Biology subjects

Mishra, J.

Publications and source records attributed to Mishra, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Medulloblastoma Forms Symbiotic Metabolic Partnerships with Macrophages to Establish Leptomeningeal Metastases

Leptomeningeal metastases are the primary source of morbidity and mortality for pediatric medulloblastoma patients. Due to limited surgical sampling of metastases in patients, little is understood of the mechanisms of metastasis. Here, we identify biologically distinct quiescent small metastases (designated as micrometastases) and mitotically active larger metastases (macrometastases). Macrometastases are more metabolically active than micrometastases and contain higher levels of lipids, particularly cholesterol. Macrometastases secrete CXCL12, which attracts lipid-laden macrophages into the tumor. Lipid-laden macrophages upregulate the cholesterol transporter ABCG1, promoting the efflux of free cholesterol, which is then taken up by tumor cells via the HDL receptor SCARB1. CXCL12-driven macrophage recruitment and exogenous cholesterol are sufficient and necessary to drive progression of medulloblastoma leptomeningeal metastases in vivo. High fat diets drive metastatic progression in vivo. Dietary or pharmacological interventions targeting the CXCL12-SCARB1-cholesterol axis represent therapeutic strategies to either prevent or treat medulloblastoma leptomeningeal metastases.

cancer biology↗

bioRxiv2026

SARS-CoV-2 nucleocapsid protein engages with viral RNA and ERGIC lipids to drive viral core assembly

Severe acute respiratory syndrome coronavirus 2 assembles at the ER-Golgi intermediate compartment (ERGIC), yet the molecular basis of nucleocapsid (N) protein interactions with host membranes remains unclear. Using in vitro reconstituted lipid membranes and viral RNA- N complexes, we show that full-length N binds phosphatidylinositol (PI)- and phosphatidylserine (PS)-containing membranes and induces lipid clustering, an effect amplified by viral RNA and ERGIC-like membrane lipid composition. The isolated N-terminal domain lacks this activity, whereas the C-terminal domain retains membrane-associated multimerization. Although, lipid bilayers promote co-clustering of N and PI lipids, facilitating ribonucleoprotein (RNP) assembly, even on simple membranes. Importantly, ERGIC- mimicking membranes enhances this co-clustering further stabilizing RNPs of dimensions matching the viral core. In cells, viral RNA enhances N clustering without altering particle production. These findings reveal cooperative interactions between N, viral RNA, and ERGIC lipids as key drivers of lipid-dependent viral core formation, providing a mechanistic framework for the early steps of viral assembly.

biophysics↗

bioRxiv2026

Curved microtubule regions mark sites of lattice compaction in cells and neurons

Angstrom-scale changes in microtubule (MT) lattice spacing regulate the selective recruitment of MT-associated proteins, yet how these structural states operate in cells remains poorly understood. Here, we show that MT lattice expansion, induced by protein-based expanders or microtubule-stabilizing agents such as Taxol and epothilone D, drives the relocalization of compact lattice-binding proteins, including tau, doublecortin (DCX), and the C1 domain-containing signaling protein GEF-H1, into highly curved MT-associated domains, whereas the compaction-inducing agent laulimalide suppresses this response. In contrast, the tumor suppressor RASSF1A preferentially associates with expanded lattice states, revealing differential lattice sensitivity among closely related C1 domain-containing proteins. These short, curved assemblies are enriched at MT intersections and discrete MT segments, revealing spatially heterogeneous lattice states within individual microtubules. At substoichiometric levels, compact lattice-binding proteins behave as both MT compactors and curvature sensors. Changes in osmotic pressure selectively promote dissociation of compact lattice-binding proteins, whereas expanded lattice-binding proteins remain largely unaffected. Using curved filament formation as an in-cellulo readout of compact lattice regions, we identify widespread lattice-state sensitivity across diverse MT-associated and signaling proteins. Finally, we show that these principles extend to neurons, where somatic, but not axonal, tau exhibits sensitivity to lattice expansion despite the expanded lattice architecture of distal axonal microtubules, suggesting additional neuron-specific regulation of lattice accessibility. Together, our findings identify the MT lattice as a dynamic mechanochemical platform whose nanoscale structural states spatially organize protein recruitment and signaling in cells and neurons.

