Biology subjects

Chaudhuri, R.

Publications and source records attributed to Chaudhuri, R..

14 recordsLinked to original sources

bioRxiv2026

Safe Redosable Low-Immunogenic In Vivo CAR-T Therapy for B Cell Malignancies and Solid Tumors

In vivo CAR-T cell therapy eliminates manufacturing complexities associated with ex vivo autologous approaches, but safety concerns have limited adoption. We developed viroVbot, a next-generation in vivo CAR-T platform, by combining computational immunogenicity prediction (CIMMEXTM) with envelope engineering. Screening 22,562 glycoprotein sequences, we identified 641 vesiculovirus homologs, from which we selected Piry virus glycoprotein (PIRYV) as the optimal candidate. PIRYV exhibited lower MHC-epitope density, reduced human seroprevalence, with decreased T cell activation compared to VSV-G. To enhance targeting specificity, we engineered receptor-binding-deficient PIRYV (ePIRYVRBD) displaying CD3/CD7 nanobodies for T cell-selective transduction. To maximize safety, we engineered CAR-TRAP producer cells to eliminate unwanted B cell transduction and incorporated machine learning-optimized T cell-specific promoters that restrict CAR activation exclusively to lymphocytes. Additional modifications suppressed hepatocyte expression and prevented phagocytic uptake. In humanized xenograft models, viroVbot3 generated potent BCMA/CD19 specific CAR-T responses against multiple myeloma and Claudin18.2-targeting gastric cancer, demonstrating sequential redosing with alternative envelopes. Critically, viroVbot3 exhibited minimal off-target organ biodistribution with CAR expression restricted to T lymphocytes. These findings establish viroVbot as a low-immunogenic platform for scalable in vivo CAR-T manufacturing with capability for sequential redosing across hematologic and solid tumors.

bioengineering↗

bioRxiv2026

Molecular analysis of Lancefield group C/G streptococci causing human infections in Sheffield, UK.

Lancefield group C/G streptococci (GCS/GGS) are increasingly recognised as significant human pathogens that cause a disease spectrum similar to Streptococcus pyogenes. Despite their high clinical burden in the UK, their genomic diversity remains poorly understood. We performed whole-genome sequencing (WGS) on a prospective collection of 109 consecutive GCS/GGS isolates from all infection types in Sheffield, UK, over five months in 2020. Streptococcus dysgalactiae subsp. equisimilis (SDSE) accounted for 104 isolates, while five were identified as Streptococcus canis. The SDSE population was highly diverse, comprising 15 genomic clusters and 38 unique emm-ST combinations. We identified the presence of the ST20/stG62647 international lineage (24% of isolates), a cluster globally associated with severe invasive disease. Antimicrobial resistance genes were prevalent (49%), predominantly linked to mobile genetic elements carrying tetracycline and macrolide resistance. Furthermore, a variation in the penicillin-binding protein PBP2X (P601L) was linked to reduced penicillin sensitivity (MIC 0.03 mg/L). There were few or no genetic changes in isolates obtained from the same patient, even when they were collected 8-10 weeks apart, indicating long-term persistence within a host. The unexpected detection of S. canis in human infections and the high diversity of SDSE, persistence and virulence-associated regions underscore the need for enhanced national genomic surveillance to track emerging virulent and antibiotic-resistant SDSE lineages. Impact statementLancefield group C and G streptococci, most often the species Streptococcus dysgalactiae subsp. equisimilis (SDSE), are an increasingly significant human pathogen, often mirroring the severity of infections caused by Lancefield group A Streptococcus (S. pyogenes). Despite its clinical importance, we know little about the population of SDSE circulating in the UK. This study provides the first comprehensive genomic analysis of SDSE isolates from a single UK region, identifying a highly diverse population comprising 15 distinct genomic clusters but with evidence of long-term persistence within a single host. Notably, we confirm the presence of the international stG62647/ST20 lineage in the UK, which is globally associated with severe invasive disease. Our findings also reveal a high prevalence of antimicrobial resistance genes ([~]49%), primarily linked to mobile genetic elements, and the presence of a specific variation in the penicillin-binding protein PBP2X that reduces penicillin sensitivity. Additionally, the unexpected detection of S. canis in human infections rather than animals highlights a need for monitoring. By defining the UKs SDSE population structure and its resistance landscape, this research underscores the critical need for enhanced national genomic surveillance to track emerging high-virulence and antibiotic-resistant lineages Data summarySequence files for isolates from Sheffield used for this study have been uploaded to the sequence read archive with project accession number PRJNA1333937 and accession numbers provided in Supplementary Dataset 1. The completed genome for SDE096 been deposited on GenBank with the accession number JBSXMJ000000000.

