Biology subjects

Samuel, S.

Publications and source records attributed to Samuel, S..

7 recordsLinked to original sources

bioRxiv2026

Headbutting goats self-inflict traumatic brain injury

Traumatic brain injury (TBI) is a characteristic feature of neurodegenerative diseases such as Alzheimers disease and chronic traumatic encephalopathy. Small animal models have been used to establish clinically relevant biomarkers of neuropathology, however, they show significant anatomical differences from humans and are affected by artificial experimental manipulations, making them often unsuitable for longitudinal study of repetitive mild TBI. There is a need for more diverse and translationally relevant animal models to better understand disease onset and development. Building on a previous study of neuropathology in headbutting bovids in the wild, this pilot study investigated whether freely headbutting domestic goats, which naturally engage in low-intensity, high-frequency head impacts, accumulate measurable biomarkers of neurodegeneration in cerebrospinal fluid (CSF) and brain tissue. Over a six-month period, three male goats (Capra hircus) were allowed to freely headbutt under continuous video surveillance. Monthly CSF samples were collected, and concentrations of key neurodegeneration biomarkers were measured via multiplex immunoassays, including amyloid-{beta} peptides (A{beta}40, A{beta}42), total and phosphorylated tau (tTau and pTau), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), and neurofilament M (NF-M). Imaging studies were completed for non-invasive assessment of glucose metabolism ([18F]-FDG) and neuroinflammation via translocator protein (TSPO, [18F]DPA-714). Postmortem immunohistochemistry was conducted on prefrontal cortical tissues using antibodies targeting pTau, GFAP, and S100B. Head impact kinematics were quantified using horn-mounted accelerometer and inclinometer sensors that recorded linear acceleration, rotational velocity, and head orientation during naturally occurring headbutting events. Several notable trends were observed. Phosphorylated tau as well as reactive astrocytes were detected in the brain tissue, mirrored by elevated GFAP detected in the CSF. PET TSPO did not illustrate a significant signal, however, PET FDG revealed frontal-dominant activity in all goats, and one with asymmetrical activation. Overall, the goats sustained 5,000-7,000 head impacts each over six months. Accelerometer measurements recorded forces up to 388 N and peak acceleration up to 16.5 g. This multi-modal observational study is the first to characterize neurodegeneration biomarkers and kinematics in headbutting goats. Even at one year old, the combination of pTau and gliosis in both the brain tissue and CSF indicates that the goats repetitive head impacts begin to show neurodegenerative consequences early in life. Likely, the severity of these consequences increases with headbutts and age, eventually resulting in chronic neurodegeneration. This system shows promise as a large-animal model for the longitudinal study of the onset and progression of neurodegenerative disease.

neuroscience↗

bioRxiv2025

Metabolite correlation networks reveal complex phenotypes of adaptation-driving mutations

Living organisms are organized into hierarchical levels of increasing complexity. As mutational effects propagate through these levels, multiple phenotypes are produced. However, identifying which phenotypes influence fitness and drive selection remains a key challenge in understanding genotype-phenotype-fitness relationships. Here, we demonstrate that mutation-induced structural changes in metabolite correlation networks--an organizational level with emergent properties shaped by the cumulative effects of multiple biochemical reactions and regulatory mechanisms--constitute complex phenotypes linking mutations to bacterial fitness. We engineered a metabolically suboptimal E. coli strain by replacing the metK gene encoding methionine adenosyltransferase (MAT) with an ortholog from U. urealyticum and subjected it to laboratory evolution. Analysis of correlation networks constructed from 2,118 untargeted metabolites revealed that adaptive mutations enhanced the strains fitness by reducing network density, removing node hubs, and extensively rewiring connectivity. These changes yielded smaller, more cohesive, and better-interconnected network clusters. Moreover, evolution shifted the node representing S-adenosylmethionine (SAM), the product of the MAT-catalyzed reaction, from a peripheral role to a key connector between network clusters with a significantly increased betweenness. None of the accumulated mutations potentially driving this transition directly influenced MAT activity or SAM metabolism, indicating that the shift in SAMs role is an adaptive phenotype emerging from the metabolic systems complexity. Targeted metabolomics of key nodes displaying similar network transitions unveiled additional metabolites involved in SAM-related pathways. We propose the construction and analysis of metabolite correlation networks as an experimental and analytical framework for mapping genotype-phenotype-fitness relationships and exploring the mechanisms of metabolic adaptation.

