Biology subjects

Noble, R.

Publications and source records attributed to Noble, R..

5 recordsLinked to original sources

bioRxiv2026

A neonatal rat sepsis score captures the time course and severity of disease in a clinically relevant rat peritonitis model.

BackgroundNeonatal sepsis is a major cause of infant morbidity and mortality worldwide, particularly in preterm and very low birthweight babies. Fundamental differences between neonates and adults warrant clinically relevant models of neonatal sepsis. Here, we describe a preclinical fecal-slurry (FS)-induced peritonitis model of polymicrobial sepsis in neonatal rats, along with a novel neonatal rat sepsis score (nRSS) to monitor illness severity. MethodsPeritonitis was induced in 3-day-old Sprague Dawley rats by intraperitoneal injection of various doses (0.3-1.5mg/g body weight) of fecal slurry (FS); control pups received equivalent doses of vehicle. All pups received analgesics (buprenorphine), antibiotics (ampicillin and gentamicin), and fluids (saline) to model clinical standards of sepsis treatment. Time-dependent changes in circulating cytokines (IL-6, IL-1{beta}) and biomarkers of sepsis pathology (hemoglobin, glucose, alanine transaminase [ALT] levels) were assessed and correlated with nRSS scores. ResultsFS administration caused a dose-dependent increase in severity of sepsis over time, as indicated by increases in mortality rates (based on predefined criteria for euthanasia), nRSS scores, as well as time-dependent changes in circulating glucose, hemoglobin, IL-6, IL-1{beta}, and ALT activity levels. nRSS scores correlated with all quantitative measures of sepsis pathology. Notably, females showed higher mortality and higher early NRSS scores than males at moderate to high FS doses, yet biochemical markers and time of death did not differ between sexes, suggesting that the apparent female vulnerability may reflect more conspicuous behavioral manifestations of illness rather than greater underlying physiological severity. ConclusionInduction of peritonitis in rats at postnatal day 3 produced a consistent and reproducible model of polymicrobial neonatal sepsis. Illness severity was monitored using a newly developed nRSS. By minimizing distress and incorporating standards of care, this model and scoring system may serve as a platform for future investigations into the underlying mechanisms and potential therapeutic interventions for neonatal sepsis. ImpactO_LIA clinically relevant rat model of neonatal polymicrobial sepsis was developed, incorporating standards of care (analgesics, antibiotics, and fluid resuscitation) to better reflect the clinical context in which preclinical findings must ultimately translate. C_LIO_LIA novel neonatal rat sepsis scoring system (nRSS) was developed and validated, providing a sensitive, non-invasive measure of disease severity that correlates with biochemical markers and predicts mortality. C_LIO_LIFemale pups showed higher mortality and earlier behavioral signs of illness than males despite equivalent biochemistry, highlighting that clinical scores may capture sex-dependent vulnerability not apparent in standard biochemical measures. C_LIO_LITogether, this model and scoring system offer a refined platform for mechanistic and therapeutic studies of neonatal sepsis while advancing the welfare-conscious 3Rs principles essential to rigorous preclinical research C_LI

physiology↗

bioRxiv2026

Phylogenetically distinct Vibrio mediterranei lineages confer robust protection under thermal stress against oyster pathogens

