The new critical metals database “HTMET”: High tech trace element characteristics of sulphides from base metal provinces in the variscan basement and adjacent sedimentary rocks in Germany

High tech (HT) trace elements such as germanium, gallium and indium gain rising importance in the development of innovative technologies. The database “HTMET” forms the first nationwide metal-ore database for Germany, created to visualise HT metal characteristics of base metal ores from important mining districts. Mineralogical and geochemical investigations on 478 samples and ore concentrates from 109 Pb-Zn-Cu occurrences were carried out using analytical methods with high spatial resolution and bulk sample methods. The database provides aggregated data based on 17,000 geochemical data sets, compiled information on regional infrastructure and environmental risks as well as data on innovative raw material-efficient processing techniques. Evaluation of combined data provides interactive maps revealing new potentials for specific HT metals in Germany. Differences in regional distribution of these trace elements and dependency of their concentration levels in the ore on the genetic deposit type became apparent. Sphalerite from the sediment-hosted massive sulphide (SHMS) deposit “Rammelsberg” and skarn deposits in the Erzgebirge contain elevated indium contents (median 14–119 ppm), whereas the SHMS deposit “Meggen” is poor in HT metals. Germanium forms the predominant HT trace element in colloform sphalerite of Mississippi-Valley-Type (MVT) deposits (median 29–147 ppm); in contrast, crystalline sphalerite is low in germanium in this deposit type. Sphalerite in all hydrothermal vein deposits shares a distinct enrichment in gallium (median 6–81 ppm); however, germanium and indium concentrations vary significantly depending on the metal source and fluid conditions. The Ruhrgebiet and the Schwarzwald ore veins show an enrichment in germanium (median 55–73 ppm), whilst vein sphalerite from the Erzgebirge is specialised in indium (median 33 ppm). The data demonstrate that the HT trace element inventory of the studied base metal sulphides is not only a function of the genetic ore deposit type, but is also triggered by locally variable geology such as source rock and fluid composition and organic content of the rock. Gallium seems to derive from adjacent lithologies, whereas indium and germanium may have more distant sources

PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites.

Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes. A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD. We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility

The Qualification of Silicon Microstrip Detector Modules for the CMS Inner Tracking Detector

For the construction of the CMS inner tracking detector 15,232 silicon microstrip detectors had to be produced. This large number required a fast, easy to use and cost-efficient test setup for the quality assurance at different production steps in all laboratories participating in the production of the detector modules. This article describes typical faults occurring on modules as well as the test procedures used to identify and classify them provided by the APV Readout Controller (ARC) system. To establish the final test procedures the data of more than 500 tracker endcap modules had been analysed in detail. An optimal combination of measures was found that prove to be extremely efficient in detecting and properly identifying all relevant failure modes of a detector module. Finally the quality of all modules for the CMS silicon microstrip tracker is quoted

Severe Atherosclerosis and Hypercholesterolemia in Mice Lacking Both the Melanocortin Type 4 Receptor and Low Density Lipoprotein Receptor

Dysfunction of the melanocortin system can result in severe obesity accompanied with dyslipidemia and symptoms of the metabolic syndrome but the effect on vascular atherogenesis is not known. To study the impact of obesity and dyslipidemia on the cardiovascular system, we generated mice double-deficient for the melanocortin type 4 receptor (Mc4r(mut) mice) and the LDL receptor (Ldlr(-/-) mice). Mc4r(mut) mice develop obesity due to hyperphagia. Double-mutant mice (Mc4r(mut);Ldlr(-/-)) exhibited massive increases in body weight, plasma cholesterol and triacylglycerol levels and developed atherosclerosis. Atherosclerotic lesion size was affected throughout the aortic root and brachiocephalic artery not only under semisynthetic, cholesterol-containing diet but also under cholesterol-free standard chow. The Mc4r(mut) mice developed a hepatic steatosis which contributes to increased plasma cholesterol levels even under cholesterol-free standard chow. Transcripts of cholesterol biosynthesis components and liver cholesterol levels did not significantly differ between wild-type and all mutant mouse strains but RNA sequencing data and biochemical measurements point to an altered bile acid elimination in Mc4r(mut);Ldlr(-/-). Therefore, the unchanged endogenous cholesterol biosynthesis together with a reduced hepatic VLDL and LDL-cholesterol clearance most likely led to increased plasma lipid levels and consequently to atherosclerosis in this animal model. Our data indicate that dysfunction of the melanocortin-regulated food intake and the resulting obesity significantly add to the proatherogenic lipoprotein profile caused by LDL receptor deficiency and, therefore, can be regarded as relevant risk factor for atherosclerosis

Intestinal DMBT1 Expression Is Modulated by Crohn’s Disease-Associated IL23R Variants and by a DMBT1 Variant Which Influences Binding of the Transcription Factors CREB1 and ATF-2

Objectives: DMBT is an antibacterial pattern recognition and scavenger receptor. In this study, we analyzed the role of DMBT1 single nucleotide polymorphisms (SNPs) regarding inflammatory bowel disease (IBD) susceptibility and examined their functional impact on transcription factor binding and downstream gene expression. Methods: Seven SNPs in the DMBT1 gene region were analyzed in 2073 individuals including 818 Crohn’s disease (CD) patients and 972 healthy controls in two independent case-control panels. Comprehensive epistasis analyses for the known CD susceptibility genes NOD2, IL23R and IL27 were performed. The influence of IL23R variants on DMBT1 expression was analyzed. Functional analysis included siRNA transfection, quantitative PCR, western blot, electrophoretic mobility shift and luciferase assays. Results: IL-22 induces DMBT1 protein expression in intestinal epithelial cells dependent on STAT3, ATF-2 and CREB1. IL-22 expression-modulating, CD risk-associated IL23R variants influence DMBT1 expression in CD patients and DMBT1 levels are increased in the inflamed intestinal mucosa of CD patients. Several DMBT1 SNPs were associated with CD susceptibility. SNP rs2981804 was most strongly associated with CD in the combined panel (p = 3.0×10−7, OR 1.42; 95% CI 1.24–1.63). All haplotype groups tested showed highly significant associations with CD (including omnibus P-values as low as 6.1×10−18). The most strongly CD risk-associated, non-coding DMBT1 SNP rs2981804 modifies the DNA binding sites for the transcription factors CREB1 and ATF-2 and the respective genomic region comprising rs2981804 is able to act as a transcriptional regulator in vitro. Intestinal DMBT1 expression is decreased in CD patients carrying the rs2981804 CD risk allele. Conclusion: We identified novel associations of DMBT1 variants with CD susceptibility and discovered a novel functional role of rs2981804 in regulating DMBT1 expression. Our data suggest an important role of DMBT1 in CD pathogenesis