cell biology↗

bioRxiv2026

Mechanical tension expands the microtubule lattice stepwise and modulates kinesin-1 binding in an isoform-dependent manner

Recent work has shown that the microtubule lattice possesses remarkable structural plasticity, with its conformation modulated by microtubule-associated proteins and motor proteins. However, how this plasticity responds to mechanical forces remains poorly understood. Here, we developed optical tweezers and fluorescence microscopy assays to measure the effect of tensile forces on single microtubules. Quantum dot decoration enabled nanometre-precision measurement of lattice distortions of [~]0.33% under a change of mean tensile force of [<]{Delta}F[>] = 10.6 pN, within the range Fmin = 1.29 pN to Fmax = 22.3 pN -- comparable to forces from one to three kinesin-1 motors. Within this force range, the binding rate of kinesin-1 isoform KIF5B decreased reversibly within seconds by [~]20% and the dissociation rate increased by [~]10%, reducing mean run length, that in extreme cases decreased by up to 46%. Substantial heterogeneity was also observed along individual microtubules, where distinct lattice regions responded differently to applied force, implying that lattice expansion is not always uniform. Consistent heterogeneity was observed in cells, where MAPs with competing conformational preferences assembled in non-overlapping patches along the same microtubule. A cooperatively-switching lattice Ising model based on tubulin conformational bistability, supported by dynamics simulations, quantitatively reproduces these observations with a critical switching force Fc = 8.5 pN, similar to established mechanosensory proteins such as talin and E-catenin. Strikingly, no significant effects were observed for KIF5C, revealing a kinesin isoform-dependent mechanoresponse. Together, these findings establish microtubules as mechanochemical signal transducers, converting mechanical forces into biochemical signals with the speed, spatial precision and sensitivity required for rapid cellular responses. Significance StatementMicrotubules have been implicated as mechanotransducers in both mammalian and plant cells, yet a physical characterization of how mechanical forces are sensed and transduced into biochemical signals has been lacking. The present study demonstrates that modest tensile forces of less than 20 pN are sufficient to expand cooperatively the microtubule lattice by [~]0.3%, which in turn modulates its biochemical interactions with kinesin-1 in an isoform-dependent manner, selectively affecting KIF5B motor activity but not KIF5C. Strikingly, this mechanotransduction occurs on a timescale of seconds, implying that microtubules are highly efficient conduits for propagating mechanical information across the cell body. These findings establish microtubules as bona fide mechanochemical signal transducers with the speed and sensitivity required for rapid cellular responses.

biophysics↗

bioRxiv2026

Therapy-associated mutagenesis at CTCF binding sites is shaped by chromatin context and DNA repair capacity

Genotoxic cancer therapies introduce DNA damage that can be fixed as somatic mutations in surviving tumor cells. However, the impact of therapy-associated mutagenesis on regulatory elements remains unclear. CTCF binding sites (CBS) are chromatin architectural elements that exhibit recurrent localized mutation enrichment in cancer genomes. We asked whether treatment exposure is associated with increased mutagenesis at CBS in 4,870 whole-genome sequences from metastatic tumors across 17 cancer types and 45 therapies. Radiotherapy and trifluridine exposure in metastatic colorectal cancer were associated with increased mutation enrichment at CBS. This enrichment was pronounced at motif-containing sites and in low-expression or late-replicating genomic contexts. Alterations in DNA damage response genes, including BRCA2, were associated with increased CBS mutation enrichment following radiotherapy. Together, these findings indicate that therapy-associated mutagenesis at CTCF binding sites is shaped by chromatin context and DNA repair capacity, extending the mutational consequences of cancer treatment to regulatory genome architecture.

