Biology subjects

Chakravarty, S.

Publications and source records attributed to Chakravarty, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Integrative Multi-Tissue Analysis Identifies Synaptic Gene Networks Specific to Major Depressive Disorder in Women

Major Depressive Disorder (MDD) shows marked gender differences in prevalence and molecular signatures. Transcriptomic studies of post-mortem human brain tissue have reported alterations in the expression of synapse-related genes in MDD, including gender-specific patterns. But it remains unclear whether transcriptional changes observed in the brains of women with MDD are detectable in peripheral blood and conserved in experimental stress models. Whole-blood RNA sequencing was performed in women with MDD (n = 6) and matched healthy controls (n = 4). Differentially expressed genes (DEGs) were compared with previously reported female-specific blood and post-mortem brain transcriptomic datasets where selected overlapping synapse-associated genes were evaluated in the hippocampus and prefrontal cortex of female mice exposed to Chronic Variable Mild Stress (CVMS). Peripheral blood analysis identified DEGs enriched for synaptic organization, neuronal structure, and ion transport pathways. A substantial proportion of DEGs overlapped with previously reported datasets from peripheral blood, female MDD brain transcriptomic studies, and genes showing exclusive/enriched expression in the normal human brain. Network-based prioritization identified seven synapse-associated genes (SHANK2, SHANK3, CACNG8, GPHN, PICK1, NRXN2 and DNM2) for further analysis. In the female CVMS model, several of these genes showed altered expression in the hippocampus and/or prefrontal cortex, alongside behavioural changes and reduced dendritic spine density. These findings highlight shared transcriptional signals across human blood and human brain datasets, as well as in the mouse brain. However, larger studies are required to confirm and validate these observations.

neuroscience↗

bioRxiv2026

The CYP27A1 - VDR Feedback Rheostat Controls Mitochondrial Protein Homeostasis and Preserves Hippocampal - Striatal Network Integrity to rescue Cognitive impairment in HD condition

Emerging evidence links vitamin D (VD) deficiency to cognitive and motor dysfunction in Huntingtons disease (HD), yet the underlying mechanism remains unclear. Here, we combine in vitro genetic and 3-nitropropionic acid (3-NP)-induced in vivo models of HD to define the mechanistic basis of VD-mediated neuroprotection. We demonstrate that VD supplementation restores cognitive and motor deficits while improving mitochondrial function and cellular survival. Mechanistically, VD enhances mitochondrial fusion and rescues complex II expression, a key defect in HD pathology. We identify the mitochondrial enzyme CYP27A1 as a critical mediator of this effect, as its expression is reduced in HD models but restored upon VD treatment. Overexpression of CYP27A1 recapitulates the protective effects of VD, confirming its central role in maintaining mitochondrial integrity. Furthermore, VD promotes vitamin D receptor (VDR)-dependent transcriptional activation of CYP27A1 and additional nuclear- and mitochondrial-encoded genes, establishing a regulatory feedback loop that supports mitochondrial biogenesis and function. VD supplementation also improves proteostasis via attenuating endoplasmic reticulum stress. Together, our findings uncover a previously unrecognized VD-CYP27A1 axis that links mitochondrial dysfunction to HD pathology and highlight CYP27A1 as a potential therapeutic target.

neuroscience↗

bioRxiv2025

Replicating the Gold Standard: A Novel Female Chronic Social Defeat Stress Model (femCSDS) for Studying Sex Differences in Depression

Depression shows significant sex differences in prevalence and neurobiological underpinnings, yet preclinical research investigating the pathophysiology of depression and the efficacy of antidepressants has predominantly relied on male models. Here, we establish a novel female chronic social defeat stress paradigm by leveraging the natural aggression of parous CD1 females, co-housed with castrated males to induce aggression while eliminating confounding sexual behaviors and without hormonal or surgical manipulations. Selected aggressive females reliably displayed offensive behaviors toward C57BL/6NCrl intruders across repeated encounters. Defeated female mice exhibited pronounced depression-like behaviors, including social withdrawal, anhedonia, behavioral despair, and elevated anxiety-like responses. Biochemical analysis revealed elevated glutamate levels in Nucleus Accumbens (NAc) and caudate putamen (CPu). Alterations in EAAT1, GRIN2B, and Neurabin expression were observed in CPu, indicating excitotoxic stress and compromised synaptic integrity. Label free Quantitative MS-MS analysis of NAc revealed 1194 significantly dysregulated proteins. Ingenuity Pathway Analysis highlighted canonical pathway disruptions in synaptogenesis signaling pathway and glutamate signaling pathway. Disease and function analysis revealed enrichment in neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. Given the extensive literature on male CSDS and its established pathophysiology, we aimed and successfully developed female-specific replica model of traditional male CSDS, enabling direct comparison and elucidation of sex differences in depression pathophysiology.

