Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries.

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10 CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 nea

Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

Purpose Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear. Methods We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF. Results Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 x 10(-11)). Conclusion Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.Developmen

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.1668F is a founder variant among Ashkenazi Jews (allele frequency of -.2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.Genetics of disease, diagnosis and treatmen

Common genetic variants contribute to risk of transposition of the great arteries

Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus

Analyzing Intensive Intrusion Alerts Via Correlation

Traditional intrusion detection systems (IDSs) focus on low-level attacks or anomalies, and raise alerts independently, though there may be logical connections between them. In situations where there are intensive intrusions, not only will actual alerts be mixed with false alerts, but the amount of alerts will also become unmanageable. As a result, it is difficult for human users or intrusion response systems to understand the alerts and take appropriate actions

Phytochemical Profiles, Antioxidant, Cytotoxic, and Anti-Inflammatory Activities of Traditional Medicinal Plants: Centaurea pichleri subsp. pichleri, Conyza canadensis, and Jasminum fruticans

Centaurea pichleri subsp. pichleri, Conyza canadensis, and Jasminum fruticans are traditionally used plants grown in Turkey. Methanol extracts were obtained from these plants and pharmacological activity studies and phytochemical analyses were carried out. To evaluate the phytochemical composition, spectrophotometric and chromatographic techniques were used. The extracts were evaluated for antioxidant activity by DPPH●, ABTS●+ radical scavenging, and FRAP assays. The cytotoxic effects of the extracts were investigated on DU145 prostate cancer and A549 lung cancer cell lines. The anti-inflammatory effects of extracts were investigated on the NO amount, TNF-α, IFN-γ, and PGE 2 levels in lipopolysaccharide-stimulated Raw 264.7 cells. The richest extract in terms of phenolic compounds (98.19 ± 1.64 mgGAE/gextract) and total flavonoids (21.85 ± 0.64 mgCA/gextract) was identified as C. pichleri subsp. pichleri methanol extract. According to antioxidant activity determinations, the C. pichleri subsp. pichleri extract was found to be the most active extract. Finally, the C. pichleri subsp. pichleri methanol extract was revealed to be the most effective inhibitor of viability in the cytotoxic activity investigation, and the extract with the best anti-inflammatory action. The findings point to C. pichleri subsp. pichleri as a promising source of bioactive compounds in the transition from natural sources to industrial uses, such as new medications, cosmeceuticals, and nutraceuticals

Fraud detection in ERP systems using scenario matching

ERP systems generally implement controls to prevent certain common kinds of fraud. In addition however, there is an imperative need for detection of more sophisticated patterns of fraudulent activity as evidenced by the legal requirement for company audits and the common incidence of fraud. This paper describes the design and implementation of a framework for detecting patterns of fraudulent activity in ERP systems. We include the description of six fraud scenarios and the process of specifying and detecting the occurrence of those scenarios in ERP user log data using the prototype software which we have developed. The test results for detecting these scenarios in log data have been verified and confirm the success of our approach which can be generalized to ERP systems in general

Acute presentation of autoimmune hepatitis in a patient with myasthenia gravis, thymoma, Hashimoto thyroiditis and connective tissue disorder

Myasthenia gravis is an antibody-mediated autoimmune disease at the neuromuscular junctions. It can be associated with many other autoimmune diseases. We report a case of acute presentation of autoimmune hepatitis with myasthenia gravis, thymoma, Hashimoto thyroiditis and connective tissue disorder. © 2012 The Japan Society of Hepatology