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

On the role of NOS1 ex1f-VNTR in ADHD – allelic, subgroup, and meta-analysis

Attention deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co-morbidity analysis. Our previous finding held true in the extended sample, and also meta-analysis demonstrated an association of NOS1 ex1fVNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post-mortem brain samples. These data validate the role of NOS-I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association.PostprintPeer reviewe

Perovskite Solar Cells with Carbon-Based Electrodes – Quantification of Losses and Strategies to Overcome Them

Funder: UNIQUEFunder: National University of Ireland Travelling StudentshipFunder: Engineering and Physical Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000266Funder: Cambridge Trust ScholarshipFunder: Robert Gardiner ScholarshipCarbon-based electrodes represent a promising approach to improve stability and up-scalability of perovskite photovoltaics. The temperature at which these contacts are processed defines the absorber grain size of the perovskite solar cell: in cells with low-temperature carbon-based electrodes (L-CPSCs), layer-by-layer deposition is possible, allowing perovskite crystals to be large (>100 nm), while in cells with high-temperature carbon-based contacts (H-CPSCs), crystals are constrained to 10-20 nm size. To enhance the power conversion efficiency of these devices, the main loss mechanisms were identified for both systems. Measurements of charge carrier lifetime, quasi-Fermi level splitting (QFLS) and light-intensity-dependent behavior, supported by numerical simulations, clearly demonstrate that H-CPSCs strongly suffer from non-radiative losses in the perovskite absorber, primarily due to numerous grain boundaries. In contrast, large crystals of L-CPSCs provide long carrier lifetime (1.8 µs) and exceptionally high QFLS of 1.21 eV for an absorber bandgap of 1.6 eV. These favorable characteristics explain the remarkable open-circuit voltage (VOC) of over 1.1 V in hole-selective layer-free L-CPSCs. However, the low photon absorption and poor charge transport in these cells limit their potential. Finally, effective strategies are provided to reduce non-radiative losses in H-CPSCs, transport losses in L-CPSCs and to improve photon management in both cell types.This work has been partially funded within the projects PROPER financed from the German Ministry of Education and Research under funding number 01DR19007 and UNIQUE supported under umbrella of SOLAR-ERA.NET_cofund by ANR, PtJ, MIUR, MINECO-AEI and SWEA, within the EU's HORIZON 2020 Research and Innovation Program (cofund ERA-NET Action No. 691664). D. B. acknowledges the scholarship support of the German Federal Environmental Foundation (DBU) and S. Z. acknowledges the scholarship support of the German Academic Exchange Service (DAAD). B.Y. and A.Ha. acknowledge the funding from the European Union’s Horizon 2020 research and innovation program ESPRESSO under the agreement No.: 764047. This work has also been partially funded by Swiss National Science Foundation with Project No. 200020_185041. T.D. acknowledges a National University of Ireland Travelling Studentship. K.F. acknowledges a George and Lilian Schiff Studentship, Winton Studentship, the Engineering and Physical Sciences Research Council (EPSRC) studentship, Cambridge Trust Scholarship, and Robert Gardiner Scholarship. S.S. acknowledges support from the Royal Society and Tata Group (UF150033). M.A. acknowledges funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No.841386. The authors would like to thank Maryamsadat Heydarian and Laura Stevens for their EQE and AFM measurements. The authors thank the EPSRC (EP/R023980/1) for funding

Perovskite Solar Cells with Carbon-Based Electrodes – Quantification of Losses and Strategies to Overcome Them

