Generierung eines Mausmodells für Mastozytose durch kontrollierte Ausprägung eines mutierten, konstitutiv aktiven Kit-Rezeptors

Mastozytose ist eine seltene Erkrankung, die durch abnormale Zahlen von Mastzellen in Haut und innerern Organen gekennzeichnet ist. Die Erkrankung, die durch eine starke Variation bezüglich ihrer klinischen Manifestationen charakterisiert ist, konnte mit (meist) somatischen Mutationen des Kit-Genes assoziert werden, die zur konstitutiven, Ligand-unabhängigen Aktivierung der Rezeptortyrosinkinase Kit führen. Der Kit-Signalweg kontrolliert Differenzierung, Proliferation und Überleben von hämatopoetischen Vorläuferzellen und Mastzellen. Die klinische Ausprägung der Erkrankung scheint wesentlich durch das Differenzierungsstadium der vom ursprünglichen Mutationsereignis getroffenen Zelle abzuhängen. Ziel der Arbeit war die Generierung eines Tiermodells für Mastozytose, bei dem die Ausprägung eines mutierten Kit-Rezeptors zeitlich und räumlich kontrollierbar ist. In ein "bacterial artificial chromosome", das die gesamte Sequenz des Kit-Gens und weite flankierende Bereiche enthielt, wurde die aktivierende Punktmutation KitD814V, das murine Homolog der am häufigsten in Mastozytosepatienten beobachteten Mutation KitD816V, eingebracht. Eine konditionale Expression des transgenen KitD814Vflox-Allels wurde durch Cre/loxP-mediierte Exzision eines im ersten Intron platzierten Stopp-Elementes ermöglicht. Das Konstrukt wurde durch Pronukleusinjektion in das murine Genom eingeführt. Die Expression des mutierten Kit in adulten Tieren, unter anderem in hämatopoetischen Vorläuferzellen, führte zu rascher, progressiver Mastzellinfiltration der Haut und war häufig von einer B-Zellneoplasie und fokaler Colitis begleitet. Beschränkung der KitD814V Expression auf reife Mastzellen resultierte in vergleichbarer Mastzellhyperplasie und Colitis, die sich jedoch deutlich langsamer entwickelten. Die embryonale Expression des konstitutiv aktiven Kit-Transgens führte zu einer massiv gesteigerten Erythropoese und perinataler Lethalität. Die wenigen überlebenden Tiere entwickelten ebenfalls eine starke Mastzellhyperplasie und Darmentzündung. Die Ergebnisse zeigen, dass KitD814V-Effekte stark vom Entwicklungszeitpunkt und Differenzierungsstadium der Zelle abhängen, in welcher die Mutation auftritt

Netzsituation in Deutschland bleibt stabil

Auch im zweiten Jahr nach dem Kernkraftwerksmoratorium vom März 2011 bleibt die Lage im deutschen Stromübertragungsnetz stabil. Auch wenn die Realisierung einiger Ausbauprojekte um einige Jahre hinter dem ursprünglichen Zeitplan liegt, schreitet der Netzumbau kontinuierlich voran. Bei einigen kritischen Leitungen wurden im vergangenen Jahr erhebliche Fortschritte gemacht, unter anderem bei Verbindungen zwischen den neuen und den alten Bundesländern. Die aktuellen Verzögerungen stellen angesichts der bestehenden Eingriffsmöglichkeiten der Netzbetreiber zur Systemstabilisierung keinen Grund zur Besorgnis dar. Maßnahmen zur Kontrolle von Netzengpässen betreffen nur einen sehr geringen Teil des Stromverbrauchs. Zudem könnten sie durch eine bessere Koordinierung zwischen den vier Netzbetreibern deutlich kostengünstiger gestaltet werden. Die Methodik der langfristigen Netzausbauplanung führt tendenziell zu einer Überschätzung des Ausbaubedarfs. Dies gilt insbesondere für zwei der im Bundesbedarfsplangesetz vorgesehenen Höchstspannungsgleichstromübertragungsleitungen (Strom-Autobahnen).In the second year after the shutdown of seven nuclear power plants in March 2011, the situation of the German high voltage electricity transmission grid remained robust. Even though some expansion projects are behind schedule, the grid reconstruction advances steadily as several essential lines have made considerable progress during the last year - inter alia connections between the old and new federal states. Due to the effectiveness of existing congestion management measures, the current delay in the realization of some projects causes no concern. Measures of congestion management only comprise a very small share of the actual electricity demand; moreover, they could be carried out in a much more cost-effective fashion by coordinating them appropriately. The current methodology for the long-run grid expansion planning tends to overestimate the expansion needs - especially for two of the high voltage direct current lines (electricity highways) that are included in the Law on National Electricity Grid Expansion Requirements (Bundesbedarfsplangesetz)