Marine bivalve mortality events cause substantial economic losses in aquaculture and threaten global food security. While pathogenic Vibrio species are frequently implicated, growing evidence suggests that loss of beneficial microbes can increase host susceptibility to disease. We previously observed that Vibrio mediterranei was consistently isolated from healthy oysters but systematically disappeared prior to mortality events, coinciding with proliferation of pathogenic Vibrio species. Here, we test whether this pattern reflects a protective functional role. Pre-colonization with V. mediterranei strain Vm02 increased Crassostrea virginica oyster larval survival from 10-19% (pathogen-only controls) to 94-97% when challenged with V. harveyi or V. coralliilyticus, representing near-complete protection from pathogen-induced mortality. Protection was maintained at both ambient (28{degrees}C) and thermal stress (32{degrees}C) temperatures where pathogen virulence is enhanced, rapid (effective from co-inoculation), and durable (maintained for >96 hours). Fluorescence microscopy confirmed stable colonization of larval digestive tissues by fluorescently-tagged Vm02. Larval colonization by eleven V. mediterranei strains revealed three distinct phenotypes - protective, pathogenic, and intermediate - corresponding to monophyletic clades with 97.1-97.8% average nucleotide identity between protective and pathogenic lineages. Pangenome analysis identified 230 protective-specific versus 80 pathogenic-specific orthogroups. Protective strains encode unique regulatory systems, stress tolerance mechanisms, and metabolic versatility while lacking Type I and Type VI secretion system variants associated with pathogenicity. Together, these findings demonstrate that beneficial versus pathogenic phenotypes are phylogenetically constrained within distinct V. mediterranei lineages. This supports reports that V. mediterranei acts as both a pathogen and potential symbiont in marine hosts and reveals a clade that provides robust protection against oyster pathogens. ImportanceAquaculture disease management has traditionally emphasized either prophylactic treatment using antibiotics to avoid disease and dysbiosis or has focused entirely on pathogen detection. Both of these approaches have overlooked the potential contributions of beneficial microbes to host defense and grow-out performance. Developing beneficial probiotic tools for disease prevention represents an emerging opportunity for sustainable aquaculture management. This study demonstrates that specific lineages of Vibrio mediterranei function as protective symbionts capable of rescuing oyster larvae from near-complete pathogen-induced mortality. By integrating field observations of microbial succession during mortality events with experimental validation and comparative genomics, we show that protective versus pathogenic phenotypes are phylogenetically constrained within V. mediterranei clades separated by 97.1-97.8% average nucleotide identity. This resolution of strain-level functional variation provides fundamental insights into how host-microbe mutualisms evolve within species complexes that also harbor pathogens. The unique genomic markers identified here enable reliable screening for protective symbionts, while the temperature-stable and durable protection demonstrated in this study highlights the potential for biological control strategies in shellfish hatcheries increasingly affected by warming oceans and Vibrio-driven mortality events.

microbiology↗

bioRxiv2026

Eastern oyster larvae assemble a core bacterial microbiome distinct from hatchery water treatment systems

Eastern oyster (Crassostrea virginica) larvae undergo rapid microbial colonization during early development, a process that may influence larval growth, performance, and hatchery production outcomes. However, the sources and assembly mechanisms of larval-associated bacterial communities remain poorly understood, limiting evidence-based strategies for managing beneficial microbiomes in hatchery settings. We characterized bacterial community composition in 5-day post-fertilization C. virginica larvae and across hatchery water treatment stages using 16S rRNA gene V3-V4 amplicon sequencing. Larval microbiomes were statistically distinct from all sampled water sources (PERMANOVA q [≤] 0.030), exhibited 1.9-fold lower Shannon diversity, and showed no relationship to sequential water treatment steps, which themselves did not differ in bacterial composition (all pairwise q = 0.107). We identified 39 core bacterial genera present in [≥]70% of larval samples, collectively representing 90% of larval sequences and dominated by Rhodobacteraceae/Paracoccaceae (39.5% abundance) and Alteromonadaceae/Marinomonadaceae (24.1%). Critically, 46.2% of core larval sequences belonged to genera highly abundant in larvae but rare (< 0.01%) in all water sources, indicating selective recruitment rather than passive environmental acquisition. Core larval microbiome composition closely parallels that of other marine invertebrates, suggesting conserved host-associated enrichment patterns during early life stages. These results indicate that host-mediated selection dominates larval oyster microbiome assembly, with implications for hatchery management strategies focused on promoting beneficial microbial functions and targeted community supplementation to support consistent larval growth and production efficiency. IMPORTANCEEastern oysters generate over $200 million annually in U.S. aquaculture and provide critical ecosystem services including water filtration and coastal habitat formation. Successful hatchery production depends not only on preventing disease and mortality, but also on promoting consistent larval growth, development, and yield. Microbial colonization during early larval stages is increasingly recognized as an important contributor to these outcomes, yet the origins and assembly of beneficial larval microbiomes remain poorly understood. Here, we show that oyster larvae do not simply reflect the microbial composition of hatchery water, but instead actively select a consistent set of bacterial partners in early development. This core larval microbiome is dominated by bacterial families associated with antimicrobial activity, nutrient provisioning, and host growth in other marine systems. Notably, these same bacterial families occur in the larvae of distantly related marine invertebrates, suggesting conserved and potentially beneficial host-microbe associations. Our findings indicate that hatchery water treatment alone is unlikely to determine larval microbiome composition. Instead, targeted strategies that promote or supplement beneficial larval-associated bacteria during early development may provide a more effective path toward improving growth, performance, stability, and overall production efficiency in oyster hatcheries.

