Biology subjects

Pradhan, R.

Publications and source records attributed to Pradhan, R..

10 recordsLinked to original sources

bioRxiv2026

Innate immune stress pathway activation underlies heterochromatin dysfunction pathology

Heterochromatin loss disrupts nuclear architecture, gene regulation and repetitive element silencing, and is associated with diverse human diseases. However, mechanisms linking heterochromatin dysfunction to pathological phenotypes remain unclear. Using genetic interaction screening and genomic analyses in C. elegans, we identify secondary activation of the Intracellular Pathogen Response (IPR), an innate immune stress pathway, as a major contributor to heterochromatin mutant phenotypes. Constitutive IPR activation phenocopies slow growth and indirect transcriptional changes observed in these mutants. Depletion of genetic enhancers further increased, whereas suppressor RNAi attenuated IPR activation, with direct heterochromatin targets remaining substantially deregulated. Notably, many suppressors encode active chromatin components, and mild reduction of RNA polymerase II activity ameliorates growth defects in C. elegans HP1 mutants and human HP1-deficient cells. Our findings reveal secondary stress response activation as an important mechanism linking heterochromatin dysfunction to pathology and identify transcriptional dampening as a potential therapeutic strategy for mitigating these effects.

genetics↗

bioRxiv2025

lncRNA 3222401L13Rik/ENSG00000272070 modulates microglial inflammatory programs in association with PU.1

Long non-coding RNAs (lncRNAs) are emerging as key regulators of brain function, but their contribution to microglial aging and neurodegenerative disease remains largely unknown. Because only 1.5% of the human genome encodes proteins, whereas the vast majority of transcripts belong to the largely unexplored non-coding RNAome, elucidating the functions of non-coding RNAs provides an unprecedented opportunity to expand the space for therapeutic discovery. We recently identified the glia-enriched lncRNA 3222401L13Rik as upregulated in the aging mouse hippocampus. Here, we investigated its function in microglia and its human homolog ENSG00000272070. We found that 3222401L13Rik is expressed in both astrocytes and microglia and increases with age. Knockdown of 3222401L13Rik in primary microglia led to enhanced expression of pro-inflammatory cytokines, including TNF, and increased phagocytic activity. RNA-sequencing revealed widespread transcriptional changes enriched for TNF and complement signaling pathways. The human homolog ENSG00000272070 showed conserved functions in iPSC-derived microglia, where its loss similarly promoted inflammatory gene expression and phagocytosis. Mechanistically, 3222401L13Rik interacts with the microglial transcription factor PU.1, and its depletion overlapped with PU.1-driven transcriptional programs. Consistent with these findings, ENSG00000272070 expression was significantly reduced in postmortem Alzheimers disease (AD) brains, and AD-associated genes were enriched among 3222401L13Rik-regulated targets. Together, our results identify 3222401L13Rik/ENSG00000272070 as a conserved, aging-associated lncRNA that modulates microglial inflammatory states through interaction with PU.1. This work links glial lncRNA regulation to AD-related neuroinflammation and suggests 3222401L13Rik as a potential molecular target to fine-tune microglial activity in neurodegenerative diseases. HighlightsO_LI3222401L13Rik is a glia-enriched long non-coding RNA regulating microglial state C_LIO_LIKnockdown of 3222401L13Rik increases TNF signaling C_LIO_LIThe human homolog ENSG00000272070 shows reduced expression in AD brains C_LIO_LI3222401L13Rik interacts with the AD-associated transcription factor PU.1 C_LIO_LIA conserved 3222401L13Rik-PU.1 axis modulates microglial inflammation in aging and disease C_LI

neuroscience↗

bioRxiv2025

Sertraline enhances bacterial control by improving the pharmacodynamic -pharmacokinetic properties of frontline TB drugs

Given the need for innovative interventions for tackling the burden of TB, host directed therapies have emerged as a promising alternative in recent times. The combination of sertraline with frontline TB drugs has shown excellent promise in the murine models of infection in imparting better bacterial control and increasing host survival. We tested if the addition of sertraline worked to increase bacterial clearance in the random bred guinea pig model of TB infection that mimics the inter individual heterogeneity observed in the human response to infection. The combination of sertraline and frontline TB drugs effectively reduced bacterial burdens in the tissues of guinea pigs significantly better than the drugs alone with a marked betterment of lung histopathology. In order to evaluate the effect of sertraline on the pharmacodynamic properties of TB drugs, concentrations of the drugs were estimated in tissues at different time intervals over a period of 24h of administration to rats. Overall, addition of sertraline did not alter TB drug distribution or clearance from the animals, although enriching drug amounts transiently between 3-6 h in the different tissues. We thus highlight the advantage of an adjunct TB therapy with the inclusion of sertraline, an FDA approved antidepressant, in improving the PKPD of TB drugs and imparting better infection control in diverse models of infection.

