Biology subjects

Patel, D. M.

Publications and source records attributed to Patel, D. M..

5 recordsLinked to original sources

bioRxiv2025

Mechanistic insights and clinical implications of cross-reactive anti-prophage antibodies and bacterial heteroresistance on phage therapeutic failure

Phage therapy is an exciting strategy against antimicrobial-resistant bacterial infections, but critical knowledge gaps regarding its clinical application persist. Studying a patient with a life-threatening, chronic bacterial infection who failed phage therapy, we uncovered important biological concepts with direct translational impact. Using longitudinal clinical samples, we found that patients can harbour pre-existing antibodies against active prophages induced from the genome of the causative pathogen. Notably, these antibodies can contribute to clinical failure by cross-reacting with and effectively neutralising therapeutic phage. We also uncovered bacterial heteroresistance, characterised by bacterial subpopulations from the initial infection with reduced phage susceptibility, as a further contributor to treatment failure. These findings highlight the intricate interplay between host immunology, bacterial genetic diversity and phage biology, bearing broad significance for clinical phage therapy. Future phage therapy patients, especially those with chronic infections, should be screened for antiphage immunity and bacterial heteroresistance prior to phage treatment.

microbiology↗

bioRxiv2024

Unravelling biological processess and EGFR pathway regulation by the receptor-like protein tyrosine phosphatase PTPRH in non-small cell lung cancer

The balance of protein phosphorylation is often disrupted in cancer, with hyperactivity of kinases and inactivation of phosphatases driving cell proliferation and survival pathways. PTPRH, a protein tyrosine phosphatase, is mutated in [~]5% of non-small cell lung cancers (NSCLC). However, how PTPRH contributes to biological processes and tumorigenesis was unknown. We uncovered PTPRHs candidate interactors and associated pathways by applying a proximity-dependent biotinylation assay (BioID) and generating a signature transcriptome in two NSCLC cell lines derived from the primary tumor (NCI-H23) or a metastatic site (NCI-H2023), followed by functional validation. Candidate interactors included signaling molecules and structural proteins linked to integrins and focal adhesions, adherens junctions, migration, and the cytoskeleton, in addition to interactions with the receptor tyrosine kinases EGFR, EPHA2, and ROR2, and the phosphatases PTPN3 and PTPRJ. Considering the importance of EGFR in lung cancers and the role of EPHA2 in regulating cell adhesion, we examined how PTPRH regulates their signaling. Overexpression of PTPRH decreased EGFR phosphorylation at tyrosine 1173. It also reduced phospho-EPHA2, with one of the target tyrosine residues identified as the ligand-dependent Y588. At the cellular level, PTPRH and EPHA2 colocalize, with PTPRH gain inducing morphological alterations, such as increased eccentricity, smaller size and changes in the cytoskeleton organization in NCI-H23 cells. These changes are accompanied by increased FAK Y397 phosphorylation, but reduced cell adhesion to the ECM. Additionally, pathway enrichment analysis revealed downregulation of multiple oncogenic, metabolic, and cell adhesion signaling pathways, with increased levels of PTPRH leading to reduced migration in vitro, suppressed tumor growth and lung colonization and tumor differentiation in vivo. Interestingly, some alterations may be independent of PTPRH catalytic activity and tailored to a cell lines site of origin and genetic background. These results indicate that PTPRH regulates key signaling, structural networks, and tumor behavior with loss facilitating NSCLC progression.

cancer biology↗

bioRxiv2024

Spleen gene expression is associated with mercury content in three-spined stickleback populations

Mercury can be very toxic at low environmental concentrations by impairing immunological, neurological, and other vital pathways in humans and animals. Aquatic ecosystems are heavily impacted by mercury pollution, with evidence of biomagnification through the food web. We examined the effect of mercury toxicity on the spleen, one of the primary immune organs in fish, in natural populations of the three-spined stickleback (Gasterosteus aculeatus Linnaeus, 1758). Our aim was to better understand adaptation to high mercury environments by investigating transcriptomic changes in the spleen. Three stickleback populations with mean Hg muscle concentrations above and three populations with mean Hg muscle concentrations below the European Biota Quality Standard of 20 ng/g wet weight were selected from the Scheldt and Meuse basin in Belgium. We then conducted RNA sequencing of the spleen tissue of 22 females from these populations. We identified 136 differentially expressed genes between individuals from populations with high and low mean mercury content. The 129 genes that were upregulated were related to the neurological system, immunological activity, hormonal regulation, and inorganic cation transporter activity. Seven genes were downregulated and were all involved in pre-mRNA splicing. The results are indicative of our ability to detect molecular alterations in natural populations that exceed an important environmental quality standard. This allows us to assess the biological relevance of such standards, offering an opportunity to better describe and manage mercury-associated environmental health risks in aquatic populations.

ecology↗

bioRxiv2024

Growth parameters of the clupeids Limnothrissa miodon and Stolothrissa tanganicae in northern Lake Tanganyika (Bujumbura sub-basin)

The analysis of growth parameters in fish stocks, such as the asymptotic length (L{infty}) and the curvature parameter (K), is crucial for the estimation of production rates and total mortality rates in fisheries management. Here, we estimated the growth parameters of the clupeids Limnothrissa miodon and Stolothrissa tanganicae in the northern part of Lake Tanganyika (Bujumbura sub-basin). Both species are important targets of pelagic fisheries, but the available estimates are based on scarce size frequency data, and rarely on size as a function of age data. We provide new estimates of L{infty} and K based on size as a function of age data, with age being inferred from otolith weights. Furthermore, we reanalyze several existing length frequency datasets using advanced statistical procedures to test if growth parameters estimated by length frequency analysis are consistent with those obtained from size as a function of age. We found that length frequency analysis consistently underestimates L{infty} and overestimates K as compared to length-at-age data. We recommend that length-at-age data are collected at a much broader spatial and temporal scale than currently available to advance our understanding of the growth dynamics of these two sardine species. This will improve the assessment of stock productivity of Lake Tanganyikas pelagic fisheries and the conservation of these economically important fish species.

ecology↗

bioRxiv2021

Immune and malignant cell phenotypes of ovarian cancer are determined by distinct mutational processes

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, intratumoral heterogeneity and intraperitoneal spread. We investigated determinants of immune recognition and evasion in HGSOC to elucidate co- evolutionary processes underlying malignant progression and tumor immunity. Mutational processes and anatomic sites of tumor foci were key determinants of tumor microenvironment cellular phenotypes, inferred from whole genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumor sites from 42 treatment-naive HGSOC patients. Homologous recombination-deficient (HRD)-Dup (BRCA1 mutant-like) and HRD- Del (BRCA2 mutant-like) tumors harbored increased neoantigen burden, inflammatory signaling and ongoing immunoediting, reflected in loss of HLA diversity and tumor infiltration with highly- differentiated dysfunctional CD8+ T cells. Foldback inversion (FBI, non-HRD) tumors exhibited elevated TGF{beta} signaling and immune exclusion, with predominantly naive/stem-like and memory T cells. Our findings implicate distinct immune resistance mechanisms across HGSOC subtypes which can inform future immunotherapeutic strategies. HIGHLIGHTSO_LIMulti-region, multi-modal profiling of malignant and immune cell phenotypes in ovarian cancer C_LIO_LIAnatomic site specificity is a determinant of cancer cell and intratumoral immune phenotypes C_LIO_LITumor mutational processes impact mechanisms of immune control and immune evasion C_LIO_LISpatial topology of HR-deficient tumors is defined by immune interactions absent from immune inert HR-proficient subtypes C_LI

cancer biology↗