Biology subjects

Kundu, P.

Publications and source records attributed to Kundu, P..

At least 19 recordsLinked to original sources

bioRxiv2026

Mechanistic insights into proteolytic activation ofmembrane-bound NAC transcription factor SlNACMTF3 intomato plants under heat stress

Stress is perceived at the cellular membrane, where membrane-bound transcription factors (MTFs) are activated, initiating a rapid gene-regulation cascade. We previously demonstrated the multifaceted role of tomato MTF, SlNACMTF3, in regulating expression of biotic and abiotic stress responsive genes. However, the molecular mechanism underlying its activation following stress perception remained unknown. Here, we show that the membrane rhomboid protease SlRP3 recognizes an ISK motif near the transmembrane domain of SlNACMTF3 for cleavage and releasing the transcription factor from the membrane. SlRP3 and SlNACMTF3 co-localize within the same plasma membrane microdomain and interact directly. Molecular dynamics simulations supported the proposed mechanism, in which heat-induced conformational switching of SlRP3, driven by reorientation of the L5 loop, enhances substrate accessibility and proteolytic activity. Furthermore, mutation of key SlRP3 residues involved in substrate interaction impaired SlNACMTF3 activation and reduced the expression of stress33 responsive genes. Analysis with SlNACMTF3-overexpressing tomato lines and SlRP3 transient knockdown leaves further revealed that transcription factor activation, stress35 responsive gene regulation, and cellular ROS detoxification occur coordinately. Collectively, these findings provide mechanistic insight into stress-triggered SlNACMTF3 activation and identify SlRP3 as a novel membrane-associated stress sensor that activates a major transcriptional regulator to enhance stress preparedness in economically important tomato plants.

plant biology↗

bioRxiv2026

Mediation Analysis with Compositional Exposures

Understanding the causal pathways linking the gut microbiome to downstream biomarkers and clinical outcomes is central to microbiome research. When the microbiome acts as the exposure, the high dimensionality and compositional structure of the data introduce unique methodological challenges for mediation analysis. To address these challenges, we propose a latent variable mediation framework that captures variation in microbial composition through a microbial balance, defined as the log-ratio between two unknown subsets of taxa. This balance serves as a latent scalar exposure and simplifies the estimation of the overall indirect effect at the community level, while simultaneously identifying specific taxa that contribute to the overall direct and indirect effects. We describe the model's estimation and inference, and illustrate the method using data from the Multiethnic Cohort--Adiposity Phenotype Study, where we examine the mediation pathway from the gut microbiome through lipopolysaccharide-binding protein, a marker of metabolic endotoxemia, to percent liver fat.

bioinformatics↗

bioRxiv2026

Enhancers require an active resetting phase after transcriptional activation

Signal-responsive enhancers must activate transcription and then return to a competent but inactive state, yet whether this transition is passive or actively driven has remained unresolved. We define this process as enhancer resetting and identify the androgen receptor (AR) as the factor that executes it as an endogenous response to estrogen signaling, independent of exogenous androgen. As estrogen receptor- (ER) undergoes ligand-induced proteasomal degradation during late-phase signaling, AR progressively accumulates in the nucleus and preferentially occupies highly active, persistent ER enhancers in a transcriptionally silent manner. This late-phase AR binding evicts the pioneer factor FOXA1 from chromatin while preserving baseline accessibility, a handoff mechanism that decouples chromatin openness from active transcription. Conversely, augmenting AR activity by DHT treatment or AR overexpression accelerates FOXA1 eviction, while disrupting AR chromatin binding, either by AR knockdown or a DNA-binding-deficient mutant, prevents it, leaving enhancers in an aberrantly permissive state that drives amplified ER rebinding and transcriptional hyperactivation upon subsequent estrogen stimulation. These findings establish active enhancer resetting as a mechanism safeguarding the fidelity of repeated transcriptional responses. Failure of this mechanism may underlie the transcriptional dysregulation that drives tumor progression and endocrine therapy resistance in ER-positive breast cancer, where estrogen signaling is chronic and cyclic.

