Biology subjects

Babu, P.

Publications and source records attributed to Babu, P..

7 recordsLinked to original sources

bioRxiv2026

Natural Compound-Mediated SUMOylation Rewires Host Immunity Against Klebsiella pneumoniae

Klebsiella pneumoniae is a major cause of multidrug-resistant and hypervirulent infections worldwide, highlighting the urgent need for host-directed therapeutic strategies that complement conventional antibiotics. Emerging evidence suggests that K. pneumoniae promotes intracellular persistence by suppressing host SUMOylation, a reversible post-translational modification that regulates protein stability, cellular signaling, and innate immune response. This decrease in SUMOylation perturbs NF-{kappa}B signaling, leading to dysregulation of inflammation that promotes bacterial survival, rather than effective immune clearance. Clove Bud Oil (CBO), a natural product derived from Syzygium aromaticum, has previously been shown to possess anti-virulence as well as immunomodulatory properties. In this regard, we investigated the capability of CBO to restore host SUMOylation and enhance innate immune response during infection with classical as well as hypervirulent K. pneumoniae. In macrophages, classical and hypervirulent K. pneumoniae impaired global host SUMOylation, disrupting IKK{beta}-RelA/NF-{kappa}B signalling and uncoupling inflammatory regulation from effective antimicrobial defense to facilitate intracellular persistence. CBO restored SUMOylation-dependent immune homeostasis by attenuating sustained IKK{beta} phosphorylation and degradation, thereby constraining aberrant RelA nuclear translocation, rebalancing pro-inflammatory cytokine responses, and restricting intracellular bacterial survival. These findings demonstrate that restoration of host SUMOylation acts as a key driver of the immunomodulatory activity of CBO, leading to coordinated innate immune responses and enhanced intracellular bacterial clearance. Collectively, our study identifies host SUMOylation as a critical pathway targeted during K. pneumoniae infection and highlights restoration of SUMOylation-mediated immune homeostasis as a promising host-directed therapeutic strategy against multidrug-resistant and hypervirulent K. pneumoniae.

immunology↗

bioRxiv2025

Targeting RAD52 overcomes PARP inhibitor resistance in preclinical Brca2-deficient ovarian cancer model

AbstractBRCA-mutated ovarian cancer commonly develops resistance to poly (ADP-ribose) polymerase (PARP) inhibitors. Here, we investigated the DNA repair protein RAD52 as a potential target to overcome resistance. In analysis of The Cancer Genome Atlas datasets and immunohistochemistry of tissue microarrays, elevated RAD52 expression correlated with poor overall survival in patients with high-grade serous ovarian cancers. We tested two PARP inhibitor-resistant Brca2-deficient mouse ovarian cancer models, ID8-OR and HGS2-OR. HGS2- OR cells had higher RAD52 expression than parental lines. Rad52 knockout or knockdown restored PARP inhibitor sensitivity in both models. In syngeneic mice, ID8-OR cells in which Rad52 was knocked out yielded lower tumor burden and longer overall survival than control cells. Rad52 depletion impaired single-strand annealing and homologous recombination and led to accumulation of DNA double-strand breaks after PARP inhibitor treatment. RNA sequencing demonstrated that PARP inhibitor treatment induced Polq expression in Brca2- and Rad52-deficient cells, suggesting a switch to microhomology-mediated end joining. Finally, the RAD52 inhibitor D-I03 synergized with a PARP inhibitor to reduce cell viability and tumor burden and prolong survival. Collectively, our findings establish RAD52 as a promising therapeutic target to overcome PARP inhibitor resistance in BRCA2-mutated ovarian cancer and offer mechanistic insights to inform future clinical strategies.

cancer biology↗

bioRxiv2025

A NEST-based framework unlocks massively parallel simulation of networks of multicompartment neurons with customizable subcellular dynamics.

