Biology subjects

Chaudhary, A.

Publications and source records attributed to Chaudhary, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Pan-Coronavirus Protease Engagement and Differentiated Pharmacology of Antiviral Candidate CMX990

COVID-19 highlighted the need for antivirals that can be rapidly deployed against both current and future coronavirus threats. CMX990 is a clinical stage coronavirus main protease (Mpro) inhibitor bearing a unique trifluoromethoxymethyl ketone warhead. Here, we broadly evaluate its pan-coronavirus target engagement, antiviral breadth, and pharmacologic differentiation. Across a reporter panel of 24 Mpro enzymes spanning alpha-, beta-, delta-, and gamma-coronaviruses, CMX990 retained robust potent activity, including against nirmatrelvir-resistant SARS-CoV-2 variants. In direct comparison, nirmatrelvir and ensitrelvir showed diminished potency against non-SARS-CoV-2 coronaviruses. Live-virus assays corroborated this breadth, with potent, selective activity against SARS-CoV-2, SARS-CoV-1, MERS-CoV, and additional human coronaviruses. Structural studies revealed a conserved covalent binding mode centered on the catalytic Cys of coronavirus Mpro. In serial-passage studies, resistance emerged only after approximately twice as many serial passages under CMX990 selection as under nirmatrelvir selection, without selecting for the canonical nirmatrelvir-resistance substitution E166V. Extracellular washout experiments revealed superior persistence of antiviral activity relative to nirmatrelvir, consistent with durable target engagement. In a murine SARS-CoV-2 infection model, once-daily CMX990 protected against weight loss and reduced lung viral titers to near baseline levels. Collectively, these findings identify CMX990 as a structurally and functionally validated pan-coronavirus protease inhibitor supporting its potential as a pandemic-ready antiviral candidate.

pharmacology and toxicology↗

bioRxiv2026

Linking sugar sensing to immunity in plants via O-glycosylation

Interaction with microbes can reprogram metabolism and alter nutrient availability in plant cells. How metabolic changes modulate immune responses remains unknown. Here, we show that sugar-sensing O-glycosylation of immune-signaling kinases mediates metabolic regulation of immunity. Under sugar-replete conditions, the MAP kinase kinases (MKK4 and MKK5), key components of pattern-triggered immunity (PTI), are glycosylated with O-GlcNAc and O-fucose on their activation loops, blocking their phosphorylation by upstream kinases and thereby restricting PTI. Pathogen infection or sugar starvation reduces O-glycosylation of MKK4/5 and enhances immune signaling; these effects are reversed by GDP-fucose treatment, demonstrating that reduced sugar availability decreases O-fucosylation and enhances immune signaling in infected cells. Chemical inhibition of O-fucosylation enhances immunity and pathogen resistance in both Arabidopsis and tomato. Our findings establish O-glycosylation of MKKs as a metabolic rheostat that fine-tunes immune responses according to sugar availability during plant-microbe interactions, providing a new strategy for improving crop health.

plant biology↗

bioRxiv2026

Rapid Isolation and Genomic Characterization of Sewage-Derived Bacteriophages Targeting Multidrug-Resistant Avian Pathogenic Escherichia coli in Poultry

Antimicrobial resistance (AMR) in Escherichia coli is a major threat to global poultry production, particularly for controlling colibacillosis caused by avian pathogenic E. coli (APEC). Intensive antibiotic use has accelerated the emergence of multidrug-resistant (MDR) strains, undermining treatment efficacy and facilitating zoonotic transmission of resistance genes. This study evaluated bacteriophage therapy as a targeted, antibiotic-independent strategy to control MDR E. coli in Nepalese poultry systems. Seventeen E. coli isolates were obtained from commercial broiler and local-breed chicken farms. Using the double-layer agar method, 18 lytic phages were isolated from three urban sewage samples, infecting eight isolates. Real Time PCR screening revealed extensive AMR profiles in six isolates; one broiler-derived strain (EcI8) harbored 30 resistance genes, including carbapenemases, ESBLs, aminoglycoside, quinolone, and last-resort antibiotic determinants associated with class 1 and 3 integrons. Purified phages were whole-genome sequenced and all of them belonged to the genera Tequatrovirus, Phapecoctavirus, Vequintavirus, and Gamaleyavirus--lineages previously used in veterinary and human phage therapy. Several exhibited broad host ranges (up to seven isolates) and lacked detectable virulence or resistance genes; they also encoded potent lytic enzymes, including endolysins, holins, spanins, and transglycosylases. Notably, one Phapecoctavirus (PG7) showed close similarity to established APEC-infecting phages. These findings demonstrate that sewage can be a readily accessible source of safe, therapeutically relevant phages targeting highly resistant poultry E. coli. Phage cocktails and derived enzybiotics delivered through drinking water or feed offer a scalable alternative for preventing and treating colibacillosis, reducing antibiotic dependence, and mitigating zoonotic AMR risks. This study establishes a rapid, reproducible pipeline for local phage isolation and genomic validation, supporting field deployment of tailored phage-based interventions in resource-limited poultry systems.