neuroscience↗

bioRxiv2025

Altered perceptual integration and learning in autism revealed by games inspired by rodent operant tasks

Altered perception is a key feature of autism spectrum disorder (ASD), yet its precise nature and variability across individuals remain unclear. We developed an online video game, inspired by rodent operant tasks, to assess visual evidence integration. The game employs nonverbal, reward-based training and a pulsed stimulus design for precise control of sensory input, enabling detailed individual-level behavioral analysis. It was playable by typically developing adolescents and their autistic siblings, who spanned the spectrum, including those with profound autism. Game performance correlated with standard ASD survey scores, with ASD participants exhibiting slower learning and altered perceptual integration. Behavioral data were well fit by computational models in which perceptual and learning deficits in ASD arose from increased noise in higher- order visual processing. Our findings reveal that deficits in perceptual integration are widespread across ASD, correlate with symptom severity in social and adaptive domains, and may arise from instability of sensory representations.

neuroscience↗

bioRxiv2024

Noise Reduction in Resource-Coupled Multi-Module Gene Circuits through Antithetic Feedback Control

Gene circuits within the same host cell often experience coupling, stemming from the competition for limited resources during transcriptional and translational processes. This resource competition introduces an additional layer of noise to gene expression. Here we present three multi-module antithetic control strategies: negatively competitive regulation (NCR) controller, alongside local and global controllers, aimed at reducing the gene expression noise within the context of resource competition. Through stochastic simulations and fluctuation-dissipation theorem (FDT) analysis, our findings highlight the superior performance of the NCR antithetic controller in reducing noise levels. Our research provides an effective control strategy for attenuating resource-driven noise and offers insight into the development of robust gene circuits.

synthetic biology↗

bioRxiv2024

A cross-species framework for investigating perceptual evidence accumulation

Cross-species studies are important for a comprehensive understanding of brain functions. However, direct quantitative comparison of behaviors across species presents a significant challenge. To enable such comparisons in perceptual decision-making, we developed a synchronized evidence accumulation task for human and non-human animals, by aligning mechanics, stimuli, and training. The task was readily learned by rats, mice and humans, with each species exhibiting qualitatively similar performance. Quantitative model comparison revealed that all three species employed an evidence accumulation strategy, but differed in speed, accuracy, and key decision parameters. Human performance prioritized accuracy, whereas rodent performance was limited by internal time-pressure. Rats optimized reward rate, while mice appeared to switch between evidence accumulation and other strategies trial-to-trial. Together, these results reveal striking similarities and species-specific priorities in decision-making. Furthermore, the synchronized behavioral framework we present may facilitate future studies involving cross-species comparisons, such as evaluating the face validity of animal models of neuropsychiatric disorders. HighlightsO_LIDevelopment of an evidence accumulation task for rats and mice C_LIO_LISynchronized video game allows direct comparisons with humans C_LIO_LIRat, mouse and human behavior are well fit by the same decision models C_LIO_LIModel parameters reveal species-specific priorities in accumulation strategy C_LI

animal behavior and cognition↗

bioRxiv2024

Multiomics analysis reveals B. MO1 as a distinct Babesia species and provides insights into its evolution and virulence.

