Remotely acting SMCHD1 gene regulatory elements: in silico prediction and identification of potential regulatory variants in patients with FSHD

Background: Facioscapulohumeral dystrophy (FSHD) is commonly associated with contraction of the D4Z4 macro-satellite repeat on chromosome 4q35 (FSHD1) or mutations in the SMCHD1 gene (FSHD2). Recent studies have shown that the clinical manifestation of FSHD1 can be modified by mutations in the SMCHD1 gene within a given family. The absence of either D4Z4 contraction or SMCHD1 mutations in a small cohort of patients suggests that the disease could also be due to disruption of gene regulation. In this study, we postulated that mutations responsible for exerting a modifier effect on FSHD might reside within remotely acting regulatory elements that have the potential to interact at a distance with their cognate gene promoter via chromatin looping. To explore this postulate, genome-wide Hi-C data were used to identify genomic fragments displaying the strongest interaction with the SMCHD1 gene. These fragments were then narrowed down to shorter regions using ENCODE and FANTOM data on transcription factor binding sites and epigenetic marks characteristic of promoters, enhancers and silencers

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

Supramolecular thermoplastics and thermoplastic elastomer materials with self-healing ability based on oligomeric charged triblock copolymers

Supramolecular polymeric materials constitute a unique class of materials held together by non-covalent interactions. These dynamic supramolecular interactions can provide unique properties such as a strong decrease in viscosity upon relatively mild heating, as well as self-healing ability. In this study we demonstrate the unique mechanical properties of phase-separated electrostatic supramolecular materials based on mixing of low molar mass, oligomeric, ABA-triblock copolyacrylates with oppositely charged outer blocks. In case of well-chosen mixtures and block lengths, the charged blocks are phase separated from the uncharged matrix in a hexagonally packed nanomorphology as observed by transmission electron microscopy. Thermal and mechanical analysis of the material shows that the charged sections have a T-g closely beyond room temperature, whereas the material shows an elastic response at temperatures far above this T-g ascribed to the electrostatic supramolecular interactions. A broad set of materials having systematic variations in triblock copolymer structures was used to provide insights in the mechanical properties and and self-healing ability in correlation with the nanomorphology of the materials

Applied violin instruction : factors and strategies contributing to effective teaching of three master teachers in Sydney

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IL-17 Expression in the Time Course of Acute Anti-Thy1 Glomerulonephritis

Background Interleukin-17 (IL-17) is a new pro-inflammatory cytokine involved in immune response and inflammatory disease. The main source of IL-17 is a subset of CD4+ T-helper cells, but is also secreted by non-immune cells. The present study analyzes expression of IL-17 in the time course of acute anti- thy1 glomerulonephritis and the role of IL-17 as a potential link between inflammation and fibrosis. Methods Anti-thy1 glomerulonephritis was induced into male Wistar rats by OX-7 antibody injection. After that, samples were taken on days 1, 5, 10 (matrix expansion phase), 15 and 20 (resolution phase). PBS-injected animals served as controls. Proteinuria and histological matrixes score served as the main markers for disease severity. In in vitro experiments, NRK-52E cells were used. For cytokine expressions, mRNA and protein levels were analyzed by utilizing RT-PCR, in situ hybridization and immunofluorescence. Results Highest IL-17 mRNA-expression (6.50-fold vs. con; p<0.05) was found on day 5 after induction of anti-thy1 glomerulonephritis along the maximum levels of proteinuria (113 ± 13 mg/d; p<0.001), histological glomerular-matrix accumulation (82%; p<0.001) and TGF-β1 (2.2-fold; p<0.05), IL-6 mRNA expression (36-fold; p<0.05). IL-17 protein expression co-localized with the endothelial cell marker PECAM in immunofluorescence. In NRK-52E cells, co-administration of TGF-β1 and IL-6 synergistically up-regulated IL-17 mRNA 4986-fold (p<0.001). Conclusions The pro-inflammatory cytokine IL-17 is up-regulated in endothelial cells during the time course of acute anti-thy1 glomerulonephritis. In vitro, NRK-52E cells secrete IL-17 under pro-fibrotic and pro-inflammatory conditions

