Continuously fluctuating selection reveals fine granularity of adaptation.

Temporally fluctuating environmental conditions are a ubiquitous feature of natural habitats. Yet, how finely natural populations adaptively track fluctuating selection pressures via shifts in standing genetic variation is unknown1,2. Here we generated genome-wide allele frequency data every 1-2 generations from a genetically diverse population of Drosophila melanogaster in extensively replicated field mesocosms from late June to mid-December (a period of approximately 12 total generations). Adaptation throughout the fundamental ecological phases of population expansion, peak density and collapse was underpinned by extremely rapid, parallel changes in genomic variation across replicates. Yet, the dominant direction of selection fluctuated repeatedly, even within each of these ecological phases. Comparing patterns of change in allele frequency to an independent dataset procured from the same experimental system demonstrated that the targets of selection are predictable across years. In concert, our results reveal a fitness relevance of standing variation that is likely to be masked by inference approaches based on static population sampling or insufficiently resolved time-series data. We propose that such fine-scaled, temporally fluctuating selection may be an important force contributing to the maintenance of functional genetic variation in natural populations and an important stochastic force impacting genome-wide patterns of diversity at linked neutral sites, akin to genetic draft.

A Family of Cyclic Lipopeptides Found in Human Isolates of Bacillus Ameliorates Acute Colitis via Direct Agonism of Toll-Like Receptor 2 in a Murine Model of Inflammatory Bowel Disease.

BACKGROUND: The Bacillus-derived cyclic lipopeptides (surfactin, iturin, and fengycin) form potent Heterogeneous Lipopeptide Micelle (HeLM) complexes. HeLM is a small molecule that has been shown to have immunomodulatory effects. However, how HeLM regulates inflammation is not clear, moreover its application to Inflammatory Bowel Disease (IBD), specifically Ulcerative Colitis (UC), has not been tested before. AIMS: To use a murine model of IBD and determine the effects of HeLM and related molecular mechanisms of action. METHODS: Colitis was induced in mice by administration of 4% Dextran Sodium Sulfate. Three preparations were tested against negative and positive controls: Purified HeLM, the wild-type strain that produces it, and an isogenic mutant that does not produce HeLM. Clinical, biochemical, and histological scoring systems were used to assess the severity of colitis. RT-qPCR and cell cultures were used to determine the levels of molecular signaling. Fecal samples were processed for metagenomic analysis. RESULTS: Purified HeLM, and the wild-type strain, significantly decreased the severity of colitis as determined by the disease activity index (DAI), mouse colitis histology index (MCHI), fecal calprotectin, and colonic length. This effect was not seen in the mutant. HeLM was found to be an agonist to TLR-2, seemingly activating the Toll-Like Receptor 2/IL-10 pathway, with subsequent downregulation of inflammatory cytokines (TNF-α, IL-1ß, and IL-6). At higher concentrations HeLM inhibited lipopolysaccharide ligands from activating TLR-4. The reduction in colitis was not due to microbiome modulation, as had previously been hypothesized. CONCLUSION: Our results indicate that HeLM ameliorates colitis by TLR-2-induced IL-10 production and possibly via the inhibition of lipopolysaccharide.

Intranasal administration of DSM 32444 Bacillus subtilis spores: safety and tolerability.

Introduction. Administered nasally, spores of the Gram-positive bacterium Bacillus subtilis have been shown to be able to induce innate immunity sufficient to confer protection to influenza and respiratory syncytial virus.Hypothesis. Although members of the aerobiome, intranasal delivery of high numbers of live spores carries potential safety issues.Aim. To address the potential safety risk of using live spores, we assessed the safety of spores that had been completely inactivated using heat sterilization.Methodology. Using autoclaved, and therefore killed, spores of a generally recognized as safe-notified B. subtilis strain (DSM 32444), safety was assessed in vitro (biotype, genome and cell based cytoxicity) and in vivo, using intranasal administration in rodent models and lastly in human volunteers.Results. Using a 15-day, repeat-dose, regimen in a rodent model, no indication of toxicity was observed. In a registered human study (NCT05984004), a formulated preparation of inactivated DSM 32444 spores referred to as SPEROVID was developed, and tolerance in human volunteers was assessed following 7 days of nasal dosing (2-4 times/day).Conclusion. Our study demonstrated that in humans an intranasal dose of up to 3×108 killed spores was safe and well tolerated.

Isofagomine Inhibits Multiple TcdB Variants and Protects Mice from Clostridioides difficile-Induced Mortality.

Clostridioides difficile causes life-threatening diarrhea and is one of the leading causes of nosocomial infections. During infection, C. difficile releases two gut-damaging toxins, TcdA and TcdB, which are the primary determinants of disease pathogenesis and are important therapeutic targets. Once in the cytosol of mammalian cells, TcdA and TcdB use UDP-glucose to glucosylate host Rho GTPases, which leads to cytoskeletal changes that result in a loss of intestinal integrity. Isofagomine inhibits TcdA and TcdB as a mimic of the glucocation transition state of the glucosyltransferase reaction. However, sequence variants of TcdA and TcdB across the clades of infective C. difficile continue to be identified, and therefore, evaluation of isofagomine inhibition against multiple toxin variants is required. Here, we show that isofagomine inhibits the glucosyltransferase domain of multiple TcdB variants and protects TcdB-induced cell rounding of the most common full-length toxin variants. Furthermore, we demonstrate that isofagomine protects against C. difficile-induced mortality in two murine models of C. difficile infection. Isofagomine treatment of mouse C. difficile infection also permitted the recovery of the gastrointestinal microbiota, an important barrier to preventing recurring C. difficile infection. The broad specificity of isofagomine supports its potential as a prophylactic to protect against C. difficile-induced morbidity and mortality.

Atmospheric drying and soil drying: Differential effects on grass community composition.

Global surface temperatures are projected to increase in the future; this will modify regional precipitation regimes and increase global atmospheric drying. Despite many drought studies examining the consequences of reduced precipitation, there are few experimental studies exploring plant responses to atmospheric drying via relative humidity and vapor pressure deficit (VPD). We examined eight native California perennial grass species grown in pots in a greenhouse in Los Angeles, California for 34 weeks. All pots were well-watered for 21 weeks, at which point we reduced watering to zero and recorded daily growth and dormancy for 3 weeks. We used this information to better understand the drought tolerance of our species in a larger soil drying × atmospheric drying experiment. In this larger experiment, we grew all eight species together in outdoor mesocosms and measured changes in community composition after 4 years of growth. Soil drying in our small pot experiment mirrored compositional shifts in the larger experiment. Namely, our most drought-tolerant species in our pot experiment was Poa secunda, due to a summer dormancy strategy. Similarly, the grass community shifted toward P. secunda in the driest soils as P. secunda was mostly unaffected by either soil drying or atmospheric drying. We found that some species responded strongly to soil drying (Elymus glaucus, Festuca idahoensis, and Hordeum b. californicum), while others responded strongly to atmospheric drying (Bromus carinatus and Stipa cernua). As result, community composition shifted in different and interacting ways in response to soil drying, atmospheric drying, and their combination. Further study of community responses to increasing atmospheric aridity is an essential next step to predicting the future consequences of climate change.