Babesiosis, caused by protozoan parasites of the genus Babesia, is an emerging tick-borne disease of significance for both human and animal health. Babesia parasites infect erythrocytes of vertebrate hosts where they develop and multiply rapidly to cause the pathological symptoms associated with the disease. The identification of various Babesia species underscores the ongoing risk of new zoonotic pathogens capable of infecting humans, a concern amplified by anthropogenic activities and environmental shifts impacting the distribution and transmission dynamics of parasites, their vectors, and reservoir hosts. One such species, Babesia MO1, previously implicated in severe cases of human babesiosis in the midwestern United States, was initially considered closely related to B. divergens, the predominant agent of human babesiosis in Europe. Yet, uncertainties persist regarding whether these pathogens represent distinct variants of the same species or are entirely separate species. We show that although both B. MO1 and B. divergens share similar genome sizes, comprising three nuclear chromosomes, one linear mitochondrial chromosome, and one circular apicoplast chromosome, major differences exist in terms of genomic sequence divergence, gene functions, transcription profiles, replication rates and susceptibility to antiparasitic drugs. Furthermore, both pathogens have evolved distinct classes of multigene families, crucial for their pathogenicity and adaptation to specific mammalian hosts. Leveraging genomic information for B. MO1, B. divergens, and other members of the Babesiidae family within Apicomplexa provides valuable insights into the evolution, diversity, and virulence of these parasites. This knowledge serves as a critical tool in preemptively addressing the emergence and rapid transmission of more virulent strains.

microbiology↗

bioRxiv2023

RAmbler: de novo genome assembly of complex repetitive regions

Complex repetitive regions (also called segmental duplications) in eukaryotic genomes often contain essential functional and regulatory information. Despite remarkable algorithmic progress in genome assembly in the last twenty years, modern de novo assemblers still struggle to accurately reconstruct these highly repetitive regions. When sequenced reads will be long enough to span all repetitive regions, the problem will be solved trivially. However, even the third generation of sequencing technologies on the market cannot yet produce reads that are sufficiently long (and accurate) to span every repetitive region in large eukaryotic genomes. In this work, we introduce a novel algorithm called RAmbler to resolve complex repetitive regions based on high-quality long reads (i.e., PacBio HiFi). We first identify repetitive regions by mapping the HiFi reads to the draft genome assembly and by detecting un-usually high mapping coverage. Then, (i) we compute the k-mers that are expected to occur only once in the genome (i.e., single copy k-mers, which we call unikmers), (ii) we barcode the HiFi reads based on the presence and the location of their unikmers, (iii) we compute an overlap graph solely based on shared barcodes, (iv) we reconstruct the sequence of the repetitive region by traversing the overlap graph. We present an extensive set of experiments comparing the performance of RAmbler against Hifiasm, HiCANU and Verkko on synthetic HiFi reads generated over a wide range of repeat lengths, number of repeats, heterozygosity rates and depth of sequencing (over 140 data sets). Our experimental results indicate that RAmbler outperforms Hifiasm, HiCANU and Verkko on the large majority of the inputs. We also show that RAmbler can resolve several long tandem repeats in Arabidopsis thaliana using real HiFi reads. The code for RAmbler is available at https://github.com/sakshar/rambler. CCS CONCEPTSApplied computing [->] Bioinformatics; Computational genomics; Molecular sequence analysis; * Theory of computation [->] Graph algorithms analysis.

bioinformatics↗

bioRxiv2023

Incorporating Radiopacity into Implantable Polymeric Biomedical Devices for Clinical Radiological Monitoring

Longitudinal radiological monitoring of biomedical devices is increasingly important, driven by risk of device failure following implantation. Polymeric devices are poorly visualized with clinical imaging, hampering efforts to use diagnostic imaging to predict failure and enable intervention. Introducing nanoparticle contrast agents into polymers is a potential method for creating radiopaque materials that can be monitored via computed tomography. However, properties of composites may be altered with nanoparticle addition, jeopardizing device functionality. This, we investigated material and biomechanical response of model nanoparticle-doped biomedical devices (phantoms), created from 0-40wt% TaOx nanoparticles in polycaprolactone, poly(lactide-co-glycolide) 85:15 and 50:50, representing non-, slow and fast degrading systems, respectively. Phantoms degraded over 20 weeks in vitro, in simulated physiological environments: healthy tissue (pH 7.4), inflammation (pH 6.5), and lysosomal conditions (pH 5.5), while radiopacity, structural stability, mechanical strength and mass loss were monitored. The polymer matrix determined overall degradation kinetics, which increased with lower pH and higher TaOx content. Importantly, all radiopaque phantoms could be monitored for a full 20-weeks. Phantoms implanted in vivo and serially imaged, demonstrated similar results. An optimal range of 5-20wt% TaOx nanoparticles balanced radiopacity requirements with implant properties, facilitating next-generation biomedical devices.

