Biology subjects

Mahadevan, A.

Publications and source records attributed to Mahadevan, A..

12 recordsLinked to original sources

bioRxiv2026

Plasma Extracellular Vesicle Lipidomics Reveals an SMPD1-Driven Sphingomyelin Salvage Pathway Collapse in Parkinson's Disease

While lysosomal lipid dysregulation is implicated in Parkinsons disease (PD), identifying the precise enzymatic drivers remains limited by the lack of subcellularly resolved metabolic mapping. Leveraging endosome-origin plasma extracellular vesicle (PsEV) lipidomics, we identified a profound bidirectional disruption of the ceramide-sphingomyelin (SM) axis in PD, driven by asymmetric upregulation of sphingomyelin phosphodiesterase 1 (SMPD1) and sphingomyelin synthase 1 (SGMS1). BODIPY-C5 SM tracking revealed that SMPD1 perturbation severely impairs lysosomal SM turnover. Crucially, this SMPD1-driven hydrolysis forces a salvage pathway collapse, bottlenecked by SPHK1/SGPL1 downregulation, which precipitates oxidative membrane damage and PINK1/Parkin-dependent mitophagy failure. We robustly validated this multi-pathway dysfunction across orthogonal in vitro, in vivo mouse, and postmortem human brain models. Furthermore, SMPD1/SGMS1 expression distinctly stratifies clinical phenotypes, marking the aggressive Postural Instability/Gait Difficulty (PIGD) subtype. Our findings establish SMPD1-mediated lysosomal impairment and ceramide-SM imbalance as a core biochemical axis in PD pathophysiology.

neuroscience↗

bioRxiv2026

High-Frequency Spatial Feature Fusion with 3D CNN for Early Stage Schizophrenia Classification

Early detection of schizophrenia (SZ) remains challenging due to the subtlety of early-stage brain alterations and reliance on subjective clinical assessment. We propose a frequency-aware 3D convolutional neural network (CNN) pipeline that integrates NeuroMark-HiFi high-pass spatial filtering with a modified VGGNet3D architecture featuring 3D Laplacian kernel initialization and dilated convolutions. Using the FBIRN dataset (N=311; 150 healthy controls, 161 SZ) with all 53 intrinsic connectivity networks (ICNs) per subject, we evaluate four experimental conditions across two hyperparameter configurations to isolate the contributions of enhanced input representations and frequency-aware model design. Under the optimized configuration, Condition 3 (HiFi + Laplacian initialization) achieved the best mean test accuracy of 75.54% with a peak single-fold accuracy of 87.10%, representing a 5.44% absolute gain over the optimized baseline. These results demonstrate that high-frequency spatial features are more discriminative for SZ classification than raw intensities, and that aligning Laplacian-initialized kernels with HiFi-filtered input creates a beneficial inductive bias--even with a compact model of approximately 1.4M parameters.

neuroscience↗

bioRxiv2026

Experimental Evolution of Yeast Reveals Trade-offs Between Early and Late Stationary Phase

Stationary phase in yeast and other microorganisms begins when a limiting nutrient in the environment is exhausted and cell division ceases. Most cells subsequently enter quiescence and lose viability. In spent media, without metabolic byproducts being diluted, cellular processes can modify the environment and cause the relative growth rates of different genotypes to vary over the course of stationary phase. In this work we experimentally evolve S. cerevisiae in batch culture, varying the time spent in stationary phase between growth cycles. We measure the relative fitness of the resulting adaptive clones across a range of environments: with different amounts of time in stationary phase and in two different carbon sources. By comparing the inferred performance (relative growth rate during a period of the growth cycle) of a mutant to that of its ancestor, we can estimate the effects of each observed mutation on performance during various phases of growth. We show that when an adaptive mutation emerges in growth cycles that include a stationary phase, its effect on stationary phase performance is largely independent of the type of carbon source provided. However, for the same group of mutants, mutational effects on performance in early stationary phase are negatively correlated with those effects in late stationary phase, suggesting a trade-off. We also show that increased intervals of stationary phase result in larger fitness effects of adaptive mutations and distinct routes of adaptation. Together, these results demonstrate that stationary phase consists of more than one distinct fitness-related phenotype, and that the phenotypes that allow for high performance in the first few days of stationary phase trade off with those that allow for high performance in later stationary phase.

evolutionary biology↗

bioRxiv2024

4-Phenylbutyric acid modulates Connexin 43 expression restricting murine-β-coronavirus infectivity and virus-induced demyelination

