Single paternal dexamethasone challenge programs offspring metabolism and reveals multiple candidates in RNA-mediated inheritance.

Single traumatic events that elicit an exaggerated stress response can lead to the development of neuropsychiatric conditions. Rodent studies suggested germline RNA as a mediator of effects of chronic environmental exposures to the progeny. The effects of an acute paternal stress exposure on the germline and their potential consequences on offspring remain to be seen. We find that acute administration of an agonist for the stress-sensitive Glucocorticoid receptor, using the common corticosteroid dexamethasone, affects the RNA payload of mature sperm as soon as 3 hr after exposure. It further impacts early embryonic transcriptional trajectories, as determined by single-embryo sequencing, and metabolism in the offspring. We show persistent regulation of tRNA fragments in sperm and descendant 2-cell embryos, suggesting transmission from sperm to embryo. Lastly, we unravel environmentally induced alterations in sperm circRNAs and their targets in the early embryo, highlighting this class as an additional candidate in RNA-mediated inheritance of disease risk.KG was funded by the Swiss National Science Foundation early postdoc and advanced postdoc mobility a SPARK and Novartis foundation grant. Some of this work was supported by Cancer Research UK (C13474/A18583, C6946/A14492) and Wellcome (104640/Z/14/Z, 092096/Z/10/Z) to EAM. GP and MH were supported by a core grant from the Wellcome Trust. The lab of JB is currently funded by the ETH Zurich, SNSF Project Grant 310030_172889/1, ETH Research Grant ETH-20 19-1, the Kurt und Senta Herrmann-Stiftung, the Botnar Research Center for Child Health and a 3R Competence Center Project Grant. JK was supported by a Swiss-european mobility programme scholarship

Analysis of defect-related inhomogeneous electroluminescence in InGaN/GaN QW LEDs

The inhomogeneous electroluminescence (EL) of InGaN/GaN quantum well light emitting diode structures was investigated in this study. Electroluminescence hyperspectral images showed that inhomogeneities in the form of bright spots exhibited spectrally blue-shifted and broadened emission. Scanning electron microscopy combined with cathodoluminescence (SEM-CL) was used to identify hexagonal pits at the centre of approximately 20% of these features. Scanning transmission electron microscopy imaging with energy dispersive X-ray spectroscopy (STEM-EDX) indicated there may be p-doped AlGaN within the active region caused by the presence of the pit. Weak beam dark-field TEM (WBDF-TEM) revealed the presence of bundles of dislocations associated with the pit, suggesting the surface features which cause the inhomogeneous EL may occur at coalescence boundaries, supported by trends in the number of features observed across the wafer.The European Research Council has provided financial support under the European Community’s Seventh Framework Programme/ ERC grant agreement no. 279361 (MACONS).This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.spmi.2016.03.03

The vascular gene Apold1 is dispensable for normal development but controls angiogenesis under pathological conditions

The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of Apold1 (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of Apold1 is restricted to the vasculature and that Apold1 expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using Apold1$^{-/-}$ mice, we find that Apold1 is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, Apold1$^{-/-}$ mice display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of Apold1 and that Apold1 deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, Apold1 is activated in ECs upon growth factor stimulation as well as in hypoxia, and Apold1 intrinsically controls EC proliferation but not migration. Our data demonstrate that Apold1 is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation

Radiation hardness qualification of PbWO4 scintillation crystals for the CMS Electromagnetic Calorimeter

This is the Pre-print version of the Article. The official published version can be accessed from the link below - Copyright @ 2010 IOPEnsuring the radiation hardness of PbWO4 crystals was one of the main priorities during the construction of the electromagnetic calorimeter of the CMS experiment at CERN. The production on an industrial scale of radiation hard crystals and their certification over a period of several years represented a difficult challenge both for CMS and for the crystal suppliers. The present article reviews the related scientific and technological problems encountered

The importance of understanding individual differences in Down syndrome

In this article, we first present a summary of the general assumptions about Down syndrome (DS) still to be found in the literature. We go on to show how new research has modified these assumptions, pointing to a wide range of individual differences at every level of description. We argue that, in the context of significant increases in DS life expectancy, a focus on individual differences in trisomy 21 at all levels—genetic, cellular, neural, cognitive, behavioral, and environmental—constitutes one of the best approaches for understanding genotype/phenotype relations in DS and for exploring risk and protective factors for Alzheimer’s disease in this high-risk population

Natural products in modern life science

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science

Mutation D816V Alters the Internal Structure and Dynamics of c-KIT Receptor Cytoplasmic Region: Implications for Dimerization and Activation Mechanisms

The type III receptor tyrosine kinase (RTK) KIT plays a crucial role in the transmission of cellular signals through phosphorylation events that are associated with a switching of the protein conformation between inactive and active states. D816V KIT mutation is associated with various pathologies including mastocytosis and cancers. D816V-mutated KIT is constitutively active, and resistant to treatment with the anti-cancer drug Imatinib. To elucidate the activating molecular mechanism of this mutation, we applied a multi-approach procedure combining molecular dynamics (MD) simulations, normal modes analysis (NMA) and binding site prediction. Multiple 50-ns MD simulations of wild-type KIT and its mutant D816V were recorded using the inactive auto-inhibited structure of the protein, characteristic of type III RTKs. Computed free energy differences enabled us to quantify the impact of D816V on protein stability in the inactive state. We evidenced a local structural alteration of the activation loop (A-loop) upon mutation, and a long-range structural re-organization of the juxta-membrane region (JMR) followed by a weakening of the interaction network with the kinase domain. A thorough normal mode analysis of several MD conformations led to a plausible molecular rationale to propose that JMR is able to depart its auto-inhibitory position more easily in the mutant than in wild-type KIT and is thus able to promote kinase mutant dimerization without the need for extra-cellular ligand binding. Pocket detection at the surface of NMA-displaced conformations finally revealed that detachment of JMR from the kinase domain in the mutant was sufficient to open an access to the catalytic and substrate binding sites