Linkage and association analysis of GAW15 simulated data: fine-mapping of chromosome 6 region

We performed linkage and family-based association analysis across chromosomes 1–22 in Replicates 1–5 of the Genetic Analysis Workshop 15 simulated data. Linkage analysis was performed using the Kong and Cox allele-sharing test as implemented in the program Merlin. Association analysis was performed using the transmission/disequilibrium test (TDT). A region on chromosome 6 was consistently highlighted as showing significant linkage to and association with the disease trait. We focused in on this region and performed fine-mapping using stepwise regression approaches using the case/control and family-based data. In this region, we also applied several new methods, implemented in the computer programs LAMP and Graphminer, respectively, that have recently been proposed for association analysis with family and/or case/control data. All methods confirmed the highly significant associations previously observed. Differentiating between potentially causal single nucleotide polymorphisms (SNPs) and other non-causal loci (associated with disease merely due to linkage disequilibrium) proved to be problematic. However, in most replicates we did identify two SNPs (either SNPs 3437 and 3439 from the dense SNP set, or SNPs 153 and 3437 from the combined non-dense/dense SNP set) that together explain most of the observed disease association in the DR/C locus region, and an additional SNP (3931 or 3933) that accounts for the association 5 cM away at locus D

Venous outflow system in rabbit gastric mucosa

The purpose of this work was to compare the organisation of the gastric mucosal venous system in larger animals, exemplified by rabbits, with that of the rat and the hamster which we have described previously. Rabbits were given atropine and hexamethonium followed by intravital ligation of all veins draining the stomach, causing strong hyperaemia. The distribution of vessels was studied in the non-mounted mucosa, in mounts of mucosa cleared in light mineral oil and in paraffin or semi-thin plastic sections. We found that blood from rabbit gastric mucosa is drained by collecting venules, running from the subepithelial layer towards the muscularis mucosae. The collecting venules join the paramuscular vessels parallel and adjacent to the muscularis mucosae. Neighbouring venules form numerous arcade-like connections and gradually enlarge. Two venules and an arteriole form triplets initially situated at the luminal face of the muscularis mucosae and gradually passing onto its abluminal surface. In rats vascular triplets were absent and the collecting venules drained into paramuscular vessels joining submucosal veins. In hamsters both connections between paramuscular vessels and submucosal veins and the passing of vascular triplets across muscularis mucosae were observed. Contraction/relaxation of the muscularis mucosae may regulate the amount of blood in the venous system of the mucosa and change the intramucosal pressure, affecting movement of the tissue fluid and, indirectly, the function of the gastric cells

Electrical polarization switching in bulk single crystal GaFeO3_{3}

The electrical polarization switching on stoichiometric GaFeO$_{3}$ single crystal was measured, and a new model of atomic displacements responsible for the polarization reverse was proposed. The widely adapted mechanism of polarization switching in GaFeO$_{3}$ can be applied to stoichiometric, perfectly ordered crystals. However, the grown single crystals, as well as thin films of Ga-Fe-O, show pronounced atomic disorder. By piezoresponse force microscopy, the electrical polarization switching on a crystal surface perpendicular to the electrical polarization direction was demonstrated. Atomic disorder in the crystal was measured by X-ray diffraction and M\"ossbauer spectroscopy. These measurements were supported by ab initio calculations. By analysis of atomic disorder and electronic structure calculations, the energies of defects of cations in foreign cationic sites were estimated. The energies of the polarization switch were estimated, confirming the proposed mechanism of polarization switching in GaFeO$_{3}$ single crystals

Three-dimensional numerical model of heat losses from district heating network pre-insulated pipes buried in the ground

The purpose of the paper is to investigate the challenges in modelling the energy losses of heating networks and to analyse the factors that influence them. The verification of the simulation was conducted on a test stand in-situ and based on the measurements of the testing station, a database for the final version of the numerical model was developed and a series of simulations were performed. Examples of the calculated results are shown in the graphs. The paper presents an innovative method of identify the energy losses of underground heating network pipelines and quantify the temperature distribution around them, in transient working conditions. The presented method makes use of numerical models and measured data of actual objects.The dimensions of the pipelines used were 6m wide, 8m high and 1m in depth, while they were simulated under conditions of zero heat flow in the ground, in the perpendicular to the sides direction of the calculated area and considering the effects of ground's thermal conductivity. The mesh was developed using advanced functions, which resulted its high quality with the average orthogonal quality of 0.99 (close to 1.00) and Skewness of 0.05 (between 0.00 and 0.25). To achieve better accuracy of the simulation model, the initial conditions were determined based on the numerical results of a three-dimensional analysis of heat losses, in steady state conditions in a single moment. The validation process confirmed the high quality of the model, as the differences between the ground temperatures were approximately 0.1°C

Polygenic risk scores for major depressive disorder and neuroticism as predictors of antidepressant response:Meta-analysis of three treatment cohorts

There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 760). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10–5 MDD-PRS at 4 weeks, β = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, β = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts

Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?

Abstractα-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson's disease (PD). Since SNCA multiplications increase SNCA expression, and REP1 genotypes that increase the risk of developing PD show increased SNCA expression in cell-culture systems, animal models, and human blood and brain, PD therapies seek to reduce SNCA expression. We conducted an observational study of 1098 PD cases to test the hypothesis that REP1 genotypes correlated with reduced SNCA expression are associated with better motor and cognitive outcomes. We evaluated the association of REP1 genotypes with survival free of Hoehn and Yahr stages 4 or 5 (motor outcome) and of Modified Telephone Interview for Cognitive Status score ≤27 or Alzheimer's Disease Dementia Screening Interview score ≥2 (cognitive outcome). Median disease duration at baseline was 3.3 years and median lag time from baseline to follow-up was 7.8 years. Paradoxically, REP1 genotypes associated with increased risk of developing PD and increased SNCA expression were associated with better motor (HR = 0.87, p = 0.046, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.020, covariate-adjusted time-scale analysis) and cognitive outcomes (HR = 0.90, p = 0.12, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.023, covariate-adjusted time-scale analysis). Our findings raise the possibility that SNCA has a dual, opposing, and time-dependent role. This may have implications for the development of therapies that target SNCA expression