Biology subjects

Arora, V.

Publications and source records attributed to Arora, V..

10 recordsLinked to original sources

bioRxiv2025

Diverse haplotypes at a complex Solanum americanum locus confer resistance to Phytophthora infestans and P. capsici

Plants encounter diverse pathogens and have evolved a two-layered innate immune system to detect pathogen molecules and activate defense mechanisms that restrict infection. Most cloned plant Resistance (R) genes encode NLR immune receptors. NLR genes are often found in clusters of paralogs with sequence and copy number variation; whether these NLR clusters evolve in response to single or multiple pathogens has been unclear. We report here the isolation of a Phytophthora capsici resistance gene, Rpc2, along with a novel P. infestans resistance gene, Rpi-amr5, from two Solanum americanum accessions. These orthologous genes reside in the Rpi-amr1 cluster, which has previously been associated with resistance to P. infestans. By screening RXLR effector libraries of P. infestans and P. capsici, we identified multiple effectors recognized by both NLRs. Our findings highlight the complexity of NLR clusters and evolution driven by interactions with multiple pathogens. This work will underpin efforts to elevate resistance against Phytophthora pathogens and enhances our understanding of NLR evolution.

plant biology↗

bioRxiv2025

Diagnosing linearity along the carbon cascade in terrestrial biosphere models

Elevated carbon dioxide (eCO2) fertilises photosynthesis, driving an increase in terrestrial gross primary production (GPP). However, it is unclear how effectively increased GPP propagates along the "carbon (C) cascade" to increase net primary production (NPP) and vegetation C stocks (Cveg) in different plant compartments. Vegetation models simulate divergent C cycle projections and have been criticised for being overly photosynthesis-driven (source-driven), neglecting processes that lead to non-linear behaviour in response to the GPP increase, which may attenuate (or amplify) changes in NPP and vegetation C stocks. Here, we introduce an analytical framework to diagnose linearity (L) of the land C cycle as the ratio of relative changes in linked fluxes and pools and apply it to outputs from 16 models of the TRENDY v11 ensemble. We found widely varying patterns in L across models and for the different links. Six models showed a clear dominance of larger relative changes in NPP than in GPP in global simulations (LNPP:GPP >1 for >60% of gridcells), indicating increased carbon use efficiency under eCO2. Only three models had LNPP:GPP < 1 for >60% of gridcells. Four models showed a clear dominance of larger relative changes in steady-state Cveg than in NPP, while five models showed an opposite pattern - in both cases with a large spread of LCveg*:NPP across gridcells within models. Three models showed a larger relative increase in root C than in Cveg, while two models showed a clear dominance of the opposite pattern. Widely differing distributions of L across models and links reveal a strong influence of alternative process representations (nonlinear behaviour) in individual models. However, for all links, L deviations from 1 were roughly balanced across the model ensemble, leading to an overall linear behaviour of terrestrial C cycle representations.

ecology↗

bioRxiv2023

Kinase inhibitor-induced cell-type specific vacuole formation in the absence of canonical ATG5-dependent autophagy

Pyridinyl imidazole class p38 MAPK/{beta} (MAPK14/MAPK11) inhibitors including SB202190 have been shown to induce a cell-type specific defective autophagy response resulting in micron-scale vacuole formation, autophagy-dependent death, and tumor growth suppression in vivo. We had earlier shown that this is an off-target effect of SB202190. Here we provide evidence that the cell-type specific vacuole formation is independent of canonical autophagy pathway. While SB202190 seems to interfere with autophagic flux in many cell lines in parallel to vacuolation, autophagy-deficient DU-145 cells and CRISPR/Cas9 gene-edited ATG5 knockout A549 cells also undergo vacuolation upon SB202190 treatment. Late-endosomal GTPase RAB7 colocalizes with these compartments and RAB7 GTP-binding seems to be essential for SB202190-induced vacuolation. RAB7 is a driver of tumor progression and interfering with RAB7-positive endo/lysosomal compartments may enhance cytotoxicity. A screen for modulators of SB202190-induced vacuolation revealed molecules including multi-kinase inhibitor Sorafenib as inhibitor of vacuolation and sorafenib co-treatment enhanced the cytotoxicity of SB202190. Moreover VE-821, an ATR kinase inhibitor was found to phenocopy the cell-type specific vacuolation response of SB202190. To identify the factors determining the cell-type specificity of the vacuolation response induced by SB-compounds and VE-821, we compared the transcriptomics data from vacuole forming and non-vacuole forming cancer cell lines and identified a gene expression signature which may define sensitivity of cancer cells to these small-molecule kinase inhibitors. Further analyses using the small molecule tools and the gene signature discovered here, could reveal novel mechanisms regulating this interesting phenotype relevant to anti-cancer therapy.