molecular biology↗

bioRxiv2026

Thalamocortical orchestration of human theory of mind

Reasoning about others thoughts or beliefs is central to human social behavior. This ability, known as theory of mind (ToM), has been primarily attributed to cortical regions of the default network (DN). However, whether and how subcortical structures, particularly the thalamus, contribute to this high-level computation remains unknown. Here, we investigated human thalamocortical dynamics during a naturalistic ToM movie watching condition, taking a rare dual-modality approach by combining high-field 7T fMRI and intracranial stereoelectroencephalography (sEEG). Across both modalities, ToM events reliably activated the DN, whereas the thalamus lacked canonical local activation. Despite this absence of local activation, the thalamus shared ToM-related representational structure and exhibited enhanced bidirectional interactions with the DN during mentalizing across methods. Crucially, sEEG revealed that the thalamus coordinated DN activity via cross-frequency phase-amplitude coupling (PAC), whereby thalamic low-frequency phase unidirectionally modulated DN high-frequency activity. Furthermore, the strength of thalamic-DN PAC predicted both the activity magnitude and the representational quality of ToM-related information within the dorsomedial DN subsystem. Together, these findings identify the human thalamus as a regulatory hub that gates DN computations during ToM without exhibiting observable localized activity, revealing a previously unrecognized mechanism by which thalamic dynamics coordinate high-level social cognition in humans.

neuroscience↗

bioRxiv2026

The GA4GH Categorical Variation Representation Specification: A Unified Computational Framework for Reasoning over Genomic Variant Categories

Categorical variants, or sets of genomic alterations constrained by shared properties, are pervasive across clinical, regulatory, and research domains in the biomedical ecosystem, yet their inconsistent and non-computable representation hinders data interoperability and clinical interpretation. We surveyed genomic knowledgebases spanning regulatory approvals and the biomedical literature and found that categorical variants underpin a substantial proportion of clinical genomics knowledge, but are largely described using incompatible bespoke models. To address this, we developed the GA4GH Categorical Variation Representation Specification (Cat-VRS), a constraint-based framework that provides a unified computable representation for both precise and intentionally broad categories across molecular and systemic variant domains. Cat-VRS enables harmonization of genomic knowledgebases, computable category-based search, and automated matching between assayed variants and categorical entities in clinical and research contexts. By providing a principled, extensible model for categorical variation, Cat-VRS enables computable reasoning over genomic variant categories and establishes a foundation for the standardized representation and exchange of genomic knowledge.

genomics↗

bioRxiv2026

3D Light Sheet Microscopy Reveals Aging Osteoarthritis-associated Joint-innervated Nerve Remodeling in Mouse Knee Joints

ObjectivesOsteoarthritis (OA) is a prevalent age related joint disease-causing chronic pain. This study investigated how nociceptive and sympathetic nerve innervation in the mouse knee joint changes with age and OA progression, and how these changes relate to pain and disease severity. MethodsThirty-eight mice were assigned to four groups: young male (My), aged male (Ma), young female (Fy), and aged female (Fa). Pain sensitivity was evaluated via Pressure Application Measurement (PAM), and joint damage was graded using OARSI scoring. CGRP and PIEZO2 expressions in dorsal root ganglia (DRG) were also assessed. We employed iDISCO tissue clearing and 3D light sheet fluorescence microscopy to visualize total (PGP9.5), nociceptive (CGRP), and sympathetic (TH) nerve fibers in anterior regions of mouse knee joints. A MATLAB-based tool quantified nerve architecture. ResultsThe Ma group displayed the highest OA severity and markedly lower mechanical withdrawal thresholds compared with My (H = 11.59, {varepsilon}{superscript 2} = 0.64), suggesting an age effect on pain-related behavior. This phenotype was accompanied by a higher total PGP9.5 nerve fiber density in the knee joint (mean difference -0.3127, 95% CI -0.4551 to -0.1704) and increased CGRP nociceptive innervation. In contrast, female mice showed no age-dependent change in PAM withdrawal thresholds, consistent with preserved cartilage integrity and stable OARSI scores, and no detectable age-related differences in PGP9.5 or CGRP innervation. The TH sympathetic fiber distribution was comparable across sexes and ages. Consistent with joint-level findings, DRG analyses demonstrated increased CGRP and PIEZO2 expression in the Ma group, whereas females exhibited no significant change. ConclusionEnhanced nociceptive but not sympathetic nerve remodeling in knee cavities is associated with increased OA severity and knee pain in the Ma group. These findings emphasize the role of peripheral sensory plasticity in OA pain and demonstrate the value of 3D imaging for visualizing neuroanatomical changes in joint disorders.

neuroscience↗

bioRxiv2022

The structure of a Plasmodium vivax Tryptophan Rich Antigen suggests a lipid binding function for a pan-Plasmodium multi-gene family

