Biology subjects

Ganguli, S.

Publications and source records attributed to Ganguli, S..

At least 19 recordsLinked to original sources

bioRxiv2026

A predictive theory of experimental design for inferring neural population geometry in large-scale recordings

Ongoing technological advances will lead to recordings with progressively increasing numbers of neurons, while trial counts may only increase modestly. The analysis of such large-scale data increasingly relies on extracting collective neural population geometry. These combined recording and analysis trends raise the fundamental need for a predictive theory of experimental design that can tell us how accurately we will be able to infer such geometry in future larger scale recordings with more neurons and trials, by extrapolating from past smaller recordings. We derive such a theory for the simplest and most widely used method for extracting population geometry: principal component analysis. Our theory can predict how the dimensionality of neural data will grow with more neurons and trials and how accurate and reliable neuronal correlations and individual neural modes of the population geometry will be. Importantly, we find a blessing of dimensionality in which recording more neurons allows population geometry to be inferred accurately with fewer trials. The need for fewer trials in larger recordings will allow for the design of new experiments with more diverse trial types. Moreover, we derive scaling laws for the performance of neural prediction, setting the stage for the derivation of scaling laws for foundation models in neuroscience. We successfully test our theory across diverse species and recording modalities.

neuroscience↗

bioRxiv2026

Nanoarchaeosome-mediated epirubicin delivery induces sustained intracellular stress and suppresses adaptive glioblastoma phentoypes

Although anthracyclines such as epirubicin are potent DNA-damaging agents, their application in glioblastoma (GBM) is limited by poor intracellular penetration, lack of durable responses and rapid emergence of adaptive tumor phenotypes. Here, we demonstrate that nanoarchaeosome-mediated delivery of epirubicin (NanoEpi) enables functional reprogramming of GBM survival under therapeutic stress. Nanoarchaeosomes composed of archaeal ether lipids exhibited high encapsulation efficiency ([~]96%) and nanoscale stability. Although both Epi and NanoEpi showed similar bulk uptake, both in established (U251-MG) and patient-derived (Gli5) glioblastoma models, NanoEpi induced significantly greater cytotoxicity than free epirubicin, indicating enhanced intracellular drug engagement. NanoEpi induced enhanced DNA damage, elevated reactive oxygen species, and mitochondrial depolarisation, leading to cytoskeletal collapse. In 3D gliomasphere systems, NanoEpi showed improved penetration and sustained retention, resulting in suppression of core viability and invasion. This correlates with its increased uptake by the lysosomes. Notably, even a transient exposure led to depletion of sphere-initiating capacity and complete loss of clonogenic recovery, indicating targeting of the stem-like compartment. This was accompanied by attenuation of MMP-2/9 activity and reduced angiogenic signalling in a chorioallantoic membrane model. These findings establish nanoarchaeosomes as a robust lysosome-directed delivery platform that extends beyond passive drug transport to sustain intracellular stress and suppress invasive adaptation and limit recurrence in GBM.

cancer biology↗

bioRxiv2026

Amino acid repeat mosaics shape protein functional landscape

How combinations of functional units such as repeats and motifs within disordered regions influence protein functions remains poorly understood. Here, we investigate how co-occurring amino acid homorepeats of different types within the same protein (HR-mosaics) shape molecular outcomes. Using a novel evolutionary co-occurrence metric, human HR-mosaics were classified as segregated (each HR independently influences distinct outcomes), concerted-disjunct (both HRs jointly shape protein functionality without modulating each other), or concerted-conjunct (both HRs affect functionality through mutual influence). Molecular studies of naturally occurring polyGly-polyPro mosaic in DDX17 and chimeric mosaics of polyAla and polyHis demonstrate that HR-mosaics influence protein abundance, localisation, mobility and interaction landscape. Segregated HR-mosaics expand functional space, concerted-disjunct additionally confer biological context, and concerted-conjunct mosaics further enable rheostatic regulation between HRs. These design principles underscore amino acid type, length and relative positioning of HRs as central architects of HR-mosaic functionality, with implications in protein design and engineering and understanding repeat-associated pathologies.

