Biology subjects

Raju, R.

Publications and source records attributed to Raju, R..

6 recordsLinked to original sources

bioRxiv2025

BC-Predict Database: A Curated Resource of Experimentally Validated Markers in Multidrug Resistance in Breast Cancer

BackgroundIn this study, we aim to develop a yearly updatable database that could predict chemotherapeutic drug resistance and overall survival probability in breast cancer patients. Existing drug sensitivity databases depend on correlation-based predictions. In our study, candidates involved in drug resistance are chosen based on cell line validation (overexpression or downregulation or inhibition of candidates) studies, curated manually. Method28,773 mRNA expression signatures from 914 breast cancer patients were extracted from cProsite. 106 of these patients had clinical information and log2 fold change information required for this study. We categorized these patients into deceased and surviving groups from TCGA. To prepare a database that can predict drug resistance and overall survival, we included mRNAs that were over-expressed in at least 80% of the breast cancer patients and mRNAs over-expressed in deceased and surviving groups. In addition, we also reported breast cancer-associated drug resistance candidates which have been reported in cell-line based studies. The database matrix preparation involved an approximate of 15000 manual searches of cell validated studies. (750 candidates x 20 drugs). The database was validated using a publicly available breast cancer patient proteomics data. ResultsOur analysis identified a list of top priority candidates associated with multidrug resistance, categorized based on their resistance to >15 drugs, 5-15 drugs, and 2-4 drugs. Analysis of patient profiles in the database revealed that the number of proteins contributing to drug resistance was high in the poor prognosis category compared to the good prognosis category. ConclusionsOur study highlights the probable gaps in breast cancer drug resistance research, as only a small subset of overexpressed mRNA candidates found in patients are studied in vitro or in vivo experiments focusing on drug resistance. We also identified candidates involved in multidrug resistance, whose role in drug resistance has not been studied in more than 15 drugs. After further validations, this will benefit the clinicians and upcoming CRISPR gene therapeutics.

cancer biology↗

bioRxiv2024

The role of cholinergic signaling in multi-sensory gamma stimulation induced perivascular clearance of amyloid

Modulatory neurotransmitters exert powerful control over neurons and the brain vasculature. Gamma Entrainment Using Sensory Stimuli (GENUS) promotes amyloid clearance via increased perivascular cerebral spinal fluid (CSF) flux in mouse models of Alzheimers Disease. Here we use whole-brain activity mapping to identify the cholinergic basal forebrain as a key region responding to GENUS. In line with this, GENUS promoted cortical acetylcholine release, vascular dilation, vasomotion and perivascular clearance. Inhibiting cholinergic signaling abolished the effects of GENUS, including the promotion of arterial pulsatility, periarterial CSF influx, and the reduction of cortical amyloid levels. Our findings establish cholinergic signaling as an essential component of the brains ability to promote perivascular amyloid clearance via non-invasive sensory stimulation.

neuroscience↗

bioRxiv2024

Tendon-associated gene expression precedes osteogenesis in mid-palatal suture establishment

Orthodontic maxillary expansion relies on intrinsic mid-palatal suture mechanobiology to induce guided osteogenesis, yet establishment of the mid-palatal suture within the continuous secondary palate and causes of maxillary insufficiency remain poorly understood. In contrast, advances in cranial suture research hold promise to improve surgical repair of prematurely fused cranial sutures in craniosynostosis to potentially restore the obliterated signaling environment and ensure continual success of the intervention. We hypothesized that mid-palatal suture establishment is governed by shared principles with calvarial sutures and involves functional linkage between expanding primary ossification centres with the midline mesenchyme. We characterized establishment of the mid-palatal suture from late embryonic to early postnatal timepoints. Suture establishment was visualized using histological techniques and multimodal transcriptomics. We identified that mid-palatal suture formation depends on a spatiotemporally controlled signalling milieu in which tendon-associated genes play a significant role. We mapped relationships between extracellular matrix-encoding gene expression, tenocyte markers, and novel suture patency candidate genes. We identified similar expression patterns in FaceBase-deposited scRNA-seq datasets from cranial sutures. These findings demonstrate shared biological principles for suture establishment, providing further avenues for future development and understanding of maxillofacial interventions.

developmental biology↗

bioRxiv2023

Dkk2 interacts with Pax9 in palate mesenchyme to pattern and tune osteogenesis

Multiple genetic and environmental etiologies contribute to the pathogenesis of cleft palate, which constitutes the most common among the inherited disorders of the craniofacial complex. Insights into the molecular mechanisms regulating osteogenic differentiation and patterning in the palate during embryogenesis are limited and needed for the development of innovative diagnostics and cures. This study utilized the Pax9-/- mouse model with a consistent phenotype of cleft secondary palate to investigate the role of Pax9 in the process of palatal osteogenesis. While prior research had identified upregulation of Wnt pathway modulators Dkk1 and Dkk2 in Pax9-/- palate mesenchyme, limitations of spatial resolution and technology restricted a more robust analysis. Here, data from single-nucleus transcriptomics and chromatin accessibility assays validated by in situ highly multiplex targeted single-cell spatial profiling technology suggest a distinct relationship between Pax9+ and osteogenic populations. Loss of Pax9 results in spatially restricted osteogenic domains bounded by Dkk2, which normally interfaces with Pax9 in the mesenchyme. These results suggest that Pax9-dependent Wnt signaling modulators influence osteogenic programming during palate formation, potentially contributing to the observed cleft palate phenotype.

developmental biology↗

bioRxiv2023

Integrated spatiotemporal transcriptomic resolution of embryonic palate osteogenesis

The differentiation of osteoblasts and the subsequent formation of bone marks an important terminal phase in palate formation that leads to the separation of the oral and nasal cavities. While the developmental events that precede palatal osteogenesis are well explored, major gaps remain in our understanding of the molecular mechanisms that lead to the bony union of fusing palatal shelves. Herein, the timeline of osteogenic transcriptional programming is unveiled in the embryonic palate by way of integrated bulk, single-cell, and spatially resolved RNA-seq analyses. We define spatially restricted expression patterns of key marker genes, both regulatory and structural, that are differentially expressed during palatal fusion, including the identification of several novel genes (Deup1, Dynlrb2, Lrrc23) spatially restricted in expression to the palate, providing a relevant framework for future studies that identify new candidate genes for cleft palate anomalies in humans as well as the timing of mammalian embryonic palatal osteogenesis.

developmental biology↗

bioRxiv2019

Robust lysosomal rewiring in Mtb infected macrophages mediated by Mtb lipids restricts the intracellular bacterial survival

Intracellular pathogens commonly manipulate the host lysosomal system for their survival, however whether this affects the organization and functioning of the lysosomal system itself is not known. Here, we show using in vitro and in vivo infections that the lysosomal content and activity is globally elevated in M. tuberculosis infected macrophages. The enhanced lysosomal state is sustained over time and defines an adaptive homeostasis of the infected cell. Lysosomal alterations are caused by mycobacterial surface components, notably the cell wall lipid SL-1, which functions through the mTORC1-TFEB axis. Mtb mutant defective for SL-1 levels shows reduced lysosomal content and activity compared to wild type. Importantly, this phenotype is conserved during in vivo infection. The alteration in lysosomal phenotype in mutant Mtb lead to decreased lysosomal delivery of Mtb, and importantly, increased survival of intracellular Mtb. These results define the global alterations in the host lysosomal system as a crucial distinguishing feature of Mtb infected macrophages that is host protective and contribute to the containment of the pathogen.

cell biology↗