioRxiv2026

Integration of iPSC-derived microglia into human midbrain organoids enhances microglial maturation and inflammatory signaling

Microglia are the resident immune cells of the central nervous system and play key roles in the healthy brain during development and adulthood, as well as during neurodegenerative diseases - including Parkinsons disease (PD). Yet the role of microglia in PD pathogenesis has not been fully elucidated. Limitations of 2D cell culture and animal models in simulating human microglia in the brain parenchyma have contributed to this knowledge gap. Human midbrain organoids (hMOs) provide a promising model that can recapitulate elements of PD pathology but lack microglial cells. Here we adapt protocols for the differentiation of hMOs and human iPSC-derived microglia (iMG) to generate iMG-hMO assembloids. Within assembloids, integrated iMG (intMG) express canonical microglia markers and induce the release of cytokines and chemokines. Transcriptomic profiling by single cell RNA sequencing reveals that intMG adopt a more mature and inflammation-responsive state compared to 2D iMG. The integration of microglia results in increased signaling through inflammatory and trophic pathways that drive altered transcriptional signatures of dopaminergic neurons and astrocytes within assembloids. Overall, iMG-hMO assembloids have the potential to more faithfully model the role of microglia and neuroinflammation in PD pathogenesis.

neuroscience↗

bioRxiv2026

The impact of low-frequency genetic variants on serum protein levels

The mapping of protein quantitative trait loci (pQTLs) can provide molecular links between genotype and phenotype. Most such studies focus on common variants, but the effects of low-frequency (LF) variants remain underexplored. Focusing on cis-pQTLs, we integrated serum measurements of 7,596 proteins with genomic data, including LF variants (minor allele frequency [MAF] 0.1-1%), in 5,291 Icelanders to identify independent cis-pQTLs for 2,166 SOMAmers. Incorporating LF variants increased the number of detected genetic signals per protein, demonstrating widespread allelic heterogeneity in cis-acting regulation of serum proteins. LF pQTLs were enriched for coding variants in the respective protein-encoding gene, but also among distal secondary signals, revealing additional regulatory layers not captured by common variants alone. Proteins affected by common variant cis-pQTLs were more often secreted and exhibited tissue-specific expression, whereas proteins exclusively affected by LF variants were primarily from more constrained and biologically essential pathways. Expanding both protein coverage and the allele-frequency spectrum reveals a more complex and heterogeneous cis-regulatory architecture of circulating proteins.

genomics↗

bioRxiv2025

Long-term temporal stability of circulating proteins in older adults

Circulating proteins reflect diverse biological processes and can offer critical insights into an individual s overall health and aging trajectory. The circulating proteome is shaped by a complex interplay of genetic, biological, and environmental factors across the lifespan. However, little is known about which factors influence its long-term temporal stability. Here we used SomaScan proteomics to evaluate the five-year temporal stability of 7,288 proteins measured in serum from 3,093 participants (mean age 76 years) of the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study. We observed a wide variability in the temporal stability of individual proteins, with temporally stable proteins more often being extracellular and associated with diseases, while temporally variable proteins are typically involved in intracellular housekeeping functions. We demonstrate that temporal stability of circulating proteins does not reflect that of transcriptomic stability in tissues, and that genetic effects and disease stage are two major contributors to protein temporal stability in the circulation. Our findings underscore the protein-specific differences in long-term temporal stability, and the genetic and biological factors influencing them, which are particularly important to consider in the context of biomarker development and precision medicine.

genomics↗

bioRxiv2024

Biomarker Identification by Proteomic Analysis of Vitreous Humor and Plasma in Diabetic Retinopathy

