Biology subjects

Khandelwal, N.

Publications and source records attributed to Khandelwal, N..

At least 19 recordsLinked to original sources

bioRxiv2026

Oxidized protein states define metastatic fitness in lung cancer

AbstractReactive oxygen species (ROS) are a pervasive feature of human cancers, yet the protein targets through which ROS-regulated cell states shape tumor biology remains poorly understood. Here, using cysteine chemical proteomics, we define signatures of protein states under distinct cellular ROS environments that capture protein oxidation and conformational changes. Quantifying these signatures in primary lung tumors and brain metastases revealed a surprising enrichment of oxidative states in metastasis. To determine how these states support fitness, we performed genome-wide CRISPR screens and identified the mitochondrial Complex I subunit NDUFA10 as a key oxidation-dependent vulnerability. Oxidation of NDUFA10*Cys253 supports Complex I function through a previously unrecognized nucleotide kinase activity that maintains mitochondrial DNA levels. Enforcing a reduced conformation in NDUFA10 disrupts brain metastatic colonization in vivo. These findings establish ROS regulated protein states as a functional layer of tumor fitness, providing a framework for identifying redox-dependent mechanisms that support cancer progression.

Cancer Biology↗

bioRxiv2026

Multifaceted immune resistance landscapes in human oligodendrocytes protect against cytotoxic T cells and are dysregulated in MS brain cell subsets

Multiple sclerosis (MS) is a progressive neuroinflammatory demyelinating disease of the central nervous system (CNS) that remains incurable. Autoreactive myelin-specific T cells contribute to immunopathology by directly targeting and damaging oligodendrocytes in situ. In oligodendrocytes, several immune-modulatory functions have been described that can ameliorate immune damage. However, a systematic discovery of cell-intrinsic mechanisms that protect oligodendrocytes against T cell-derived cytotoxic mechanisms has not been performed. We used human MO3.13 oligodendrocytic cells and human antigen-specific cytotoxic T cells to conduct a high-throughput (HTP) RNAi-based screen with altogether 4155 genes to identify oligodendrocyte-intrinsic immune resistance genes (IRGs). The screen revealed 133 candidate IRGs. Among them, we validated 32, which exerted a strong immuno-protective phenotype. We studied IRG expression landscapes in human brain cell subsets from postmortem brain tissues of MS and control individuals. This revealed clustered expression of IRGs in a cell-type and oligodendrocyte subset-specific manner and differential IRG expression between MS patients and controls in distinct oligodendrocyte subclusters. ChEA3 analysis revealed cell type-specific expression of transcription factors that can drive expression of respective IRGs. Explorative molecular mode of action analyses of five selected IRGs, STK11, KCNH8, ABCA2, SLC1A3 and CHRNA1 revealed that these prevented death receptor-mediated apoptosis induced by T cell-derived cytotoxic molecules. In particular, they controlled TRAIL-induced apoptosis by suppressing JNK1 activation through interfering with several upstream pathways regulating metabolic, potassium, cholesterol, glutamate and acetylcholine homeostasis. In addition, STK11, ABCA2, and CHRNA1 regulated TRAIL-R2 surface expression contributing to increased TRAIL-sensitivity whereas KCNH8 expression in oligodendrocytes inhibited secretion of inflammatory cytokines by cytotoxic T cells. Taken together, we here demonstrate the existence of multiple co-expressed IRGs in human oligodendrocytes that regulate multifaceted mechanisms of T cell resistance and are dysregulated in oligodendrocyte subsets of MS patients.

immunology↗

bioRxiv2025

Generating ecological baselines on short-grass formations or grazing lawns in Central Terai landscape

Short-grass formations or the "grazing lawns" as they are popularly called support large congregations of mammalian herbivores globally. These systems are known to be maintained by cyclic process of grazing and nutrient deposition in the soil by foraging animals. The basic ecological characteristics of these short-grass systems have extensively been studied in the African context with little understanding particularly from the Himalayan foothills in Terai. In this study, we focused on understanding the ecological baselines such as grass species associations and associated nutrient content in these grazing lawns and tall grass formations across two protected areas of the Uttar Pradesh Terai in India. Our results show that, the protected areas had relatively similar grass species composition and associated nutrient content in the short-grass formations. However, when compared with tall grass formations, the grazing lawns differed markedly in both their grass associations and thus forage quality. Therefore, the results from this study indicate the need to maintain such grazing lawn habitats within the characteristic tall-wet grasslands of the Terai. This also indicates the importance of short-grass formations in providing palatable forage to the mammalian herbivores particularly in peak dry seasons of autumn and winters.