Systems Biology↗

bioRxiv2026

Intrinsic space-time couplings governing multi-scale cortical dynamics

The neocortex covers a vast expanse of the mammalian brain and represents the principal target of clinical neuromodulation; however, the global principles of neocortical operation have been challenging to identify. In this regard, a limitation has been tracking activity with cortex-wide spatial coverage while maintaining access to the millisecond temporal resolution of neuronal firing-- a crucial combination not achievable with existing recording technologies. Here we introduce and apply conformal immersion microscopy, enabling activity tracking across the entire dorsal cortex with millisecond temporal resolution and 100 {micro}m spatial resolution (thus spanning five orders of magnitude in time and four in space), at sufficient sensitivity to resolve single-trial activity beyond 100 Hz. Drawing on physics-based frameworks, we apply multiscale analysis to identify a fundamental frequency-dependent coherence length that partitions the neocortex into discrete dynamical elements with well-defined propagation speeds, boundaries, and scale-invariant dynamics. These dynamical elements were found to be conserved from sub-threshold to suprathreshold (neuronal firing) regimes of neural activity, and were robust to diverse pharmacological, optogenetic, and genetic interventions. However, it was possible to identify and establish conditions allowing elemental boundaries to be selectively overridden, and to allow perturbation of specific elements even while conserving global dynamical architecture. Together, these findings enable measurement of intrinsic spatiotemporal parameters governing the dynamical organization of neocortex, which may provide a foundation for mechanistically-informed basic and translational understanding.

neuroscience↗

bioRxiv2026

The inositol pyrophosphate 5-InsP7 promotes DNA repair by disrupting RAD51 binding to the C-terminus of BRCA2

The inositol pyrophosphate 5-InsP7, composed of an inositol ring substituted with five monophosphates and one diphosphate, modulates diverse cellular functions by protein pyrophosphorylation, during which its {beta}-phosphate moiety is transferred to a pre-phosphorylated serine residue on the target protein. In mammals, the synthesis of 5-InsP7 from its precursor InsP6 is catalyzed by a family of enzymes called IP6Ks. We report that during recovery from genotoxic stress, cells lacking the IP6K isoform IP6K1 exhibit prolonged persistence of DNA damage foci marked by the homologous recombination repair protein RAD51. Expression of catalytically active but not inactive IP6K1 reverses this defect, implying that 5-InsP7 supports the dissolution of RAD51 foci. Upon DNA damage, we observe an increase in IP6K1 activity, contingent on its phosphorylation by the protein kinases CK2 and CDK1. IP6K1 is recruited to sites of DNA damage, and interacts with RAD51, CDK1, and the C-terminal domain (CTD) of BRCA2. Disruption of binding between RAD51 and BRCA2-CTD is known to support the disassembly of RAD51 foci. We show that 5-InsP7 can pyrophosphorylate RAD51, and that the presence of 5-InsP7 diminishes RAD51 binding to BRCA2-CTD. Our findings provide a mechanism by which 5-InsP7 synthesized by IP6K1 facilitates the removal of RAD51 from sites of DNA repair. Summary statementInositol hexakisphosphate kinase 1, an enzyme that catalyses the synthesis of the inositol pyrophosphate 5-InsP7, localises to DNA double strand breaks, and engages in interactions with proteins involved in homologous recombination (HR)-mediated DNA repair. 5-InsP7 disrupts the interaction between RAD51 and the C-terminus of BRCA2, promoting dislodgement of RAD51 from DNA damage sites post-repair.

cell biology↗

bioRxiv2026

Gaussian Process Inference Reveals Non-separability of Positionand Velocity Tuning in Grid Cells

