@article{JanzWalzCirnuetal.2024, author = {Janz, Anna and Walz, Katharina and Cirnu, Alexandra and Surjanto, Jessica and Urlaub, Daniela and Leskien, Miriam and Kohlhaas, Michael and Nickel, Alexander and Brand, Theresa and Nose, Naoko and W{\"o}rsd{\"o}rfer, Philipp and Wagner, Nicole and Higuchi, Takahiro and Maack, Christoph and Dudek, Jan and Lorenz, Kristina and Klopocki, Eva and Erg{\"u}n, S{\"u}leyman and Duff, Henry J. and Gerull, Brenda}, title = {Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes}, series = {Molecular Metabolism}, volume = {79}, journal = {Molecular Metabolism}, issn = {2212-8778}, doi = {10.1016/j.molmet.2023.101859}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350393}, year = {2024}, abstract = {Highlights • Loss of DNAJC19's DnaJ domain disrupts cardiac mitochondrial structure, leading to abnormal cristae formation in iPSC-CMs. • Impaired mitochondrial structures lead to an increased mitochondrial respiration, ROS and an elevated membrane potential. • Mutant iPSC-CMs show sarcomere dysfunction and a trend to more arrhythmias, resembling DCMA-associated cardiomyopathy. Background Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. Methods We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca\(^{2+}\) kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tv\(_{HeLa}\)). Results Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca\(^{2+}\) concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation. Conclusions Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca\(^{2+}\) kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.}, language = {en} } @article{LodhaMuchsinJuergesetal.2023, author = {Lodha, Manivel and Muchsin, Ihsan and J{\"u}rges, Christopher and Juranic Lisnic, Vanda and L'Hernault, Anne and Rutkowski, Andrzej J. and Prusty, Bhupesh K. and Grothey, Arnhild and Milic, Andrea and Hennig, Thomas and Jonjic, Stipan and Friedel, Caroline C. and Erhard, Florian and D{\"o}lken, Lars}, title = {Decoding murine cytomegalovirus}, series = {PLOS Pathogens}, volume = {19}, journal = {PLOS Pathogens}, number = {5}, issn = {1553-7374}, doi = {10.1371/journal.ppat.1010992}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350480}, year = {2023}, abstract = {The genomes of both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) were first sequenced over 20 years ago. Similar to HCMV, the MCMV genome had initially been proposed to harbor ≈170 open reading frames (ORFs). More recently, omics approaches revealed HCMV gene expression to be substantially more complex comprising several hundred viral ORFs. Here, we provide a state-of-the art reannotation of lytic MCMV gene expression based on integrative analysis of a large set of omics data. Our data reveal 365 viral transcription start sites (TiSS) that give rise to 380 and 454 viral transcripts and ORFs, respectively. The latter include 200 small ORFs, some of which represented the most highly expressed viral gene products. By combining TiSS profiling with metabolic RNA labelling and chemical nucleotide conversion sequencing (dSLAM-seq), we provide a detailed picture of the expression kinetics of viral transcription. This not only resulted in the identification of a novel MCMV immediate early transcript encoding the m166.5 ORF, which we termed ie4, but also revealed a group of well-expressed viral transcripts that are induced later than canonical true late genes and contain an initiator element (Inr) but no TATA- or TATT-box in their core promoters. We show that viral upstream ORFs (uORFs) tune gene expression of longer viral ORFs expressed in cis at translational level. Finally, we identify a truncated isoform of the viral NK-cell immune evasin m145 arising from a viral TiSS downstream of the canonical m145 mRNA. Despite being ≈5-fold more abundantly expressed than the canonical m145 protein it was not required for downregulating the NK cell ligand, MULT-I. In summary, our work will pave the way for future mechanistic studies on previously unknown cytomegalovirus gene products in an important virus animal model.