Evaluation of models to estimate the bioaccumulation of organic chemicals in earthworms.

Modelling approaches to estimate the bioaccumulation of organic chemicals by earthworms are important for improving the realism in risk assessment of chemicals. However, the applicability of existing models is uncertain, partly due to the lack of independent datasets to test them. This study therefore conducted a comprehensive literature review on existing empirical and kinetic models that estimate the bioaccumulation of organic chemicals in earthworms and gathered two independent datasets from published literature to evaluate the predictive performance of these models. The Belfroid et al. (1995a) model is the best-performing empirical model, with 91.2% of earthworm body residue simulations within an order of magnitude of observation. However, this model is limited to the more hydrophobic pesticides and to the earthworm species Eisenia fetida or Eisenia andrei. The kinetic model proposed by Jager et al. (2003b) which out-performs that of Armitage and Gobas (2007), predicted uptake of PCB 153 in the earthworm E. andrei to within a factor of 10. However, the applicability of Jager et al.'s model to other organic compounds and other earthworm species is unknown due to the limited evaluation dataset. The model needs to be parameterised for different chemical, soil, and species types prior to use, which restricts its applicability to risk assessment on a broad scale. Both the empirical and kinetic models leave room for improvement in their ability to reliably predict bioaccumulation in earthworms. Whether they are fit for purpose in environmental risk assessment needs careful consideration on a case by case basis.

Earthworm lipid content and size help account for differences in pesticide bioconcentration between species.

The uptake and elimination kinetics of pesticides from soil to earthworms are important in characterising the risk of pesticides to soil organisms and the risk from secondary poisoning. However, the understanding of the relative importance of chemical, soil, and species differences in determining pesticide bioconcentration into earthworms is limited. Furthermore, there is insufficient independent data in the literature to fully evaluate existing predictive bioconcentration models. We conducted kinetic uptake and elimination experiments for three contrasting earthworm species (Lumbricus terrestris, Aporrectodea caliginosa, Eisenia fetida) in five soils using a mixture of five pesticides (log Kow 1.69 - 6.63). Bioconcentration increased with pesticide hydrophobicity and decreased with soil organic matter. Bioconcentration factors were comparable between earthworm species for hydrophilic pesticides due to the similar water content of earthworm species. Inter-species variations in bioconcentration of hydrophobic pesticides were primarily accounted for by earthworm lipid content and specific surface area (SSA). Existing bioconcentration models either failed to perform well across earthworm species and for more hydrophilic compounds (log Kow < 2) or were not parameterised for a wide range of compounds and earthworm species. Refined models should incorporate earthworm properties (lipid content and SSA) to account for inter-species differences in pesticide uptake from soil.

Intermediate-tier options in the environmental risk assessment of plant protection products for soil invertebrates-Synthesis of a workshop.

The European environmental risk assessment (ERA) of plant protection products follows a tiered approach. The approach for soil invertebrates currently consists of two steps, starting with a Tier 1 assessment based on reproduction toxicity tests with earthworms, springtails, and predatory mites. In case an unacceptable risk is identified at Tier 1, field studies can be conducted as a higher-tier option. For soil invertebrates, intermediate tiers are not implemented. Hence, there is limited possibility to include additional information for the ERA to address specific concerns when the Tier 1 fails, as an alternative to, for example, a field study. Calibrated intermediate-tier approaches could help to address risks for soil invertebrates with less time and resources but also with sufficient certainty. A multistakeholder workshop was held on 2-4 March 2022 to discuss potential intermediate-tier options, focusing on four possible areas: (1) natural soil testing, (2) single-species tests (other than standard species), (3) assessing recovery in laboratory tests, and (4) the use of assembled soil multispecies test systems. The participants acknowledged a large potential in the intermediate-tier options but concluded that some issues need to be clarified before routine application of these approaches in the ERA is possible, that is, sensitivity, reproducibility, reliability, and standardization of potential new test systems. The definition of suitable assessment factors needed to calibrate the approaches to the protection goals was acknowledged. The aims of the workshop were to foster scientific exchange and a data-driven dialog, to discuss how the different approaches could be used in the risk assessment, and to identify research priorities for future work to address uncertainties and strengthen the tiered approach in the ERA for soil invertebrates. This article outlines the background, proposed methods, technical challenges, difficulties and opportunities in the ERA, and conclusions of the workshop. Integr Environ Assess Manag 2024;20:780-793. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Quantum-enhanced greedy combinatorial optimization solver.

