Thiolfunktionalisierte 1,2,4-Triazoliumsalze als NHC-Vorläufer

N-heterozyklische Carbene (NHC) können in vielfältiger Weise modifiziert werden, indem zusätzliche Funktionalitäten über die Stickstoffatome des heterozyklischen Rings eingeführt werden. Viele verschiedene donorfunktionalisierte NHC, ihre Übergangsmetall-Komplexe und ihre Verwendung in der homogenen Katalyse wurden bisher untersucht. Während Stickstoff-, Sauerstoff- oder Phosphordonoren häufig auftreten, sind NHC mit einer Schwefelfunktionalität relativ selten. Beispiele schwefelfunktionalisierter NHC enthalten meist eine Thioethergruppe und nur selten das reaktivere freie Thiol. In dieser Arbeit wurden die Synthese von 1,2,4-Triazoliumsalzen mit einem Thiophenolsubstituenten und deren Anwendung als NHC-Thiolato-Liganden erarbeitet. Durch eine modulare Synthesestrategie konnten neben thiolsubstituierten Mono- und symmetrischen Bistriazoliumsalzen auch unsymmetrische Bistriazoliumsalze erhalten werden, in denen eine thiolsubstituierte Triazolium-Einheit mit einer zweiten, nicht weiter funktionalisierten Triazolium-Einheit verbunden ist. Die Freisetzung des Thiols durch Abspaltung der Schutzgruppe bildete in der Syntheseroute jeweils den letzten Schritt. Bei der Oxidiation der so erhaltenen Ligandenvorläufer mit Dimethylsulfoxid wurde beobachtet, dass nicht die zu erwartenden Disulfide entstehen, sondern das Triazoliumsalz unter Ringschluss zum Benzothiazol oxidiert wird. Nach Deprotonierung konnte das thiolsubstituierte Triazoliumsalz als C,S-Chelatligand an verschiedene Übergangsmetalle koordiniert werden. Die resultierenden Palladium- und Nickel-Komplexe wurden erfolgreich als Katalysatoren in Kreuzkupplungsreaktionen eingesetzt. Im Falle der unsymmetrischen Bistriazoliumsalze konnte das thiolfunktionalisierte Triazolium-Fragment mit einer milden Base deprotoniert werden, während die andere Triazolium-Einheit unter diesen Bedingungen unberührt blieb. Durch eine solche selektive Deprotonierung des Bis(NHC)-Liganden ist es gelungen, stufenweise zunächst Palladium und danach Kupfer bzw. Gold unter Bildung von heterobimetallischen Komplexen einzuführen

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

PI3K: A master regulator of brain metastasis‐promoting macrophages/microglia

Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis-promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan-PI3K Class I inhibitor with a good blood-brain-barrier penetrance, reduced their metastasis-promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re-educates the metastasis-promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment

Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia

Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF

Human exome and mouse embryonic expression data implicateZFHX3,TRPS1, andCHD7in human esophageal atresia

Introduction Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutationalde novoevents in genes involved in foregut development. Methods To identify mutationalde novoevents in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmedde novovariants were prioritized usingin silicoprediction tools. To investigate the embryonic role of genes harboring prioritizedde novovariants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results In total we prioritized 14 novelde novovariants in 14 different genes (APOL2,EEF1D,CHD7,FANCB,GGT6,KIAA0556,NFX1,NPR2,PIGC,SLC5A2,TANC2,TRPS1,UBA3, andZFHX3) and eight rarede novovariants in eight additional genes (CELSR1,CLP1,GPR133,HPS3,MTA3,PLEC,STAB1, andPPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rarede novovariant inZFHX3.In silicoprediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritizedCHD7,TRPS1, andZFHX3as EA/TEF candidate genes. Re-sequencing ofZFHX3in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. Conclusion Our study suggests that rare mutationalde novoevents in genes involved in foregut development contribute to the development of EA/TEF

First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 x 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 x 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 x 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% +/- 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes

