Biology subjects

Nagar, S.

Publications and source records attributed to Nagar, S..

9 recordsLinked to original sources

bioRxiv2026

Genome-resolved metagenomics reveals metabolically versatile Actinobacteria with extensive biosynthetic capacity in Hawaiian steam vents

Geothermally active lava caves and hydrothermal steam vents are chemically heterogeneous subsurface environments that harbor diverse microbial communities, yet the ecological and metabolic roles of Actinobacteria in these systems remain poorly characterized. Here, we reconstructed and analyzed 58 actinobacterial metagenome-assembled genomes (MAGs) representing five classes. Comparative genomic analyses revealed broad metabolic versatility, including pathways for amino acid biosynthesis and utilization, central carbon metabolism, fatty acid degradation, and potential chemolithotrophic processes involving carbon monoxide and sulfur compounds. The MAGs also encoded diverse carbohydrate-active enzymes and peptidases suggesting substantial capacity for complex organic carbon and protein utilization. Genome mining identified 219 biosynthetic gene clusters spanning terpenes, ribosomally synthesized and post-translationally modified peptides, nonribosomal peptide synthetases, polyketide synthases, and {beta}-lactones, highlighting extensive secondary-metabolite biosynthetic potential. Antibiotic resistance-associated genes were also detected in several MAGs, with glycopeptide-resistance-associated van genes particularly prevalent among Thermoleophilia. Sequence similarity network analysis revealed that several van-associated proteins from Thermoleophilia and UBA4738 shared substantial sequence similarity with homologs from other environmental Actinobacteria, suggesting broad conservation of these protein families. Collectively, these findings reveal metabolically and functionally diverse Actinobacteria with the genomic potential to participate in carbon and nutrient cycling, microbial interactions, secondary metabolism, and antibiotic resistance in geothermally active ecosystems.

microbiology↗

bioRxiv2025

Integrative Transcriptomics and Phytochemical Screening Reveal Pratenol B, Eriodictyol, Losbanine, and Isookanin, as Potential EGFR and HRAS Inhibitors in Indian Oral Squamous Cell Carcinoma Patients

Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer, with India contributing nearly one-third of the global cases. Management of OSCC remains difficult due to increasing risk factors, limited therapeutic options, severe side effects, and rising drug resistance. Therefore, novel and safer treatment strategies are urgently needed. This study explores the potential of phytochemicals as targeted inhibitors of key dysregulated biomarkers in Indian OSCC patients. RNA sequencing and pathway analysis revealed significant alterations in the MAPK signaling pathway, highlighting EGFR and HRAS as crucial therapeutic targets. Given the limited clinical success of existing EGFR-targeted therapies and the scarcity of HRAS inhibitors, a natural product-based approach was adopted. Molecular docking of 17,000 phytochemicals identified Pratenol B, Eriodictyol, Losbanine, and Isookanin as promising inhibitors, with Pratenol B showing dual inhibition of EGFR and HRAS. These compounds exhibited strong binding affinities, favorable pharmacokinetic profiles, high bioavailability, and low toxicity. Molecular dynamics simulations confirmed the stability of Pratenol B with both target proteins, surpassing reference inhibitors. Utilizing vast medicinal plant diversity presents a cost-effective and low-toxicity avenue for OSCC therapy. Further in vitro, in vivo, and clinical studies are warranted to validate these phytochemicals as potential therapeutics.

cancer biology↗

bioRxiv2025

SieveAI: Development of an Automated extensible and customisable drug discovery pipeline and its validation

Systematic Interaction Evaluation and Virtual Enhancement Analysis Interface (SieveAI) is an automated drug discovery pipeline developed to enhance the efficiency of virtual screening and computer-aided drug discovery processes. The molecular docking workflow encompasses acquiring, modeling, and pre-processing of molecular structure files, conducting docking with various algorithms, and subsequent analysis and interpretation of the outcomes by visualising or tabulating the results. While several open-source software tools are available to assist these operations at different steps of molecular docking, they often necessitate manual user intervention at every stage. To streamline and automate this extensive manual process and develop a comprehensive solution, we have developed an innovative, fully extensible, molecular docking pipeline SieveAI ((C)L-129927/2023). The same has been demonstrated in this manuscript. SieveAI works with a range of open-source libraries, packages, and programs to facilitate automated drug discovery using established programs and software. The package is accessible at https://miRNA.in/SieveAI.

bioinformatics↗

bioRxiv2024

The multimodal transcriptional response of denervated skeletal muscle involves alterations in cholesterol homeostasis impacting muscle size

