Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis

published_or_final_versio

Overcoming obstacles associated with other learning experiences and school-based assessment: Perspectives of high school students with visual impairment in Hong Kong - Collaborative research project report

published_or_final_versio

Depression und Suizidalität

Even if the freedom to suicide is part of our human existence, about 90% of all suicides occur in the context of psychiatric disorders and thus in states of limited power of judgment. Depressive disorders represent the most frequent cause for suicides. Thus, optimization of medical care for depressive patients is one of the most promising strategies to prevent suicides. In the context of the `Nuremberg Alliance Against Depression' it came to an obvious reduction of suicidal acts compared to a baseline year and compared to the control region of Wurzburg. The reduction could be reached by a cooperation with GPs, multipliers such as teachers, priests, geriatric caregivers and the media, through intensive public relations work and through support of self help activities. This approach is carried forward within the Germany-wide `Alliance Against Depression' and within the `European Alliance Against Depression' ( EAAD) which is funded by the European Commission. In the last part of the article the suicide- preventive, but also the possible suicide-inducing effect of antidepressants is discussed

Understanding the role of growth factors in modulating stem cell tenogenesis

Current treatments for tendon injuries often fail to fully restore joint biomechanics leading to the recurrence of symptoms, and thus resulting in a significant health problem with a relevant social impact worldwide. Cell-based approaches involving the use of stem cells might enable tailoring a successful tendon regeneration outcome. As growth factors (GFs) powerfully regulate the cell biological response, their exogenous addition can further stimulate stem cells into the tenogenic lineage, which might eventually depend on stem cells source. In the present study we investigate the tenogenic differentiation potential of human- amniotic fluid stem cells (hAFSCs) and adipose-derived stem cells (hASCs) with several GFs associated to tendon development and healing; namely, EGF, bFGF, PDGF-BB and TGF-β1. Stem cells response to biochemical stimuli was studied by screening of tendon-related genes (collagen type I, III, decorin, tenascin C and scleraxis) and proteins found in tendon extracellular matrix (ECM) (Collagen I, III, and Tenascin C). Despite the fact that GFs did not seem to influence the synthesis of tendon ECM proteins, EGF and bFGF influenced the expression of tendon-related genes in hAFSCs, while EGF and PDGF-BB stimulated the genetic expression in hASCs. Overall results on cellular alignment morphology, immunolocalization and PCR analysis indicated that both stem cell source can be biochemically induced towards tenogenic commitment, validating the potential of hASCs and hAFSCs for tendon regeneration strategies.Authors thank the Portuguese Foundation for Science and Technology (FCT) for the research project BIBS (PTDC/CVT/102972/2008) and for the post-doc fellowship grant: SFRH/BPD/86775/2012. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Mycolactone-dependent depletion of endothelial cell thrombomodulin is strongly associated with fibrin deposition in Buruli ulcer lesions

A well-known histopathological feature of diseased skin in Buruli ulcer (BU) is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on the expression of surface anticoagulant molecules involved in the protein C anticoagulant pathway. Congenital deficiencies in this natural anticoagulant pathway are known to induce thrombotic complications such as purpura fulimans and spontaneous necrosis. Mycolactone profoundly decreased thrombomodulin (TM) expression on the surface of human dermal microvascular endothelial cells (HDMVEC) at doses as low as 2ng/ml and as early as 8hrs after exposure. TM activates protein C by altering thrombin's substrate specificity, and exposure of HDMVEC to mycolactone for 24 hours resulted in an almost complete loss of the cells' ability to produce activated protein C. Loss of TM was shown to be due to a previously described mechanism involving mycolactone-dependent blockade of Sec61 translocation that results in proteasome-dependent degradation of newly synthesised ER-transiting proteins. Indeed, depletion from cells determined by live-cell imaging of cells stably expressing a recombinant TM-GFP fusion protein occurred at the known turnover rate. In order to determine the relevance of these findings to BU disease, immunohistochemistry of punch biopsies from 40 BU lesions (31 ulcers, nine plaques) was performed. TM abundance was profoundly reduced in the subcutis of 78% of biopsies. Furthermore, it was confirmed that fibrin deposition is a common feature of BU lesions, particularly in the necrotic areas. These findings indicate that there is decreased ability to control thrombin generation in BU skin. Mycolactone's effects on normal endothelial cell function, including its ability to activate the protein C anticoagulant pathway are strongly associated with this. Fibrin-driven tisischemia could contribute to the development of the tissue necrosis seen in BU lesions

Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis

published_or_final_versio

Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes

published_or_final_versio

WIMP-nucleus scattering in chiral effective theory

We discuss long-distance QCD corrections to the WIMP-nucleon(s) interactions in the framework of chiral effective theory. For scalar-mediated WIMP-quark interactions, we calculate all the next-to-leading-order corrections to the WIMP-nucleus elastic cross-section, including two-nucleon amplitudes and recoil-energy dependent shifts to the single-nucleon scalar form factors. As a consequence, the scalar-mediated WIMP-nucleus cross-section cannot be parameterized in terms of just two quantities, namely the neutron and proton scalar form factors at zero momentum transfer, but additional parameters appear, depending on the short-distance WIMP-quark interaction. Moreover, multiplicative factorization of the cross-section into particle, nuclear and astro-particle parts is violated. In practice, while the new effects are of the natural size expected by chiral power counting, they become very important in those regions of parameter space where the leading order WIMP-nucleus amplitude is suppressed, including the so-called "isospin-violating dark matter" regime. In these regions of parameter space we find order-of-magnitude corrections to the total scattering rates and qualitative changes to the shape of recoil spectra.Comment: 23 pages, 6 figures, 1 tabl

New monotonicity formulas for Ricci curvature and applications. I

Original manuscript November 21, 2011We prove three new monotonicity formulas for manifolds with a lower Ricci curvature bound and show that they are connected to rate of convergence to tangent cones. In fact, we show that the derivative of each of these three monotone quantities is bounded from below in terms of the Gromov–Hausdorff distance to the nearest cone. The monotonicity formulas are related to the classical Bishop–Gromov volume comparison theorem and Perelman’s celebrated monotonicity formula for the Ricci flow. We will explain the connection between all of these. Moreover, we show that these new monotonicity formulas are linked to a new sharp gradient estimate for the Green function that we prove. This is parallel to the fact that Perelman’s monotonicity is closely related to the sharp gradient estimate for the heat kernel of Li–Yau. In [CM4] one of the monotonicity formulas is used to show uniqueness of tangent cones with smooth cross-sections of Einstein manifolds. Finally, there are obvious parallelisms between our monotonicity and the positive mass theorem of Schoen–Yau and Witten.National Science Foundation (U.S.) (Grant DMS-11040934)National Science Foundation (U.S.). Focused Research Group (Grant DMS 0854774)National Science Foundation (U.S.) (Grant 0932078

A consistent picture for large penguins in D -> pi+ pi-, K+ K-

A long-standing puzzle in charm physics is the large difference between the D0 -> K+ K- and D0 -> pi+ pi- decay rates. Recently, the LHCb and CDF collaborations reported a surprisingly large difference between the direct CP asymmetries, Delta A_CP, in these two modes. We show that the two puzzles are naturally related in the Standard Model via s- and d-quark "penguin contractions". Their sum gives rise to Delta A_CP, while their difference contributes to the two branching ratios with opposite sign. Assuming nominal SU(3) breaking, a U-spin fit to the D0 -> K+ pi-, pi+ K-, pi+ pi-, K+ K- decay rates yields large penguin contractions that naturally explain Delta A_CP. Expectations for the individual CP asymmetries are also discussed.Comment: 24 pages, 8 figure