Biology subjects

Talukdar, A.

Publications and source records attributed to Talukdar, A..

6 recordsLinked to original sources

bioRxiv2026

Cerebral microthrombi promote focal Cav-1-dependent blood-brain barrier impairment, triggering neuroinflammation and neuronal damage after traumatic brain injury

Traumatic brain injury (TBI) is frequently accompanied by blood-brain barrier (BBB) dysfunction, yet the microvascular events that initiate barrier failure and secondary neural injury remain poorly understood. Using highly sensitive fluorescent nanoscale tracers, correlative light and electron microscopy, single-cell transcriptomics, and genetic manipulation of Caveolin-1 (Cav-1), we show that BBB leakage after TBI in mice occurs focally at sites of cerebral microthrombus formation. Endothelial cells adjacent to microthrombi remain structurally intact, but exhibit a distinct transcriptional program enriched in both thrombosis- and transcytosis-related genes, including Cav-1. Microthrombi promote Cav-1-dependent transcytosis and size-selective extravasation of blood-borne proteins, exposing the surrounding parenchyma to circulating factors and inducing focal microglia activation and neuronal damage in vivo. In human induced pluripotent stem cell-derived neurons, these proteins directly impaired neuronal structure and network function. Genetic deletion of Cav-1 markedly reduces microthrombus-associated BBB leakage, immune-cell diapedesis, microglial activation and neuronal loss, whereas endothelial re-expression of Cav-1 using AAVs restores leakage. Human TBI data reveal early dynamic coagulation dysregulation associated with adverse clinical outcome, focal cerebral vascular injury and endothelial transcriptional signatures consistent with reduced barrier integrity and increased caveolae-associated transport. Together, these findings identify cerebral microthrombi as focal sites of Cav-1-dependent BBB dysfunction and establish pathological endothelial transcytosis as a mechanistic link between post-traumatic microvascular thrombosis, blood protein extravasation and secondary neuronal injury. Targeting Cav-1-dependent transcytosis may therefore provide a strategy to limit pathological BBB permeability and secondary injury after TBI.

neuroscience↗

bioRxiv2026

Discovery of a Small-Molecule mTORC1 Pathway Activator that Enhances Adoptive T-Cell Therapy via Immuno-metabolic Reprogramming of CD8+ T Cells

Adoptive cell therapy (ACT) has transformed cancer immunotherapy; however, its clinical efficacy remains limited by progressive T cell dysfunction and inadequate metabolic fitness acquired during ex vivo expansion and within the tumor microenvironment. Here, we report the discovery of AS-3, a first-in-class small-molecule activator that enhances the therapeutic competence of CD8 T cells through RAPTOR-dependent mTORC1 activation. Identified by phenotypic screening of an in-house library of pharmacologically relevant scaffolds and subsequent medicinal chemistry optimization, AS-3 markedly increased effector cytokine production while preserving T cell viability. Mechanistically, AS-3 enhanced phosphorylation of mTORC1 downstream effectors, promoted glycolytic and mitochondrial metabolism, and sustained pathway activity under rapamycin-mediated inhibition. Transcriptomic profiling of activated human CD8 T cells revealed coordinated enrichment of mTORC1 signalling, oxidative phosphorylation, glycolysis, proliferative programs, and cytotoxic effector gene networks, consistent with comprehensive immunometabolic reprogramming. Genetic silencing of RAPTOR attenuated both mTORC1 signalling and cytokine induction, establishing pathway dependency. Ex vivo conditioning with AS-3 significantly improved antitumor efficacy in two independent adoptive T-cell therapy models, accompanied by enhanced persistence, reduced exhaustion, and superior effector function. Together, these findings establish pharmacological activation of the RAPTOR-mTORC1 axis as a strategy to generate metabolically resilient T cells and provide a clinically translatable approach to improving the durability and efficacy of next-generation ACT.

immunology↗

bioRxiv2026

Dual-action nanoconjugate for overcoming r-tPA -resistant clots

Clot resistance to pharmacological thrombolysis remains a critical challenge in ischemic stroke (IS) management. Thrombus heterogeneity, particularly the presence of thrombolysis-resistant domains composed of dense fibrin and non-fibrin components, including neutrophil extracellular traps (NETs), significantly limits the efficacy of recombinant tissue-type plasminogen activator (r-tPA) and its variant, Tenecteplase (TNK). Consequently, novel therapeutic strategies are urgently required. Emerging evidence suggests that co-administration of deoxyribonuclease I (DNase I) with r-tPA can degrade DNA fibers and enhance clot lysis. In this study, we optimized a previously developed theranostic agent--iron oxide microparticles coated with polydopamine--by dual-grafting both r-tPA and DNase to target resistant thrombi. Using functional ultrasound imaging (fUS) during the acute phase of IS, we demonstrated accelerated reperfusion with this dual-functionalized platform in a r-tPA resistant IS model. Furthermore, MRI analysis confirmed a significant reduction in lesion volume at 24 hours, correlating with improved functional recovery five days post-ischemia.