ecology↗

bioRxiv2025

TGF-β inhibitor SB431542 suppresses coronavirus replication through multistep inhibition

The COVID-19 pandemic highlighted the critical need for broad-spectrum antivirals with high resistance barriers. Here, we demonstrate that SB431542, a selective TGF-{beta} receptor I (ALK5) inhibitor, exhibits potent antiviral activity against SARS-CoV-2 through unprecedented multitargeted mechanisms. Through comprehensive in vitro, and in silico analyses, we identified that SB431542 directly binds to SARS-CoV-2 ORF3a and disrupt its canonical function in inhibiting autophagosome-lysosome fusion. This interaction restored lysosomal acidification and normalized perinuclear LAMP-1 localization, significantly impairing virion assembly as evidenced by disrupted nucleocapsid-RNA association and reduced intracellular viral titers. Additionally, SB431542 downregulated the CLEAR network genes responsible for lysosomal biogenesis, further restricting viral egress pathways. Our temporal analyses revealed that at later infection stages (36-48 hpi), SARS-CoV-2 exploits TGF-{beta}-induced lysosomal membrane permeabilization (LMP) and apoptosis for viral release--processes effectively inhibited by SB431542 through suppression of GADD45b and BAX expression. These multiple mechanisms resulted in an exceptional EC50 of 515 nM against SARS-CoV-2. In vivo efficacy was demonstrated in embryonated chicken eggs, where SB431542 conferred dose-dependent protection against lethal infectious bronchitis virus (IBV) challenge, with a favourable therapeutic index of 34.54. Remarkably, sequential passaging of SARS-CoV-2 for 50 generations under SB431542 selection pressure failed to generate resistant variants, contrasting sharply with the rapid resistance emergence typical of direct-acting antivirals. These findings establish SB431542 as a promising broad-spectrum coronavirus inhibitor with a unique triple-mechanism approach that simultaneously targets viral entry via TGF-{beta}/Smad modulation, disrupts ORF3a-mediated lysosomal dysfunction affecting assembly, and attenuates TGF-{beta}-induced apoptosis during late-stage infection-- collectively imposing multiple selective constraints that impede escape mutation development. ImportanceThe COVID-19 pandemic highlighted the urgent need for antiviral drugs with high barriers to resistance. This study reveals that SB431542, a drug previously developed to inhibit TGF-{beta} signaling, exhibits remarkable effectiveness against SARS-CoV-2 through an unprecedented triple-mechanism approach. Unlike conventional antivirals that target a single viral component, SB431542 simultaneously disrupts viral entry, assembly, and release by binding to the viral ORF3a protein and modulating host cellular processes. Most importantly, SARS-CoV-2 failed to develop resistance against SB431542 even after 50 generations of exposure--a significant advantage over current therapeutics that quickly lose effectiveness due to viral mutations. Our findings also uncover that coronaviruses exploit both lysosomal dysfunction and programmed cell death to spread efficiently, providing new targets for therapeutic intervention. This research establishes SB431542 as a promising broad-spectrum coronavirus inhibitor and demonstrates the value of targeting host-virus interactions to overcome antiviral resistance.

microbiology↗

bioRxiv2024

Systematic Targeting of Protein Complexes with Molecular COUPLrs

Molecular glues that engage protein complexes have transformed the study of cell biology and have had a direct impact on clinical oncology. However, the identification of new glue classes and their corresponding protein complexes has remained largely serendipitous. To overcome this challenge, we report the development of molecular COUPLrs, elaborated small molecules flanked by two cysteine-reactive warheads, as well as CONNECT, an integrated chemical proteomic platform for target deconvolution. By profiling a library of molecular COUPLrs across 13 cancer cell lines, we uncovered hundreds of proteins that can be coupled together, including in some cases in mutant selective fashions. We develop an advanced COUPLr for the oncogene EML4-ALK, which engages the fusion outside of its kinase domain, restricts protein dynamics, and disrupts EML4-ALK signaling. Collectively, molecular COUPLrs substantially expand the scope of proteins that can be chemically connected, providing an unbiased approach to identify small molecules that target protein complexes.

