Biology subjects

Gupta, E.

Publications and source records attributed to Gupta, E..

7 recordsLinked to original sources

bioRxiv2026

Aging, HIV Status, and Sex Differentially Influence Antiretroviral Therapy Disposition Pathways in Rectosigmoid Tissue and Peripheral Blood Mononuclear Cells

People living with human immunodeficiency virus (HIV) are increasingly surviving into older age due to the effectiveness of antiretroviral (ARV) therapy (ART), creating a growing population in whom age-related changes may influence treatment outcomes. Although aging is known to affect drug disposition, the molecular mechanisms by which aging alters ARV pharmacology remain incompletely understood, particularly within tissue compartments, including the rectosigmoid region of the colon, that serve as sites of HIV transmission and persistence. To address this knowledge gap, we used proteomics by liquid chromatography-mass spectrometry (LC-MS) to evaluate the impact of age and HIV status on proteins and pathways relevant to ARV disposition in peripheral blood mononuclear cells (PBMC) and rectosigmoid colon tissue obtained from young (18-50) HIV-seronegative adults, older (65-80) HIV-seronegative adults, and older virally suppressed people living with HIV. We found that aging and HIV infection differentially influenced proteins predominantly within nucleos(t)ide reverse transcriptase inhibitor (NRTI) pathways, in rectosigmoid tissue and PBMC. HIV-associated effects to the proteome were more prominent in PBMC, whereas aging produced broader alterations in ARV disposition-related proteins in rectosigmoid tissue, including proteins involved in drug transport, intracellular drug activation, dephosphorylation, and nucleotide homeostasis. Several age-associated changes were further influenced by biologic sex, suggesting that aging may not affect ARV disposition uniformly across populations. To place these findings within a broader context, pathway analyses were performed that identified extensive tissue-specific remodeling associated with aging and HIV infection involving drug disposition, immune regulation, cellular metabolism, and disease-related pathways. Notably, aging was associated with alterations in pathways relevant to nucleotide metabolism and gastrointestinal tissue function, suggesting that processes beyond traditional drug transport and metabolism pathways may contribute to variability in ARV disposition with advancing age. Together, these findings identify aging as an important modifier of pathways that regulate ARV disposition within compartments relevant to HIV transmission and persistence. While the clinical consequences of our findings are unknown, these data provide a mechanistic foundation for future studies investigating whether age-associated changes influence the effectiveness of ART and HIV pre-exposure prophylaxis in older adults.

pharmacology and toxicology↗

bioRxiv2026

Actin-dependent mechanotransduction controls nucleocytoplasmic partitioning of DNMT3a through ERK1/2 signaling during cutaneous wound healing

Cutaneous wound healing is a multifaceted physiological process that requires a cell state transition from homeostasis to tissue repair. An important contributor to this reprogramming is the wound-induced mechanical cues that are perceived by epidermal keratinocytes. Previously we identified that the nuclear translocation of the de novo DNA methyltransferase 3A (DNMT3a) upon wounding as an important regulator of this cell-state transition. However, the molecular mechanisms linking mechanotransduction to epigenetic regulation remain incompletely understood. Here we show that under homeostasis, active ERK1/2 phosphorylates DNMT3a, intramolecularly masking its nuclear localization signal (NLS), resulting in its cytoplasmic sequestration. Upon wounding actin cytoskeleton remodeling leads to the downregulation of the Extracellular Signal-Related Kinase 1/2 (ERK 1/2) pathway. Wound-induced ERK1/2 inactivation unmasks the NLS, enabling DNMT3a nuclear translocation. Collectively, these findings define a mechanotransduction-driven signaling axis linking cytoskeletal dynamics to epigenetic regulation and confirms an active role for differentiated keratinocytes in initiating early wound repair programs.

cell biology↗

bioRxiv2024

Statins attenuate Wnt/β-catenin signaling by targeting SATB family proteins in colorectal cancer