microbiology↗

bioRxiv2026

The Epigenetic Regulator Histone Demethylase KDM5A is Activated and Pathogenic in a Mouse Model of Heart Failure

Heart failure is a complex disease characterized by the dysregulation of gene expression that culminates in cardiac dysfunction. Epigenetic regulators play a critical role in control of transcription and are increasingly implicated in the pathogenesis of heart failure. We recently showed that the histone demethylase KDM5A is reactivated in the heart of human patients and mouse models of heart failure. However, its pathogenic role in heart failure remained unknown. Utilizing a mouse model of heart failure caused by the deletion of the Lmna gene in cardiomyocytes and referred to as LMNA-cardiomyopathy (LMNA-CMP), we show that KDM5A is activated, and expression levels of genes involved in myocyte structure and function, including oxidative phosphorylation (OXPHOS), are suppressed. To determine the pathogenic role of KDM5A in heart failure, the Kdm5a gene was specifically deleted in cardiomyocytes in LMNA-CMP mice (Myh6-Cre:LmnaF/F:Kdm5aF/F). The deletion of the Kdm5a gene improved cardiac function, prolonged survival, attenuated fibrosis, and reduced cell death in LMNA-CMP mice. Transcriptome analysis showed that the deletion of the Kdm5a gene restored the expression of over 1,400 dysregulated genes, including those involved in fatty acid metabolism, myogenesis, and OXPHOS in the Myh6-Cre:LmnaF/F:Kdm5aF/F mice. Genome-wide profiling of the epigenetic histone mark H3 lysine 4 trimethylation (H3K4me3), the main target of KDM5A, by CUT&RUN assay showed that deletion of the Kdm5a gene partially restored H3K4me3 deposits at loci encoding cardiac transcription factors and metabolic regulators, including Tbx5 and Esrrg, with concomitant rescue of their downstream targets. These findings identify KDM5A as a key epigenetic regulator of cardiomyocyte gene expression and uncover a mechanistic role for KDM5A in the pathogenesis of heart failure.

genetics↗

bioRxiv2025

Population-level temporal decoding and dynamical structure in frontostriatal circuits during decision making

Perceptual decisions unfold over time, requiring neural circuits to evaluate sensory evidence, track elapsed time, and commit to an action. To investigate how these computations are distributed across corticostriatal circuits, we recorded large-scale neural population activity using Neuropixels probes in the rat frontal orienting field (FOF) and anterior dorsal striatum (ADS) during a free-response auditory change detection task. Both regions exhibited structured, highly dynamic population activity during task performance. Using single-trial population decoding, we found that both FOF and ADS robustly encoded retrospective time from stimulus onset and prospective time preceding the decision report. Using a new approach to analyze temporal encoding to identify the dynamical structure supporting decoding, we found that time encoding could be decomposed into two primary dynamical motifs: monotonic ramp-like trajectories and transient bump-like trajectories. While these modes were similarly expressed during early evidence evaluation, FOF exhibited more pronounced decision-aligned changes near the time of the decision report, possibly reflecting a state transition at commitment. Population geometry analyses further revealed stable low-dimensional subspaces during evidence evaluation that transitioned at decision commitment, with significantly larger subspace changes in FOF than ADS. Together, these results reveal a common dynamical framework during evidence evaluation across corticostriatal circuits, while identifying a selective reorganization of FOF dynamics associated with decision commitment.