Tryptophan Rich Antigens (TRAgs) are encoded by a multi-gene family in all Plasmodium species, significantly expanded in P. vivax, but their function is not currently known. We show that multiple P. vivax TRAgs are expressed on the merozoite surface and that one, PVP01_0000100 binds red blood cells with a strong preference for reticulocytes. Solving the structure of the C-terminal tryptophan rich domain that defines the TRAg family revealed a three-helical bundle that is conserved across Plasmodium and has homology with lipid-binding BAR domains involved in membrane remodelling. Biochemical assays confirmed that this domain has lipid binding activity with preference for sulfatide, a glycosphingolipid present in the outer leaflet of plasma membranes. Deletion of the putative orthologue in P. knowlesi, PKNH_1300500, impacts invasion in reticulocytes, suggesting a role for membrane remodelling during this essential process. Together, this work suggests a molecular function for the TRAg family for the first time.

microbiology↗

bioRxiv2021

Increased pattern similarity in two major olfactory cortices despite higher sparseness levels

Pattern separation is a fundamental process that enhances discrimination of similar stimuli and can be achieved by sparsening the neural activity and expanding the coding space. Odor stimuli evoke patterns of activity in the olfactory bulb (OB) and these activity patterns are projected to several cortical regions that contain larger numbers of neurons and show sparser activity levels. However, whether these projected patterns are better separated is still unclear. Here we compared odor responses in the OB, anterior piriform cortex (aPC) and anterior olfactory nucleus (AON) to the exact same odor stimuli. We found that odor representations are more similar, noisier and less distinctive in aPC and AON than in the OB. The increase in similarity was observed for both similar and dissimilar odors. Modeling odor transformation from the OB to the olfactory cortex using simulated as well as actual OB odor responses as inputs, demonstrates that the observed rise in odor representation similarity can be explained by assuming biologically plausible variation in the number of OB inputs each cortical neuron receives. We discuss the possible advantages of our findings to odor processing in the aPC and AON. HighlightsO_LIOdor representations in the aPC and AON are more correlated despite increase in sparseness levels. C_LIO_LIOdor identity is best represented in the OB. C_LIO_LIVariance in the number of inputs from OB can explain the reduction in odor separation. C_LI

neuroscience↗

bioRxiv2021

Functional architecture of the aging brain

The intrinsic functional organization of the brain changes into older adulthood. Age differences are observed at multiple spatial scales, from global reductions in modularity and segregation of distributed brain systems, to network-specific patterns of dedifferentiation. Whether dedifferentiation reflects an inevitable, global shift in brain function with age, circumscribed, experience dependent changes, or both, is uncertain. We employed a multi-method strategy to interrogate dedifferentiation at multiple spatial scales. Multi-echo (ME) resting-state fMRI was collected in younger (n=181) and older (n=120) healthy adults. Cortical parcellation sensitive to individual variation was implemented for precision functional mapping of each participant, while preserving group-level parcel and network labels. ME-fMRI processing and gradient mapping identified global and macroscale network differences. Multivariate functional connectivity methods tested for microscale, edge-level differences. Older adults had lower BOLD signal dimensionality, consistent with global network dedifferentiation. Gradients were largely age-invariant. Edge-level analyses revealed discrete, network-specific dedifferentiation patterns in older adults. Visual and somatosensory regions were more integrated within the functional connectome; default and frontoparietal control network regions showed greater connectivity; and the dorsal attention network was more integrated with heteromodal regions. These findings highlight the importance of multi-scale, multi-method approaches to characterize the architecture of functional brain aging.

neuroscience↗

bioRxiv2021

Piriformospora indica employs hosts putrescine for growth promotion in plants

Growth promotion by endosymbiont Piriformospora indica has been observed in various plants; however, specific functional metabolites involved in P. indica mediated growth promotion are unknown. A GC-MS based untargeted metabolite analysis was used to identify Solanum lycopersicum metabolites altered during P. indica mediated growth promotion. Metabolomic analysis showed primary metabolites altered and specifically putrescine to be maximally induced in roots during the interaction. P. indica induced putrescine biosynthetic gene SlADC1 in S. lycopersicum and acts via arginine decarboxylase (ADC) mediated pathway. P. indica did not promote growth in Sladc-VIGS (virus induced gene silencing of SlADC gene) lines of S. lycopersicum and when the ADC enzyme was inhibited with an inhibitor, DL--(Difluoromethyl) arginine. In Arabidopsis adc knock-out mutants, P. indica do not promote growth and this response was rescued upon exogenous application of putrescine. Putrescine promoted growth by elevation of auxin (indole-3-acetic acid) and gibberellin (GA4, GA7) levels in S. lycopersicum. Putrescine is also important for P. indica hyphal growth indicating that it is co-adapted by both host and microbe. Hence, we conclude that putrescine is an essential metabolite and its biosynthesis in plants is crucial for P. indica mediated growth promotion and fungal growth.

