University of Hamburg

About: University of Hamburg is a education organization based out in Hamburg, Germany. It is known for research contribution in the topics: Population & Laser. The organization has 45564 authors who have published 89286 publications receiving 2850161 citations. The organization is also known as: Hamburg University.

Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K + channels causes epilepsy

Abstract: Epilepsy affects more than 0.5% of the world's population and has a large genetic component1. It is due to an electrical hyperexcitability in the central nervous system. Potassium channels are important regulators of electrical signalling, and benign familial neonatal convulsions (BFNC), an autosomal dominant epilepsy of infancy, is caused by mutations in the KCNQ2 or the KCNQ3 potassium channel genes2,3,4. Here we show that KCNQ2 and KCNQ3 are distributed broadly in brain with expression patterns that largely overlap. Expression in Xenopus oocytes indicates the formation of heteromeric KCNQ2/KCNQ3 potassium channels with currents that are at least tenfold larger than those of the respective homomeric channels. KCNQ2/KCNQ3 currents can be increased by intracellular cyclic AMP, an effect that depends on an intact phosphorylation site in the KCNQ2 amino terminus. KCNQ2 and KCNQ3 mutations identified in BFNC pedigrees compromised the function of the respective subunits, but exerted no dominant-negative effect on KCNQ2/KCNQ3 heteromeric channels. We predict that a 25% loss of heteromeric KCNQ2/KCNQ3-channel function is sufficient to cause the electrical hyperexcitability in BFNC. Drugs raising intracellular cAMP may prove beneficial in this form of epilepsy.

Economic Growth and Judicial Independence: Cross Country Evidence Using a New Set of Indicators

Abstract: Rational politicians are interested in judicial independence (JI) in order to make their promises credible. But if politicians' preferences deviate from the dicta of the judiciary, they also have incentives to renege on judicial independence. These two conflicting aspects are measured by two indicators: (i) de iure JI focusing on its legal foundations and (ii) a de facto JI focusing on countries' actual experience. Whether JI affects economic growth is tested for a cross section of 57 countries. While de iure JI does not have an impact on real GDP growth per capita, de facto JI positively influences it.

ClC-5 Cl - -channel disruption impairs endocytosis in a mouse model for Dent's disease

Abstract: Dent's disease is an X-linked disorder associated with the urinary loss of low-molecular-weight proteins, phosphate and calcium, which often leads to kidney stones It is caused by mutations in ClC-5, a renal chloride channel that is expressed in endosomes of the proximal tubule Here we show that disruption of the mouse clcn5 gene causes proteinuria by strongly reducing apical proximal tubular endocytosis Both receptor-mediated and fluid-phase endocytosis are affected, and the internalization of the apical transporters NaPi-2 and NHE3 is slowed At steady state, however, both proteins are redistributed from the plasma membrane to intracellular vesicles This may be caused by an increased stimulation of luminal parathyroid hormone (PTH) receptors owing to the observed decreased tubular endocytosis of PTH The rise in luminal PTH concentration should also stimulate the hydroxylation of 25(OH) vitamin D3 to the active hormone However, this is counteracted by a urinary loss of the precursor 25(OH) vitamin D3 The balance between these opposing effects, both of which are secondary to the defect in proximal tubular endocytosis, probably determines whether there will be hypercalciuria and kidney stones

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Abstract: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.