Introduction of the DiaGene study: clinical characteristics, pathophysiology and determinants of vascular complications of type 2 diabetes

Background: Type 2 diabetes is a major healthcare problem. Glucose-, lipid-, and blood pressure-lowering strategies decrease the risk of micro- and macrovascular complications. However, a substantial residual risk remains. To unravel the etiology of type 2 diabetes and its complications, large-scale, well-phenotyped studies with prospective follow-up are needed. This is the goal of the DiaGene study. In this manuscript, we describe the design and baseline characteristics of the study. Methods: The DiaGene study is a multi-centre, prospective, extensively phenotyped type 2 diabetes cohort study with concurrent inclusion of diabetes-free individuals at baseline as controls in the city of Eindhoven, The Netherlands. We collected anthropometry, laboratory measurements, DNA material, and detailed information on medication usage, family history, lifestyle and past medical history. Furthermore, we assessed the prevalence and incidence of retinopathy, nephropathy, neuropathy, and diabetic feet in cases. Using logistic regression models, we analyzed the association of 11 well known genetic risk variants with type 2 diabetes in our study. Results: In total, 1886 patients with type 2 diabetes and 854 controls were included. Cases had worse anthropometric and metabolic profiles than controls. Patients in outpatient clinics had higher prevalence of macrovascular (41.9% vs. 34.8%; P = 0.002) and microvascular disease (63.8% vs. 20.7%) compared to patients from primary care. With the exception of the genetic variant in KCNJ11, all type 2 diabetes susceptibility variants had higher allele frequencies in subjects with type 2 diabetes than in controls. Conclusions: In our study population, considerable rates of macrovascular and microvascular complications are present despite treatment. These prevalence rates are comparable to other type 2 diabetes populations. While planning genomics, we describe that 11 well-known type 2 diabetes genetic risk variants (in TCF7L2, PPARG-P12A, KCNJ11, FTO, IGF2BP2, DUSP9, CENTD2, THADA, HHEX, CDKAL1, KCNQ1) showed similar associations compared to literature. This study is well-suited for multiple omics analyses to further elucidate disease pathophysiology. Our overall goal is to increase the understanding of the underlying mechanisms of type 2 diabetes and its complications for developing new prediction, prevention, and treatment strategies

Practice variation in the management of first trimester miscarriage in the Netherlands: a nationwide survey

Objectives. To survey practice variation in the management of first trimester miscarriage in The Netherlands. Methods. We sent an online questionnaire to gynecologists in eight academic, 37 nonacademic teaching, and 47 nonteaching hospitals. Main outcome measures were availability of a local protocol; estimated number of patients treated with curettage, misoprostol, or expectant management; misoprostol regimen; and estimated number of curettages performed after initial misoprostol treatment. Outcomes were compared to the results of a previous nationwide survey. Results. The response rate was 100%. A miscarriage protocol was present in all academic hospitals, 68% of nonacademic teaching hospitals, and 38% of nonteaching hospitals (P = 0.008). Misoprostol was first-choice treatment for 41% of patients in academic hospitals versus 34% and 27% in teaching-and nonteaching hospitals (P = 0.045). There were 23 different misoprostol regimens. Curettage was first-choice treatment in 29% of patients in academic hospitals versus 46% and 50% in nonacademic teaching or nonteaching hospitals (P = 0.007). In 30% of patients, initial misoprostol treatment was followed by curettage. Conclusions. Although the percentage of gynaecologists who are aware of the availability of misoprostol for miscarriage treatment has doubled to almost 100% since 2005, practice variation is still large. This practice variation underlines the need for a national guideline.Marianne A. C. Verschoor, Marike Lemmers, Malu Z. Wekker, Judith A. F. Huirne, Mariëtte Goddijn, Ben Willem J. Mol, and Willem M. Anku