Biology subjects

Singh, V. P.

Publications and source records attributed to Singh, V. P..

15 recordsLinked to original sources

bioRxiv2026

Active gaze behavior organizes V1 activity in freely-moving marmosets

Human and nonhuman primates rely heavily on vision to actively explore and navigate their environment. Although primate visual cortex has been studied extensively in head-fixed animals, little is known about how the primate visual system supports natural, active vision in freely moving animals. Here, we address this gap in the primary visual cortex (V1) by leveraging a head-mounted eye-tracking system while simultaneously recording the activity of ensembles of single V1 neurons in freely moving marmosets. Our results reveal that primate neural activity is tightly driven by visual input and organized by the temporal structure of natural gaze behavior, and these gaze-related responses are largely abolished in the absence of visual input. We further show that distinct phases of gaze movement, i.e. rapid redirection (gaze shift) and subsequent stabilization (fixation), engage separable suppression and enhancement of the V1 responses. The enhancement during fixation was clearly linked to visual input. Moreover, the amplitudes of naturally-occurring gaze shifts organize RF input across successive fixations, and adaptively shapes fixation-associated enhancement. These findings define the dynamics in V1 that link natural gaze behavior and stimulus-driven responses in freely moving primates. The work opens a previously inaccessible but fundamental regime of primate vision and establishes freely moving paradigms as a foundation for understanding real-world visual processing during ethologically relevant behaviors.

neuroscience↗

bioRxiv2026

Pathology of dose dependent inocula of H5N8 avian influenza viruses in experimentally infected chicken

In the present study, we assessed the pathogenicity of H5N8 avian influenza viruses belongs to the clade 2.3.4.4b in chicken. Birds of three different dose groups, 102, 104, and 106 EID50 were used in the study. No mortality was observed in 102 EID0 group. Percent cumulative mortality of 104 and 106 EID50 group was 66.67 and 100 %, respectively. Varying duration of MDT of 3.2 and 2 days was observed in 104 and 106 EID50 group, respectively. The CID50 of virus was found to be 104.5 EID50. High no. of viral RNA copies were found both in oropharyngeal and cloacal swabs and in various organs of birds infected in 104 and 106 EID50 group. Significant gross and histological changes and presence of viral antigen in various organs were observed in 104 and 106 EID50 group. So, the study concludes that Indian HPAI, H5N8 isolates are highly pathogenic in nature to chicken by affecting most organs systemically. CID50 of this H5N8 virus indicates poor adaption in chicken and it implies poor transmission possibility of this virus for host species in field condition. Though this virus is highly pathogenic in nature as that of HPAI, H5N1 viruses, absence of endothelial staining in most organ attributes variation in replication process and pathogenesis from HPAI, H5N1 viruses. Hence, further studies need to be done to elucidate the pathobiology of this virus in various bird species. HighlightsO_LIH5N8 virus belong to the clade 2.3.4.4b, Indian isolate is highly pathogenic in nature as that of HPAIV, H5N1. C_LIO_LIThe dose inocula, 102 EID50 is noninfectious to chicken. C_LIO_LIThe dose inocula, 104 and 106 EID50 had caused significant mortality in the inoculated chicken with MDT of 2 and 3.2 days, respectively. C_LIO_LIH5N8 virus was detected with high viral titres in clocal and oral shedding and in multiple organ with the dose inocula, 104 and 106 EID50. C_LIO_LI104 and 106 EID50 of H5N8 inocula virus caused significant gross and histological changes in multiple organs and viral antigens were detected in respective organs. C_LI

microbiology↗

bioRxiv2026

Reprogramming BCMA-Targeted CAR-T Cells through γ-Secretase Modulation Blocks Antigen Shedding and Extends CAR-T Longevity

B-cell maturation antigen (BCMA) shedding by {gamma}-secretase generates soluble BCMA (sBCMA), which diminishes membrane antigen density, and limits the durability of BCMA-directed immunotherapies in multiple myeloma (MM). Here, using AI-driven diffusion modeling, we identify peptide inhibitors that selectively block {gamma}-secretase-mediated BCMA cleavage, stabilizing membrane-bound BCMA (mBCMA) without compromising cellular viability. The lead peptide, P5, suppresses sBCMA and restores mBCMA in vitro and in xenograft models. To create sustained, cell-intrinsic inhibition, we engineered Shedding Deterrent Locked-in (SHEDLOCK) CAR-T cells that locally secrete {gamma}-secretase-modulatory peptides. SHEDLOCK-1 CAR-T cells secreting P5 exhibits enhanced cytotoxicity and persistence relative to conventional CAR-T cells. Building on this, SHEDLOCK-2 CAR-T cells were generated, which secrete a modified, naturally derived peptide (nxP) that directly engages the {gamma}-secretase catalytic site, concurrently preventing BCMA shedding, and surprisingly enhancing CAR-T cell longevity by preserving telomere integrity and metabolic fitness. In MM xenograft and patient-derived models, SHEDLOCK-2 CAR-T cells demonstrate durable antitumor activity with a favorable safety profile. Together, these findings establish SHEDLOCK as a next-generation CAR-T platform and provide a strong preclinical foundation for Phase I clinical evaluation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/700575v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@3cd38aorg.highwire.dtl.DTLVardef@164167borg.highwire.dtl.DTLVardef@1ffed21org.highwire.dtl.DTLVardef@1294d06_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Investigations into genetic control of six spike traits with a focus on breeding for terminal heat stress tolerance in common wheat

