Biology subjects

Talukder, P.

Publications and source records attributed to Talukder, P..

3 recordsLinked to original sources

bioRxiv2025

Mitotic polarity oscillation promotes epithelial tumor progression

Mitosis of epithelial cells requires a transient loss of epithelial polarity [1-5]. However, the nature of this mitotic polarity oscillation and its functional consequences for epithelial development are not fully understood. Here we show that the Crumbs (Crb) complex, a key regulator of epithelial polarity, is lost from the membrane during mitosis, and the Crb mutant phenotype is ameliorated when cell division is inhibited. Remarkably, an essential requirement of Crb for epithelial polarity is fully suspended when cell division is blocked in conjunction with inhibition of either cell ingression or cell intercalation. We conclude that the amount of morphogenetic stress induced by mitosis, ingression, and intercalation determines the requirement for Crb. Increased cell division and loss of cell polarity are two main drivers of epithelial cancer [6-8]. Maintaining epithelial polarity is important for limiting proliferation. Whether the loss of polarity during mitosis impacts tissue growth is less clear. We show that increasing cell division in a morphogenetically quiet epithelium not only increases tissue size but also causes hyperplastic to neoplastic transition. Conversely, reducing cell division restores epithelial polarity in neoplastic tissue of tumor mutants. Taken together, our study revealed that a major function of polarity factors in epithelial maintenance is to counteract morphogenetic stress. Moreover, we propose a feedforward mechanism that links cell division and the loss of polarity as a key driver of epithelial cancer.

cell biology↗

bioRxiv2025

Identifying a next-generation antimalarial trioxolane in a landscape of artemisinin partial resistance

For over two decades, artemisinin-based combination therapy (ACT) has been the standard of care for the treatment of uncomplicated falciparum malaria. However, artemisinin partial resistance (ART-R) is now prevalent in Southeast Asia and has emerged in eastern Africa, threatening ACT efficacy. Mechanistically, ART-R results from an endocytosis defect that limits concentrations of host-derived free heme in the parasite digestive vacuole, allowing early ring-stage parasites to survive exposure to the artemisinin component of ACT. The artemisinin-inspired 1,2,4-trioxolane artefenomel exhibits an extended pharmacokinetic exposure profile that predicts efficacy against ART-R parasites. Unfortunately, the development of artefenomel was halted recently after almost a decade of clinical trials. Herein, we describe the discovery of RLA-4735 and its single-enantiomer form RLA-5764, next-generation antimalarial trioxolanes that exhibit excellent in vitro potency against Plasmodium falciparum and single-exposure efficacy in a murine P. berghei model, thus retaining many of the favorable pharmacokinetic and pharmacodynamic properties of artefenomel while markedly improving solubility and development potential. In P. falciparum samples collected from patients in Uganda in 2019 and 2023, ex vivo ring-stage survival assays revealed the emergence of the ART-R phenotype over this timeframe, and furthermore demonstrated markedly superior activity of artefenomel and RLA-4735 as compared to dihydroartemisinin (the active metabolite of artemisinin components of ACTs) against ART-R parasites. Overall, our findings suggest a role for next-generation trioxolanes in addressing ART-R, and present a potent new, artefenomel-adjacent chemotype with good potential to deliver new development candidates. Summary SentenceKlope et. al. described the discovery and in vivo characterization of antimalarial endoperoxides effective against artemisinin-resistant parasites as potential development candidates for uncomplicated, blood-stage malaria.

pharmacology and toxicology↗

bioRxiv2022

Route of mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells

Respiratory tract resident memory T cells (Trm), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory Trm. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron-based nanoparticles. Here we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influence influenza-specific cell-mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 Trm in lung and draining lymph node. Contralateral, compared to ipsilateral, intramuscular boosting broadened the distribution of LN Trm and T follicular helper cells, but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory, but augmented distribution to the respiratory mucosa. Of note, combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung Trm. Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung Trm that can be further enhanced by an additional intranasal immunization.

immunology↗