Biology subjects

Chaudhary, T.

Publications and source records attributed to Chaudhary, T..

4 recordsLinked to original sources

bioRxiv2026

Protein import-driven mitochondrial hyperactivation dictates angiogenesis independently of HIF-1α

Angiogenesis is essential for sustained neoplastic progression, yet its initiation has largely been framed through hypoxia-dependent HIF signalling. In OXPHOS driven tumours, how mitochondrial function contributes to angiogenic induction remains poorly understood. Here, we uncover a non-canonical mechanism linking tumour cell mitochondrial hyperactivity to a pro-angiogenic response. Mitochondrial function critically depends on the import of nuclear-encoded proteins, largely mediated by TIM23 translocase. We found Timm44, the central scaffold of this translocase, to be broadly upregulated across angiogenesis-dependent malignancies. Using gain-of-function system that recapitulate tumour-associated Timm44 amplification, we enhanced mitochondrial protein import capacity, thereby remodelling mitochondrial gene expression and driving hyperactivation of the electron transport chain, particularly Complex I. This hyperactive mitochondrial state generated a signalling-competent ROS-enrich environment that induces VEGFA expression independently of HIF-1 stabilization, via a redox-licensed TRX-ASK1-p38MAPK-SP1 axis, thereby promoting endothelial sprouting and proliferation. These findings define protein import-driven mitochondrial hyperfunction as an alternative driver of tumour angiogenesis, extending current paradigms beyond classical hypoxia-dependent mechanisms and highlighting new therapeutic vulnerabilities.

cancer biology↗

bioRxiv2023

Niche homeostasis in multi-lineage stem cell populations is maintained through intercellular redox gradients

Reactive oxygen species (ROS), predominantly derived from mitochondrial respiratory complexes, have emerged as key molecules influencing cell fate decisions like maintenance and differentiation. These redox-dependent events are mainly considered to be cell intrinsic in nature, on the contrary our observations indicate involvement of these oxygen-derived entities as intercellular communicating agents. In Drosophila male germline, Germline Stem Cells (GSCs) and neighbouring Cyst Stem Cells (CySCs) maintain differential redox thresholds where CySC have higher redox-state compared to the adjacent GSCs. Disruption of the redox equilibrium between the two adjoining stem cell populations by depleting Superoxide Dismutases (SODs) especially Sod1 results in deregulated niche architecture and loss of GSCs, which was mainly attributed to loss of contact-based receptions and uncontrolled CySC proliferation due to ROS-mediated activation of self-renewing signals. Our observations hint towards the crucial role of differential redox states where CySCs containing higher ROS function not only as a source of their own maintenance cues but also serve as non-autonomous redox moderators of GSCs. Our findings underscore the complexity of niche homeostasis and predicate the importance of intercellular redox communication in understanding stem cell microenvironments.

developmental biology↗

bioRxiv2022

ComBat Harmonization: Empirical Bayes versus Fully Bayes Approaches

Studying small effects or subtle neuroanatomical variation requires large-scale sample size data. As a result, combining neuroimaging data from multiple datasets is necessary. Variation in acquisition protocols, magnetic field strength, scanner build, and many other non-biologically related factors can introduce undesirable bias into studies. Hence, harmonization is required to remove the bias-inducing factors from the data. ComBat is one of the most common methods applied to features from structural images. ComBat models the data using a hierarchical Bayesian model and uses the empirical Bayes approach to infer the distribution of the unknown factors. The empirical Bayes harmonization method is computationally efficient and provides valid point estimates. However, it tends to underestimate uncertainty. This paper investigates a new approach, fully Bayesian ComBat, where Monte Carlo sampling is used for statistical inference. When comparing fully Bayesian and empirical Bayesian ComBat, we found Empirical Bayesian ComBat more effectively removed scanner strength information and was much more computationally efficient. Conversely, fully Bayesian ComBat better preserved biological disease and age-related information while performing more accurate harmonization on traveling subjects. The fully Bayesian approach generates a rich posterior distribution, which is useful for generating simulated imaging features for improving classifier performance in a limited data setting. We show the generative capacity of our model for augmenting and improving the detection of patients with Alzheimers disease. Posterior distributions for harmonized imaging measures can also be used for brain-wide uncertainty comparison and more principled downstream statistical analysis. Code for our new fully Bayesian ComBat extension is available at https://github.com/batmanlab/BayesComBat.

neuroscience↗

bioRxiv2020

Protein Corona Composition and Dynamics on Carbon Nanotubes in Blood Plasma and Cerebrospinal Fluid

When a nanoparticle enters a biological environment, the surface is rapidly coated with proteins to form a "protein corona". Presence of the protein corona surrounding the nanoparticle has significant implications for applying nanotechnologies within biological systems, affecting outcomes such as biodistribution and toxicity. Herein, we measure protein corona formation on single-stranded DNA wrapped single-walled carbon nanotubes (ssDNA-SWCNTs), a high-aspect ratio nanoparticle ideal for sensing and delivery applications, and polystyrene nanoparticles, a model nanoparticle system. The protein corona of each nanoparticle is studied in human blood plasma and cerebrospinal fluid. We characterize corona composition by proteomic mass spectrometry to determine abundant and differentially enriched vs. depleted corona proteins. High-binding corona proteins on ssDNA-SWCNTs include proteins involved in lipid binding and transport (clusterin and apolipoprotein A-I), complement activation (complement C3), and blood coagulation (fibrinogen). Of note, albumin is the most common blood protein (55% w/v), yet exhibits low-binding affinity towards ssDNA-SWCNTs, displaying 1300-fold lower bound concentration relative to native plasma. We investigate the role of electrostatic and entropic interactions driving selective protein corona formation, and find that hydrophobic interactions drive inner corona formation, while shielding of electrostatic interactions allows for outer corona formation. Lastly, we study real-time binding of proteins on ssDNA-SWCNTs and find relative agreement between proteins that are enriched and bind strongly, such as fibrinogen, and proteins that are depleted and bind marginally, such as albumin. Interestingly, certain proteins express contrary behavior in single-protein experiments than within the whole biofluid, highlighting the importance of cooperative mechanisms driving selective corona adsorption on the SWCNT surface. Knowledge of the protein corona composition, dynamics, and structure informs translation of engineered nanoparticles from in vitro design to effective in vivo application.

bioengineering↗