Combinatorial optimization is a broadly attractive area for potential quantum advantage, but no quantum algorithm has yet made the leap. Noise in quantum hardware remains a challenge, and more sophisticated quantum-classical algorithms are required to bolster their performance. Here, we introduce an iterative quantum heuristic optimization algorithm to solve combinatorial optimization problems. The quantum algorithm reduces to a classical greedy algorithm in the presence of strong noise. We implement the quantum algorithm on a programmable superconducting quantum system using up to 72 qubits for solving paradigmatic Sherrington-Kirkpatrick Ising spin glass problems. We find the quantum algorithm systematically outperforms its classical greedy counterpart, signaling a quantum enhancement. Moreover, we observe an absolute performance comparable with a state-of-the-art semidefinite programming method. Classical simulations of the algorithm illustrate that a key challenge to reaching quantum advantage remains improving the quantum device characteristics.

Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency.

Mevalonate kinase deficiency (MKD) is characterized by recurrent fevers and flares of systemic inflammation, caused by biallelic loss-of-function mutations in MVK. The underlying disease mechanisms and triggers of inflammatory flares are poorly understood because of the lack of in vivo models. We describe genetically modified mice bearing the hypomorphic mutation p.Val377Ile (the commonest variant in patients with MKD) and amorphic, frameshift mutations in Mvk. Compound heterozygous mice recapitulated the characteristic biochemical phenotype of MKD, with increased plasma mevalonic acid and clear buildup of unprenylated GTPases in PBMCs, splenocytes, and bone marrow. The inflammatory response to LPS was enhanced in compound heterozygous mice and treatment with the NLRP3 inflammasome inhibitor MCC950 prevented the elevation of circulating IL-1ß, thus identifying a potential inflammasome target for future therapeutic approaches. Furthermore, lines of mice with a range of deficiencies in mevalonate kinase and abnormal prenylation mirrored the genotype-phenotype relationship in human MKD. Importantly, these mice allowed the determination of a threshold level of residual enzyme activity, below which protein prenylation is impaired. Elevated temperature dramatically but reversibly exacerbated the deficit in the mevalonate pathway and the defective prenylation in vitro and in vivo, highlighting increased body temperature as a likely trigger of inflammatory flares.

Analysing intracellular isoprenoid metabolites in diverse prokaryotic and eukaryotic microbes.

Isoprenoids, also known as terpenes or terpenoids, are a very large and diverse group of natural compounds. These compounds fulfil a myriad of critical roles in biology as well as having a wide range of industrial uses. Isoprenoids are produced via two chemically distinct metabolic pathways, the mevalonate (MVA) pathway and the methylerythritol phosphate (MEP) pathway. Downstream of these two pathways is the shared prenyl phosphate pathway. Because of their importance in both basic physiology and industrial biotechnology, extraction, identification, and quantification of isoprenoid pathway intermediates is an important protocol. Here we describe methods for extraction and analysis of intracellular metabolites from the MVA, MEP, and prenyl phosphate pathways for five key model microbes: the yeast Saccharomyces cerevisiae, the bacterium Escherichia coli, the diatom Phaeodactylum tricornutum, the green algae Chlamydomonas reinhardtii, and the cyanobacterium Synechocystis sp. PCC 6803. These methods also detect several central carbon intermediates. These protocols will likely work effectively, or be readily adaptable, to a variety of related microorganisms and metabolic pathways.

Elevation of fatty acid desaturase 2 in esophageal adenocarcinoma increases polyunsaturated lipids and may exacerbate bile acid-induced DNA damage.