To unravel the genetic architecture of six spike traits under heat stress, we used a doubled-haploid (DH) population (177 lines), developed from a cross between a heat-sensitive cultivar (PBW343) and a heat-tolerant genotype (KSG1203). This DH population and the two parents were phenotyped under timely, late, and very late sown conditions across 15 environments over three years and two locations. Best linear unbiased estimates and a high-density genetic map (5,710 SNP markers) were used for QTL mapping. A total of 51 QTL were detected in timely (17), late (10), and very late (18) sown conditions, with six common across environments with phenotypic variation explained ranging from 7.1% to 23.6%. A set of 14 stable, major QTL were validated in high-yielding DH lines and are recommended for marker-assisted recurrent selection. Several QTL co-localized with known genes responsible for important traits including grain yield (TaGW2-B1, PI1-1B). Seventy heat-responsive candidate genes associated with QTL were identified, encoding 33 proteins. A KASP marker for floret fertility QTL (QFf.ccsu-3A), and gene-based SSR markers for five key genes were developed and validated alongside Indels and SNPs. The generated genomic resources could be used in future studies and to breed heat-tolerant, high-yielding wheat varieties and germplasm. HighlightIdentified and validated stable QTL for spike traits across 15 environments, promising candidate genes for thermotolerance and spike traits, novel KASP and gene-based markers, providing genomic resources for breeding high-yielding, heat-tolerant wheat. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=153 HEIGHT=200 SRC="FIGDIR/small/662399v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@1e3cc33org.highwire.dtl.DTLVardef@734b17org.highwire.dtl.DTLVardef@146e3a5org.highwire.dtl.DTLVardef@10b9fbc_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2025

Induction of hypoxic response despite normoxic conditions associated with vascular mitochondrial dysfunction in diet induced metabolic syndrome

Reduced mitochondrial function is one of the various cellular pathologies in cardio-metabolic syndrome. Elevated asymmetric dimethyl arginine (ADMA) levels is known to induce hypoxia driven mitochondrial dysfunction in the lungs, despite normoxic conditions. This alteration is known to be caused by interleukin-4 (IL-4). In addition to asthma, IL-4 and ADMA are also known to be elevated in metabolic syndrome (MetS), but the existence of hypoxic response in arterial tissue remains elusive. Since, MetS and asthma are correlated; we explored whether hypoxia exists in vascular tissue and is associated with IL-4 and ADMA levels. To induce MetS, C57BL/6 mice were fed chow, high-fat or high-fructose diets for six months. Interestingly, MetS was associated with the induction of the hypoxic response in aortic tissue. Further, IL-4 and ADMA, which induce aberrant hypoxic response despite normoxia in the lungs, were elevated in the aorta of mice with MetS. Additionally, significant reductions in the levels of mitochondrial biogenesis factors (TFAM, PGC1) and respiratory chain complexes (Complex I and Complex IV) activities were observed in MetS mice. Mitochondrial dysfunction in the aorta of mice with MetS perturbed mitochondrial inner membrane integrity and was associated with the leakage of cytochrome c in the cytosol. These results collectively suggest that elevated levels of IL-4 and ADMA in the aorta of mice with MetS correlates with induced vascular mitochondrial dysfunction and hypoxic response.

molecular biology↗

bioRxiv2024

Explicitly Acquired Interrelations Among Mental Schema Reduces Cognitive Load and Facilitates Emergence of Novel Responses in Mice and Artificial Neural Networks.

