From widespread faulting to localised rifting: Evidence from K-Ar fault gouge dates from the Norwegian North Sea rift shoulder

Although seismic and stratigraphic well information put tight constraints on rift basin evolution, eroded rift shoulders commonly expose polydeformed prerift basement whose deformation history may be difficult to constrain. In this work, we apply K-Ar dating of fault gouge samples from 18 faults to explore the brittle deformation of the well-exposed eastern rift margin to the northern North Sea rift. We find evidence of clay gouge formation since the Late Devonian, with distinct Permian and Jurassic fault activity peaks that closely match early stages of the two well-established North Sea rift phases. A marked decay in fault density away from the rift margin confirms a close relationship between rifting and onshore faulting. The results show that initial rift-related extension affected a much wider area than the resulting offshore rift. Hence our data support a rift model where strain is initially distributed over a several 100 km wide region, as a prelude to the development of the ~150–200 km wide Permo-Triassic northern North Sea rift as defined by large marginal faults. Towards the end of the second rift phase, strain localises even more strongly to the 25–50 km wide Viking Graben. Interestingly, a period of early widespread extension is seen for both phases of North Sea rifting and may be a general characteristic of continental rifting. The documented prerift faulting and fracturing of the basement since the Devonian weakened the basement and probably facilitated the widespread initial extension that subsequently localised to form the northern North Sea rift, with further localisation to its relatively narrow central part (Viking Graben).publishedVersio

Tracking the Oman Ophiolite to the surface: new fission track and (U–Th)/He data from the Aswad and Khor Fakkan Blocks, United Arab Emirates

The Oman Ophiolite in the United Arab Emirates (UAE) was formed in a supra-subduction zone environment at about 95Ma andwas almost immediately obducted onto the eastern margin of Arabia. The timing of obduction is well constrained, but the post-obduction tectonic, uplift and exhumation history of the ophiolite and associated rocks are less well understood.We present twenty-one new fission track and (U–Th)/He analyses of apatite and zircon from the Hajar Mountains. The data show that the Oman Ophiolite had a complex exhumation history to present exposure levels in the Khor Fakkan and Aswad Blocks, resulting from at least three distinct exhumation events: 1) initial ophiolite obduction between ca. 93 and 83Ma is characterised by tectonic exhumation and rapid cooling, as revealed by zircon (U–Th)/He and apatite fission-track data, but it is not associated with major erosional exhumation; 2) data from the lower part of the ophiolite and the metamorphic sole document a second exhumation event at ca. 45–35Ma, interpreted to represent an early phase of the Zagros orogeny that led to reactivation of pre-existing structures and the differential exhumation of the Khor Fakkan Block along the Wadi Ham Shear Zone. This event led to significant erosional exhumation and deposition of a thick sedimentary succession in the Ras Al Khaimah foreland basin; and 3) Neogene exhumation is recorded by ca. 20–15 Ma apatite (U–Th)/He data and a single apatite fission track date from the lowermost part of the metamorphic sole. This event can be linked to the main phase of the Zagros orogeny, which is manifested in large fans with ophiolitederived debris (Barzaman Formation conglomerates). During this period, the metamorphic sole of the Masafi window stayed at temperatures in excess of ca. 120 °C, corresponding to ca. 4 km of overburden, only later to be eroded to present day levels

Minimizing coherent risk measures of shortfall in discrete-time models with cone constraints

This paper studies the problem or minimizing coherent risk measures or shortfall for general discrete-time financial models with cone-constrained trading strategies, as developed by Pham and Touzi (1999) and Pham (1999). We show that the optimal strategy is obtained by super-hedging a contingent claim, which is represented as a .Xeyman-Pearson-type random variable

From Gondwana to Europe: The journey of Elba Island (Italy) as recorded by U–Pb detrital zircon ages of Paleozoic metasedimentary rocks

Elba Island, located midway between Corsica and mainland Italy, is a small but important fragment of the Adria Plate. It has a rich sedimentary record preserved in a stack of tectonic nappes of both continental margin and oceanic origin. Especially the detrital zircons in early Paleozoic to early Mesozoic metasedimentary rocks provide an archive of many important geological events in the island's history. Elba Island and Adria originated along the northern margin of Gondwana, but drifted north in Silurian times to become part of Europe. A large new dataset of LA-ICP-MS and SIMS U-Pb zircon ages allows us to trace this history. Three main stratigraphic units have been investigated. The oldest Porto Azzurro Unit was deposited in the early Cambrian and has zircon age distributions indicating a typical northern African provenance, most likely sourced from the Saharan Metacraton. The Ortano Unit has a simple, mostly unimodal Ordovician age distribution that is entirely dominated by metavolcanic rocks and their erosional products; a sample of the metavolcanic Ortano Porphyroids provided a SIMS U-Pb zircon age of 460. ±. 3. Ma. This phase of intense volcanism is related to the subduction of the Rheic Ocean beneath Gondwana, terminating with initial rifting and subsequent opening of the Paleotethys. This also marks the onset of the separation of a range of European terranes, including Adria and future Elba Island, from Gondwana. The Permo-Triassic Monticiano-Roccastrada Unit is the first to show a European provenance with the appearance of large amounts of Variscan and late to post-Variscan detritus. The presence of Variscan detrital zircons in the Permo-Triassic sediments is unexpected, since a Variscan age signature is so far not well recorded in the Adria Plate. This dataset is the most comprehensive detrital zircon dataset so far available for the Adria Plate and documents Adria's close affinity to Africa in the Lower Paleozoic, as well as its initial rifting within an active continental margin setting during the Ordovician and its final separation and independent evolution since late Palaeozoic times