BACKGROUND: The risk of esophageal adenocarcinoma (EAC) is associated with gastro-esophageal reflux disease (GERD) and obesity. Lipid metabolism-targeted therapies decrease the risk of progressing from Barrett's esophagus (BE) to EAC, but the precise lipid metabolic changes and their roles in genotoxicity during EAC development are yet to be established. METHODS: Esophageal biopsies from the normal epithelium (NE), BE, and EAC, were analyzed using concurrent lipidomics and proteomics (n = 30) followed by orthogonal validation on independent samples using RNAseq transcriptomics (n = 22) and immunohistochemistry (IHC, n = 80). The EAC cell line FLO-1 was treated with FADS2 selective inhibitor SC26196, and/or bile acid cocktail, followed by immunofluorescence staining for γH2AX. RESULTS: Metabolism-focused Reactome analysis of the proteomics data revealed enrichment of fatty acid metabolism, ketone body metabolism, and biosynthesis of specialized pro-resolving mediators in EAC pathogenesis. Lipidomics revealed progressive alterations (NE-BE-EAC) in glycerophospholipid synthesis with decreasing triglycerides and increasing phosphatidylcholine and phosphatidylethanolamine, and sphingolipid synthesis with decreasing dihydroceramide and increasing ceramides. Furthermore, a progressive increase in lipids with C20 fatty acids and polyunsaturated lipids with ≥4 double bonds were also observed. Integration with transcriptome data identified candidate enzymes for IHC validation: Δ4-Desaturase, Sphingolipid 1 (DEGS1) which desaturates dihydroceramide to ceramide, and Δ5 and Δ6-Desaturases (fatty acid desaturases, FADS1 and FADS2), responsible for polyunsaturation. All three enzymes showed significant increases from BE through dysplasia to EAC, but transcript levels of DEGS1 were decreased suggesting post-translational regulation. Finally, the FADS2 selective inhibitor SC26196 significantly reduced polyunsaturated lipids with three and four double bonds and reduced bile acid-induced DNA double-strand breaks in FLO-1 cells in vitro. CONCLUSIONS: Integrated multiomics revealed sphingolipid and phospholipid metabolism rewiring during EAC development. FADS2 inhibition and reduction of the high polyunsaturated lipids effectively protected EAC cells from bile acid-induced DNA damage in vitro, potentially through reduced lipid peroxidation.

Modelling the effects of variability in feeding rate on growth - a vital step for DEB-TKTD modelling.

A major limitation of dietary toxicity studies on rodents is that food consumption often differs between treatments. The control treatment serves as a reference of how animals would have grown if not for the toxicant in their diet, but this comparison unavoidably conflates the effects of toxicity and feeding rate on body weight over time. A key advantage of toxicity models based on dynamic energy budget theory (DEB) is that chemical stress and food consumption are separate model inputs, so their effects on growth rate can be separated. To reduce data requirements, DEB convention is to derive a simplified feeding input, f, from food availability; its value ranges from zero (starvation) to one (food available ad libitum). Observed food consumption in dietary toxicity studies shows that, even in the control treatment, rats limit their food consumption, contradicting DEB assumptions regarding feeding rate. Relatively little work has focused on addressing this mismatch, but accurately modelling the effects of food intake on growth rate is essential for the effects of toxicity to be isolated. This can provide greater insight into the results of chronic toxicity studies and allows accurate extrapolation of toxic effects from laboratory data. Here we trial a new method for calculating f, based on the observed relationships between food consumption and body size in laboratory rats. We compare model results with those of the conventional DEB method and a previous effort to calculate f using observed food consumption data. Our results showed that the new method improved model accuracy while modelled reserve dynamics closely followed observed body fat percentage over time. The new method assumes that digestive efficiency increases with body size. Verifying this relationship through data collection would strengthen the basis of DEB theory and support the case for its use in ecological risk assessment.

Exon-independent recruitment of SRSF1 is mediated by U1 snRNP stem-loop 3.

