Biology subjects

Maurya, A. K.

Publications and source records attributed to Maurya, A. K..

12 recordsLinked to original sources

bioRxiv2026

A SRC-Annexin A2 axis that couples membrane repair to microRNA export during radiation stress in glioblastoma

Repair of ionizing-radiation (IR)-induced membrane damage is essential for cell survival, and Annexin A2 (ANXA2) mediates this repair by promoting shedding of microvesicles containing both damaged lipid and ANXA2. Here, we show that coupling this process to microRNA export contributes to radiation resistance of glioblastoma, the most common adult brain cancer. Structural modeling and mutational analysis identify that ANXA2 tyrosine 23 (Y23) phosphorylation, required for its IR-induced localization to damaged membranes, is also essential for binding miR-603, a critical regulator of glioblastoma cell state. This binding is required for IR-induced miR-603 export, indicating that the repair program recruiting ANXA2 also positions it to load miR-603 into microvesicles. Mutations that abolish ROS-induced sulfenylation and activation of SRC (SRC-C185A/C245A) suppressed ANXA2-Y23 phosphorylation, microvesicle shedding, and miR-603 export. The epistatic interaction between ANXA2-Y23A, SRC-C185A/C245A, and miR-603 delineates a therapeutically targetable radiation-response network that couples membrane repair with miRNA export.

cancer biology↗

bioRxiv2025

BiomarkerML: A cloud-based proteomics ML workflow for biomarker discovery

BackgroundHigh-throughput affinity and mass-spectrometry-based proteomic studies of large clinical cohorts generate high-dimensional proteomic data useful for accelerated disease biomarker discovery. A powerful approach to realizing the potential of these big, complex, and non-linear data, whilst ensuring reproducible results, is to use automated machine learning (ML) and deep learning (DL) pipelines for their analysis. However, there remains a gap in comprehensive ML workflows tailored to proteomic biomarker discovery and designed for biomedical researchers who need pipelines to optimally self-configure and automatically avoid over-fitting. FindingsWe present BiomarkerML, a cloud-based workflow for automated, reproducible, and efficient ML/DL analysis of proteomic data for biomarker discovery, designed for novice-ML users and implemented in Python, R and Workflow Description Language (WDL). BiomarkerML: ingests proteomic and clinical data alongside sample labels; pre-processes data for model fitting and optionally performs dimensionality reduction and visualization; fits a catalogue of ML and DL classification and regression models; and calculates model performance metrics for model comparison. Next, the workflow applies mean SHapley Additive exPlanations (SHAP) to quantify the contribution of each protein to model predictions across all samples. Finally, proteins with high mean SHAP values, and their co-expressed protein network interactors, are identified as candidate biomarkers. Importantly, hyperparameters - configuration variables set prior to training models - are automatically fine-tuned via grid-search, and BiomarkerML employs weighted, nested cross-validation to avoid model over-fitting and data leakage. ConclusionsBiomarkerML is scalable, provides a standardized, user-friendly interface, and streamlines analyses to ensure reproducibility of results. Overall, BiomarkerML is a significant advancement, enabling novice-ML researchers to use cutting-edge ML/DL tools to identify disease biomarkers in complex proteomic data.

bioinformatics↗

bioRxiv2025

A novel host-encoded protein, ETP2, plays an important role in endosymbiont division in the trypanosomatid Angomonas deanei

A single {beta}-proteobacterial endosymbiont, Candidatus Kinetoplastibacterium crithidii, resides in the cytosol of the trypanosomatid Angomonas deanei, and divides at a defined stage of its hosts cell cycle. This endosymbiont has a highly reduced genome of 0.8 Mb and, notably, has lost most essential genes involved in bacterial cell division, resulting in a loss of division autonomy. It has been previously demonstrated that a host-encoded dynamin-like protein, ETP9, plays an indispensable role in the division of the endosymbiont. In this study, we identified a second nucleus-encoded component of the endosymbiont division machinery, termed ETP2, currently annotated as a hypothetical protein. We observed that ETP2 localizes in a cell cycle-dependent manner at the bacterial division site, alongside the bacterium-encoded FtsZ. Furthermore, we demonstrated that ETP2 plays an important role for timely endosymbiont division and segregation, as a large fraction of cells in an etp2 deletion mutant cell line exhibited either long, filamentous endosymbionts accompanied by severely distorted host cells or host daughter cells lacking endosymbionts. In silico analyses revealed that ETP2 is found exclusively in endosymbiont-harboring trypanosomatids and is most likely an intrinsically disordered protein. Collectively, our data suggests that ETP2, alongside the previously described ETP9, is an integral component of the endosymbiont division machinery. This finding highlights the evolution of a complex host-derived molecular mechanism that exerts tight control over its endosymbiont without requiring gene transfers from the bacterium.

