Biology subjects

Yadav, S. S.

Publications and source records attributed to Yadav, S. S..

6 recordsLinked to original sources

bioRxiv2026

Rpl12 paralog dependent TOR-signaling controls the expression of ribosome preservation factor Stm1

Ribosomes are increasingly recognized as heterogeneous regulators of gene expression, yet how ribosomal protein paralogs interface with nutrient signaling remains poorly understood. In Saccharomyces cerevisiae, ribosomal protein gene expression is governed by duplicated gene pairs, many of which exhibit functional divergence despite high sequence identity. A central regulator of ribosome biogenesis and translational control is the Target of Rapamycin (TOR) pathway, which integrates nutrient signals to modulate growth, stress adaptation, and lifespan. Target of Rapamycin Complex 1 (TORC1) influences ribosome activity by phosphorylating ribosomal protein S6 (Rps6), a modification that links nutrient availability to translational output. Here, we investigated the functional divergence of the Rpl12 ribosomal stalk protein paralogs RPL12a and RPL12b and found that rpl12b{Delta} produces phenotypes consistent with reduced TOR activity, including decreased Rps6 phosphorylation, G2/M cell-cycle accumulation, and significant extension of chronological lifespan as compared to rpl12a{Delta} and wildtype strain. Multi-omics analyses further indicate translational and metabolic reprogramming consistent with activation of a stress-adaptive program associated with Gcn4. Importantly, loss of RPL12b also reduces levels of the ribosome preservation factor Stm1, a TORC1-regulated protein required for stabilization of 80S ribosomes under stress. This finding links ribosomal stalk composition to ribosome stability and nutrient-responsive signaling. Together, our results demonstrate that ribosomal paralog specialization provides an additional regulatory layer connecting translation, TOR signaling, and cellular longevity.

cell biology↗

bioRxiv2025

Structural Validation of the Intermediate Leptomeningeal Layer in the Human Central Nervous System

Traditionally, the human central nervous system (CNS) is described as having three meningeal layers, from outer to inner: dura mater, arachnoid mater, and pia mater. The arachnoid and pia mater are called the leptomeninges, and the space between them is filled with cerebrospinal fluid (CSF). Using gross dissection, light microscopy, and ultrastructural analysis of fresh postmortem and cadaveric CNS specimens spanning fetal to adult ages (N=61), we demonstrate a fibrocellular intermediate leptomeningeal layer (ILL) from the cortex to the caudal end of the spinal cord. The ILL divides the subarachnoid space (SAS) into two distinct structural compartments, through which vessels and nerves pass. The ILL shows unique structural features, such as dips into the brains sulci and fissures, as a double-fold membrane that bears intra-layer trabeculae, carries vessels, and forms the perivascular sheath. Moreover, throughout the CNS, it appears to be a non-sieved barrier, characterized by the presence of tight and adherens junctions. ILL, predominantly in the spinal cord, contains macrophage-like cells, indicating its layer-specific immune properties. The ILL warrants recognition as a distinct human meningeal layer with potential barrier and immune functions. SignificanceO_ST_ABSAn Intermediate Leptomeningeal Layer encloses the Central Nervous System in HumansC_ST_ABSThe integrated analysis of our macroscopic, microscopic, and ultrastructural study provides robust support for an intermediate leptomeningeal layer (ILL) in the subarachnoid space (SAS) of the human central nervous system (CNS) along the entire neural axis. The ILL is a fibrocellular macroscopic structure, with restricted permeability, that divides the cerebrospinal fluid (CSF)-filled SAS into two distinct structural compartments. Uniquely, ILL revealed the presence of cells with macrophage-like properties, suggesting a possible role in immune surveillance. The ILL may redefine the established concept of protective coverings of CNS, CSF circulation dynamics, and the role of leptomeninges in health and disease, including drug delivery.

neuroscience↗

bioRxiv2024

BLM Aggregation-Prone Ability and Similarity to Intrinsically Disordered Proteins Indicate its Potential Role in Neurodegenerative Diseases