SRSF1 protein and U1 snRNPs are closely connected splicing factors. They both stimulate exon inclusion, SRSF1 by binding to exonic splicing enhancer sequences (ESEs) and U1 snRNPs by binding to the downstream 5' splice site (SS), and both factors affect 5' SS selection. The binding of U1 snRNPs initiates spliceosome assembly, but SR proteins such as SRSF1 can in some cases substitute for it. The mechanistic basis of this relationship is poorly understood. We show here by single-molecule methods that a single molecule of SRSF1 can be recruited by a U1 snRNP. This reaction is independent of exon sequences and separate from the U1-independent process of binding to an ESE. Structural analysis and cross-linking data show that SRSF1 contacts U1 snRNA stem-loop 3, which is required for splicing. We suggest that the recruitment of SRSF1 to a U1 snRNP at a 5'SS is the basis for exon definition by U1 snRNP and might be one of the principal functions of U1 snRNPs in the core reactions of splicing in mammals.

Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages.

Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.

Simultaneous quantification of 26 NAD-related metabolites in plasma, blood, and liver tissue using UHPLC-MS/MS.

Nicotinamide adenine dinucleotide (NAD) is a key metabolic intermediate found in all cells and involved in numerous cellular functions. Perturbances in the NAD metabolome are linked to various diseases such as diabetes and schizophrenia, and to congenital malformations and recurrent miscarriage. Mouse models are central to the investigation of these and other NAD-related conditions because mice can be readily genetically modified and treated with diets with altered concentrations of NAD precursors. Simultaneous quantification of as many metabolites of the NAD metabolome as possible is required to understand which pathways are affected in these disease conditions and what are the functional consequences. Here, we report the development of a fit-for-purpose method to simultaneously quantify 26 NAD-related metabolites and creatinine in mouse plasma, whole blood, and liver tissue using ultra-high performance liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS). The included metabolites represent dietary precursors, intermediates, enzymatic cofactors, and excretion products. Sample preparation was optimized for each matrix and included 21 isotope-labeled internal standards. The method reached adequate precision and accuracy for the intended context of use of exploratory pathway-related biomarker discovery in mouse models. The method was tested by determining metabolite concentrations in mice fed a special diet with defined precursor content.

Earthworm distributions are not driven by measurable soil properties. Do they really indicate soil quality?

Abundance and distribution of earthworms in agricultural fields is frequently proposed as a measure of soil quality assuming that observed patterns of abundance are in response to improved or degraded environmental conditions. However, it is not clear that earthworm abundances can be directly related to their edaphic environment, as noted in Darwin's final publication, perhaps limiting or restricting their value as indicators of ecological quality in any given field. We present results from a spatially explicit intensive survey of pastures within United Kingdom farms, looking for the main drivers of earthworm density at a range of scales. When describing spatial variability of both total and ecotype-specific earthworm abundance within any given field, the best predictor was earthworm abundance itself within 20-30 m of the sampling point; there were no consistent environmental correlates with earthworm numbers, suggesting that biological factors (e.g. colonisation rate, competition, predation, parasitism) drive or at least significantly modify earthworm distributions at this spatial level. However, at the national scale, earthworm abundance is well predicted by soil nitrate levels, density, temperature and moisture content, albeit not in a simple linear fashion. This suggests that although land can be managed at the farm scale to promote earthworm abundance and the resulting soil processes that deliver ecosystem services, within a field, earthworm distributions will remain patchy. The use of earthworms as soil quality indicators must therefore be carried out with care, ensuring that sufficient samples are taken within field to take account of variability in earthworm populations that is unrelated to soil chemical and physical properties.

Arable fields as potential reservoirs of biodiversity: Earthworm populations increase in new leys.

