Biology subjects

Vijayakumar, S.

Publications and source records attributed to Vijayakumar, S..

14 recordsLinked to original sources

bioRxiv2026

Stimulus predictability rather than inter-trial interval itself affects motor evoked potential amplitudes

The inter-trial interval (ITI) of transcranial magnetic stimulation (TMS) can modulate motor-evoked potential (MEP) amplitude and may thus confound assessments of corticospinal excitability. We tested whether this effect depends on the ITI duration per se or the associated temporal predictability and whether intracortical inhibitory processes mediate these effects on. In 26 healthy participants, we recorded single-pulse MEPs and paired-pulse measures of short-interval intracortical inhibition (SICI; 2-ms interstimulus interval) and long-interval intracortical inhibition (LICI; 100-ms interstimulus interval) at ITIs of 2, 5, and 10 s. ITIs were presented in different Patterns, i.e., separate fixed blocks (FXD), randomly intermingled within blocks (RND), or randomly intermingled but auditorily cued at 950 ms pre-TMS (RNDC). MEPs showed significant effects of ITI, Pattern, and their interaction, being smaller at 2 s than at longer ITIs in FXD but not in RND and RNDC. However, RNDC produced marked MEP suppression across all ITI. SICI showed a Pattern x ITI interaction but no main effect of Pattern or between-pattern differences per ITI, whereas LICI showed complex Pattern x ITI interaction and both main effects. Notably, ITI affected SICI and LICI oppositely. While GABA-A-receptor mediated inhibition (SICI) showed an ITI dependency compatible with the ITI effects on single-pulse MEPs, it was unlikely mediating the predictability effects but may rather relate to an independent ITI driven suppression. In contrast, GABA-B-receptor mediated inhibition (LICI), was clearly modulated by predictability, but incompatible with the observed ITI effects on MEP amplitude. In summary, the effect of ITI duration on MEP amplitude seems to be largely explained by anticipatory suppression of corticospinal excitability based on the predictability of TMS pulses as derived from their temporal context, being easier for shorter and more regular ITIs and maximal for explicit cues immediately preceding the TMS pulse. SICI and LICI are modulated by ITI as well, with the latter affected by predictability, but neither can explain the observed predictability effects on single-pulse MEP amplitudes.

neuroscience↗

bioRxiv2025

Biological Sex Differences after High and Low Doses of Influenza A Virus Infection in a Diet-induced Obesity Mouse Model

Obesity is an independent risk factor for influenza A virus (IAV) pathogenesis. In non-obese hosts, following IAV infection, adult females develop more severe disease than males. Limited research on biological sex differences following IAV infection in individuals with obesity forms the basis for this study. Male and female C57BL/6J mice were treated with high-fat or low-fat diets to obtain mice with or without obesity. They were inoculated intranasally with a high (103) or low dose (101.5 TCID50) of mouse-adapted A/California/04/2009 H1N1 IAV and followed for 21 days post-infection (dpi) for morbidity. Subsets of mice were euthanized at different dpi to measure lung virus titers, histopathological changes, cellular infiltration, and cytokine induction. After a high-dose infection, females with obesity demonstrated shorter median survival time, greater parenchymal inflammation, and heightened induction of inflammatory markers than males with obesity. After a low-dose infection, females than males, and mice with obesity than the non-obese mice, exhibited severe morbidity. Female mice with obesity exhibited the greatest disease severity, where 25% (2/8) reached humane endpoint. Delayed but persistent inflammatory changes were observed in females with obesity, characterized by relatively lower pathological changes, lesser induction of cytokines and chemokines, and reduced myeloid and lymphoid infiltration in the lungs at 3 dpi followed by sustained pathological changes and cytokine and chemokine induction at 21 dpi. Our study suggests that the biological sex difference following IAV infection persists during obesity. Females with obesity experience greater influenza disease severity than males, possibly driven by more severe dysregulation of inflammatory responses. ImportanceThe prevalence of obesity is increasing worldwide. The risk of developing severe disease following influenza virus infection is higher in individuals with obesity. Males and females with obesity differ in terms of fat deposition and inflammatory and metabolic biomarkers. These differences can alter the outcomes of influenza-induced disease pathogenesis. The observation of sex differences in IAV pathogenesis among non-obese hosts underscores the importance of determining whether similar differences occur in the context of obesity. Indeed, our study suggested that females with obesity experience greater disease severity than males with obesity after IAV infection. Understanding the immunological mechanisms of such differences will advance precision medicine approaches to develop safer and more effective preventive and therapeutic strategies against influenza for the high-risk populations with obesity.

