Biology subjects

Mathur, D.

Publications and source records attributed to Mathur, D..

9 recordsLinked to original sources

bioRxiv2026

Targeting alpha-ketoglutarate starvation within the tumor-immune microenvironment rescues T cell effector function in cancer immunotherapy

Given its status as the leading cause of global cancer mortality, there is a critical need to enhance immunotherapy strategies for lung cancer to overcome widespread resistance to current treatments. Immunotherapy recruits the patient's immune system to attack and destroy cancer cells. While highly effective in a subset of patients, chronic exposure of immune cells to cancer cells leads to a progressive loss of effector T cell function and progression of T cell exhaustion; now considered two well-established hallmarks of immunotherapy resistance. The tumor-immune microenvironment (TIME)-driven differentiation into the exhausted T cell phenotype is marked by a loss of metabolic plasticity and epigenome-wide changes in distribution of repressive histone marks such as histone H3 subunit methylation at lysine 27 (H3K27me3). Here, we studied how these processes are connected to metabolite availability within the TIME. In vitro, chronic antigen stimulation and hypoxia led to rapid loss of effector function, associated with a suppression of alpha-ketoglutarate (aKG) intracellular concentrations in T cells. Supplementation of cell-permeable aKG led to a rescue of effector cytokine production and to improved cytotoxic capacity despite chronic antigen stimulation and hypoxia. Increased intracellular aKG levels restored the activity of H3K27 demethylases UTX and JMJD3, consistent with epigenome-wide decreased H3K27me3. In vivo, dietary supplementation with commercially available calcium-aKG (Ca-aKG) supplements led to an elevation of serum and intratumoral aKG levels associated with a significant increase of immunotherapy effectiveness in mouse models of NSCLC. Clinical samples from patients with NSCLC contained significantly decreased serum aKG levels in older NSCLC patients (>65 years of age). Analysis identified a novel association between serum aKG levels and poor immunotherapy response. Thus, our work demonstrates that intratumoral metabolite starvation can be therapeutically exploited to improve immunotherapy outcomes in non-small cell lung cancer (NSCLC).

cancer biology↗

bioRxiv2026

Synaptic and Extrasynaptic NMDA Receptors Oppositely Regulate Dendritic Syntaphilin Intrusion in Multiple Sclerosis

Neurodegeneration is a major determinant of disability progression in multiple sclerosis (MS), yet the pathophysiological mechanisms associating inflammation to neuronal insult remain poorly understood. We recently identified Dendritic Syntaphilin Intrusion (DSI), a novel excitoxicity pathway in which the axonal mitochondrial anchor syntaphilin (SNPH) aberrantly translocates into dendrites, causing neurodegeneration in a non-inflammatory model of MS. However, whether this protein intrudes abruptly into dendrites in inflammatory MS pathology is still not clear. Here, we investigated the role of synaptic and extrasynaptic NMDA receptors (NMDAR) in regulating the intrusion of Syntaphilin into dendrites. Using primary hippocampal neuronal cultures, we examined how the balance between synaptic GluN2A-containing and extrasynaptic GluN2B-containing NMDARs influences DSI under inflammatory conditions. Pharmacological and viral-mediated approaches were employed to manipulate NMDAR subtype activity and evaluate their impact on DSI. Inflammatory cytokines discernibly sensitized neurons to DSI. Our results revealed that blockade of synaptic NMDARs significantly increased DSI, whereas inhibition of extrasynaptic NMDARs reduced DSI. These findings demonstrate opposing roles of NMDAR subtypes, with GluN2A-containing synaptic receptors inhibiting DSI and fostering neuronal survival, while GluN2B-containing extrasynaptic receptors enhancing DSI and neurodegenerative signaling. Manipulation of the GluN2A/GluN2B balance showed opposite effect on DSI, suggesting a relationship between NMDAR subtype signaling and SNPH mislocalization. Overall, our findings extend the relevance of DSI from non-inflammatory MS to inflammatory MS and identify DSI as a downstream convergence point linking inflammatory cytokines and excitotoxic NMDAR signaling to neuronal insult. These results reveal DSI as a potential mechanistic link between inflammatory signaling and excitotoxic neuronal injury and indicate that modulation of GluN2B-dependent pathways warrants further investigation in inflammatory neurodegenerative disorders.

neuroscience↗

bioRxiv2026

The Georgetown Reading in Aging Neuroimaging Dataset (GRAND): Reading and multimodal MRI data in older adults

