The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia : further evidence and meta-analysis

NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ. interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia. PostprintPeer reviewe

Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drug-eluting stent type

Aim To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES). Methods and results Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43). Conclusion A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957

Roadmap on organic inorganic hybrid perovskite semiconductors and devices

Metal halide perovskites are the first solution processed semiconductors that can compete in their functionality with conventional semiconductors, such as silicon. Over the past several years, perovskite semiconductors have reported breakthroughs in various optoelectronic devices, such as solar cells, photodetectors, light emitting and memory devices, and so on. Until now, perovskite semiconductors face challenges regarding their stability, reproducibility, and toxicity. In this Roadmap, we combine the expertise of chemistry, physics, and device engineering from leading experts in the perovskite research community to focus on the fundamental material properties, the fabrication methods, characterization and photophysical properties, perovskite devices, and current challenges in this field. We develop a comprehensive overview of the current state of the art and offer readers an informed perspective of where this field is heading and what challenges we have to overcome to get to successful commercializatio

Nonlinear and linear bottom interaction effects in shallow water

Spectral wave transformation in shallow water is investigated by examining nonlinear and linear bottom interaction effects. The effect of nonlinear wave-wave interaction in shallow water is investigated by including the depth dependent dispersion relationship in the nonlinear calculations. Dissipative mechanisms examined are bottom friction, percolation within the sand layer, and wave motion in the mud layer induced by hydrodynamic forces acting at the mud line. Comparisons with observations suggest that bottom motion can be one order of magnitude more pronounced than friction or percolation when soft mud occupies the top layer such as found in the Gulf of Mexico. In the North Sea (JONSWAP area) coarse sand with mean grain diameter ≥ 0.3 mm is found in the top sediment layer. Here swell energy dissipation can be explained by the linear percolation mechanism. When bottom sand is fine (mean grain diameter ≤ 0.4 mm), such as found offshore of Panama City and Marine-land, Florida, nonlinear bottom friction is found to explain swell dissipation adequately. A nonlinear bottom scattering mechanism was investigated by Long (1973) who found the effect to be possibly important in the JONSWAP area but required detailed directional wave measurements to derive conclusive results. This paper examines five different data sets on wave transformation in shallow water and offers explanations in terms of bottom interaction mechanism

Goal-Oriented Approach to Enable New Business Models for SME Using Smart Products

Part 2: Collaborative Environments and New Product DevelopmentInternational audienceThe manufacturing industry has to exploit trends like “Industrie 4.0” and digitization not only to design production more efficiently, but also to create and develop new and innovative business models [1, p. 2]. New business models ensure that even SMEs are able to open up new markets and canvass new customers [2, p. 82ff.]. This means that in order to stay competitive, SMEs must transform their existing business models [3, p. 2ff.]. The creation of new business models require smart products [4, p. 1, 5, p. 235, 6, p. 13, 7, p. 2, 8, p. 322, 9, p. 7]. The required data base for new business models cannot be provided by SMEs alone, whereas smart products are able to provide a foundation, given the creation of smart data and smart services they enable [5, p. 235]. These services then expand functions and functionality of smart products and define new business models [10, 6f.]. However, the development of smart products by small and medium-sized enterprises is still lined with obstacles [11, p. 640]. Regarding the product development process the inclusion of smart products means that new and SME-unknown domains diffuse during the process [12, p. 2]. Although there are many models regarding this process there appears to be a substantial lack of taking into account the competencies enabled by the implementation of digital technologies. Hence, several SME-supporting approaches fail to address the two major challenges these enterprises are faced with [13, p. 8]. This paper generally describes valid objectives containing relevant stakeholders and their allocation to the phases of the product life cycle. Within each objective the potential benefit for customers and producers is analyzed. The model given in this paper helps SMEs in defining the initiation of a product development project more precisely and hence also eases project scoping and targeting for the smartification of an already existing product