Early stage litter decomposition across biomes

Through litter decomposition enormous amounts of carbon is emitted to the atmosphere. Numerous large-scale decomposition experiments have been conducted focusing on this fundamental soil process in order to understand the controls on the terrestrial carbon transfer to the atmosphere. However, previous studies were mostly based on site-specific litter and methodologies, adding major uncertainty to syntheses, comparisons and meta-analyses across different experiments and sites. In the TeaComposition initiative, the potential litter decomposition is investigated by using standardized substrates (Rooibos and Green tea) for comparison of litter mass loss at 336 sites (ranging from −9 to +26 °C MAT and from 60 to 3113 mm MAP) across different ecosystems. In this study we tested the effect of climate (temperature and moisture), litter type and land-use on early stage decomposition (3 months) across nine biomes. We show that litter quality was the predominant controlling factor in early stage litter decomposition, which explained about 65% of the variability in litter decomposition at a global scale. The effect of climate, on the other hand, was not litter specific and explained <0.5% of the variation for Green tea and 5% for Rooibos tea, and was of significance only under unfavorable decomposition conditions (i.e. xeric versus mesic environments). When the data were aggregated at the biome scale, climate played a significant role on decomposition of both litter types (explaining 64% of the variation for Green tea and 72% for Rooibos tea). No significant effect of land-use on early stage litter decomposition was noted within the temperate biome. Our results indicate that multiple drivers are affecting early stage litter mass loss with litter quality being dominant. In order to be able to quantify the relative importance of the different drivers over time, long-term studies combined with experimental trials are needed.This work was performed within the TeaComposition initiative, carried out by 190 institutions worldwide. We thank Gabrielle Drozdowski for her help with the packaging and shipping of tea, Zora Wessely and Johannes Spiegel for the creative implementation of the acknowledgement card, Josip Dusper for creative implementation of the graphical abstract, Christine Brendle for the GIS editing, and Marianne Debue for her help with the data cleaning. Further acknowledgements go to Adriana Principe, Melanie Köbel, Pedro Pinho, Thomas Parker, Steve Unger, Jon Gewirtzman and Margot McKleeven for the implementation of the study at their respective sites. We are very grateful to UNILEVER for sponsoring the Lipton tea bags and to the COST action ClimMani for scientific discussions, adoption and support to the idea of TeaComposition as a common metric. The initiative was supported by the following grants: ILTER Initiative Grant, ClimMani Short-Term Scientific Missions Grant (COST action ES1308; COST-STSM-ES1308-36004; COST-STM-ES1308-39006; ES1308-231015-068365), INTERACT (EU H2020 Grant No. 730938), and Austrian Environment Agency (UBA). Franz Zehetner acknowledges the support granted by the Prometeo Project of Ecuador's Secretariat of Higher Education, Science, Technology and Innovation (SENESCYT) as well as Charles Darwin Foundation for the Galapagos Islands (2190). Ana I. Sousa, Ana I. Lillebø and Marta Lopes thanks for the financial support to CESAM (UID/AMB/50017), to FCT/MEC through national funds (PIDDAC), and the co-funding by the FEDER, within the PT2020 Partnership Agreement and Compete 2020. The research was also funded by the Portuguese Foundation for Science and Technology, FCT, through SFRH/BPD/107823/2015 (A.I. Sousa), co-funded by POPH/FSE. Thomas Mozdzer thanks US National Science Foundation NSF DEB-1557009. Helena C. Serrano thanks Fundação para a Ciência e Tecnologia (UID/BIA/00329/2013). Milan Barna acknowledges Scientific Grant Agency VEGA (2/0101/18). Anzar A Khuroo acknowledges financial support under HIMADRI project from SAC-ISRO, India

Early stage litter decomposition across biomes

[Departement_IRSTEA]Territoires [TR1_IRSTEA]SEDYVINInternational audienceThrough litter decomposition enormous amounts of carbon is emitted to the atmosphere. Numerous large-scale decomposition experiments have been conducted focusing on this fundamental soil process in order to understand the controls on the terrestrial carbon transfer to the atmosphere. However, previous studies were mostly based on site-specific litter and methodologies, adding major uncertainty to syntheses, comparisons and meta-analyses across different experiments and sites. In the TeaComposition initiative, the potential litter decomposition is investigated by using standardized substrates (Rooibos and Green tea) for comparison of litter mass loss at 336 sites (ranging fro