Biology subjects

Tiwari, G.

Publications and source records attributed to Tiwari, G..

6 recordsLinked to original sources

bioRxiv2026

Molecular Mechanism of Lipid Recognition and Membrane-Guided Gating in Plant Minimal START Proteins

The hydrophobic nature of lipids requires specialized transport mechanisms, and one such non-vesicular transport mechanism involves START (StAR-related lipid transfer) domain proteins. START domains either occur as a part of multidomain proteins or occur solo as in minimal START proteins. Unlike well-studied multidomain variants, plant minimal START proteins remain poorly understood, leaving their ligand specificity, structural dynamics, and biological roles largely uncharacterized. Integrating structural screening with experimental validation, we analyzed representative plant minimal START proteins and confirmed their specific binding to amphipathic lipids, primarily myristic acid and lysophosphatidylcholine. The ligand binding involves a bipartite mechanism, in which basic residues within the cavity interact with polar lipid headgroups, while the hydrophobic tails are accommodated deeper within the cavity. Mechanistically, ligand binding induced closure of a lid-like gate at the cavity entrance, whereas membrane proximity promoted reopening of the gate and ligand release, collectively suggesting a membrane-guided gating mechanism for lipid exchange. Consistent with this model, localization studies show that these proteins associate with the endoplasmic reticulum, plastids, Golgi apparatus, and plasma membrane, major sites of lipid metabolism. Together, our findings establish plant minimal START proteins as bona fide lipid-binding proteins that utilize a bipartite ligand-binding mechanism coupled with membrane-responsive gating dynamics.

biochemistry↗

bioRxiv2026

Integrated Artificial Intelligence and Quantum Chemistry Approach for the Rational Design of Novel Antibacterial Agents against Ralstonia solanacearum.

Antimicrobial resistance (AMR) in plant pathogenic bacteria poses a serious threat to global agriculture, necessitating the development of novel antibacterial agents targeting virulence mechanisms. This study presents an integrated bioinformatics-driven framework for the rational design and computational validation of Solres, a newly designed small molecule targeting key virulence proteins in phytopathogenic bacteria. Approximately 10,000 active compounds from PubChem BioAssay (AID: 588726) were analyzed using structural clustering and scaffold mining to identify conserved molecular motifs associated with antibacterial activity. Guided by high-frequency substructures, Solres was designed de novo and screened for structural novelty against PubChem, ChEMBL, and WIPO databases. Drug-likeness evaluation using Lipinskis Rule of Five confirmed favorable physicochemical properties. Molecular docking was performed against essential virulence regulators, including PhcA, PhcR, HrpB, PehA, and Egl from Ralstonia solanacearum and Xanthomonas spp., with active sites predicted using CaspFold. Docking analyses revealed strong binding affinities and stable interactions with key catalytic and regulatory residues. Complex stability and conformational integrity were further validated through molecular dynamics simulations. Quantum chemical descriptors, including HOMO-LUMO energy gap and dipole moment, supported the electronic suitability and reactivity profile of Solres. Collectively, this study demonstrates the effective integration of cheminformatics, structural bioinformatics, molecular simulations, and quantum chemical analyses for plant-focused antibacterial discovery. The compound Solres represents a promising lead candidate for mitigating bacterial wilt disease and provides a computational framework for future experimental validation and sustainable crop protection strategies against AMR-driven phytopathogens.

bioinformatics↗

bioRxiv2026

Blood Biochemical Responses to Acute Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC)

Exercise benefits numerous organ systems and tissues, however limited knowledge exists about its underlying molecular pathways. Identifying the exercise-induced biochemical changes that occur in the circulation may provide further insights into how exercise confers systemic health changes. Here, we perform large-scale plasma proteomic, metabolomic, and whole blood transcriptional profiling in sedentary human participants undergoing acute endurance exercise (EE), resistance exercise (RE), or a non-exercise control (CON) in up to 7 timepoints over a 24 hour period. We observe 7066 transcript, 189 protein, and 448 metabolite changes in response to EE or RE compared to CON. Our analyses reveal numerous shared biochemical responses between EE and RE modes, but also differences in immune cell responses, lipid metabolism, and pathways reflective of tissue repair and angiogenesis. Taken together, our findings highlight novel temporal and exercise mode-specific blood-based molecular responses to acute exercise, and provide a new resource for the scientific community.