neuroscience↗

bioRxiv2025

SEASONAL PM2.5 DIFFERENTIALLY REGULATES JAK2/STAT3 SIGNALING IN RURAL AND URBAN COHORTS

Ambient particulate matter (PM2.5) is a major environmental carcinogen linked to lung cancer, yet its molecular insights on asymptomatic non-smokers remains unclear. This study examined the effect of seasonal fluctuations of PM2.5 on oxidative stress and pro-oncogenic signaling in rural (RU) and urban (UR) cohorts from West Bengal, India. Environmental monitoring revealed higher PM2.5 and associated benzo[]pyrene in UR, during winter, induced oxidative stress (elevated ROS, 8-OHdG), reduced antioxidants (SOD, catalase, GPx), and promoted airway inflammation. Transcriptomic and bioinformatic analyses identified activation of IL-6/EGFR-driven JAK2/STAT3 signaling and its crosstalk with Ras/Raf/MAPK, leading to increased expression of downstream effectors (BCL-2, MCL-1, c-MYC, cyclin D1) and repression of tumor suppressors (BAX, p21). Notably, downregulation of JAK/STAT inhibitors PIAS2 and SOCS2 suggested persistent activation of oncogenic signaling. Linear mixed-effects models linked winter PM2.5 surges to oxidative stress, inflammation, and altered JAK2/STAT3 signaling, while regression models showed stronger responses in UR. Risk modeling predicted significantly higher lung cancer mortality in UR, underscoring the role of seasonal PM2.5 surges in JAK2/STAT3-driven carcinogenic susceptibility and the urgent need for targeted interventions.

cancer biology↗

bioRxiv2025

Not a global map, but a local hash: grid cells decorrelate the representation of position and scramble long-range distance information

Grid cells in the medial entorhinal cortex construct an intriguing multiperiodic representation of space whose properties have been the subject of much theoretical speculation. Here we combine modeling with analyses of neural population data from mice and rats to show that the grid cell representation is ideally set up to decorrelate and assign easily distinguishable labels to inputs, thus acting as a pattern separation device, much like a hash function in computing rather than a global map or metric. The multiple modules of the grid cell system allow the threshold for pattern separation to be controlled. We also extend these arguments to show how grid cells can perform pattern separation in abstract and higher-dimensional spaces. This pattern separation ability may serve to enhance episodic memory in the hippocampal formation by reducing interference between similar patterns.

neuroscience↗

bioRxiv2025

Time-adaptive modulation of evidence evaluation in rat posterior parietal cortex

A crucial component of successful decision making is determining the optimal timescale over which to evaluate evidence. For example, when detecting transient changes in the environment, it is best to focus evaluation on the current evidence as opposed to older evidence. However, it is unclear how this adjustment in timescale is achieved in the brain in terms of how the neurons that process evidence adjust their dynamics. To address this question, we used Neuropixel probes to record spiking activity from neurons in the posterior parietal cortex (PPC) of rats performing a free-response auditory change detection task in which subjects evaluate sensory evidence over short timescales to determine when a change occurs in a noisy sensory stream. Consistent with longer timescale temporal integration tasks, we found that PPC neurons modulated their activity by the strength of evidence leading to decisions, were selective for the rats choices, and had opposing populations of neurons that were positively versus negatively modulated by evidence. However, in contrast to temporal integration tasks, responses of neurons to individual pulses of evidence were transient, such that the effect of the evidence on activity tapered off over a timescale corresponding to the subjects behavioral timescale of evidence evaluation. Intriguingly, PPC also exhibited "gain changes" in the influence of evidence as a function of decision time that were consistent with changes in behavioral urgency. In addition, reversible inactivation revealed an important role for PPC in this auditory change detection, such that PPC inactivation altered choice behavior and the timescale over which rats evaluated evidence. Together, our results suggest important contributions of PPC to free-response decisions that involve adjusting timescales of evidence evaluation.

neuroscience↗

bioRxiv2024

Posterior Parietal Cortex Regulates Intrinsic Neural Timescales and Attentional Processing in Frontal Eye Field

