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Cancers of the mesothelium, such as malignant mesothelioma (MM), historically have been attributed solely to exposure to asbestos. Recent large scale genetic and genomic functional studies now show that approximately 20% of all human mesotheliomas are causally linked to highly penetrant inherited (germline) pathogenic mutations in numerous cancer related genes. The rarity of these mutations in humans makes it difficult to perform statistically conclusive genetic studies to understand their biological effects. This has created a disconnect between functional and epidemiological studies. However, since the molecular pathogenesis of MM in mice accurately recapitulates that of human disease, this disconnect between functional and epidemiological studies can be overcome by using inbred mouse strains that harbor mutation(s) in genes involved in the disease. Most mouse studies have focused on the effect of asbestos exposure, leaving the effects of genetic mutations in the absence of exposure understudied. Here, using existing peer-reviewed studies, we investigate the rate of spontaneous MM among mice with and without germline genetic mutations, in the absence of asbestos exposure. We leveraged these published data to generate a historical control dataset (HCD) to allow us to improve statistical power and account for genetic heterogeneity between studies. Our Bayesian analyses indicate that the odds of spontaneous MM among germline BAP1 mutant mice is substantially larger than that of wildtype mice. These results support the existing biological study findings that mesotheliomas can arise in the presence of pathogenic germline mutations, independently of asbestos exposure., Competing Interests: Declarations. Competing interests: DMN declares no competing interests. MH, MZ and LvZ are employees of ArrayXpress Inc., which is a genomics company that provides research and scientific expert witness consultation in civil tort cases, among other services. LvZ serves as an expert witness in personal injury litigation. GC is an employee of Lumanity Clinical and Regulatory, which is a consultative company providing research and expert services in legal matters., (© 2024. The Author(s).)

The flavan-3-ol (-)-epigallocatechin gallate (EGCG) blunts obesity in inbred mice, but human clinical trials have yielded mixed results. Genetic homogeneity in preclinical models may explain translational disconnect between rodents and humans. The Diversity Outbred (DO) mouse model provides genotype and phenotype variability for characterization of gene x environment (i.e., diet) interactions. We conducted a longitudinal phenotyping study in DO mice. Mice (n = 50) were fed a high-fat diet for 8 weeks and then a high-fat diet + 0.3% EGCG for 8 weeks. We hypothesized that obesity and any protective effects of EGCG would exhibit extreme variability in these genetically heterogeneous mice. As anticipated, DO mice exhibited extreme variation in body composition at baseline (4%-13.9% fat), after 8 weeks of high-fat diet (6.5%-38.1% fat), and after 8 weeks of high-fat diet + EGCG (7.6%-42.6% fat), greater than what is observed in inbred mice. All 50 mice gained body fat on the high-fat diet (changes from baseline of +5% ± 640%). Intriguingly, adiposity variability increased when EGCG was added to the diet (changes from the high-fat diet alone of -52% ± 390%), with 11/50 mice losing body fat. We postulate that the explanation for this variability is genetic heterogeneity. Our data confirm the promise for EGCG to manage obesity but suggest that genetic factors may exert significant control over the efficacy of EGCG. Larger studies in DO mice are needed for quantitative trait loci mapping to identify genetic loci governing EGCG x obesity interactions and translate these findings to precision nutrition in humans., Competing Interests: Author declarations None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Arctic shorelines are vulnerable to climate change impacts as sea level rises, permafrost thaws, storms intensify, and sea ice thins. Seventy-five years of aerial and satellite observations have established coastal erosion as an increasing Arctic hazard. However, other hazards at play-for instance, the cumulative impact that sea-level rise and permafrost thaw subsidence will have on permafrost shorelines-have received less attention, preventing assessments of these processes' impacts compared to and combined with coastal erosion. Alaska's Arctic Coastal Plain (ACP) is ideal for such assessments because of the high-density observations of topography, coastal retreat rates, and permafrost characteristics, and importance to Indigenous communities and oilfield infrastructure. Here, we produce 21st-century projections of Arctic shoreline position that include erosion, permafrost subsidence, and sea-level rise. Focusing on the ACP, we merge 5 m topography, satellite-derived coastal lake depth estimates, and empirical assessments of land subsidence due to permafrost thaw with projections of coastal erosion and sea-level rise for medium and high emissions scenarios from the Intergovernmental Panel on Climate Change's AR6 Report. We find that by 2100, erosion and inundation will together transform the ACP, leading to 6-8x more land loss than coastal erosion alone and disturbing 8-11x more organic carbon. Without mitigating measures, by 2100, coastal change could damage 40 to 65% of infrastructure in present-day ACP coastal villages and 10 to 20% of oilfield infrastructure. Our findings highlight the risks that compounding climate hazards pose to coastal communities and underscore the need for adaptive planning for Arctic coastlines in the 21st century., Competing Interests: Competing interests statement:The authors declare no competing interest.

The use of infant formulas (IFs) based on hydrolyzed cow's milk proteins to prevent cow's milk allergy (CMA) is highly debated. The risk of sensitization to milk proteins induced by IFs may be affected by the degree of hydrolysis (DH) as well as other physicochemical properties of the cow's milk-based protein hydrolysates within the IFs. The immunogenicity (specific IgG1 induction) and sensitizing capacity (specific IgE induction) of 30 whey- or casein-based hydrolysates with different physicochemical characteristics were compared using an intraperitoneal model of CMA in Brown Norway rats. In general, the whey-based hydrolysates demonstrated higher immunogenicity than casein-based hydrolysates, inducing higher levels of hydrolysate-specific and intact-specific IgG1. The immunogenicity of the hydrolysates was influenced by DH, peptide size distribution profile, peptide aggregation, nano-sized particle formation, and surface hydrophobicity. Yet, only the surface hydrophobicity was found to affect the sensitizing capacity of hydrolysates, as high hydrophobicity was associated with higher levels of specific IgE. The whey- and casein-based hydrolysates exhibited distinct immunological properties with highly diverse molecular composition and physicochemical properties which are not accounted for by measuring DH, which was a poor predictor of sensitizing capacity. Thus, future studies should consider and account for physicochemical characteristics when assessing the sensitizing capacity of cow's milk-based protein hydrolysates., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DMN, HFC, LNJ, HB, and LVS are employees at Arla Foods Ingredients. KLB has ongoing collaboration with and received funding from the company Arla Foods Ingredients. The other authors declare no conflict of interest. The funding agency played no role in study design, data acquisition, data analysis, interpretation, manuscript preparation, or the decision to publish., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)