microbiology↗

bioRxiv2025

Brassinosteroids promote sugar synthesis by inhibiting BIN2 phosphorylation of phosphoenolpyruvate carboxykinase

Sugar is both an essential energy source and the major substrate for cell wall biosynthesis during plant growth, yet how growth-promoting hormones regulate sugar synthesis remains unclear. Here, we show that the brassinosteroids (BRs) promote gluconeogenic and photosynthetic sugar synthesis by activating phosphoenolpyruvate carboxykinase (PCK), which catalyzes the conversion of oxaloacetate to phosphoenolpyruvate, a central step in primary metabolism. Arabidopsis BR-deficient mutants display reduced PCK1 activity and elevated phosphorylation at conserved Ser-62 and Thr-66 residues. BR treatment induces PCK1 dephosphorylation and activation, whereas the GSK3-like kinase BIN2 phosphorylates these sites, altering quaternary structure and inhibiting PCK1. Phospho-blocking mutations of Ser-62/Thr-66 confer BR-independent PCK1 activity and enhance seedling growth, while phosphomimetic mutations reduce PCK1 activity and impair seedling growth and establishment. BR also promotes PCK dephosphorylation and activation in photosynthetic leaves of maize and sorghum. Our study demonstrates that BR regulates primary metabolism via GSK3/BIN2-mediated phosphorylation of PCK, thereby promoting gluconeogenesis and photosynthesis.

plant biology↗

bioRxiv2025

Divergent effects of a Treg selective IL-2 mutein on Influenza-specific T cell responses

Enhancing regulatory T cell (Treg) function offers a compelling therapeutic strategy for autoimmune disease. Engineered IL-2 muteins selectively expand functional Tregs with minimal impact on other immune cells, but their potential to compromise antiviral immunity remains largely unexplored. Here, we used a murine model of Influenza A virus (Flu) infection to determine how IL-2 mutein shapes T cell responses to respiratory virus infection. IL-2 mutein administration prior to infection suppressed Flu-specific (Flu-sp) CD8 T cell responses and altered their localization and phenotype within the lungs, without affecting bystander CD8 T cells. This suppression correlated with reduced antigen presentation molecule expression on conventional dendritic cells (cDCs) early after infection but did not impact Flu-sp CD8 T cell priming. In contrast, administering IL-2 mutein during infection exacerbated disease and drove CD25-dependent expansion of Flu-sp CD8 T cells. Despite these opposing effects on effector responses, Fc.Mut24-treated mice generated robust antibody responses and protective T cell memory which were maintained for at least 170 days. These findings reveal that Fc.Mut24 has temporally distinct effects on antiviral immunity, dampening early effector responses when given before infection, but enhancing effector expansion and disease severity when delivered during infection. Our results provide critical context for the therapeutic application of IL-2 muteins and highlight the importance of treatment timing in balancing immune modulation with protective immunity.

immunology↗

bioRxiv2025

Identification of HIV Tat and NF-κB binding proteins associated with semen-derived extracellular vesicles