systems biology↗

bioRxiv2023

FOXP1 regulates the development of excitatory synaptic inputs onto striatal neurons and induces phenotypic reversal with reinstatement

Long-range glutamatergic inputs from the cortex and thalamus are critical for motor and cognitive processing in the striatum. Transcription factors that orchestrate the development of these inputs are largely unknown. We investigated the role of a transcription factor and high-risk autism-associated gene, FOXP1, in the development of glutamatergic inputs onto spiny projection neurons (SPNs) in the striatum. We find that FOXP1 robustly drives the strengthening and maturation of glutamatergic input onto dopamine receptor 2-expressing SPNs (D2 SPNs) but has a comparatively milder effect on D1 SPNs. This process is cell-autonomous and is likely mediated through postnatal FOXP1 function at the postsynapse. We identified postsynaptic FOXP1-regulated transcripts as potential candidates for mediating these effects. Postnatal reinstatement of FOXP1 rescues electrophysiological deficits, reverses gene expression alterations resulting from embryonic deletion, and mitigates behavioral phenotypes. These results provide support for a possible therapeutic approach for individuals with FOXP1 syndrome.

neuroscience↗

bioRxiv2023

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap, an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF{kappa}B1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF{kappa}B1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.

systems biology↗

bioRxiv2023

p38-MAPK is prerequisite for the synthesis of SARS-CoV-2 protein

The inhibition of p38 mitogen-activated protein kinase (p38-MAPK) by small molecule chemical inhibitors was previously shown to impair severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) replication, however, mechanisms underlying antiviral activity remains unexplored. In this study, reduced growth of SARS-CoV-2 in p38- knockout Vero cells, together with enhanced viral yield in cells transfected with construct expressing p38, suggested that p38-MAPK is essential for the propagation of SARS-CoV-2. The SARS-CoV-2 was also shown to induce phosphorylation (activation) of p38, at time when transcription/translational activities are considered to be at the peak levels. Further, we demonstrated that p38 supports viral RNA/protein synthesis without affecting viral attachment, entry, and budding in the target cells. In addition, we demonstrated that long-term culture of SARS-CoV-2 in the presence of p38 inhibitor SB203580 does not easily select resistant viral mutants. In conclusion, we provide mechanistic insights on the regulation of SARS-CoV-2 replication by p38 MAPK.

microbiology↗

bioRxiv2023

Compensation between FOXP transcription factors maintains proper striatal function

Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors Foxp1 and Foxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs. Utilizing mice with a D1-SPN specific loss of Foxp1, Foxp2, or both and a combination of behavior, electrophysiology, and cell-type specific genomic analysis, loss of both genes results in impaired motor and social behavior as well as increased firing of the D1-SPNs. Differential gene expression analysis implicates genes involved in autism risk, electrophysiological properties, and neuronal development and function. Viral mediated re-expression of Foxp1 into the double knockouts was sufficient to restore electrophysiological and behavioral deficits. These data indicate complementary roles between Foxp1 and Foxp2 in the D1-SPNs.

neuroscience↗

bioRxiv2023

An extra-circadian function for human CLOCK in the neocortex

Core circadian-related proteins such as the transcription factor CLOCK are ubiquitously expressed and important for regulating molecular pathways underlying circadian rhythms. Previous work has suggested that CLOCK has evolved human neocortex-specific gene regulation and therefore may have extra-circadian functions. To test this in vivo, we generated a mouse model that recapitulates human cortical expression of CLOCK. The CLOCK humanized (HU) mice show enhanced cognitive flexibility, which is associated with the alteration in spatiotemporal expression of CLOCK. Cell type specific genomic profiling of HU mice identified upregulated genes related to dendritic growth and spine formation in excitatory neurons. Consistent with this result, we found that excitatory neurons in HU mice have increased complexity of dendritic branching and spine density, as well as a greater frequency of excitatory postsynaptic currents, suggesting an increase in neural connectivity. In contrast, CLOCK knockout in human induced pluripotent stem cell-induced neurons showed reduced complexity of dendrites and lower density of presynaptic puncta. Together, our data demonstrate that CLOCK evolved extra-circadian gains of function via altered spatiotemporal gene expression and these functions may underlie human brain specializations.