cancer biology↗

bioRxiv2026

Pairwise genomic alterations identify prognostic tumor states in multiple cancer types

Genomic models of cancer prognosis usually rely on individual genomic alterations, potentially overlooking clinically meaningful combinations of events. We analyzed genomic and clinical data from nearly 10,000 primary tumors across major cancer types to identify prognostic genomic interactions (PGIs), defined as pairs of genomic alterations whose joint status was associated with patient outcome beyond either alteration alone. By systematically integrating survival associations with pairwise combinations of recurrent copy-number alterations and frequently mutated driver genes, we identified 57 PGIs. These PGIs refined prognostic stratification and were linked to distinct transcriptomic programs representing immune-response, epithelial-mesenchymal transition, and proliferation-related themes. Gene-level mapping highlighted dosage-sensitive candidate genes within recurrent copy-number regions, and gene essentiality profiles supported subsets of PGI-derived gene pairs. Two PGIs were validated in independent datasets. Together, these results establish a framework for identifying prognostic combinations of genomic alterations and connecting them to pathway programs, candidate genes, and functional dependencies in human tumors.

cancer biology↗

bioRxiv2026

Dopamine vesicles are specified by mechanisms overriding canonical synaptic vesicle size constraints

Dopaminergic neurons contain distinct synaptic vesicle (SV) populations that segregate dopamine from glutamate, but the molecular basis of this segregation remains unclear. Using an established in vitro SV reconstitution system in fibroblasts, we show that synaptogyrin family proteins--synaptogyrin 1, synaptogyrin 2 and synaptogyrin 3--but not synaptophysin, selectively associate with VMAT2-positive dopamine vesicles in the presence of synapsin. Despite the known role of synaptophysin and synaptogyrin family proteins in generating small SVs (40-50 nm), VMAT2 vesicles retain a larger size (50-80 nm) when co-expressed with synaptogyrins, while remaining segregated from synaptophysin-containing vesicles. SV2 family proteins (SV2A, SV2B, and SV2C) localize to both VMAT2- and synaptophysin-positive vesicle populations, with SV2C preferentially enriched on VMAT2-positive dopamine vesicles. Consistent with the selective dystrophy of SV2C/VMAT2/DAT-positive dopaminergic terminals in parkinsonism-associated SJ1RQKI mice, iPSC-derived dopaminergic neurons carrying the same mutation accumulate small and enlarged SV-like organelles within autophagosomes, indicating defective SV clearance. Together, our findings suggest that dopamine vesicles are regulated by distinct trafficking mechanisms that override canonical SV size control, providing insight into the selective vulnerability of dopaminergic terminals in Parkinsons disease.

neuroscience↗

bioRxiv2026

Cortical oscillations reflect opponent ensemble dynamics through coordinated multifrequency activity

Neural oscillations are widely used as proxies for neuronal activity, where power in individual frequency bands is commonly interpreted as functionally indexing neural circuit engagement. However, power in individual frequency bands shows heterogeneous and sometimes opposing relationships with neuronal activity across regions and behavioral contexts, challenging the assumption of a stable frequency-to-circuit mapping. Here we show that glutamatergic population activity in rat medial prefrontal cortex is not stably linked with power in isolated frequency bands, but rather with dynamically recurring multi-frequency amplitude co-fluctuations. These multi-frequency patterns, termed spectral motifs, occurred in opponent pairs with nearly identical frequency composition but inverted relationships to population calcium activity. This opponent motif structure, observed across cortical regions and species, provides a key component for understanding how oscillations are linked to neuronal activity. We found that shifts in motif opponency balance explained changes in glutamatergic activity that occur during brain-computer interface learning better than models based on frequency band power alone. Furthermore, opponent motifs map selectively onto opponent cell ensembles and enable bidirectional mapping between local field potentials and ensemble activity. These findings identify multi-frequency opponent motifs as a conserved organizational principle linking oscillatory dynamics to population-level circuit states and challenge the notion that individual frequency bands can serve as interpretable functional units mapping onto neural circuit activity.