Semen-derived extracellular vesicles (SEVs) have been shown to inhibit transactivation of the long terminal repeat (LTR) in human immunodeficiency virus type 1 (HIV-1, or HIV) and, hence, viral replication by blocking the interaction of the viruss transcriptional activator Tat and host transcription factors NF-{kappa}B and Sp1. The ability of SEVs to regulate the activities of transcription factors suggests that SEVs may contain transcription activators and repressors. Here, we identified host proteins in human SEVs that interacted with the Tat and NF-{kappa}B subunit p65. Integrative network and pathway enrichment analyses of these complexes revealed associations with an array of biological functions regulating genome transcription. In particular, several proteins in SEVs could bind to both Tat and NF-{kappa}B: the scaffolding and cell signaling regulatory protein AKAP9, the G protein signaling regulator ARHGEF28, the small nuclear RNA processor INTS1, the epigenetic reader BRD2, and the transcription elongation inhibitor NELFB. NF-{kappa}B p65-bound NELFB also interacted with HEXIM1, another transcription elongation inhibitor, suggesting that SEVs may inhibit HIV propagation through networks of transcriptional regulation and repression. One Sentence SummaryProteins in vesicles shed from human semen may repress HIV by targeting transcription factors.

molecular biology↗

bioRxiv2025

Preclinical Evaluation of P4B-2412 as Phosphodiesterase 4B Radioligand for Positron Emission Tomography Imaging

Phosphodiesterase 4B (PDE4B) plays a critical role in cAMP hydrolysis and is highly expressed in brain regions associated with neuroinflammation and neurodegenerative disorders. Selective PDE4B radioligands hold significant potential for elucidating disease mechanisms and enabling target occupancy measurements. In this study, we developed [18F]P4B-2412, a novel PDE4B-selective radioligand, and evaluated its utility for PET imaging. [18F]P4B-2412 was synthesized with high radiochemical yield (27.2%), excellent radiochemical purity (99%), and favorable molar activity (66.2 {+/-} 2.5 GBq/mol). In vitro autoradiography revealed high PDE4B binding, while dynamic PET imaging demonstrated high in vivo specificity for PDE4B in rodent brain regions. Notably, [18F]P4B-2412 exhibited excellent metabolic stability in vitro and in vivo. These findings establish [18F]P4B-2412 as a promising PET probe for imaging PDE4B in vivo, offering a valuable tool for investigating neuroinflammation and advancing CNS drug development.

neuroscience↗

bioRxiv2024

Synovial fluid transcriptome dynamics in osteoarthritis progression: Implications in pathogenesis

BackgroundOsteoarthritis, a degenerative joint disease associated with various pathological manifestations in the joint including cartilage loss, alterations in subchondral bone and synovial inflammation. ObjectiveThis study aimed to elucidate the transcriptional and molecular changes in synovial fluid associated with OA progression, focusing on differential gene expression and pathway enrichment across OA grades. MethodologyPatients with different OA grades were recruited from PGIMER, Chandigarh, following the KL classification. Microarray analysis was conducted to study the transcriptional profiles in different OA grades using a fold-change (FC) cutoff of 2 and a p-value cutoff of 0.05, followed by pathway analysis performed using GSEA and STRING database. Selected genes from microarray and pathway analysis were validated using qRT-PCR. ResultsMicroarray analysis reveals distinct gene expression patterns corresponding to different OA stages (KL grade 2 to KL grade 4). Notably, the upregulation of AMTN and DKK2, alongside the downregulation of MSLN, highlighted their roles in pathological mineralization and disrupted bone remodeling in OA. Pathway enrichment analysis revealed significant changes in immune response, inflammation related pathways and cellular processes such as autophagy and programmed cell death, indicating their involvement in disease progression. Furthermore, mitochondrial dysfunction and impaired autophagy were linked to increased inflammation in advanced OA. ConclusionThese findings suggest that targeting mineralization and inflammatory pathways could offer novel therapeutic avenues for OA management.

pathology↗

bioRxiv2024

The differential effect of optogenetic serotonergic manipulation on sustained motor actions and stationary waiting for future rewards in mice