Grid cells in medial entorhinal cortex (MEC) support spatial navigation by responding to multiple variables, including position, speed, and head direction. While tuning curves for each of these variables have been examined individually at the level of single-cells, less is known about the conjunctive coding of grid cells for these properties. To investigate this, we analyzed neural recordings of freely foraging rats and constructed four-dimensional (4D) tuning curves across 2D position and 2D velocity. In order to combat the sparse sampling of such a large behavioral space, we applied Gaussian Process (GP) methods to estimate firing rates at un-sampled points. Comparing GP model-derived tuning curves to those predicted by a fully separable model revealed that some cells exhibited significant non-separability of position and velocity tuning, and suggested a data coverage threshold necessary to observe this non-separability. In summary, our use of GPs allowed us to distinguish interactions in position-velocity tuning across a 4D behavioral space that have not been apparent in 2D analyses.

neuroscience↗

bioRxiv2025

Large-scale cellular-resolution read/write of activity enables discovery of cell types defined by complex circuit properties

The complexity of the mammalian brains vast population of interconnected neurons poses a formidable challenge to elucidate its underlying mechanisms of coordination and computation. A key step forward will be technologies that can perform large-scale, cellular-resolution monitoring and interrogation of distributed brain circuit activity in behaving animals. Here, we present an all-optical strategy for precise optogenetic activity control of [~]103 neurons and simultaneous activity monitoring of [~]104 neurons within and across areas of mouse cortex--an order-of-magnitude leap beyond previous capabilities. Tracking population responses following delivery of precisely-defined widely-distributed activity patterns to the visual cortex of awake mice, we were surprised to identify neurons robustly responsive to stimulation of diverse ensembles, defying conventional like-to-like wiring rules. These cells were primarily deep L2/3 somatostatin-positive (SST) interneurons with functional properties distinct from other SST neurons, and appeared to play a role in brain dynamics that could only have been identified through broad cellular-resolution circuit interrogation. Our work reveals the value of measuring large-scale circuit-dynamical properties of functionally-resolved single cells, beyond genetic and anatomical classification, to define and explore the roles of cell types in brain function.

neuroscience↗

bioRxiv2025

Interpretable Machine Learning Identifies an Emergent Absence Seizure Mechanism

Absence seizures are widespread spike-and-wave oscillations disrupting consciousness. Several consciousness frameworks emphasize intercortical/thalamocortical feedback dynamics, but we lack explicit dynamical mechanisms for how seizures disrupt these circuits. Using interpretable machine learning, we derived dynamical equations directly from seizure electrocorticogram data, reproducing seconds-long multi-regional local field potentials with precision matching inter-mouse variability. The model contained a low-dimensional chaotic seizure attractor emerging from between-region synchronization at preferred phase-lags. Unit recordings revealed corresponding spiking synchrony at single-neuron resolution, linking somatosensory and motor cortex with posterior thalamic nucleus (PO). Model coupling terms predicted tonic and burst firing spatiotemporal organization across regions and guided multisite-optogenetic stimulations. These stimulations showed PO controls corticocortical connectivity gain and that motor/somatosensory corticocortical functional connectivity varies at predicted phase-lags to drive seizures. Our results define absence seizures as dynamics confined to a chaotic attractor within a circuit implicated in anesthetic unconsciousness, linking distributed network chaos to loss of consciousness.

neuroscience↗

bioRxiv2025

Small RNA-Mediated Metabolic Reprogramming Enables Ciprofloxacin Utilization in Klebsiella sp. SG01

Small regulatory RNAs (sRNAs) play a key role in the complex regulatory networks that bacteria use to adapt to antibiotic stress. This study clarifies how sRNAs help Klebsiella sp. SG01 metabolically adapts to ciprofloxacin (CIP). Nine potential sRNAs that target important metabolic and stress-response pathways were identified by transcriptomic profiling, including glmZ, sgrS, gcvB, and spot42, as well as an FMN riboswitch. TargetRNA3 and IntaRNA functional annotation predicted regulatory effects on TCA cycle flux, redox balance, and the transport of sugars and amino acids. Interestingly, repression of CRP and upregulation of spot42 imply that byproducts of CIP degradation resemble a glucose-rich state. This conjecture was supported by metabolomics, which verified the buildup of short-chain acids and purine intermediates. A change in regulation was also noted, with ProQ and CsrA levels rising in tandem with Hfqs downregulation. Our knowledge of microbial metabolic plasticity under xenobiotic pressure has been expanded by these findings, which collectively reveal a novel post-transcriptional mechanism that permits antibiotic assimilation and stress resilience in bacteria.

