Biology subjects

Ganesan, K.

Publications and source records attributed to Ganesan, K..

8 recordsLinked to original sources

bioRxiv2026

Loss of the Y chromosome drives basal identity and metastatic potential via epigenetic reprogramming in pancreatic cancer

Loss of the Y chromosome (LOY) has been largely unexplored in pancreatic ductal adenocarcinoma (PDAC), and no mechanistic framework previously explained its role in tumor biology. We identify LOY as a recurrent, functionally consequential alteration affecting ~50% of male PDAC patients across two independent cohorts, with strong enrichment in advanced disease and, critically, in the basal subtype, establishing LOY as a clinically actionable biomarker. Comprehensive genomic profiling positions LOY as a distinct genetic event associated with TP53 mutations, implicating it in aggressive tumor evolution. Integrative analyses across bulk tumors, single-cell datasets and CRISPR-engineered PDAC models converge on epithelial-to-mesenchymal transition (EMT) as the dominant LOY-driven program. Y-chromosome deletion alone induces EMT transcriptional states, mesenchymal morphology and enhanced metastatic ability. Mechanistically, LOY disrupts epigenetic regulation through loss of Y-linked chromatin modifiers, reshaping DNA methylation at EMT- and basal-defining loci and reducing chemotherapy sensitivity. These findings establish LOY as a causal genetic driver of PDAC progression and a clinically accessible biomarker with direct therapeutic relevance.

cancer biology↗

bioRxiv2026

Mitochondrial turnover at central GABAergic synapses governs vulnerability to epileptic seizures

Mitochondrial dysfunction has long been known to underlie neurodegeneration, yet the contribution of mitochondrial turnover dynamics to functional aspects of defined synaptic circuits remains poorly understood. Here, we show that the mitochondrial proteome and turnover rates of hippocampal glutamatergic and GABAergic neurons is differentially remodelled by experience, with distal axon terminals of somatostatin-positive neurons exhibiting most dramatic changes, suggesting a form of metabolic plasticity at GABAergic synapses coupled to circuit activity. Conditional ablation of the mitochondrial transport proteins MIRO1 or TRAK1 (whose human mutations cause congenital epilepsy) stalled turnover at axon terminals driving loss of cristae, without affecting synapse or neuron integrity. The resulting reduction in synaptic GABA levels destabilized network oscillations and led to hyperexcitability, culminating in recurrent seizures and premature death. Post-weaning gene therapy efficiently reversed mitochondrial alterations and ameliorated the epileptic phenotype, underscoring the crucial role of mitochondrial turnover at central GABAergic synapses for balancing network excitability.

neuroscience↗

bioRxiv2026

75 Years of Mathematical Oncology

Constructing a comprehensive overview of any scientific field requires accurate literature selection, yet conventional keyword-based searches are susceptible to false positives. This problem is magnified in growing or interdisciplinary fields such as mathematical modeling in oncology that contain a rich but heterogeneous body of literature. Here, a generalizable, context-enriched artificial intelligence pipeline based on large language models (LLMs) curates large scientific corpora according to a user-defined field: mathematical modeling in oncology (>35k publications). Benchmarking against expert evaluation demonstrates high accuracy (ROC AUC[~]0.95) and agreement with human judgement (correlation[~]0.68), outperforming zero-shot LLM curation Analysis of the curated corpus ([~]14k) suggests that Mathematical Oncology s distinct from either Systems Biology and Pharmacokinetics/Pharmacodynamics despite employing overlapping methods. Co-occurring citation network analysis defines nine research clusters focused on a range of applications including drug delivery, optimal control, stochastic modeling, tumor microenvironment, radiation, cancer evolution, and spatial multiscale modeling. Significance StatementA generalizable, context-enriched artificial intelligence pipeline accurately curates large scientific corpora Analysis of the curated dataset applied to the se of mathematics n oncology provides comprehensive view of mathematical modeling in oncology across 140 years, revealing its shift from fundamental cancer biology towards therapeutic modelling.

cancer biology↗

bioRxiv2025

PhytClust: efficient and optimal node clustering in phylogenetic trees

Phylogenetic trees play a fundamental role in elucidating evolutionary relationships among taxa. Clustering taxa remains a major challenge across diverse biological domains such as cancer genomics, microbial systematics, and phylogenomics. Several methods partition taxa in phylogenetic trees into clusters, but these approaches face key limitations. Many rely on user-defined distance thresholds, whose choice often depends on prior knowledge and may be difficult to justify consistently across datasets. More broadly, existing methods often differ in how clusters are defined and commonly rely on heuristics or user-specified criteria to make the search space tractable for large trees. Here, we present PhytClust, a threshold-free algorithm that partitions trees into monophyletic subtrees (clusters) by identifying groups of taxa with low within-cluster dispersion. For a fixed number of clusters, PhytClust finds the exact global optimum under this objective and then selects the optimal number of clusters using a cluster-validity index. The resulting partitions are reproducible and reflect both tree topology and branch lengths. In simulated datasets, PhytClust outperforms existing methods in both speed and accuracy and scales to trees with more than a hundred thousand taxa. We apply PhytClust across cancer genomics, avian phylogenomics, bacterial and archaea phylogenetics, and plant genomics to demonstrate PhytClusts varied applicability. By providing a standardized method for taxa clustering within phylogenetic trees, PhytClust yields reproducible, optimal and computationally efficient clusters.