Serotonin is an essential neuromodulator that affects behavioral and cognitive functions. Previous studies have shown that activation of serotonergic neurons in the dorsal raphe nucleus (DRN) promotes patience to wait for future rewards. However, it is still unclear whether serotonergic neurons also regulate persistence to act for future rewards. Here we used optogenetic activation and inhibition of DRN serotonergic neurons to examine their effects on sustained motor actions for future rewards. We trained mice to perform stationary waiting and repeated lever-pressing tasks with variable reward delays and tested effects of optogenetic activation and inhibition of DRN serotonergic neurons on task performance. Interestingly, in the lever-pressing task, mice tolerated longer delays as they repeatedly pressed a lever than in the stationary waiting task, suggesting that lever-pressing actions may not simply be costly, but may also be subjectively rewarding. Optogenetic activation of DRN serotonergic neurons prolonged waiting in the stationary waiting task, consistent with previous studies, but it did not affect lever pressing time or numbers. While optogenetic inhibition decreased waiting, it did not affect lever pressing time or numbers. In generalized linear model analysis that incorporated the time during each session and the number of sessions, however, optogenetic activation negatively affected the number and the speed of lever pressing. These results revealed that the necessity of motor actions may increase motivation for delayed rewards and that DRN serotonergic neurons more significantly promote stationary waiting rather than persistent motor actions for future rewards.

animal behavior and cognition↗

bioRxiv2024

Global review of meta-analyses reveals key data gaps in agricultural impact studies on biodiversity in croplands

AimAgriculture depends heavily on biodiversity, yet unsustainable management practices continue to affect a wide range of organisms and ecosystems at unprecedented levels worldwide. Addressing the global challenge of biodiversity loss requires access to consolidated knowledge across management practices, spatial levels, and taxonomic groups. LocationGlobal Time period1994 to 2022 Major taxa studiedAnimals, microorganisms, plants. MethodsWe conducted a comprehensive literature review synthesising data from all meta-analyses about the impacts of agricultural management practices on biodiversity in croplands, covering field, farm, and landscape levels. From 200 retained meta-analyses, we extracted 1,885 mean effect sizes (from 69,850 comparisons between a control and treatment) assessing the impact of management practices on biodiversity, alongside characterising over 9,000 primary papers. ResultsSeven high-income countries, notably the USA, China, and Brazil dominate agricultural impact studies with fertiliser use, phytosanitary interventions and crop diversification receiving widespread attention. The focus on individual practices overshadows research at the farm and landscape level. Taxonomically, Animalia, especially arthropods, are heavily studied while taxa such as annelids and plants receive comparatively less attention. Effect sizes are predominantly calculated from averaged abundance data. Significant gaps persist in terms of studies on the effects of agricultural interventions on specific taxonomic groups (e.g. annelids, mammals) and studies analysing functional traits. Main conclusionsOur study highlights the importance of analysing the effects of combined practices to accurately reflect real-world farming contexts. While abundance metrics are common, reflecting several biodiversity facets and adopting a more balanced research approach across taxa are crucial for understanding biodiversity responses to agricultural changes and informing conservation strategies. Given the unbalanced evidence on impacts of agricultural practices on biodiversity, caution is required when utilising meta-analytical findings for informing public policies or integrating them into global assessment models like life-cycle assessments or global flux models.

ecology↗

bioRxiv2024

Screening of glucose binding proteins for the development of biosensors

Selecting suitable glucose-binding proteins (GBPs) is vital for biosensor development for medical diagnostics and quality control in the food industry. Biosensors offer advantages such as high specificity, selectivity, fast response time, continuous measurement, and cost-effectiveness. The current work utilized a combination of molecular docking, molecular dynamics (MD) simulations, and free energy calculations to develop a high-throughput bioinformatics pipeline to select GBP candidates from an extensive protein database (37,325 proteins). Using molecular docking, GBPs with good binding affinity to glucose (1,447 candidates) were virtually screened from the Protein Data Bank. MD simulations ascertained the binding dynamics of a few selected candidates. Further, steered MD (Brownian dynamics fluctuation-dissipation-theorem) was used to estimate binding free energies of the ligand-protein complex. Correlations between ligand-binding parameters obtained from longer MD simulations and binding parameters interpreted from significantly faster docking simulations were investigated. The correlation plots suggested that a combination of threshold values of the following three docking parameters: docking binding energy, binding cavity depth, and the number of hydrogen bonds between the ligand and binding site residues can be used to predict candidate GBPs reliably. Thus, a high-throughput and accurate protein selection process based on relatively faster docking simulations was proposed to screen GBPs for glucose biosensing.

bioinformatics↗

bioRxiv2023

A non-canonical role of somatic CYCLIN D/CYD-1 in oogenesis and reproductive aging, dependent on the FOXO/DAF-16 activation state