AAV6.βARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model

AIMS: G protein-coupled receptor kinase 2 (GRK2), which is markedly upregulated in failing human myocardium, has been implicated as a contributing factor or consequence of heart failure (HF). Importantly, cardiac-specific GRK2 knockout mice have recently proved the pathological nature of GRK2 in HF. Targeted inhibition of GRK2 is possible using a peptide inhibitor known as the βARKct, which has rescued several disparate small animal HF models. This study was designed to evaluate long-term βARKct expression in a clinically relevant large animal HF model, using stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6). METHODS AND RESULTS: A porcine model of HF subsequent to left ventricular (LV) myocardial infarction (MI) was used to study the effects of retrograde injection into the anterior interventricular vein of either AAV6.βARKct or AAV6.luciferase as a control 2 weeks after MI. Echocardiography and LV hemodynamics were performed before and 6 weeks after gene transfer. Robust and long-term βARKct expression was found after AAV6-mediated delivery, leading to significant amelioration of LV haemodynamics and contractile function in HF pigs compared with AAV6.luciferase-treated control animals that showed a continued decline in cardiac function. Interestingly, the neurohormonal axis was virtually normalized in AVV6.βARKct-treated HF animals, represented by reductions in plasma norepinephrine levels, whereas AAV6.luciferase-treated pigs showed further increases in plasma catecholamine levels. As a result, LV remodelling and foetal gene expression was reversed by AVV6.βARKct gene therapy. CONCLUSION: These data—showing sustained amelioration of cardiac function in a post-MI pig HF model—demonstrate the therapeutic potential of βARKct gene therapy for HF

Clonal heterogeneity of FLT3-ITD detected by high-throughput amplicon sequencing correlates with adverse prognosis in acute myeloid leukemia

In acute myeloid leukemia (AML), internal tandem duplications (ITDs) of FLT3 are frequent mutations associated with unfavorable prognosis. At diagnosis, the FLT3-ITD status is routinely assessed by fragment analysis, providing information about the length but not the position and sequence of the ITD. To overcome this limitation, we performed cDNA-based high-throughput amplicon sequencing (HTAS) in 250 FLT3-ITD positive AML patients, treated on German AML Cooperative Group (AMLCG) trials. FLT3-ITD status determined by routine diagnostics was confirmed by HTAS in 242 out of 250 patients (97%). The total number of ITDs detected by HTAS was higher than in routine diagnostics (n = 312 vs. n = 274). In particular, HTAS detected a higher number of ITDs per patient compared to fragment analysis, indicating higher sensitivity for subclonal ITDs. Patients with more than one ITD according to HTAS had a significantly shorter overall and relapse free survival. There was a close correlation between FLT3-ITD mRNA levels in fragment analysis and variant allele frequency in HTAS. However, the abundance of long ITDs (≥75nt) was underestimated by HTAS, as the size of the ITD affected the mappability of the corresponding sequence reads. In summary, this study demonstrates that HTAS is a feasible approach for FLT3-ITD detection in AML patients, delivering length, position, sequence and mutational burden of this alteration in a single assay with high sensitivity. Our findings provide insights into the clonal architecture of FLT3-ITD positive AML and have clinical implications

AAV6. ARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model

AIMS: G protein-coupled receptor kinase 2 (GRK2), which is markedly upregulated in failing human myocardium, has been implicated as a contributing factor or consequence of heart failure (HF). Importantly, cardiac-specific GRK2 knockout mice have recently proved the pathological nature of GRK2 in HF. Targeted inhibition of GRK2 is possible using a peptide inhibitor known as the βARKct, which has rescued several disparate small animal HF models. This study was designed to evaluate long-term βARKct expression in a clinically relevant large animal HF model, using stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6). METHODS AND RESULTS: A porcine model of HF subsequent to left ventricular (LV) myocardial infarction (MI) was used to study the effects of retrograde injection into the anterior interventricular vein of either AAV6.βARKct or AAV6.luciferase as a control 2 weeks after MI. Echocardiography and LV hemodynamics were performed before and 6 weeks after gene transfer. Robust and long-term βARKct expression was found after AAV6-mediated delivery, leading to significant amelioration of LV haemodynamics and contractile function in HF pigs compared with AAV6.luciferase-treated control animals that showed a continued decline in cardiac function. Interestingly, the neurohormonal axis was virtually normalized in AVV6.βARKct-treated HF animals, represented by reductions in plasma norepinephrine levels, whereas AAV6.luciferase-treated pigs showed further increases in plasma catecholamine levels. As a result, LV remodelling and foetal gene expression was reversed by AVV6.βARKct gene therapy. CONCLUSION: These data—showing sustained amelioration of cardiac function in a post-MI pig HF model—demonstrate the therapeutic potential of βARKct gene therapy for HF

The <em>NPM1</em> mutation type has no impact on survival in cytogenetically normal AML.

NPM1 mutations represent frequent genetic alterations in patients with acute myeloid leukemia (AML) associated with a favorable prognosis. Different types of NPM1 mutations have been described. The purpose of our study was to evaluate the relevance of different NPM1 mutation types with regard to clinical outcome. Our analyses were based on 349 NPM1-mutated AML patients treated in the AMLCG99 trial. Complete remission rates, overall survival and relapse-free survival were not significantly different between patients with NPM1 type A or rare type mutations. The NPM1 mutation type does not seem to play a role in risk stratification of cytogenetically normal AML