Reading is a critical skill in modern society. Most research on reading is conducted in school age children or young adults. However, acquired brain disorders often affect reading ability, and these disorders tend to occur in older adults. It is therefore critical to examine the normative distribution of reading behavior and the brain basis of reading in older adults. Here, we provide trial-wise single word and pseudoword oral reading and lexical decision data, as well as structural, functional, and diffusion-weighted MRI data from 116 neurotypical adults aged 22 to 84 years (mean = 59). Accuracy, response times, and errors are provided for corpora that are parametrically modulated in frequency, imageability, and regularity for real words and consistency of spelling-sound mapping for pseudowords. This dataset includes both minimally processed behavior (trial-wise data) and MRI data, and participant- and item-wise summary metrics and processed MRI data. These data serve both as a normative sample for reading behavior in older adults, but also as a valuable resource for identifying novel brain-behavioral relationships.

neuroscience↗

bioRxiv2026

In-Situ ssDNA Isolation from dsDNA Sources as a Streamlined Pathway to DNA Origami Assembly and Testing

Scaffolded DNA origami has become a valuable nanoscale tool for applications in biomedical and physical sciences. Critical to leveraging the modular and programmable properties of DNA origami nanodevices is access to the scaffold strand, a long single-stranded DNA (ssDNA) of precise length and sequence, which is folded into a compact shape via piecewise base-pairing with many staple strands, short ssDNA oligonucleotides. Current methods to produce and manipulate long ssDNA scaffolds can be costly, time-consuming, and cumbersome. In contrast, methods to produce and manipulate the sequence of double-stranded DNA (dsDNA) are efficient and scalable. Here, we present a method for the rapid isolation of target ssDNA sequences from a variety of dsDNA sources using oligonucleotides as blocking strands that bind continuously to the undesired strand, thereby releasing the target scaffold strand. We report successful ssDNA isolation from linear and supercoiled dsDNAs of various sequences and lengths, ranging from 769 to 15,101 nucleotides. In addition to isolating ssDNA, we demonstrated this approach enables folding of DNA origami directly from dsDNA templates using both blocking and staple strands in a single-pot thermally controlled reaction. Furthermore, we explore multi-scaffold and gene-encoding DNA origami structures, expanding the framework for application-based designs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/709872v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@f7ada7org.highwire.dtl.DTLVardef@a9bab8org.highwire.dtl.DTLVardef@121b695org.highwire.dtl.DTLVardef@5a1dea_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2026

Tensile Expansion Microscopy Applies Mechanical Force to Super-resolve Fixed and Image Live Cellular Samples

Understanding biophysical phenomena requires techniques that access biologically relevant spatial and temporal scales. Expansion Microscopy (ExM) is a sample preparation approach which achieves super-resolution spatial scales by leveraging osmotic forces in a swellable hydrogel to physically separate structures to distances larger than the diffraction limit of light. Yet, in traditional osmotic ExM only pre- and post- expanded samples can be imaged. Further, fragmentation, hydrogel deformation, and signal loss are common while requiring samples to be chemically fixed. Therefore, there is little control of the expansion, reproducibility can be challenging, and dynamics of biological samples at applicable temporal scales cannot be observed. Here, we develop Tensile Expansion Microscopy (TExM) to mechanically expand fixed and, notably, living cellular samples. Highly-stretchable and tough double network alginate- Ca2+/polyacrylamide hydrogels are expanded by tensile forces applied using an electromechanical iris expansion device during continuous imaging on a fluorescence microscope. We incorporate two-photon polymerized microscale fluorescent fiducial markers to track samples and distortion during expansion. The hydrogels controllably and repeatedly expand up to 3.3x with distortions less than 12 {micro}m across 1.3 mm2. TExM is first applied to fixed NIH 3T3 fibroblast cells with immunohistochemistry-stained microtubules, achieving super-resolutions of 100 nm. Then, TExM is demonstrated with living HeLa cells with internal fluorescent reporters showing increased cell size and cell-to-cell separation under 3.2x linear expansion. Overall, TExM allows for continuous, stepwise, and precise temporal modulation of lateral substrate strain, enabling real time monitoring of dynamics of both fixed and viable live cell processes at higher spatial resolutions. TExM can further investigate broad biophysical questions due to its compatibility with other analytical imaging methods that are sensitive to water or fixatives used in traditional osmotic ExM.

biophysics↗

bioRxiv2025

A Novel Mechanism for Tauopathy in Progressive Multiple Sclerosis: Excitotoxic Misplacement of a Mitochondrial Anchor into Dendrites Driven by Tau-hyperphosphorylation