cell biology↗

bioRxiv2022

Syngap1 Regulates Cortical Circuit Assembly by Controlling Membrane Excitability

Gene expression intersects with neural activity to produce cortical circuits during brain development. However, the cell biological mechanisms linking gene expression to activity-dependent cortical circuit assembly remain unclear. Here, we demonstrate in mice that a newly discovered function of the neurodevelopmental disorder gene, Syngap1, is to cell-autonomously control intrinsic membrane excitability (IME) in developing cortical glutamatergic neurons. Syngap1 regulation of IME was mechanistically linked to wiring of a cortical circuit motif required for sensory processing and behavioral action. Restoring depressed IME in Syngap1 deficient neurons through genetic targeting of hyper-functional potassium currents unleashed deficient dendritic morphogenesis in upper lamina sensory cortex pyramidal neurons. Furthermore, enhancing dendritic morphogenesis was sufficient to stimulate assembly of translaminar feed-forward excitatory circuit motifs. Thus, Syngap1 promotes excitatory circuit assembly during cortical development by maintaining IME in a range that enables trophic neuronal activity to maximize pyramidal cell somatodendritic maturation and subsequent synapse formation. HighlightsO_LISyngap1 cell-autonomously tunes cortical pyramidal neuron IME in vivo C_LIO_LISyngap1-IME is regulated in part by control of neuronal potassium currents C_LIO_LISyngap1 enhancement of IME drives dendritic maturation in pyramidal cells C_LIO_LISyngap1 tuning of IME-regulated dendritic maturation promotes circuit assembly C_LI

neuroscience↗

bioRxiv2021

Endogenous Syngap1 Alpha Splice Forms Promote Cognitive Function and Seizure Protection

Loss-of-function variants in SYNAGP1 cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. SYNGAP1 splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs. However, it remains unknown how these different splice sequences function in vivo to regulate neuronal function and behavior. Reduced expression of SynGAP-1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of 1/2 expression improved learning and increased seizure latency. Mice expressing 1-specific mutations, which disrupted SynGAP cellular functions without altering protein expression, promoted seizure, disrupted synapse plasticity, and impaired learning. These findings demonstrate that endogenous SynGAP isoforms with 1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP- expression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.

neuroscience↗

bioRxiv2021

Dual Effects of NV-CoV-2 Biomimetic Polymer: An Antiviral regimen against COVID-19

Remdesivir (RDV) is the only antiviral drug so far approved for COVID-19 therapy by the FDA. However its efficacy is limited in vivo due to its low stability in presence of plasma. This paper compared the stability of RDV encapsulated with our platform technology based polymer NV-387 (NV-CoV-2), in presence of plasma in vitro and in vivo. Furthermore, a non- clinical pharmacology studies of NV-CoV-2 (Polymer) and NV-CoV-2-R (Polymer encapsulated Remdesivir) in both NL-63 infected and uninfected rats were done. In an in vitro cell culture model experiment, antiviral activity of NV-CoV-2 and NV-CoV-2-R are also compared with RDV. The results are (i) NV-CoV-2 polymer encapsulation protects RDV from plasma- mediated catabolism in vitro and in vivo, too. (ii) Body weight measurements of the normal (uninfected) rats after administration of the test materials (NV-CoV-2, and NV-CoV-2-R) show no toxic effects on them. (iii) NL-63 infected rats body weights and their survival length were like uninfected rats after treatment with NV-CoV-2 and NV-CoV-2-R, and the efficacy as an antiviral regimen were found in the order as below: NV-CoV-2-R > NV-CoV-2 > RDV. In brief, our platform technology based NV-387-encapsulated-RDV (NV-CoV-2-R) drug has a dual effect on coronaviruses. First, NV-CoV-2 itself as an antiviral regimen. Secondly, RDV is protected from plasma-mediated degradation in transit, rendering altogether the safest and an efficient regimen against COVID-19.

pharmacology and toxicology↗

bioRxiv2021

Nanoviricides platform technology based NV-CoV-2 polymer increases the half-life of Remdesivir in vivo