bioengineering↗

bioRxiv2022

Mathematical bridge between epidemiological and molecular data on cancer and beyond

BackgroundAt least six different mathematical models of cancer and their count-less variations and combinations have been published to date in the scientific literature that reasonably explain epidemiological prediction of multi-step carcinogenesis. Each one deals with a particular set of problems at a given organizational level ranging from populations to genes. Any of the models adopted in those articles so far do not account for both epidemiological and molecular levels of carcinogenesis. MethodsWe have developed a mathematically rigorous system to derive those equations satisfying the basic assumptions of both epidemiology and molecular biology without incorporating arbitrary numerical coefficients or constants devoid of any causal explanation just to fit the empirical data. The dataset we have used encompasses 21 major categories of cancer, 124 selected populations, 108 cancer registries, 5 continents, and 14,067,894 individual cases. ResultsWe generalized all the epidemiological and molecular data using our derived equations through linear and non-linear regression and found all the necessary coefficients to explain the data. We also tested our equations against non-neoplastic conditions satisfying equivalent mathematical assumptions. ConclusionThe aim of this treatise is not only to provide some novel insight into the mathematical modeling of malignant transformation but also to revive the classical tools we already have at our disposal to pave the way towards novel insight into integrated approaches in cancer research.

cancer biology↗

bioRxiv2022

Decoding The Nuclear Genome of The Human Pathogen Babesia duncani Shed Light on its Virulence, Drug Susceptibility and Evolution among Apicomplexa

Babesia species are tick-transmitted apicomplexan pathogens and the causative agents of babesiosis, a malaria-like disease of major medical and veterinary importance. Of the different species of Babesia reported so far, Babesia duncani causes severe to lethal infection in patients. Despite the highly virulent nature of this parasite and the risk it may pose as an emerging pathogen, little is known about its biology, metabolic requirements, and pathogenesis. B. duncani is unique among apicomplexan parasites that infect red blood cells in that it can be continuously cultured in vitro in human erythrocytes but can also infect mice leading to fulminant babesiosis infection and death. Here we have taken advantage of the recent advances in the propagation of this parasite in vitro and in vivo to conduct detailed molecular, genomic and transcriptomic analyses and to gain insights into its biology. We report the assembly, 3D structure, and annotation of the nuclear genome of this parasite as well as its transcriptomic profile and an atlas of its metabolism during its intraerythrocytic life cycle. Detailed examination of the B. duncani genome and comparative genomic analyses identified new classes of candidate virulence factors, suitable antigens for diagnosis of active infection, and several attractive drug targets. Translational analyses and efficacy studies identified highly potent inhibitors of B. duncani thus enriching the pipeline of small molecules that could be developed as effective therapies for the treatment of human babesiosis.

