Biology subjects

Mohan, C.

Publications and source records attributed to Mohan, C..

6 recordsLinked to original sources

bioRxiv2025

New proteomic biomarkers identified in plasma extracellular vesicles in sarcoidosis: a case-control matched study

BACKGROUNDSarcoidosis is a heterogeneous disease with unknown mechanisms, nonspecific therapies, and multiple etiologies. The role of blood extracellular vesicles (EVs) in the diagnosis and pathogenesis of sarcoidosis remains obscure. AIMS/OBJECTIVES. This study aims to test the hypothesis that the EV proteins in the blood can serve as phenotypic biomarkers of sarcoidosis. METHODS. We combined EV proteomics with machine learning algorithms to identify and prioritize biomarkers, enrich their functions, and cluster networks in case-control matched ACCESS patients. RESULTS. In total, 278 plasma EV proteins were significantly upregulated or downregulated in 40 sarcoidosis patients compared with 40 matched healthy controls. We identified 97 proteins that could serve as biomarkers with an AUC > 0.75. Of these, the AUC was > 0.90 for 13 proteins. 62 differentially expressed EV proteins strongly correlated with 20 clinical variables of severity, chest X-ray findings, and/or laboratory results. Functional annotation and network analysis suggest that these differentially expressed proteins regulate endocytosis, host responses to external stimuli, and transcription processes. Moreover, the top three ranked pathways were clathrin-mediated endocytosis, Hsp90 chaperone cycle, and spliceosome. CONCLUSIONS. This study demonstrates that plasma EV proteins can serve as biomarkers of various clinical phenotypes of the disease. At a Glance CommentaryCurrent Scientific Knowledge on the Subject: Sarcoidosis is a heterogeneous condition affecting multiple organs. The role of blood extracellular vesicles in the diagnosis and pathogenesis of this condition remains unknown. What This Study Adds to the Field: We identified differentially expressed proteins in plasma EVs by combining proteomics and machine learning algorithms. Top-ranked proteins can serve as diagnostic biomarkers and potential mechanisms for the development of sarcoidosis.

molecular biology↗

bioRxiv2023

FASlpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus

Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate dosage effects of FASlpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (sle1homo.lprhet) and compared it with B6.Faslpr/lpr(lprhomo), B6.Sle1/Sle1 (sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, sle1homo.lprhet mice exhibited significantly elevated serum anti-dsDNA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1, IL-2, and IL-27. Taken together, sle1homo.lprhet mice emerge as a more faithful model of human SLE, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing.

immunology↗

bioRxiv2020

A monotonicity-based gene clustering algorithm for enhancing clarity in single-cell RNA sequencing data

MotivationSingle-cell RNA sequencing (scRNA-seq) technologies and analysis tools have allowed researchers to achieve remarkably detailed understandings of the roles and relationships between cells and genes. However, conventional distance metrics, such as Euclidean, Pearson, and Spearman distances, fail to simultaneously take into account the high dimensionality, monotonicity, and magnitude of gene expression data. To address several shortcomings in these commonly used metrics, we present a magnitude-contingent monotonic correlation metric called Polaratio which is designed to enhance the quality of scRNA-seq data analysis. ResultsWe integrate three interpretable clustering algorithms - Single-Cell Consensus Clustering (SC3), Hierarchical Clustering (HC), and K-Medoids (KM) - through a consensus cell clustering procedure, which we evaluate on various biological datasets to benchmark Polaratio against several well-known metrics. Our results demonstrate Polaratios ability to improve the accuracy of cell clustering on 5 out of 7 publicly available datasets. Availabilityhttps://github.com/dubai03nsr/Polaratio Contactpcicalese@uh.edu

bioinformatics↗

bioRxiv2018

Non-monotonic regulation of gene expression, neural progenitor fate and brain growth by the chromatin remodeller CHD8

