Epigenetische and posttranslationale Regulation der Disintegrin und Metalloproteasen ADAM17 und ADAMTS-16

ADAM17 is the best characterized member of the (A) Disintegrin And Metalloproteases (ADAM) protease family. However, how the ADAM17-mediated substrate release is regulated is not understood so far. Recently, we found evidence that phosphatidylserine (PS)-exposure might be the distinctive step in the stimulated ADAM17-mediated shedding. While PS is normally located in the inner membrane leaflet, it is transiently exposed upon stimulation with diverse stimuli. A PS-binding motif in the membrane-proximal domain of ADAM17 has been identified that binds to the exposed PS, enabling substrate shedding. Interestingly, another potential extracellular membrane interaction motif has been described and named Conserved ADAM seventeeN Dynamic Interaction Sequence (CANDIS). This sequence resembles an amphipathic alpha helix which has been shown to bind to lipid bilayers. This lipid binding property suggests a second putative membrane interaction between ADAM17 and the plasma membrane. One aim of this thesis was to evaluate whether the lipid binding ability of the CANDIS region contributes to the ADAM17 shedding activity. Strikingly, mutations in the hydrophobic site, that destroyed the hydrophobic face of the helix, completely abolished ADAM17-mediated shedding of transforming growth factor alpha (TGF-α). By contrast, mutations in the hydrophilic site of CANDIS had no impact on TGF-α shedding. The abolishment of TGF-α shedding correlated with the loss of the lipid binding ability. Therefore, the hydrophobic site of the CANDIS region is essential for ADAM17-mediated shedding and may modulate the shedding mechanism by interacting with the plasma membrane.ADAM17 ist das am besten charakterisierte Mitglied der Disintegrin und Metalloproteasen (ADAM) Proteasefamilie. Wie die ADAM17-vermittelte Substratfreisetzung reguliert wird, ist bisher kaum verstanden. Vor Kurzem haben wir Hinweise gefunden, dass Phosphatidylserin (PS)-Exposition der entscheidende Schritt in der Aktivierung der stimulierten ADAM17-vermittelten Substratfreisetzung sein könnte. PS ist normalerweise in der inneren Lipiddoppelschicht der Membran lokalisiert, wird aber durch verschiedene Stimuli transient nach außen exponiert. Ein potenzielles PS-Bindungsmotiv in der membranproximalen Domäne von ADAM17 wurde identifiziert, welches das extrazellulär exponierte PS bindet und dadurch Substrat-Shedding ermöglicht. Interessanterweise wurde ein weiteres potenzielles, extrazelluläres Membraninteraktionsmotiv beschrieben. Es wurde gezeigt, dass diese Sequenz eine amphipathische Alpha-Helix Struktur besitzt und Lipiddoppelschichten binden kann. Diese Lipidbindungseigenschaft weist darauf hin, dass möglicherweise eine zweite Membraninteraktion zwischen ADAM17 und der Plasmamembran von entscheidender Bedeutung für das ADAM17-vermittelte Shedding sein könnte. Ein Ziel dieser Arbeit war es zu untersuchen, ob die Lipidbindungsfähigkeit der CANDIS Region zum ADAM17-vermittelten Substrat-Shedding beiträgt. Interessanterweise führten Mutationen in der hydrophoben Seite der amphipathischen Helix zum vollständigen Erliegen des ADAM17-vermittelten Transformierender Wachstumsfaktor Alpha (TGF-α) Sheddings. Mutationen in der hydrophilen Seite hingegen hatten keine Auswirkungen auf das TGF-α Shedding. Der Verlust der Fähigkeit von ADAM17 TGF-α zu prozessieren, korrelierte dabei mit dem Verlust der Fähigkeit von CANDIS, Lipide zu binden. Die hydrophobe Seite der CANDIS Region ist daher wichtig für das ADAM17-vermittelte Shedding und könnte den Sheddingmechanismus durch eine Interaktion mit der Plasmamembran modulieren

Large-scale motorised prospection along the “SuedLink” route in Lower Franconia

Large-scale archaeological prospection has proven itself as an essential tool in advance of a linear infrastructure project. The non-destructive survey is a basis for infrastructural planning and the protection of archaeological sites. More than 410 ha of high-resolution motorized geomagnetics were surveyed within six weeks. Such infrastructure projects can also be seen as an opportunity for archaeological research

ADRIA LITHOSPHERE INVESTIGATION ALPHA - Cruise No. M86/3, January 20 - February 04, 2012, Brindisi (Italy) - Dubrovnik (Croatia)