plant biology↗

bioRxiv2020

A multifaceted microRNA turnover complex from Caenorhabditis elegans

microRNAs are known to regulate expression of more than two third of all the eukaryotic genes by post-transcriptional means, and regulation of these tiny regulators play an important role in determining their activities. Here, we report a macromolecular microRNA turnover complex, whose components are crucial to microRNA homeostasis and development in Caenorhabditis elegans. Biochemical investigations with the purified complex in an isolated system not only unfolded the roles of the individual subunits critical for the functionality of the complex, but also unraveled the different modes of operations and regulatability of this biological machine. Our results reveal that this complex is highly receptive and capable of switching between an ATP-dependent and ATP-independent mode of operation depending on the availability of ATP in its environment, which might allow the complex to function dynamically during different physiological conditions.

molecular biology↗

bioRxiv2020

Efficient long-range conduction in cable bacteria through nickel protein wires

Filamentous cable bacteria display unrivalled long-range electron transport, generating electrical currents over centimeter distances through a highly ordered network of fibers embedded in their cell envelope. The conductivity of these periplasmic wires is exceptionally high for a biological material, but their chemical structure and underlying electron transport mechanism remain unresolved. Here, we combine high-resolution microscopy, spectroscopy, and chemical imaging on individual cable bacterium filaments to demonstrate that the periplasmic wires consist of a conductive protein core surrounded by an insulating shell layer. The core proteins contain a sulfur-ligated nickel cofactor, and conductivity decreases when nickel is oxidized or selectively removed. The involvement of nickel as the active metal in biological conduction is remarkable, and suggests a hitherto unknown form of electron transport that enables efficient conduction in centimeter-long protein structures.

microbiology↗

bioRxiv2020

Differential functional neural circuitry behind autism subtypes with marked imbalance between social-communicative and restricted repetitive behavior symptom domains

Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here we developed a phenotypic stratification model that makes highly accurate (97-99%) out-of-sample SC=RRB, SC>RRB, and RRB>SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n=509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC>RRB and visual association circuitry in SC=RRB. The SC=RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry.

neuroscience↗

bioRxiv2020

Neuronal Hyperexcitability is a DLK-dependent Trigger of HSV-1 Reactivation that can be Induced by IL-1

Herpes Simplex Virus (HSV) establishes a latent infection in neurons and periodically reactivates to cause disease. The neuronal stimuli that trigger HSV reactivation have not been fully elucidated. Here we demonstrate that HSV reactivation can be induced by neuronal hyperexcitability. Neuronal stimulation-induced reactivation was dependent on voltage-gated ion and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, demonstrating that neuronal activity is required for reactivation. Hyperexcitability-induced reactivation was dependent on the neuronal pathway of DLK/JNK activation and progressed via an initial wave of viral gene expression that was independent of histone demethylase activity and linked to histone phosphorylation. IL-1{beta} induces neuronal hyperexcitability and is released under conditions of stress and fever; both known triggers of clinical HSV reactivation. IL-1{beta} induced histone phosphorylation in sympathetic neurons, and importantly HSV reactivation, which was dependent on DLK and neuronal excitability. Thus, HSV co-opts an innate immune pathway resulting from IL-1 stimulation of neurons to induce reactivation.

microbiology↗

bioRxiv2019

Resting state functional connectivity in early post-anesthesia recovery is characterized by globally reduced anticorrelations

Though a growing body of literature is addressing the possible longer-term cognitive effects of anesthetics, to date no study has delineated the normal trajectory of neural recovery due to anesthesia alone in older adults. We obtained resting state functional magnetic resonance imaging scans on 62 healthy human volunteers between ages forty and eighty before, during, and after sevoflurane (general) anesthesia, in the absence of surgery, as part of a larger study on cognitive function post-anesthesia. Resting state networks expression decreased consistently one hour after emergence from anesthesia. This corresponded to a global reduction in anticorrelated functional connectivity post-anesthesia, seen across individual regions-of-interest. Positively correlated functional connectivity remained constant across peri-anesthetic states. All measures returned to baseline 1 day later, with individual regions-of-interest essentially returning to their pre-anesthesia connectivity levels. These results define normal peri-anesthetic changes in resting state connectivity in healthy older adults.