immunology↗

bioRxiv2025

Females with Obesity Exhibit Greater Influenza Vaccine-induced Immunity and Protection than Males in a Mouse Model

IntroductionObesity is increasing globally, and it negatively impacts influenza vaccine efficacy. Although sex differences in influenza vaccine responses are studied in non-obese hosts, studies investigating sex differences in influenza vaccine-induced immunity and protection during obesity are limited. Materials and methodsUsing the C57BL/6J mouse model of high-fat diet (HFD)-induced obesity or low-fat diet controls, we investigated sex differences in influenza vaccine-induced immunity and protection during obesity. Male and female mice with or without obesity were vaccinated intramuscularly twice at a 3-week interval with an inactivated 2009 H1N1 influenza A virus (IAV) vaccine. At 35 days post-vaccination (dpv), antibody responses in plasma and B- and T-cell responses in spleen and bone marrow were quantified. At 42 dpv, mice were intranasally challenged with a drift variant of the H1N1 IAV, and disease severity was assessed by monitoring the change in body mass up to 21 days post-challenge (dpc). Subsets of mice were euthanized at 3 dpc to determine pulmonary virus replication (TCID50 assay), histopathology (H&E staining), and cytokine/chemokine responses (multiplex ELISA). ResultsFemale mice, irrespective of diet and obesity status, developed higher antibody responses and were better protected compared to males. Vaccinated males with obesity mounted the poorest antibody responses, experienced a more severe disease, were unable to clear replicating virus from the lungs effectively, and demonstrated heightened pulmonary inflammation. Despite these differences, splenic B- and T-cell frequencies were comparable, suggesting the inefficiency of B cells to produce antibodies in males but not in females with obesity. DiscussionOur findings suggest that sex differences is observed in influenza vaccine-induced immunity and protection during obesity, where males are more severely affected. These findings highlight the importance of considering biological sex and obesity status in influenza vaccine design and testing.

immunology↗

bioRxiv2025

Erucamide regulates retinal neurovascular crosstalk

Neurovasculoglial crosstalk is critical in establishing and maintaining a functional neurovascular unit. Breakdown in the unit is central to many neurodegenerative disorders of the CNS of which the retina is a component. A growing literature indicated that primary fatty acid amides (PFAMs) can regulate this crosstalk between vasculature and neuronal tissues. In this study we describe a central role for erucamide, a 22:1 mono-unsaturated omega-9 fatty acid amide, in degenerating retinal tissues. Using high-resolution global mass spectrometry-based metabolomics, we cataloged metabolites in murine models of retinal degeneration and show that while PFAMs, in general, are highly dysregulated, erucamide is the one most significantly diminished during photoreceptor atrophy. Using rodent models of retinal degeneration and novel organosilane-modified porous silicon nanoparticles (pSiNPs) for the in vivo delivery of erucamide, we demonstrate that erucamide activates CD11b+ myeloid cells, leading to the upregulation of angiogenic and neurotrophic cytokines that stabilize retinal degeneration. We identified TMEM19 as a novel binding protein for erucamide that is crucial for human iPSC-derived macrophage precursor cells activation and subsequent neurotrophic and angiogenic factor production. These findings reveal a previously unknown PFAM pathway that is modulated during retinal degenerative diseases, demonstrating that erucamide or functional analogues and their action through TMEM19 may be useful as a therapeutic alternative to neuroprotective and stem cell-based approaches for the treatment of retinal degenerative diseases.

neuroscience↗

bioRxiv2025

Single-cell Transcriptomics Unravel Stereocilia Degeneration as a Key Contributor to Age-related Vestibular Dysfunction in Mice and Humans

Age-related vestibular dysfunction (ARVD) is a prevalent, debilitating condition in the elderly. The etiology and molecular mechanisms are poorly understood. We focused on mechanosensitive hair cells (HCs) as they are vulnerable to aging. Using single-cell RNA-seq transcriptomes of young and old mouse vestibular HCs, we show that aging vestibular HCs display both universal molecular signatures, such as genomic instability, mitochondrial dysfunction, and impaired proteostasis, and cell type-specific changes associated with deterioration of hair bundles and mechanotransduction. In alignment with transcriptomic findings, imaging and electrophysiological recordings from aged vestibular sensory epithelia confirmed the degeneration of the hair bundles and a reduction in mechanotransduction. Importantly, this deterioration of hair bundles and vestibular function precedes HC loss, highlighting impaired mechanotransduction as a key contributor to ARVD. Furthermore, molecular and cellular changes associated with aging signatures are less pronounced in vestibular HCs than in cochlear HCs, underscoring tissue-specific age-related differences between the two sensory epithelia in the inner ear.

