Biology subjects

Arun, A.

Publications and source records attributed to Arun, A..

10 recordsLinked to original sources

bioRxiv2026

RePurpose: An LLM-Assisted, Source-Traceable Drug Repurposing Tool with Retrospective Validation on Clemastine in Multiple Sclerosis

Summary Thus far, evidence for drug repurposing is contained in target-, drug-, trial-, and literature-based data sources that are challenging to synthesize for non-specialists. Here, we introduce RePurpose, a web-based tool that takes as input a topic written in plain language and returns candidate drugs built from data in Open Targets, ClinicalTrials.gov, UniProt, and PubMed. For queries in the form of a goal, RePurpose filters candidate drugs by whether they modulate all targets implicated in the goal in the corresponding direction. Every candidate has a source that contributes evidence: a structured database, a clinical trial, or a proposal from a large language model. An adjustable ranking adjusts the order of candidates from well-studied to less well-known candidate drugs. We retrospectively tested RePurpose with the trial drug clemastine, which was being considered as a remyelinating agent in multiple sclerosis (MS). RePurpose retrieved clemastine in each replicate of the mechanism-worded queries, but in no replicates of the disease-worded queries, and no structured query retrieved it without the language model enabled. Its ranked outputs reflected the evidence supporting clemastine but not later evidence of harm in progressive MS, which was reachable only through an on-demand literature search. Our results imply that RePurpose may be better at tracing evidence around a hypothesis than generating new hypotheses. Availability and Implementation RePurpose Pharma is freely accessible at https://www.repurposepharma.com/. For code and more information on the application, see: https://github.com/nayagamnitin-hub/RePurpose-Pharma.

pharmacology and toxicology↗

bioRxiv2026

Morpheus-3D: Structural Diversity-Guided Detection and Localization of Protein Fold Switching

Proteins that reversibly adopt multiple stable folds challenge the classical sequence-structure paradigm, yet their discovery remains limited because fold switching is difficult to detect experimentally and current computational methods fail to resolve the underlying conformationally plastic regions. Here we present Morpheus-3D, a sequence-based framework that quantifies residue-level tertiary structural diversity using entropy profiles derived from the Foldseek 3Di structural alphabet. By capturing variation in tertiary interaction environments rather than secondary structure alone, Morpheus-3D identifies fold-switching proteins while simultaneously localizing the sequence regions responsible for structural transitions. The framework outperforms existing predictors, accurately recovers experimentally characterized switching regions, generalizes to recently discovered natural and engineered fold-switching proteins absent from training, and detects conformational plasticity inaccessible to secondary-structure-based approaches. Application to 57 representative proteomes reveals that fold-switching potential is widespread but enriched in regulatory, pathogenic, and environmentally adaptive lineages. Integration with ancestral sequence reconstruction further un-covers evolutionary trajectories through which conformational plasticity emerges. To make these predictions directly accessible, we implemented Morpheus-3D as an interactive web platform (https://morpheus.slicearrow.com/), in which per-residue entropy profiles, sequence and three-dimensional structure are displayed together and respond as one, allowing predicted fold-switching regions to be mapped onto the structure and exported for downstream analysis. Morpheus-3D provides a scalable framework for discovering metamorphic proteins and investigating the origins, mechanisms, and evolution of structural plasticity directly from sequence.

biophysics↗

bioRxiv2026

A novel lipid-triggered allosteric site modulates LC3-LIR receptor binding activity

Membrane recruitment is a fundamental regulator of protein function. However, the allosteric mechanisms by which lipid binding controls protein activity remain poorly understood. In autophagy, the ubiquitin-like protein LC3 is lipid-anchored to autophagosomes, where it is essential for receptor recruitment and vesicle formation. While LC3-receptor interactions are structurally well defined, how membrane engagement governs LC3 functional dynamics has remained enigmatic. Here, we uncover that membrane binding triggers a major conformational transition in LC3, exposing functional pockets that are occluded in its cytosolic form. We demonstrate that this shift is mediated by dynamic coupling between the allosteric site (3- loop5-{beta}3-loop6) and the functional binding pockets. To conclusively test this mechanism, we utilised an ensemble-based protein design strategy guided by molecular dynamics to engineer the allosteric site. From a series of mutants, two variants emerged that stabilized LC3 conformation in either active or inactive state on the membrane. X-ray crystal structures of mutant LC3, biophysical assays, super-resolution microscopy, and TEM confirmed that the activated allosteric site mutant facilitates receptor binding and cargo capture. In contrast, the inactive variant is functionally inert on the membrane. Our work identifies a fundamental lipid-triggered allosteric site in LC3 that is critical for autophagy regulation and broader implication of membrane-dependent reprogrammable protein activities.