Heterozygous CHD8 mutations are associated with autism and macrocephaly with high penetrance in the human population. The reported mutations may have loss-of-function (haploinsufficient), hypomorphic or dominant negative effects on protein function. To determine the effects of reducing CHD8 protein function below haploinsufficient levels on brain development, we established a Chd8 allelic series in the mouse. Chd8 heterozygous mice exhibited relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. In comparison, mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia, and significantly altered expression of over 2000 genes. Autism-associated genes were downregulated and neural progenitor proliferation genes upregulated. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, affecting genes and pathways that largely overlapped with those dysregulated in the mild hypomorphs. By contrast, homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in the induction of p53 target genes, cell cycle exit, apoptosis and pronounced brain hypoplasia. Intriguingly, increased progenitor proliferation in hypomorphs was primarily restricted to TBR2+ intermediate progenitors, suggesting critical roles for CHD8 in regulating the expansion of this population. Given the importance of these progenitors in human cortical growth, this observation suggests that human brain development might be more sensitive to CHD8 deficiency than the mouse. We conclude that brain development is acutely sensitive to CHD8 dosage and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage can result in non-linear effects on gene transcription and brain growth.

neuroscience↗

bioRxiv2017

Beyond Autoantibodies: Biological Roles Of Human Autoreactive B Cells In Rheumatoid Arthritis Revealed By Whole Transcriptome Profiling

Although the contribution of B-cell derived autoreactive antibodies to rheumatoid arthritis (RA) has been studied extensively, the autoantibody-independent roles of B cells in the progression of the disease is not well-defined. Here we present the first comprehensive transcriptome profile of human autoreactive B cells in an autoimmune disease by performing RNA-sequencing of citrulline-specific B cells from RA patients. In order to facilitate a comprehensive understanding of the profile of these citrulline-specific (RA-CCPPOS) B cells, we performed comparative analyses to both citrulline-negative (RA-CCPNEG) B cells from the same donors, and identified 431 differentially expressed genes (DEGs); and hemagglutinin-specific (HA) B cells from healthy individuals and identified 1658 DEGs. Three-way comparisons of these B cell populations demonstrated that RA-CCPPOS B cells, in comparison to the RA-CCPNEG B cells, demonstrate a potential role in protein citrullination and inflammation; RA-CCPPOS B cells in comparison to HA-specific B cells demonstrate RA-specific signatures like the expression of pro-inflammatory cytokines, chemokines, costimulatory molecules and B-cell activation cascades; and all B cells from RA patients demonstrated a significant impact of the multitude of TNF signaling pathways. Furthermore, transcription factor profiling suggested that cyclic AMP (cAMP) related pathways and downstream signaling molecules are selectively enriched in RA-CCPPOS cells in comparison to the other two B cell subsets. We advanced the understanding of the citrulline reactive B cells in RA pathophysiology by documenting and validating two novel observations in independent cohorts of patients: (1) the expression of IL15R is restricted to citrulline-specific cells within RA patients and the concentration of soluble IL15R is elevated in the sera of RA patients, (2) B cells from RA patients are capable of producing epidermal growth factor ligand, amphiregulin (AREG) which in turn has a direct impact on the mechanistic effectors of RA, osteoclasts and fibroblastlike synoviocytes (FLS). Overall, our comprehensive dataset identifies several existing FDA-approved drugs that can potentially be repurposed for RA and can serve as a foundation for studying the multi-faceted roles of B cells in other autoimmune diseases.

immunology↗

bioRxiv2017

Distinctive Behavioural Anomalies, Structural Brain Phenotypes And Cortical Hyper-Connectivity In Chd8-Deficient Mice

Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. To investigate how reduced Chd8 gene dosage may disrupt brain development and predispose individuals to ASD, we generated a Chd8 heterozygous mouse model. In line with clinical observations, we found that Chd8 heterozygous mice displayed subtle brain hyperplasia and hypertelorism, coupled with increased postnatal brain weight. Chd8 heterozygous mice displayed anomalous behaviours, but autism-like social deficits, repetitive and restricted behaviours were not present. Only minor gene expression changes were observed in the embryonic neocortex at E12.5, with more pronounced gene expression changes in postnatal cortex at P5. Differentially expressed genes showed highly significant enrichment for known autism candidates. Amongst the down-regulated transcripts, genes involved in cell adhesion and axon guidance were particularly prominent, implicating impaired connectivity as a potential mechanism underlying the ASD phenotype. To probe this further, we performed resting state functional fMRI and found increased synchronised activity in cortico-hippocampal and auditory-parietal networks, hinting at impaired sensory processing. Together, these data show that Chd8 heterozygous mice recapitulate key clinical features found in patients with CHD8 mutations and show a unique combination of behavioural phenotypes, which may be underpinned by a distinctive disruption of brain connectivity and sensory processing.

neuroscience↗