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The IFITM3 protein is a prominent restriction factor of influenza virus that has been shown to antagonise the cellular entry of influenza virus. In 2012, the minor allele of a synonymous SNP in IFITM3, known as rs12252 (major T, minor C), was shown to be associated with severe influenza virus infection. Numerous studies have corroborated this association, showing clear links between the C allele and increased risk of severe influenza virus infection in East Asian and European populations. It was hypothesised that the observed effects of rs12252-C were related to aberrant splicing of IFITM3, causing an isoform coding for an N-terminally truncated variant of the protein. More recently, additional IFITM3-associated genetic risk factors for severe influenza virus infection have also been uncovered. In this thesis, we investigated the molecular mechanisms of rs12252. In chapter 3, we show that the IFITM3 splicing profile is consistently dominated by the canonical isoform, and that truncated isoforms are produced at extremely low levels regardless of rs12252 genotype. In chapter 4, we investigated associations between rs12252 and expression of IFITM3 at mRNA and protein level, using in vitro systems and healthy donors. We show that rs12252 is an expression Quantitative Trait Locus (eQTL) for IFITM3, and its activity is potentially tissue dependent. We also uncovered potential effects of this SNP on blood transcriptional signature. Next, in chapter 5, we identified two novel eQTLs for IFITM3, which may be risk variants for severe influenza virus infection. Finally, in chapter 6, we analysed the association between rs12252 and severe influenza infection using several model systems. These findings uncovered potential associations between rs12252 and differential interferon signalling, although further experimentation is required to confirm this.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits. Postprint

Dimethylsulphide (DMS) has an important role in the global sulphur cycle and atmospheric chemistry. Microorganisms using DMS as sole carbon, sulphur or energy source, contribute to the cycling of DMS in a wide variety of ecosystems. The diversity of microbial populations degrading DMS in terrestrial environments is poorly understood. Based on cultivation studies, a wide range of bacteria isolated from terrestrial ecosystems were shown to be able to degrade DMS, yet it remains unknown whether any of these have important roles in situ. In this study, we identified bacteria using DMS as a carbon and energy source in terrestrial environments, an agricultural soil and a lake sediment, by DNA stable isotope probing (SIP). Microbial communities involved in DMS degradation were analysed by denaturing gradient gel electrophoresis, high-throughput sequencing of SIP gradient fractions and metagenomic sequencing of phi29-amplified community DNA. Labelling patterns of time course SIP experiments identified members of the Methylophilaceae family, not previously implicated in DMS degradation, as dominant DMS-degrading populations in soil and lake sediment. Thiobacillus spp. were also detected in 13C-DNA from SIP incubations. Metagenomic sequencing also suggested involvement of Methylophilaceae in DMS degradation and further indicated shifts in the functional profile of the DMS-assimilating communities in line with methylotrophy and oxidation of inorganic sulphur compounds. Overall, these data suggest that unlike in the marine environment where gammaproteobacterial populations were identified by SIP as DMS degraders, betaproteobacterial Methylophilaceae may have a key role in DMS cycling in terrestrial environments.

Cross sections of epoxy adhesive joints (DGEBA and DETA) of Al or Cu PVD substrates were prepared by ultra-microtomy and studied with STEM, EELS and EDX to reveal the metal concentration profile after curing and after ageing in moist-warm air for 360 clays After curing, ca 0 3 at% of aluminium is detected in a thin interphase of less than 50 nm thickness Up to 0 5 at% of copper is found within 20-75 nm from the interface and it is still detected at 1000 nm distance to the Substrate In aged samples, no further diffusion of Al species into the polymer took place whereas the Cu Substrate shows a higher toughness and varying thickness after ageing Accordingly, up to 0 9 at% of Cu is detected within the first 20-120 nm from the substrate Thus, corrosive dissolution of the surface oxide layer and the metallic copper Substrate and diffusion of Cu species into the polymer proceed under moist-warm conditions

In dit project is een competentieprofiel ontwikkeld voor vier doelgroepen die betrokken zijn bij onderwijsinnovatie met gebruik van ICT: ontwikkelaars van digitale materialen, opleidingsmanagers, docenten en onderwijsexperts. Het doel is een overzicht te geven van relevante competenties voor deze doelgroepen zodat het huidige en toekomstige scholingsaanbod van de DU getoetst kan worden aan professionaliseringsbehoeften.

SHRIMP-dating of zircons from ultramafic, mafic and metasedimentary high-pressure (HP) rocks of Cabo Ortegal gave the following results: The MORB-type protoliths of the eclogites are Cambrian (507±7 7 Ma). Their transformation into eclogites occurred during a Devonian subduction that was accompanied by partial melting of the mantle wedge, giving rise to the formation of pyroxenites. The lon-microprobe-data suggest a single HP-loop around 392 Ma that involved all analyzed rocks La datación de zircones, mediante SHRIMP de rocas ultramáficas, máficas y rocas metasedimentarías de alta presión (HP) del complejo de Cabo Ortegal, muestra los siguientes resultados: Los protolitos de tipo MORB de las eclogitas son Cámbricos (507±7 7 Ma). Su transformación a eclogitas tuvo lugar durante una subducción Devónica que estuvo acompañada de una fusión parcial en la cuña mantélica produciendo la formación de piroxenitas. Los datos producidos mediante la microsonda-iónica sugieren un único episodio metamórfico de alta presión alrededor de los 392 Ma para todas las rocas analizadas