Intrinsic neural timescales quantify how long spontaneous neuronal activity patterns persist, reflecting dynamics of endogenous fluctuations. We measured intrinsic timescales of frontal eye field (FEF) neurons and examined their changes during posterior parietal cortex (PPC) inactivation. We observed two distinct classes of FEF neurons based on their intrinsic timescales: short-timescale neurons ([~]25 ms) or long-timescale neurons ([~]100 ms). Short-timescale neurons showed stronger transient visual responses, suggesting their role in rapid visual processing, whereas long-timescale neurons exhibited pronounced sustained attentional modulation, suggesting their role in maintaining stimulus-driven attention. During PPC inactivation, intrinsic timescales increased in both neuron types, with a significantly larger effect in short-timescale neurons. In addition, PPC inactivation reduced attentional modulation, particularly in long-timescale neurons. Our findings provide the first causal evidence linking intrinsic local neural timescales to long-range inter-area communications. These findings also suggest the presence of at least two distinct network motifs that support different neuronal dynamics and functional computations within the FEF.

neuroscience↗

bioRxiv2023

High-capacity flexible hippocampal associative and episodic memory enabled by prestructured ''spatial'' representations

Hippocampal circuits in the brain enable two distinct cognitive functions: the construction of spatial maps for navigation and the storage of sequential episodic memories. This dual role remains an enduring enigma. While there have been advances in modeling spatial representations in the hippocampus, we lack good models of its role in episodic memory. Here we present a neocortical-entorhinal-hippocampal network model that implements a high-capacity general associative memory, spatial memory, and episodic memory by factorizing content storage from the dynamics of generating error-correcting stable states. Unlike existing neural memory models, which exhibit a memory cliff, the circuit (which we call Vector-HaSH, Vector Hippocampal Scaffolded Heteroassociative Memory) exhibits a graceful tradeoff between number of stored items and detail. Next, we show that structured internal scaffold states are essential for constructing episodic memory: they enable high-capacity sequence memorization by abstracting the chaining problem into one of learning low-dimensional transitions. Finally, we show that previously learned spatial sequences in the form of cortico-hippocampal location-landmark associations can in turn be used as larger scaffolds and associated with neocortical inputs for a high-fidelity one-shot memory, providing the first circuit model of the "memory palaces" used in the striking feats of memory athletes.

neuroscience↗

bioRxiv2022

Common population codes produce extremely nonlinear neural manifolds

Populations of neurons represent sensory, motor and cognitive variables via patterns of activity distributed across the population. The size of the population used to encode a variable is typically much greater than the dimension of the variable itself, and thus the corresponding neural population activity occupies lower-dimensional subsets of the full set of possible activity states. Given population activity data with such lower-dimensional structure, a fundamental question asks how close the low-dimensional data lies to a linear subspace. The linearity or non-linearity of the low-dimensional structure reflects important computational features of the encoding, such as robustness and generalizability. Moreover, identifying such linear structure underlies common data analysis methods such as Principal Component Analysis. Here we show that for data drawn from many common population codes the resulting point clouds and manifolds are exceedingly nonlinear, with the dimension of the best-fitting linear subspace growing at least exponentially with the true dimension of the data. Consequently, linear methods like Principal Component Analysis fail dramatically at identifying the true underlying structure, even in the limit of arbitrarily many data points and no noise.

neuroscience↗

bioRxiv2022

Identification of candidate virulence loci in Striga hermonthica, a devastating parasite of African cereal crops