microbiology↗

bioRxiv2025

NeuID, a novel neuron-specific lncRNA, resolved a key epigenetic mechanisms linking gene silencing to Alzheimer's disease

The increasing evidence that non-coding RNAs can become deregulated during pathogenesis is dramatically expanding the space for drug discovery beyond the protein-coding genome. Long noncoding RNAs (lncRNAs) are emerging as key regulators of cellular function, yet most remain uncharacterized. Here, we identify a previously unstudied lncRNA, which we named Neuronal Identity (NeuID)--a conserved, brain-enriched transcript expressed exclusively in neurons. NeuID is downregulated in the brains of Alzheimers disease (AD) patients. Mechanistically, NeuID maintains neuronal identity by repressing developmental and glial genes via interaction with the PRC2 subunit EZH2 and regulation of H3K27me3. Knockdown of NeuID disrupts this repression, leading to impaired neuronal activity and memory formation. Importantly, CRISPRa-mediated NeuID overexpression restores neuronal function in A{beta}42-treated neurons. These findings identify NeuID as a critical regulator of neuronal plasticity and position it as a promising therapeutic target for AD. One sentence summaryWe identify NeuID, a novel brain and neuron-specific long non-coding RNA downregulated in Alzheimers disease, as a key regulator of neuronal identity and a promising therapeutic target to restore neuronal function.

neuroscience↗

bioRxiv2024

Continuous Monitoring of Glucose and Oxygen using an Insertable Biomaterial-based Multianalyte Barcode Sensor

Chronic diseases including diabetes, cardiovascular diseases, and microvascular complications contribute significantly to global morbidity and mortality. Multiplexing technologies offer a promising approach for the simultaneous detection and management of comorbidities, providing comprehensive disease insights. In this work, we describe a miniaturized optical "barcode" sensor with high biocompatibility for continuous monitoring of glucose and oxygen. This enzymatic sensor relies on oxygen consumption in proportion to local glucose levels and the phosphorescence reporting of tissue oxygen with a lifetime-based probe. The sensor was designed to operate in a tissue environment with low levels of dissolved oxygen. The barcode sensor consists of a poly(ethylene) glycol diacrylate (PEGDA) hydrogel with four discrete compartments separately filled with glucose or oxygen-sensing phosphorescent microparticles. We evaluated the response of the barcode hydrogels to fluctuating glucose levels over the physiological range under low oxygen conditions, demonstrating controlled tuning of dynamic range and sensitivity. Moreover, the barcode sensor exhibited remarkable storage stability over 12 weeks, along with full reversibility and excellent reproducibility ([~]6% variability in phosphorescence lifetime). Electron beam sterilization had a negligible impact on the glucose response of the barcode sensors. Furthermore, our investigation revealed minimal phosphorescence lifetime changes in oxygen compartments while exhibiting increased lifetime in glucose-responsive compartments when subjected to alternating glucose concentrations (0 and 200 mg/dL), showcasing the sensors multianalyte sensing capabilities without crosstalk between compartments. Additionally, evaluation of tissue response to sensors inserted in pigs revealed appropriate biocompatibility of the barcodes.

bioengineering↗

bioRxiv2024

A role for astrocytic miR-129-5p in Frontotemporal Dementia

Frontotemporal dementia is a debilitating neurodegenerative disorder characterized by frontal and temporal lobe degeneration, resulting in behavioral changes, language difficulties, and cognitive decline. In this study, smallRNA sequencing was conducted on postmortem brain tissues obtained from FTD patients with GRN, MAPT, or C9ORF72 mutations, focusing on the frontal and temporal lobes. Our analysis identified miR-129-5p as consistently deregulated across all mutation conditions and brain regions. Functional investigations revealed a novel role of miR-129-5p in astrocytes, where its loss led to neuroinflammation and impaired neuronal support functions, including reduced glutamate uptake. Depletion of miR-129-5p in astrocytes resulted in the loss of neuronal spines and altered neuronal network activity. These findings highlight miR-129-5p as a potential therapeutic target in neurodegenerative diseases and also sheds light on the role of astrocytes in Frontotemporal dementia pathogenesis.