pathology↗

bioRxiv2026

Transforming off-the-shelf personal glucose meter into a sustainable and decentralized label-free nucleic acid and NAAT detection platform

In todays world, point-of-care nucleic acid detection still remains extensively constrained and limited by the heavy dependence on centralized urban instrumentation facilities and complex assay workflows. Here, we elucidate a glucometer-based analytical platform that enables label-free detection of nucleic acids and the nucleic acid amplification products through a simple redox-mediated mechanism. The approach leverages the potassium ferricyanide (K3[Fe(CN)6])/ potassium ferrocyanide (K4[Fe(CN)6]), redox system, which is intrinsic to commercial glucometers, complementing with interactions between methylene blue (MB) and nucleic acids. These interactions transduce concentration differences in nucleic acids into quantifiable electrochemical signal readouts. Distinct varied signal outputs are observed between single-stranded and double-stranded DNA, enabling the direct detection as well as integration with nucleic acid amplification tests (NAATs), including polymerase chain reaction, rolling circle amplification, and loop-mediated isothermal amplification. Optimization of reaction parameters and conditions leads to enhancement of the overall signal discrimination and sensitivity across various assay formats. This innovation repurposes widely available off-the-shelf glucometers as a low-cost, portable nucleic acid detectors, thus eliminating the need for any specialized instrumentation. Our results enumerate and establish a generalized and scalable strategy for nucleic acid sensing. The platform thus supports sustainable and environmentally responsible point-of-care testing, thereby enabling improved accessibility and public health monitoring at resource-limited and remote settings.

biochemistry↗

bioRxiv2025

Evaluating horseradish peroxidase-mimic DNAzyme transducer for glucometer readout: roles of various components and their optimization

The Development of decentralized disease detection elements is integral towards ensuring democratized access to healthcare. Personal glucometers, thanks to their low cost, ease of usage, and universal availability, are increasingly being identified as a central tenet of democratized disease detection. Towards this objective, it will first be critical to establish whether glucometers can be integrated with established molecular diagnosis workflows such as enzyme-linked absorbent assay (ELISA) or its analogous techniques such as enzyme-linked aptasorbent assays (ELASA). In ELISA or its analogous assays, horseradish peroxidase (HRP) or its mimics, such as hemin DNAzyme conjugated to biorecognition elements (e.g., antibody or aptamers), serve as the signal transducers. These transducers generate colorimetric or electrochemical signals measurable in centralized instruments such as ELISA readers or potentiostats. To become compatible with ELISA readouts in decentralized settings, the glucometers should therefore be able to quantify the activity of HRP mimics such as hemin DNAzyme. The current work thus explores the possibility of the use of glucometers as a general readout instrument for hemin DNAzyme transducer activity involving potassium ferrocyanide as a novel redox substrate. Using both absorbance and glucometer readout, we systematically investigated the role of buffer, pH, redox mediator, and H2O2 in achieving optimal readout conditions. It also probed the prospective DNAzyme operational range under these assay conditions. In addition, transferability of optimized assay parameters in other commercial glucometer brands, as well as preliminary suitability in HRP enzyme, was explored. Altogether, our study explores the possibility of using DNAzymes as transducers for glucometers as a democratized alternative to ELISA readers, multimode readers, or potentiostats towards equitable access to disease diagnosis.

biochemistry↗

bioRxiv2020

Emergence of multiple variants of SARS-CoV-2 with signature structural changes

This study explores the divergence pattern of SARS-CoV-2 using whole genome sequences of the isolates from various COVID-19 affected countries. The phylogenomic analysis indicates the presence of at least four distinct groups of the SARS-CoV-2 genomes. The emergent groups have been found to be associated with signature structural changes in specific proteins. Also, this study reveals the differential levels of divergence patterns for the protein coding regions. Moreover, we have predicted the impact of structural changes on a couple of important viral proteins via structural modelling techniques. This study further advocates for more viral genetic studies with associated clinical outcomes and hosts response for better understanding of SARS-CoV-2 pathogenesis enabling better mitigation of this pandemic situation.

evolutionary biology↗