evolutionary biology↗

bioRxiv2025

T7 RNA polymerase-based gene expression from a transcriptionally silent rDNA spacer in the endosymbiont-harboring trypanosomatid Angomonas deanei

Eukaryotic life has been shaped fundamentally by the integration of bacterial endosymbionts. The trypanosomatid Angomonas deanei that contains a {beta}-proteobacterial endosymbiont, represents an emerging model to elucidate initial steps in symbiont integration. Although the repertoire of genetic tools for A. deanei is growing, no conditional gene expression system is available yet, which would be key for the functional characterization of essential or expression of toxic proteins. Development of a conditional expression system based on endogenous RNA polymerase II (POLII) is hampered by the absence of information on transcription signals in A. deanei as well as the unusual genetic system used in the Trypanosomatidae that relies on read-through transcription. This mode of transcription can result in polar effects when manipulating expression of genes in their endogenous loci. Finally, only few resistance markers are available for A. deanei yet, restricting the number of genetic modifications that can be introduced into one strain. To increase the range of possible genetic manipulations in A. deanei, and in particular, build the base for a conditional expression system that does not interfere with the endogenous gene expression machinery, here we (i) implemented two new drug resistance markers, (ii) identified the spacer upstream of the rDNA array on chromosome 13 as transcriptionally silent genomic locus, and (iii) used this locus for engineering an ectopic expression system that depends on the T7 RNA polymerase expressed from the {delta}-amastin locus. We show that transgene expression in this system is independent of the activity of endogenous RNA polymerases, reaches expression levels similar to the previously described POLII-dependent expression from the {gamma}-amastin locus, and can be applied for studying endosymbiosis. In sum, the new tools expand the possibilities for genetic manipulations of A. deanei and provide a solid base for the development of an ectopic conditional expression system.

genetics↗

bioRxiv2024

Role of miRNA 383 in regulating the mitochondrial machinery and carcinogenesis

MicroRNAs are a class of small non-coding RNAs, which regulate the expression pattern of various genes in a mechanism similar to RNAi. Along with their importance in normal physiology, microRNAs play crucial role in cancer initiation and progression. Various microRNAs have been reported to be associated with the important hallmarks of the cancer including altered mitochondrial machinery. With our in-silico analysis we found that miR 383 has targets on crucial mitochondrial genes involved in electron transport chain. So, next we checked the role of miR 383 in modulation of the mitochondrial machinery and effect of this alteration in the process of carcinogenesis. The results suggested that miR 383 contribute to carcinogenesis, possibly by modulating the mitochondrial machinery via targeting ND4L and ATP6 genes involved in the complex 1 & 5 of electron transport chain.

cancer biology↗

bioRxiv2024

MicroRNA 21 induces carcinogenesis in hepatic cells by modulating mitochondrial metabolism

Mitochondria plays crucial role in cells survivability and normal functioning. But in the case of cancer, the mitochondrial machinery (ETC) is altered and glycolytic pathway is activated as an alternate source of energy. The main reason behind the reprogramming of mitochondrial machinery could be mutations in mitochondrial genes or suppression of genes involved in normal functioning of the mitochondria. MicroRNAs could be a key player in modulating the mitochondrial metabolism, as they have targets on various important mitochondrial genes involved in the Electron Transport Chain of the mitochondria. Any alteration in the expression pattern of the mitochondrial genes would directly contribute to the modulation of normal functioning of the mitochondrial machinery. Micro RNA 21 is an oncomiR, located at q arm of the 17th chromosome. MiR 21 has been reported to be involved in many types of cancer. MiR 21 is reported to have targets on many important genes, crucial for cell survivability and proliferation, most of which falls in the category of tumor suppressor genes. With our bioinformatics analysis, we found that miR 21 has targets on important mitochondrial genes involved in the ETC. So, we tried to elucidate the role of miR 21 in modulation of the mitochondrial machinery and role of this alteration in the mitochondrial mechanism in carcinogenesis. Our results revealed that miR 21 have targets on the Cytochrome C Oxidase 1 (Cox1), which is directly involved in the Complex 4 of the electron transport chain. Next we checked the phenotypic effects of this down regulation of Cox1 by measuring the oxygen consumption by the mitochondria and found that O2 consumption goes significantly down in miR 21 over expressing cells. Along with this, we also checked if exosomes from miR 21 overexpressing cancer cells could induce the carcinogenesis in the normal hepatic cells and found that miR 21 accelerates the rate of cellular migration and enhances the colony formation. The results together suggest that miR 21 posses carcinogenic property, possibly by modulating mitochondrial machinery.