microbiology↗

bioRxiv2024

Consumption of Ciprofloxacin as the sole Carbon and energy source and Phenomenal Transformation to a Culturable nanometer-sized- bacterium demonstrated by a hospital-waste-water isolate Klebsiella&nbsp sp. SG01

Antimicrobial resistance is a global crisis. Biodegradation by bacteria is an effective strategy to remove the micropollutant from the environment. In this study, we demonstrate that a persistent fluoroquinolone, ciprofloxacin (CIP) can be degraded by a multidrug-resistant Klebsiella sp. SG01 and used as its only carbon source. The degradation was quantified using UV-vis spectroscopy and the degraded product was less toxic than the parent compound as tested against a susceptible Escherichia coli K12. SG01 changes into nano-sized cells as culturable nanobacterium, passes through a 0.22 m pore-size filter while growing on ciprofloxacin, and shows a shorter generation time than cells grown on glucose or rich medium. The basis for the changed growth phenotype of nano-SG01 cells and metabolic changes was partially established by the whole-genome transcriptome. ImportanceFluoroquinolones (FQs) constitute a class of persistent antimicrobials, having a high affinity for sludge, sediments, and soil with reported half-lives of 10.6 days in surface waters and up to 580 days in soil matrices. However, more than 50% consumption or degradation of CIP at higher concentration ([~]2g/L) within 48 hours is not yet reported. Also, the isolate transforms into a nano-form to consume the antibiotic and economizes its metabolism to degrade CIP. From the One Health Approach perspective, nanobacterial transformation is an alarming concern as such viable nanobacteria continue to proliferate and may trigger infection in host. The strategy should be to utilize this powerful strain for the biodegradation of CIP.

microbiology↗

bioRxiv2024

RNA binding protein Musashi1 interacts with the viral genomic RNA and restricts SARS-CoV-2 infection by repressing translation

Musashi RNA binding proteins are important post-transcriptional regulators of stem cell homeostasis and are known to be involved in viral infections. However, their role in SARS-CoV-2 infection remains largely unknown. Using computational studies, in vivo RNA immunoprecipitation and biochemical assays, here, we establish that Musashi1 (Msi1) interacts with viral genomic RNA through direct binding to the SARS-CoV-2 3UTR. Importantly, binding of Msi1 to the viral 3UTR results in translational repression mediated by inhibition of Poly (A) binding protein (PABP). Conversely, Msi1 knockout promotes robust viral replication and increased viral protein expression. Using 2D cell cultures, stem cells and 3D organoids, we show that depletion of Msi1 in intestinal cells augments infection. This finding explains why the human intestine serves as a reservoir for the SARS-CoV-2 virus, wherein differentiated enterocytes, which have negligible levels of Msi1, are highly affected. Contrarily, stem cells which are enriched for Msi1 expression, are known to be less permissive to SARS-CoV-2 infection despite expressing the entry receptors. Our findings show how translation repression of SARS-CoV-2 by stem cell RNA binding proteins such as Msi1 could help evasion of infection.