Managing soil to support biodiversity is important to sustain the ecosystem services provided by soils upon which society depends. There is increasing evidence that functional diversity of soil biota is important for ecosystem services, and has been degraded by intensive agriculture. Importantly, the spatial distribution of reservoirs of soil biota in and surrounding arable fields is poorly understood. In a field experiment, grass-clover ley strips were introduced into four arable fields which had been under continuous intensive/conventional arable rotation for more than 10 years. Earthworm communities in arable fields and newly established grass-clover leys, as well as field boundary land uses (hedgerows and grassy field margins), were monitored over 2 years after arable-to-ley conversions. Within 2 years, earthworm abundance in new leys was 732 ± 244 earthworms m-2, similar to that in field margin soils (619 ± 355 earthworms m-2 yr-1) and four times higher than in adjacent arable soil (185 ± 132 earthworms m-2). Relative to the arable soils, earthworm abundance under the new leys showed changes in community composition, structure and functional group, which were particularly associated with an increase in anecic earthworms; thus new leys became more similar to grassy field margins. Earthworm abundance was similar in new leys that were either connected to biodiversity reservoirs i.e. field margins and hedgerows, or not (installed earthworm barriers). This suggests that, for earthworm communities in typical arable fields, biodiversity reservoirs in adjacent field margins and hedgerows may not be critical for earthworm populations to increase. We conclude that the increase in earthworm abundance in the new leys observed over 2 years was driven by recruitment from the existing residual population in arable soils. Therefore, arable soils are also potential reservoirs of biodiversity.

Krüppel-like factor 1 is a core cardiomyogenic trigger in zebrafish.

Cardiac regeneration requires dedifferentiation and proliferation of mature cardiomyocytes, but the mechanisms underlying this plasticity remain unclear. Here, we identify a potent cardiomyogenic role for Krüppel-like factor 1 (Klf1/Eklf), which is induced in adult zebrafish myocardium upon injury. Myocardial inhibition of Klf1 function does not affect heart development, but it severely impairs regeneration. Transient Klf1 activation is sufficient to expand mature myocardium in uninjured hearts. Klf1 directs epigenetic reprogramming of the cardiac transcription factor network, permitting coordinated cardiomyocyte dedifferentiation and proliferation. Myocardial expansion is supported by Klf1-induced rewiring of mitochondrial metabolism from oxidative respiration to anabolic pathways. Our findings establish Klf1 as a core transcriptional regulator of cardiomyocyte renewal in adult zebrafish hearts.

Mechanistic Effect Modeling of Earthworms in the Context of Pesticide Risk Assessment: Synthesis of the FORESEE Workshop.

Earthworms are important ecosystem engineers, and assessment of the risk of plant protection products toward them is part of the European environmental risk assessment (ERA). In the current ERA scheme, exposure and effects are represented simplistically and are not well integrated, resulting in uncertainty when the results are applied to ecosystems. Modeling offers a powerful tool to integrate the effects observed in lower tier laboratory studies with the environmental conditions under which exposure is expected in the field. This paper provides a summary of the (In)Field Organism Risk modEling by coupling Soil Exposure and Effect (FORESEE) Workshop held 28-30 January 2020 in Düsseldorf, Germany. This workshop focused on toxicokinetic-toxicodynamic (TKTD) and population modeling of earthworms in the context of ERA. The goal was to bring together scientists from different stakeholder groups to discuss the current state of soil invertebrate modeling and to explore how earthworm modeling could be applied to risk assessments, in particular how the different model outputs can be used in the tiered ERA approach. In support of these goals, the workshop aimed at addressing the requirements and concerns of the different stakeholder groups to support further model development. The modeling approach included 4 submodules to cover the most relevant processes for earthworm risk assessment: environment, behavior (feeding, vertical movement), TKTD, and population. Four workgroups examined different aspects of the model with relevance for risk assessment, earthworm ecology, uptake routes, and cross-species extrapolation and model testing. Here, we present the perspectives of each workgroup and highlight how the collaborative effort of participants from multidisciplinary backgrounds helped to establish common ground. In addition, we provide a list of recommendations for how earthworm TKTD modeling could address some of the uncertainties in current risk assessments for plant protection products. Integr Environ Assess Manag 2021;17:352-363. © 2020 SETAC.

Dual stresses of flooding and agricultural land use reduce earthworm populations more than the individual stressors.