evolutionary biology↗

bioRxiv2023

An RNA foundation model enables discovery of disease mechanisms and candidate therapeutics

Accurately modeling and predicting RNA biology has been a long-standing challenge, bearing significant clinical ramifications for variant interpretation and the formulation of tailored therapeutics. We describe a foundation model for RNA biology, "BigRNA", which was trained on thousands of genome-matched datasets to predict tissue-specific RNA expression, splicing, microRNA sites, and RNA binding protein specificity from DNA sequence. Unlike approaches that are restricted to missense variants, BigRNA can identify pathogenic non-coding variant effects across diverse mechanisms, including polyadenylation, exon skipping and intron retention. BigRNA accurately predicted the effects of steric blocking oligonucleotides (SBOs) on increasing the expression of 4 out of 4 genes, and on splicing for 18 out of 18 exons across 14 genes, including those involved in Wilson disease and spinal muscular atrophy. We anticipate that BigRNA and foundation models like it will have widespread applications in the field of personalized RNA therapeutics.

bioinformatics↗

bioRxiv2022

Cinemeducation improves early clinical exposure to Inborn Errors of Metabolism

BackgroundCinemeducation has been shown to be an effective tool to help the students develop humanistic skills. However, there is a dearth of studies to find out if this can also be utilized to improve the interest and satisfaction of students learning about rare diseases such as the Inborn Errors of Metabolism. The aim was to introduce cinemeducation as part of early clinical exposure in teaching the inborn errors of metabolism for first-year MBBS students in the Department of Biochemistry. The Objectives were 1) to develop, validate and assess the feasibility of structured modules on Cinemeducation in teaching the Inborn Errors of Metabolism, 2) to study the impact of Cinemeducation on the satisfaction, interest, and academic performance of first-year MBBS students and 3) to study the perception of students and faculty towards Cinemeducation MethodsThis was a quasi-experimental, cross-over study involving 100 MBBS students in the Department of Biochemistry, AIIMS Kalyani. Movie clips prepared from Lorenzos Oil (for Lipid metabolism) and Extraordinary Measures (for Lysosomal Storage Disease) and corresponding paper-based cases; questionnaires and feedback forms were validated by expert group review. Analysis of quantitative data was performed in GraphPad, MS Excel and MAXQDA2022 software. Findings, Discussions and ConclusionsStudents academic performance was found to be improved in the groups where the Extraordinary Measures movie was used for Cinemeducation. Both learners and facilitators were satisfied with Cinemeducation. Cinemeducation was effectively introduced for teaching Inborn Errors of Metabolism in the Department of Biochemistry.

scientific communication and education↗

bioRxiv2022

ImmunoTyper-SR: A Novel Computational Approach for Genotyping Immunoglobulin Heavy Chain Variable Genes using Short Read Data

Human immunoglobulin heavy chain (IGH) locus on chromosome 14 includes more than 40 functional copies of the variable gene (IGHV), which, together with the joining genes (IGHJ), diversity genes (IGHD), constant genes (IGHC) and immunoglobulin light chains, code for antibodies that identify and neutralize pathogenic invaders as a part of the adaptive immune system. Because of its highly repetitive sequence composition, the IGH locus has been particularly difficult to assemble or genotype through the use of standard short read sequencing technologies. Here we introduce ImmunoTyper-SR, an algorithmic method for genotype and CNV analysis of the germline IGHV genes using Illumina whole genome sequencing (WGS) data. ImmunoTyper-SR is based on a novel combinatorial optimization formulation that aims to minimize the total edit distance between reads and their assigned IGHV alleles from a given database, with constraints on the number and distribution of reads across each called allele. We have validated ImmunoTyper-SR on 12 individuals with Illumina WGS data from the 1000 Genomes Project, whose IGHV allele composition have been studied extensively through the use of long read and targeted sequencing platforms, as well as nine individuals from the NIAID COVID Consortium who have been subjected to WGS twice. We have then applied ImmunoTyper-SR on 585 samples from the NIAID COVID Consortium to investigate associations between distinct IGHV alleles and anti-type I IFN autoantibodies which have been linked to COVID-19 severity.

