Sacral agenesis: a pilot whole exome sequencing and copy number study

Background: Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes. Method: Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations. Results: In this pilot study, exome sequencing and copy number variation (CNV) analyses implicate a number of candidate genes, including SPTBN5, MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous). Importantly, predicted damaging mutations in PTEN (heterozygous), in its direct regulator GLTSCR2 (compound heterozygous) and in VANGL1 (heterozygous) were identified. These genes had previously been linked with the CRS phenotype. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype. Conclusion: Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients

Alternating and distance learning as a catalyst for school dropout? Experiences and perceptions of school administrations regarding the development and processing of dropout

Das Phänomen, dass Schüler*innen die Schule ohne Schulabschluss verlassen, ist von bildungspolitischer Brisanz. Untersuchungen zum Wechsel- und Distanzunterricht rücken (erneut) Schüler*innen in sozioökonomisch deprivierter Lage in den Fokus, vernachlässigen aber mögliche Auswirkungen auf deren Dropoutrisiken. Der Beitrag stellt Befunde zu Wahrnehmungen und Erfahrungen von Schulleitungen zur Entwicklung von Dropout sowie zu auf Einzelschulebene getroffenen präventiven und interventiven Maßnahmen vor. (DIPF/Orig.)The phenomenon of students leaving school without a school-leaving certificate is of great importance for educational policy. Studies on change and distance learning (again) focus on students in socio-economically deprived situations but neglect possible effects on their dropout risks. The article presents findings on the perceptions and experiences of school administrators concerning the development of dropout as well as on preventive and interventive measures taken at the individual school level. (DIPF/Orig.

G6PD genetic variations in neonatal Hyperbilirubinemia in Indonesian Deutromalay population

Background: Neonatal jaundice is a common finding in newborns in Asia, including Indonesia. In some cases, the serum total bilirubin levels exceeds the 95th percentile for hours of life (neonatal hyperbilirubinemia). Severe neonatal hyperbilirubinemia (NH) could lead to kernicterus and neonatal death. Glucose-6-Phosphage Dehydrogenase (G6PD) genetic variations and deficiency have been reported in several studies to be associated with NH. This study aimed to analyze the G6PD genetic variations a

Calcium Binding Properties of the Kingella kingae PilC1 and PilC2 Proteins Have Differential Effects on Type IV Pilus-Mediated Adherence and Twitching Motility

Kingella kingae is an emerging bacterial pathogen that is being recognized increasingly as an important etiology of septic arthritis, osteomyelitis, and bacteremia, especially in young children. The pathogenesis of K. kingae disease begins with bacterial adherence to respiratory epithelium, which is dependent on type IV pili and is influenced by two PilC-like proteins called PilC1 and PilC2. Production of either PilC1 or PilC2 is necessary for K. kingae piliation and bacterial adherence. In this study, we set out to further investigate the role of PilC1 and PilC2 in type IV pilus-associated phenotypes. We found that PilC1 contains a functional 9-amino-acid calcium-binding (Ca-binding) site with homology to the Pseudomonas aeruginosa PilY1 Ca-binding site and that PilC2 contains a functional 12-amino-acid Ca-binding site with homology to the human calmodulin Ca-binding site. Using targeted mutagenesis to disrupt the Ca-binding sites, we demonstrated that the PilC1 and PilC2 Ca-binding sites are dispensable for piliation. Interestingly, we showed that the PilC1 site is necessary for twitching motility and adherence to Chang epithelial cells, while the PilC2 site has only a minor influence on twitching motility and no influence on adherence. These findings establish key differences in PilC1 and PilC2 function in K. kingae and provide insights into the biology of the PilC-like family of proteins

Ecology and application of haloalkaliphilic anaerobic microbial communities

Haloalkaliphilic microorganisms that grow optimally at high-pH and high-salinity conditions can be found in natural environments such as soda lakes. These globally spread lakes harbour interesting anaerobic microorganisms that have the potential of being applied in existing technologies or create new opportunities. In this review, we discuss the potential application of haloalkaliphilic anaerobic microbial communities in the fermentation of lignocellulosic feedstocks material subjected to an alkaline pre-treatment, methane production and sulfur removal technology. Also, the general advantages of operation at haloalkaline conditions, such as low volatile fatty acid and sulfide toxicity, are addressed. Finally, an outlook into the main challenges like ammonia toxicity and lack of aggregation is provided.This work was performed in the TTIW- cooperation framework of Wetsus, European Centre of Excel- lence for Sustainable Water Technology (www.wetsus.nl). Wetsus is funded by the Dutch Ministry of Economic Affairs, the European Union Regional Development Fund, the Province of Fryslân, the City of Leeuwarden and the EZ/Kompas program of the“ Samenwerkingsverband Noord-Nederland”. The authors would like to thank the participants of the research theme "Sulfur", namely Paqell, for fruitful discussions and financial suppor

Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese

published_or_final_versio

Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

Background: The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings: We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr-/- mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl-/- mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. Conclusion/Significance: Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels

Fabry disease: recent advances in pathology, diagnosis, treatment and monitoring

<p>Abstract</p> <p>Background</p> <p>In Fabry disease (α-galactosidase A deficiency) accumulation of Globotriaosylceramide (Gb3) leads to progressive organ failure and premature death. The introduction of enzyme replacement therapy (ERT) was the beginning of a new era in this disorder, and has prompted a broad range of research activities. This review aims to summarize recent developments and progress with high impact for Fabry disease.</p> <p>Methods</p> <p>A Pubmed analysis was performed using the search terms "Fabry disease", "Anderson-Fabry disease", "alpha-galactosidase A" and "Gb3". Of the given publications by 31st January 2009 only original articles recently published in peer reviewed journals were included for this review. Case reports were included only when they comprised a new aspect. In addition we included relevant conference abstracts when the results had not already been published as original articles.</p> <p>Results</p> <p>Apart from Gb3-accumulation cellular and organ specific damages may be related also to inflammatory and immunological consequences. It will be interesting whether this may lead to new therapeutic strategies in the treatment of Fabry disease. Since newborn screening is still difficult in Fabry disease, detection of patients in populations at risk is of great importance. Undiagnosed patients with Fabry disease may still be found in cohorts of subjects with renal diseases, cardiomyopathy and TIA or stroke. Efforts should be undertaken to identify these individuals and initialise ERT in order to hault disease progression. It has also been demonstrated that Gb3-accumulation leads to pre-clinical damages and it is believed that early treatment may be the only possibility so far to prevent irreversible organ damage.</p