The development and maintenance of the neuromuscular junction (NMJ) requires reciprocal signals between the nerve terminals and the multinucleated skeletal muscle fiber (myofiber). This interaction leads to highly specialized transcription in the sub-synaptic or NMJ myonuclei within mature myofibers leading to clustering of acetylcholine receptors (AChRs). Here, we utilized single-nucleus RNA sequencing (snRNA-seq) to delineate the transcriptional response of myonuclei to denervation. Through snRNA-seq on skeletal muscle from two independent mouse models of denervation, sciatic nerve transection and amyotrophic lateral sclerosis, we identify a multimodal transcriptional response of NMJ-enriched genes and an alteration in cholesterol homeostasis in both slow and fast myofibers. Gramd1, a family of genes involved in non-vesicular cholesterol transport, are enriched at the NMJ in innervated muscle and upregulated in both models of denervation by the NMJ and extrasynaptic myonuclei. In vivo gain and loss of function studies indicate that NMJ-enriched Gramd1 genes regulate myofiber sizes independent of an obvious impact on AChR clustering. We uncovered a dynamic transcriptional response of myonuclei to denervation and highlight a critical role for cholesterol transport to maintain myofiber sizes.

cell biology↗

bioRxiv2024

Integrated multi-platform approaches to gain insights into ecosystems fundamental ecology and habitat specific alterations

The increasing availability of metagenome-assembled genomes and environmental metagenomes provides unprecedented access to the metabolic potential and functional differences within the habitats. The hot spring microbiome with its diverse habitats and relatively well-characterized microbial inhabitants offers an opportunity to investigate core and habitat specific community structures at an ecosystem scale. Here, we employed tailored genome-resolved metagenomics and a novel approach that offers metagenomic overlaps to investigate the core and habitat-specific microbial diversity and multifunctionality of microbial residents of three habitats: microbial mat, sediment and water. We recovered 6% of the Ecosystem core community (ECC) in the habitats suggesting the widespread acquisition of Proteobacteria involving in the diverging trajectories of the hot spring and 72% of the Habitat specific community (HSC) in microbial mat, sediment and water habitats offers insights into specific adaptations due to extreme conditions. Strain-level resolution of metagenome-assembled genomes defined the habitat specific genotypes (HSGs) and comparative metagenomic analysis exposed ecosystem-core genotypes (ECGs). Further, the functional attributes of ECGs revealed a complete metabolic potential of nitrate reduction, ammonia assimilation and sulfate reduction. The highest cycling entropy scores (H) of N cycle suggested the enrichment of nitrogen fixing microbes commonly present in all three habitats. While specifically HSGs possessed the amino acid transport and metabolism functions in microbial mat (9.5%) and water (13%) and 19% of translation, ribosomal structure and biogenesis in sediment. Our findings provide insights into population structure and multifunctionality in the different habitats of hot spring and form specific hypotheses about habitat adaptation. The results illustrated the supremacy of using genome-resolved metagenomics and ecosystem core metagenomics postulating the differential ecological functions rather than that of explaining the presence of functions within ecosystem.

microbiology↗

bioRxiv2022

Monkey Pox Virus (MPXV): Phylogenomics, Host-Pathogen Interactome, and Mutational Cascade

While the world is still managing to recover from Covid-19 pandemic, Monkeypox awaits to bring in another global outbreak as a challenge to the entire mankind. However, Covid-19 pandemic have taught us lessons to move fast in viral genomic research to implement prevention and treatment strategies. One of the important aspects in Monkeypox virus should be immediately taken up is to gather insights of its evolutionary lineage based on the genomic studies. We have thus analysed the genome sequences of reported isolates of Monkeypox in the present study through phylogenomics. Host-pathogen interactions, mutation prevalence and evolutionary dynamics of this virus were investigated for all the documented isolates. Phylogenetic exploration revealed the clustering of strain Israel 2018 (MN 648051.1) from Clade I with the four isolates reported from the recent outbreak. An in-depth scrutiny of the host-pathogen interactome identified protein E3, serine protease inhibitor-2 (SPI-2), protein K7, and cytokine response-modifying protein B (CrmB) as the major regulatory hubs. Among these, the CrmB protein (dN/dS {approx} 1.61) was detected to be operating through positive selection. It possibly attests a selective advantage with the monkeypox virus in protecting the infected cells from antiviral responses elicited by the host. Studies also revealed that CrmB protein exhibited several mutations, the majority of which were destabilizing ({Delta}{Delta}G >0). While this study identified a large number of mutations within the newly outbreak clade, it also reflected that we need to move fast with the genomic analysis of the newly detected strains from around the world to develop better prevention and treatment methods

microbiology↗

bioRxiv2022

Genome-resolved metagenomics reveals cohesive metabolic dynamics, metal resistance genes (MRGs) and biogeochemical cycling in a hot spring system