BLM helicase is a member of the RecQ family of DNA helicases, enzymes that play a critical role in maintaining genome stability. The BLM protein is named after Bloom syndrome (BS), a rare genetic disorder caused by mutations in the helicase domain of BLM gene. BLM role has mostly been studied in DNA repair, replication, and recombination; however, a recent study has highlighted the RNA binding capability of the BLM protein. Several proteins, including TDP43, Tau, and alpha-synuclein, are known to play key roles in neurodegenerative diseases. These proteins possess residues prone to parallel aggregation and fibril formation, the key contributor to neurodegenerative disease development. We utilized various in-silico tools like PASTA 2.0, SIFT, PolyPhen 2, and PhD SNP, SNP&GO, Meta-SNP, and SNAP, etc., to identify the molecular signature of the BLMs protein. Our in-silico analysis suggests that the BLMs HRDC domain has ability of parallel aggregation and fibril formation. Moreover, structural similarity with proteins like -synuclein, TDP-43, and Tau and its interactions with PARP1 suggests it may have a role in neurodegenerative diseases. Furthermore, we identified deleterious mutations in the HRDC domain of BLM protein that may compromise its stability and alter its function. Hence, these findings suggest that in addition to BLMs well-known functions, the protein may have ability to form parallel aggregation and fibril formation and its role in neurodegenerative disease need to further be explored. Author SummaryThis paper higlights the importance of considering the structural and physical characteristics of the BLM protein, which may have been previously overlooked in the context of disease pathology. Through in-silico analyses, we identified that the BLM protein possesses residues within the HRDC domain that are prone to parallel aggregation and fibril formation. Moreover, the structural similarity of BLM to proteins such as -synuclein, TDP-43, and Tau indicates a potential role for BLM in neurodegenerative processes. Additionally, we identified deleterious mutations within the HRDC domain that could compromise the stability of the protein. Furthermore, our findings suggest that the association between BLM and PARP1 may involve a regulatory mechanism that could significantly influence BLMs function.

bioinformatics↗

bioRxiv2024

Comprehensive Analysis of Exportins Expression and its Prognostic Significance in Colon Adenocarcinoma: Insights from Public Databases

Colon cancer remains a significant health burden globally, necessitating deeper investigation. Identification and targeting of prognostic markers can significantly improve the current therapeutic approaches for colon cancer. The differential nuclear transport (import and export) of cellular proteins, plays an important role in tumor progression. Exportins, critical mediators of nuclear export, have emerged as potential players in cancer pathogenesis. However, their precise roles and prognostic significance in colon adenocarcinoma remain elusive. This study was designed to comprehensively analyse the expression and prognostic significance of all seven exportins in Colon Adenocarcinoma (COAD) using the online public database. We used public databases UALCAN, C-Bio portal, Human Protein Atlas (HPA), and DAVID, to investigate exportins in COAD patients. Kaplan-Meier plotter, Gene ontology (GO), TIMER, STRING, and KEGG were used to analyse data and draw conclusions. Our observations showed a significant correlation of exportins expression with clinical parameters, used to predict a patients prognosis in general, such as advancing tumor stage, overall/relapse-free survival, and immune cell infiltrations. Mutation analysis showed the presence of amplifications, missense mutations in XPO2 and XPO4, and deep deletions in XPO7 genes contributing to disease progression and patients survival. This study highlights the potential use of exportins as novel prognostic biomarkers and therapeutic targets for colon adenocarcinoma progression and management.

cancer biology↗

bioRxiv2023

Molecular pathways and cellular subsets associated with adverse clinical outcomes in overlapping immune-related myocarditis and myositis

Immune checkpoint therapies (ICTs) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we obtained heart and skeletal muscle biopsies for single-cell RNA sequencing in living patients with cancers treated with ICTs admitted to the hospital with myocarditis and /or myositis (overlapping myocarditis plus myositis, n=10; myocarditis-only, n=1) compared to ICT-exposed patients ruled out for toxicity utilized as controls (n=9) within 96 hours of clinical presentation. Analyses of 58,523 cells revealed clonally expanded CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of tissue-resident myeloid cells expressed Fc{gamma}RIIIa, which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d that were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL-1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results are the first to recognize these myeloid subsets in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/556590v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@b5895forg.highwire.dtl.DTLVardef@4dec8corg.highwire.dtl.DTLVardef@1e50cb9org.highwire.dtl.DTLVardef@a653fd_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2018

Epigenetic analysis identifies factors driving racial disparity in prostate cancer

Prostate cancer (PCa) is the second most leading cause of death in men worldwide. African American men (AA) represent more aggressive form of PCa as compared to Caucasian (CA) counterparts. Evidence suggests that genetic and other biological factors could account for the observed racial disparity. We analyzed the cancer genome atlas (TCGA) dataset (2015) for existing epigenetic variation in AA and CA prostate cancer patients, and carried out Reduced Representation Bisulphite Sequencing (RRBS) analysis to identify global methylation changes in AA and CA prostate cancer patients. The TCGA dataset analysis revealed that the epigenetic heterogeneity could be categorized into 4 classes, where AA associated primarily to methylation cluster 1 (p value 0.048), and CA associated to methylation cluster 3 (p value 0.000146). We identified enrichment of Wnt signaling genes in both AA and CA, however they were differentially activated in terms of canonical and non-canonical Wnt signaling pathway activation. This was further validated using the GenomeDx expression data. Our RRBS data also suggested distinct methylation patterns in AA compared to CA, and in part validated our TCGA findings. Survival analysis using the RRBS data suggested hypomethylated genes to be significantly associated with recurrence of prostate cancer in CA (p=6.07x10-6) as well as in AA (p=0.0077). Overall, the observed racial disparity in the molecular mechanism involved in the pathogenesis of prostate cancer suggests diverse heterogeneity that potentially could affect survival and should be considered during prognosis and treatment.

cancer biology↗