microbiology↗

bioRxiv2021

Closed-Loop Control of Anesthetic State in Non-Human Primates

Continuous monitoring of electroencephalogram (EEG) recordings in humans under general anesthesia (GA) has demonstrated that changes in EEG dynamics induced by an anesthetic drug are reliably associated with the altered arousal states caused by the drug. This observation suggests that an intelligent, closed-loop anesthesia delivery (CLAD) system operating in real-time could track EEG dynamics and control the infusion rate of a programmable pump to precisely maintain unconsciousness. The United States FDA acknowledges the potential benefits of such automatic physiological closed-loop control devices for patient care. Bringing these devices into clinical practice requires establishing their feasibility in suitable animal models. Therefore, given the close neurophysiological proximity between human and non-human primates (NHPs), we address this problem by developing and validating a propofol CLAD system in rhesus macaques. Our CLAD system has three key components: (1) a data acquisition system that records cortical local field potentials (LFPs) from an NHP in real-time; (2) a computer executing our CLAD algorithm that takes in the LFP signals as input and outputs infusion rates; and (3) a computer-controlled infusion pump that administers intravenous propofol. Our CLAD system controls an empirically-determined LFP marker of unconsciousness (MOU) at a user-prescribed target value by updating every 20 seconds the propofol infusion rate based on real-time processing of the LFP signal. The MOU is the instantaneous power in the 20 to 30 Hz band of the LFP spectrogram. Every cycle (duration{approx} 20 sec), our CLAD algorithm updates the MOU estimate and uses a robust optimal control strategy to adjust the propofol infusion rate based on the instantaneous error. This error is computed as the difference between the current and the user-prescribed target MOU values. Using neural recordings from multiple NHP anesthesia sessions, we first established that our chosen MOU signal was strongly correlated with propofol-induced decreased spiking activity which itself has been shown earlier to be associated with the level of unconsciousness in NHPs. Then we designed robust optimal control strategies that used subject-specific pharmacokinetic-pharmacodynamic models describing the MOU dynamics due to propofol infusion rate changes. Finally, we achieved safe and efficient closed-loop control of level of unconsciousness in 9 CLAD experiments involving 2 NHPs and 2 different 125 min long target MOU profiles with three target MOU changes within a given experiment. Our CLAD system performs stably, accurately and robustly across a total of 1125 min of closed-loop control. The CLAD performance measures, represented as median (25th percentile, 75th percentile), are 3.13 % (2.62%, 3.53%) for inaccuracy, 0.54 %(-0.31%, 0.89%) for bias, -0.02%/min (-0.06%/min, 0.00%/min) for divergence, and 3% (2.49%, 3.59%) for wobble. These performance measures were comparable or superior to previously reported CLAD performance measures from clinical studies (conducted outside USA) as well as rodent-based studies. The key innovations here are: (1) a pre-clinical NHP model for CLAD development and testing, (2) a neuroscience-informed LFP-based MOU for CLAD, (3) parsimonious, pharmacology-informed models to describe MOU dynamics under propofol infusion in rhesus macaques, (4) a novel numerical testing framework for propofol CLAD that incorporates a principled optimal robust control strategy for titrating propofol, and finally (5) experimental findings demonstrating the feasibility of stable, accurate and robust CLAD in the NHP model. Our NHP-based CLAD framework provides a principled pre-clinical research platform that can form the foundation for future clinical studies.

bioengineering↗

bioRxiv2021

Clonal evolution and specificity of the human T follicular helper cell response to Plasmodium falciparum circumsporozoite protein

T follicular helper (TFH) cells play a crucial role in the development of long-lived, quality-improved B cell responses after infection and vaccination. However, little is known about their clonal evolution. Here we assessed the cell phenotype, clonal dynamics, and TCR specificity of human circulating TFH (cTFH) cells at monoclonal level during successive malaria immunizations with radiation-attenuated Plasmodium falciparum (Pf) sporozoites. Repeated parasite exposures induced a dynamic, polyclonal cTFH response with high frequency of cells specific to the Pf circumsporozoite protein (PfCSP), the main surface protein of sporozoites and a validated vaccine target. Repeated immunizations were required to induce detectable PfCSP-reactive cTFH cell responses to a small number of epitopes. HLA-restrictions and differences in TCR generation probability explain the high targeting frequency of the polymorphic Th2R/T* region over the conserved T1 epitope. The vast majority of anti-Th2R/T* TCRs failed to tolerate natural polymorphisms in their target peptide sequence suggesting that parasite diversity limits natural boosting of the cTFH cell response in endemic areas and protection from non-vaccine strains. Among convergent anti-Th2R/T* TCRs with high sequence similarity, subtle differences in CDR3 composition discriminated cross-reactive from non-cross-reactive cTFH cells. Thus, our study provides deep molecular and cellular insights into the kinetics, fine specificity and HLA-restrictions of the anti-cTFH cell response that are of direct relevance for the design of PfCSP-based malaria vaccines by guiding the selection of PfCSP peptides that induce optimal B cell help.

immunology↗

bioRxiv2021

Knockout of Anopheles stephensi immune gene LRIM1 by CRISPR-Cas9 reveals its unexpected role in reproduction and vector competence

