Biology subjects

Rajendran, V.

Publications and source records attributed to Rajendran, V..

5 recordsLinked to original sources

bioRxiv2025

Integrative network modeling of colorectal cancer reveals diagnostic signatures and therapeutic targets

Emerging evidence suggests that the interplay between multiple signaling pathways and the immune microenvironment influences tumorigenesis in cancers such as colorectal cancer (CRC). To gain an in-depth understanding of CRC mechanisms and identify novel therapeutic targets, we constructed a molecular interaction map (MIM) integrating key signaling pathways from cancer cells and immune cells within the tumor microenvironment. This map comprises 218 molecules and 328 interactions, curated using PubMed references and official gene symbols. We dynamically simulated the MIM for individual pathways and combinations via stimulus-response and perturbation analyses, calibrating the model with two CRC datasets: GSE1323 (primary tumor-to-metastasis progression) and GSE8671 (normal mucosa-to-adenoma progression), which served as experimental conditions. Simulations revealed distinct disease signatures for GSE1323, including (1) simultaneous activation of TNF/TNFRSF1A,B and EGF/EGFR with inactivation of ERE/ESR, and (2) simultaneous activation of TNF/TNFRSF1A,B and TLR4 with inactivation of ERE/ESR. For GSE8671, the signature was simultaneous activation of TNF/TNFRSF1A,B and TLR4. In silico perturbation analysis identified potent anti-cancer effects from concurrent inhibition of MAPK3 and STAT3 (GSE1323), and ELK1/ATF2 and STAT3 or MAPK14 and STAT3 (GSE8671), significantly reducing epithelial-mesenchymal transition (EMT), proliferation, and inflammation while increasing apoptosis. Disease signatures and therapeutic targets were validated using patient data through Kaplan-Meier survival analysis and machine learning. This integrative model recapitulates cancer biology, predicts biomarkers and therapeutic targets, and is extensible to other immunogenic cancers.

systems biology↗

bioRxiv2023

Mesoscale Ca2+ imaging reveals networks of Purkinje cell dendritic and somatic modulation, with divergent roles of activity versus correlation during behavior

A major challenge in cerebellar physiology is determining how the stereotypic, conserved circuitry of the cerebellar cortex, with its dominant parasagittal and transverse architectures, underlies its fundamental computations and contributions to behavior. To interrogate Purkinje cell dynamics at this parasagittal and transverse spatial scale, we implemented a novel approach for awake, chronic, wide-field Ca2+ imaging of the cerebellar cortex. We observe two functionally and spatially distinct Purkinje cell networks, reflecting their dendritic and somatic activities, respectively. Both dendritic and somatic networks exhibit bilateral, widespread activation during behavior, but with diverse patterns of spatial correlations occurring primarily along the parasagittal and transverse directions, consistent with the main geometry of the cerebellar cortex. Somatic network correlation dynamics are robustly modulated by prediction errors, and even reflect ultimate behavioral outcomes. These results provide a novel link between cerebellar structure and function, with the correlation dynamics of Purkinje cell activity a key feature.

neuroscience↗

bioRxiv2021

The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent potentially lethal monogenic disorder. Approximately 78% of cases are caused by mutations in the PKD1 gene, which encodes polycystin-1 (PC1). PC1 is a large 462-kDa protein that undergoes cleavage in its N and C-terminal domains. C-terminal cleavage produces fragments that translocate to mitochondria. We show that transgenic expression of a protein corresponding to the final 200 amino acid residues of PC1 in a Pkd1-KO orthologous murine model of ADPKD dramatically suppresses cystic phenotype and preserves renal function. This suppression depends upon an interaction between the C-terminal tail of PC1 and the mitochondrial enzyme Nicotinamide Nucleotide Transhydrogenase. This interaction modulates tubular/cyst cell proliferation, the metabolic profile, mitochondrial function and the redox state. Together, these results suggest that a short fragment of PC1 is sufficient to suppress cystic phenotype and open the door to the exploration of gene therapy strategies for ADPKD.

physiology↗

bioRxiv2020

Miniaturized head-mounted device for whole cortex mesoscale imaging in freely behaving mice

The advent of genetically encoded calcium indicators, along with surgical preparations such as thinned skulls or refractive index matched skulls, have enabled mesoscale cortical activity imaging in head-fixed mice. Such imaging studies have revealed complex patterns of coordinated activity across the cortex during spontaneous behaviors, goal-directed behavior, locomotion, motor learning, and perceptual decision making. However, neural activity during unrestrained behavior significantly differs from neural activity in head-fixed animals. Whole-cortex imaging in freely behaving mice will enable the study of neural activity in a larger, more complex repertoire of behaviors not possible in head-fixed animals. Here we present the "Mesoscope," a wide-field miniaturized, head-mounted fluorescence microscope compatible with transparent polymer skulls recently developed by our group. With a field of view of 8 mm x 10 mm and weighing less than 4 g, the Mesoscope can image most of the mouse dorsal cortex with resolution ranging from 39 to 56 {micro}m. Stroboscopic illumination with blue and green LEDs allows for the measurement of both fluorescence changes due to calcium activity and reflectance signals to capture hemodynamic changes. We have used the Mesoscope to successfully record mesoscale calcium activity across the dorsal cortex during sensory-evoked stimuli, open field behaviors, and social interactions. Finally, combining the mesoscale imaging with electrophysiology enabled us to measure dynamics in extracellular glutamate release in the cortex during the transition from wakefulness to natural sleep.

neuroscience↗

bioRxiv2018

Draft genome of the liver fluke Fasciola gigantica

Fascioliasis is a neglected food-borne disease caused by liver flukes (genus Fasciola) and affects more than 200 million people worldwide. Despite technological advances, little is known about the molecular biology and biochemistry of the fluke. We present the draft genome of Fasciola gigantica for the first time. The assembled draft genome has a size of ~1.04 Gb with an N50 of 129 kb. A total of 20,858 genes were predicted. The de novo repeats identified in the draft genome were 46.85%. In pathway analysis, all the genes of glycolysis, Krebs cycle and fatty acid metabolism were found to be present, but the key genes for fatty acid production in fatty acid biosynthesis were missing. This indicates that the fatty acid required for the survival of the fluke may be acquired from the host bile. The genomic information will provide a comprehensive resource to facilitate the development of novel interventions for fascioliasis control.

bioinformatics↗