On April 2nd, 2025, the FDA approved a Fast Track Designation for Biogen to use Antisense Oligonucleotides (ASO) to treat tauopathy in clinical trials for Alzheimers Disease (AD) to meet an unmet medical need [1]. For Multiple Sclerosis (MS), there is a similar unmet medical need regarding tauopathy when MS transitions into the late, or Progressive MS that is currently incurable. AD and MS share commonality: there is comorbidity between AD and MS [2], and the recent awareness that progressive MS may be considered a secondary tauopathy [3]. This study lays the basic science foundation for a future repurposing of ASO tauopathy therapy from AD to MS. The central hypothesis is that in Progressive MS, tauopathy is not a passive bystander but an active contributor to synaptic degeneration through a novel toxic target known as DSI (Dendritic Syntaphilin Intrusion) discovered in our laboratory. In this hypothesis, the excitotoxic N-methyl-D-aspartate receptor (NMDAR) GluN2B activates Tau hyperphosphorylation (p-Tau), leading to the mislocalization or intrusion of a mitochondrial anchor SNPH into neuronal dendrites (DSI). This causes mitochondrial damage and subsequent synapse/dendrite disintegration. In support of this hypothesis that tauopathy is a key driver of DSI, we demonstrated using primary neuronal cultures that inhibitors of p-Tau kinases and Tau-KO both completely abolish DSI. We propose that a therapy for Progressive MS is repurpose the existing FDA-approved ASO Tau knockdown therapy from AD to treat MS. FundingNIH R01 MSN233781 to SY Chiu

neuroscience↗

bioRxiv2022

PrePCI: A structure- and chemical similarity-informed database of predicted protein compound interactions

We describe the Predicting Protein Compound Interactions (PrePCI) database which comprises over 5 billion predicted interactions between nearly 7 million chemical compounds and 19,797 human proteins. PrePCI relies on a proteome-wide database of structural models based on both traditional modeling techniques and the AlphaFold Protein Structure Database. Sequence and structural similarity-based metrics are established between template proteins in the Protein Data Bank, T, that bind small molecules, C, and proteins in the models database, Q. When these metrics pass a sequence threshold value, it is assumed that C also binds to Q with a probability derived from machine learning. If the relationship is based on structure, this probability is based on a scoring function that measures the extent to which C is compatible with the binding site of Q as described in the LT-scanner algorithm. For every predicted complex derived in this way, chemical similarity based on the Tanimoto Coefficient identifies other small molecules that may bind to Q. A likelihood ratio for the binding of C to Q is obtained from naive Bayesian statistics. The PrePCI algorithm performs well under different validations. It can be queried by entering a UniProt ID for a protein and obtaining a list of compounds predicted to bind to it along with associated probabilities. Alternatively, entering an identifier for the compound outputs a list of proteins it is predicted to bind. Specific applications of the database are described and a strategy is introduced to use PrePCI as a first step in a docking screen.

systems biology↗

bioRxiv2020

Divergent use of metabolic fluxes in breast cancer metastasis

Breast cancers can metastasize to many organs. But how do disseminated cells from a primary tumor adapt to distal tissues? Here we combined metabolomics, flux measurements, and mathematical modeling to study metabolic fluxes in breast cancer cells adapted to home to different organs. We found that lung-homing cells maintain high glycolytic flux despite low levels of glycolytic intermediates, by constitutively activating a pathway sink into lactate. Their distinct behavior--a strong Warburg effect--has a gene expression signature: a high ratio of lactate dehydrogenase to pyruvate dehydrogenase gene expression, which also correlates with lung metastases in patients with breast cancer. Surprisingly, this strong Warburg effect does not necessarily increase cellular growth rate, suggesting that lactate secretion may be a trait under selection in lung metastasis. Our results stress that metabolic fluxes may not correlate with metabolic intermediates, a finding relevant for metastatic tropism.

cancer biology↗

bioRxiv2019

SAPdb: A database of nanostructures formed by self-assembly of short peptides

BackgroundNanostructures generated by self-assembly of peptides yield nanomaterial that has many therapeutic applications, including drug delivery and biomedical engineering, due to their low cytotoxicity and higher uptake by targeted cells owing to their high affinity and specificity towards cell surface receptors. Despite the promising implications of this rapidly expanding field, there is no dedicated resource to study peptide nanostructures. ResultThis study endeavours to create a dedicated repository of short peptides, which may prove to be the best models to study ordered nanostructures formed by peptide self-assembly. SAPdb has a repertoire of 1,049 entries of experimentally validated nanostructures formed by the self-assembling of small peptides. It includes 701 entries are of dipeptides, 328 entries belong to tripeptides, and 20 entries of single amino acid with some conjugated partners. Each entry encompasses comprehensive information about the peptide such as chemical modifications in the peptide sequences, the type of nanostructure formed, and experimental conditions like pH, temperature, and solvent required for the self-assembly of the peptide, etc. Further, our analysis has shown that the occurrence of aromatic amino acids favours the formation of self-assembling nanostructures, as indicated by a large number of entries in SAPdb contain aromatics amino acids. Besides, we have observed that these peptides form different nanostructures under different experimental conditions. SAPdb provides this comprehensive information in a hassle-free tabulated manner at a glance. User-friendly browsing, searching, and analysis modules are integrated for easy retrieval and comparison of data and examination of properties. We anticipate SAPdb to be a valuable repository for researchers engaged in the burgeoning arena of nanobiotechnology. AvailabilityThe database can be accessed on the web at https://webs.iiitd.edu.in/raghava/sapdb.

bioinformatics↗