Mammalian brain has evolved to infer from past experiences and elicit context relevant novel behavioural responses hitherto unexpressed by the animal. However, little is known about how prior knowledge influences the emergence of such responses. Remarkably, the brain not only arrives at these responses through logical inferences based on previous leanings, but also acquire new related information, without causing catastrophic interference. Mental schemas have often been proposed as the framework for this phenomenon. In this study, using mice as a model animal, we show that schematic networks not only enhance the cognitive load handling capacity (CLHC) and prevent catastrophic interference, but also facilitate the generation of novel, contextually relevant responses. Interestingly, when the animals were trained in a paradigm that did not invoke the pre-formed mental schema, we observed neither an enhancement to CLHC nor a generation of novel context relevant responses. Based on the principles of mental schemas discovered in our animal experiments, we developed a biologically plausible artificial neural network (ANN) that avoids catastrophic interference and captures the learning properties observed in our experiments. The custom architecture of this ANN enables it to generate responses similar to those of animals in novel scenarios. Significance StatementLittle is known about the role of mental schemas in preventing memory interference--a process in which overlapping or similar memories hinder the acquisition and retention of related information. In this study, we demonstrate that mental schemas enhance cognitive load handling capacity and improve the ability to solve novel but related problems. Using mice as a model, we show that the mere existence of a mental schema is not enough for improved cognitive load handling; instead, the relationship between existing and new information must be explicitly established during the learning process. Based on these findings, we developed a minimalistic artificial neural network (ANN) that effectively mimics this behaviour. These insights pave the way for developing more efficient learning and teaching strategies.

neuroscience↗

bioRxiv2024

Active vision in freely moving marmosets using head-mounted eye tracking

Our understanding of how vision functions as primates actively navigate the real-world is remarkably sparse. As most data have been limited to chaired and typically head-restrained animals, the synergistic interactions of different motor actions/plans inherent to active sensing -e.g. eyes, head, posture, movement, etc.-on visual perception are largely unknown. To address this considerable gap in knowledge, we developed an innovative wireless head-mounted eye tracking system called CEREBRO for small mammals, such as marmoset monkeys. Our system performs Chair-free Eye-Recording using Backpack mounted micROcontrollers. Because eye illumination and environment lighting change continuously in natural contexts, we developed a segmentation artificial neural network to perform robust pupil tracking in these conditions. Leveraging this innovative system to investigate active vision, we demonstrate that although freely-moving marmosets exhibit frequent compensatory eye movements equivalent to other primates, including humans, the predictability of the visual behavior (gaze) is higher when animals are freely-moving relative to when they are head-fixed. Moreover, despite increases in eye/head-motion during locomotion, gaze stabilization remains steady because of an increase in VOR gain during locomotion. These results demonstrate the efficient, dynamic visuo-motor mechanisms and related behaviors that enable stable, high-resolution foveal vision in primates as they explore the natural world. Significance StatementVision is arguably the most thoroughly understood of all neural systems in the primate brain. Yet there is little known about how vision functions in real-world contexts in which individuals freely move and explore an environment. This dearth in knowledge is largely due to the lack of technology that can accurately track eye-movements in freely-moving individuals with the speed and resolution needed to quantify primate vision. Here we developed an innovative wireless head-mounted eye-tracking system for marmosets that meets these technical needs and enabled us to quantify facts of primate vision in a manner not previously possible, including a set of discoveries that are likely to transform our understanding of this keystone system.

neuroscience↗

bioRxiv2021

Obesity impairs therapeutic efficacy of mesenchymal stem cells by inhibiting cardiolipin-dependent mitophagy and intercellular mitochondrial transfer in mouse models of airway allergic inflammation

Mesenchymal stem cell (MSC) transplantation alleviates metabolic defects in diseased recipient cells by intercellular mitochondrial transport (IMT). However, the effect of host metabolic conditions on MSCs in general, and IMT in particular, has largely remained unexplored. This study has identified a molecular pathway that primarily governs the metabolic function and IMT of MSCs. We found underlying mitochondrial dysfunction, impaired mitophagy, and reduced IMT in MSCs derived from high-fat diet (HFD)-induced obese mice (MSC-Ob). Mechanistically, MSC-Ob failed to sequester their damaged mitochondria into LC3-dependent autophagosomes due to decrease in mitochondrial cardiolipin content, which we propose as a putative mitophagy receptor for LC3 in MSCs. Functionally, MSC-Ob exhibited diminished potential to rescue metabolic deficits and cell death in stress-induced epithelial cells. In a small molecule screen, we found pyrroloquinoline quinone (PQQ) as a regulator of mitophagy and IMT. Long-term culture of MSC-Ob with PQQ (MSC-ObPQQ) restored cardiolipin content and sequestration of mitochondria to autophagosomes with concomitant activation of mitophagy. Upon co-culture, MSC-ObPQQ rescued cell death in stress-induced epithelial cells by enhancing IMT. The beneficial effect of PQQ was also evident in MSCs derived from human subjects in an in vitro model. In two independent mice models, the transplantation of MSC-ObPQQ restored IMT to airway epithelial cells, improved their mitochondrial metabolism and attenuated features of allergic airway inflammation (AAI). However, unmodulated MSC-Ob failed to do so. In summary, we uncover the molecular mechanism leading to the therapeutic decline of obese-derived MSCs and highlight the importance of pharmacological modulation of these cells for therapeutic intervention.