PfSPZ Vaccine against malaria is composed of Plasmodium falciparum (Pf) sporozoites (SPZ) manufactured using aseptically reared Anopheles stephensi mosquitoes. Immune response genes of Anopheles mosquitoes such as Leucin-Rich protein (LRIM1), inhibit Plasmodium SPZ development (sporogony) in mosquitoes by supporting melanization and phagocytosis of ookinetes. With the aim of increasing PfSPZ infection intensities, we generated an A. stephensi LRIM1 knockout line , {Delta}aslrim1 , by embryonic genome editing using CRISPR-Cas9. {Delta}aslrim1 mosquitoes had a significantly increased midgut bacterial load and an altered microbiome composition, including elimination of commensal acetic acid bacteria. The alterations in the microbiome caused increased mosquito mortality and unexpectedly, significantly reduced sporogony. The survival rate of {Delta}aslrim1 and their ability to support PfSPZ development, were partially restored by antibiotic treatment of the mosquitoes, and fully restored to baseline when {Delta}aslrim1 mosquitoes were produced aseptically. Deletion of LRIM1 also affected reproductive capacity: oviposition, fecundity and male fertility were significantly compromised. Attenuation in fecundity was not associated with the altered microbiome. This work demonstrates that LRIM1s regulation of the microbiome has a major impact on vector competence and longevity of A. stephensi. Additionally, LRIM1 deletion identified an unexpected role for this gene in fecundity and reduction of sperm transfer by males.

microbiology↗

bioRxiv2020

Genome Wide Association Studies on 7 Yield-relatedTraits of 183 Rice Varieties in Bangladesh

MotivationRice genetic diversity is regulated by multiple genes and is largely dependent on various environmental factors. Uncovering the genetic variations associated with the diversity in rice populations is the key to breed stable and high yielding rice varieties. ResultsWe performed Genome Wide Association Studies (GWAS) on 7 rice yielding traits (grain length, grain width, grain weight, panicle length, leaf length, leaf width and leaf angle) based on a population of 183 rice landraces of Bangladesh. Our GWA studies reveal various chromosomal regions and candidate genes that are associated with different traits in Bangladeshi rice varieties. Noteworthy was the recurrent implication of chromosome 10 in all three grain shape related traits (grain length, grain width, and grain weight), indicating its pivotal role in shaping rice grain morphology. Our study also underscores the involvement of transposon gene families across these three traits. For leaf related traits, chromosome 10 was found to harbor regions that are significantly associated with leaf length and leaf width. The results of these association studies support previous findings as well as provide additional insights into the genetic diversity of rice. ConclusionsThis is the first known GWAS study on various yield-related traits in the varieties of Oryza sativa available in Bangladesh - the fourth largest rice-producing country. We believe this study will accelerate rice genetics research and breeding stable high-yielding rice in Bangladesh.

bioinformatics↗

bioRxiv2020

Mapping of safe and early chemo-attenuated live Plasmodium falciparum immunization identifies immune signature of vaccine efficacy

Potent protection against malaria can be induced by attenuated live-immunization with Plasmodium falciparum (Pf) sporozoites (SPZ). However, a better understanding of the critical processes involved in the establishment of protective immunity is needed. We explored the safety and vaccine efficacy of early chemo-attenuation of PfSPZ under atovaquone-proguanil (AP). AP caused early arrest of P. berghei liver stages. Despite the absence of replication, robust protection in mice correlated with parasite-specific effector-memory CD8+ T-cell responses. In a phase I clinical trial a single dose of AP prevented Pf infections in the liver of adult, human subjects who received three doses of 5.12x104 or 1.5x105 PfSPZ by direct venous inoculation combined with oral AP. However, only 2 of 8 (25%) and 2 of 10 (20%), respectively, were protected against controlled human malaria infection (CHMI) 10 weeks after the last vaccine dose, despite levels of IgG antibodies to the Pf circumsporozoite protein (PfCSP) comparable to those achieved in fully protected volunteers after immunization with 5.12x104 PfSPZ with chloroquine chemoprophylaxis active only against subsequent blood stages. We identify lower IgG recognition of the secreted liver stage-specific antigens LISP2 and LSA1 and the multi-stage antigen MSP5 as immune signatures of inferior vaccine efficacy compared to PfSPZ with chloroquine chemoprophylaxis. In conclusion, we show that immune signatures of liver stage antigens, but neither an established rodent malaria model nor concentrations of antibodies against the major surface protein of sporozoites, permit prediction of vaccine efficacy. Thus, this study provides a clear rationale for the development of live sporozoite vaccination protocols that boost exposure to Pf liver stage antigens. Significance StatementOur research demonstrates that attenuation of liver infection of high doses of Plasmodium falciparum sporozoites by concomitant single-dose administration of atovaquone-proguanil is safe in humans. However, vaccine efficacy was modest when compared to an identical protocol using chloroquine that acts only on the subsequent blood infection. Immune signatures of secreted P. falciparum liver stage antigens, but neither an established rodent malaria model nor concentrations of sporozoite antibodies, permit prediction of vaccine efficacy.