cell biology↗

bioRxiv2024

Adaptation of retinal discriminability to natural scenes

Sensory systems discriminate between stimuli to direct behavioral choices, a process governed by two distinct properties - neural sensitivity to specific stimuli, and neural variability that importantly includes correlations between neurons. Two questions that have received extensive investigation and debate are whether visual systems are optimized for natural scenes, and whether correlated neural variability contributes to this optimization. However, the lack of sufficient computational models has made these questions inaccessible in the context of the normal function of the visual system, which is to discriminate between natural stimuli. Here we take a direct approach to analyze discriminability under natural scenes for a population of salamander retinal ganglion cells using a model of the retinal neural code that captures both sensitivity and variability. Using methods of information geometry and generative machine learning, we analyzed the manifolds of natural stimuli and neural responses, finding that discriminability in the ganglion cell population adapts to enhance information transmission about natural scenes, in particular about localized motion. Contrary to previous proposals, correlated noise reduces information transmission and arises simply as a natural consequence of the shared circuitry that generates changing spatiotemporal visual sensitivity. These results address a long-standing debate as to the role of retinal correlations in the encoding of natural stimuli and reveal how the highly nonlinear receptive fields of the retina adapt dynamically to increase information transmission under natural scenes by performing the important ethological function of local motion discrimination.

neuroscience↗

bioRxiv2023

Interaction with IP6K1 supports pyrophosphorylation of substrate proteins by the inositol pyrophosphate 5-IP7

Inositol pyrophosphates (PP-IPs) are a sub-family of water soluble inositol phosphates that possess one or more diphosphate groups. PP-IPs can transfer their {beta}-phosphate group to a phosphorylated Ser residue to generate pyrophosphorylated Ser. This unique post-translational modification occurs on Ser residues that lie in acidic stretches within an intrinsically disordered protein sequence. Serine pyrophosphorylation is dependent on the presence of Mg2+ ions, but does not require an enzyme for catalysis. The mechanisms by which cells can regulate this enzyme-independent modification are still unknown. Here, we show that IP6K1, an enzyme responsible for the synthesis of the PP-IP 5-IP7, interacts with several proteins that undergo 5-IP7 mediated pyrophosphorylation, and with CK2, a protein kinase that phosphorylates Ser residues prior to pyrophosphorylation. We characterized the interaction of IP6K1 with AP3B1, the {beta} subunit of the AP3 adaptor protein complex, which is a known pyrophosphorylation substrate. We observe the formation of a protein complex between IP6K1, AP3B1, and the catalytic -subunit of CK2, and show that disrupting IP6K1 binding to AP3B1 lowers its in vivo pyrophosphorylation. We propose that assembly of a substrate-CK2-IP6K complex would allow for coordinated pre-phosphorylation and pyrophosphorylation of the target serine residue, and provide a mechanism to regulate this enzyme-independent modification.

cell biology↗

bioRxiv2023

On prefrontal working memory and hippocampal episodic memory: Unifying memories stored in weights and activation slots

Remembering events in the past is crucial to intelligent behaviour. Flexible memory retrieval, beyond simple recall, requires a cognitive map, or model of how sensations, actions, and latent environmental or task states are all related to one another. Two key brain systems are implicated in this process: the hippocampal episodic memory (EM) system and the prefrontal working memory (WM) system. While an understanding of the hippocampal system, from computation to algorithm and representation, is emerging, less is understood about how the prefrontal WM system can give rise to flexible computations beyond simple memory retrieval, and even less is understood about how the two systems relate to each other. Here we develop a mathematical theory relating the algorithms and representations of EM and WM by unveiling a duality between storing memories in synapses versus neural activity. In doing so, we develop a formal theory of the algorithms and representations of prefrontal WM in terms of structured, and controllable, neural subspaces (termed activity slots) that together can represent a dynamic cognitive map without any need for synaptic plasticity. By building models using this formalism, we elucidate the differences, similarities, and trade-offs between the hippocampal and prefrontal algorithms. Lastly, we show that several prefrontal representations in tasks ranging from list learning to cue dependent recall are unified as controllable activity slots. Our results unify frontal and temporal representations of memory, and offer a new basis for understanding dynamic prefrontal representations of WM.