cancer biology↗

bioRxiv2024

MicroRNA 106b: Role in the reprograming of mitochondrial machinery and carcinogenesis in hepatic cells

Cancer is a disease of unregulated cell growth. The process of initiation and progression of cancer is called carcinogenesis and the factors possessing ability to induce carcinogenesis are called carcinogens. Along with the coding sequence, the non-coding sequence also play very crucial role in the process of carcinogenesis. MicroRNAs are small non-coding RNAs having targets on both the classes of genes important in cancer i.e., oncogenes and tumour suppressor genes, thus act as key play in carcinogenesis. Dysfunctional mitochondrial metabolism has been widely reported in cancer and this malfunctioning could be brought in by suppression of the expression pattern of important mitochondrial genes by microRNAs. Our in-silico analysis revealed that miR 106b possess targets on several important mitochondrial genes involved in various complexes of electron transport chain. Further, we checked the role of miR 106b in reprogramming of the mitochondrial mechanism and carcinogenesis. The results suggested that miR 106b contributes to carcinogenesis in hepatic cells by modulating the mitochondrial metabolism.

cancer biology↗

bioRxiv2024

ELUCIDATION OF THE ROLE OF miRNA 4263 IN DYSREGULATED MITOCHONDRIAL ENERGETICS AND CARCINOGENESIS

Dysfunctional mitochondria have been reported to be associated with several pathological conditions and in cancer, dysregulated mitochondrial metabolism is considered as an important hallmark of the disease. Cancer cells alter their mitochondrial machinery and activate glycolytic pathway as an alternate source of continuous energy, required for their indefinite growth. This modulation of the mitochondria could be due to the dysrupted expression of important mitochondrial genes involved in the normal functioning of the mitochondria. MicroRNAs are known to regulate the expression pattern of a variety of genes. With our in-silico analysis, we found that miR 4263 has targets on important mitochondrial genes, involved in mitochondrial energetics. Next, we checked the role of miR 4263 in modulating the mitochondrial metabolism and impact of this alteration on carcinogenesis. The results revealed that miR 4263 contributes to carcinogenesis in hepatic cells by altering the mitochondrial energetics.

cancer biology↗

bioRxiv2024

In-silico analysis of important mitochondrial microRNAs and their differential expression in mitochondria

Mitochondria, often called as the power house of cell, serves important role in cellular physiology and survivability. It plays crucial role in the normal functioning of the cell. Dysfunctional mitochondria have been found to be associated with various pathological conditions including cancer. The modulation of mitochondrial machinery could be due to the suppression of the expression pattern of important mitochondrial genes and microRNAs could be considered as the key player in reprograming of the mitochondrial metabolism. Apart from the microRNAs coded by mitochondrial genome, nuclear coded microRNAs gets localized to the mitochondria and they influence the mitochondrial machinery by targeting the important mitochondrial genes. This group of microRNAs are called mitochondrial miRNAs or MitomiRs. In this study we selected 10 important candidate mitochondrial microRNAs and checked their abundance in the cancerous and non cancerous hepatic cell line (HepG2 and WRL68), followed by their differential expression in the mitochondria of the respective cell line. The results shown an inverse relation in the expression pattern of the candidate microRNAs with mitochondrial target genes, suggesting their direct targeting, as predicted by our in-silico data.

cancer biology↗

bioRxiv2021

xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and MAK kinase cascade to regulate cilia morphology

