Biology subjects

Dwivedi, N.

Publications and source records attributed to Dwivedi, N..

11 recordsLinked to original sources

bioRxiv2025

Restored rigidity sensing fails to induce anoikis in cancer cells due to Akt activation and cell cell interactions

Rigidity sensing enables cells to detect and respond to extracellular matrix stiffness, directing survival and apoptotic decisions. Tropomyosin 2.1 (Tpm2.1), a key actin-binding protein, is essential for this process and is frequently downregulated in cancer. While Tpm2.1 overexpression restores rigidity sensing and suppresses malignant growth, the downstream pathways governing cell fate remain poorly defined. Here, we show that Tpm2.1-mediated rigidity sensing represses anchorage-independent growth by downregulating oncogenic networks, including PI3K-Akt and EphA2 signaling. Unexpectedly, a majority of Tpm2.1-overexpressing cells remained viable in suspension, revealing a previously unrecognized decoupling between rigidity sensing and anoikis. Transcriptomic profiling of apoptotic and non-apoptotic cells in suspension identified compensatory survival programs marked by PI3K-Akt activation and induction of cell-cell adhesion genes. These findings uncover a dominant anoikis-resistant state that persists despite cytoskeletal normalization, suggesting that rigidity sensing alone is insufficient to reestablish anchorage dependence in cancer cells.

cell biology↗

bioRxiv2025

Combining population genomics with ancient DNA to understand island colonization history of the Madagascar turtle dove

The Mascarene archipelago (Mauritius, Reunion and Rodrigues), characterized by first human arrival being recent, offers a unique setting to study species colonization. Here we use a combination of modern and ancient DNA data as a case study to investigate the recent colonization history of a species of concern in relation to conservation programs - the Madagascar turtle dove (Nesoenas picturata) on Mauritius and Reunion. We generated a reference genome and re-sequenced genomes from contemporary N. picturata populations, as well as genome-wide data from relevant subfossils. A combination of model-free inferences, site frequency spectrum (SFS) based demographic modelling, and analyses of population structure including that of subfossils indicate that N. picturata colonized both islands independently and naturally from Madagascar, long before human arrival. Summary statistics and SFS-based modeling reveal large effective population sizes (Ne) and high genetic diversity in island populations, conflicting with historical accounts of human-induced demographic collapse. Based on goodness-of-fit, genetic structure and diversity indices do not discriminate between two solutions, one of which posits large recent Ne and negligible translocation rates, while the other supports recent severe bottlenecks followed by high post-human translocation from Madagascar. Nonetheless, linkage disequilibrium provides stronger evidence for the latter scenario, which may also explain high genetic diversity. Both modern and ancient DNA data sources independently support the classification of N. picturata as native to both islands. Our findings highlight the importance of validating demographic models with multiple summary statistics, and potential of using a combination of different data sources to resolve colonization history in recent time.

evolutionary biology↗

bioRxiv2025

An unsuspected physiological role for mGluRIII glutamate receptors in hippocampal area CA1

Group III metabotropic glutamate receptors (mGluRIII) are expressed broadly throughout the neocortex and hippocampus but are thought to inhibit neurotransmitter release only at a subset of synapses and in a target cell- specific manner. Accordingly, previous slice physiology experiments in hippocampal area CA1 showed that mGluRIII receptors inhibit glutamate and GABA release only at excitatory and inhibitory synapses formed onto GABAergic interneurons, not onto pyramidal cells. Here, we show that the supposed target cell-specific modulation of GABA release only occurs when the extracellular calcium concentration in the recording solution is higher than its physiological concentration in the cerebrospinal fluid. Under more physiological conditions, mGluRIII receptors inhibit GABA release at synapses formed onto both interneurons and pyramidal cells but limit glutamate release only onto interneurons. This previously unrecognized form of mGluRIII-dependent, pre-synaptic modulation of inhibition onto pyramidal cells is accounted for by a reduction in the size of the readily releasable pool, mediated by protein kinase A and its vesicle-associated target proteins, synapsins. Using in vivo whole-cell recordings in behaving mice, we demonstrate that blocking mGluRIII activation in the intact CA1 network results in net effects consistent with decreased inhibition and significantly alters CA1 place cell activity. Together, these findings challenge our current understanding of the role of mGluRIII receptors in the control of synaptic transmission and encoding of spatial information in the hippocampus.