biophysics↗

bioRxiv2024

Hypometabolism in Autism Spectrum Disorder: Insights from Brain and Blood Transcriptomics

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by challenges in social communication, repetitive behaviors, and restricted interests. Recent research has emphasized the importance of metabolic dysfunctions in the pathophysiology of ASD. This study investigates metabolic alterations associated with ASD by analyzing transcriptomic data obtained from the prefrontal cortex (bulk tissue and single-nucleus) and data from peripheral blood mononuclear cells (PBMC). We assessed the metabolic activity of each patient based on gene expression profiles, revealing significant downregulation of vital metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation, indicative of hypometabolism. Our analysis also highlighted dysregulation in lipid, vitamin, amino acid, and heme metabolism, which may contribute to the neurodevelopmental delays associated with ASD. Cell-specific metabolic activities in the ASD brain showed altered pathways in astrocytes, oligodendrocytes, excitatory neurons, and interneurons. Furthermore, we identified critical metabolic pathways and genes from PBMC gene expression data that distinguish ASD patients from typically developing individuals. Our findings demonstrate a consistent pattern of metabolic dysfunction across brain and blood samples. This research provides a comprehensive understanding of metabolic alterations in ASD, paving the way for exploring potential therapeutic strategies targeting metabolic dysregulation.

systems biology↗

bioRxiv2023

Pneumococcal Extracellular Vesicles Mediate Horizontal Gene Transfer via the Transformation Machinery

Bacterial cells secrete extracellular vesicles (EVs), the function of which is a matter of intense investigation. Here, we show that the EVs secreted by the human pathogen Streptococcus pneumoniae (pneumococcus) are associated with bacterial DNA on their surface and can deliver this DNA to the transformation machinery of competent cells. These findings suggest that EVs contribute to gene transfer in Gram-positive bacteria, and in doing so, may promote the spread of drug resistance genes in the population. SignificanceThis work extends our understanding of horizontal gene transfer and the roles of extracellular vesicles in pneumococcus. This bacterium serves as the model for transformation, a process by which bacteria can take up naked DNA from the environment. Here we show that extracellular vesicles secreted by the pneumococcus have DNA on their surface, and that this DNA can be imported by the transformation machinery facilitating gene transfer. Understanding EV-mediated gene transfer may provide new avenues to manage the spread of antibiotic drug resistance.

microbiology↗

bioRxiv2020

Cambium-specific Transcriptome Analysis of Paulownia to Study the Molecular Impacts of Winter and Spring Seasons on Tree Growth

Paulownia (Paulownia elongata) is a fast-growing, multipurpose deciduous hardwood species that grows in a wide range of temperatures from -30 {degrees}C to 45 {degrees}C. Seasonal cues influence the secondary growth of tree stems, including cambial activity, wood chemistry, and transition to latewood formation. In this study, a de novo transcriptome approach was conducted to identify the transcripts expressed in vascular cambial tissue from senescent winter and actively growing spring seasons. Illumina paired-end sequenced cambial transcriptome generated 297,049,842 clean reads which finally yielded 61,639 annotated unigenes. Based on non- redundant protein database analyses, Paulownia cambial unigenes shared highest homology (64.8%) with Erythranthe guttata. A total of 35,471 unigenes resulted from KEGG annotation that were mapped to 128 pathways with metabolic pathways dominated among all. Additionally, DEG analysis showed that 2,688 and 7,411 genes were significantly upregulated and downregulated, respectively in spring compared to winter. Interestingly, quite a number of transcripts belonging to heat shock proteins were upregulated in spring season. RT-qPCR expression results of fifteen wood-forming candidate genes involved in hemicellulose, cellulose, lignin, auxin and cytokinin pathways showed that the hemicellulose genes (CSLC4, FUT1, AXY4, GATL1, and IRX19) were significantly upregulated in spring season tissues when compared to winter tissues. In contrast, lignin pathway genes CCR1 and CAD1 were upregulated in winter cambium. Finally, a transcriptome-wide marker analysis identified 11,338 Simple Sequence Repeat (SSRs). The AG/CT dinucleotide repeat predominately represented all SSRs. Altogether, the cambial transcriptomic analysis reported here highlights the molecular events of wood formation during winter and spring. The identification of candidate genes involved in the cambial growth provides a roadmap of wood formation in Paulownia and other trees for the seasonal growth variation.

plant biology↗

bioRxiv2020

Mosaic evolution of molecular pathways for sex pheromone communication in a butterfly