cell biology↗

bioRxiv2021

Artificial Intelligence uncovers carcinogenic human metabolites

The genome of a eukaryotic cell is often vulnerable to both intrinsic and extrinsic threats due to its constant exposure to a myriad of heterogeneous compounds. Despite the availability of innate DNA damage response pathways, some genomic lesions trigger cells for malignant transformation. Accurate prediction of carcinogens is an ever-challenging task due to the limited information about bona fide (non)carcinogens. We developed Metabokiller, an ensemble classifier that accurately recognizes carcinogens by quantitatively assessing their electrophilicity as well as their potential to induce proliferation, oxidative stress, genomic instability, alterations in the epigenome, and anti-apoptotic response. Concomitant with the carcinogenicity prediction, Metabokiller is fully interpretable since it reveals the contribution of the aforementioned biochemical properties in imparting carcinogenicity. Metabokiller outperforms existing best-practice methods for carcinogenicity prediction. We used Metabokiller to unravel cells endogenous metabolic threats by screening a large pool of human metabolites and predicted a subset of these metabolites that could potentially trigger malignancy in normal cells. To cross-validate Metabokiller predictions, we performed a range of functional assays using Saccharomyces cerevisiae and human cells with two Metabokiller-flagged human metabolites namely 4-Nitrocatechol and 3,4-Dihydroxyphenylacetic acid and observed high synergy between Metabokiller predictions and experimental validations.

bioinformatics↗

bioRxiv2021

Natural infection of SARS-CoV-2 delta variant in Asiatic lions (Panthera leo persica) in India

In May 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in nine Asiatic lions (Panthera leo persica) in Arignar Anna Zoological Park, Chennai, Tamil Nadu, India. Sequence and phylogenetic analysis showed that the SARS-CoV-2 viruses belong to a variant of concern (VOC, delta variant, B.1.617.2 lineage) and that these viruses clustered with B.1.617.2 lineage viruses of the same geographical region detected in the same month.

microbiology↗

bioRxiv2020

Adhatoda Vasica ameliorates cellular hypoxia dependent mitochondrial dysfunction in acute and severe asthmatic mice.

Severe asthma is a chronic airway disease that exhibits poor response to conventional asthma therapies. Growing evidence suggests that elevated hypoxia increases the severity of asthmatic inflammation among patients and in model systems. In this study, we elucidate the therapeutic effects and mechanistic basis of Adhatoda Vasica (AV) aqueous extract on mouse models of acute allergic as well as severe asthma subtypes at physiological, histopathological, and molecular levels. Oral administration of AV extract attenuates the increased airway resistance and inflammation in acute allergic asthmatic mice and alleviates the molecular signatures of steroid (dexamethasone) resistance like IL-17A, KC, and HIF-1 (hypoxia inducible factor-1alpha) in severe asthmatic mice. AV inhibits HIF-1 levels through restoration of expression of its negative regulator-PHD2 (prolyl hydroxylase domain-2). Alleviation of hypoxic response mediated by AV is further confirmed in the acute and severe asthma model. AV reverses cellular hypoxia-induced mitochondrial dysfunction in human bronchial epithelial cells - evident from bioenergetic profiles and morphological analysis of mitochondria. In silico docking of AV constituents reveal higher negative binding affinity for C and O-glycosides for HIF-1, IL-6, Janus kinase 1/3, TNF- and TGF-{beta}-key players of hypoxia-inflammation. This study for the first time provides a molecular basis of action and effect of AV whole extract that is widely used in Ayurveda practice for diverse respiratory ailments. Further, through its effect on hypoxia-induced mitochondrial dysfunction, the study highlights its potential to treat severe steroid-resistant asthma. Significance StatementSevere asthma is a global health concern with a large fraction unresponsive to current treatment modalities involving corticosteroids. Recent findings suggest that elevated hypoxia has a critical role in severity of asthma. Here, we report therapeutic treatment with aqueous extract of Adhatoda Vasica (AV), an ayurvedic medicine, attenuates sever steroid insensitive asthmatic features in mice. The observed effects of AV are through inhibition of hypoxic response, both in vivo and in vitro. AV also reverses mitochondrial dysfunction, a key consequence associated with hypoxia, and asthma. This study highlights the translational potential of AV for the treatment of severe asthma and provides opportunities for its usage in other disease conditions where hypoxia is pertinent.

