Biology subjects

Hasan, S. S.

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

12 recordsLinked to original sources

bioRxiv2026

TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia

During respiratory virus infection, CD8 T cells kill infected cells and establish antigen-specific memory, but mechanisms regulating these functions remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM)-dependent mitochondrial fitness as a regulator of CD8 T cell function during influenza infection. Human CD8 T cells exhibited an age-associated decline in TFAM expression and mitochondrial function. To model this physiologically relevant decline and determine its consequences for antiviral immunity, we generated CD8 T cell-specific TFAM-haploinsufficient mice. TFAM insufficiency disrupted mitochondrial integrity and bioenergetics and increased mitochondrial DNA and oxidative stress. During influenza infection, TFAM-insufficient CD8 T cells exhibited increased cytotoxic and inflammatory activity associated with lung immunopathology without improved viral control. This early phenotype was followed by loss of effector function, diminished antigen-specific responses, reduced protection following adoptive transfer, and impaired heterosubtypic recall immunity. Thus, TFAM-dependent mitochondrial fitness is a cell-intrinsic regulator that limits immunopathology while sustaining recall immunity.

immunology↗

bioRxiv2026

Structure-Guided Design and Dynamic Evaluation of VP4-Targeting siRNAs Against Rotavirus A

Rotavirus is a major cause of severe diarrheal disease in children under the age of five, with reduced vaccine effectiveness in low-resource settings causing substantial morbidity and mortality. In the absence of approved antiviral therapeutics, treatment is largely supportive, urging the need for targeted and precision-based interventions. VP4 protein plays an essential role in viral attachment, entry, and infectivity, making it a suitable target for targeted therapy. In this context, RNA interference is a specific method for inhibiting viral gene expression with its efficacy depending on sequence conservation, target accessibility, and compatibility with the RISC-loading machinery. In the present study, an integrative in silico approach was employed to design and evaluate siRNAs targeting conserved regions of the VP4 gene across six geographically diverse countries. Candidate siRNAs were screened using established design rules and regression-based scoring with off-target filtering. Three optimized siRNAs were further assessed through structural modeling, molecular docking, and molecular dynamics simulations to examine interactions with human Dicer, TRBP, and Argonaute-2. Comparative dynamic analyses identified one siRNA with enhanced structural compatibility, reduced conformational fluctuations, and stable interactions with RISC-loading proteins. These findings provide a rational computational basis for VP4-targeted siRNA development, facilitating experimental validation.

bioinformatics↗

bioRxiv2025

An unconventional HxD motif orchestrates coatomer-dependent coronavirus morphogenesis

Assembly of infectious coronaviruses requires spike (S) protein trafficking by host coatomer, typically via a dibasic signal in the S cytoplasmic tail. However, the human embecoviruses HKU1 and OC43, as well as the model virus MHV, lack this motif. Here we identify a conserved His-x-Asp (HxD) sequence that functions as an unconventional coatomer-binding signal. Structural and biochemical analyses show that the MHV HxD motif engages coatomer subunits through distinct conformations, while cellular imaging demonstrates its role in directing S to assembly sites with the viral M-protein. Disruption of HxD-coatomer interactions impairs S incorporation and provokes compensatory viral adaptations, including emergence of a canonical dibasic motif or mutations in M-protein. Electron microscopy further reveals profound alterations in virion surface architecture. These findings uncover HxD as a previously unrecognized coatomer-targeting motif, highlighting an unexpected flexibility in coronavirus assembly pathways and broadening understanding of the cellular machinery that shapes coronavirus morphogenesis.

biochemistry↗

bioRxiv2025

Linking Genomic Landscape to Disease Mechanism: Core Genetic Factors Underlying Pathogenesis and Antimicrobial Resistance in Diarrheal Pathogens

BackgroundDiarrheal diseases remain a major global health burden, as they severely affect children, particularly in Bangladesh. After decades of research, the molecular mechanisms of diarrheal pathogens for disease pathogenesis and antibiotic resistance are still unknown, notably in Gram-negative bacteria. This pilot study fills the gap by employing whole genome sequencing and pan-genome analysis to analyze Bangladeshi diarrheal pathogens to identify genetic variables that cause disease pathogenesis and antibiotic resistance. ResultsHence, we investigated the genetic diversity of bacterial isolates from 31 clinical stool samples by a combination of whole-genome sequencing (WGS) and pan-genomic analysis. A core group of 50 genes, conserved across a significant number of strains, was identified via pan-genomic analysis, with considerable variation in accessory genes. This signifies a significant degree of genetic flexibility. Gene ontology analysis yielded substantial insights into prospective therapeutic targets by emphasizing the critical function of these core genes in bacterial survival and pathogenicity. Furthermore, the findings of the antimicrobial susceptibility test (AST) revealed concerning resistance trends, particularly to fluoroquinolones and beta-lactams, underscoring the necessity for enhanced surveillance and alternative therapeutic approaches. ConclusionThis study provides a comprehensive genetic framework to improve understanding of the complexity of diarrheal infections and the mechanisms underlying their resistance, fostering opportunities for potential therapeutic advancements.