The European Commission has initiated a forum for the coordination of pesticide fate models and their use : FOCUS. The working group on Surface Water models has prepared this final report. An overview of the input and fate models concerning surface water is presented. Highlighted are input processes like run-off, drainage, drift and atmospheric deposition. Currently available models are inventored, evaluated and judged on their regulatory use, user friendliness, availability, data requirements, output facilities and validation status. Also, the available surface water fate models are considered with respect to the same topics. Using an example scenario calculation, the use and interaction of the different models is elucidated. Finally, some conclusions and recommendations for further research are outlined., A la demande de la Commision européenne (DG VI), le groupe de travail FOCUS (Forum for the coordination of pesticide fate models and their use) " Eaux de Surface " a élaboré ce rapport qui présente les principaux modèles actuellement utilisés pour évaluer le transfert des produits phytosanitaires vers les eaux de surface. Sont distingués les modèles de dérive, drainage, ruissellement, transport atmosphérique et transport dans les cours d'eau. Une réflexion est menée sur leurs capacités et limites ainsi que sur leur niveau de validation et leur possible utilisation à des fins réglementaires. La définition de scénarios agro-pédo-climatiques de mise en oeuvre des modèles dans cet objectif est initiée.

SHRIMP-dating of zircons from ultramafic, mafic and metasedimentary high-pressure (HP) rocks of Cabo Ortegal gave the following results: The MORB-type protoliths of the eclogites are Cambrian (507±7 7 Ma). Their transformation into eclogites occurred during a Devonian subduction that was accompanied by partial melting of the mantle wedge, giving rise to the formation of pyroxenites. The lon-microprobe-data suggest a single HP-loop around 392 Ma that involved all analyzed rocks, La datación de zircones, mediante SHRIMP de rocas ultramáficas, máficas y rocas metasedimentarías de alta presión (HP) del complejo de Cabo Ortegal, muestra los siguientes resultados: Los protolitos de tipo MORB de las eclogitas son Cámbricos (507±7 7 Ma). Su transformación a eclogitas tuvo lugar durante una subducción Devónica que estuvo acompañada de una fusión parcial en la cuña mantélica produciendo la formación de piroxenitas. Los datos producidos mediante la microsonda-iónica sugieren un único episodio metamórfico de alta presión alrededor de los 392 Ma para todas las rocas analizadas

We present entropy estimates based on molecular dynamics simulations of models of the molten globule state of the protein alpha-lactalbumin at low pH. The entropy calculations use the covariance matrix of atom-positional fluctuations and yield the complete configurational entropy. The configurational entropy of the entire protein and of each of its side chains is calculated. Exposed side chains show a larger entropy compared to buried side chains. A comparison to data from rotamer counting is made and significant differences are found.

The prevalence of complicated hypertension is increasing in America and Europe. This survey was undertaken to assess the status quo of primary care management of hypertension in patients with the high-risk comorbid diseases metabolic syndrome (MetS) and/or type 2 diabetes mellitus (non-insulin depending diabetes mellitus (NIDDM)). Data of anti-hypertensive treatment of 4594 Swiss patients were collected over 1 week. We identified patients with exclusively NIDDM (N = 95), MetS (N = 168), and both (N = 768). Target blood pressure (TBP) attainment, frequency of prescribed substance-classes, and correlations to comorbidities/end-organ damages were assessed. In addition, we analyzed the prescription of unfavorable beta-blockers (BB) and high-dose diuretics (Ds). In NIDDM, Ds (61%), angiotensin receptor blockers (ARBs) (40%), and angiotensin converting enzyme inhibitors (ACEIs) (31%) were mostly prescribed, while in MetS, drugs prevalence was Ds (68%), ARBs (48%), and BB (41%). Polypharmacy in patients with MetS correlated with body mass index; older patients (65 years) were more likely to receive dual-free combinations. TBP was attained in 25.2% of NIDDM and in 28.7% of MetS patients. In general, low-dose Ds use was more prevalent in NIDDM and MetS, however, overall, Ds were used excessively (NIDDM: 61%, MetS: 68%), especially in single-pill combination. Patients with MetS were more likely to receive ARBs, ACEIs, CCBs, and low-dose Ds than BBs and/or high-dose Ds. Physicians recognize DM and MetS as high-risk patients, but select inappropriate drugs. Because the majority of patients may have both, MetS and NIDDM, there is an unmet need to define TBP for this specific population considering the increased risk in comparison to patients with MetS or NIDDM alone.

Background There are only a few trials for the very elderly population (>79 years). No consensus, which blood pressure (BP) goals and substances should be applied, has been found yet. This survey was undertaken to investigate how octogenarians are treated and attain BP targets in the Swiss primary care. Methods Data from 4594 hypertensive patients were collected within 7 days. Eight hundred and seventy-seven patients met the requirement to be >79 years. We assessed substances/combinations and investigated pulse pressure and target blood pressure attainment (TBPA) using three different recommendations [Canadian Hypertension Education Program (CHEP), Swiss Society of Hypertension (SSH), European Society of Hypertension-European Society of Cardiology (ESH-ESC)]. Secondarily, we compared TBPA attained by angiotensin-converting enzyme inhibitor (ACEI)/diuretic (D), angiotensin receptor blocker (ARB)/D and calcium channel blocker (CCB)/D with any other dual therapy and investigated whether Ds/beta-blockers (BBs) or Ds/renin angiotensin-converting enzyme inhibitors (RAAS-Is) lead to higher TBPA. Finally, we assessed the impact of drug administration, practical work experience, location and specialization of GPs on TBPA. Results Octogenarians attained target blood pressure (TBP) between 44% (ESH-ESC) and 74% (SSH). Optimal/normal BP was reached in 22.8% of patients. Pulse pressure