For the optimal survival of a species, an organism coordinates its reproductive decisions with the nutrient availability of its niche. Thus, nutrient-sensing pathways like insulin-IGF-1 signaling (IIS) play an important role in modulating cell division, oogenesis, and reproductive aging. Lowering of the IIS leads to the activation of the downstream FOXO transcription factor (TF) DAF-16 in Caenorhabditis elegans which promotes oocyte quality and delays reproductive aging. However, less is known about how the IIS axis responds to changes in cell cycle proteins, particularly in the somatic tissues. Here, we show a new aspect of the regulation of the germline by this nutrient- sensing axis. First, we show that the canonical G1-S cyclin, cyclin D/cyd-1, regulates reproductive aging from the uterine tissue of wild-type worms. Then, we show that knocking down cyd-1 in the uterine tissue of an IIS receptor mutant arrests oogenesis at the pachytene stage of meiosis-1 in a FOXO/DAF-16-dependent manner. We find that activated FOXO/DAF-16 destroys the somatic gonad tissues like the sheath cells, and transcriptionally prevents the spermatogenesis-to- oogenesis switch to orchestrate this arrest. Deleting FOXO/DAF-16 releases the arrest and restores the somatic gonad but leads to the production of poor-quality oocytes. Together, our study reveals the unrecognized cell non-autonomous interaction of CYD-1 and FOXO/DAF-16 in reproductive aging and the regulation of oogenesis.

developmental biology↗

bioRxiv2023

UNLOCKING ROBOTIC POTENTIAL THROUGH MODERN ORGANSEGMENTATION

AO_SCPLOWBSTRACTC_SCPLOWDeep learning has revolutionized the approach to complex data-driven problems, specifically in medical imaging, where its techniques have significantly raised efficiency in organ segmentation. The urgent need to enhance the depth and precision of organ-based classification is an essential step towards automation of medical operation and diagnostics. The research aims to investigate the effect and potential advantages transformer models have on binary semantic segmentation, the method utilized for the project. Hence, I employed the SegFormer model, for its lightweight architecture, as the primary deep learning model, alongside the Unet. A custom 2D computerized tomography (CT) scan dataset was assembled, CT-Org2D through meticulous operations. Extensive experiments showed that, in contrast to the selected models, the tasks simplicity required a redesigned Unet architecture with reduced complexity. This model yielded impressive results: Precision, Recall, and IOU scores of 0.91, 0.92, and 0.85 respectively. The research serves as a starting point, motivating further exploration, through different methodologies, to achieve even greater efficiency in organ segmentation.

bioengineering↗

bioRxiv2023

Brassinosteroid recruits FERONIA to safeguard cell expansion in Arabidopsis

Plant cell expansion is driven by turgor pressure and regulated by hormones. How plant cells avoid cell wall rupture during hormone-induced cell expansion remains a mystery. Here we show that brassinosteroid (BR), while stimulating cell elongation, promotes the plasma membrane (PM) accumulation of the receptor kinase FERONIA (FER), which monitors cell wall damage and in turn attenuates BR-induced cell elongation to prevent cell rupture. The GSK3-like kinase BIN2 phosphorylates FER, resulting in reduced FER accumulation and translocation from endoplasmic reticulum to PM. By inactivating BIN2, BR signaling promotes dephosphorylation and increases PM accumulation of FER, thereby enhancing the surveillance of cell wall integrity. Our study reveals a vital signaling circuit that coordinates hormone signaling with mechanical sensing to prevent cell bursting during hormone-induced cell expansion. One-Sentence SummaryBrassinosteroid recruits a cell wall integrity monitor to prevent growth-induced cell wall damage.

plant biology↗

bioRxiv2023

Trends in mosquito species distribution modeling: insights for vector surveillance and disease control

Species distribution modeling (SDM) has become an increasingly common approach to explore questions about ecology, geography, outbreak risk, and global change as they relate to infectious disease vectors. Here, we conducted a systematic review of the scientific literature, screening 563 abstracts and identifying 204 studies that used SDMs to produce distribution estimates for mosquito species. While the number of studies employing SDM methods has increased markedly over the past decade, the overwhelming majority used a single method (MaxEnt) and focused on human infectious disease vectors or their close relatives. The majority of regional models were developed for areas in Africa and Asia, while more localized modeling efforts were most common for North America and Europe. Findings from this study highlight gaps in taxonomic, geographic, and methodological foci of current SDM literature for mosquitoes that can guide future efforts to study the geography of mosquito-borne disease risk.