}, language = {en} } @article{CerezoEchevarriaKehlBeitzingeretal.2023, author = {Cerezo-Echevarria, Argi{\~n}e and Kehl, Alexandra and Beitzinger, Christoph and M{\"u}ller, Tobias and Klopfleisch, Robert and Aupperle-Lellbach, Heike}, title = {Evaluating the histologic grade of digital squamous cell carcinomas in dogs and copy number variation of KIT Ligand — a correlation study}, series = {Veterinary Sciences}, volume = {10}, journal = {Veterinary Sciences}, number = {2}, issn = {2306-7381}, doi = {10.3390/vetsci10020088}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304824}, year = {2023}, abstract = {Dark-haired dogs are predisposed to the development of digital squamous cell carcinoma (DSCC). This may potentially suggest an underlying genetic predisposition not yet completely elucidated. Some authors have suggested a potential correlation between the number of copies KIT Ligand (KITLG) and the predisposition of dogs to DSCC, containing a higher number of copies in those affected by the neoplasm. In this study, the aim was to evaluate a potential correlation between the number of copies of the KITLG and the histological grade of malignancy in dogs with DSCC. For this, 72 paraffin-embedded DSCCs with paired whole blood samples of 70 different dogs were included and grouped according to their haircoat color as follow: Group 0/unknown haircoat color (n = 11); Group 1.a/black non-Schnauzers (n = 15); group 1.b/black Schnauzers (n = 33); group 1.c/black and tan dogs (n = 7); group 2/tan animals (n = 4). The DSCCs were histologically graded. Additionally, KITLG Copy Number Variation (CNV) was determined by ddPCR. A significant correlation was observed between KITLG copy number and the histological grade and score value. This finding may suggest a possible factor for the development of canine DSCC, thus potentially having an impact on personalized veterinary oncological strategies and breeding programs.}, language = {en} } @article{SianHulsmannRiederer2021, author = {Sian-Hulsmann, Jeswinder and Riederer, Peter}, title = {The nigral coup in Parkinson's Disease by α-synuclein and its associated rebels}, series = {Cells}, volume = {10}, journal = {Cells}, number = {3}, issn = {2073-4409}, doi = {10.3390/cells10030598}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234073}, year = {2021}, abstract = {The risk of Parkinson's disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson's disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.}, language = {en} } @article{KuehnischHerbstAl‐Wakeel‐Marquardetal.2019, author = {K{\"u}hnisch, Jirko and Herbst, Christopher and Al-Wakeel-Marquard, Nadya and Dartsch, Josephine and Holtgrewe, Manuel and Baban, Anwar and Mearini, Giulia and Hardt, Juliane and Kolokotronis, Konstantinos and Gerull, Brenda and Carrier, Lucie and Beule, Dieter and Schubert, Stephan and Messroghli, Daniel and Degener, Franziska and Berger, Felix and Klaassen, Sabine}, title = {Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3}, series = {Clinical Genetics}, volume = {96}, journal = {Clinical Genetics}, number = {6}, doi = {10.1111/cge.13645}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213958}, pages = {549 -- 559}, year = {2019}, abstract = {The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next-generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38\%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.}, language = {en} } @article{GerullBrodehl2020, author = {Gerull, Brenda and Brodehl, Andreas}, title = {Genetic Animal Models for Arrhythmogenic Cardiomyopathy}, series = {Frontiers in Physiology}, volume = {11}, journal = {Frontiers in Physiology}, number = {264}, issn = {1664-042X}, doi = {10.3389/fphys.2020.00624}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206903}, year = {2020}, abstract = {Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell-cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.