neuroscience↗

bioRxiv2024

Iron deprivation activates aboveground cell wall biosynthesis in Populus and the role of PtrbHLH011

Lack of mechanistic understanding of the environmental plasticity of secondary cell wall (SCW) biosynthesis hinders the massive bioenergy production on marginal lands. Growing bioenergy crops on marginal lands is appealing to minimize competition for arable land. However, abiotic stresses, particularly iron deficiency stress, are widespread to perturb SCW biosynthesis. In poplar, a major bioenergy crop, we demonstrated that iron deprivation activates stem SCW biosynthesis and identified transcription factor PtrbHLH011 as a possible underlying regulator. PtrbHLH011 is a potent repressor of SCW, whose overexpression resulted in a reduction of stem SCW by over 65%. Our genomic and molecular studies discovered that PtrbHLH011 binds to the AAAGACA sequence and represses essential genes for SCW biosynthesis, flavonoid biosynthesis, and iron homeostasis. Wood formation and iron deprivation downregulates PtrbHLH011 to release the transcriptional repression. Our findings reveal a regulatory mechanism coordinating SCW biosynthesis in response to environmental iron availability and suggest that PtrbHLH011 manipulation may help engineer bioenergy crops with improved performance under marginal conditions.

plant biology↗

bioRxiv2023

In vitro and in vivo evidences propound therapeutic potential of Lipocalin 2 in cervical carcinoma

Cervical cancer (CC), the second most common in developing countries and the third most common in developed nations, is the fourth most common type of cancer in women overall. The HPV16 high-risk genotype of the virus, which is responsible for about 61% of cervical cancer incidences, was found to have higher LCN2 levels in advanced clinical CC stages. In this study, we assessed the impact of suppressing LCN2 activity after treatment with an anti-LCN2 monoclonal antibody (MAb) in both in vitro and in vivo settings. Anti-LCN2 antibody was found to reduce proliferation and invasion of HeLa cells, the first immortal cells from a HPV positive aggressive adenocarcinoma of the cervix. LCN2 and its ligand MMP9 was found to be highly expressed in the cells and abrogated on treatment with anti-LCN2. The five receptors of LCN2 - SLC22A17, MC1R, MC2R, MC4R and LRP2 were barely detected with or without treatment. Anti-LCN2 Mab caused tumors to regress and soften in vivo, in a xenograft mouse model. Analysis of histology images of the treated and untreated tumor established the necrotic capability of the therapeutic molecule explaining the regression and softening of the tumor. Differential gene expression analysis between untreated and treated tumor proved that LCN2 inhibition abolished the migratory, invasive, and hypoxic pathways while significantly increasing the necrosis and cell death pathways in tumor after treatment with the monoclonal antibody. LCN2 inhibition was shown molecularly to lead to tumor regression via a negative feedback loop of LCN2 through the TNF-IL17 axis exponentially increasing the effect of the anti-LCN2 monoclonal antibody. In conclusion, LCN2 appears to be a viable therapeutic target, and the monoclonal antibody used in this study can be further developed for clinical usage in cervical cancer.

