Search bioRxiv⌕ Search

Biology subjects

Bharati, A.

Publications and source records attributed to Bharati, A..

2 recordsLinked to original sources

Integrative genomics reveals shared and stress-specific adaptive pathways underlying acidic soil-associated metal toxicity in rice

Soil acidity-associated toxicities of aluminum (Al), cadmium (Cd), and manganese (Mn) severely constrain rice productivity in upland ecosystems. To investigate the genomic basis of adaptation to acidic soil-related metal stress, we conducted an integrated meta-QTL (M-QTL) and functional genomics analysis in rice. Meta-analysis of 681 QTLs and MTAs from 53 QTL mapping and GWAS studies identified 79 robust M-QTLs, including ten overlapping regions associated with Al-, Cd-, and Mn-responsive traits. A multi-criteria prioritization framework identified 98 candidate genes supported by positional overlap, transcriptomic recurrence, and functional annotation, enriched for ion transport, detoxification, and redox regulation pathways. M-QTL10.9 emerged as a major hotspot enriched for glutathione-S-transferase genes, whereas M-QTL9.5 contained the highest density of prioritized candidates linked to Al and Cd responses. Comparative physiological & biochemical analyses of the contrasting rice genotypes Sahasarang and IR64 revealed genotype-dependent differences in antioxidant responses, metal partitioning, metabolic regulation, and cell wall remodeling under individual and combined metal stresses. Expression profiling of prioritized candidate genes, including OsACO family genes, OsZIP10, and OsGSTU10, further revealed genotype-dependent transcriptional divergence under combined stress. The identification of overlapping M-QTLs across Al, Cd, and Mn datasets suggests both shared and stress-specific adaptive responses to acidic soil-associated metal stress in rice.

genomics↗

Modulation of blood-tumor barrier transcriptional programs improves intra-tumoral drug delivery and potentiates chemotherapy in GBM

Glioblastoma (GBM) is the most common malignant primary brain tumor. GBM has an extremely poor prognosis and new treatments are badly needed. Efficient drug delivery to GBM is a major obstacle as the blood-brain barrier (BBB) prevents passage of the majority of cancer drugs into the brain. It is also recognized that the blood-brain tumor barrier (BTB) in the growing tumor represents a challenge. The BTB is heterogeneous and poorly characterized, but similar to the BBB it can prevent therapeutics from reaching effective intra-tumoral doses, dramatically hindering their potential. Here, we identified a 12-gene signature associated with the BTB, with functions related to vasculature development, morphogenesis and cell migration. We identified CDH5 as a core molecule in this set and confirmed its over-expression in GBM vasculature using spatial transcriptomics of GBM patient specimens. We found that the indirubin-derivative, 6-bromoindirubin acetoxime (BIA), could downregulate CDH5 and other BTB signature genes, causing endothelial barrier disruption in endothelial monolayers and BBB 3D spheroids in vitro. Treatment of tumor-bearing mice with BIA enabled increased intra-tumoral accumulation of the BBB non-penetrant chemotherapeutic drug cisplatin and potentiated cisplatin-mediated DNA damage by targeting DNA repair pathways. Finally, using an injectable BIA nanoparticle formulation, PPRX-1701, we significantly improved the efficacy of cisplatin in patient-derived GBM xenografts and prolonged their survival. Overall, our work reveals potential targets at the BTB for improved chemotherapy delivery and the bifunctional properties of BIA as a BTB modulator and potentiator of chemotherapy, supporting its further development.

cancer biology↗