neuroscience↗

bioRxiv2026

Mutational signatures in cancer genomes alter protein sequence motifs in cellular signaling networks

Somatic mutations in cancer genomes arise from distinct, context-specific mutational processes, yet their functional consequences at the protein and network level remain incompletely understood. Here, we show that mutational processes of single-nucleotide variants (SNVs) can systematically rewire signaling networks by inducing amino acid substitutions in short linear motifs (SLiMs) that mediate interactions with kinases and other signaling proteins. By analysing 11,000 cancer genomes and 144 classes of SLiMs, we identify motif-rewiring SNVs (rwSNVs) that create or disrupt SLiMs or remove phosphorylated residues. Mutational processes of methylcytosine deamination, APOBEC activity, and ultraviolet light exposure emerge as major contributors to motif rewiring. rwSNVs are enriched in cancer driver genes and pathways, linking mutation etiology to functional consequences. rwSNVs at the BRAF V600E hotspot associated with UV-related mutagenesis are predicted to generate a phosphorylation motif recognized by PLK1 kinase. Together, these findings reveal how mutational processes shape oncogenic signaling and tumor heterogeneity.

cancer biology↗

bioRxiv2025

AKNA drives neural stem cell fate transition through differential localization and coordinating the modulation of chromatin from H3K27me3 to H3K27ac

Neuronal stem cells (NSCs) play pivotal role in adult neurogenesis, however, detail mechanisms of obtaining pluripotency or undergoing differentiation remain unknown. Herein, how AT-hook protein AKNA regulates pluripotency and stemness in neuroblastoma cells is demonstrated by gene knockdown, immunofluorescence, chromatin immunoprecipitation (ChIP), localization of AKNA, signaling interactions and transcriptional activity. AKNA was abundant and mostly nuclear during induction of pluripotency and its knockdown reduced stemness, even in presence of other pluripotency factors, including OCT4 and SOX2. During the course of induction of differentiation, AKNA remain localized in the cytosol, essential for regulated differentiation. Cytosolic retention of AKNA is possibly driven by FAK signaling. In the nucleus, AKNA promotes KDM6B demethylase for H3K27me3 demethylation to H3K27, and subsequently promotes CBP/p300 to acetylate H3K27 to H3K27ac deposition on promoter region of respective genes to trigger their transcription. Data obtained from knockdown and overexpression of AKNA and KDM6B further reinforce its importance that, they physically interact to drive pluripotency and stemness. These findings establish AKNA as a critical regulator for NSCs fate determination in association with epigenetic modifiers and signaling pathway, offering potential targets for neuroblastoma therapies and regenerative medicines for neurodegenerative diseases.

molecular biology↗

bioRxiv2024

Combinations of genomic alterations and immune microenvironmental features associate with patient survival in multiple cancer types

Oncogenesis and tumor progression are shaped by somatic alterations in the cancer genome and features of the tumor immune microenvironment (TME). How interactions of these two systems influence tumor development and clinical outcomes remains incompletely understood. To address this challenge, we developed the multi-omics analysis framework PACIFIC to systematically integrate genetic cancer drivers and infiltration profiles of immune cells with clinical information. In an analysis of 8500 cancer samples, we report 34 immunogenomic interactions (IGXs) in 13 cancer types in which context-specific combinations of genomic alterations and immune cell activities associate with disease outcomes. Risk associations of IGXs are potentially explained by tumor-intrinsic and microenvironmental metrics of immunogenicity and differential expression of therapeutic targets. In luminal-A breast cancer, MEN1 deletion combined with reduced neutrophils is associated with poor prognosis and deregulation of immune signalling pathways. These findings help elucidate how cancer drivers interact with TME to contribute to tumorigenesis.

cancer biology↗

bioRxiv2024

Intermittent Theta Burst Stimulation Drives Bi-Directional Changes in Excitability in Prefrontal Cortex