}, language = {en} } @article{MuellerGirardHopfneretal.2016, author = {M{\"u}ller, Stefanie H. and Girard, Simon L. and Hopfner, Franziska and Merner, Nancy D. and Bourassa, Cynthia V. and Lorenz, Delia and Clark, Lorraine N. and Tittmann, Lukas and Soto-Ortolaza, Alexandra I. and Klebe, Stephan and Hallett, Mark and Schneider, Susanne A. and Hodgkinson, Colin A. and Lieb, Wolfgang and Wszolek, Zbigniew K. and Pendziwiat, Manuela and Lorenzo-Betancor, Oswaldo and Poewe, Werner and Ortega-Cubero, Sara and Seppi, Klaus and Rajput, Alex and Hussl, Anna and Rajput, Ali H. and Berg, Daniela and Dion, Patrick A. and Wurster, Isabel and Shulman, Joshua M. and Srulijes, Karin and Haubenberger, Dietrich and Pastor, Pau and Vilari{\~n}o-G{\"u}ell, Carles and Postuma, Ronald B. and Bernard, Genevi{\`e}ve and Ladwig, Karl-Heinz and Dupr{\´e}, Nicolas and Jankovic, Joseph and Strauch, Konstantin and Panisset, Michel and Winkelmann, Juliane and Testa, Claudia M. and Reischl, Eva and Zeuner, Kirsten E. and Ross, Owen A. and Arzberger, Thomas and Chouinard, Sylvain and Deuschl, G{\"u}nther and Louis, Elan D. and Kuhlenb{\"a}umer, Gregor and Rouleau, Guy A.}, title = {Genome-wide association study in essential tremor identifies three new loci}, series = {Brain}, volume = {139}, journal = {Brain}, doi = {10.1093/brain/aww242}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186541}, pages = {3163-3169}, year = {2016}, abstract = {We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.}, language = {en} } @article{SadovnickTraboulseeBernalesetal.2016, author = {Sadovnick, A. Dessa and Traboulsee, Anthony L. and Bernales, Cecily Q. and Ross, Jay P. and Forwell, Amanda L. and Yee, Irene M. and Guillot-Noel, Lena and Fontaine, Bertrand and Cournu-Rebeix, Isabelle and Alcina, Antonio and Fedetz, Maria and Izquierdo, Guillermo and Matesanz, Fuencisla and Hilven, Kelly and Dubois, B{\´e}n{\´e}dicte and Goris, An and Astobiza, Ianire and Alloza, Iraide and Antig{\"u}edad, Alfredo and Vandenbroeck, Koen and Akkad, Denis A. and Aktas, Orhan and Blaschke, Paul and Buttmann, Mathias and Chan, Andrew and Epplen, Joerg T. and Gerdes, Lisa-Ann and Kroner, Antje and Kubisch, Christian and K{\"u}mpfel, Tania and Lohse, Peter and Rieckmann, Peter and Zettl, Uwe K. and Zipp, Frauke and Bertram, Lars and Lill, Christina M. and Fernandez, Oscar and Urbaneja, Patricia and Leyva, Laura and Alvarez-Cerme{\~n}o, Jose Carlos and Arroyo, Rafael and Garagorri, Aroa M. and Garc{\´i}a-Mart{\´i}nez, Angel and Villar, Luisa M. and Urcelay, Elena and Malhotra, Sunny and Montalban, Xavier and Comabella, Manuel and Berger, Thomas and Fazekas, Franz and Reindl, Markus and Schmied, Mascha C. and Zimprich, Alexander and Vilari{\~n}o-G{\"u}ell, Carles}, title = {Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients}, series = {G3: Genes Genomes Genetics}, volume = {6}, journal = {G3: Genes Genomes Genetics}, number = {7}, doi = {10.1534/g3.116.030841}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165405}, pages = {2073-2079}, year = {2016}, abstract = {Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95\% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.}, language = {en} } @article{VonaNandaShehataDieleretal.2017, author = {Vona, Barbara and Nanda, Indrajit and Shehata-Dieler, Wafaa and Haaf, Thomas}, title = {Genetics of Tinnitus: Still in its Infancy}, series = {Frontiers in Neuroscience}, volume = {11}, journal = {Frontiers in Neuroscience}, number = {236}, doi = {10.3389/fnins.2017.00236}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170926}, year = {2017}, abstract = {Tinnitus is the perception of a phantom sound that affects between 10 and 15\% of the general population. Despite this considerable prevalence, treatments for tinnitus are presently lacking. Tinnitus exhibits a diverse array of recognized risk factors and extreme clinical heterogeneity. Furthermore, it can involve an unknown number of auditory and non-auditory networks and molecular pathways. This complex combination has hampered advancements in the field. The identification of specific genetic factors has been at the forefront of several research investigations in the past decade. Nine studies have examined genes in a case-control association approach. Recently, a genome-wide association study has highlighted several potentially significant