Global climate change is leading to a significant increase in flooding events in many countries. Current practices to prevent damage to downstream urban areas include allowing the flooding of upstream agricultural land. Earthworms are ecosystem engineers, but their abundances in arable land are already reduced due to pressure from farming practices. If flooding increases on agricultural land, it is important to understand how earthworms will respond to the dual stresses of flooding and agricultural land use. The earthworm populations under three land uses (pasture, field margin, and crops), across two UK fields, were sampled seasonally over an 18-month period in areas of the fields which flood frequently and areas which flood only rarely. Earthworm abundance in the crop and pasture soils and total earthworm biomass in the crop soils was significantly lower in the frequently flooded areas than in the rarely flooded areas. The relative percentage difference in the populations between the rarely and frequently flooded areas was greater in the crop soils (-59.18% abundance, -63.49% biomass) than the pasture soils (-13.39% abundance, -9.66% biomass). In the margin soils, earthworm abundance was significantly greater in the frequently flooded areas (+140.56%), likely due to higher soil organic matter content and lower bulk density resulting in soil conditions more amenable to earthworms. The findings of this study show that earthworm populations already stressed by the activities associated with arable land use are more susceptible to flooding than populations in pasture fields, suggesting that arable earthworm populations are likely to be increasingly at risk with increased flooding.

Characterization and validation of a preventative therapy for hypertrophic cardiomyopathy in a murine model of the disease.

Currently there is an unmet need for treatments that can prevent hypertrophic cardiomyopathy (HCM). Using a murine model we previously identified that HCM causing cardiac troponin I mutation Gly203Ser (cTnI-G203S) is associated with increased mitochondrial metabolic activity, consistent with the human condition. These alterations precede development of the cardiomyopathy. Here we examine the efficacy of in vivo treatment of cTnI-G203S mice with a peptide derived against the α-interaction domain of the cardiac L-type calcium channel (AID-TAT) on restoring mitochondrial metabolic activity, and preventing HCM. cTnI-G203S or age-matched wt mice were treated with active or inactive AID-TAT. Following treatment, targeted metabolomics was utilized to evaluate myocardial substrate metabolism. Cardiac myocyte mitochondrial metabolic activity was assessed as alterations in mitochondrial membrane potential and flavoprotein oxidation. Cardiac morphology and function were examined using echocardiography. Cardiac uptake was assessed using an in vivo multispectral imaging system. We identified alterations in six biochemical intermediates in cTnI-G203S hearts consistent with increased anaplerosis. We also reveal that AID-TAT treatment of precardiomyopathic cTnI-G203S mice, but not mice with established cardiomyopathy, restored cardiac myocyte mitochondrial membrane potential and flavoprotein oxidation, and prevented myocardial hypertrophy. Importantly, AID-TAT was rapidly targeted to the heart, and not retained by the liver or kidneys. Overall, we identify biomarkers of HCM resulting from the cTnI mutation Gly203Ser, and present a safe, preventative therapy for associated cardiomyopathy. Utilizing AID-TAT to modulate cardiac metabolic activity may be beneficial in preventing HCM in "at risk" patients with identified Gly203Ser gene mutations.

Chronic High-Fat Diet Induces Early Barrett's Esophagus in Mice through Lipidome Remodeling.

Esophageal adenocarcinoma (EAC) incidence has been rapidly increasing, potentially associated with the prevalence of the risk factors gastroesophageal reflux disease (GERD), obesity, high-fat diet (HFD), and the precursor condition Barrett's esophagus (BE). EAC development occurs over several years, with stepwise changes of the squamous esophageal epithelium, through cardiac metaplasia, to BE, and then EAC. To establish the roles of GERD and HFD in initiating BE, we developed a dietary intervention model in C57/BL6 mice using experimental HFD and GERD (0.2% deoxycholic acid, DCA, in drinking water), and then analyzed the gastroesophageal junction tissue lipidome and microbiome to reveal potential mechanisms. Chronic (9 months) HFD alone induced esophageal inflammation and metaplasia, the first steps in BE/EAC pathogenesis. While 0.2% deoxycholic acid (DCA) alone had no effect on esophageal morphology, it synergized with HFD to increase inflammation severity and metaplasia length, potentially via increased microbiome diversity. Furthermore, we identify a tissue lipid signature for inflammation and metaplasia, which is characterized by elevated very-long-chain ceramides and reduced lysophospholipids. In summary, we report a non-transgenic mouse model, and a tissue lipid signature for early BE. Validation of the lipid signature in human patient cohorts could pave the way for specific dietary strategies to reduce the risk of BE in high-risk individuals.