Electricity sector data for policy-relevant modeling: Data documentation and applications to the German and European electricity markets

[Summary] The dataset for the European electricity system needs a variety of data to cover the relevant characteristics of the industry. The more general data on aggregated generation capacities, historic generation, and consumption can be found with a consistent data specification for most European countries in databases like EUROSTAT. On the other hand, more detailed data like generation capacities for conventional and renewable sources are usually not publicly available, sometimes not even on a national basis, and henceforth appropriate assumptions or commercial databases are required to retrieve the necessary information. Due to the already mentioned issue with regard to available information, setting up a consistent dataset for the European electricity system is more difficult in comparison to the German electricity system, where mostly consistent data is publicly available. Similar projects on a European level could be helpful for a consistent dataset. Having set up a dataset for Europe, the model application shows that the general tendencies on regional generation and import/export pattern can be captured. However, differences are obvious in particular regions where the model shows different results than the historic values which may be based either on the rough modeling approach or on an insufficient data supply. To that end, the presented dataset and model application are a continuous process, and further steps are required to improve the data quality as well as the modeling. Among others, the implementation of cogeneration restrictions, improvement of renewable generation and their distribution, and an intertemporal model calibration are potential improvements for the future

Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity

Defects of the intracellular enzyme 3' repair exonuclease 1 (Trex1) cause the rare autoimmune condition Aicardi-Goutières syndrome and are associated with systemic lupus erythematosus. Trex1(-/-) mice develop type I IFN-driven autoimmunity, resulting from activation of the cytoplasmic DNA sensor cyclic GMP-AMP synthase by a nucleic acid substrate of Trex1 that remains unknown. To identify cell types responsible for initiation of autoimmunity, we generated conditional Trex1 knockout mice. Loss of Trex1 in dendritic cells was sufficient to cause IFN release and autoimmunity, whereas Trex1-deficient keratinocytes and microglia produced IFN but did not induce inflammation. In contrast, B cells, cardiomyocytes, neurons, and astrocytes did not show any detectable response to the inactivation of Trex1. Thus, individual cell types differentially respond to the loss of Trex1, and Trex1 expression in dendritic cells is essential to prevent breakdown of self-tolerance ensuing from aberrant detection of endogenous DNA

Loss of Function of TET2 Cooperates with Constitutively Active KIT in Murine and Human Models of Mastocytosis

Systemic Mastocytosis (SM) is a clonal disease characterized by abnormal accumulation of mast cells in multiple organs. Clinical presentations of the disease vary widely from indolent to aggressive forms, and to the exceedingly rare mast cell leukemia. Current treatment of aggressive SM and mast cell leukemia is unsatisfactory. An imatinib-resistant activating mutation of the receptor tyrosine kinase KIT (KIT D816V) is most frequently present in transformed mast cells and is associated with all clinical forms of the disease. Thus the etiology of the variable clinical aggressiveness of abnormal mast cells in SM is unclear. TET2 appears to be mutated in primary human samples in aggressive types of SM, suggesting a possible role in disease modification. In this report, we demonstrate the cooperation between KIT D816V and loss of function of TET2 in mast cell transformation and demonstrate a more aggressive phenotype in a murine model of SM when both mutations are present in progenitor cells. We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Mast cell-specific Cre/loxP-mediated recombination in vivo

Mast cells are important effectors of type I allergy but also essential regulators of innate and adaptive immune responses. The aim of this study was to develop a Cre recombinase-expressing mouse line that allows mast cell-specific inactivation of genes in vivo. Following a BAC transgenic approach, Cre was expressed under the control of the mast cell protease (Mcpt) 5 promoter. Mcpt5-Cre transgenic mice were crossed to the ROSA26-EYFP Cre excision reporter strain. Efficient Cre-mediated recombination was observed in mast cells from the peritoneal cavity and the skin while only minimal reporter gene expression was detected outside the mast cell compartment. Our results show that the Mcpt5 promoter can drive Cre expression in a mast cell-specific fashion. We expect that our Mcpt5-Cre mice will be a useful tool for the investigation of mast cell biology