Biology subjects

Ranjan, M.

Publications and source records attributed to Ranjan, M..

6 recordsLinked to original sources

bioRxiv2025

Tissue Kallikrein 1 cleaves complement factor C3 and activates the alternative complement pathway

Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), characterized by microvascular endothelial damage and severe renal injury, negatively affects HSCT survivorship with high mortality and long-term renal morbidity. After HSCT, innate immunity and inflammation are often dysregulated. The alternative complement pathway (AP) of the innate immune system is overactivated in HSCT-TMA, but the mechanisms of its initiation are poorly described. Complement component C3 of the AP can be cleaved by proteases outside of the AP. Because mRNA expression of tissue kallikrein 1 (KLK1), an inflammatory serine protease that produces kinins, has been found to be markedly elevated in the renal endothelium of inflamed mice, we hypothesized that increased KLK1 activity during inflammation contributes to AP overactivation and endothelial injury in HSCT-TMA. We assessed AP activation, KLK1 activity, endothelial injury, and renal function in HSCT-TMA experimental models and disease settings and investigated C3 cleavage and AP activation by KLK1. We found that patients with HSCT-TMA had significantly increased AP activation and decreased KLK1 inactivation at TMA diagnosis compared to pre-HSCT. Mice challenged with HSCT-TMA triggers cyclosporine A (CsA) and lipopolysaccharide (LPS) exhibited increased AP activation, renal endothelial injury, and impaired renal function in the setting of decreased KLK1 inactivation. We further demonstrated that KLK1 cleaved AP component C3 to C3b that functionally activated the AP. Our data indicate a noncanonical mechanism for AP activation by KLK1 in settings of HSCT-TMA. Key PointsO_LITissue kallikrein (KLK1) functionally cleaves complement factor C3. C_LIO_LIReduced KLK1 inhibition is associated with activation of the alternative pathway of complement. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/674260v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@8f260aorg.highwire.dtl.DTLVardef@a6511org.highwire.dtl.DTLVardef@7160f6org.highwire.dtl.DTLVardef@194d36d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO HSCT-TMA triggers (e.g. inflammation, immunosuppression) upregulate expression of the inflammatory serine protease KLK1, which cleaves C3 to initiate AP activation and amplification, leading to renal endothelial injury. Created with BioRender.com under its Academic License Terms with Baylor College of Medicine. C_FIG

molecular biology↗

bioRxiv2023

Composition of nasopharyngeal microbiota in individuals with SARS-COV-2 infection across three COVID-19 waves in India

Multiple variants of the SARS-CoV-2 virus have been plaguing the world through successive waves of infection over the past three years. Studies by independent research groups across geographies have shown that the microbiome composition in COVID-19 patients (CP) differ from that of healthy individuals (CN). However, such observations were based on limited-sized sample-sets collected primarily from the early days of the pandemic. Here, we study the nasopharyngeal microbiota in COVID-19 patients, wherein the samples have been collected across the three COVID-19 waves witnessed in India, which were driven by different variants of concern. We also present the variations in microbiota of symptomatic vs asymptomatic COVID-19 patients. The nasopharyngeal swabs were collected from 589 subjects providing samples for diagnostics purposes at Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India. CP showed a marked shift in the microbial diversity and composition compared to CN, in a wave-dependent manner. Rickettsiaceae was the only family that was noted to be consistently depleted in CP samples across the waves. The genera Staphylococcus, Anhydrobacter, Thermus, and Aerococcus were observed to be highly abundant in the symptomatic CP patients when compared to the asymptomatic group. In general, we observed a decrease in the burden of opportunistic pathogens in the host microbiota during the later waves of infection. To our knowledge, this is the first longitudinal study which was designed to understand the relation between the evolving nature of the virus and the changes in the human nasopharyngeal microbiota. Such studies not only pave way for better understanding of the disease pathophysiology but also help gather preliminary evidence on whether interventions to the host microbiota can help in better protection or faster recovery.

microbiology↗

bioRxiv2020

Exposure of mammary cells to lipid activates gene expression changes associated with ER-negative breast cancer via chromatin remodeling.

Improved understanding of local breast biology that favors the development of estrogen receptor negative (ER-) breast cancer (BC) would foster better prevention strategies. We have previously shown that overexpression of specific lipid metabolism genes is associated with the development of ER- BC. We now report results of exposure of MCF-10A cells and mammary organoids to representative medium- and long-chain polyunsaturated fatty acids. This exposure caused a dynamic and profound change in gene expression, accompanied by changes in chromatin packing density, chromatin accessibility and histone posttranslational modifications (PTMs). We identified 38 metabolic reactions that showed significantly increased activity, including reactions related to one-carbon metabolism. Among these reactions are those that produce S-adenosyl-L-methionine for histone PTMs. Utilizing both an in-vitro model and samples from women at high risk for ER- BC, we show that lipid exposure engenders gene expression, signaling pathway activation, and histone marks associated with the development of ER- BC.