neuroscience↗

bioRxiv2022

Evaluation of the safety, immunogenicity and efficacy of a new live-attenuated lumpy skin disease vaccine in India

Lumpy skin disease (LSD) was reported for the first time in India in 2019 and since then, it has become endemic. Since a homologous (LSD-virus based) vaccine was not available in the country, goatpox virus (GPV)-based heterologous vaccine was authorized for mass immunization against LSD in cattle. This study describes the evaluation of safety, immunogenicity and efficacy of a new live-attenuated LSD vaccine developed using an Indian field strain (LSDV/India/2019/Ranchi). The virus was attenuated by continuous passage (P=50) in Vero cells. The vaccine (50th LSDV passage in Vero cells, named as Lumpi-ProVacInd) did not induce any local or systemic reaction upon its experimental inoculation in calves (n=10). At day 30 post-vaccination (pv), the vaccinated animals were shown to develop antibody- and cell-mediated immune response and exhibited complete protection upon virulent LSDV challenge. We observed a minimum Neethling response (0.018% animals; 5 out of 26940 animals) of the vaccine in field trials among 26940 animals. There was no significant reduction in the milk yield in lactating animals (n=10108), besides there was no abortion or any other reproductive disorder in the pregnant animals (n=2889). Sero-conversion was observed in 85.18% animals in the field by day 30 pv.

microbiology↗

bioRxiv2021

hnRNPA1 regulates early translation to replication switch in SARS-CoV-2 life cycle

Our study suggests that methylation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA is essential for its optimal replication in the target cells. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1, an RNA-binding protein) was shown to mediate deposition of N6-methyladenosine (m6A) in internal SARS-CoV-2 RNA. The levels of hNRNPA1 expression and extent of methylation varied, depending on the course of SARS-CoV-2 life cycle. The recruitment of eIF4E (translational initiation factor) facilitated viral RNA translation at 1 hour post infection (1 hpi). However, at 2 hpi, methylation of internal SARS-CoV-2 RNA recruited hNRNPA1 which facilitated viral RNA transcription but resulted in translational repression, a phenomenon contributing in understanding the early translation to replication switch in the viral life cycle. Besides, the abrogation of methylation also produced a defective 5 cap of viral RNA which failed to interact with eIF4E, thereby resulting in a decreased synthesis of viral proteins. To conclude, methylation of the internal and 5 cap of SARS-CoV-2 RNA was shown to regulate transcription and translation of SARS-CoV-2 in a time dependent manner. IMPORTANCERNA modifications are found in all life forms and have been linked to development, health and diseases. Our study reveals that internal SARS-CoV-2 RNA methylation (m6A) is essential for interaction with hNRNPA1 to effectively synthesize viral genome. Besides, m6A-marked RNA and hRNPA1 interaction was also shown to regulate early translation to replication switch in SARS-CoV-2 life cycle. Blocking SARS-CoV-2 RNA methylation resulted in reduced virus yield, suggesting epitranscriptomic machinery (methylation) facilitates SARS-CoV-2 replication and might represent potential target for new antiviral drugs against COVID-19.

microbiology↗

bioRxiv2020

Emetine as an antiviral agent suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E: An in vitro study

Emetine is a FDA-approved drug for the treatment of amebiasis. In the recent times we had also demonstrated the antiviral efficacy of emetine against some RNA and DNA viruses. Following emergence of the COVID-19, we further evaluated thein vitro antiviral activity of emetine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The therapeutic index of emetine was determined to be 10910.4, at a cytotoxic concentration 50 (CC50) of 1603.8 nM and effective concentration 50 (EC50) of 0.147 nM.Besides, we also demonstrated the protective efficacy of emetine against lethal challenge with infectious bronchitis virus (IBV; a chicken coronavirus) in the embryonated chicken egg infection model. Emetine treatment was shown to decrease viral RNA and protein synthesis without affecting other steps of viral life cycle such as attachment, entry and budding.In a chromatin immunoprecipitation (CHIP) assay, emetine was shown to disrupt the binding of SARS-CoV-2 RNA with eIF4E (eukaryotic translation initiation factor 4E, a cellular cap-binding protein required for initiation ofprotein translation). Further, SARS-CoV-2 was shown to exploit ERK/MNK1/eIF4E signalling pathwayfor its effective replication in the target cells. To conclude, emetine targets SARS-CoV-2 protein synthesis which is mediated via inhibiting the interaction of SARS-CoV-2 RNA with eIF4E. This is a novel mechanistic insight on the antiviral efficacy of emetine. In vitro antiviral efficacy against SARS-CoV-2 and its ability to protect chicken embryos against IBV suggests that emetine could be repurposed to treat COVID-19.