Intermittent Theta Burst Stimulation (iTBS) is a patterned stimulation protocol FDA-cleared to treat depression, yet its outcomes are variable and mechanistically unclear. Here, using a combination of calcium imaging, histology, optogenetics and behavior, we show that one parameter of iTBS, the inter-train interval (ITI) between stimulation trains, plays a critical role in modulating GABAergic (and especially parvalbumin) neuronal activity, modulating subsequent neuronal plasticity and antidepressant effects. Shorter ITI stimulation protocols (4-10Ssinter-train intervals) activate GABA neurons, limiting resulting changes in cortical excitability and plasticity compared to extended interval TBS protocols (eTBS, with a 20s ITI). eTBS also drives the largest changes in synaptic / spine plasticity and leads to rapid and durable antidepressant-like effects after only a single stimulation session. Optogenetic activation of GABAergic neurons during eTBS blocks synaptic plasticity and rapid antidepressant effects. Together, these findings reveal a temporal control principle for TBS-induced cortical plasticity and provides a physiology-based strategy to improve TBS efficacy. HighlightsO_LIInter-train interval (ITI) controls excitatory-inhibitory balance during theta burst stimulation C_LIO_LIShort ITIs strongly activate PV interneurons limiting longer-term changes in glutamatergic excitatory plasticity C_LIO_LIExtended ITI (20s in particular) reduces inhibitory activity while maintaining sufficient activation of glutamatergic neurons to promote post-stimulation plasticity C_LIO_LIeTBS produces rapid and durable antidepressant-like effects that are blocked by GABAergic co-activation C_LI Graphical AbstractInter-train interval (ITI) determines the balance between excitation and inhibition during theta burst stimulation (TBS), an FDA-cleared treatment for depression. (A) Short ITIs (4s) drive concurrent glutamatergic and GABAergic activation, with inhibitory dominance during stimulation and suppressed long-term modulation of excitability. Extending the ITI to 20s (eTBS) reduces GABAergic recruitment during stimulation, promoting sustained long-term glutamatergic modulation resulting cortical disinhibition, leading to rapid and durable antidepressant-like effects (B). Optogenetic activation of GABAergic interneurons during eTBS abolishes synaptic and antidepressant effects, demonstrating that reduced inhibitory recruitment during eTBS is required for the rapid and durable behavioral effects observed with that protocol. O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/608693v3_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@15a7decorg.highwire.dtl.DTLVardef@1220forg.highwire.dtl.DTLVardef@63258forg.highwire.dtl.DTLVardef@13707e7_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

An Endogenous Aryl Hydrocarbon Receptor Ligand Induces Preeclampsia-like Phenotypes: Transcriptome, Phosphoproteome, and Cell Functions

BackgroundPreeclampsia (PE) is one hypertensive disorder and a leading cause of maternal and fetal mortality and morbidity during human pregnancy. Aryl hydrocarbon receptor (AhR) is a transcription factor, which regulates vascular functions. Exogenous and endogenous AhR ligands can induce hypertension in animals. However, if dysregulation of endogenous AhR ligands contributes to the pathophysiology of PE remains elusive. MethodsWe measured AhR activities in human maternal and umbilical vein sera. We also applied physiological, cellular, and molecular approaches to dissect the role of endogenous AhR ligands in vascular functions during pregnancy using pregnant rats and primary human umbilical vein endothelial cells (HUVECs) as models. ResultsPE elevated AhR activities in human umbilical vein sera. Exposure of pregnant rats to an endogenous AhR ligand, 2-(1H-indole-3-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) increased blood pressure and proteinuria, while decreased uteroplacental blood flow and reduced fetal and placental weights, all of which are hallmarks of PE. ITE dampened vascular growth and fetal sex-specifically altered immune cell infiltration in rat placentas. ITE also decreased cell proliferation and cell monolayer integrity in HUVECs in vitro. RNA sequencing analysis revealed that ITE dysregulated transcriptome in rat placentas and HUVECs in a fetal sex-specific manner. Bottom-up phosphoproteomics showed that ITE disrupted phosphoproteome in HUVECs. These ITE-dysregulated genes and phosphoproteins were enriched in biological functions and pathways which are highly relevant to diseases of heart, liver, and kidney, vascular functions, inflammation responses, cell death, and kinase inhibition. ConclusionsDysregulation of endogenous AhR ligands during pregnancy may lead to the development of PE with underlying impaired vascular functions, fetal sex-specific immune cell infiltration and transcriptome, and phosphoproteome. Thus, this study has provided a novel mechanism for the development of PE and potentially other forms of hypertensive pregnancies. These AhR ligand-activated genes and phosphoproteins might represent promising therapeutic and fetal sex-specific targets for PE-impaired vascular functions.