Primary cilia are microtubule (MT)-based organelles that mediate sensory functions in multiple cell types. Disruption of cilia structure or function leads to a diverse collection of diseases termed ciliopathies (1-3). Mutations in the DUF3719 domain-containing protein FAM149B1 have recently been shown to elongate cilia via unknown mechanisms and result in the ciliopathy Joubert syndrome (4). The highly conserved CCRK and MAK/RCK kinases negatively regulate cilia length and structure in Chlamydomonas, C. elegans, and mammalian cells (5-11). How the activity of this kinase cascade is tuned to precisely regulate cilia architecture is unclear. Here we identify XBX-4, a DUF3719 domain-containing protein related to human FAM149B1, as a novel regulator of the DYF-18 CCRK and DYF-5 MAK kinase pathway in C. elegans. As in dyf-18 and dyf-5 mutants (11), sensory neuron cilia are elongated in xbx-4 mutants and exhibit altered axonemal MT stability. XBX-4 promotes DYF-18 CCRK activity to regulate DYF-5 MAK function and localization. We find that Joubert syndrome-associated mutations in the XBX-4 DUF3719 domain also elongate cilia in C. elegans. Our results identify a new metazoan-specific regulator of this highly conserved kinase pathway, and suggest that FAM149B1 may similarly act via the CCRK/MAK kinase pathway to regulate ciliary homeostasis in humans.

cell biology↗

bioRxiv2019

Acute toxicity of the plant volatile indole depends on herbivore specialization

Herbivore-induced plant volatiles (HIPVs) provide direct benefits to plants as antimicrobials and herbivore repellents, but their potential as direct toxins to herbivores is unclear. Here we assayed the larvicidal activity of six common HIPVs from three different biochemical pathways and tested the hypothesis that the larvicidal activity of HIPVs is related to the host specialization of the insect pest. We first assessed {beta}-caryophyllene, linalool, z-3-hexenyl acetate, z-3-hexenol, e-2-hexenol, and indole against the beet armyworm (Spodoptera exigua), and found that indole was 7-fold more toxic compared to the other volatiles when incorporated into diet. Then, we tested the larvicidal activity of indole against six common, destructive pest caterpillars with varying host ranges. Consistent with our hypothesis, indole toxicity varied with caterpillar host range: indole toxicity was seven-fold higher in more specialized insect species relative to generalist insect species. That said, the LC50 of indole was comparable to other reported anti-herbivore agents even against the generalist caterpillars. Yet, indole in headspace had neither larvicidal nor ovicidal activity on any caterpillar species tested. These results support a key ecological precept regarding tradeoffs between host specialization and chemical detoxification, and also indicate that indole functions as a direct defense against herbivores that could be potentially useful in integrated pest management strategies.\n\nKey messageO_LIWe measured the direct toxicity of six common HIPVs against the beet armyworm.\nC_LIO_LIIndole was the most toxic HIPV against the beet armyworm.\nC_LIO_LIWe determined the toxicity of indole against six different pest caterpillar species.\nC_LIO_LIToxicity of indole was associated with the host preference of the insect species.\nC_LIO_LIIndole exposure in headspace had no effect on egg hatching or caterpillar survival.\nC_LIO_LIIndole has the potential to be developed as an insecticide against crop pests.\nC_LI\n\nAuthor Contribution StatementCJF and AKM designed research. AKM and RCP conducted experiments. AKM and CJF analyzed data and wrote the manuscript. All authors read and approved the manuscript.

plant biology↗

bioRxiv2019

Plant seeds are primed by herbivore-induced plant volatiles

Mature plants can detect and respond to herbivore-induced plant volatiles (HIPVs) by priming or directly activating defenses against future herbivores. Whether other plant life stages can respond to HIPVs in similar manners is poorly understood. For example, seeds are known to respond to a variety of environment cues that are essential for proper germination timing and survival. Seeds may also be exposed to HIPVs prior to germination, and such exposure may affect the growth, development, and defense profiles when the seeds grow into mature plants. Here, we investigated the effect of seed exposure to common HIPVs on growth, reproduction and defense characteristics in the model plants Arabidopsis thaliana and Medicago truncatula. Of all the HIPVs tested, indole specifically reduced both beet armyworm growth on A. thaliana and pea 33 aphid fecundity on M. truncatula. Induction of defense genes was not affected by seed exposure to indole in either plant species, suggesting that seed priming operates independently of induced resistance. Moreover, neither species showed any negative effect of seed exposure to HIPVs on vegetative and reproductive growth. Rather, M. truncatula plants derived from seeds exposed to z-3-hexanol and z-3-hexenyl acetate grew faster and produced larger leaves compared to controls. Our results indicate that seeds are sensitive to specific HIPVs, which represents a novel ecological mechanism of plant-to-plant communication.

plant biology↗