pathways that are implicated in tinnitus. Two twin studies have calculated a moderate heritability for tinnitus and disclosed a greater concordance rate in monozygotic twins compared to dizygotic twins. Despite the more recent data alluding to genetic factors in tinnitus, a strong association with any specific genetic locus is lacking and a genetic study with sufficient statistical power has yet to be designed. Future research endeavors must overcome the many inherent limitations in previous study designs. This review summarizes the previously embarked upon tinnitus genetic investigations and summarizes the hurdles that have been encountered. The identification of candidate genes responsible for tinnitus may afford gene based diagnostic approaches, effective therapy development, and personalized therapeutic intervention.}, language = {en} } @article{HofmannKarlSommeretal.2017, author = {Hofmann, Lukas and Karl, Franziska and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0180601}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170745}, pages = {e0180601}, year = {2017}, abstract = {Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the na{\"i}ve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in na{\"i}ve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and na{\"i}ve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors.}, language = {en} } @article{WaiderPoppLangeetal.2017, author = {Waider, J and Popp, S and Lange, MD and Kern, R and Kolter, JF and Kobler, J and Donner, NC and Lowe, KR and Malzbender, JH and Brazell, CJ and Arnold, MR and Aboagye, B and Schmitt-B{\"o}hrer, A and Lowry, CA and Pape, HC and Lesch, KP}, title = {Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice}, series = {Translational Psychiatry}, volume = {7}, journal = {Translational Psychiatry}, number = {e1246}, doi = {10.1038/tp.2017.209}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170239}, year = {2017}, abstract = {Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2\(^{-/-}\)) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph\(^{+/-}\)) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala.}, language = {en} } @article{VigoritoKuchenbaeckerBeesleyetal.2016, author = {Vigorito, Elena and Kuchenbaecker, Karoline B. and Beesley, Jonathan and Adlard, Julian and Agnarsson, Bjarni A. and Andrulis, Irene L. and Arun, Banu K. and Barjhoux, Laure and Belotti, Muriel and Benitez, Javier and Berger, Andreas and Bojesen, Anders and Bonanni, Bernardo and Brewer, Carole and Caldes, Trinidad and Caligo, Maria A. and Campbell, Ian and Chan, Salina B. and Claes, Kathleen B. M. and Cohn, David E. and Cook, Jackie and Daly, Mary B. and Damiola, Francesca and Davidson, Rosemarie and de Pauw, Antoine and Delnatte, Capucine and Diez, Orland and Domchek, Susan M. and Dumont, Martine and Durda, Katarzyna and Dworniczak, Bernd and Easton, Douglas F. and Eccles, Diana and Ardnor, Christina Edwinsdotter and Eeles, Ros and Ejlertsen, Bent and Ellis, Steve and Evans, D. Gareth and Feliubadalo, Lidia and Fostira, Florentia and Foulkes, William D. and Friedman, Eitan and Frost, Debra and Gaddam, Pragna and Ganz, Patricia A. and Garber, Judy and Garcia-Barberan, Vanesa and Gauthier-Villars, Marion and Gehrig, Andrea and Gerdes, Anne-Marie and Giraud, Sophie and Godwin, Andrew K. and Goldgar, David E. and Hake, Christopher R. and Hansen, Thomas V. O. and Healey, Sue and Hodgson, Shirley and Hogervorst, Frans B. L. and Houdayer, Claude and Hulick, Peter J. and Imyanitov, Evgeny N. and Isaacs, Claudine and Izatt, Louise and Izquierdo, Angel and Jacobs, Lauren and Jakubowska, Anna and Janavicius, Ramunas and Jaworska-Bieniek, Katarzyna and Jensen, Uffe Birk and John, Esther M. and Vijai, Joseph and Karlan, Beth Y. and Kast, Karin and Khan, Sofia and Kwong, Ava and Laitman, Yael and Lester, Jenny and Lesueur, Fabienne and Liljegren, Annelie and Lubinski, Jan and Mai, Phuong L. and Manoukian, Siranoush and Mazoyer, Sylvie and Meindl, Alfons and Mensenkamp, Arjen R. and Montagna, Marco and Nathanson, Katherine L. and Neuhausen, Susan L. and Nevanlinna, Heli and Niederacher, Dieter