Unraveling the origin of molecular pathways underlying the evolution of adaptive traits is essential for understanding how new lineages emerge, including the relative contribution of conserved, ancestral traits, and newly evolved, derived traits. Here, we investigated the evolutionary divergence of sex pheromone communication from moths (mostly nocturnal) to butterflies (mostly diurnal) that occurred ~98 million years ago. In moths, females typically emit pheromones to attract male mates, but in butterflies pheromones and used by females for mate choice. The molecular bases of sex pheromone communication are well understood in moths, but have remained virtually unexplored in butterflies. We used a combination of transcriptomics, real time qPCR, and phylogenetics, to identify genes involved in different steps of sex pheromone communication in the butterfly Bicyclus anynana. Our results show that the biosynthesis and reception of sex pheromones relies both on moth-specific gene families (reductases) and on more ancestral insect gene families (desaturases, olfactory receptors, odorant binding proteins). Interestingly, B. anynana further appears to use what was believed to be the moth-specific neuropeptide Pheromone Biosynthesis Activating Neuropeptide (PBAN) for regulation of sex pheromone production. Altogether, our results suggest that a mosaic pattern best explains how sex pheromone communication evolved in butterflies, with some molecular components derived from moths, and others conserved from more ancient insect ancestors. This is the first large-scale analysis of the genetic pathways underlying sex pheromone communication in a butterfly.

evolutionary biology↗

bioRxiv2019

Synergistic interactions of quercetin with antibiotics against biofilm associated clinical isolates of Pseudomonas aeruginosa in vitro

Development of extreme resistance to multiple antibiotics is the major concern in infections due to biofilm forming Pseudomonas aeruginosa. The existing antibiotics have become ineffective against biofilm associated infections and hence, in this study, the combinatorial efficacy of antibiotics with a quorum sensing inhibitor (quercetin) was tested against biofilm forming P. aeruginosa isolates. The effect of drug combinations was studied by the checkerboard method. The fractional inhibitory concentration index (FICI) was calculated for determining the synergistic effect. Additionally, biofilm cell viability, time-kill and live-dead assays were performed to study the combinatorial effect. MIC of quercetin against all the P. aeruginosa strains was 500 g/mL. However, quercetin at 125 g/mL showed synergistic effect with [1/2] x MIC or [1/4] x MIC of all the antibiotics against all the strains. Quercetin (125 g/mL) with [1/2] MIC of levofloxacin and tobramycin combinations were highly effective with [≥]80% killing of biofilm associated cells. Increasing the concentration to 250 g/mL with [1/2] x MIC antibiotics could completely inhibit the biofilm cell viability in quercetin combination with amikacin and tobramycin. The findings show that quercetin combinations can enhance the treatment outcome against P. aeruginosa infection and this approach may reduce antibiotic overuse and selection pressure.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC=\"FIGDIR/small/601336_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (27K):\norg.highwire.dtl.DTLVardef@1cca26dorg.highwire.dtl.DTLVardef@1bbcc0forg.highwire.dtl.DTLVardef@5216b5org.highwire.dtl.DTLVardef@150c53d_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

microbiology↗

bioRxiv2018

Convergent recruitment of life cycle regulators to direct sporophyte development in two eukaryotic supergroups

Three amino acid loop extension homeodomain transcription factors (TALE HD TFs) act as life cycle regulators in green algae and land plants. In mosses these regulators are required for the deployment of the sporophyte developmental program. We demonstrate that mutations in either of two TALE HD TF genes, OUROBOROS or SAMSARA, in the brown alga Ectocarpus result in conversion of the sporophyte generation into a gametophyte. The OUROBOROS and SAMSARA proteins heterodimerise in a similar manner to TALE HD TF life cycle regulators in the green lineage. These observations demonstrate that TALE-HD-TF-based life cycle regulation systems have an extremely ancient origin, and that these systems have been independently recruited to regulate sporophyte developmental programs in at least two different complex multicellular eukaryotic supergroups, Archaeplastida and Chromalveolata.

plant biology↗

bioRxiv2018

Type-I interferons inhibit interleukin-10 signaling and favor type 1 diabetes development in NOD mice

Destruction of insulin-producing {beta}-cells by autoreactive T lymphocytes leads to the development of type 1 diabetes. Type I interferons (TI-IFN) and interleukin-10 (IL-10) have been connected with the pathophysiology of this disease; however, their interplay in the modulation of diabetogenic T cells remains unknown. We have discovered that TI-IFN cause a selective inhibition of IL-10 signaling in effector and regulatory T cells, altering their responses. This correlates with diabetes development in NOD mice, where the inhibition is also spatially localized to T cells of pancreatic and mesenteric lymph nodes. IL-10 signaling inhibition is reversible and can be restored via blockade of TI-IFN/IFN-R interaction, paralleling with the resulting delay in diabetes onset and reduced severity. Overall, we propose a novel molecular link between TI-IFN and IL-10 signaling that helps better understand the complex dynamics of autoimmune diabetes development and reveals new strategies of intervention.\n\nAbbreviations

immunology↗