Gap junction intercellular communication, particularly involving Connexin 43 and Connexin 47, plays a critical role in maintaining CNS homeostasis and has been implicated in Multiple Sclerosis (MS) pathology. Thus, warranting further studies in experimental animal models to understand how modulation of Cx43 expression can influence MS pathology. Intracranial infection with murine-{beta}-coronavirus Mouse Hepatitis Virus (MHV-A59) in mice results in acute pathology characterized by high viral titers, glial activation in the brain and chronic neuroinflammatory demyelination, effectively mimicking key pathological hallmarks of MS and serving as a robust model to investigate its viral etiology. MHV-A59 infection leads to a pronounced downregulation of Cx43 during the acute phase, emphasizing its critical role in virus-induced CNS pathology. In this study, we investigated the potential of in vivo 4-phenylbutyric acid (4-PBA) administration in modulating Cx43 expression in this MHV-induced model and its consequence on chronic virus-induced demyelination. Our results reveal that 4-PBA treatment reduced acute MHV-A59 infectivity and viral spread in the brain while modulating the glial cell response, mounting host immunity. Treatment with 4-PBA effectively preserved the expression of both Cx43 and Cx47 in infected CNS cells, counteracting their infection-induced downregulation. Furthermore, MHV-A59 infection downregulated the expression of ER-resident thioredoxin family protein (ERp29), a well-known molecular chaperone of Cx43, which was rescued by 4-PBA treatment. We further validated if such downregulation of ERp29 is also evident in MS demyelinating plaques. In human MS patient-derived brain tissue, reduced Cx43 and ERp29 staining was observed in demyelinating plaques. Our studies revealed that 4-PBA treatment not only limits viral replication and spread throughout the brain but also protects the mice against severe chronic neuroinflammatory demyelination. These findings suggest that targeting Cx43 with 4-PBA holds significant therapeutic potential for addressing virus-induced neuroinflammatory demyelination and MS by preserving gap junction intercellular communication.

neuroscience↗

bioRxiv2023

Variant Mapping Application: Customize And Annotate Figures Of Voltage-Gated Sodium Channel

Voltage-gated sodium ion channels allow for the initiation and transmission of action potentials. There is a high interest in research and drug development to selectively target these ion channels to treat epilepsy and other disorders such as pain. Scientific literature and presentations often incorporate maps of these integral membrane proteins with markers indicating gene mutations to highlight genotype/phenotype correlations. There is a need for automated tools to create high quality figures with mutation (variant) locations displayed on these channel maps. This manuscript introduces a simple application to create visualization for mutations on alpha voltage-gated sodium channels, created using the D3.js library. The application allows for mapping of variant sequences, as well as important properties like the type of variant and the phenotypes linked to the variant. It also allows for customizability and the production of high-quality images for publication. This application and code base can further be extrapolated to other ion channels as well.

neuroscience↗

bioRxiv2023

3D-intrusions transport active surface microbial assemblages to the dark ocean

Subtropical oceans contribute significantly to global primary production, but the fate of the picophytoplankton that dominate in these low nutrient regions is poorly understood. Working in the subtropical Mediterranean, we demonstrate that subduction of water at ocean fronts generates 3D intrusions with uncharacteristically high carbon, chlorophyll, and oxygen that extend below the sunlit photic-zone into the dark ocean. These contain "fresh" picophytoplankton assemblages that resemble the photic-zone regions where the water originated. Intrusions propagate depth-dependent seasonal variations in microbial assemblages into the ocean interior. Strikingly, the intrusions included dominant biomass contributions from non-photosynthetic bacteria and enrichment of enigmatic heterotrophic bacterial lineages. Thus, the intrusions not only deliver material that differs in composition and nutritional character from sinking detrital particles, but also drive shifts in bacterial community composition, organic matter processing, and interactions between surface and deep communities. Modeling efforts paired with global observations demonstrate that subduction can flux similar magnitudes of particulate organic carbon as sinking export, but is not accounted for in current export estimates and carbon cycle models. Intrusions formed by subduction are a particularly important mechanism for enhancing connectivity between surface and upper mesopelagic ecosystems in stratified subtropical ocean environments that are expanding due to the warming climate.

ecology↗

bioRxiv2022

An Improved Algorithm for Inferring Mutational Parameters from Bar-Seq Evolution Experiments

Genetic barcoding provides a high-throughput way to simultaneously track the frequencies of large numbers of competing and evolving microbial lineages. However making inferences about the character of the evolution that is taking place remains a difficult task. Here we describe a step toward more accurate inference of fitness effects and establishment times of beneficial mutations, which builds upon a prior method by enforcing self-consistency between the population mean fitness and the individual effects of mutations within lineages. By testing our inference method on a simulation of 40,000 barcoded lineages evolving in serial batch culture, we find that this new method outperforms its predecessor, identifying more adaptive mutations and more accurately inferring their mutational parameters. We have made available our code for the joint Bayesian inference of population mean fitness and lineage-specific mutational parameters, in the hope that it can find broader use by the microbial evolution community.