bioinformatics↗

bioRxiv2020

Extensive proteomic and transcriptomic changes quench the TCR/CD3 activation signal of latently HIV-1 infected T cells

Although the ability of HIV-1 to reside in a latent state in CD4+ T cells constitutes a critical hurdle to a curative therapy, the biomolecular mechanisms by which latent HIV-1 infection is established and maintained are only partially understood. Ex vivo studies have shown that T cell receptor/CD3 stimulation only triggered HIV-1 reactivation in a fraction of the latently infected CD4+ T cell reservoir, suggesting that parts of the T cell population hosting latent HIV-1 infection events are altered to be TCR/CD3-activation-inert. We provide experimental evidence that HIV-1 infection of primary T cells and T cell lines indeed generates a substantial amount of TCR/CD3 activation-inert latently infected T cells. HIV-1 induced host cell TCR/CD3 inertness is thus a conserved mechanism that contributes to the stability of latent HIV-1 infection. Proteomic and genome-wide RNA-level analysis comparing CD3-responsive and CD3-inert latently HIV-1 infected T cells, followed by software-based integration of the data into protein-protein interaction networks (PINs) suggested two phenomena to govern CD3-inertness: (i) the presence of extensive transcriptomic noise that affected the efficacy of CD3 signaling and (ii) defined changes to specific signaling pathways. Validation experiments demonstrated that compounds known to increase transcriptomic noise further diminished the ability of TCR/CD3 stimulation to trigger HIV-1 reactivation. Conversely, targeting specific central nodes in the generated PINs such as STAT3 improved the ability of TCR/CD3 activation to trigger HIV-1 reactivation in T cell lines and primary T cells. The data emphasize that latent HIV-1 infection is largely the result of extensive, stable biomolecular changes to the signaling network of the host T cells harboring latent HIV-1 infection events. In extension, the data imply that therapeutic restoration of host cell TCR/CD3 responsiveness could enable gradual reservoir depletion without the need for therapeutic activators, driven by cognate antigen recognition. AUTHOR SUMMARYA curative therapy for HIV-1 infection will at least require the eradication of a small pool of CD4+ helper T cells in which the virus can persist in a latent state, even after years of successful antiretroviral therapy. It has been assumed that activation of these viral reservoir T cells will also reactivate the latent virus, which is a prerequisite for the destruction of these cells. Remarkably, this is not the case and following application of even the most potent stimuli that activate normal T cells through their T cell receptor, a large portion of the latent virus pool remains in a dormant state. Herein we demonstrate that a large part of latent HIV-1 infection events reside in T cells that have been rendered activation inert by the actual infection event. We provide a systemwide, biomolecular description of the changes that render latently HIV-1 infected T cells activation inert and using this description, devise pharmacologic interference strategies that render initially activation inert T cells responsive to stimulation. This in turn allows for efficient triggering of HIV-1 reactivation in a large part of the latently HIV-1 infected T cell reservoir.

microbiology↗

bioRxiv2018

Silencing of ANKRD12 circRNA induces molecular and functional changes associated with invasive phenotypes

Circular RNAs (circRNA) that form through non-canonical backsplicing events of pre-mRNA transcripts are evolutionarily conserved and abundantly expressed across species. However, the functional relevance of circRNAs remains a topic of debate. In this study, we identified and characterized a circular RNA derived from Exon 2 and Exon 8 of the ANKRD12 gene, termed here as circANKRD12. We show that this circRNA is abundantly expressed in breast and ovarian cancers. The circANKRD12 is RNase R resistant and predominantly localized in the cytoplasm in contrast to its source gene mRNA. We confirmed the expression of this circRNA across a variety of cancer cell lines and provide evidence for its functional relevance through downstream regulation of several tumor invasion genes. We show that silencing of circANKRD12 induces a phenotypic change by significantly regulating cell cycle, increasing invasion and migration, altering the metabolism in cancer cells. These results reveal the functional significance of circANKRD12 and provide evidence of a regulatory role for this circRNA in cancer progression.

cancer biology↗