neuroscience↗

bioRxiv2023

In Silico Transcriptome-based Screens Identify Epidermal Growth Factor Receptor Inhibitors as Therapeutics for Noise-induced Hearing Loss

Noise-Induced Hearing Loss (NIHL) represents a widespread disease for which no therapeutics have been approved by the Food and Drug Administration (FDA). Addressing the conspicuous void of efficacious in vitro or animal models for high throughput pharmacological screening, we utilized an in silico transcriptome-oriented drug screening strategy, unveiling 22 biological pathways and 64 promising small molecule candidates for NIHL protection. Afatinib and zorifertinib, both inhibitors of the Epidermal Growth Factor Receptor (EGFR), were validated for their protective efficacy against NIHL in experimental zebrafish and murine models. This protective effect was further confirmed with EGFR conditional knockout mice and EGF knockdown zebrafish, both demonstrating protection against NIHL. Molecular analysis using Western blot and kinome signaling arrays on adult mouse cochlear lysates unveiled the intricate involvement of several signaling pathways, with particular emphasis on EGFR and its downstream pathways being modulated by noise exposure and Zorifertinib treatment. Administered orally, Zorifertinib was successfully detected in the perilymph fluid of the inner ear in mice with favorable pharmacokinetic attributes. Zorifertinib, in conjunction with AZD5438 - a potent inhibitor of cyclin dependent kinase 2 - produced synergistic protection against NIHL in the zebrafish model. Collectively, our findings underscore the potential application of in silico transcriptome-based drug screening for diseases bereft of efficient screening models and posit EGFR inhibitors as promising therapeutic agents warranting clinical exploration for combatting NIHL. HighlightsO_LIIn silico transcriptome-based drug screens identify pathways and drugs against NIHL. C_LIO_LIEGFR signaling is activated by noise but reduced by zorifertinib in mouse cochleae. C_LIO_LIAfatinib, zorifertinib and EGFR knockout protect against NIHL in mice and zebrafish. C_LIO_LIOrally delivered zorifertinib has inner ear PK and synergizes with a CDK2 inhibitor. C_LI

neuroscience↗

bioRxiv2022

On the synergies between ribosomal assembly and machine learning tools for microbial identification

Genome assembly tools are used to reconstruct genomic sequences from raw sequencing data, which are then used for identifying the organisms present in a metagenomic sample. More recently, machine learning approaches have been applied to a variety of bioinformatics problems, and in this paper, we explore their use for organism identification. We start out by evaluating several commonly used metagenomic assembly tools, including PhyloFlash, MEGAHIT, MetaSPAdes, Kraken2, Mothur, UniCycler, and PathRacer, and compare them against state-of-the art deep learning-based machine learning classification approaches represented by DNABERT and DeLUCS, in the context of two synthetic mock community datasets. Our analysis focuses on determining whether ensembling metagenome assembly tools with machine learning tools has the potential to improve identification performance relative to using the tools individually. We find that this is indeed the case, and analyze the level of effectiveness of potential tool ensembling for organisms with different characteristics (based on factors such as repetitiveness, genome size, and GC content). Author SummaryMetagenomic studies focus on the challenging problem of identifying the presence and abundance of different species in a sample. This process typically involves the creation of digital reads from the sample which correspond to small parts of the genome sequence, and then have to be assembled together by a genome assembly tool. More recently, machine learning approaches have been applied to a variety of bioinformatics problems, and in this paper, we explore their use for organism identification, and how they might complement traditional bioinformatics approaches. We conduct experiments with two representative state-of-the-art machine learning approaches and six metagenomic assembly tools in the context of two synthetic datasets. We find that for organisms with certain characteristics (levels of repetitiveness, GC content, and genome size), ensembling metagenome assembly tools with machine learning tools has the potential to improve species identification performance relative to using the tools individually.

bioinformatics↗

bioRxiv2022

Genomic rearrangements of mobile genetic elements associated with carbapenem resistance of Acinetobacter baumannii

