Explore the vast range of titles available.

Ischemia/reperfusion injury (IRI) is crucial in the pathology of major cardiovascular diseases, such as stroke and myocardial infarction. Paradoxically, both the lack of oxygen during ischemia and the replenishment of oxygen during reperfusion can cause tissue injury. Clinical outcome is also determined by a third, post-reperfusion phase characterized by tissue remodeling and adaptation. Increased levels of reactive oxygen species (ROS) have been suggested to be key players in all three phases. As a second paradox, ROS seem to play a double-edged role in IRI, with both detrimental and beneficial effects. These Janus-faced effects of ROS may be linked to the different sources of ROS or to the different types of ROS that exist and may also depend on the phase of IRI. With respect to therapeutic implications, an untargeted application of antioxidants may not differentiate between detrimental and beneficial ROS, which might explain why this approach is clinically ineffective in lowering cardiovascular mortality. Under some conditions, antioxidants even appear to be harmful. In this review, we discuss recent breakthroughs regarding a more targeted and promising approach to therapeutically modulate ROS in IRI. We will focus on NADPH oxidases and their catalytic subunits, NOX, as they represent the only known enzyme family with the sole function to produce ROS. Similar to ROS, NADPH oxidases may play a dual role as different NOX isoforms may mediate detrimental or protective processes. Unraveling the precise sequence of events, i.e., determining which role the individual NOX isoforms play in the various phases of IRI, may provide the crucial molecular and mechanistic understanding to finally effectively target oxidative stress.

Purpose: Tumour hypoxia activates hypoxia-inducible factor-1 (HIF-1) and indluences angiogenesis, cell survival and invasion. Prolyl hydroxylase-3 (PHD3) regulates degradation of HIF-1 α . The effects of PHD3 in tumour growth are largely unknown. Experimental design: PHD3 expression was analysed in human pancreatic cancer tissues and cancer cell lines by real-time quantitative PCR and immunohistochemistry. PHD3 overexpression was established by stable transfection and downregulation by short interfering RNA technology. VEGF was quantified by enzyme-linked immunosorbent assay. Matrigel invasion assays were performed to examine tumour cell invasion. Apoptosis was measured by annexin-V staining and caspase-3 assays. The effect of PHD3 on tumour growth in vivo was evaluated in an established orthotopic murine model. Results: PHD3 was upregulated in well-differentiated human tumours and cell lines, and regulated hypoxic VEGF secretion. PHD3 overexpression mediated tumour cell growth and invasion by induction of apoptosis in a nerve growth factor-dependent manner by the activation of caspase-3 and phosphorylation of focal adhesion kinase HIF-1 independently. In vivo , PHD3 inhibited tumour growth by abrogation of tumour angiogenesis. Conclusion: Our results indicate essential functions of PHD3 in tumour growth, apoptosis and angiogenesis and through HIF-1-dependent and HIF-1-independent pathways.

BackgroundGeleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterised by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2).MethodsFollowing this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n=20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n=19).ResultsThe main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features.ConclusionsIt is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene.

The Diebold-Mariano ( ) test was intended for comparing forecasts; it has been, and remains, useful in that regard. The test was not intended for comparing models. Much of the large ensuing literature, however, uses -type tests for comparing models, in pseudo-out-of-sample environments. In that case, simpler yet more compelling full-sample model comparison procedures exist; they have been, and should continue to be, widely used. The hunch that pseudo-out-of-sample analysis is somehow the \"only,\" or \"best,\" or even necessarily a \"good\" way to provide insurance against in-sample overfitting in model comparisons proves largely false. On the other hand, pseudo-out-of-sample analysis remains useful for certain tasks, perhaps most notably for providing information about comparative predictive performance during particular historical episodes.