Funder: UNIQUEFunder: National University of Ireland Travelling StudentshipFunder: Engineering and Physical Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000266Funder: Cambridge Trust ScholarshipFunder: Robert Gardiner ScholarshipCarbon-based electrodes represent a promising approach to improve stability and up-scalability of perovskite photovoltaics. The temperature at which these contacts are processed defines the absorber grain size of the perovskite solar cell: in cells with low-temperature carbon-based electrodes (L-CPSCs), layer-by-layer deposition is possible, allowing perovskite crystals to be large (>100 nm), while in cells with high-temperature carbon-based contacts (H-CPSCs), crystals are constrained to 10-20 nm size. To enhance the power conversion efficiency of these devices, the main loss mechanisms were identified for both systems. Measurements of charge carrier lifetime, quasi-Fermi level splitting (QFLS) and light-intensity-dependent behavior, supported by numerical simulations, clearly demonstrate that H-CPSCs strongly suffer from non-radiative losses in the perovskite absorber, primarily due to numerous grain boundaries. In contrast, large crystals of L-CPSCs provide long carrier lifetime (1.8 µs) and exceptionally high QFLS of 1.21 eV for an absorber bandgap of 1.6 eV. These favorable characteristics explain the remarkable open-circuit voltage (VOC) of over 1.1 V in hole-selective layer-free L-CPSCs. However, the low photon absorption and poor charge transport in these cells limit their potential. Finally, effective strategies are provided to reduce non-radiative losses in H-CPSCs, transport losses in L-CPSCs and to improve photon management in both cell types.This work has been partially funded within the projects PROPER financed from the German Ministry of Education and Research under funding number 01DR19007 and UNIQUE supported under umbrella of SOLAR-ERA.NET_cofund by ANR, PtJ, MIUR, MINECO-AEI and SWEA, within the EU's HORIZON 2020 Research and Innovation Program (cofund ERA-NET Action No. 691664). D. B. acknowledges the scholarship support of the German Federal Environmental Foundation (DBU) and S. Z. acknowledges the scholarship support of the German Academic Exchange Service (DAAD). B.Y. and A.Ha. acknowledge the funding from the European Union’s Horizon 2020 research and innovation program ESPRESSO under the agreement No.: 764047. This work has also been partially funded by Swiss National Science Foundation with Project No. 200020_185041. T.D. acknowledges a National University of Ireland Travelling Studentship. K.F. acknowledges a George and Lilian Schiff Studentship, Winton Studentship, the Engineering and Physical Sciences Research Council (EPSRC) studentship, Cambridge Trust Scholarship, and Robert Gardiner Scholarship. S.S. acknowledges support from the Royal Society and Tata Group (UF150033). M.A. acknowledges funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No.841386. The authors would like to thank Maryamsadat Heydarian and Laura Stevens for their EQE and AFM measurements. The authors thank the EPSRC (EP/R023980/1) for funding

A mouse model for Sorsby fundus dystrophy

purpose. Sorsby fundus dystrophy (SFD) is a rare, late-onset macular dystrophy caused by mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) gene. The known mutations introduce potentially unpaired cysteine residues in the C terminus of the protein and result in the formation of higher-molecular-weight protein complexes of as yet unknown composition and functional consequences in the pathologic course of SFD. To facilitate in vivo investigation of mutant TIMP3, the authors generated a knock-in mouse carrying a disease-related Ser156Cys mutation in the orthologous murine Timp3 gene. methods. Site-directed mutagenesis and homologous recombination in embryonic stem (ES) cells was used to generate mutant ES cells carrying the Timp3 S156C allele. Chimeric animals were obtained, of which two displayed germline transmission of the mutated allele. Molecular genetic, biochemical, electron microscopic, and electrodiagnostic techniques were used for characterization. results. At 8 months of age, knock-in mice showed abnormalities in the inner aspect of Bruch’s membrane and in the organization of the adjacent basal microvilli of the retinal pigment epithelium (RPE). Changes resembling those in the mutant animals were also present to some extent in normal littermates, but only at an advanced age of 30 months. Long-term electrodiagnostic recordings indicated normal retinal function throughout life. The biochemical characteristics of the mutant protein appear similar in humans and knock-in mice, suggesting common molecular pathways in the two species. The localization of the mutant protein in the eye is normal, although there is evidence of increased Timp3 levels in Bruch’s membrane of mutant animals. conclusions. The knock-in mice display early features of age-related changes in Bruch’s membrane and the RPE that may represent the primary clinical manifestations of SFD. In addition, our immunolabeling studies and biochemical data support a model proposing that site-specific excess rather than absence or deficiency of functional Timp3 may be the primary consequence of the known Timp3 mutations

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