ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

An ensemble-based approach is presented to explore the conformational space sampled by a multidomain protein showing moderate interdomain dynamics in terms of translational and rotational motions. The strategy was applied on a complex of calmodulin (CaM) with the IQ-recognition motif from the voltage-gated calcium channel Ca v 1.2 (IQ), which adopts three different interdomain orientations in the crystal. The N60D mutant of calmodulin was used to collect pseudocontact shifts and paramagnetically induced residual dipolar couplings for six different lanthanide ions. Then, starting from the crystal structure, pools of conformations were generated by free MD. We found the three crystal conformations in solution, but four additional MD-derived conformations had to be included into the ensemble to fulfill all the paramagnetic data and cross-validate optimally against unused paramagnetic data. Alternative approaches led to similar ensembles. Our "ensemble" approach is a simple and efficient tool to probe and describe the interdomain dynamics and represents a general method that can be used to provide a proper ensemble description of multidomain proteins.

The launch of both battery electric vehicles (BEVs) and autonomous vehicles (AVs) on the global market has triggered ongoing radical changes in the automotive sector. On the one hand, the new characteristics of the BEV powertrain compared to the combustion type have resulted in new central parameters, such as vehicle range, which then become an important selling point. On the other hand, electric components are as yet not optimized and the sensors needed for autonomous driving are still expensive, which introduces changes to the vehicle cost structure. This transformation is not limited to the vehicle itself but also extends to its mobility and the necessary infrastructure. The former is shaped by new user behaviors and scenarios. The latter is impacted by the BEV powertrain, which requires a charging and energy supply infrastructure. To enable manufacturers and researchers to develop and optimize BEVs and AVs, it is necessary to first identify the relevant parameters and costs. To this end, we have conducted an extensive literature review. The result is a complete overview of the relevant parameters and costs, divided into the categories of vehicle, infrastructure, mobility, and energy.

Three not of a kind: A NMR HNP experiment can distinguish between all three possible single‐ and double‐phosphorylated histidines without requiring pKa or chemical shift information (see picture). The method is tested on phosphorylated histidines and phosphocarrier protein HPr. It detects phosphorylation in phosphotransferase system regulation domain I (PRDI).

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