microbiology↗

bioRxiv2020

Isolation and characterization of lumpy skin disease virus from cattle in India

Lumpy skin disease (LSD) has devastating economic impact. During the last decade, LSD had spread to climatically new and previously disease-free countries, which also includes its recent emergence in the Indian subcontinent (2019). This study deals with the LSD outbreak(s) from cattle in Ranchi (India). Virus was isolated from the scabs (skin lesions) in the primary goat kidney cells. Phylogenetic analysis based on nucleotide sequencing of LSD virus (LSDV) ORF011, ORF012 and ORF036 suggested that the isolated virus (LSDV/Bos taurus-tc/India/2019/Ranchi) is closely related to Kenyan LSDV strains. Further, we adapted the isolated virus in Vero cells, an alternative cell line that was found suitable for LSDV propagation. In addition, kinetics of viral DNA synthesis and one-step growth curve analysis suggested that LSDV initiates synthesizing its genome at [~]24 hours post-infection (hpi) with a peak level at [~]96 hpi whereas evidence of progeny virus particles was observed at 36-48 hours (h) with a peak titre at [~]120 h. This study reports the first successful isolation of LSDV in India, besides describing alternative cells for virus isolation (primary goat kidney cells) and in vitro propagation (Vero cells) as well as providing some insights on LSDV life cycle. Author SummaryThis study describes the first successful isolation of LSDV in India. Nucleotide sequencing of LSDV ORF011, ORF012 and ORF036 suggested that the isolated virus is closely related to Kenyan LSDV strains. This is in accordance with the previous (only) study, thereby suggesting that a single LSDV strain is circulating in India. For the first time, we employed primary goat kidney (PGK) cells for the isolation of LSDV, where PGK cells were found more sensitive for LSDV isolation as compared to the primary lamb testicle (PLT) and primary goat testicle (PGT) cells. We also adapted the isolated virus in Vero cells and demonstrated that Vero cells are also suitable for in vitro propagation of LSDV. Besides, we also provide some insights on the LSDV life cycle.

microbiology↗

bioRxiv2020

FOXP1 negatively regulates intrinsic excitability in D2 striatal projection neurons by promoting inwardly rectifying and leak potassium currents

Heterozygous loss-of-function mutations in the transcription factor FOXP1 are strongly associated with autism. Dopamine receptor 2 expressing (D2) striatal projection neurons (SPNs) in heterozygous Foxp1 (Foxp1+/-) mice have higher intrinsic excitability. To understand the mechanisms underlying this alteration, we examined SPNs with cell-type specific homozygous Foxp1 deletion to study cell-autonomous regulation by Foxp1. As in Foxp1+/- mice, D2 SPNs had increased intrinsic excitability with homozygous Foxp1 deletion. This effect involved postnatal mechanisms. The hyperexcitability was mainly due to down-regulation of two classes of potassium currents: inwardly rectifying (KIR) and leak (KLeak). Single-cell RNA sequencing data from D2 SPNs with Foxp1 deletion indicated the down-regulation of transcripts of candidate ion channels that may underlie these currents: Kcnj2 and Kcnj4 for KIR and Kcnk2 for KLeak. This Foxp1-dependent regulation was neuron-type specific since these same currents and transcripts were either unchanged, or very little changed, in D1 SPNs with cell-specific Foxp1 deletion. Our data are consistent with a model where FOXP1 negatively regulates the excitability of D2 SPNs through KIR and KLeak by transcriptionally activating their corresponding transcripts. This, in turn, provides a novel example of how a transcription factor may regulate multiple genes to impact neuronal electrophysiological function that depends on the integration of multiple current types - and do this in a cell-specific fashion. Our findings provide initial clues to altered neuronal function and possible therapeutic strategies not only for FOXP1-associated autism but also for other autism forms associated with transcription factor dysfunction.

