The C-mannosylome of human induced pluripotent stem cells implies a role for ADAMTS16 C-mannosylation in eye development

C-mannosylation is a modification of tryptophan residues with a single mannose and can affect protein folding, secretion, and/or function. To date, only a few proteins have been demonstrated to be C-mannosylated, and studies that globally assess protein C-mannosylation are scarce. To interrogate the C-mannosylome of human induced pluripotent stem cells, we compared the secretomes of CRISPR–Cas9 mutants lacking either the C-mannosyltransferase DPY19L1 or DPY19L3 to WT human induced pluripotent stem cells using MS-based quantitative proteomics. The secretion of numerous proteins was reduced in these mutants, including that of A Disintegrin And Metalloproteinase with ThromboSpondin Motifs 16 (ADAMTS16), an extracellular protease that was previously reported to be essential for optic fissure fusion in zebrafish eye development. To test the functional relevance of this observation, we targeted dpy19l1 or dpy19l3 in embryos of the Japanese rice fish medaka (Oryzias latipes) by CRISPR–Cas9. We observed that targeting of dpy19l3 partially caused defects in optic fissure fusion, called coloboma. We further showed in a cellular model that DPY19L1 and DPY19L3 mediate C-mannosylation of a recombinantly expressed thrombospondin type 1 repeat of ADAMTS16 and thereby support its secretion. Taken together, our findings imply that DPY19L3-mediated C-mannosylation is involved in eye development by assisting secretion of the extracellular protease ADAMTS16

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Low-Temperature NOx Reduction by H2 in Diesel Engine Exhaust

For the NOx removal from diesel exhaust, the selective catalytic reduction (SCR) and lean NOx traps are established technologies. However, these procedures lack efficiency below 200 °C, which is of importance for city driving and cold start phases. Thus, the present paper deals with the development of a novel low-temperature deNOx strategy implying the catalytic NOx reduction by hydrogen. For the investigations, a highly active H2-deNOx catalyst, originally engineered for lean H2 combustion engines, was employed. This Pt-based catalyst reached peak NOx conversion of 95 % in synthetic diesel exhaust with N2 selectivities up to 80 %. Additionally, driving cycle tests on a diesel engine test bench were also performed to evaluate the H2-deNOx performance under practical conditions. For this purpose, a diesel oxidation catalyst, a diesel particulate filter and a H2 injection nozzle with mixing unit were placed upstream to the full size H2-deNOx catalyst. As a result, the Worldwide harmonized Light vehicles Test Cycle (WLTC), urban cycle segment of the Common Artemis Driving Cycle (CADC UC) and Transport for London Urban Inter Peak (TfL UIP) driving cycle revealed NOx conversions up to 90 % at temperatures as low as 80 °C. However, outside the low-temperature region, H2-deNOx activity dropped significantly evidencing the need for an additional underfloor SCR system. Moreover, slight N2O formation was observed in the engine tests making further catalyst development necessary, since N2O is considered a critical component due to its global warming potential. Additionally, the H2 demand for low-temperature deNOx in diesel passenger cars was estimated and a novel on-board H2 production strategy based on DEF electrolysis was developed. This method provided both H2 as well as gaseous NH3. Subsequent simulations of H2 production demonstrate small size factors (≤ 525 cm3) and rather low energy consumption of the H2 supply unit, e.g. 0.25 kWh for the TfL UIP driving cycle

Highway to Hitler

Can infrastructure investment win "hearts and minds"? We analyze a famous case in the early stages of dictatorship - the building of the motorway network in Nazi Germany. The Autobahn was one of the most important projects of the Hitler government. It was intended to reduce unemployment, and was widely used for propaganda purposes. We examine its role in increasing support for the NS regime by analyzing new data on motorway construction and the 1934 plebiscite, which gave Hitler great powers as head of state. Our results suggest that road building was highly effective, reducing opposition to the nascent Nazi regime

Genetics of migraine: Insights into the molecular basis of migraine disorders

Migraine is a complex, debilitating neurovascular disorder, typically characterized by recurring, incapacitating attacks of severe headache often accompanied by nausea and neurological disturbances. It has a strong genetic basis demonstrated by rare migraine disorders caused by mutations in single genes (monogenic), as well as familial clustering of common migraine which is associated with polymorphisms in many genes (polygenic). Hemiplegic migraine is a dominantly inherited, severe form of migraine with associated motor weakness. Family studies have found that mutations in three different ion channels genes, <em>CACNA1A</em>, <em>ATP1A2</em>, and <em>SCN1A</em> can be causal. Functional studies of these mutations has shown that they can result in defective regulation of glutamatergic neurotransmission and the excitatory/inhibitory balance in the brain, which lowers the threshold for cortical spreading depression, a wave of cortical depolarization thought to be involved in headache initiation mechanisms. Other putative genes for monogenic migraine include <em>KCKN18</em>, <em>PRRT2</em>, and <em>CSNK1D</em>, which can also be involved with other disorders. There are a number of primarily vascular disorders caused by mutations in single genes, which are often accompanied by migraine symptoms. Mutations in <em>NOTCH3</em> causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebrovascular disease that leads to ischemic strokes and dementia, but in which migraine is often present, sometimes long before the onset of other symptoms. Mutations in the <em>TREX1</em> and <em>COL4A1</em> also cause vascular disorders, but often feature migraine. With respect to common polygenic migraine, genome-wide association studies have now identified single nucleotide polymorphisms at 38 loci significantly associated with migraine risk. Functions assigned to the genes in proximity to these loci suggest that both neuronal and vascular pathways also contribute to the pathophysiology of common migraine. Further studies are required to fully understand these findings and translate them into treatment options for migraine patients