immunology↗

bioRxiv2019

Proteomics Analysis of Differential Expression of Lung Proteins in Response to Highly Pathogenic Avian Influenza Virus Infection in Chicken

Elucidation of molecular pathogenesis underlying virus-host interaction is important for the development of new diagnostic and therapeutic strategies against highly pathogenic avian influenza (HPAI) infection in chicken. However, chicken HPAI viral pathogenesis is not completely understood. To elucidate the intracellular signaling pathways and critical host proteins associated with influenza pathogenesis, we characterized the lung proteome of chicken infected with HPAI H5N1 virus (A/duck/India/02CA10/2011/Agartala). The chicken mass spectra data sets comprised1, 47, 451 MS scans and 19, 917 MS/MS scans. At local FDR 5% level, we identified total 3313 chicken proteins with presence of at least one unique peptide. At 12 hrs, 247 proteins are downregulated while 1754 proteins are downregulated at 48 hrs indicating that the host has succumbed to infection. There is expression of proteins of the predominant signaling pathways, such as TLR, RLR, NLR and JAK-STAT signaling. Activation of these pathways is associated with cytokine storm effect and thus may be the cause of severity of HPAI H5N1 infection in chicken. Further we identified proteins like MyD88, IKBKB, IRAK4, RELA, and MAVS involved in the critical signaling pathways and some other novel proteins(HNF4A, ELAVL1, FN1, COPS5, CUL1, BRCA1 and FYN) as main hub proteins that might play important roles in influenza pathogenesis in chicken. Taken together, we characterized the signaling pathways and the proteomic determinants responsible for disease pathogenesis in chicken infected with HPAI H5N1 virus.

immunology↗

bioRxiv2019

Three complete genome sequences of Penguin megrivirus from ornithogenic soil, Adelie penguin and Weddell seal of Antarctica

We report the complete genome sequences of Penguin megriviruses from three different sources from Antarctica namely feces of Adelie penguin, feces of Weddell seal and ornithogenic soil. Phylogenetic analysis indicates the prevalence of very similar viruses in different sources of Antarctic environment. These genome sequences aid to understand the evolution of megriviruses in Antarctic ecology and reveal their place in global megrivirus phylogeny.

microbiology↗

bioRxiv2018

The application of text mining algorithms in summarizing trends in anti-epileptic drug research

1.Content summarization is an important area of research in traditional data mining. The volume of studies published on anti-epileptic drugs (AED) has increased exponentially over the last two decades, making it an important area for the application of text mining based summarization algorithms. In the current study, we use text analytics algorithms to mine and summarize 10,000 PubMed abstracts related to anti-epileptic drugs published within the last 10 years. A Text Frequency - Inverse Document Frequency based filtering was applied to identify drugs with highest frequency of mentions within these abstracts. The US Food and Drug database was scrapped and linked to the results to quantify the most frequently mentioned modes of action and elucidate the pharmaceutical entities marketing these drugs. A sentiment analysis model was created to score the abstracts for sentiment positivity or negativity. Finally, a modified Latent Dirichlet Allocation topic model was generated to extract key topics associated with the most frequently mentioned AEDs. Results of this study provide accurate and data intensive insights on the progress of anti-epileptic drug research.

systems biology↗

bioRxiv2017

Quantitative Analysis on the role of Raffinose Synthase in Hippocampal Neurons

1A diminished level of endogenous antioxidant in cells/tissues is associated with reduced resistance to oxidative stress. Raffinose synthase (RFS), a protective molecule regulates gene expression/function by controlling reactive oxygen species (ROS) levels, which has shown to be involved in a number of degenerative diseases. We confirmed the ubiquitous expression of this antioxidant protein in both human hippocampal neuron (HNN) and mouse hippocampal (HHPC-43) cell lines by an immunoblot and reverse transcriptase PCR (RT-PCR). Using a construct of RFS protein linked to CXCR-4, the transduction domain from HPV-1 CXCR-4 protein, we showed that RFS was transduced into both HNN, as well as HHPC-43 by the means of a western blot analysis. Further we proved that the protein was biologically active, and was shown to actively reduce the oxidative stress produced by paraquat and serum depletion in both human and mouse neuronal cell lines, increasing the viability of the cells. The results suggest that the intracellular delivery of RFS using CXCR-4 can be used to lower increased levels of ROS inside the cells and hence can be further investigated as a therapeutic tool in various ROS related neurodegenerative disorders.

neuroscience↗