The Adriatic Sea and underlying lithosphere remains the least investigated part of the Mediterranean Sea. To shed light on the plate tectonic setting in this central part of southern Europe, R/V METEOR cruise M86/3 set out to acquire deep penetrating seismic data in the Adriatic Sea. M86/3 formed the core of an amphibious investigation crossing Adria from the Italian Peninsula into Montenegro/Albania. A total of 111 OBS/OBH deployments were successfully carried out, in addition to 47 landstations both in Italy and Montenegro/Albania, which recorded the offshore airgun shots. In the scope of this shoreline-crossing study, the aim is to quantify the shallow geometry, deep boundaries and the architecture of the southern Adriatic crust and lithosphere and to provide insights on a possible decoupling zone between the northern and southern Adriatic domains. Investigating the structure of the Adriatic crust and lithospheric mantle and analyzing the tectonic activity are essential for understanding the mountain-building processes that underlie the neotectonics and earthquake hazard of the Periadriatic region, especially in the vicinity of local decoupling zones

Energy exchange in a dense urban environment Part II: impact of spatial heterogeneity of the surface

The centre of cities, characterised by spatial and temporal complexity, are challenging environments for micrometeorological research. This paper considers the impact of sensor location and heterogeneity of the urban surface on flux observations in the dense city centre of London, UK. Data gathered at two sites in close vicinity, but with different measurement heights, were analysed to investigate the influence of source area characteristics on long-term radiation and turbulent heat fluxes. Combining consideration of diffuse radiation and effects of specular reflections, the non-Lambertian urban surface is found to impact the measurements of surface albedo. Comparisons of observations from the two sites reveal that turbulent heat fluxes are similar under some flow conditions. However, they mostly observe processes at different scales due to their differing measurement heights, highlighting the critical impact of siting sensors in urban areas. A detailed source area analysis is presented to investigate the surface controls influencing the energy exchanges at the different scale

IgG Fc N-glycosylation translates MHCII haplotype into autoimmune skin disease

The major histocompatibility complex haplotype represents the most prevalent genetic risk factor for the development of autoimmune diseases. However, the mechanisms by which major histocompatibility complex-associated genetic susceptibility translates into autoimmune disease are not fully understood. Epidermolysis bullosa acquisita is an autoimmune skin-blistering disease driven by autoantibodies to type VII collagen. Here, we investigated autoantigen-specific plasma cells, CD4(+) T cells, and IgG fraction crystallizable glycosylation in murine epidermolysis bullosa acquisita in congenic mouse strains with the disease-permitting H2s or disease-nonpermitting H2b major histocompatibility complex II haplotypes. Mice with an H2s haplotype showed increased numbers of autoreactive CD4(+) T cells and elevated IL-21 and IFN-gamma production, associated with a higher frequency of IgG autoantibodies with an agalactosylated, proinflammatory N-glycan moiety. Mechanistically, we show that the altered antibody glycosylation leads to increased ROS release from neutrophils, the main drivers of autoimmune inflammation in this model. These results indicate that major histocompatibility complex II-associated susceptibility to autoimmune diseases acuminates in a proinflammatory IgG fraction crystallizable N-glycosylation pattern and provide a mechanistic link to increased ROS release by neutrophils.Proteomic

ADAMDEC1 maintains a growth factor signaling loop in cancer stem cells

Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSCs), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by GSCs. ADAMDEC1 rapidly solubilizes fibroblast growth factor-2 (FGF2) to stimulate FGF receptor 1 (FGFR1) expressed on GSCs. FGFR1 signaling induces upregulation of Zinc-finger E-box-binding homeobox 1 (ZEB1) via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GB

Role of dead ice in morphogenesis of Grudziądz Basin and Świecie Basin : landforms and sediments

W artykule przedstawiono przegląd dowodów na obecność brył martwego lodu w Dolinie Dolnej Wisły między Bydgoszczą i Grudziądzem. Omówiono oddziaływanie spływów gliniastych w dnie doliny, form szczelinowych, teras kemowych, zagłębień wytopiskowych, ostańców terasowych, rynien subglacjalnych reprodukowanych w osadach fluwialnych i fluwioglacjalnych oraz zastoisk „włożonych” we wcześniej ukształtowaną formę dolinną na morfogenezę doliny. Na podstawie wyników badań sformułowano tezę, że dolina Wisły w omawianym fragmencie była w większości uformowana jeszcze przed ostatnim nasunięciem lądolodu w fazie poznańskiej górnego vistulianu. Proces kształtowania systemu terasowego musiał mieć szybki przebieg, szybszy niż tempo wytapiania brył martwego lodu.In the paper there are presented proofs for existence of dead ice in the Vistula valley between Bydgoszcz and Grudziądz. There is discussed the significance of specific landforms and sediments for the valley morphogenesis among them of till debrites on the valley floor, forms of ice crevasses infilling, kame terraces, terrace remnants, subglacial channels reproduced within fluvial and glacifluvial sediments and proglacial ice dammed lakes embedded in the river valley. The material presented inclines to suggestion that lower Vistula valley, in the discussed area, was formed in broad outline already before the last glacial advance during the main/upper vistulian stadial. The terraces system had developed very quickly, much quicker than the rate of dead ice disintegration