immunology↗

bioRxiv2020

Hypoxia induced sex-difference in zebrafish brain proteome profile reveals the crucial role of H3K9me3 in recovery from acute hypoxia

Understanding the molecular basis of sex differences in neural response to acute hypoxic insult has profound implications for the effective prevention and treatment of ischemic stroke. Global hypoxic-ischemic induced neural damage has been studied recently under the well-controlled, non-invasive, reproducible conditions using zebrafish model. Our earlier report on sex difference in global acute hypoxia induced neural damage and recovery in zebrafish prompted us for comprehensive study on the mechanisms underlying the recovery. An omics approach for studying quantitative changes in brain proteome upon hypoxia insult following recovery was undertaken using iTRAQ-based LC-MS/MS approach. The results shed light on altered expression of many regulatory proteins in zebrafish brain upon acute hypoxia following recovery. The sex difference in differentially expressed proteins along with the proteins expressed in uniform direction in both the sexes was studied. Core expression analysis by Ingenuity Pathway analysis (IPA) showed a distinct sex difference in the disease function heatmap. Most of the upstream regulators obtained through IPA were validated at the transcriptional level. Translational upregulation of H3K9me3 in male led us to elucidate the mechanism of recovery by confirming transcriptional targets through ChIP-qPCR. The upregulation of H3K9me3 level in male at 4 hr post-hypoxia appears to affect the early neurogenic markers nestin, klf4 and sox2, which might explain the late recovery in male, compared to female. Acute hypoxia-induced sex-specific comparison of brain proteome led us to reveal many differentially expressed proteins, which can be further studied for the development of novel targets for better therapeutic strategy.

neuroscience↗

bioRxiv2020

Molecular Basis of Sex Difference in Neuroprotection induced by Hypoxia preconditioning in zebrafish

Hypoxia, the major cause of ischemia, leads to debilitating disease in infants via birth asphyxia and cerebral palsy, whereas in adults via heart attack and stroke. A widespread, natural protective phenomenon termed Hypoxic Preconditioning occurs when prior exposures to hypoxia eventually results in robust hypoxia resistance. Accordingly, we have developed a novel model of sex-specific hypoxic preconditioning in adult zebrafish to mimic the tolerance of mini stroke(s) in human, which appears to protect against the severe damage inflicted by a major stroke event. Remarkable difference in the progression pattern of neuroprotection between preconditioning hypoxia followed by acute hypoxia (PH) group, and acute hypoxia (AH) group were observed with noticeable sex difference. Since gender difference has been reported in stroke, it was pertinent to investigate whether any such sex difference also exists in PHs protective mechanism against acute ischemic stroke. In order to elucidate the neural molecular mechanisms behind sex difference in neuroprotection induced by PH, a high throughput proteomics approach utilizing iTRAQ was performed, followed by protein enrichment analysis using Ingenuity Pathway Analysis. Out of thousands of altered proteins in zebrafish brain, the ones having critical role either in neuroglial proliferation/differentiation or neurotrophic functions, were validated by analyzing their expression levels in PH, AH and normoxia groups. Results indicate that female zebrafish brains are more protected against the severity of AH. The study also sheds light on the involvement of many signaling pathways underlying sex difference in pre-conditioning induced neuroprotective mechanism, which can be further validated for the therapeutic approach.

neuroscience↗