Search

The term Computational Thinking (CT) was introduced in 2006 by J. M. Wing to indicate a set of analytical skills regarded necessary for the youth in the modern information society [11]. We describe an ongoing research project on CT skills in the Netherlands, focusing on the computer science (CS) course in the upper grades of secondary education. In the first phase of the project we explore the occurrence and nature of CT aspects in the CS teaching materials and policy documents as well as teachers' pedagogical content knowledge (PCK). In this poster we describe the research design and the method of the first phase of the project and we report and discuss the results obtained so far, focusing on the teachers' perspective.

Restarts are an important technique to make search more robust. This paper is concerned with how to maintain and propagate nogoods recorded from restarts efficiently. It builds on reduced nld-nogoods introduced for restarts and increasing nogoods introduced for symmetry breaking. The paper shows that reduced nld-nogoods extracted from a single restart are in fact increasing, which can thus benefit from the efficient propagation algorithm of the incNGs global constraint. We present a lighter weight filtering algorithm for incNGs in the context of restart-based search using dynamic event sets (dynamic subscriptions). We show formally that the lightweight version enforces GAC on each nogood while reducing the number of subscribed decisions. The paper also introduces an efficient approximation to nogood minimization such that all shortened reduced nld-nogoods from the same restart are also increasing and can be propagated with the new filtering algorithm. Experimental results confirm that our lightweight filtering algorithm and approximated nogood minimization successfully trade a slight loss in pruning for considerably better efficiency, and hence compare favorably against existing state-of-the-art techniques.

For many macromolecular NMR ensembles from the Protein Data Bank (PDB) the experiment-based restraint lists are available, while other experimental data, mainly chemical shift values, are often available from the BioMagResBank. The accuracy and precision of the coordinates in these macromolecular NMR ensembles can be improved by recalculation using the available experimental data and present-day software. Such efforts, however, generally fail on half of all NMR ensembles due to the syntactic and semantic heterogeneity of the underlying data and the wide variety of formats used for their deposition. We have combined the remediated restraint information from our NMR Restraints Grid (NRG) database with available chemical shifts from the BioMagResBank and the Common Interface for NMR structure Generation (CING) structure validation reports into the weekly updated NRG-CING database (http://nmr.cmbi.ru.nl/NRG-CING). Eleven programs have been included in the NRG-CING production pipeline to arrive at validation reports that list for each entry the potential inconsistencies between the coordinates and the available experimental NMR data. The longitudinal validation of these data in a publicly available relational database yields a set of indicators that can be used to judge the quality of every macromolecular structure solved with NMR. The remediated NMR experimental data sets and validation reports are freely available online.

In chronic GVHD after BMT, the conjunctiva represents a target organ. GVHD can lead to severe inflammation and dry-eye syndrome (sicca syndrome). The molecular mechanisms are largely unknown. We examined the expression of chemokines in the conjunctiva in cases of chronic GVHD. In this study, we included 10 patients with chronic GVHD and 10 healthy controls. Clinical data were collected and tear film analysis and conjunctival cytology were carried out. Conjunctival biopsies were taken from all participants. Gene expression profiles of chemokines and their corresponding receptors were evaluated by means of quantitative real-time PCR. Chemokine protein expression was analysed by immunohistochemical analyses. Expressions of the Th1-associated chemokines, chemokine (C-X-C motif) ligand (CXCL) 9 (Mig), CXCL10 (IP-10), and their receptor chemokine (C-X-C motif) receptor 3 (CXCR3) were significantly increased in GVHD patients. Immunohistochemical analysis confirmed marked expression of the inflammatory CXCR3 ligands. A total of six patients had a moderate or severe sicca syndrome. Impression cytology revealed a mild keratinisation, moderate keratinisation or severe squamous metaplasia in three patients, respectively. Chronic GVHD of the conjunctiva is characterised by the expression of Th1-associated chemokines. Taken together, our results confirm that the conjunctiva is a target organ in this T cell-mediated process and add to molecular understanding of conjunctival GVHD.

Objective: SPG7 is one of the most frequent causes of autosomal recessive Hereditary Spastic Paraplegias and spastic ataxias. Ala510Val is the most common mutation, with a frequency of up to 1% in the general population. The exact pathology caused by SPG7 and, in particular, the Ala510Val mutation,[for full text, please go to the a.m. URL], 60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN)