pathology↗

bioRxiv2023

Mitochondrial Ca2+ uniporter (MCU) variants form plasma-membrane channels

MCU is widely recognized as a responsible gene for encoding a pore-forming subunit of highly mitochondrial-specific and Ca2+-selective channel, mitochondrial Ca2+ uniporter complex (mtCUC). Here, we report a novel short variant derived from the MCU gene (termed MCU-S) which lacks mitochondria-targeted sequence and forms a Ca2+- permeable channel outside of mitochondria. MCU-S was ubiquitously expressed in all cell-types/tissues, with particularly high expression in human platelets. MCU-S formed Ca2+ channels at the plasma membrane, which exhibited similar channel properties to those observed in mtCUC. MCU-S channels at the plasma membrane served as an additional Ca2+ influx pathway for platelet activation. Our finding is completely distinct from the originally reported MCU gene function and provides novel insights into the molecular basis of MCU variant-dependent cellular Ca2+ handling.

cell biology↗

bioRxiv2023

Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer

Cancer cells experiencing hypoxic stress employ Epithelial-Mesenchymal Transition (EMT) to undergo metastasis through rewiring chromatin landscape, epigenetics, and importantly alternative splicing. Here, we investigated the role of CTCF, chromatin, epigenetic and alternative splicing modulator under hypoxia to promote EMT. Our result shows that hypoxia-induced epigenetic changes upregulate CTCF expression in breast cancer. We delineate that CTCF is a direct target of HIF1 and the hypoxia-induced HIF1-CTCF axis functionally contributes to promoting EMT in breast cancer cells. Finally, our work uncovers COL5A1, an EMT gene, as a direct target of CTCF. We demonstrated that hypoxia-mediated CTCF enrichment on COL5A1 promoter regulates expression as well as alternative splicing events to promote EMT. Here, we put forward an intricate mechanism of alternative splicing where CTCF-mediated promoter-exon upstream looping regulates DNA de-methylation and CTCF-mediated RNA Pol II pausing at COL5A1 exon 64A. Our global analysis of CTCF-ChIP-seq data reveals that the hypoxia-induced differential CTCF occupancy possibly regulates gene expression and alternative splicing events of many genes that are enriched in the EMT pathway, cancer cell motility and invasion, angiogenesis, and stemness under hypoxia, similarly to the proposed model. Finally, we employed the epigenetic modulator dCas9-DNMT3A system to specifically disrupt HIF1 or CTCF binding under hypoxia and hence the HIF1-CTCF-COL5A1exon64A axis that alleviates the EMT potential of breast cancer cells that may represent a novel therapeutic target in breast cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/539689v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@e15c15org.highwire.dtl.DTLVardef@1649a71org.highwire.dtl.DTLVardef@1d77481org.highwire.dtl.DTLVardef@21f148_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

molecular biology↗

bioRxiv2022

PKM2-mediated epigenetic reprogramming regulates hypoxic expression of PFKFB3 to promote breast cancer progression