neuroscience↗

bioRxiv2020

Isolation and characterization of bovine herpes virus 5 (BHV5) from cattle in India

Bovine herpesvirus 1 (BHV1) and 5 (BHV5) are genetically and antigenically related alphaherpesviruses. Infection with one virus induces protective immunity against the other. However, disease associated with BHV1 and BHV5 varies significantly; whereas BHV1 infection is usually associated with rhinotracheitis and abortion, BHV5 causes encephalitis in cattle. BHV5 outbreaks are sporadic and mainly restricted to the South American countries. We report BHV5 infection for the first time from aborted cattle in India. Based on the characteristic cytopathic effects in MDBK cells, amplification of the viral genome in PCR, differential PCR for BHV1/BHV5, nucleotide sequencing and restriction endonuclease patterns, identity of the virus was confirmed as BHV5 subtype A. Serum samples from the aborted cattle strongly neutralized both BHV1 and BHV5 suggesting an active viral infection in the herd. Upon UL27, UL44 and UL54 gene-based sequence and phylogenetic analysis, the isolated virus clustered with BHV5 strains and showed highest similarity with the Brazilian BHV5 strains. Author SummaryBHV5 causes fatal meningoencephalitis that may result in a mortality rate of up to 100% in cattle. BHV5 is rarely associated with abortion and its distribution is restricted to South American countries. Only a few cases of this disease have been reported from other countries. For the first time, we provide a strong evidence of BHV5 infection from aborted cattle in India. The finding may necessitate inclusion of BHV5 test protocol in testing of semen for sexually transmitted diseases. Also, the isolated virus would be useful for developing diagnostic, prophylactic and therapeutic agents to combat BHV5 disease in the country.

microbiology↗

bioRxiv2018

Inhibitor of sarco/endoplasmic reticulum calcium-ATPase impairs paramyxovirus replication

Sarco/endoplasmic reticulum calcium-ATPase (SERCA) is a membrane bound cytosolic enzyme that is known to regulate the uptake of calcium into the sarco/endoplasmic reticulum. Herein, we demonstrate for the first time that SERCA can also regulate paramyxovirus [Peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV)] replication. Treatment of Vero cells with SERCA specific inhibitor (Thapsigargin) at a concentration that is nontoxic to the cells significantly reduced virus replication. Conversely, overexpression of SERCA rescued the inhibitory effect of Thapsigargin on virus replication. PPRV/NDV infection induced SERCA expression in Vero cells which could be blocked by Thapsigargin. With the help of time-of-addition and virus step-specific assays, it was observed that Thapsigargin specifically inhibits viral entry and subcellular localization of the viral proteins. Furthermore, NDV, but not PPRV acquired a significant resistance to Thapsigargin on long-term passage (P=70) in Vero cells. To the best of our knowledge, this is the first report describing virus supportive role of SERCA and a rare report suggesting that viruses may acquire resistance even in the presence of an inhibitor that targets a cellular factor. This study will contribute in understanding paramyxovirus replication and development of antiviral therapeutics using SERCA (host factor) as a candidate drug target.

microbiology↗

bioRxiv2018

Hippocampal knockdown of Piwil1 and Piwil2 enhances contextual fear memory in mice

The Piwi pathway is a conserved gene regulatory mechanism comprised of Piwi-like proteins and Piwi-interacting RNAs, which modulates gene expression via RNA interference and epigenetic mechanisms. The mammalian Piwi pathway has been defined by its role in transposon control during spermatogenesis, and despite an increasing number of studies demonstrating its expression in the nervous system, relatively little is known about its function in neurons or potential contribution to gene regulation in the brain. We have discovered that all three Piwi-like genes are expressed in several regions of the mouse brain, and that simultaneous knockdown of Piwil1 and Piwil2 in the adult mouse hippocampus enhances contextual fear memory without affecting generalised anxiety. Our results implicate the Piwi pathway in control of plasticity-related gene expression in the adult mammalian brain.

neuroscience↗