Biology subjects

Kelly, R. L.

Publications and source records attributed to Kelly, R. L..

5 recordsLinked to original sources

bioRxiv2025

Lab-in-the-loop therapeutic antibody design with deep learning

Therapeutic antibody design is a complex multi-property optimization problem with substantial promise for improvement with the application of machine-learning methods. Towards realizing that promise, we introduce "Lab-in-the-loop," a new approach that orchestrates state-of-the-art repertoire mining methods, generative machine learning models, multi-task property predictors, active learning ranking and selection, and in vitro experimentation in a semi-autonomous, iterative optimization loop. By automating the design of antibody variants, property prediction, ranking and selection of designs to assay in the lab, and ingestion of in vitro data, we enable an end-to-end approach to developing computationally-informed therapeutic antibody design pipelines. We apply lab-in-the-loop to eleven seed antibodies obtained via animal immunization with four clinically relevant antigen targets: EGFR, IL-6, HER2, and OSM. Over 1,800 unique antibody variants are tested throughout four rounds of iterative optimization identifying 3-100x better binding variants for all targets and 10/11 seeds, with the best binders exceeding 100 pM affinity, demonstrating a process by which end-to-end machine learning can be developed for therapeutic antibody development.

bioengineering↗

bioRxiv2024

Iron limitation differentially affects viral replication in key marine microbes

Viral lysis accounts for much of microbial mortality in the ocean, and iron (Fe) is a critical micronutrient that can limit phytoplankton growth, yet interactions between Fe-nutrition and viral lysis are not well known. Here, we present viral infection dynamics under Fe-limited and Fe-replete conditions for three distinct marine microbes, the photosynthetic picoeukaryote Ostreococcus lucimarinus, the cyanobacterium Synechococcus, and two strains of the heterotrophic bacterium Vibrio. Iron limitation of Ostreococcus resulted in slowed growth, and a corresponding decrease in viral burst sizes was observed; this is similar to results from studies of larger eukaryotic phytoplankton (Slagter et al. 2016; Kranzler et al. 2021), where reduced viral replication under Fe-limitation is attributed to the viral reliance on host metabolism and replication machinery. For one strain of Vibrio, Fe-limitation similarly impacted viral dynamics, increasing the latent period before infected cells burst to release new virus, and reducing the number of infective viral particles released upon viral lysis. Unexpectedly, for another strain of Vibrio, Fe-limitation had no discernible effect on viral replication. Furthermore, dynamics of three Synechococcus cyanophages was not affected by Fe-limitation of the host, either in terms of latent period or burst size. The results illuminate the extraordinary ability of some marine viruses, particularly cyanophages, to highjack host metabolism to produce new viral particles, even when host growth is compromised. This has implications for marine ecology and carbon cycling in Fe-limited regions of the global ocean.

microbiology↗

bioRxiv2023

Brazilin is a Natural Product Inhibitor of the NLRP3 Inflammasome

Excessive or aberrant NLRP3 inflammasome activation has been implicated in the progression and initiation of many inflammatory conditions; however, currently no NLRP3 inflammasome inhibitors have been approved for therapeutic use in the clinic. Here we have identified that the natural product brazilin effectively inhibits both priming and activation of the NLRP3 inflammasome in cultured murine macrophages, a human iPSC microglial cell line and in a mouse model of acute peritoneal inflammation. Through computational modelling, we predict that brazilin can adopt a favourable binding pose within a site of the NLRP3 protein which is essential for its conformational activation. Our results not only encourage further evaluation of brazilin as a therapeutic agent for NLRP3-related inflammatory diseases, but also introduce this small-molecule as a promising scaffold structure for the development of derivative NLRP3 inhibitor compounds.

molecular biology↗

bioRxiv2022

Open science resources from the Tara Pacific expedition across coral reef and surface ocean ecosystems

AbstractThe Tara Pacific expedition (2016-2018) sampled coral ecosystems around 32 islands in the Pacific Ocean and the ocean surface waters at 249 locations, resulting in the collection of nearly 58,000 samples. The expedition was designed to systematically study warm coral reefs and included the collection of corals, fish, plankton, and seawater samples for advanced biogeochemical, molecular, and imaging analysis. Here we provide a complete description of the sampling methodology, and we explain how to explore and access the different datasets generated by the expedition. Environmental context data were obtained from taxonomic registries, gazetteers, almanacs, climatologies, operational biogeochemical models, and satellite observations. The quality of the different environmental measures has been validated not only by various quality control steps but also through a global analysis allowing the comparison with known environmental large-scale structures. Such a wide released datasets opens the perspective to address a wide range of scientific questions.

ecology↗

bioRxiv2020

Characterization of a RAD51C-Silenced High Grade Serous Ovarian Cancer Model During PARP Inhibitor Resistance Development

Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated in the tumor, leading to homologous recombination deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived xenograft PH039, which lacks demonstrable repair gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by repeated 21-day niraparib treatments in vivo. PH039 acquired PARPi resistance by the third cycle of treatment and demonstrated unimpeded growth during subsequent exposure to either niraparib or rucaparib. Transcriptional profiling throughout the time course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of RAD51C methylation in patient tumor samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated that loss of RAD51C methylation prior to on-study biopsy was associated with limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide an important model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.

cancer biology↗