microbiology↗

bioRxiv2025

APDeeM: A machine Learning strategy towards Effective Peptide Vaccine Candidates Identification against Different Types of Viruses

Viral infections pose significant global health challenges, underscoring the urgent need for improved medications. Nevertheless, traditional medicinal approaches depend significantly on labor-intensive laboratory tests, which impede efficient identification and prolong vaccine development, particularly when screening a huge number of samples. To address these obstacles, we present a comprehensive Antiviral Peptide (AVP) Detection Dataset, comprising 14 unique features to improve the characterization of antiviral and non-antiviral peptides. Subsequently, we introduce the Antiviral Peptide detection enhanced by Ensemble Machine Learning (APDeeM) system. This advanced computational framework considerably reduces the time required for AVP detection by utilizing ensemble learning methodologies. The APDeeM system incorporates Gradient Boosting, Random Forest, K-Nearest Neighbors (KNN), and AdaBoost algorithms to facilitate the swift selection of AVP candidates without requiring urgent laboratory testing. Our proposed ensemble methodology showed superior performance, with an accuracy of 85.99%, F1 score of 87.60%, recall of 88.91%, and precision of 86.32%, exceeding the efficacy of all tested antiviral peptide prediction models in this research. The APDeeM approach signifies a substantial improvement over conventional detection techniques, expediting the identification of prospective vaccine candidates and facilitating the advancement of more effective antiviral peptides. The most promising AVP candidates may urge laboratory validation, optimize resources, and accelerate vaccine development.

bioinformatics↗

bioRxiv2024

Dissecting Breast Cancer Heterogeneity Through Transcriptomics Insights of Diverse Etiological Factors for Common Biomarker Discovery

Breast cancer has many different causes, and the key to finding effective treatments is understanding the diseases heterogeneity. The present study used three gene expression datasets from 110 female samples related to stress, drug and hormonal imbalance, diet and nutrition, and physical activity and light exposure at night to predict differential gene expression. Interestingly, all gene expression datasets shared 22 upregulated and 4 downregulated genes, regardless of etiology. This suggests these genes share the core molecular mechanism and the biological pathway that causes breast cancer. Notably, these genes were significantly enriched in some important pathways, including cycle regulation, endoplasmic reticulum stress, and transcriptional regulation, demonstrating their potential as therapeutic targets. Further, we found UBE2J2 from upregulated genes and ZCCHC7 from downregulated genes as the top hub and bottleneck genes, which may help network connectivity and functional gene interactions. Computational study further asserted the strong binding affinity of drug-target complexes. Later, molecular dynamics simulations confirmed the predicted drug-target complexes stability and dynamic behavior, demonstrating these two genes as potential therapeutic targets. The findings from this analysis provide the molecular basis into the complex interplay between diverse etiologic factors and breast cancer pathogenesis, paving the way for innovative biomarker-targeted therapies.

bioinformatics↗

bioRxiv2024

Mapping the PTEN Mutation Landscape: Structural and Functional Drivers of Lung Cancer

Lung cancer is the predominant form of cancer globally, arising from the dysfunction of genetic mutations. Although PTEN mutation is crucial in the aetiology of lung cancer, the mapping of these major drivers has to be determined. We leverage computational algorithms on 43,855 SNPs of PTEN to discover the mutational impact contributing to lung cancer. Fifteen variations were identified as detrimental, and no pertinent studies have previously addressed their structural and functional aspects. Notably, seven variations were identified as the most significant contributors to lethal effects in functional aberration, as demonstrated by the computational assessment. Subsequently, molecular simulation elucidated the structural instability associated with these alterations. Furthermore, drug binding experiments at the mutational site corroborated the destabilization experiments by demonstrating the conformational alteration of the structure, resulting in varied amino acid interactions. In summary, the present study elucidates the influence of mutations in PTEN structure on its functional architecture.

cancer biology↗

bioRxiv2023

A single C-terminal residue controls SARS-CoV-2 spike trafficking and virion assembly

The spike (S) protein of SARS-CoV-2 is delivered to the virion assembly site in the ER-Golgi Intermediate Compartment (ERGIC) from both the ER and cis-Golgi in infected cells1-3. However, the relevance and modulatory mechanism of this bidirectional trafficking are unclear. Here, using structure-function analyses, we show that S incorporation into virions and viral fusogenicity are determined by coatomer-dependent S delivery from the cis-Golgi and restricted by S-coatomer dissociation. Although S mimicry of the host coatomer-binding dibasic motif ensures retrograde trafficking to the ERGIC, avoidance of the host-like C-terminal acidic residue is critical for S-coatomer dissociation and therefore incorporation into virions or export for cell-cell fusion. Because this C-terminal residue is the key determinant of SARS-CoV-2 assembly and fusogenicity, our work provides a framework for the export of S protein encoded in genetic vaccines for surface display and immune activation.