evolutionary biology↗

bioRxiv2025

A genetic signature predicts aggressive paraganglioma sensitivity to dual PI3K-CDK4/6 inhibition therapy

Effective medical therapies for metastatic paraganglioma (mPPGL) are currently lacking, leading to dismal prognosis. Building on our knowledge of molecular mechanisms driving PPGL progression, we assessed the therapeutic potential of targeting two critical processes: PI3K signaling and cell cycle regulation. The efficacy of buparlisib (PI3Ki) and ribociclib (CDK4/6i), individually and combined, was assessed in vitro using PPGL cell lines, rat- and patient-derived primary cells, and in vivo using PPGL cells-derived mouse xenografts. The combination therapy demonstrated superior antitumor activity compared to single agents, particularly in vivo. Mechanistically, the efficacy of the combination therapy was associated to the downregulation of FOXM1-controlled genes implicated in mitotic spindle assembly and chromosomal segregation, leading to mitotic catastrophe. Data mining and qRT-PCR showed this genetic signature to be upregulated in human mPPGLs. This suggests that aggressive PPGLs exhibit heightened vulnerability to dual PI3K and CDK4/6 inhibition, offering a promising therapeutic avenue for these challenging cancers.

cancer biology↗

bioRxiv2024

Dorsomedial striatal neuroinflammation causes excessive goal-directed action control by disrupting homeostatic astrocyte function

Compulsive actions are typically thought to reflect the dominance of habits over goal-directed action. To address this, we mimicked the striatal neuroinflammation that is frequently exhibited in individuals with compulsive disorders in rats, by injecting the endotoxin lipopolysaccharide into the posterior dorsomedial striatum, and assessed the consequences for behavioural control. Surprisingly, this manipulation caused rats to acquire and maintain goal-directed actions under conditions that would otherwise produce habits. Immunohistochemical analyses indicated that these behaviours were a result of astrocytic proliferation. To probe this further, we chemogenetically activated the Gi-pathway in striatal astrocytes, which altered the firing properties of nearby medium spiny neurons and modulated goal-directed action control. Together, results show that striatal neuroinflammation is sufficient to bias action selection toward excessive goal-directed control via dysregulated astrocyte function. If translatable, our findings suggest that, contrary to conventional views, individuals with striatal neuroinflammation might be more prone to maladaptive goal-directed actions than habits, and future interventions should aim to restore appropriate action control.

animal behavior and cognition↗

bioRxiv2024

Hippocampal neuroinflammation causes sex-specific disruptions in instrumental conditioning, Pavlovian approach, and neuronal excitation

Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt such behaviour is unknown. We investigated this question here using mice. First, the application of an endotoxin to primary cultures containing only hippocampal neurons did not affect their activation. However, when the same endotoxin was applied to mixed neuronal/glial cultures it did increase neuronal activation, providing initial indications of how it might be able to effect behavioural change. We next demonstrated neuroinflammatory effects on behaviour directly, demonstrating that intra-hippocampal administration of the same endotoxin increased locomotor activity and accelerated goal-directed learning in both male and female mice. In contrast, hippocampal neuroinflammation caused sex-specific disruptions to the acquisition of instrumental actions and to Pavlovian food-approach memories. Finally, we showed that hippocampal neuroinflammation had a sexually dimorphic effect on neuronal activation: increasing it in females and decreasing it in males.

animal behavior and cognition↗

bioRxiv2020

Visual speech differentially modulates beta, theta, and high gamma bands in auditory cortex

Speech perception is a central component of social communication. While principally an auditory process, accurate speech perception in everyday settings is supported by meaningful information extracted from visual cues (e.g., speech content, timing, and speaker identity). Previous research has shown that visual speech modulates activity in cortical areas subserving auditory speech perception, including the superior temporal gyrus (STG), potentially through feedback connections from the multisensory posterior superior temporal sulcus (pSTS). However, it is unknown whether visual modulation of auditory processing in the STG is a unitary phenomenon or, rather, consists of multiple temporally, spatially, or functionally distinct processes. To explore these questions, we examined neural responses to audiovisual speech measured from intracranially implanted electrodes within the temporal cortex of 21 patients undergoing clinical monitoring for epilepsy. We found that visual speech modulates auditory processes in the STG in multiple ways, eliciting temporally and spatially distinct patterns of activity that differ across theta, beta, and high-gamma frequency bands. Before speech onset, visual information increased high-gamma power in the posterior STG and suppressed beta power in mid-STG regions, suggesting crossmodal prediction of speech signals in these areas. After sound onset, visual speech decreased theta power in the middle and posterior STG, potentially reflecting a decrease in sustained feedforward auditory activity. These results are consistent with models that posit multiple distinct mechanisms supporting audiovisual speech perception and provide a crucial map for subsequent studies to identify the types of visual features that are encoded by these separate mechanisms.

neuroscience↗