evolutionary biology↗

bioRxiv2022

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and ex vivo seizures

Voltage-gated sodium channels (Nav) are essential for the initiation and propagation of action potentials in neurons. Of the different channel subtypes, Nav1.1, Nav1.2 and Nav1.6 are prominently expressed in the adult central nervous system (CNS). All three of these sodium channel subtypes are sensitive to block by the neurotoxin tetrodotoxin (TTX), with TTX being almost equipotent on all three subtypes. In the present study we have used TTX to determine the fractional block of Nav channels required to impair action potential firing in pyramidal neurons and reduce network seizure-like activity. Using automated patch-clamp electrophysiology, we first determined the IC50s of TTX on mouse Nav1.1, Nav1.2 and Nav1.6 channels expressed in HEK cells, demonstrating this to be consistent with previously published data on human Nav channels. We then compared this data to the potency of block of Nav current measured in pyramidal neurons from neocortical brain slices. Interestingly, we found that it requires nearly 10-fold greater concentration of TTX over the IC50 to induce significant block of action potentials using a current-step protocol. In contrast, concentrations near the IC50 resulted in a significant reduction in AP firing and increase in rheobase using a ramp protocol. Surprisingly, a 20% reduction in action potential generation observed with 3 nM TTX resulted in significant block of seizure-like activity in the 0 Mg2+ model of epilepsy. Additionally, we found that approximately 50% block in pyramidal cell intrinsic excitability is sufficient to completely block all seizure-like events. These data serve as a critical starting point in understanding how fractional block of Nav channels affect intrinsic neuronal excitability and seizure-like activity. It further suggests that seizures can be controlled without significantly compromising intrinsic neuronal activity and determines the required fold over IC50 for novel and clinically relevant Nav channel blockers to produce efficacy and limit side effects.

neuroscience↗

bioRxiv2022

Spatiotemporal Ecological Chaos Enables Gradual Evolutionary Diversification Without Niches or Tradeoffs

Ecological and evolutionary dynamics are intrinsically entwined. On short time scales, ecological interactions determine the fate of new mutants and changes in the community they induce, while on longer time scales evolution shapes the whole community. How eco-evolutionary dynamics gives rise to the extensive coexisting diversity of strains found in many bacterial species is a major puzzle. In this paper we study the evolution of large numbers of closely related strains with generalized Lotka Volterra interactions but no niche structure. The host-pathogen-like interactions drive the ecological dynamics into a spatiotemporally chaotic state characterized by continual local blooms and busts. Upon the slow serial introduction of new strains, the community is found to diversify indefinitely, accommodating arbitrarily large numbers of strains in the absence of any kind of stabilizing niche interactions. This diversifying phase is robust to changes in evolutionary parameters, and persists even in the presence of a distribution of general, nonspecific fitness differences between individual strains, which explicitly break the assumption of tradeoffs inherent in much previous work. However, gradual increase of the general fitnesses in the ecosystem slows down the diversification. Quantitative analysis of the range of behaviors is carried out by a combination of analytical methods and simulations. Building on a dynamical-mean field-theory understanding of the ecological dynamics, an approximate effective model captures the effects of evolution on the distributions of key properties, such as strain abundances. This work establishes a potential scenario and a theoretical framework for understanding how the interplay between evolution and ecology can give rise to extensive fine-scale diversity. Future avenues for investigation are suggested, including the effects of the build-up of relatedness between strains, how conditioning on the evolutionary history affects the ecological interactions and dynamics, and application to coevolution of the diversity of a bacterial and a phage species.

evolutionary biology↗

bioRxiv2022

Xenon LFP Analysis Platform is a Novel Graphical User Interface for Analysis of Local Field Potential from Large-Scale MEA Recordings