systems biology↗

bioRxiv2025

Acute cold exposure in humans shifts the circulating proteome to a cardioprotective and anti-aging profile

Cold exposure has been proposed to provide a constellation of salutary effects, yet its molecular correlates remain largely unknown. Brown adipose tissue (BAT) is the main site of adaptive thermogenesis, and its prevalence is linked with cardiometabolic health. Since the benefits of BAT activation and cold exposure more generally may be mediated through blood-borne factors, we conducted an extensive analysis of the circulating proteome linked with an acute cold challenge in healthy adults. Our goal was to uncover early molecular changes triggered by cooling and establish their specific relationships with the human brown adipocyte secretome as well as various phenotypic traits. Based on comprehensive inter-cohort validations, we provide the first reproducible proteomic signature of cold exposure in humans. Our data demonstrate that cooling favorably modulates circulating mediators linked with chronological aging, as well as metabolic and cardiovascular diseases, providing new potential biochemical transducers of the benefits associated with cold therapy. HighlightsO_LICooling alters the plasma proteome with striking concordance in independent human cohorts. C_LIO_LICooling represses circulating proteins linked with type 2 diabetes, hypercholesterolemia, hypertension, coronary heart disease and heart failure. C_LIO_LIThe circulating signature of cooling resembles a cardioprotective and anti-aging profile. C_LI

physiology↗

bioRxiv2023

Lac-Phe mediates the anti-obesity effect of metformin

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformins effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levels in vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformins anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformins effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

physiology↗

bioRxiv2022

Transcriptome analysis of alcohol dependence and stress interactions in the nucleus of the solitary tract

Stress exposure contributes to the development of drug and alcohol use disorders. In animal models, stress exacerbates escalations in alcohol consumption in alcohol-dependent animals. The nucleus of the solitary tract (NTS) is a critical brainstem region for integrating and relaying peripheral signals to regulate stress responses. To define the molecular adaptions within this brain region that may contribute to stress-induced alcohol drinking, we exposed animals to chronic intermittent bouts of ethanol vapor (CIE), forced swim stress (FSS), or both (CIE + FSS) and then transcriptionally profiled the NTS at three different timepoints after the last vapor exposure (0-hr, 72-hr, and 186-hr). We identified interferon (IFN) signaling as a critical gene network correlated with alcohol consumption levels. Using a likelihood ratio test, we identified genes that were differentially expressed across time and between groups. Clustering analysis of these genes to identify unique expression patterns identified a subset of genes that fail to normalize in the CIE + FSS group, but not the others. These genes were enriched for cell-to-cell interaction and cellular movement pointing to long-term structural and functional changes in this brain region caused by the unique interaction of alcohol dependence and stress. Specific genes of interest identified in this group include Aqp4, Il16, Reln, Grm4, Gabrd, and Gabra6. We also compared gene expression changes in the NTS to the PFC and found a significant overlap of genes between the two brain regions. Overlapping NTS/PFC genes in the CIE + FSS group were enriched for type I IFN signaling. Finally, we tested the hypothesis that activation of type I IFN signaling increases alcohol consumption based on the three lines of evidence identifying type I IFN signaling as critical for escalations in alcohol intake. Mice treated with recombinant IFN{beta} showed significantly elevated levels of alcohol intake in a two-bottle choice procedure compared to saline-treated controls. Overall, these results define the transcriptomic changes across time in the NTS that may be critical to the development of stress-induced increases in alcohol consumption and alcohol dependence.

molecular biology↗