Biology subjects

Vinod, A.

Publications and source records attributed to Vinod, A..

3 recordsLinked to original sources

bioRxiv2026

Multiple pathways couple kinetochore orientation to the meiotic spindle cycle

Meiosis generates haploid gametes from a diploid progenitor. In meiosis I, homologous chromosomes segregate while sister chromatids co-orient toward the same spindle pole. The mechanisms underlying this specialized segregation pattern remain incompletely understood. Here we identify pathways required for meiosis I chromosome segregation through a forward genetic screen in Saccharomyces cerevisiae. We find that meiosis I is highly sensitive to perturbations in diverse components of the segregation machinery and define key functional interfaces within complexes important for this division. These include meiosis I-specific regulators that establish the specialized chromosome pattern, namely the monopolin complex that directs sister kinetochore co-orientation and the Spo13MOKIR-Cdc5Polo module that promotes meiosis I chromosome segregation. In addition, we identify mutations affecting the core segregation machinery, including the spindle pole body, spindle midzone, and outer kinetochore, which can disrupt coupling between the chromosome segregation program and the meiotic spindle cycle. Together, our findings reveal that multiple pathways coordinate chromosome segregation with the meiotic divisions and highlight the unique demands of meiosis I.

cell biology↗

bioRxiv2025

Pathway Anchored Multimodal Clustering Reveals Circuit Level Signatures in Parkinsons Disease

Parkinsons disease is increasingly understood as a disorder of distributed brain circuits, yet most imaging analyses do not explicitly respect pathway structure. We introduce a pathway-anchored, multimodal clustering framework based on Scalable Robust Variational Compositional Co-clustering (SRVCC) that integrates structural MRI, free-water-corrected diffusion MRI, and DAT-SPECT in anatomically defined circuits. For each pathway, we derive a simple Multimodal Pathway Integrity Score (MPIS) that aggregates z-normalised volume, microstructural, and dopaminergic measures into an interpretable summary of imaging integrity. In the PPMI cohort, SRVCC identifies stable imaging-derived patient clusters and feature modules under explicit model selection and bootstrap/stability checks, with covariate-adjusted analyzes controlling for age, sex, education, and medication. MPIS shows coherent but modest structure-function associations: lower nigrostriatal and frontostriatal integrity relates to higher motor burden (UPDRS-III), while reduced sensory/visuospatial and limbic integrity is linked to lower global cognition (MoCA); microvascular markers robustly stratify imaging profiles but display minimal cross-sectional coupling to these global scales. Feature-level reports highlight dominant region-by-modality contributors (e.g., striatal DAT-SBR, thalamic and cerebellar morphology, white-matter hyperintensity metrics), providing a transparent bridge from multimodal data to circuit-level signatures. This pathway-aware representation offers a principled, reproducible way to summarise multimodal imaging in PD and may support future work on circuit-informed stratification, prognosis, and targeted outcome measures.

neuroscience↗

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↗