and Olah, Edith and Olopade, Olufunmilayo I. and Ong, Kai-ren and Osorio, Ana and Park, Sue Kyung and Paulsson-Karlsson, Ylva and Pedersen, Inge Sokilde and Peissel, Bernard and Peterlongo, Paolo and Pfeiler, Georg and Phelan, Catherine M. and Piedmonte, Marion and Poppe, Bruce and Pujana, Miquel Angel and Radice, Paolo and Rennert, Gad and Rodriguez, Gustavo C. and Rookus, Matti A. and Ross, Eric A. and Schmutzler, Rita Katharina and Simard, Jacques and Singer, Christian F. and Slavin, Thomas P. and Soucy, Penny and Southey, Melissa and Steinemann, Doris and Stoppa-Lyonnet, Dominique and Sukiennicki, Grzegorz and Sutter, Christian and Szabo, Csilla I. and Tea, Muy-Kheng and Teixeira, Manuel R. and Teo, Soo-Hwang and Terry, Mary Beth and Thomassen, Mads and Tibiletti, Maria Grazia and Tihomirova, Laima and Tognazzo, Silvia and van Rensburg, Elizabeth J. and Varesco, Liliana and Varon-Mateeva, Raymonda and Vratimos, Athanassios and Weitzel, Jeffrey N. and McGuffog, Lesley and Kirk, Judy and Toland, Amanda Ewart and Hamann, Ute and Lindor, Noralane and Ramus, Susan J. and Greene, Mark H. and Couch, Fergus J. and Offit, Kenneth and Pharoah, Paul D. P. and Chenevix-Trench, Georgia and Antoniou, Antonis C.}, title = {Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {7}, doi = {10.1371/journal.pone.0158801}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166869}, pages = {e0158801}, year = {2016}, abstract = {Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95\%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95\%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.}, language = {en} } @article{KuenstnerHoffmannFraseretal.2016, author = {K{\"u}nstner, Axel and Hoffmann, Margarete and Fraser, Bonnie A. and Kottler, Verena A. and Sharma, Eshita and Weigel, Detlef and Dreyer, Christine}, title = {The Genome of the Trinidadian Guppy, Poecilia reticulata, and Variation in the Guanapo Population}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {12}, doi = {10.1371/journal.pone.0169087}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166755}, pages = {e0169087}, year = {2016}, abstract = {For over a century, the live bearing guppy, Poecilia reticulata, has been used to study sexual selection as well as local adaptation. Natural guppy populations differ in many traits that are of intuitively adaptive significance such as ornamentation, age at maturity, brood size and body shape. Water depth, light supply, food resources and predation regime shape these traits, and barrier waterfalls often separate contrasting environments in the same river. We have assembled and annotated the genome of an inbred single female from a high-predation site in the Guanapo drainage. The final assembly comprises 731.6 Mb with a scaffold N50 of 5.3 MB. Scaffolds were mapped to linkage groups, placing 95\% of the genome assembly on the 22 autosomes and the X-chromosome. To investigate genetic variation in the population used for the genome assembly, we sequenced 10 wild caught male individuals. The identified 5 million SNPs correspond to an average nucleotide diversity (π) of 0.0025. The genome assembly and SNP map provide a rich resource for investigating adaptation to different predation regimes. In addition, comparisons with the genomes of other Poeciliid species, which differ greatly in mechanisms of sex determination and maternal resource allocation, as well as comparisons to other teleost genera can begin to reveal how live bearing evolved in teleost fish.