Technical note: Determination of binary gas-phase diffusion coefficients of unstable and adsorbing atmospheric trace gases at low temperature – arrested flow and twin tube method

Gas-phase diffusion is the first step for all heterogeneous reactions under atmospheric conditions. Knowledge of binary diffusion coefficients is important for the interpretation of laboratory studies regarding heterogeneous trace gas uptake and reactions. Only for stable, nonreactive and nonpolar gases do well-established models for the estimation of diffusion coefficients from viscosity data exist. Therefore, we have used two complementary methods for the measurement of binary diffusion coefficients in the temperature range of 200 to 300 K: the arrested flow method is best suited for unstable gases, and the twin tube method is best suited for stable but adsorbing trace gases. Both methods were validated by the measurement of the diffusion coefficients of methane and ethane in helium and air as well as nitric oxide in helium. Using the arrested flow method the diffusion coefficients of ozone in air, dinitrogen pentoxide and chlorine nitrate in helium, and nitrogen were measured. The twin tube method was used for the measurement of the diffusion coefficient of nitrogen dioxide and dinitrogen tetroxide in helium and nitrogen

Targeted next generation sequencing as a reliable diagnostic assay for the detection of somatic mutations in tumours using minimal DNA amounts from formalin fixed paraffin embedded material

Background Targeted Next Generation Sequencing (NGS) offers a way to implement testing of multiple genetic aberrations in diagnostic pathology practice, which is necessary for personalized cancer treatment. However, no standards regarding input material have been defined. This study therefore aimed to determine the effect of the type of input material (e.g. formalin fixed paraffin embedded (FFPE) versus fresh frozen (FF) tissue) on NGS derived results. Moreover, this study aimed to explore a standardized analysis pipeline to support consistent clinical decision-making. Method We used the Ion Torrent PGM sequencing platform in combination with the Ion AmpliSeq Cancer Hotspot Panel v2 to sequence frequently mutated regions in 50 cancer related genes, and validated the NGS detected variants in 250 FFPE samples using standard diagnostic assays. Next, 386 tumour samples were sequenced to explore the effect of input material on variant detection variables. For variant calling, Ion Torrent analysis software was supplemented with additional variant annotation and filtering. Results Both FFPE and FF tissue could be sequenced reliably with a sensitivity of 99.1%. Validation showed a 98.5%concordance between NGS and conventional sequencing techniques, where NGS provided both the advantage of low input DNA concentration and the detectio

Genetic determinants of complement activation in the general population

Complement is a fundamental innate immune response component. Its alterations are associated with severe systemic diseases. To illuminate the complement's genetic underpinnings, we conduct genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways in the Cooperative Health Research in South Tyrol study (n = 4,990). We identify seven loci, encompassing 13 independent, pathway-specific variants located in or near complement genes (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining up to 74% of complement pathways' genetic heritability and implicating long-range haplotypes associated with LP at MBL2. Two-sample Mendelian randomization analyses, supported by transcriptome- and proteome-wide colocalization, confirm known causal pathways, establish within-complement feedback loops, and implicate causality of ABO on LP and of CFHR2 and C7 on AP. LP causally influences collectin-11 and KAAG1 levels and the risk of mouth ulcers. These results build a comprehensive resource to investigate the role of complement in human health

Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study

Background: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type. Methods: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation. Results: Cell line screens indicated several genes, such as PTEN (P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit (P = 0.046; Fisher's exact test). Conclusion: Loss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies

Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study.

BACKGROUND: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). METHODS AND FINDINGS: We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. CONCLUSIONS: Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips were funded by the French National Foundation on Alzheimer's disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer's Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC–10–196728.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pmed.100184

Advanced electron cyclotron heating and current drive experiments on the stellarator Wendelstein 7-X

During the first operational phase (OP 1.1) of Wendelstein 7-X (W7-X) electron cyclotron resonance heating (ECRH) was the exclusive heating method and provided plasma start-up, wall conditioning, heating and current drive. Six gyrotrons were commissioned for OP1.1 and used in parallel for plasma operation with a power of up to 4.3 MW. During standard X2-heating the spatially localized power deposition with high power density allowed controlling the radial profiles of the electron temperature and the rotational transform. Even though W7-X was not fully equipped with first wall tiles and operated with a graphite limiter instead of a divertor, electron densities of n e > 3·1019 m-3 could be achieved at electron temperatures of several keV and ion temperatures above 2 keV. These plasma parameters allowed the first demonstration of a multipath O2-heating scenario, which is envisaged for safe operation near the X-cutoff-density of 1.2·1020 m-3 after full commissioning of the ECRH system in the next operation phase OP1.2