ObjectiveWe developed a validated index for assessing histological disease activity in UC and established its responsiveness.MethodsTwo hundred biopsies were scored. The outcome was the Global Visual Evaluation (GVE). Eight histological features were tested. The Nancy index was developed by multiple linear regression and bootstrap process to create an index that best matched the GVE. Goodness of fit was assessed by the adjusted R squared (adjusted R2). The second step was the validation of the index: 100 biopsies were scored for the Nancy index by three pathologists from different centres. Inter-reader reliability was evaluated for each reader. The relationship between the change of the Nancy index and the Geboes index was assessed to assess the responsiveness.ResultsAfter backward selection with bootstrap validation, 3/8 items were selected: ulceration (adjusted R2=0.55), acute inflammatory infiltrate (adjusted R2=0.88) and chronic inflammatory infiltrate (adjusted R2=0.79). The Nancy index is defined by a 5-level classification ranging from grade 0 (absence of significant histological disease activity) to grade 4 (severely active disease). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.88 (95% CI 0.82 to 0.92) and the index had good inter-reader reliability (ICC=0.86 (0.81 to 0.99)). The correlation between the Nancy index and the Geboes score or the GVE was very good. The index had a good responsiveness with a high correlation between changes in the Geboes score and changes in the Nancy index (0.910 (0.813 to 0.955)).ConclusionsA three descriptor histological index has been validated for use in clinical practice and clinical trials.

We use LASSO methods to shrink, select, and estimate the high-dimensional network linking the publicly traded subset of the world’s top 150 banks, 2003–2014. We characterize static network connectedness using full-sample estimation and dynamic network connectedness using rolling-window estimation. Statically, we find that global bank equity connectedness has a strong geographic component, whereas country sovereign bond connectedness does not. Dynamically, we find that equity connectedness increases during crises, with clear peaks during the Great Financial Crisis and each wave of the subsequent European Debt Crisis, and with movements coming mostly from changes in cross-country as opposed to within-country bank linkages.

The Elite Quality Index (EQx) attempts to measure the propensity of elites—on aggregate—to create value, rather than to rent seek. The index has attracted worldwide media and press attention. In their articles, journalists have based their analyses primarily on their own countries’ position in the EQx ranking. But how meaningful is the EQx ranking? How do the uncertainties underlying some of the assumptions made in the index propagate to the country rankings? We conduct a global uncertainty and sensitivity analysis (UA and SA) of the EQx and compute Sobol’ first and total order sensitivity indices using state of the art estimators, in order to scrutinise the implications of index assumptions and assess the reliability of the EQx ranking. The UA suggests that the EQx ranking of 2021 (EQx2021) is largely stable for the top 50 countries, but exhibits considerable uncertainties especially for middle and lower performing countries. The SA highlights the handling of missing data, the normalisation process and the weighting scheme as most important methodological choices, while the largest potential for improvement is observed in how raw missing indicator data is handled.

Compensating a polar surfaceAn ionic crystal surface can be electrostatically unstable, and the surface must reconstruct in some way to avoid this “polar catastrophe.” Setvin et al. used scanning probe microscopies and density functional theory to study the changes in the polar surface of the perovskite KTaO3. They observed several structural reconstructions as the surface cleaved in vacuum was heated to higher temperatures. These ranged from surface distortions to the formation of oxygen vacancies to the development of KO and TaO2 stripes. Hydroxylation after exposure to water vapor also stabilized the surface.Science, this issue p. 572The stacking of alternating charged planes in ionic crystals creates a diverging electrostatic energy—a “polar catastrophe”—that must be compensated at the surface. We used scanning probe microscopies and density functional theory to study compensation mechanisms at the perovskite potassium tantalate(KTaO3) (001) surface as increasing degrees of freedom were enabled. The as-cleaved surface in vacuum is frozen in place but immediately responds with an insulator-to-metal transition and possibly ferroelectric lattice distortions. Annealing in vacuum allows the formation of isolated oxygen vacancies, followed by a complete rearrangement of the top layers into an ordered pattern of KO and TaO2 stripes. The optimal solution is found after exposure to water vapor through the formation of a hydroxylated overlayer with ideal geometry and charge.