}, language = {en} } @article{IslesIngasonLowtheretal.2016, author = {Isles, Anthony R. and Ingason, Andr{\´e}s and Lowther, Chelsea and Walters, James and Gawlick, Micha and St{\"o}ber, Gerald and Rees, Elliott and Martin, Joanna and Little, Rosie B. and Potter, Harry and Georgieva, Lyudmila and Pizzo, Lucilla and Ozaki, Norio and Aleksic, Branko and Kushima, Itaru and Ikeda, Masashi and Iwata, Nakao and Levinson, Douglas F. and Gejman, Pablo V. and Shi, Jianxin and Sanders, Alan R. and Duan, Jubao and Willis, Joseph and Sisodiya, Sanjay and Costain, Gregory and Werge, Thomas M. and Degenhardt, Franziska and Giegling, Ina and Rujescu, Dan and Hreidarsson, Stefan J. and Saemundsen, Evald and Ahn, Joo Wook and Ogilvie, Caroline and Girirajan, Santhosh D. and Stefansson, Hreinn and Stefansson, Kari and O'Donovan, Michael C. and Owen, Michael J. and Bassett, Anne and Kirov, George}, title = {Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders}, series = {PLoS Genetics}, volume = {12}, journal = {PLoS Genetics}, number = {5}, doi = {10.1371/journal.pgen.1005993}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166706}, pages = {e1005993}, year = {2016}, abstract = {Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76\% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033\% compared to 0.0069\% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50\% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.}, language = {en} } @article{AppelScholzMuelleretal.2015, author = {Appel, Mirjam and Scholz, Claus-J{\"u}rgen and M{\"u}ller, Tobias and Dittrich, Marcus and K{\"o}nig, Christian and Bockstaller, Marie and Oguz, Tuba and Khalili, Afshin and Antwi-Adjei, Emmanuel and Schauer, Tamas and Margulies, Carla and Tanimoto, Hiromu and Yarali, Ayse}, title = {Genome-Wide Association Analyses Point to Candidate Genes for Electric Shock Avoidance in Drosophila melanogaster}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0126986}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-152006}, pages = {e0126986}, year = {2015}, abstract = {Electric shock is a common stimulus for nociception-research and the most widely used reinforcement in aversive associative learning experiments. Yet, nothing is known about the mechanisms it recruits at the periphery. To help fill this gap, we undertook a genome-wide association analysis using 38 inbred Drosophila melanogaster strains, which avoided shock to varying extents. We identified 514 genes whose expression levels and/or sequences covaried with shock avoidance scores. We independently scrutinized 14 of these genes using mutants, validating the effect of 7 of them on shock avoidance. This emphasizes the value of our candidate gene list as a guide for follow-up research. In addition, by integrating our association results with external protein-protein interaction data we obtained a shock avoidance- associated network of 38 genes. Both this network and the original candidate list contained a substantial number of genes that affect mechanosensory bristles, which are hairlike organs distributed across the fly's body. These results may point to a potential role for mechanosensory bristles in shock sensation. Thus, we not only provide a first list of candidate genes for shock avoidance, but also point to an interesting new hypothesis on nociceptive mechanisms.}, language = {en} } @article{BauneKonradGrotegerdetal.2012, author = {Baune, Bernhard T. and Konrad, Carsten and Grotegerd, Dominik and Suslow, Thomas and Birosova, Eva and Ohrmann, Patricia and Bauer, Jochen and Arolt, Volker and Heindel, Walter and Domschke, Katharina and Sch{\"o}ning, Sonja and Rauch, Astrid V. and Uhlmann, Christina and Kugel, Harald and Dannlowski, Udo}, title = {Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain}, series = {Journal of Neuroinflammation}, volume = {9}, journal = {Journal of Neuroinflammation}, number = {125}, doi = {10.1186/1742-2094-9-125}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130804}, year = {2012}, abstract = {Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e. g., Stampa algorigthm), yielding a capture 97.08\% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results In a whole-brain analysis, the polymorphism rs1800795 (-174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = -10, z = -15; F(2,286) = 8.54, p(uncorrected) = 0.0002; p(AlphaSim-corrected) = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.