Biology subjects

Stokes, J.

Publications and source records attributed to Stokes, J..

6 recordsLinked to original sources

bioRxiv2025

SyntheMol-RL: a flexible reinforcement learning framework for designing novel and synthesizable antibiotics

The rise of antibiotic-resistant pathogens such as Staphylococcus aureus has created an urgent need for new antibiotics. Generative artificial intelligence (AI) has shown promise in drug discovery, but existing models often fail to propose compounds that are both effective and synthetically tractable. To address these challenges, we introduce SyntheMol-RL, a reinforcement learning-based generative model that can rapidly design synthetically accessible small molecule drug candidates from a massive chemical space of 46 billion compounds. SyntheMol-RL improves upon our prior Monte Carlo Tree Search (MCTS)-based SyntheMol model by generalizing across chemically similar building blocks and enabling multi-parameter optimization. We applied SyntheMol-RL to generate candidate antibiotics against S. aureus by optimizing for both antibacterial activity and aqueous solubility, and we found that SyntheMol-RL generated molecules with improved predicted properties compared to both the previous MCTS version of SyntheMol as well as an AI-based virtual screening baseline. We synthesized 79 SyntheMol-RL compounds that were unique relative to the training dataset and found that 13 showed potent in vitro activity, of which seven were structurally novel after detailed literature searches. Furthermore, one hit compound, synthecin, demonstrated efficacy in a murine wound infection model of methicillin-resistant S. aureus (MRSA). These results validate SyntheMol-RLs ability to generate novel and synthetically accessible candidate antibiotics and position SyntheMol-RL as a powerful tool for drug design across therapeutic domains.

biochemistry↗

bioRxiv2025

Investigation of the global transportation of Culicoides biting midges, vectors of livestock and equid arboviruses, from flower-packing plants in Kenya

BackgroundIn recent decades there has been a huge increase in the export of cut flowers from countries in Africa and elsewhere to European flower markets, with the vast majority first entering the Netherlands for local use or for export. Coincidentally, two significant livestock disease outbreaks caused by viruses associated with Africa or other tropical regions, were first detected in the Netherlands (bluetongue virus, BTV, 2006) and in western Germany about 200 km from the Netherlands border (Schmallenberg virus, SBV, 2011). This study aimed to determine whether Culicoides biting midges, the vectors of BTV and SBV, are present within flower-packaging plants in East Africa, and therefore whether Culicoides could be unknowingly exported during the shipping of cut flowers. MethodsField sampling was undertaken at a flower-packaging facility in Kenya, East Africa. The facility undertook all stages of cut flower production from maintaining rootstock through to packaging and shipping to an airport for international export. Trapping was undertaken at each stage of production (rootstock, propagation, inside growing greenhouses, in the packing-house, inside cold-storage rooms, during transportation) using CDC Light Emitting Diode (LED) light traps. Hand-held aspirators were used to obtain individual insects directly from flowers and around composting sites, while emergence traps studied insect emergence from compost, leaf-litter and flowers discarded at quality control checkpoints. ResultsA maximum nightly catch of 269 Culicoides were identified on a half-acre smallholding, containing 15 ruminants and 40 birds, located 20 m from the nearest greenhouse. Greatest numbers of Culicoides were trapped at a pond (n = 23) and leaf-litter compost site (n = 19) within the curtilage of the flower-packaging plant. Of the seven greenhouses sampled, three had Culicoides trapped overnight (mean = 4, range: 1-9), and no Culicoides were trapped in the propagation units. No Culicoides were trapped in the pack house, cold-store, or during transportation of the flowers to the airport for shipment. No Culicoides emerged from emergence traps or were trapped when aspirating directly from flowers. ConclusionsThis is the first study to investigate whether Culicoides are present within flower packaging plants in Africa. The results highlight that although present in small numbers both outside and within greenhouses, the presence of Culicoides declined with each stage of production. Therefore, the risk of exporting Culicoides with packaged cut flowers is non-zero but likely very small.

ecology↗

bioRxiv2021

Leukocyte proliferation mediates disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of Leigh syndrome. Directly depleting leukocytes with a colony-stimulating factor 1 receptor (CSF1R) inhibitor dramatically attenuates disease, including complete prevention of CNS lesion formation and substantial extension of survival. Leukocyte depletion rescues a range of symptoms including hyperlactemia, seizures, respiratory function, and neurologic symptoms. These data provide a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement directly drives disease. These findings have significant implication for the mechanisms of disease resulting from mitochondrial dysfunction, and may lead to novel therapeutic strategies. One-Sentence SummaryPharmacologic targeting of leukocytes prevents CNS lesions, neurological disease, and metabolic dysfunction in the Ndufs4(KO) mouse model of Leigh syndrome.

pathology↗

bioRxiv2020

Mechanisms underlying neonate specific metabolic effects of volatile anesthetics

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well-documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood {beta}-hydroxybutarate ({beta}-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. {beta}-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of {beta}-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.

physiology↗

bioRxiv2019

The biofilm matrix scaffold of Pseudomonas species consists of non-canonically base paired extracellular DNA and RNA

While extracellular DNA (eDNA) is recognized as a critical biofilm matrix component, it is not understood how it contributes to biofilm function. Here we isolate eDNA from Pseudomonas biofilms using ionic liquids, and discover that its key biophysical signatures, i.e. fluid viscoelasticity, nucleic acid conformation, and temperature and pH dependencies of gel to solution transitions, are maintained. Solid-state analysis of isolated eDNA, as a proxy for eDNA structure in biofilms, revealed non-canonical Hoogsteen base pairs, triads or tetrads involving guanine and thymine or uracil. These were less abundant in chromosomal DNA and undetected as eDNA underwent gel-sol transition. Purine-rich RNA was present in the eDNA network, which potentially enables eDNA to be the main cross-linking exopolymer in the matrix through non-canonical nucleobase interactions. Our study suggests that Pseudomonas assemble extracellular DNA and RNA into a network with viscoelastic properties, which underpin their persistence and spreading, and may aid the development of more effective controls for biofilm-associated infections.

biochemistry↗

bioRxiv2017

Infant Weight Gain Trajectories Linked To Oral Microbiome Composition

Gut and oral microbiome perturbations have been observed in obese adults and adolescents. Less is known about how weight gain in early childhood is influenced by gut, and particularly oral, microbiomes. Here we analyze the relationships among weight gain and gut and oral microbiomes in 226 two-year-olds who were followed during the first two years of life, as part of a larger study, with weight and length measured at seven time points. We used these data to identify children with rapid weight gain (a strong risk factor for childhood obesity), and to derive growth curves with novel Functional Data Analysis (FDA) techniques. The childrens oral and gut microbiomes were sampled at the end of the two-year period, and surveyed with 16S sequencing. First, we show that growth curves are associated negatively with diversity and positively with Firmicutes-to-Bacteroidetes ratio of the oral microbiome - a relationship that is also observed in children with rapid (vs. non-rapid) weight gain. We also demonstrate an association between the gut microbiome and child growth, but only when considering the effect of diet on the microbiome. Lastly, we identify several bacterial genera that are associated with child growth patterns. These results suggest that by the age of two, the oral microbiome may have already begun to establish patterns often seen in older obese individuals. They also suggest that the gut microbiome, while strongly influenced by diet, at age two does not harbor obesity signatures many researchers identified in later life stages.

genomics↗