In this study, Mendelian randomization was used to study genes known to modify iron levels, and the effect of iron on Parkinson's disease (PD) risk was estimated. Based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date, the findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson's disease for every 10 µg/dL increase in iron. The results of this analysis have potentially important implications for future research into the prevention of Parkinson's disease. Please see later in the article for the Editors' Summary, Background Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. Methods and Findings We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; p = 0.001) per 10 µg/dl increase in serum iron. Conclusions Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. Please see later in the article for the Editors' Summary, Editors' Summary Background Parkinson disease is a degenerative disorder of the central nervous system caused by the death of dopamine-generating cells in the substania nigra, a region of the midbrain. The earliest symptoms are usually movement-related and include tremor, slow movements, and difficulty walking, and later cognitive and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease. Parkinson disease affects around ten million people world-wide and incidence increases with age, with men more affected than women. To date, the causes of Parkinson disease remain unknown although a combination of genetic and environmental factors is thought to play a role. Identifying possible modifiable risks is an important step in the possible prevention of Parkinson disease. Why Was This Study Done? Previous studies have shown a possible association between lower blood levels of iron in people with Parkinson disease compared with controls, although the quality of these studies makes this finding difficult to interpret. So in this study, the researchers used a mendelian randomization approach to investigate whether there was any evidence of an effect of blood iron levels on the risk of Parkinson disease and if so to further explore the direction and scale of any link. Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in situations where it is inappropriate to perform a randomized controlled trial. What Did the Researchers Do and Find? The researchers estimated the effect of blood iron levels on the risk of Parkinson disease using three polymorphisms in two genes, HFE and TMPRSS6. For each polymorphism, they performed a meta-analysis combining the results of studies investigating the genetic effect on iron levels, which included almost 22,000 people from Europe and Australia, and a meta-analysis of studies investigating the genetic effect on the risk of Parkinson disease, which included a total of 20,809 people with Parkinson disease and 88,892 controls from Europe and North America. They then performed three separate mendelian randomization analyses to estimate the effect of iron on Parkinson disease for the three polymorphisms. By combining the three estimates, they obtained a statistically significant odds ratio of 0.97 for Parkinson disease per 10 µg/dl increase in iron, corresponding to a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in blood iron. Since genotype influences on blood iron levels represent differences that generally persist throughout adult life, the combined mendelian randomization estimate reflects an effect of iron over the course of a lifetime. What Do These Findings Mean? These findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in iron. This finding is important as it suggests that increased blood iron levels may have a protective effect against Parkinson disease, although the underlying mechanism remains unclear. Furthermore, although mendelian randomization is an increasingly used approach to address the issue of classical confounding, there may be remaining confounding factors specific of mendelian randomization that may influence the interpretation of this study. Nevertheless, the results of this analysis have potentially important implications for future research into the prevention of Parkinson disease. Further studies on the underlying mechanisms are needed before any specific treatment recommendations can be proposed. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001462. The National Institutes of Neurological Disorder and Stroke, MedlinePlus, and NHS Choices have several pages with comprehensive information on Parkinson disease Wikipedia gives an explanation of mendelian randomization (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Importance Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. Objectives To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Design, Setting, and Participants Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. Main Outcomes and Measures The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Results Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK , HLA-DRB5 , LRRK2 , and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA , LRRK2 , MAPT , TRIM10 , and SE TD1A in PD. Among the novel genes discovered, WNT3 , KANSL1 , CRHR1 , BOLA2 , and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. Conclusions and Relevance The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

To the Editor: Tsuji and colleagues (July 18 issue)1 report that variants in the gene encoding coenzyme Q2 (COQ2) increase the risk of multiple-system atrophy. They observed homozygous COQ2 variants encoding the substitutions M78V and V343A in a consanguineous Japanese family with multiple-system atrophy subtype P and noted an association between V343A and sporadic multiple-system atrophy (minor-allele frequency [MAF], 4.8% of cases vs. 1.6% of controls; odds ratio, 3.05; 95% confidence interval, 1.65 to 5.85). However, the authors erroneously labeled human COQ2 variability from the fourth ATG start codon in exon 1, which encodes the smallest protein isoform and does not functionally complement the yeast coq2-null mutant.2 On the basis of the National Center for Biotechnology Information (NCBI) Reference Sequence (NM_015697.7), M78V should be labeled COQ2 c.382A→G (p.M128V) and V343A should be labeled c.1178T→C (p.V393A). We sequenced COQ2 in 299 Korean persons with multiple-system atrophy and 365 unaffected Korean persons and observed heterozygous COQ2 c.320G→C (encoding p.S107T) and c.382A→T (encoding p.M128R) in 2 patients with sporadic multiple-system atrophy; COQ2 c.1178T→C (p.V393A) was not associated with multiple-system atrophy (MAF, 2.7% of cases vs. 2.6% of controls). It is a challenge to reconcile recessive linkage of homozygous COQ2 mutations in familial multiple-system atrophy with a heterozygous, presumably dominant-negative association in sporadic multiple-system atrophy. Respectfully, we suggest that Tsuji and colleagues reconsider whether variations in COQ2 represent a risk factor for multiple-system atrophy. Genomic multiplications of the SNCA 6.4-Mb locus telomeric to COQ2 have previously been implicated in parkinsonism and multiple-system atrophy3; copy number analysis of linked loci, or genomewide analysis, should be considered.

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10-16). We also show six risk loci associated with proximal gene expression or DNA methylation. © 2014 Nature America, Inc. All rights reserved.

Contains fulltext : 216327.pdf (Publisher’s version ) (Open Access) ISSEP 2014 : 7th International Conference on Informatics in Schools: Situation, Evolution and Perspectives, 22-25 September 2014 Istanbul, Turkey

Poster Abstract