While the implementation of learning and memory in the brain is governed in large part by subcellular mechanims in the dendrites of neurons, large-scale network simulations featuring such processes remain challenging to achieve. This can be attributed to a lack of appropriate software tools, as neuroscientific simulation software focuses on the one hand on highly detailed models, and on the other hand on massive networks featuring point-neurons. Here, we fill this gap by implementing a framework for the massively parallel simulation of simplified dendrite models with customizable subcellular dynamics. To achieve this, we leverage the NEural Simulation Tool (NEST), the neuroscientific reference with respect to efficient massively parallel simulations of point neuron networks. By co-opting the already existing model descriptions language NESTML, we generate C++ code implementing user-configurable subcellular dynamics. Through benchmarking and profiling, we show that the generated models run efficiently, leading to scalable NEST network simulations. We demonstrate relevant functionalities by showing that a key sensory computation - the association of top-down context arriving at distal dendrites in layer 1 and feedforward sensory input arriving perisomatically - can be achieved in a single shot fashion through apical calcium dynamics. Our work thus unlocks the study of how dendritic processes shape learning, and in particular of how brain-wide communication through long-range, layer 1-targetting connections steers perisomatic plasticity.

neuroscience↗

bioRxiv2022

Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies

Reactivation of fetal hemoglobin (HbF) is the commonly adapted strategy to ameliorate {beta}-hemoglobinopathies. However, the continued production of defective adult hemoglobin (HbA) limits the HbF tetramer production affecting the therapeutic benefits. Here, we tested various deletional hereditary persistence of fetal hemoglobin (HPFH) mutations and identified a 11 kb sequence, encompassing Putative Repressor Region (PRR) to {beta}-globin Exon-1 ({beta}E1), as the core deletion that ablates HbA and exhibit superior production of HbF compared to HPFH or other well-established targets. The PRR-{beta}E1 edited hematopoietic stem and progenitor cells (HSPCs) retained engraftment potential to repopulate for long-term hematopoiesis in immunocompromised mice generating HbF+ cells in vivo. Importantly, the editing induces therapeutically relevant levels of HbF to reverse the phenotypes of both sickle cell disease and {beta}-thalassemia major. These results indicate that the PRR-{beta}E1 gene editing in patient HSPCs can potentially lead to superior therapeutic outcomes for {beta}-hemoglobinopathies gene therapy.

biochemistry↗

bioRxiv2021

miR2Trait: an integrated resource for investigating miRNA-disease associations

MicroRNAs are key components of cellular regulatory networks, and breakdown in miRNA function could lead to cascading effects culminating in pathophenotypes. A better understanding of the role of miRNAs in diseases would aid human health. Here, we have devised a method for comprehensively mapping the associations between miRNAs and diseases by merging on a common key between two curated omics databases. The resulting bidirectional resource, miR2Trait, is more detailed than earlier catalogues, uncovers new relationships, and includes analytical utilities to interrogate and extract knowledge from these datasets. The resource could aid in identifying the disease enrichment of a user-given set of miRNAs and analyzing the miRNA profile of a specified diseasome. miR2Trait is available as both a web-server (https://sas.sastra.edu/pymir18) and an open-source command-line interface (https://github.com/miR2Trait) under MIT license for both commercial and non-commercial use. The datasets are available for download at: https://doi.org/10.6084/m9.figshare.8288825.

bioinformatics↗

bioRxiv2021

Human milk oligosaccharides reduce murine group B Streptococcus vaginal colonization with minimal impact on the vaginal microbiota