With the excessive genome plasticity, Acinetobacter baumannii has the capability to acquire and disseminate antimicrobial resistance genes that are often associated with mobile genetic elements (MGE). Analyzing the genetic environment of resistance genes often provides valuable information on the origin, emergence, evolution and spread of resistance. Thus, we characterized the genomic features of some clinical isolates of carbapenem-resistant A. baumannii to understand the role of diverse MGE and their genetic context that are responsible for the dissemination of carbapenem resistance genes. For this, a total of 17 clinical isolates of A. baumannii obtained from multiple hospitals in India between the years 2018 and 2019 were analysed. Antimicrobial resistance determinants, genetic context of resistance genes and molecular epidemiology were studied using whole genome sequencing. A high prevalence of blaOXA-23 was observed followed by the presence of dual carbapenemase, blaOXA-23 and blaNDM. Three novel Oxford sequence types were identified. Majority of the isolates belonged to dominant clone, IC2 followed by less prevalent clones such as IC7 and IC8. Complex diverse AbaR4 like and AbGRI-like islands belonging to IC2 lineage were identified. To the best of our knowledge, this is the first study that provides a comprehensive profiling of resistance islands along with the MGE, acquired antimicrobial resistance genes and the distribution of clonal lineages of carbapenem resistant A. baumannii from India.

microbiology↗

bioRxiv2022

In silico transcriptomics identifies FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss

Acquired hearing loss is a major health problem that affects 5-10% of the world population. However, there are no FDA-approved drugs for the treatment or prevention of hearing loss. Employing the Connectivity Map (CMap) that contains >54,000 compounds, we performed an unbiased in silico screen using the transcriptomic profiles of cisplatin-resistant and -sensitive cancer cell lines. Pathway enrichment analysis identified gene-drug targets for which 30 candidate drugs were selected with potential to confer protection against cisplatin-induced ototoxicity. In parallel, transcriptomic analysis of a cisplatin-treated cochlear-derived cell line identified common enriched pathway targets. We subsequently tested these top 30 candidate compounds, 15 (50%) of which are FDA-approved for other indications, and 26 (87%) of which were validated for their protective effects in either a cochlear-derived cell line or zebrafish lateral line neuromasts, thus confirming our in silico transcriptomic approach. Among these top compounds, niclosamide, a salicyanilide drug approved by the FDA for treating tapeworm infections for decades, protected from cisplatin- and noise-induced hearing loss in mice. Finally, niclosamide and ezetimibe (an Nrf2 agonist) exerted synergistic protection against cisplatin-ototoxicity in zebrafish, validating the Nrf2 pathway as part of niclosamides mechanism of action. Taken together, employing the CMap, we identified multiple pathways and drugs against cisplatin ototoxicity and confirmed that niclosamide can effectively be repurposed as an otoprotectant for future clinical trials against cisplatin- and noise-induced hearing loss. Significant StatementEmploying the Connectivity Map as our in silico transcriptomic screening strategy we identified FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss.

neuroscience↗

bioRxiv2021

Genome sequencing and molecular characterisation of XDR Acinetobacter baumannii reveal complexities in resistance: Novel combination of Sulbactam-Durlobactam holds promise for therapeutic intervention

Acinetobacter baumannii is an emerging nosocomial strain expressing extensive drug resistance (XDR). Whole-genome sequencing and molecular characterisation analysis revealed the presence of carbapenemase in 92.86% of studied Indian isolates having blaOXA-51, blaOXA-23, blaOXA-58, and blaNDM genes, with a few evidences of dual carbapenemase genes. As per the MLST scheme, IC2Oxf/CC2Pas was the predominant clone, with 57.14% isolates belonging to this lineage. The presence of {beta}-lactamases has rendered sulbactam (SUL) resistance (MIC: 16-256{micro}g/ml) in all the studied isolates. The efficacy of novel durlobactam (DUR) in inhibiting {beta}-lactamases and PBP2 was assessed through in-silico inter-molecular interaction analysis. Several non-synonymous single nucleotide polymorphisms (nsSNPs) were identified in PBP2 (G264S, I108V, S259T) and PBP3 (A515V, T526S) sequences. Minimal variations were recorded in the protein-backbone dynamics in active-site motifs of wild-type (WT) and mutants (MT), which correlated with the negligible binding energy fluctuations for PBP3-SUL (-5.85{+/-}0.04Kcal/mol) and PBP2-DUR (-5.16{+/-}0.66Kcal/mol) complexes. Furthermore, stronger binding affinities and low inhibition constants were noted in DUR complexed with OXA23 (-7.36Kcal/mol; 4.01{micro}M), OXA58 (-6.44Kcal/mol; 19.07{micro}M) and NDM (-6.82Kcal/mol; 10.01{micro}M) when compared with conventional drugs avibactam and aztreonam. Stable interaction profiles of DUR, can possibly restore SUL activity against both PBP3WT and PBP3MTs. The study establishes the efficacy of novel SUL-DUR combination as a successful treatment strategy to combat emerging XDR strains.