neuroscience↗

bioRxiv2023

A novel miR-99b-5p-Zbp1 pathway in microglia contributes to the pathogenesis of schizophrenia

Schizophrenia is a psychiatric disorder that is still not readily treatable. Pharmaceutical advances in the treatment of schizophrenia have mainly focused on the protein coding part of the human genome. However, the vast majority of the human transcriptome consists of non-coding RNAs. MicroRNAs are small non-coding RNAs that control the transcriptome at the systems level. In the present study we analyzed the microRNAome in blood and postmortem brains of controls and schizophrenia patients and found that miR-99b-5p was downregulated in both the prefrontal cortex and blood of patients. At the mechanistic level we show that inhibition of miR-99b-5p leads to schizophrenia-like phenotypes in mice and induced inflammatory processes in microglia linked to synaptic pruning. The miR-99b-5p-mediated inflammatory response in microglia depended on Z-DNA binding protein 1 (Zbp1) which we identified as a novel miR-99b-5p target. Antisense oligos (ASOs) against Zbp1 ameliorated the pathological phenotypes caused by miR-99b-5p inhibition. In conclusion, we report a novel miR-99b-5p-Zbp1 pathway in microglia that contributes to the pathogenesis of schizophrenia. Our data suggest that strategies to increase the levels of miR-99b-5p or inhibit Zbp1 could become a novel therapeutic strategy.

neuroscience↗

bioRxiv2022

Spatial positioning and matrix programs of cancer-associated fibroblasts promote T cell exclusion in human lung tumors

It is currently accepted that activated cancer-associated fibroblasts (CAF) participate in T cell exclusion from tumor nests, but it remains unclear how they promote barrier phenotypes, and whether specific subsets are involved. Here, using single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors, we identify four main CAF populations, of which only two are associated with T cell exclusion: (i) MYH11+SMA+ CAF, which are present in early-stage tumors and form a single-cell layer lining cancer aggregates, and (ii) FAP+SMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both CAF populations show a contractility phenotype together with dense and aligned matrix fiber deposition compared to the T cell-permissive CAF. Yet they express distinct matrix genes, including COL4A1/COL9A1 (MYH11+SMA+ CAF) and COL11A1/COL12A1 (FAP+SMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors. SIGNIFICANCEThe cellular and molecular programs driving T cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to develop new strategies targeting T cell-excluding CAF.

cancer biology↗

bioRxiv2021

Postnatal SETD1B is essential for learning and the regulation of neuronal plasticity genes

Histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Amongst these enzymes SET domain containing 1b (SETD1B) has been linked to syndromic intellectual disability but its role in the postnatal brain has not been studied yet. Here we employ mice that lack Setd1b from excitatory neurons of the postnatal forebrain and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that SETD1B controls the expression of genes with a broad H3K4me3 peak at their promoters that represent neuronal enriched genes linked to learning and memory function. Comparative analysis to corresponding data from conditional Kmt2a and Kmt2b knockout mice suggests that this function is specific to SETD1B. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-mediated regulation of H3K4me levels in postnatal neurons is critical for cognitive function.

neuroscience↗

bioRxiv2019

Serum proteomic approach for differentiation of frail and non-frail elderly

Frail elderly is very common in Indian society and extremely difficult to manage in the clinical practice. Blood proteomic study may able to improve the specific diagnostic profiles and therapeutic templates for improving quality of life in elderly. The purpose of present study is to differentiate between frail and non-frail elderly on the basis of serum markers. The proteomic profile of 10 frail and 10 non-frail elderly diagnosed according to deficit accumulation model of Rockwood was identified by 2D-electrophoresis and analyzed using ImageMaster 2DPlatinum7.0 software. The proteins were identified by MALDI-TOF/TOF and performed gene ontology study by PANTHER 7.0 software. Overall 105 spots were identified in the study groups. In frail 22spots and in non-frail 12spots were found to be differentially expressed. Mass spectroscopy analysis of 13 spots showed up-regulated Haptoglobin, Serum amyloidA1, TRAK1, sp110, NLRC3, MMP12, Mortalin, NDK3 and downregulated PSRC1, NKG2A proteins in frail elderly. The differential expression of proteins in frailty are mostly associated with pro-inflammation and is well-known that frailty syndrome increases all inflammatory parameters. It can be summarized from the present proteomic study that these proteins can be used as potential biomarkers for early detection of frailty in the elderly.

biophysics↗