Individual diet specialization (IS) has important community- and population-level implications and its ecological drivers are actively investigated. Here, to test the hypothesis that local environmental conditions may influence IS in wild populations, we analyzed the stomach contents of 395 individuals from eight populations of five allopatric species of European cave salamanders (genus Hydromantes). We assessed whether their degree of individual diet specialization i) scaled positively with the respective niche widths, in agreement with Van Valen's niche variation hypothesis (NVH), and ii) could be predicted by satellite-derived climatic and vegetation characteristics of the sites where the populations live. Consistent with the NVH, the degree of individual diet specialization increased with the populations' total niche width. Furthermore, two variables describing local non-arboreal vegetation cover and habitat heterogeneity successfully predicted the variation in individual specialization across the eight populations. Climatic factors had a generally low predictive power, with individual specialization in low- and high-elevation populations showing contrasting patterns of co-variation with air temperature in the warmest quarter of the year. However, independently from elevation, specialization peaked under conditions of high non-arboreal vegetation cover and high precipitation regimes. We discussed the results against two mutually non-exclusive scenarios hypothesizing different mechanisms linking environmental factors to salamanders' trophic strategy at an individual and population level. We concluded that satellite-derived climatic and vegetation variables, to date generally adopted to model Grinnellian niches, might also be useful in predicting spatial variations in dietary habits of populations, i.e. their Eltonian niches. This article is protected by copyright. All rights reserved.The king cobra (Ophiophagus hannah) is an iconic elapid snake species distributed throughout tropical forests from southwestern India to the Philippines, and southern China to the Indonesian archipelago (Stuart et al., 2012). As the generic epithet suggests, king cobras are thought to specialize on snake prey. Documenting feeding habits of snakes in nature can be difficult due to their low detectability and long intervals between feeding bouts (Maritz et al., 2018). Radiotelemetry allows researchers to reliably locate individuals, making it possible to document predation by direct observation in the field. This article is protected by copyright. All rights reserved.CYP3A4 induction is an important cause of drug-drug interactions, making early identification of drug candidates with CYP3A4 induction liability in drug development a prerequisite. Here, we present 3D spheroid cultures of primary human hepatocytes (PHH) as a novel CYP3A4 induction screening model. Screening of 25 drugs (12 known CYP3A4 inducers in vivo and 13 negative controls) at physiologically relevant concentrations revealed a 100% sensitivity and 100% specificity of the system. Three of the in vivo CYP3A4 inducers displayed much higher CYP3A4 induction capacity in 3D spheroid cultures as compared to in 2D monolayer cultures. Among those, we identified AZD1208, a PIM kinase inhibitor terminated in phase I of development due to unexpected CYP3A4 autoinduction, as a CYP3A4 inducer only active in 3D spheroids but not in 2D monolayer cultures. Gene knockdown experiments revealed that AZD1208 requires PXR to induce CYP3A4. Rifampicin requires solely PXR to induce CYP3A4 and CYP2B6, while phenobarbital-mediated induction of these CYPs did not show absolute dependency on either PXR or CAR suggesting its ability to switch nuclear receptor activation. Mechanistic studies into AZD1208 uncovered an involvement of the MAPK/ERK pathway in CYP3A4 induction that is sensitive to the culture format used, as revealed by its inhibition of ERK1/2 Tyr204 phosphorylation and sensitivity to EGF pressure. In line, we also identified lapatinib, a dual EGFR/HER2 inhibitor, as another CYP3A4 inducer only active in 3D spheroid culture. Our findings offer insights into the pathways involved in CYP3A4 induction and suggest PHH spheroids for preclinical CYP3A4 induction screening. This article is protected by copyright. All rights reserved.Regulators wish to understand whether real-world evidence (RWE) can be used for secondary indications of biologics. Using the secondary indication of adalimumab for ulcerative colitis (UC) as an example, we aimed to replicate the ULTRA-2 RCT finding on the effectiveness of adalimumab in patients with UC using real world data analyses. Adalimumab, a TNF-alpha receptor inhibitor initially approved for Crohn's disease, was approved for moderate to severe UC in 2012. The ULTRA-2 trial had shown improved remission against placebo in patients with UC. Using claims data (2006-2012), we conducted a cohort study of patients with UC who initiated adalimumab and compared them to 1) non-users and 2) new users of infliximab using propensity score matching. The co-primary endpoints were corticosteroid (CS) discontinuation within 8 weeks and 1 year of treatment. We computed hazard ratios (HR) and 95% confidence intervals (CIs). We identified 398 matched pairs of adalimumab users vs non-users and 326 pairs of adalimumab vs infliximab users. Adalimumab users were 28% more likely to achieve CS-discontinuation compared to non-users over 1 year (HR=1.28, 95% CI 0.94 to 1.73). However, unlike in ULTRA-2, this effect was not observed in the first 8 weeks (HR 0.79, 95% CI 0.65-0.97). Compared against infliximab, adalimumab initiators showed no incremental benefit over 1 year (HR=1.08; 0.80 to 1.04), but showed a 22% reduction (HR=0.78; 0.64-0.95) during the first 8 weeks of treatment. In summary, our results highlight opportunities and some limitations of database analysis to identify treatment effects for secondary indications. This article is protected by copyright. All rights reserved.Individual studies have suggested that the association between occupational exposure to solar ultraviolet radiation (UVR) and the development of keratinocyte cancers (KC) may only be valid in populations of European ancestry living in certain geographic regions. Comparative global data are scarce and so this review aimed to summarize current evidence on the association between occupational exposure to solar UVR and the development of KC, with a specific focus on geographic location and skin colour. Ovid Medline, PubMed, EMBASE, and Web of Science were searched for potentially relevant records. Extracted data was summarised by study, country, and region. We included one prospective cohort study and 18 case-control studies (N=15,233) from 12 countries in regions where the majority of the population is white-skinned (Americas, Europe, and Oceania).  https://www.selleckchem.com/products/Thiazovivin.html  Eighteen of the 19 studies reported effect estimates suggesting an increased risk of basal cell carcinoma (BCC) and/or squamous cell carcinoma (SCC) among outdoor workers.