The hypoxic milieu is a critical modulator of aerobic glycolysis, yet the regulatory mechanisms existing between the key glycolytic enzymes in hypoxic cancer cells are largely unexplored. In particular, M2 isoform of pyruvate kinase (PKM2) - the ratelimiting enzyme of glycolysis, is well-known to confer adaptive advantages under hypoxia. Herein, we report a non-canonical role of PKM2 in functioning as a co-activator of HIF-1 to govern the transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Nuclear PKM2 enhances HIF-1 and p300 occupancy at PFKFB3 hypoxia responsive elements (HREs) resulting in its upregulation. Consequently, absence of nuclear PKM2 fails to recruit HIF-1 which activates an opportunistic occupancy of HIF-2 at PFKFB3 HREs. Enhanced binding of HDAC3 also occurs in the absence of PKM2 which prevents HIF-2 from efficiently inducing PFKFB3 to hamper proliferation of hypoxic breast cancer cells. In addition, clinical relevance of the study has been investigated by demonstrating that Shikonin blocks nuclear translocation of PKM2 to suppress PFKFB3 expression. Furthermore, MCF7 cells-derived xenograft tumors in mice exhibited substantial tumor growth inhibition when treated with shikonin, highlighting the vitality of targeting PKM2. Taken in concert, this work provides novel insights into contributions of PKM2 in modulating hypoxic transcriptome and a previously unreported molecular axis exhibited by the hypoxic breast cancer cells for ensuring the maintenance of PFKFB3 expression essential for achieving high glycolytic flux. Statement of significanceNuclear PKM2 orchestrates the binding of histone modifiers to epigenetically alter PFKFB3 promoter and affects the binding of HIF-2. Notably, targeting this axis attenuates proliferation of hypoxic breast cancer cells.

cancer biology↗

bioRxiv2022

Cortico-Striatal Beta-Oscillations as a Marker of Learned Reward Value

Single neuron correlates of reward value have been observed in brain regions along the cortico-striatal pathway including ventral striatum, orbital, and medial prefrontal cortex. Brain imaging studies in humans further validate these findings and suggest that value is represented in a network of brain regions opposed to a particular area. Neural activity oscillates at periodic frequencies to coordinate long-range communication in widespread, dynamic networks. To explore how oscillatory dynamics across brain regions may represent reward value, we measured local field potentials of male Long-Evans rats during three distinct behavioral tasks, each probing a different aspect of reward processing. Our goal was to use a data-driven approach to identify a common electrophysiology property associated with reward value. We found that reward-locked oscillations at beta frequencies, in both single units and local field potentials, were markers of positive reward valence. More importantly, Reward-locked beta-oscillations scaled with expected reward value on specific trial types and in a behaviorally relevant way across tasks. Oscillatory signatures of reward processing were observed throughout the cortico-striatal network including electrodes placed in orbitofrontal cortex, anterior insula, medial prefrontal cortex, ventral striatum, and amygdala. These data suggests that beta-oscillations reflect learned reward value in a distributed network, and this may serve as a stable and robust bio-marker for future studies.

animal behavior and cognition↗

bioRxiv2022

A Generalized Reinforcement Learning-Based Deep Neural Network (GRL-DNN) Agent Model for Diverse Cognitive Constructs

Human cognition is characterized by a wide range of capabilities including goal-oriented selective attention, distractor suppression, decision making, response inhibition, and working memory. Much research has focused on studying these individual components of cognition in isolation, whereas in several translational applications for cognitive impairment, multiple cognitive functions are altered in a given individual. Hence it is important to study multiple cognitive abilities in the same subject or, in computational terms, model them using a single model. To this end, we propose a unified, reinforcement learning-based agent model comprising of systems for representation, memory, value computation and exploration. We successfully modelled the aforementioned cognitive tasks and show how individual performance can be mapped to model meta-parameters. This model has the potential to serve as a proxy for cognitively impaired conditions, and can be used as a clinical testbench on which therapeutic interventions can be simulated first before delivering to human subjects.

neuroscience↗