Increased yield and CO2 sequestration potential with the C4 cereal Sorghum bicolor cultivated in basaltic rock dust-amended agricultural soil.

Land-based enhanced rock weathering (ERW) is a biogeochemical carbon dioxide removal (CDR) strategy aiming to accelerate natural geological processes of carbon sequestration through application of crushed silicate rocks, such as basalt, to croplands and forested landscapes. However, the efficacy of the approach when undertaken with basalt, and its potential co-benefits for agriculture, require experimental and field evaluation. Here we report that amending a UK clay-loam agricultural soil with a high loading (10 kg/m2 ) of relatively coarse-grained crushed basalt significantly increased the yield (21 ± 9.4%, SE) of the important C4 cereal Sorghum bicolor under controlled environmental conditions, without accumulation of potentially toxic trace elements in the seeds. Yield increases resulted from the basalt treatment after 120 days without P- and K-fertilizer addition. Shoot silicon concentrations also increased significantly (26 ± 5.4%, SE), with potential benefits for crop resistance to biotic and abiotic stress. Elemental budgets indicate substantial release of base cations important for inorganic carbon removal and their accumulation mainly in the soil exchangeable pools. Geochemical reactive transport modelling, constrained by elemental budgets, indicated CO2 sequestration rates of 2-4 t CO2 /ha, 1-5 years after a single application of basaltic rock dust, including via newly formed soil carbonate minerals whose long-term fate requires assessment through field trials. This represents an approximately fourfold increase in carbon capture compared to control plant-soil systems without basalt. Our results build support for ERW deployment as a CDR technique compatible with spreading basalt powder on acidic loamy soils common across millions of hectares of western European and North American agriculture.

Multi-omic profiling reveals associations between the gut mucosal microbiome, the metabolome, and host DNA methylation associated gene expression in patients with colorectal cancer.

BACKGROUND: The human gut microbiome plays a critical role in the carcinogenesis of colorectal cancer (CRC). However, a comprehensive analysis of the interaction between the host and microbiome is still lacking. RESULTS: We found correlations between the change in abundance of microbial taxa, butyrate-related colonic metabolites, and methylation-associated host gene expression in colonic tumour mucosa tissues compared with the adjacent normal mucosa tissues. The increase of genus Fusobacterium abundance was correlated with a decrease in the level of 4-hydroxybutyric acid (4-HB) and expression of immune-related peptidase inhibitor 16 (PI16), Fc Receptor Like A (FCRLA) and Lymphocyte Specific Protein 1 (LSP1). The decrease in the abundance of another potentially 4-HB-associated genus, Prevotella 2, was also found to be correlated with the down-regulated expression of metallothionein 1 M (MT1M). Additionally, the increase of glutamic acid-related family Halomonadaceae was correlated with the decreased expression of reelin (RELN). The decreased abundance of genus Paeniclostridium and genus Enterococcus were correlated with increased lactic acid level, and were also linked to the expression change of Phospholipase C Beta 1 (PLCB1) and Immunoglobulin Superfamily Member 9 (IGSF9) respectively. Interestingly, 4-HB, glutamic acid and lactic acid are all butyrate precursors, which may modify gene expression by epigenetic regulation such as DNA methylation. CONCLUSIONS: Our study identified associations between previously reported CRC-related microbial taxa, butyrate-related metabolites and DNA methylation-associated gene expression in tumour and normal colonic mucosa tissues from CRC patients, which uncovered a possible mechanism of the role of microbiome in the carcinogenesis of CRC. In addition, these findings offer insight into potential new biomarkers, therapeutic and/or prevention strategies for CRC.