cancer biology↗

bioRxiv2023

Novel CAF-identifiers via transcriptomic analysis in oral cancer patients

BackgroundCancer-associated fibroblasts (CAFs), a prominent component of the tumor microenvironment, plays an important role in tumor development, invasion, and drug resistance. The expression of distinct "CAF markers," which separates CAFs from normal fibroblasts and epithelial cells, have traditionally been used to identify them. These commonly used CAF markers have been reported to differ greatly across microenvironmental subpopulations even within a cancer site. MethodsUsing an unbiased data analysis approach utilizing publicly available and in-house gene expression data from patient derived novel CAF cells, we identified a collection of markers in oral cancer to distinguish CAF populations from tumor epithelia and normal oral fibroblasts. ResultsCOL1A1, SPARC, COL1A2, COL3A1 and TIMP-1 were identified as potential markers which can be utilized to differentiate cancer associated fibroblast from all other cell types including normal fibroblasts in oral cancer.

cancer biology↗

bioRxiv2023

Establishment and Characterization of Three Novel CAF Cell Lines from HNSCC Patients

Due to the high rates of tobacco chewers, smokers, and alcohol consumers in India, Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the primary causes of mortality. Being profoundly varied in nature, treating patients diagnosed with HNSCC can be difficult. An in vitro cell line model is needed to better comprehend the heterogeneity especially via the interaction with components of the microenvironment like Cancer Associated Fibroblasts (CAFs). The effectiveness of creating cell lines from head and neck cancers is, however, poor. Furthermore, except for the two reported earlier by us, no other CAF cell lines are available to study the cross-talk of the tumor with its microenvironment. In this study, we report three novel CAF lines, spontaneously immortalized from HPV negative male patients with habits of tobacco and diagnosed with squamous cell carcinoma of the upper alveolus, larynx and buccal mucosa as opposed to HPV positive non-habitual female patients with cancer of the tongue as previously reported. The CAFs increased the tumorigenicity of epithelial cells in indirect co-culture experiments. Negative staining with EpCAM, CD31 and CD45, while positive staining with FSP-1 determined their fibroblast specific lineage. The developed CAF cultures are the first of their kind from the mentioned sites, and they will be an invaluable tool for learning how tumor-stroma and tumor interact with one another and discovering newer targets and pathways for treating HNSCC.

cancer biology↗

bioRxiv2022

The Tryptophan Metabolizing Enzyme Indoleamine 2,3-Dioxygenase 1 Regulates Polycystic Kidney Disease Progression

Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic nephropathy, is characterized by phenotypic variability exceeding genic effects. Dysregulated metabolism and immune cell function are key disease modulators. The tryptophan metabolites, kynurenines, produced through IDO1, are known immunomodulators. Here, we study the role of tryptophan metabolism in PKD using an orthologous disease model (C57Bl/6J Pkd1RC/RC). We found elevated kynurenine and IDO1 levels in Pkd1RC/RC kidneys versus wildtype. Further, IDO1 levels were increased in ADPKD cell lines and patient cyst cells. Genetic Ido1 loss in Pkd1RC/RC animals resulted in reduced PKD severity as measured by %kidney weight/body weight and cystic index. Consistent with a immunomodulatory role of kynurenines, Pkd1RC/RC;Ido1-/- mice presented with significant changes in the cystic immune microenvironment (CME) versus controls. Of note, kidney macrophage numbers decreased and CD8+ T cell numbers increased, both known PKD modulators. Also, pharmacological IDO1 inhibition using a tryptophan analog in Pkd1RC/RC animals resulted in less severe PKD versus controls with similar changes in the CME as in the genetic model. Together, our data suggest that tryptophan metabolism is dysregulated in ADPKD and that its inhibition results in changes to the CME and slows disease progression, making IDO1 a novel therapeutic target for ADPKD.

molecular biology↗

bioRxiv2022

Establishment and characterization of novel autologous pair primary cultures from two Indian non-habitual tongue carcinoma patients

