Consortium Proposal NFDI-MatWerk

This is the official proposal the NFDI-consortium NFDI-MatWerk submitted to the DFG within the request for funding the project. Visit www.dfg.de/nfdi for more infos on the German National Research Data Infrastructure (Nationale Forschungsdateninfrastruktur - NFDI) initiative. Visit www.nfdi-matwerk.de for last infos about the project NFDI-MatWerk

Comprehensive genomic profiles of small cell lung cancer

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer

Identification of novel fusion genes in lung cancer using breakpoint assembly of transcriptome sequencing data

Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification of such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suited RNA-seq Unified Pipeline) (https://github.com/ruping/TRUP), a computational approach that combines split-read and read-pair analysis with de novo assembly for the identification of chimeric transcripts in cancer specimens. We apply TRUP to RNA-seq data of different tumor types, and find it to be more sensitive than alternative tools in detecting chimeric transcripts, such as secondary rearrangements in EML4-ALK-positive lung tumors, or recurrent inactivating rearrangements affecting RASSF8

A large-scale genome-wide association study meta-analysis of cannabis use disorder

Summary Background Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10−9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10−9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10−21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.Peer reviewe

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 x 10(-13)) and African ancestries (rs2066702; P = 2.2 x 10(-9)). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.Peer reviewe

Die Ambivalenz der Emanzipation

My dissertation explores the ambiguous legacy of psychoanalysis by analyzing a number of sociological theories which prominently integrate Freudian concepts in the field of US sociology, post WWII. It is specifically interested in the gap that opens up between the physical encounter of the originally Frankfurt based Institute for Social Research and US sociology during the Institute’s American and the delayed reception of Critical Theory, its social-philosophical legacy, which begins in the late 1960s. In the context of my research interest, psychoanalysis functions as a common reference system of otherwise conflicting approaches. I ask for the critical potential of Freudian theory and trace theoretical and personal encounters in order to illuminate a period of conformity, challenges, and changes within the disciplinary field. The analysis is twofold. Following the conceptual framework of Bourdieuian field analysis, the first to chapters trace the instrumental dynamics of competitive struggles for symbolic capital and scientific authority in the fields of American psychology and US sociology, with regard to the integration of psychoanalysis. In both fields, processes of professionalization and scientification lead to disciplinary ‘golden ages’ in the 1950s and their eventual demise in the 1960s. My analysis eventually carves out the dialectical relation of professionalization processes and psychoanalysis’s inherent emancipatory promise and points to the complex entanglement of rationalization processes and societal relations of domination. Following, with reference to Ernesto Laclau, a definition of emancipation as necessarily radical, the third and fourth chapter investigate concrete adaptations of Freudian concepts in the works of critical theorists Erich Fromm, Herbert Marcuse, Theodor W. Adorno, and US sociologists Talcott Parsons, David Riesman, and Philip Rieff. The fifth and last chapter eventually offers an analysis of the explicit or implicit emancipatory potentials and essential convergences and divergences. The investigation finally picks up on Eva Illouz’s contemporary analysis of emotional capitalism, which critically identifies a ‘therapeutic narrative’ as the core of modern self-hood. My investigation makes its own normative directedness towards radical notions of emancipation explicit. It comes to the conclusion that the abandonment of Freudian drive theory becomes a crucial marker of psychoanalysis’s rationalization which is complicit in the formation of Illouz’s therapeutic narrative; however, instead of abandoning Freudian theory altogether it mobilizes Critical Theory’s negative emancipatory potential and argues, with Adorno and Marcuse, for a critical, and dialectical, re-appropriation of Freudian drive theory

Ageing response of an Al-Mg-Mn-Sc-Zr alloy processed by laser metal deposition in thin-wall structures

The use of aluminium alloys containing Sc and Zr in additive manufacturing (AM) provides new solutions for lightweight design. Representative thin-wall structured parts were additively fabricated with a commercially available Al-4.55Mg-0.51Mn-0.65Sc-0.30Zr alloy in Laser Metal Deposition (LMD) process. A bi-directional and a uni-directional scan strategy were applied and laser power from 500 W to 600 W was used. Nanohardness tests were conducted on specimens aged at 300 °C for up to 19 h to observe the ageing responses. Fine-grained microstructures with few micro-sized precipitates containing Sc- and Zr were found in the last track of every specimen. The area formed by the track-overlapping was the opposite, but an apparent hardening was observed only after the ageing. AM-processes with local remelting are facing the challenge to exert the potential strengthening effect of aluminium alloys containing Sc. The mushy state must be suppressed to prevent the waste of the expensive rare elements