biophysics↗

bioRxiv2022

Temporally and regionally distinct morphogenetic processes govern zebrafish tail fin blood vessel network expansion

Blood vessels form elaborate networks depending on tissue-specific signalling pathways and anatomical structures to guide their growth. However, it is not clear which morphogenetic principles organize the stepwise assembly of the vasculature. We thus performed a longitudinal analysis of zebrafish tail fin vascular assembly, revealing the existence of temporally and spatially distinct morphogenetic processes. Initially, vein-derived endothelial cells (ECs) generated arteries in a reiterative process requiring Vascular Endothelial Growth Factor (VEGF), Notch and cxcr4a signalling. Subsequently, veins produced veins in more proximal fin regions, transforming pre-existing artery-vein loops into a three-vessel pattern consisting of an artery and two veins. A distinct set of vascular plexuses formed at the base of the fin. They differed by virtue of diameter, flow magnitude and marker gene expression. At later stages, intussusceptive angiogenesis occurred from veins in distal fin regions. In proximal fin regions, we observed new vein sprouts crossing the inter-ray tissue through sprouting angiogenesis. Together, our results reveal a surprising diversity among the mechanisms generating the mature fin vasculature and suggest that these might be driven by separate local cues.

developmental biology↗

bioRxiv2021

An Extended Coatomer Binding Motif in the SARS-CoV-2 Spike Protein

{beta}-Coronaviruses such as SARS-CoV-2 hijack coatomer protein-I (COPI) for spike protein retrograde trafficking to the progeny assembly site in endoplasmic reticulum-Golgi intermediate compartment (ERGIC). However, limited residue-level details are available into how the spike interacts with COPI. Here we identify an extended COPI binding motif in the spike that encompasses the canonical K-x-H dibasic sequence. This motif demonstrates selectivity for COPI subunit. Guided by an in silico analysis of dibasic motifs in the human proteome, we employ mutagenesis and binding assays to show that the spike motif terminal residues are critical modulators of complex dissociation, which is essential for spike release in ERGIC. COPI residues critical for spike motif binding are elucidated by mutagenesis and crystallography and found to be conserved in the zoonotic reservoirs, bats, pangolins, camels, and in humans. Collectively, our investigation on the spike motif identifies key COPI binding determinants with implications for retrograde trafficking.

biochemistry↗

bioRxiv2021

Semaphorin 3C exacerbates liver fibrosis

Background & AimsChronic liver disease is a growing epidemic leading to fibrosis and cirrhosis. TGF-{beta} is the pivotal pro-fibrogenic cytokine which activates hepatic stellate cells (HSC), yet, other molecules can substantially modulate TGF-{beta} signaling in the course of liver fibrosis. Expression of the axon guidance molecules Semaphorins (SEMAs), which signal through Plexins and Neuropilins (NRPs), have been associated with liver fibrosis in HBV-induced chronic hepatitis. This study aims at determining their function in the regulation of HSCs. Approach & ResultsWe analyzed publicly available patient databases and liver biopsies. We employed transgenic mice where genes are deleted only in activated HSCs to perform ex vivo analysis and animal models. SEMA3C is the most enriched member of the Semaphorin family in liver samples from cirrhotic patients. Higher expression of SEMA3C in patients with NASH, alcoholic hepatitis or HBV-induced hepatitis discriminates those with a more pro-fibrotic transcriptomic profile. SEMA3C expression is also elevated in different mouse models of liver fibrosis and in isolated HSCs upon activation. In keeping with this, deletion of SEMA3C in activated HSCs reduces myofibroblast marker expression. Conversely, SEMA3C overexpression exacerbates TGF-{beta}-mediated myofibroblast activation, as shown by increased SMAD2 phosphorylation and target gene expression. Among SEMA3C receptors, only NRP2 expression is maintained upon activation of isolated HSCs. Interestingly, lack of NRP2 in those cells reduces myofibroblast marker expression. Finally, deletion of either SEMA3C or NRP2, specifically in activated HSCs, reduces liver fibrosis in mice. ConclusionSEMA3C is a novel marker for activated HSCs that plays a fundamental role in the acquisition of the myofibroblastic phenotype and liver fibrosis.

pathology↗

bioRxiv2019

A Novel Chloroplast Super-Complex Consisting of the ATP Synthase and Photosystem I Reaction Center

Several super-complexes of individual hetero-oligomeric membrane protein complexes, whose function is to facilitate intra-membrane electron and proton transfer and harvesting of light energy, have been previously characterized in the mitochondrial cristae and chloroplast thylakoid membranes. The latter membrane is reported here to also be the location of an intra-membrane super-complex which is dominated by the ATP-synthase and photosystem I (PSI) reaction-center complexes, defined by mass spectrometry, clear-native PAGE and Western Blot analyses. This is the first documented presence of ATP synthase in a super-complex with the PSI reaction-center located in the non-appressed stromal domain of the thylakoid membrane.

biochemistry↗