Colorectal cancer is the second leading cause of cancer-related deaths worldwide, highlighting the need for improved treatments and advanced molecular research. A recent therapeutic approach focuses on repurposing drugs to target dysregulated pathways involved in tumorigenesis. Among these, statins, commonly known for lowering cholesterol, have attracted attention for their potential anti-cancer properties. Here, we provide direct evidence for the same by assessing the impact of statin treatment on lipid, transcript, and protein levels. Our findings reveal that statins specifically target key components of the Wnt/{beta}-catenin pathway, a major factor in adenoma formation, including the SATB (Special AT-rich Binding protein) family proteins. While SATB1 is recognized as a regulator of tumorigenesis, particularly under Wnt signaling, SATB2 appears to exert an opposing role. We demonstrate that statin treatment reciprocally alters the expression pattern of these proteins. Furthermore, a human clinical trial evaluating statins as an anti-cancer therapy supports the hypothesis that differential expression of SATB proteins is crucial in tumorigenic outcomes. In conclusion, this modulation by statin treatment suggests promising new therapeutic avenues through drug repurposing.

cancer biology↗

bioRxiv2023

Genomic perspectives of SARS CoV-2 in liver disease patients with its clinical correlation: A single centre retrospective study

BackgroundSevere Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2), is a causative agent of current global pandemic of Coronavirus disease-19 (COVID-19). Due to propagated outbreak and global vaccination drive an immense immunological selection pressure has been exerted on SARS CoV-2 leading to evolution of new variants. This study was performed to compare the mutational and clinical profile of liver disease patients infected with different variants of SARS CoV-2. MethodologyThis was a single-centre, retrospective, cohort study in which clinicogenomic analysis of liver disease (LD) patients infected with SARS CoV-2 was performed. Complete demographic and clinical details were retrieved from Hospital Information System (HIS). QC-threshold passed FASTA files containing sequences from COVID-19 patients (n=174) were compared with a reference genome of SARS-CoV-2 isolate named Wuhan-Hu-1 (NCBI Reference Sequence: NC_045512.2) for mutational analysis. ResultsOut of 232 finally analysed patients 137 (59.1%) were LD-CoV (+) and 95 (40.9%) were LD-CoV(-). LD patients with comorbidities were affected more with COVID-19 (p=0.002). On comparing the outcome in the terms of mortality, LD-CoV (+) had 2.29 times (OR 2.29, CI 95%, 1.25-4.29) higher of odds of succumbing to COVID-19 (p=0.006). Multivariate regression analysis revealed, abdominal distention (p=0.05), severe COVID-19 pneumonia (p=0.046) and the change in serum bilirubin levels (p=0.005) as well as Alkaline phosphatase (ALP) levels (p=0.003) to have an association with adverse outcome in LD patients with COVID-19. In Delta (22%) and Omicron (48%) groups, Spike gene harboured maximum mutations. On comparing the mutations between LD-CoV(+/D) and LD-CoV(+/O) a total of nine genes had more mutations in LD-CoV(+/O) whereas three genes had more mutations in LD-CoV(+/D). ConclusionWe concluded that LD patients are more susceptible to COVID-19 as compared to a healthy adult with associated adverse clinical outcomes in terms of mortality and morbidity. Therefore this special group should be given priority while devising and introducing new vaccination and vaccination policies. The infection with different variants did not result in different outcome in our group of patients.

microbiology↗

bioRxiv2022

Machine Learning Optimization of Candidate Antibodies Yields Highly Diverse Sub-nanomolar Affinity Antibody Libraries

