Biology subjects

Prabhu, J.

Publications and source records attributed to Prabhu, J..

4 recordsLinked to original sources

bioRxiv2024

RNA order regulates its interactions with zwitterionic lipid bilayers

RNA-lipid interactions directly influence RNA activity, which plays a crucial role in developing new applications in medicine and biotechnology. However, while specific preferential behaviors between RNA and lipid bilayers have been identified experimentally, their molecular origin remains unexplored. Here we use molecular dynamics simulations to investigate the interaction between RNA and membranes composed of zwitterionic lipids at the atomistic level. Our data reproduce and rationalize previous experimental observations, including that short-chain RNAs rich in guanine have higher affinity for gel-phase membranes compared to RNA sequences rich in other nucleotides and that RNA prefers gel-phase membranes to fluid bilayers. Our simulations reveal that RNA order is a key molecular determinant of RNA-zwitterionic phospholipid interactions. Our data provides a wealth of information at the atomic level that will help accelerating research on RNA-lipid assemblies for task-specific applications such as designing lipid-based nanocarriers for RNA delivery.

biophysics↗

bioRxiv2022

A comprehensive analysis of immune landscape of Indian triple negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous disease with a significant clinical challenge. TNBC alarmingly comprises 25-30% of breast cancers in India compared with only 10-15% in the West. However, immunotherapy was approved for high-risk early-stage TNBCs in the West. Hence, a long-standing question is whether Indian TNBCs immunologically and clinically resemble Western TNBCs such that they respond similarly to immunotherapies. Here we sought to elucidate the immune landscape of Indian TNBCs for the first time, compare them to Western disease and associate them with clinical parameters, cellular types/signaling, and immunotherapy response. MethodsWe profiled 730 immune genes in 88 retrospective Indian TNBC samples using NanoString platform, clustered them into subtypes using a machine-learning approach, and compared them with Western TNBCs (n=422; public datasets). Subtype-specific gene signatures were identified, followed by clinicopathological, immune cell type, and pathway (multiomics) analyses. We also assessed responses to (cross-cancer) immunotherapy. Tumor-infiltrating lymphocytes (TILs) and pan-macrophage marker were evaluated using hematoxilin-eosin staining and immunohistochemistry, respectively. ResultsWe identified three robust and similarly distributed TNBC immune transcriptome subtypes (Subtypes-1-3) in Indian women, and they are represented correspondingly in Western TNBCs and associated with well-known TNBC subtypes. Irrespective of the ethnicity, Subtype-1 harbored tumor microenvironmental and anti-tumor immune events associated with smaller tumors, younger age, and a better prognosis. Subtype-1 mainly represented basal-like/claudin-low breast cancer and immunomodulatory TNBC subtypes. Subtype-1 showed an increase in a cascade of events, including damage-associated molecular patterns, acute inflammation, Th1 responses, T-cell receptor-related and chemokine-specific signaling, antigen presentation, and viral-mimicry pathways. Subtype-1 was significantly (p<0.05) associated with pre-menopausal women, dense TILs and responses and/or improved prognosis to anti-PD-L1 and MAGEA3 immunotherapies. Subtype-2 was enriched for Th2/Th17 responses, CD4+ regulatory cells, basal-like/mesenchymal subtypes, and an intermediate prognosis. Subtype-3 patients expressed innate immune genes/proteins, including those representing macrophages and neutrophils, and had poor survival. ConclusionWe identified three immune-specific TNBC subtypes in Indian patients with differential clinical and immune behaviors, which largely overlapped with the Western TNBC cohorts. This study suggests cancer immunotherapy in TNBC may work similarly in both populations. Hence, this may expedite pharmaceutical adoption of immunotherapy to Indian TNBC patients.

cancer biology↗

bioRxiv2021

Re-charging your fats: Charmm36 parameters for neutral lipids triacylglycerol and diacylglycerol

Neutral lipids (NLs) are an abundant class of cellular lipids. They are characterized by the total lack of charged chemical groups in their structure, and, as a consequence, they play a major role in intracellular lipid storage. NLs that carry a glycerol backbone, such as triacylglycerols (TGs) and diacylglycerols (DGs), are also involved in the biosynthetic pathway of cellular phospholipids, and they have recently been the subject of numerous structural investigations by means of atomistic molecular dynamics (MD) simulations. However, conflicting results on the physicochemical behavior of NLs were observed depending on the nature of the atomistic force field used. Here, we show that current phospholipid-derived CHARMM36 parameters for DGs and TGs cannot reproduce adequately interfacial properties of these NLs, due to excessive hydrophilicity at the glycerol-ester region. By following a CHARMM36-consistent parameterization strategy, we develop new parameters for both TGs and DGs that are compatible with both cutoffbased and Particle Mesh Ewald (PME) schemes for the treatment of Lennard Jones interactions. We show that our new parameters can reproduce interfacial properties of NLs and their behavior in more complex lipid assemblies. We discuss the implications of our findings in the context of intracellular lipid storage and NLs cellular activity.

biophysics↗

bioRxiv2020

PTPN11/SHP2 negatively regulates growth in breast epithelial cells: implications on tumorigenesis

PTPN11/SHP2, a non-receptor protein tyrosine phosphatase is a prominent target of the receptor tyrosine kinase that participates in positive feedback signalling of the human epidermal growth factor receptors and helps in growth and migration. PTPN11/SHP2 is widely believed to be an oncoprotein, although its possible tumor-suppressor role is also reported. Our analysis of breast cancer metadata shows, PTPN11/SHP2 copy number loss in luminal A subtype is correlated to poor disease-specific survival and late-stage cancer at diagnosis. Analysis of the level 4 Reverse Phase Protein Array (RPPA) data available on the TCGA database resulted in positive correlations between the lower expression levels of constitutively active variant, the phospho-SHP2-Y542, of PTPN11/SHP2 and larger tumor size and lymph node positivity. We experimentally examined possible negative regulation of growth by PTPN11/SHP2 using MCF10A, a normal breast epithelial cell line. Knock-down of PTPN11/SHP2 resulted in increased cell migration, cell shape changes to mesenchymal morphology, and increased survival in cells treated with epirubicin, a DNA-damaging drug. However, it did not alter the rate of cell proliferation. It is possible that PTPN11/SHP2 might function as a tumor suppressor by potentiating proliferating cells with increased cell migration and resistance to apoptosis. Statement of SignificanceMolecules like PTPN11/SHP2, among many others that show dual specificity in tumorigenesis in the same tissue depending on the upstream signaling cues, present challenges in the field of targeted drug therapy. This study puts forth the importance of understanding the mechanism of one of the two outcomes and thereby helps better clinical management of a subgroup of cancer.

cancer biology↗