microbiology↗

bioRxiv2021

Colistin resistance in Acinetobacter baumannii is driven by multiple genomic traits: Evaluating the role of ISAba1-driven eptA overexpression among Indian isolates

Colistin resistance in Acinetobacter baumannii is mediated by multiple mechanisms. Recently, mutations within pmrAB two component system and overexpression of eptA due to upstream insertion of ISAba1 play a major role.To characterize colistin resistance mechanisms among the clinical isolates of A. baumannii in India. A total of 224 clinical isolates of A. baumannii collected from 2016 to 2019 were included in this study. Mutations within lipid A biosynthesis and pmrAB genes were characterized by Whole Genome Shotgun sequencing. Twenty eight complete genomes were further characterized for insertional inactivation of lpx genes and the association of ISAba1-eptA using hybrid assembly approach. Non-sysnonymous mutations like M12I in pmrA, A138T and A444V in pmrB and E117K in lpxD were identified. Four of the five colistin resistant A.baumannii isolates had insertion of ISAba1 upstream eptA. No mcr genes were identified.Overall, the present study highlights the diversity of colistin resistance mechanisms in A. baumannii. ISAba1-driven eptA overexpression could be responsible for colistin resistance among Indian isolates of colistin resistant A. baumannii.

microbiology↗

bioRxiv2019

Cytochrome P450 26b1-mediated specification of vestibular striola and central zones is required for transient responses in linear acceleration

Each vestibular sensory epithelia of the inner ear is divided into two zones, the striola and extrastriola in maculae of otolith organs and the central and peripheral zones in cristae of semicircular canals, that differ in morphology and physiology. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, the identities of the striolar/central zones were compromised, including abnormal innervating neurons and otoconia in otolith organs. Vestibular evoked potentials (VsEP) in response to jerk stimuli were largely absent. Vestibulo-ocular reflexes and standard motor performances such as forced swimming were unaffected, but mutants had head tremors and deficits in balance beam tests that were consistent with abnormal vestibular input. Thus, degradation of RA during embryogenesis is required for patterning highly specialized regions of the vestibular sensory epithelia that may provide acute feedback about head motion.

neuroscience↗

bioRxiv2019

Effect of motor learning on prosthetic finger controlwith an intuitive myoelectric decoder

Machine learning-based myoelectric control is regarded as an intuitive paradigm, because of the mapping it creates between muscle co-activation patterns and prosthesis movements that aims to simulate the physiological pathways found in the human arm. Despite that, there has been evidence that closed-loop interaction with a classification-based interface results in user adaptation, which leads to performance improvement with experience. Recently, there has been a focus shift towards continuous prosthesis control, yet little is known about whether and how user adaptation affects myoelectric control performance in dexterous, intuitive tasks. We investigate the effect of short-term adaptation with independent finger position control by conducting real-time experiments with 10 able-bodied and two transradial amputee subjects. We demonstrate that despite using an intuitive decoder, experience leads to significant improvements in performance. We argue that this is due to the lack of an utterly natural control scheme, which is mainly caused by differences in the anatomy of human and artificial hands, movement intent decoding inaccuracies, and lack of proprioception. Finally, we extend previous work in classification-based and wrist continuous control by verifying that offline analyses cannot reliably predict real-time performance, thereby reiterating the importance of validating myoelectric control algorithms with real-time experiments.

bioengineering↗

bioRxiv2019

Multi-grip classification-based prosthesis control with two sensors

In the field of upper-limb myoelectric prosthesis control, the use of statistical and machine learning methods has been long proposed as a means of enabling intuitive grip selection and actuation. Recently, this paradigm has found its way toward commercial adoption. Machine learning-based prosthesis control typically relies on the use of a large number of electrodes. Here, we propose an end-to-end strategy for multi-grip, classification-based prosthesis control using only two sensors, comprising electromyography (EMG) electrodes and inertial measurement units (IMUs). We emphasize the importance of accurately estimating posterior class probabilities and rejecting predictions made with low confidence, so as to minimize the rate of unintended prosthesis activations. To that end, we propose a confidence-based error rejection strategy using grip-specific thresholds. We evaluate the efficacy of the proposed system with real-time pick and place experiments using a commercial multi-articulated prosthetic hand and involving 12 able-bodied and two transradial (i.e., below-elbow) amputee participants. Results promise the potential for deploying intuitive, classification-based multi-grip control in existing upper-limb prosthetic systems subject to small modifications.

bioengineering↗