microbiology↗

bioRxiv2020

Drug-induced resistance evolution necessitates less aggressive treatment

Evolution of drug resistance to anticancer, antimicrobial and antiviral therapies is widespread among cancer and pathogen cell populations. Classical theory posits strictly that genetic and phenotypic variation is generated in evolving populations independently of the selection pressure. However, recent experimental findings among antimicrobial agents, traditional cytotoxic chemotherapies and targeted cancer therapies suggest that treatment not only imposes selection but also affects the rate of adaptation via altered mutational processes. Here we analyze a model with drug-induced increase in mutation rate and explore its consequences for treatment optimization. We argue that the true biological cost of treatment is not limited to the harmful side-effects, but instead realizes even more profoundly by fundamentally changing the underlying eco-evolutionary dynamics within the microenvironment. Factoring in such costs (or collateral damage) of control is at the core of successful therapy design and can unify different evolution-based approaches to therapy optimization. Using the concept of evolutionary rescue, we formulate the treatment as an optimal control problem and solve the optimal elimination strategy, which minimizes the probability of evolutionary rescue. Our solution exploits a trade-off, where increasing the drug concentration has two opposing effects. On the one hand, it reduces de novo mutations by decreasing the size of the target cell population faster; on the other hand, a higher dosage generates a surplus of treatment-induced mutations. We show that aggressive elimination strategies, which aim at eradication as fast as possible and which represent the current standard of care, can be detrimental even with modest drug-induced increases (fold change[≤] 10) to the baseline mutation rate. Our findings highlight the importance of dose dependencies in resistance evolution and motivate further investigation of the mutagenicity and other hidden collateral costs of therapies that promote resistance. Author summaryThe evolution of drug resistance is a particularly problematic and frequent outcome of cancer and antimicrobial therapies. Recent research suggests that these treatments may enhance the evolvability of the target population not only via inducing intense selection pressures but also via altering the underlying mutational processes. Here we investigate the consequences of such drug-induced evolution by considering a mathematical model with explicitly dose-dependent mutation rate. We identify, characterize and exploit a trade-off between decreasing the target population size as fast as possible and generating a surplus of treatment-induced de novo mutations. By formulating the treatment as an optimal control problem over the evolution of the target population, we find the optimal treatment strategy, which minimizes the probability of evolutionary rescue. We show that this probability changes non-monotonically with the cumulative drug concentration and is minimized at an intermediate dosage. Our results are immediately amenable to experimental investigation and motivate further study of the various mutagenic and other hidden collateral costs of treatment. Taken together, our results add to the ongoing criticism of the standard practice of administering aggressive, high-dose therapies and stimulate further clinical trials on alternative treatment strategies.

evolutionary biology↗

bioRxiv2019

Spatial structure governs the mode of tumour evolution

Characterizing the mode - the way, manner, or pattern - of evolution in tumours is important for clinical forecasting and optimizing cancer treatment. DNA sequencing studies have inferred various modes, including branching, punctuated and neutral evolution, but it is unclear why a particular pattern predominates in any given tumour.1, 2 Here we propose that differences in tumour architecture alone can explain the variety of observed patterns. We examine this hypothesis using spatially explicit population genetic models and demonstrate that, within biologically relevant parameter ranges, human tumours are expected to exhibit four distinct onco-evolutionary modes (oncoevotypes): rapid clonal expansion (predicted in leukaemia); progressive diversification (in colorectal adenomas and early-stage colorectal carcinomas); branching evolution (in invasive glandular tumours); and effectively almost neutral evolution (in certain non-glandular and poorly differentiated solid tumours). We thus provide a simple, mechanistic explanation for a wide range of empirical observations. Oncoevotypes are governed by the mode of cell dispersal and the range of cell-cell interaction, which we show are essential factors in accurately characterizing, forecasting and controlling tumour evolution.

cancer biology↗