The hot spring microbiome is a complex assemblage of micro- and geochemistry of this spring have been and macro- organisms, however, the understanding and projection of enzymatic repertoire that access earths integral ecosystem processes remains limited. The composite microbial communities drive global carbon, sulfur, oxygen, iron and nitrogen cycles and other metabolic mechanism involved in heavy metal tolerance and degradation. Interestingly, the Khirganga hot spring microbiome displayed an astounding taxonomical diversity revealed by examination of 41 high and medium qualified metagenome-assembled genomes (MAGs) from at least 12 bacterial and 2 archaeal phyla. Over 1749 genes putatively involved in crucial metabolism of elements viz. nitrogen, phosphorous, sulfur and 598 genes encoding enzymes for metals resistance from cadmium, zinc, chromium, arsenic and copper. The MAGs also possess 229 biosynthetic gene clusters dominated by bacteriocins and terpenes could be exploited in medicinal industries. Their metabolic roles found to be altering linkages in biogeochemical cycles and explored a discerned rate of carbon fixation exclusively in archaeal member Methanospirillum hungatei. Higher Pfam entropy scores in Proteobacteria members highlighting their major contribution in sequestration of ammonia, nitrate and sulfate components as electron acceptors. Through these results, we could postulate that few novel organisms within the community can conduct multiple sequential redox conversions and also considered in reducing emergent difficulties of waste water treatment plants and biotechnological applications.

microbiology↗

bioRxiv2021

Microbial ecology of sulfur biogeochemical cycling at a mesothermic hot spring atop Northern Himalayas, India

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/470874v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1dfd0d5org.highwire.dtl.DTLVardef@107811forg.highwire.dtl.DTLVardef@1ae4af6org.highwire.dtl.DTLVardef@1bb90a1_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG Sulfur Related Prokaryotes (SRP) residing in hot spring present good opportunity for exploring the limitless possibilities of integral ecosystem processes. Metagenomic analysis further expand the phylogenetic breadth of these extraordinary sulfur metabolizing microorganisms, as well a their complex metabolic networks and syntrophic interactions in environmental biosystems. Through this study, we explored and expanded the microbial genetic repertoire with focus on sulfur cycling genes through metagenomic analysis of sulfur (S) contaminated hot spring, located at the Northern Himalayas. The analysis revealed rich diversity of microbial consortia with established roles in S cycling such as Pseudomonas, Thioalkalivibrio, Desulfovibrio and Desulfobulbaceae (Proteobacteria). The major gene families inferred to be abundant across microbial mat, sediment and water were assigned to Proteobacteria as reflected from the RPKs (reads per kilobase) categorized into translation and ribosomal structure and biogenesis. Analysis of sequence similarity showed conserved pattern of both dsrAB genes (n=178) retrieved from all metagenomes while other sulfur disproportionation proteins were diverged due to different structural and chemical substrates. The diversity of sulfur oxidizing bacteria (SOB) and sulfate reducing bacteria (SRB) with conserved (r)dsrAB suggests for it to be an important adaptation for microbial fitness at this site. Here, we confirm that (i) SRBs belongs to{delta} -Proteobacteria occurring independent LGT of dsr genes to different and few novel lineages (ii) also, the oxidative and reductive dsr evolutionary time scale phylogeny, proved that the earliest (not first) dsrAB proteins belong to anaerobic Thiobacillus with other (rdsr) oxidizers. Further, the structural prediction of unassigned DsrAB proteins confirmed their relatedness with species of Desulfovibrio (TM score= 0.86; 0.98; 0.96) and Archaeoglobus fulgidus (TM score= 0.97; 0.98). We proposed that the genetic repertoire might provide the basis of studying time scale evolution and horizontal gene transfer of these genes in biogeochemical S cycling and the complementary genes could be implemented in biotechnology and bioremediation applications.

microbiology↗

bioRxiv2020

Comparative Genomic Analysis of Rapidly Evolving SARS CoV-2 Viruses Reveal Mosaic Pattern of Phylogeographical Distribution

The Coronavirus Disease-2019 (COVID-19) that started in Wuhan, China in December 2019 has spread worldwide emerging as a global pandemic. The severe respiratory pneumonia caused by the novel SARS-CoV-2 has so far claimed more than 60,000 lives and has impacted human lives worldwide. However, as the novel SARS-CoV-2 displays high transmission rates, their underlying genomic severity is required to be fully understood. We studied the complete genomes of 95 SARS-CoV-2 strains from different geographical regions worldwide to uncover the pattern of the spread of the virus. We show that there is no direct transmission pattern of the virus among neighboring countries suggesting that the outbreak is a result of travel of infected humans to different countries. We revealed unique single nucleotide polymorphisms (SNPs) in nsp13-16 (ORF1b polyprotein) and S-Protein within 10 viral isolates from the USA. These viral proteins are involved in RNA replication, indicating highly evolved viral strains circulating in the population of USA than other countries. Furthermore, we found an amino acid addition in nsp16 (mRNA cap-1 methyltransferase) of the USA isolate (MT188341) leading to shift in amino acid frame from position 2540 onwards. Through the construction of SARS-CoV-2-human interactome, we further revealed that multiple host proteins (PHB, PPP1CA, TGF-{beta}, SOCS3, STAT3, JAK1/2, SMAD3, BCL2, CAV1 & SPECC1) are manipulated by the viral proteins (nsp2, PL-PRO, N-protein, ORF7a, M-S-ORF3a complex, nsp7-nsp8-nsp9-RdRp complex) for mediating host immune evasion. Thus, the replicative machinery of SARS-CoV-2 is fast evolving to evade host challenges which need to be considered for developing effective treatment strategies.

microbiology↗