Therapeutic antibodies are an important and rapidly growing drug modality. However, the design and discovery of early-stage antibody therapeutics remain a time and cost-intensive endeavor. In this work, we present an end-to-end Bayesian, language model-based method for designing large and diverse libraries of high-affinity single-chain variable fragments (scFvs). We integrate target-specific binding affinities with information from millions of natural protein sequences in a probabilistic machine learning framework to design thousands of scFvs that are then empirically measured. In a head-to-head comparison with a directed evolution approach, we show that the best scFv generated from our method represents a 28.8-fold improvement in binding over the best scFv from the directed evolution. Additionally, 99% of the designed scFvs in our most successful library are improvements over the initial candidate scFv. By comparing a librarys predicted success to actual measurements, we demonstrate our methods ability to explore tradeoffs between library success and diversity during the design phase and prior to experimental testing. The results of our work highlight the significant impact machine learning models can have on scFv development. We expect our end-to-end method to be broadly applicable and able to provide value to other protein engineering tasks.

bioinformatics↗

bioRxiv2020

A recombinant fragment of Human surfactant protein D binds Spike protein and inhibits infectivity and replication of SARS-CoV-2 in clinical samples

RationaleCOVID-19 is an acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Human surfactant protein D (SP-D) is known to interact with spike protein of SARS-CoV, but its immune-surveillance against SARS-CoV-2 is not known. ObjectiveThis study aimed to examine the potential of a recombinant fragment of human SP-D (rfhSP-D) as an inhibitor of replication and infection of SARS-CoV-2. MethodsrfhSP-D interaction with spike protein of SARS-CoV-2 and hACE-2 receptor was predicted via docking analysis. The inhibition of interaction between spike protein and ACE-2 by rfhSP-D was confirmed using direct and indirect ELISA. The effect of rfhSP-D on replication and infectivity of SARS-CoV-2 from clinical samples was studied by measuring the expression of RdRp gene of the virus using qPCR. Measurements and Main ResultsIn-silico interaction studies indicated that three amino acid residues in the RBD of spike of SARS-CoV-2 were commonly involved in interacting with rfhSP-D and ACE-2. Studies using clinical samples of SARS-CoV-2 positive cases (asymptomatic, n=7 and symptomatic, n=8 and negative controls n=15) demonstrated that treatment with 5M rfhSP-D inhibited viral replication by ~5.5 fold and was more efficient than Remdesivir (100 M). Approximately, a 2-fold reduction in viral infectivity was also observed after treatment with 5M rfhSP-D. ConclusionsThese results conclusively demonstrate that the calcium independent rfhSP-D mediated inhibition of binding between the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike protein and human ACE-2, its host cell receptor, and a significant reduction in SARS-CoV-2 infection and replication in-vitro.

immunology↗

bioRxiv2020

Identification of potential vaccine candidates against SARS-CoV-2, A step forward to fight novel coronavirus 2019-nCoV: A Reverse Vaccinology Approach

The recent Coronavirus Disease 2019 (COVID-19) causes an immense health crisis to global public health. The COVID-19 is the etiologic agent of a recently arose disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Presently, there is no vaccine available against this emerged viral disease. Therefore, it is indeed a need of the hour to develop an effectual and safe vaccine against this decidedly pandemic disease. In the current study, we collected SARS-CoV-2 genome which is prominent in India against human host, further more using reverse vaccinology here we claim effective vaccine candidates that can be mile stone in battle against COVID19. This novel study divulged one promising antigenic peptide GVYFASTEK from surface glycoprotein (protein accession no. - QIA98583.1) of SARS-CoV-2, which was predicated to be interacted with MHC alleles and showed up to 90% conservancy and high value of antigenicity. Subsequently, the molecular docking and simulation studies were verified molecular interaction of this prime antigenic peptide with the residues of HLA-A*11-01 allele for MHC Class I. After vigorous analysis, this peptide was predicted to be suitable epitope which is capable to induce the strong cell-mediated immune response against the SARS-CoV-2. Consequences from the current study could facilitate selecting SARS-CoV-2 epitopes for vaccine production pipelines in the immediate future. This novel research will certainly pave the way for a fast, reliable and virtuous platform to provide timely countermeasure of this dangerous pandemic disease, COVID-19.

bioinformatics↗