neuroscience↗

bioRxiv2019

Conservative and disruptive modes of adolescent change in brain functional connectivity

Adolescent changes in human brain function are not entirely understood. Here we used multi-echo functional magnetic resonance imaging (fMRI) to measure developmental change in functional connectivity (FC) of resting-state oscillations between pairs of 330 cortical regions and 16 subcortical regions in N=298 healthy adolescents. Participants were aged 14-26 years and were scanned on two or more occasions at least 6 months apart. We found two distinct modes of age-related change in FC: \"conservative\" and \"disruptive\". Conservative development was characteristic of primary cortex, which was strongly connected at 14 years and became even more connected in the period 14-26 years. Disruptive development was characteristic of association cortex, hippocampus and amygdala, which were not strongly connected at 14 years but became more strongly connected during adolescence. We defined the maturational index (MI) as the signed coefficient of the linear relationship between baseline FC (at 14 years, FC14) and adolescent change in FC ({triangleup}FC14-26). Disruptive systems (with negative MI) were functionally specialised for social cognition and autobiographical memory and were significantly co-located with prior maps of aerobic glycolysis (AG), AG-related gene expression, post-natal expansion of cortical surface area, and adolescent shrinkage of cortical depth. We conclude that human brain organization is disrupted during adolescence by the emergence of strong functional connectivity of subcortical nuclei and association cortical areas, representing metabolically expensive re-modelling of synaptic connectivity between brain regions that were not strongly connected in childhood. We suggest that this re-modelling process may support emergence of social skills and self-awareness during healthy human adolescence.

neuroscience↗

bioRxiv2019

Case-only analysis of gene-environment interactions using polygenic risk scores

Investigations of gene (G)-environment (E) interactions have led to limited findings to date, possibly due to weak effects of individual genetic variants. Polygenic risk scores (PRS), which capture the genetic susceptibility associated with a set of variants, can be a powerful tool for detecting global patterns of interaction. Motivated by the case-only method for evaluating interactions with a single variant, we propose a case-only method for the analysis of interactions with a PRS in case-control studies. Assuming the PRS and E are independent, we show how a linear regression of the PRS on E in a sample of cases can be used to efficiently estimate the interaction parameter. Furthermore, if an estimate of the mean of the PRS in the underlying population is available, the proposed method can estimate the PRS main effect. Extensions allow for PRS-E dependence due to associations between variants in the PRS and E. Simulation studies indicate the proposed method offers appreciable gains in efficiency over logistic regression and can recover much of the efficiency of a cohort study. As an illustration, we apply the proposed method to investigate interactions between a PRS and epidemiologic factors on breast cancer risk in the UK Biobank study.

genetics↗

bioRxiv2018

Ultra-high field MRI reveals mood-related circuit disturbances in depression: A systematic comparison between 3-Tesla and 7-Tesla

Ultra-high field 7-Tesla (7T) MRI has the potential to advance our understanding of neuropsychiatric disorders, including major depressive disorder (MDD). To date, few studies have quantified the advantage of resting state functional MRI (fMRI) at 7T compared to 3-Tesla (3T). We conducted a series of experiments that demonstrate the improvement in temporal signal-to-noise ratio (TSNR) of a multi-echo fMRI protocol with ultra-high field 7T, compared to 3T MRI in healthy controls (HC). We also directly tested the enhancement in ultra-high field 7T fMRI signal power by examining the ventral tegmental area (VTA), a small midbrain structure that is critical to the expected neuropathology of MDD but difficult to discern with standard 3T MRI. We demonstrate 200-300% improvement in TSNR and resting state functional connectivity coefficients provided by ultra-high field 7T fMRI compared to 3T, indicating enhanced power for detection of functional neural architecture. A multi-echo based acquisition protocol and signal denoising pipeline afforded greater gain in signal power at ultra-high field compared to classic acquisition and denoising pipelines. Furthermore, ultra-high field fMRI revealed mood-related neuro-circuit disturbances in patients with MDD compared to HC, which were not detectable with 3T fMRI. Ultra-high field 7T fMRI may provide an effective tool for studying functional neural architecture relevant to MDD and other neuropsychiatric disorders.

neuroscience↗