O_LIParasites have evolved proteins, Virulence Factors (VFs), that facilitate plant colonization, yet VFs mediating parasitic plant-host interactions are poorly understood. Striga hermonthica is an obligate, root-parasitic plant of cereal hosts in sub-Saharan Africa, causing devastating yield losses. Understanding the molecular nature and allelic variation of VFs in S. hermonthica is essential for breeding resistance and delaying the evolution of parasite virulence. C_LIO_LIWe assembled the S. hermonthica genome and identified secreted proteins by in silico prediction. Pooled sequencing of parasites growing on a susceptible and a strongly resistant rice host allowed us to scan for loci where selection imposed by the resistant host had elevated the frequency of alleles contributing to successful colonisation. C_LIO_LIThirty-eight putatively secreted VFs had extremely different allele frequencies with functions including host cell wall modification, protease inhibitors, oxidoreductase and kinase activities. These candidate loci had significantly higher Tajimas D than the genomic background, consistent with balancing selection. C_LIO_LIOur results reveal diverse strategies used by S. hermonthica to overcome different layers of host resistance. Understanding the maintenance of variation at virulence loci by balancing selection will be critical to managing the evolution of virulence as a part of a sustainable control strategy. C_LI

plant biology↗

bioRxiv2020

Architecture and self-assembly of the Clostridium sporogenes/botulinum spore surface illustrate a general protective strategy across spore formers

Spores, the infectious agents of many Firmicutes, are remarkably resilient cell forms. Even distant relatives have similar spore architectures incorporating protective proteinaceous envelopes. We reveal in nanometer detail how the outer envelope (exosporium) in Clostridium sporogenes (surrogate for C. botulinum group I), and in other Clostridial relatives, forms a hexagonally symmetric molecular filter. A cysteine-rich protein, CsxA, when expressed in E. coli, self-assembles into a highly thermally stable structure identical to native exosporium. Like exosporium, CsxA arrays require harsh reducing conditions for disassembly. We conclude that in vivo, CsxA self-organises into a highly resilient, disulphide cross-linked array decorated with additional protein appendages enveloping the forespore. This pattern is remarkably similar in Bacillus spores, despite lack of protein homology. In both cases, intracellular disulphide formation is favoured by the high lattice symmetry. We propose that cysteine-rich proteins identified in distantly related spore formers may adopt a similar strategy for intracellular assembly of robust protective structures.

microbiology↗

bioRxiv2019

The population dynamics of a canonical cognitive circuit

The brain constructs distributed representations of key low-dimensional variables. These variables may be external stimuli or internal constructs of quantities relevant for survival, such as a sense of ones location in the world. We consider that the high-dimensional population-level activity vectors are the fundamental representational currency of a neural circuit, and these vectors trace out a low-dimensional manifold whose dimension and topology matches those of the represented variable. This manifold perspective -- applied to the mammalian head direction circuit across rich waking behaviors and sleep -- enables powerful inferences about circuit representation and mechanism, including: Direct visualization and blind discovery that the network represents a one-dimensional circular variable across waking and REM sleep; fully unsupervised decoding of the coded variable; stability and attractor dynamics in the representation; the discovery of new dynamical trajectories during sleep; the limiting role of external rather than internal noise in the fidelity of memory states; and the conclusion that the circuit is set up to integrate velocity inputs according to classical continuous attractor models.

neuroscience↗

bioRxiv2017

How fast is neural winner-take-all when deciding between many options?

Identifying the maximal element (max, argmax) in a set is a core computational element in inference, decision making, optimization, action selection, consensus, and foraging. We show that running sequentially through a list of N fluctuating items takes Nlog(N) time to accurately find the max, prohibitively slow for large N. The power of computation in the brain is ascribed to its parallelism, yet it is theoretically unclear whether, even on an elemental task like the max operation, leaky and noisy neurons can perform a distributed computation that cuts the required time by a factor of N, a benchmark for parallel computation. We show that conventional winner-take-all circuit models fail to realize the parallelism benchmark and worse, in the presence of noise altogether fail to produce a winner when N is large. If, however, neurons are equipped with a second nonlinearity so that weakly active neurons cannot contribute inhibition to the circuit, the network matches the accuracy of the serial strategy but does so N times faster, partially self-adjusting integration time for task difficulty and number of options and saturating the parallelism benchmark without parameter fine-tuning. Finally, in the regime of few choices (small N), the same circuit predicts Hick's law of decision making; thus Hick's law behavior is a symptom of efficient parallel computation. Our work shows that distributed computation that saturates the parallelism benchmark is possible in networks of noisy and finite-memory neurons.

neuroscience↗