Biology subjects

Muralidharan, A.

Publications and source records attributed to Muralidharan, A..

7 recordsLinked to original sources

bioRxiv2025

BC-Predict Database: A Curated Resource of Experimentally Validated Markers in Multidrug Resistance in Breast Cancer

BackgroundIn this study, we aim to develop a yearly updatable database that could predict chemotherapeutic drug resistance and overall survival probability in breast cancer patients. Existing drug sensitivity databases depend on correlation-based predictions. In our study, candidates involved in drug resistance are chosen based on cell line validation (overexpression or downregulation or inhibition of candidates) studies, curated manually. Method28,773 mRNA expression signatures from 914 breast cancer patients were extracted from cProsite. 106 of these patients had clinical information and log2 fold change information required for this study. We categorized these patients into deceased and surviving groups from TCGA. To prepare a database that can predict drug resistance and overall survival, we included mRNAs that were over-expressed in at least 80% of the breast cancer patients and mRNAs over-expressed in deceased and surviving groups. In addition, we also reported breast cancer-associated drug resistance candidates which have been reported in cell-line based studies. The database matrix preparation involved an approximate of 15000 manual searches of cell validated studies. (750 candidates x 20 drugs). The database was validated using a publicly available breast cancer patient proteomics data. ResultsOur analysis identified a list of top priority candidates associated with multidrug resistance, categorized based on their resistance to >15 drugs, 5-15 drugs, and 2-4 drugs. Analysis of patient profiles in the database revealed that the number of proteins contributing to drug resistance was high in the poor prognosis category compared to the good prognosis category. ConclusionsOur study highlights the probable gaps in breast cancer drug resistance research, as only a small subset of overexpressed mRNA candidates found in patients are studied in vitro or in vivo experiments focusing on drug resistance. We also identified candidates involved in multidrug resistance, whose role in drug resistance has not been studied in more than 15 drugs. After further validations, this will benefit the clinicians and upcoming CRISPR gene therapeutics.

cancer biology↗

bioRxiv2025

Discovery of phage defense systems through component modularity networks

Phage defense systems in bacteria exhibit high degrees of modularity, with sensing, signal transmission, and effector enzymes frequently being exchanged among phage defense gene clusters. In this study, we capitalized on this modularity to discover phage defense systems by searching for defense-associated modules in new gene contexts. This approach revealed a large and interconnected network of modular components distributed across diverse gene clusters. From over 500 candidate defense systems, we selected nine for experimental testing and validated three: Dionysus, a TerB-encoding system that disrupts early phage infection vesicle formation by Jumbo phages; Ophion, a Radical SAM-containing system that prevents the formation of the Jumbo phage nucleus; and Ambrosia, a tightly regulated RM-like system. Collectively, we demonstrate that leveraging the modular architecture of phage defense systems is an effective approach to their discovery.

microbiology↗

bioRxiv2025

Molecular basis for anti-jumbo phage immunity by AVAST Type 5

Jumbo phages protect their genomes from DNA-sensing bacterial defense systems by enclosing them within vesicles and nucleus-like compartments. Very little is known about defense systems specialized to counter these phages. Here, we show that AVAST Type 5 (Avs5) systems, part of the STAND superfamily and spanning three phylogenetic Avs5 clades, confer conserved immunity against jumbo phages. Using localization microscopy and biotin proximity labeling we demonstrate that Avs5 localizes to early infection vesicles, where it senses an essential, early expressed phage protein named JADA--Jumbophage AVAST5 Defense Activator. Recognition of phage infection triggers the Sir2-like effector domain of Avs5 across all three Avs5 clades, resulting in rapid NAD+ hydrolysis, disruption of phage nucleus formation, and arrest of infection. These findings reveal a spatially coordinated bacterial immune strategy that targets an early vulnerability in jumbo phage infection.

microbiology↗

bioRxiv2022

Accumulation of defense systems drives panphage resistance in Pseudomonas aeruginosa

Prokaryotes encode multiple distinct anti-phage defense systems in their genomes. However, the impact of carrying a multitude of defense systems on phage resistance remains unclear, especially in a clinical context. Using a collection of antibiotic-resistant clinical strains of Pseudomonas aeruginosa and a broad panel of phages, we demonstrate that defense systems contribute substantially to defining phage host range and that overall phage resistance scales with the number of defense systems in the bacterial genome. We show that many individual defense systems are specific to phage genera, and that defense systems with complementary phage specificities co-occur in P. aeruginosa genomes likely to provide benefits in phage-diverse environments. Overall, we show that phage-resistant phenotypes of P. aeruginosa with at least 19 phage defense systems exist in the populations of clinical, antibiotic-resistant P. aeruginosa strains.

microbiology↗

bioRxiv2021

Intracellular transport of electrotransferred DNA cargo is governed by coexisting ergodic and non ergodic anomalous diffusion

The ability of exogenous DNA cargo to overcome the active and viscoelastic eukaryotic cytoplasm is a principal determinant for the gene delivery efficacy. During DNA electrotransfer, DNA forms complexes with the membrane (DNA cargo) which is transported through the cytoplasm through a combination of passive diffusion and active transport. However, this process is poorly understood limiting rational optimization of DNA cargo to be delivered to different cell types. We have investigated the intracellular transport of DNA cargo (of sizes 100 bp, 250 bp and 500 bp) delivered by electrotransfer to non-cancerous and cancerous mammalian cells. We demonstrate that intracellular DNA cargo transport is governed by coexisting ergodic and non ergodic anomalous diffusion for all the tested DNA sizes and cell types. The apparent diffusion coefficient of the electrotransferred DNA cargo in the cytoplasm decreases when the DNA size is increased from 100 bp to 500 bp. Interestingly, the electrotransferred DNA cargo (500 bp) transport is strongly dependent on the cells cancer state. Intracellular electrotransferred DNA cargo transport has a higher probability of superdiffusive transport and lower probability of caging in metastatic cells compared to malignant cells followed by benign cells.

biophysics↗

bioRxiv2021

Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-CoV-2 Infection in vitro

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/432949v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@127e6c4org.highwire.dtl.DTLVardef@9f6d3aorg.highwire.dtl.DTLVardef@bbfe3borg.highwire.dtl.DTLVardef@2ffad8_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2020

A solvation induced ring puckering effect in fluorinated prolines and its inclusion in classical force-fields

Strategic incorporation of fluorinated prolines can accelerate folding and increase thermal stability of proteins. It has been suggested that this behavior emerges from puckering effects induced by fluorination of the proline ring. We use electronic structure calculations to characterize the potential energy surface (PES) along puckering coordinates for a simple dipeptide model of proline and its fluorinated derivatives. Comparison of gas phase and implicit solvent calculations shed light on the effect of solvation on electronic structure and conformational preferences of the ring. This effect is unknown in the context of prolines, however, recently reported for furanoses in carbohydrates. The PES based on implicit solvent is then utilized to construct a correction for a classical force-field. The corrected force-field accurately captures the experimental conformational equilibrium including the coupling between ring puckering and cis-trans isomerism in fluorinated prolines. This method can be extended to other rings and substituents besides fluorine.

biophysics↗