Group B Streptococcus (GBS) colonizes the vaginal mucosa of a significant percentage of healthy women and is a leading cause of neonatal bacterial infections. Currently, pregnant women are screened in the last month of pregnancy and GBS-positive women are given antibiotics during parturition to prevent bacterial transmission to the neonate. Recently, human milk oligosaccharides (HMOs) isolated from breastmilk were found to inhibit GBS growth and biofilm formation in vitro, and women that make certain HMOs are less likely to be vaginally colonized with GBS. Using in vitro human vaginal epithelial cells and a murine vaginal colonization model, we tested the impact of HMO treatment on GBS burdens and the composition of the endogenous microbiota by 16S rRNA amplicon sequencing. HMO treatment reduced GBS vaginal burdens in vivo with minimal alterations to the vaginal microbiota. HMOs displayed potent inhibitory activity against GBS in vitro, but HMO pretreatment did not alter adherence of GBS or the probiotic Lactobacillus rhamnosus to human vaginal epithelial cells. Additionally, disruption of a putative GBS glycosyltransferase ({Delta}san_0913) rendered the bacterium largely resistant to HMO inhibition in vitro and in vivo but did not compromise its adherence, colonization, or biofilm formation in the absence of HMOs. We conclude that HMOs are a promising therapeutic bioactive to limit GBS vaginal colonization with minimal impacts on the vaginal microenvironment. IMPORTANCEDuring pregnancy, GBS ascension into the uterus can cause fetal infection or preterm birth. Additionally, GBS exposure during labor creates a risk of serious disease in the vulnerable newborn and mother postpartum. Current recommended prophylaxis consists of administering broad-spectrum antibiotics to GBS-positive mothers during labor. Although antibiotics have significantly reduced GBS neonatal disease, there are several unintended consequences including altered neonatal gut bacteria and increased risk for other types of infection. Innovative preventions displaying more targeted antimicrobial activity, while leaving the maternal microbiota intact, are thus appealing. Using a mouse model, we found that human milk oligosaccharides (HMOs) reduce GBS burdens without perturbing the vaginal microbiota. We conclude that HMOs are a promising alternative to antibiotics to reduce GBS neonatal disease.

microbiology↗

bioRxiv2020

Novel Serine/Threonine-O-glycosylation with N-Acetylneuraminic acid and 3-Deoxy-D-manno-octulosonic acid by Maf glycosyltransferases

Some bacterial flagellins are O-glycosylated on surface-exposed Serine/Threonine residues with nonulosonic acids such as pseudaminic acid, legionaminic acid, and their derivatives by flagellin nonulosonic acid glycosyltransferases, also called Motility associated factors (Maf). We report here two new glycosidic linkages previously unknown in any organism, Serine/Threonine-O-linked N-Acetylneuraminic acid (Ser/Thr-O-Neu5Ac) and Serine/Threonine-O-linked 3-Deoxy-D-manno-octulosonic acid (Ser/Thr-O-KDO), both catalysed by Geobacillus kaustophilus Maf (putative flagellin sialyltransferase) and Clostridium botulinum Maf (putative flagellin legionaminic acid transferase). We identified these novel glycosidic linkages in recombinant G. kaustophilus and C. botulinum flagellins that were co-expressed with their cognate recombinant Maf protein in Escherichia coli strains producing the appropriate nucleotide sugar glycosyl donor. The glycosylation of G. kaustophilus flagellin with KDO, and that of C. botulinum flagellin with Neu5Ac and KDO indicates that Maf glycosyltransferases display donor substrate promiscuity. Maf glycosyltransferases have the potential to radically expand the scope of neoglycopeptide synthesis and posttranslational protein engineering. Significance StatementGlycosylation, the modification of proteins with sugars, is one of the most common post-translational modifications observed in proteins. While glycosylation is versatile, the most common forms of glycosylation are N-glycosylation, where the N atom of Asparagine is modified with a glycan, and O-glycosylation where the O atom of serine or threonine residues is modified with a glycan. Here, we report a novel type of O-glycosylation in the bacterial flagellin proteins of two Gram-positive bacteria, Geobacillus kaustophilus and Clostridium botulinum. We demonstrate for the first time that the enzyme flagellin Maf glycosyltransferase is capable of transferring the monosaccharides, N-acetylneuraminic acid and 3-Deoxy-D-manno-octulosonic acid, on to serine and threonine residues of these proteins.

molecular biology↗