Oral tongue squamous cell carcinoma (OTSCC) is one of the major causes of fatality in India owing to very high percentages of patients with smoking and chewing habits. Being highly heterogeneous in nature, every patient poses a different challenge clinically. To better understand disease progression, knowledge of cross talk between tumor stroma and the tumor cells becomes indispensable. Patient-derived in vitro cell line models are helpful to understand the complexity of diseases. However, they have very low efficiency of establishment from the tumor samples, especially the cancer associated fibroblasts (CAFs). In the present study, two novel autologous pairs have been immortalized spontaneously from non-habitual, HPV-positive patients, presented with tongue squamous cell carcinoma. The epithelial and fibroblast primary lines had typical polygonal and spindle shaped morphology, respectively. Positive staining with Pan-cytokeratin (PanCK) and Fibroblast Specific Protein (FSP-1) further confirmed their epithelial and fibroblast origin. Unique Short Tandem Repeat (STR) profile of the cultures confirmed their novelty, while the similarity of the STR profiles between the epithelial and fibroblast cells from the same patient, confirmed their autologous nature. DNA analysis revealed aneuploidy of the established cultures. Increase in the tumorigenic potential of the established epithelial cultures upon treatment with CAF-conditioned medium proved the "CAF-ness" of the established fibroblast cells. The established cultures are the first of their kind which would serve as an useful platform in understanding the cross talk between tumor-stroma and tumor, along with studying tongue cancer progression.

cancer biology↗

bioRxiv2019

Asamataxis: A cooperative relayed migration in response to subsurface inhomogeneity leads to long-range self-patterning of cells

Cells self-organize to give patterns that are essential for tissue functioning. While the effects of biochemical and mechanical cues are relatively well studied, the role of stiffness inhomogeneity on cellular patterning is unexplored. Using a rigid structure embedded in soft polyacrylamide (PAA) gel, we show that such mechanical inhomogeneity leads to long-range self-organized cellular patterns. Our results reveal that this patterning depends on cellular traction and cell morphology. Depending on a suitable combination of cellular morphology and traction, the information about the presence of embedded structure gets relayed outward. In response to this relay, the cells reorient their axis and migrate towards the embedded structure leading to the observed long-range (20-35 cell length) patterning. To predict the possibility of pattern formation, we present a dimensionless number f combining the governing parameters. We have also shown that the pattern can be tailor-made by pre-designing sub-surface structures, a potential tool for tissue engineering. This mechanism of directed migration driven long-range pattern formation in response to mechanical inhomogeneity may be involved during several pathophysiological conditions, a proposition that needs further investigation.\n\nOne Sentence SummarySubstrate inhomogeneity and cooperative cellular traction together lead to cellular migration and long-range pattern formation.

biophysics↗

bioRxiv2018

Analysis of genetic control and QTL mapping of essential wheat grain quality traits in a recombinant inbred population

Wheat cultivars are genetically crossed for improving end use quality for apt traits as per need of baking industry and broad consumers preferences. The processing and baking qualities of bread wheat underlie into genetic make-up of a variety and influence by environmental factors and their interactions. WL711 and C306 derived recombinant inbred lines (RILs) population of 206 was used for phenotyping of quality related traits in three different environmental conditions. The genetic analysis of quality traits showed considerable variation for measurable quality traits with normal distribution and transgressive segregation across the years. From the 206 RIL, few RILs found to be superior to those of the parental cultivars for key quality traitsindicating their potential usefor improvement of end use quality and also suggestingprobability of finding new alleles and allelic combinations from the RIL population. A genetic linkage map including 346 markers was constructed withtotal map distance of 4526.8cM andinterval distance between adjacent markersof 12.9cM. Mapping analysis identified 38 putative QTLs for 13 quality related traits with QTLs explaining 7.9% - 16.8% phenotypic variation spanning over 14 chromosomes i.e. 1A, 1B, 1D, 2A, 2D, 3B, 3D, 4A, 4B, 4D, 5D, 6A, 7A and 7B. Major novel QTLs regions for quality traits have been identified on several chromosome in studied RIL population posing their potential role in marker assisted selection for better bread making quality after validation.

genetics↗