neuroscience↗

bioRxiv2023

One-shot entorhinal maps enable flexible navigation in novel environments

Animals face the substantial challenge of navigating novel environments to find food, shelter, or mates. In mammals, hexagonal grid cells in the medial entorhinal cortex create a map-like population representation of the external environment 1-7. However, it remains unclear how the grid map can adapt to novel environmental features on a rapid, behaviorally relevant time scale. By recording over fifteen thousand grid cells in mice navigating virtual environments, we found grid cell activity was weakly anchored to landmark inputs through a fixed circuit relationship. A computational model based on this fixed circuit assumption accurately predicted grid spatial patterns in environments with novel landmark rearrangements. Finally, a medial entorhinal cortex-dependent task revealed that while grid cell firing patterns remain anchored to landmarks, behavior can adapt to changes in landmark location via a downstream region implementing behavioral time scale synaptic plasticity 8. This fixed but weak anchoring of grid cells to landmarks endows the grid map with powerful computational properties. The fixed nature allows the generation of rapid stable maps for novel environments after a single exposure. The weak nature allows these rapidly formed maps to incur only small distortions between distances traveled in real versus neural space. Overall, such rapid low distortion mapping can then mediate accurate navigational behavior in rapidly changing environments through downstream plasticity.

neuroscience↗

bioRxiv2023

Information Geometry of the Retinal Representation Manifold

The ability for the brain to discriminate among visual stimuli is constrained by their retinal representations. Previous studies of visual discriminability have been limited to either low-dimensional artificial stimuli or pure theoretical considerations without a realistic encoding model. Here we propose a novel framework for understanding stimulus discriminability achieved by retinal representations of naturalistic stimuli with the method of information geometry. To model the joint probability distribution of neural responses conditioned on the stimulus, we created a stochastic encoding model of a population of salamander retinal ganglion cells based on a three-layer convolutional neural network model. This model not only accurately captured the mean response to natural scenes but also a variety of second-order statistics. With the model and the proposed theory, we computed the Fisher information metric over stimuli to study the most discriminable stimulus directions. We found that the most discriminable stimulus varied substantially across stimuli, allowing an examination of the relationship between the most discriminable stimulus and the current stimulus. By examining responses generated by the most discriminable stimuli we further found that the most discriminative response mode is often aligned with the most stochastic mode. This finding carries the important implication that under natural scenes, retinal noise correlations are information-limiting rather than increasing information transmission as has been previously speculated. We additionally observed that sensitivity saturates less in the population than for single cells and that as a function of firing rate, Fisher information varies less than sensitivity. We conclude that under natural scenes, population coding benefits from complementary coding and helps to equalize the information carried by different firing rates, which may facilitate decoding of the stimulus under principles of information maximization.

neuroscience↗

bioRxiv2023

Oncogenic Ras deregulates cell-substrate interactions during mitotic rounding and respreading to alter cell division orientation

Oncogenic Ras has been shown to change the way cancer cells divide by increasing the forces generated during mitotic rounding. In this way, RasV12 enables cancer cells to divide across a wider range of mechanical environments than normal cells. Here, we identify a further role for oncogenic Ras-ERK signalling in division by showing that RasV12 expression alters the shape, division orientation and respreading dynamics of cells as they exit mitosis, in a manner that depends on MEK and ERK. Many of these effects appear to result from the impact of RasV12 signalling on actomyosin contractility, since RasV12 induces the severing of retraction fibres that normally guide spindle positioning and provide a memory of the interphase cell shape. In support of this idea, the RasV12 phenotype is reversed by inhibition of actomyosin contractility, and can be mimicked by the loss of cell-substrate adhesion during mitosis. Thus, the induction of oncogenic Ras-ERK signalling leads to rapid changes in division orientation that, along with the effects of RasV12 on cell growth and cell cycle progression, are likely to disrupt epithelial tissue organisation and contribute to cancer dissemination.

cell biology↗

bioRxiv2022

When and why grid cells appear or not in trained path integrators

Recent work has claimed that the emergence of grid cells from trained path-integrator circuits is a more fragile phenomenon than previously reported. In this note we critically assess the main analysis and simulation results underlying this claim, within the proper context of previously published theoretical work. Our assessment reveals that the emergence of grid cells is entirely consistent with this prior theory: hexagonal grid cells robustly emerge precisely when prior theory predicts they should, and dont when prior theory predicts they should not.

neuroscience↗