Biology subjects

Baliga, N.

Publications and source records attributed to Baliga, N..

5 recordsLinked to original sources

bioRxiv2026

Aging associated RNA loss impairs the dynamics of RNA and protein condensates

Altered biomolecular condensate dynamics are increasingly implicated in age-associated neurodegenerative disorders, yet the molecular principles governing these changes remain incompletely understood. Here, we demonstrate that aged cells across diverse cellular and organismal models harbor pre-formed, viscous, and persistent stress granules (SGs), which we term alt-SGs. These persistent condensates confer protection to senescent cells under fluctuating stress conditions. Comparative analyses reveal that alt-SGs exhibit elevated RNA-binding protein (RBP)-to-RNA ratios, underscoring a shift in condensate stoichiometry. By quantifying SG composition and dynamics in live cells and in vitro, we establish that RNA concentration is a key determinant of condensate material properties, molecular composition, and dissolution capacity. Importantly, aging cells display diminished absolute RNA concentrations due to reduced RNA metabolic activity. Reactivation of RNA metabolism restores RNA/RBP ratios within SGs and alleviates aging-associated phenotypes. Together, our findings highlight RNA metabolism as a central regulator of condensate stoichiometry and function, linking metabolic decline to altered phase behavior and cellular aging. Key findingsO_LIAging and senescence have Alt-SGs with increased protein/RNA Ratio C_LIO_LIAlt-SGs are persistent after stress removal in aging C_LIO_LIAging is associated with reduced total cellular RNA C_LIO_LIReactivating RNA metabolism rescues SG phenotypes C_LIO_LIAlt-SGs are protective for senescent cell C_LI

cell biology↗

bioRxiv2021

Mycobacterium abscessus biofilms produce an ECM and have a distinct mycolic acid profile

A non-tuberculous mycobacterium (NTM), Mycobacterium abscessus is an emerging opportunistic pathogen associated with difficult to treat pulmonary infections, particularly in patients suffering from cystic fibrosis. It is capable of forming biofilms in vitro that result in an increase of already high levels of antibiotic resistance in this bacterium. Evidence that M. abscessus forms biofilm-like microcolonies in patient lungs and on medical devices further implicated the need to investigate this biofilm in detail. Therefore, in this study we characterized the M. abscessus pellicular biofilm, formed on a liquid-air interface, by studying its molecular composition, and its transcriptional profile in comparison to planktonic cells. Using scanning electron micrographs and fluorescence microscopy, we showed that M. abscessus biofilms produce an extracellular matrix composed of lipids, proteins, carbohydrates and eDNA. Transcriptomic analysis of biofilms revealed an upregulation of pathways involved in the glyoxylate shunt, redox metabolism and mycolic acid biosynthesis. Genes involved in elongation and desaturation of mycolic acids were highly upregulated in biofilms and, mirroring those findings, biochemical analysis of mycolates revealed molecular changes and an increase in mycolic acid chain length. Together these results give us an insight into the complex structure of M. abscessus biofilms, the understanding of which may be adapted for clinical use in treatment of biofilm infections, including strategies for dispersing the ECM, allowing antibiotics to gain access to bacteria within the biofilm.

microbiology↗

bioRxiv2021

A single-cell based precision medicine approach using glioblastoma patient-specific models

Glioblastoma (GBM) is a heterogeneous tumor made up of cell states that evolve over time. Here, we modeled tumor evolutionary trajectories during standard-of-care treatment using multimodal single-cell analysis of a primary tumor sample, corresponding mouse xenografts subjected to standard of care therapy, and recurrent tumor at autopsy. We mined the multimodal data with single cell SYstems Genetics Network AnaLysis (scSYGNAL) to identify a network of 52 regulators that mediate treatment-induced shifts in xenograft tumor-cell states that were also reflected in recurrence. By integrating scSYGNAL-derived regulatory network information with transcription factor accessibility deviations derived from single-cell ATAC-seq data, we developed consensus networks that regulate subpopulations of primary and recurrent tumor cells. Finally, by matching targeted therapies to active regulatory networks underlying tumor evolutionary trajectories, we provide a framework for applying single-cell-based precision medicine approaches in a concurrent, neo-adjuvant, or recurrent setting. SummaryInference of mechanistic drivers of therapy-induced evolution of glioblastoma at single cell resolution using RNA-seq and ATAC-seq from patient samples and model systems undergoing standard-of-care treatment informs strategy for identification of tumor evolutionary trajectories and possible cell state-directed therapeutics.

systems biology↗

bioRxiv2019

Antibody-Recruiting Protein-Catalyzed Capture Agents to Combat Antibiotic-Resistant Bacteria

Antibiotic resistant infections are projected to cause over 10 million deaths by 2050, yet the development of new antibiotics has slowed. This points to an urgent need for methodologies for the rapid development of antibiotics against emerging drug resistant pathogens. We report on a generalizable combined computational and synthetic approach, called antibody-recruiting protein-catalyzed capture agents (AR-PCCs), to address this challenge. We applied the combinatorial PCC technology to identify macrocyclic peptide ligands against highly conserved surface protein epitopes of carbapenem-resistant Klebsiella pneumoniae, an opportunistic gram-negative pathogen with drug resistant strains. Multi-omic data combined with bioinformatic analyses identified epitopes of the highly expressed MrkA surface protein of K. pneumoniae for targeting in PCC screens. The top-performing ligand exhibited high-affinity (EC50[~]50 nM) to full-length MrkA, and selectively bound to MrkA-expressing K. pneumoniae, but not to other pathogenic bacterial species. AR-PCCs conjugated with immunogens promoted antibody recruitment to K. pneumoniae, leading to phagocytosis and phagocytic killing by macrophages. The rapid development of this highly targeted antibiotic implies that the integrated computational and synthetic toolkit described here can be used for the accelerated production of antibiotics against drug resistant bacteria.

bioengineering↗

bioRxiv2018

An essential mycolate remodeling program for mycobacterial adaptation in host cells

The success of Mycobacterium tuberculosis (MTB) stems from its ability to remain hidden from the immune system within macrophages. Here, we report a new technology (Path-seq) to sequence miniscule amounts of MTB transcripts within up to million-fold excess host RNA. Using Path-seq we have discovered a novel transcriptional program for in vivo mycobacterial cell wall remodeling when the pathogen infects alveolar macrophages in mice. We have discovered that MadR transcriptionally modulates two mycolic acid desaturases desA1/A2 to initially promote cell wall remodeling upon in vitro macrophage infection and, subsequently, reduces mycolate biosynthesis upon entering dormancy. We demonstrate that disrupting MadR program is lethal to diverse mycobacteria making this evolutionarily conserved regulator a prime antitubercular target for both early and late stages of infection.\n\nOne Sentence SummaryNovel technology (Path-seq) discovers cell wall remodeling program during Mycobacterium tuberculosis infection of macrophages

microbiology↗