So far, there are seven coronaviruses identified that infect humans and only 4 of them belong to the beta family of coronavirus (HCoV-HKU1, SARS-CoV-2, MERS-CoV and SARS-CoV). SARS family are known to cause severe respiratory disease in humans. In fact, SARS-CoV-2 infection caused a pandemic COVID-19 disease with high morbidity and mortality. Remdesivir (RDV) is the only antiviral drug so far approved for COVID-19 therapy by the FDA. However, the efficacy of RDV in vivo is limited due to its low stability in presence of plasma. This is the report of analysis of the non-clinical pharmacology study of NV-CoV-2 (Polymer) and NV-CoV-2-R (Polymer encapsulated Remdesivir) in both infected and uninfected rats with SARS-CoV-2. Detection and quantification of NV-CoV-2-R in plasma samples was done by MS-HPLC chromatography analyses of precipitated plasma samples from rat subjects. O_LINV-CoV-2-R show RDV peak in MS-HPLC chromatography, whereas only NV-CoV-2 does not show any RDV-Peak, as expected. C_LIO_LINV-CoV-2 polymer encapsulation protects RDV in vivo from plasma-mediated catabolism. C_LIO_LIBody weight measurements of the normal (uninfected) rats after administration of the test materials (NV-CoV-2, and NV-CoV-2-R) show no toxic effects on them. C_LI Our platform technology based NV-387-encapsulated-RDV (NV-CoV-2-R) drug has a dual effect on coronaviruses. First, NV-CoV-2 itself as an antiviral regimen. Secondly, RDV is protected from plasma-mediated degradation in transit, rendering altogether the safest and an efficient regimen against COVID-19.

pharmacology and toxicology↗

bioRxiv2021

Nanoviricides Platform Technology based NV-387 polymer Protects Remdesivir from Plasma-Mediated Catabolism in vitro:Importance of its increased lifetime for in vivo action

As of today seven coronaviruses were identified to infect humans, out of which only 4 of them belongs to beta family of coronavirus, like HCoV-HKU1, SARS-CoV-2, MERS-CoV and SARS-CoV. SARS family of viruses were known to cause severe respiratory disease in humans. SARS-CoV-2 infection causes pandemic COVID-19 disease with high morbidity and mortality. Remdesivir (RDV) is the only antiviral drug so far approved for Covid-19 therapy by FDA. However its efficacy is limited in vivo due to its low stability in presence of Plasma. Here we show the stability of RDV encapsulated with our platform technology based polymer NV-387 (NV-CoV-2-R), in presence of Plasma in vitro in comparison to naked RDV when incubated in plasma. The potential use of this polymer in vivo will be discussed, here.

cell biology↗

bioRxiv2021

De novo prediction of RNA-protein interactions with Graph Neural Networks

RNA-binding proteins (RBPs) are key co- and post-transcriptional regulators of gene expression, playing a crucial role in many biological processes. Experimental methods like CLIP-seq have enabled the identification of transcriptome-wide RNA-protein interactions for select proteins, however the time- and resource-intensive nature of these technologies call for the development of computational methods to complement their predictions. Here we leverage recent, large-scale CLIP-seq experiments to construct a de novo predictor of RNA-protein interactions based on graph neural networks (GNN). We show that the GNN method allows not only to predict missing links in an RNA-protein network, but to predict the entire complement of targets of previously unassayed proteins, and even to reconstruct the entire network of RNA-protein interactions in different conditions based on minimal information. Our results demonstrate the potential of modern machine learning methods to extract useful information on post-transcriptional regulation from large data sets.

bioinformatics↗

bioRxiv2020

Human SYNGAP1 Regulates the Development of Neuronal Activity by Controlling Dendritic and Synaptic Maturation

SYNGAP1 is a major genetic risk factor for global developmental delay, autism spectrum disorder, and epileptic encephalopathy. De novo loss-of-function variants in this gene cause a neurodevelopmental disorder defined by cognitive impairment, social-communication disorder, and early-onset seizures. Cell biological studies in mouse and rat neurons have shown that Syngap1 regulates developing excitatory synapse structure and function, with loss-of-function variants driving formation of larger dendritic spines and stronger glutamatergic transmission. However, studies to date have been limited to mouse and rat neurons. Therefore, it remains unknown how SYNGAP1 loss-of-function impacts the development and function of human neurons. To address this, we employed CRISPR/Cas9 technology to ablate SYNGAP1 protein expression in neurons derived from a human induced pluripotent stem cell line (hiPSC). Reducing SynGAP protein expression in developing hiPSC-derived neurons enhanced dendritic morphogenesis, leading to larger neurons compared to those derived from isogenic controls. Consistent with larger dendritic fields, we also observed a greater number of morphologically defined excitatory synapses in cultures containing these neurons. Moreover, neurons with reduced SynGAP protein had stronger excitatory synapses and expressed synaptic activity earlier in development. Finally, distributed network spiking activity appeared earlier, was substantially elevated, and exhibited greater bursting behavior in SYNGAP1 null neurons. We conclude that SYNGAP1 regulates the postmitotic maturation of human neurons made from hiPSCs, which influences how activity develops within nascent neural networks. Alterations to this fundamental neurodevelopmental process may contribute to the etiology of SYNGAP1-related disorders.

neuroscience↗