ecology↗

bioRxiv2022

Deep phylotaxonogenomic revision of the genus Xanthomonas within family Xanthomonadaceae and proposal of novel family Frateuriaceae within order Xanthomonadales

Genus Xanthomonas is primarily comprise phytopathogenic species. In a recent study by carrying out deep phyto-taxonogenomics, we reported that even the genera Xylella, Stenotrophomonas and Pseudoxanthomonas are miss-classified and belong to genus Xanthomonas. Hence to understand the breadth of the genus, we carried out deep phylo-taxonogenomics of the order Xanthomonadales. Such investigation revealed that at least four more genera belong to genus Xanthomonas with prominent being Lysobacter. Further order level deep phylo-taxonogenomics revealed two major families. One being the original family Xanthomonadaceae and other is proposed as Frateuriaceae fam. nov. as synonym of family Rhodanobacteraceae with novel genus Frateuria gen. nov.

microbiology↗

bioRxiv2022

Identification and Characterization of Probiotics Isolates from Indigenous Chicken (Gallus domesticus) of Nepal

BackgroundExcessive and irrational use of antibiotics as growth promoters in poultry has been one of key factors contributing to increased emergence of antibiotics resistant bacteria. Drug resistant infections are becoming major concerns in poultry production impacting both human and poultry health. Several alternatives for antibiotic growth promoters are being sought, and the search for effective probiotics to be used as feed additives is amongst the promising ones. Our study aimed to isolate and test potential probiotics bacteria from cloacal swabs of various indigenous chicken (Gallus domesticus) breeds from rural outskirts of the Kathmandu valley (Nepal). MethodsSelective isolation of probiotics was conducted by micro-aerophilic enrichment of sample in MRS Broth at 37{degrees}C, followed by culturing on MRS agar supplemented with 5 g/L of CaCO3. Isolated bacterial colonies producing transparent halo were selected as potential lactic acid bacteria (LAB), and tested for their antibacterial activity, phenotypic and biochemical characteristics, acidic yield, and tolerance to acid and bile. ResultsA total of 90 potential LAB were isolated from cloacal samples collected from 41 free-ranging chickens of indigenous breeds. Of these, 52 LAB isolates (57%) showed variable antibacterial activity to at least one bacterial pathogen. Of 52 LAB, 46 isolates fulfilled phenotypic and biochemical criteria of Lactobacillus spp. Of these, 37 isolates produced varying percentage yields of lactic acid, 27 isolates showed survival at pH 3.0, and 17 isolates showed survival tolerances in the presence of 0.3% and 0.5% bile salts for 24 hours. Phylogenetic analysis of 16SrDNA sequencing of LAB isolates fulfilling in vitro probiotics properties showed that 3 isolates had genetic identity of 99.38% with Lactobacillus plantarum, while one isolate was genetically similar (99.85%) with the clade of L. reuteri, L. antri and L. panis. ConclusionsOur study identified four Lactobacillus spp. strains having potential probiotics properties. Further investigations are needed to evaluate these isolates to be used as poultry probiotics feed supplement.

microbiology↗

bioRxiv2021

The Post-2020 Global Biodiversity Framework must safeguard the Tree of Life

Following our failure to fully achieve any of the 20 Aichi biodiversity targets, the future of biodiversity rests in the balance. The Convention on Biological Diversitys Post-2020 Global Biodiversity Framework (GBF) presents us with the opportunity to preserve Natures Contributions to People (NCPs) for current and future generations through conserving biodiversity and averting extinction across the Tree of Life. Here we call attention to our need to conserve the Tree of Life to maintain its benefits into the future as a key mechanism for achieving intergenerational equity. We highlight two indicators available for adoption in the post-2020 GBF to monitor our progress towards safeguarding the Tree of Life. The Phylogenetic Diversity indicator, adopted by IPBES, can be used to monitor biodiversitys capacity to maintain NCPs for future generations. The EDGE (Evolutionarily Distinct and Globally Endangered) Index monitors how well we are performing at averting the greatest losses across the Tree of Life by conserving the most distinctive species. By committing to safeguarding the Tree of Life post-2020, we can reduce biodiversity loss to preserve natures contributions to humanity now and into the future.

ecology↗