High-density multi-electrode array (HD-MEA) has enabled neuronal measurements at high spatial resolution to record local field potentials (LFP), extracellular spikes, and network activity with ease. Whilst we have advanced recording systems with over 4000 electrodes, capable of recording data at over 20 kHz, it still presents computational challenges to handle, process, extract, and view information from these large recordings. It can be challenging for researchers to extract and view even a single channel that has more than a billion data points, let alone process a group of channels. We have created a computational method, and an open-source toolkit built on Python, rendered on a web browser using Plotlys Dash for extracting and viewing the data, and creating interactive visualization. In addition to extracting and viewing entire or small chunks of data sampled at lower or higher frequencies, respectively, it provides a framework to collect user inputs, analyze channel groups, generate raster plots, view quick summary measures for LFP activity, detect and isolate noise channels, and generate plots and visualization in both time and frequency domain. Incorporated into our Graphical User Interface (GUI), we also have created a novel seizure detection method, which can be used to detect the onset of seizures in all or a selected group of channels and provide the following measures of seizures: distance, duration, and propagation across the region of interest. We demonstrate the utility of this toolkit, using datasets collected from the 3Brain BioCAM duplex system. For the current analysis, we demonstrate the toolkit and methods with a low sampling frequency dataset (300 Hz) and a group of approximately 400 channels. Using this toolkit, we present novel data demonstrating increased seizure propagation speed from slices of Scn1aHet mice compared to littermate controls. With advances in HD-MEA recording systems with high spatial and temporal resolution, limited tools are available for researchers to view and process these big datasets. We now provide a user-friendly toolkit to analyze LFP activity obtained from large-scale MEA recordings with translatable applications to EEG recordings, and demonstrate the utility of this new graphic user interface with novel biological findings.

neuroscience↗

bioRxiv2021

The asymmetric Pitx2 regulates intestinal muscular-lacteal development and protects against fatty liver disease

Intestinal lacteals are the essential lymphatic channels for absorption and transport of dietary lipids and drive pathogenesis of debilitating metabolic diseases. Yet, organ-specific mechanisms linking lymphatic dysfunction to disease etiology remain largely unknown. In this study, we uncover a novel intestinal lymphatic program that is linked to the left-right (LR) asymmetric transcription factor Pitx2. We show that deletion of the asymmetric Pitx2 enhancer, ASE, alters normal lacteal development through the lacteal-associated contractile smooth muscle lineage. ASE deletion leads to abnormal muscle morphogenesis induced by oxidative stress, resulting in impaired lacteal extension and defective lymphatic-dependent lipid transport. Surprisingly, activation of lymphatic-independent trafficking directs dietary lipids from the gut directly to the liver, causing diet-induced fatty liver disease. In summary, our studies reveal the molecular mechanism linking gut lymphatic development to the earliest symmetry-breaking Pitx2 and highlight the important relationship between intestinal lymphangiogenesis and gut-liver axis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/447753v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1a7e81corg.highwire.dtl.DTLVardef@77915forg.highwire.dtl.DTLVardef@1e91610org.highwire.dtl.DTLVardef@1a7911d_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG HIGHLIGHTS[~] Gut lymphangiogenesis is linked to Pitx2-driven LR asymmetry [~]Lacteal-associated smooth muscle requires ASE [~]ASE deletion leads to redox imbalance in intestinal smooth muscle lineage [~]ASE is required for the normal route of dietary lipid transport [~]Pitx2ASE/ASE neonates develop diet-induced fatty liver disease

developmental biology↗

bioRxiv2018

TH2BS12P histone mark is enriched in the unsynapsed axes of the XY body and predominantly associates with H3K4me3-containing genomic regions in mammalian spermatocytes

Various studies have focussed on understanding the repertoire and biological function of the post-translational modifications that occur on testis-specific histone variants like TH2B, Transition Proteins etc. In our attempt to decipher the unique functions of histone variant TH2B, we discovered a new modification Serine 12 phosphorylation on TH2B (TH2BS12P) in spermatocytes. Our present study is aimed at understanding the function of the TH2BS12P modification in the context of processes that occur during meiotic prophase I. Immunofluorescence studies revealed that TH2BS12P histone mark is enriched in the unsynapsed axes of the sex body and is associated with XY body axes associated proteins like Scp3, {gamma}H2AX, pATM, ATR etc. We also observe that TH2BS12P is associated with DSB initiator Spo11 and with several recombination related proteins like pATM, ATR, Rad51, {gamma}H2AX etc in vivo. This modification was also found to associate with transcription and recombination related histone marks like H3K4me3 and H3K36me3 in the context of mononucleosomes. Genome-wide occupancy studies as determined by ChIP sequencing experiments revealed that TH2BS12P is localised to subset of recombination hotspots, but majorly associated with H3K4me3 containing genomic regions like gene promoters. Mass spectrometry analysis of proteins that bind to TH2BS12P containing mononucleosomes revealed many proteins linked with the functions of pericentric heterochromatin, transcription and recombination related pathways. We propose that TH2BS12P modification could act alone or in concert with other histone marks for recruitment of appropriate transcription or recombination protein machinery at specific genomic loci. This is the first report documenting the role of a post-translational modification of a germ cell specific histone variant in meiotic prophase I related events.

cell biology↗