ImportanceIdentify detectable plasma and/or vitreous signals to potentially predict diabetic retinopathy (DR) progression for earlier disease intervention. ObjectiveTo determine the mediators and potential disease progression biomarkers of DR in vitreous humor (VH) and plasma samples using the SomaScan proteome profiling platform. DesignDifferential expression analysis was conducted on VH and plasma samples using the SomaScan Assay. SettingA non-interventional study conducted to collect and analyze VH and plasma samples from patients with diabetic retinopathy. ParticipantsSamples from DR (60 nonproliferative diabetic retinopathy/NPDR, 60 proliferative diabetic retinopathy/PDR) and 60 control patients were collected. Main outcomes and MeasuresDifferentially expressed proteins between disease and control groups were identified. Pathway enrichment analysis was conducted to identify significantly perturbed pathways in DR. Finally, a random forest model was used to identify predictive biomarkers of disease progression. ResultsSomaScan v3 is a pooled aptamer hybridization assay using 5080 SOMAmers to probe over 4100 proteoforms in VH and plasma samples from 3 groups (control, NPDR, and PDR). The most profound protein content change was observed in the VH samples of PDR patients, while minimal changes were measured in plasma samples, highlighting the regionality of PDR pathogenesis. Many key molecules and molecular pathways such as VEGF-A, erythropoietin, and inflammation-associated proteins implicated in DR were significantly affected in the VH of PDR patients. In addition to the classic pathways (hypoxia, immune response, mTORC1 signaling) known to be involved in PDR, novel signaling pathways, including HEME metabolism and adipogenesis, were identified in VH samples. Application of a machine learning algorithm identified a panel of plasma PDR predictive biomarkers and revealed SCARA5 as the top one based on the largest average Gini decrease in the model. ConclusionOur study identified profound alteration of protein expression and molecular pathways in the VH of PDR patients, supporting the key role of local pathogenic changes in DR progression compared to systemic factors. Although the systemic changes related to DR were small, a few disease progression predictive candidate biomarkers (SCARA5, PTK7, FAM3Band FAM3D) were identified, prompting further investigation. Key PointsQuestion: Are plasma/ vitreous humor (VH) proteins predictive of diabetic retinopathy (DR) progression? Findings: This study identifies substantial protein changes in the VH of proliferative diabetic retinopathy (PDR) patients, while early nonproliferative DR (NPDR) patients show minimal change. We identify multiple proteins linked to angiogenesis, inflammation, immune cells (microglia/macrophage/neutrophil), and leukostasis associated with PDR and reveal a potential plasma panel of disease progression (from NPDR to PDR) biomarkers (SCARA5, PTK7, FAM3B, FAM3D). Meaning: Identified disease progression predictive biomarkers permits potential development of prognostic tools to identify individuals most at risk for PDR progression and offering reduced disease burden by earlier intervention.

physiology↗

bioRxiv2019

Tombusvirus p19 captures RNase III-cleaved double-stranded RNAs formed by overlapping sense and antisense transcripts in E. coli

Antisense transcription is widespread in bacteria. By base pairing with overlapping sense RNAs, antisense RNAs (asRNA) can form long double-stranded RNAs (dsRNA), which are cleaved by RNase III, a dsRNA endoribonuclease. Ectopic expression of plant tombusvirus p19 in E. coli stabilizes ~21 bp dsRNA RNase III decay intermediates, which enabled us to characterize otherwise highly unstable asRNA by deep sequencing of p19-captured dsRNA and total RNA. dsRNA formed at most bacterial genes in the bacterial chromosome and in a plasmid. The most abundant dsRNA clusters were mostly formed by divergent transcription of sense and antisense transcripts overlapping at their 5-ends. The most abundant clusters included small RNAs, such as ryeA/ryeB, 4 toxin-antitoxin genes, and 3 tRNAs, and some longer coding genes, including rsd and cspD. The sense and antisense transcripts in abundant dsRNA clusters were more plentiful and had longer half-lives in RNase III mutant strains, suggesting that formation of dsRNAs promoted RNA decay at these loci. However, widespread changes in protein levels did not occur in RNase III mutant bacteria. Nonetheless, some proteins involved in antioxidant responses and glycolysis changed reproducibly. dsRNAs accumulated in bacterial cells lacking RNase III, increasing in stationary phase, and correlated with increased cell death in RNase III mutant bacteria in late stationary phase. The physiological importance of widespread antisense transcription in bacteria remains unclear but it may become important during environmental stress. Ectopic expression of p19 is a sensitive method for identifying antisense transcripts and RNase III cleavage sites in bacteria.

microbiology↗