cancer biology↗

bioRxiv2018

Integrated soybean transcriptomics, metabolomics, and chemical genomics reveal the importance of the phenylpropanoid pathway and antifungal activity in resistance to the broad host range pathogen Sclerotinia sclerotiorum

Sclerotinia sclerotiorum, a predominately necrotrophic fungal pathogen with a broad host range, causes a significant yield limiting disease of soybean called Sclerotinia stem rot (SSR). Resistance mechanisms against SSR are poorly understood, thus hindering the commercial deployment of SSR resistant varieties. We used a multiomic approach utilizing RNA-sequencing, Gas chromatography-mass spectrometry-based metabolomics and chemical genomics in yeast to decipher the molecular mechanisms governing resistance to S. sclerotiorum in soybean. Transcripts and metabolites of two soybean recombinant inbred lines, one resistant, and one susceptible to S. sclerotiorum were analyzed in a time course experiment. The combined results show that resistance to S. sclerotiorum in soybean is associated in part with an early accumulation of JA-Ile ((+)-7-iso-Jasmonoyl-L-isoleucine), a bioactive jasmonate, increased ability to scavenge reactive oxygen species (ROS), and importantly, a reprogramming of the phenylpropanoid pathway leading to increased antifungal activities. Indeed, we noted that phenylpropanoid pathway intermediates such as, 4-hydroxybenzoate, ferulic acid and caffeic acid were highly accumulated in the resistant line. In vitro assays show that these metabolites and total stem extracts from the resistant line clearly affect S. sclerotiorum growth and development. Using chemical genomics in yeast, we further show that this antifungal activity targets ergosterol biosynthesis in the fungus, by disrupting enzymes involved in lipid and sterol biosynthesis. Overall, our results are consistent with a model where resistance to S. sclerotiorum in soybean coincides with an early recognition of the pathogen, leading to the modulation of the redox capacity of the host and the production of antifungal metabolites.\n\nAuthor SummaryResistance to plant fungal pathogens with predominately necrotrophic lifestyles is poorly understood. In this study, we use Sclerotinia sclerotiorum and soybean as a model system to identify key resistance components in this crop plant. We employed a variety of omics approaches in combination with functional studies to identify plant processes associated with resistance to S. sclerotiorum. Our results suggest that resistance to this pathogen is associated in part with an earlier induction of jasmonate signaling, increased ability to scavenge reactive oxygen species, and importantly, a reprogramming of the phenylpropanoid pathway resulting in increased antifungal activities. These findings provide specific plant targets that can exploited to confer resistance to S. sclerotiorum and potentially other pathogens with similar lifestyle.

plant biology↗

bioRxiv2018

Thermal plasticity of the circadian clock is under nuclear and cytoplasmic control in wild barley

Temperature compensation, expressed as the ability to maintain clock characteristics (mainly period) in face of temperature changes, is considered a key feature of circadian clock systems. In this study, we explore the genetic basis for circadian clock plasticity under high temperatures by utilizing a new doubled haploid (DH) population derived from two reciprocal Hordeum vulgare sps. spontaneum hybrids genotypes (crosses between B1K-50-04 and B1K-09-07). Genotyping by sequencing of DH lines indicated a rich recombination landscape, with minor fixation (less than 8%), for one of the parental alleles, yet with prevalent and varied segregation distortion across seven barley chromosomes. Phenotyping was conducted with a high-throughput platform under optimal and high temperature environments. Genetic analysis, which included QxE and binary-threshold models, identified a significant influence of the maternal organelle genome (the plasmotype), as well as several nuclear quantitative trait loci (QTL), on clock phenotypes (free-running period and amplitude). Moreover, it showed the differential contribution of cytoplasmic genome clock rhythm buffering against high temperature. Resequencing of the parental chloroplast indicated the presence of several candidate genes underlying these significant effects. This first reported plasmotype-driven clock plasticity paves the way for identifying an hitherto unknown impact of nuclear and plasmotype variations on clock robustness and on plant adaptation to changing environments.\n\nHighlightCircadian clock robustness to high temperature is controlled by nuclear and plasmotype quantitative trait loci in a wild barley (Hordeum vulgare ssp. spontaneum) reciprocal doubled haploid population.

genetics↗

bioRxiv2018

ERBB2 and KRAS Alterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer

The uncommonness of gallbladder cancer has contributed to the generally poor understanding of the disease, with scant reports restricted to advance-stage tumors. Here, using an integrated analysis of whole exome and phospho-proteome, we show recurrent activating ERBB2 and KRAS somatic mutations are present in 6 and 3 of 44 early-stage rare gallbladder tumors, respectively. In vitro and in vivo cell-based and biochemical assays reveal an essential role of ErbB pathway activation for the survival of gallbladder cells. Interestingly, the genetic and pharmacological dependencies of gallbladder cells are dependent on the KRAS mutant allele status, reminiscent of the clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer. In overall, we present the first evidence that the presence of KRAS (G12V), but not KRAS (G13D) mutation, may preclude gallbladder cancer patients to respond to anti-EGFR treatment, leading to an early adoption of an approved treatment regimen for gallbladder cancer patients.

cancer biology↗