}, language = {en} } @article{ConzelmannReifJacobetal.2012, author = {Conzelmann, Annette and Reif, Andreas and Jacob, Christian and Weyers, Peter and Lesch, Klaus-Peter and Lutz, Beat and Pauli, Paul}, title = {A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity}, series = {Psychopharmacology}, volume = {224}, journal = {Psychopharmacology}, number = {4}, doi = {10.1007/s00213-012-2785-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129936}, pages = {573-579}, year = {2012}, abstract = {Rationale The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. Objectives Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. Methods We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. Results Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. Conclusions Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.}, language = {en} } @article{ConzelmannReifJacobetal.2012, author = {Conzelmann, Annette and Reif, Andreas and Jacob, Christian and Weyers, Peter and Lesch, Klaus-Peter and Lutz, Beat and Pauli, Paul}, title = {A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity}, series = {Psychopharmacology}, volume = {224}, journal = {Psychopharmacology}, number = {4}, doi = {10.1007/s00213-012-2785-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126845}, pages = {573-579}, year = {2012}, abstract = {RATIONALE: The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. OBJECTIVES: Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. METHODS: We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. RESULTS: Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. CONCLUSIONS: Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.}, language = {en} } @article{HarrisonClausJiangetal.2013, author = {Harrison, Odile B. and Claus, Heike and Jiang, Ying and Bennett, Julia S. and Bratcher, Holly B. and Jolley, Keith A. and Corton, Craig and Care, Rory and Poolman, Jan T. and Zollinger, Wendell D. and Frasch, Carl E. and Stephens, David S. and Feavers, Ian and Frosch, Matthias and Parkhill, Julian and Vogel, Ulrich and Quail, Michael A. and Bentley, Stephen D. and Maiden, Martin C. J.}, title = {Description and Nomenclature of Neisseria meningitidis Capsule Locus}, series = {Emerging Infectious Diseases}, volume = {19}, journal = {Emerging Infectious Diseases}, number = {4}, doi = {10.3201/eid1904.111799}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131703}, pages = {566-573}, year = {2013}, abstract = {Pathogenic Neisseria meningitidis isolates contain a polysaccharide capsule that is the main virulence determinant for this bacterium. Thirteen capsular polysaccharides have been described, and nuclear magnetic resonance spectroscopy has enabled determination of the structure of capsular polysaccharides responsible for serogroup specificity. Molecular mechanisms involved in N. meningitidis capsule biosynthesis have also been identified, and genes involved in this process and in cell surface translocation are clustered at a single chromosomal locus termed cps. The use of multiple names for some of the genes involved in capsule synthesis, combined with the need for rapid diagnosis of serogroups commonly associated with invasive meningococcal disease, prompted a requirement for a consistent approach to the nomenclature of capsule genes. In this report, a comprehensive description of all N. meningitidis serogroups is provided, along with a proposed nomenclature, which was presented at the 2012 XVIIIth International Pathogenic Neisseria Conference.}, language = {en} } @article{DoerhoeferLammertKraneetal.2013, author = {D{\"o}rh{\"o}fer, Lena and Lammert, Alexander and Krane, Vera and Gorski, Mathias and Banas, Bernhard and Wanner, Christoph and Kr{\"a}mer, Bernhard K. and Heid, Iris M. and B{\"o}ger, Carsten A.}, title = {Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2}, series = {BMC Medical Genetics}, volume = {14}, journal = {BMC Medical Genetics}, number = {25}, issn = {1471-2350}, doi = {10.1186/1471-2350-14-25}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122040}, year = {2013}, abstract = {Background: Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE). Methods: DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro-and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e. g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness. Discussion: DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.}, language = {en} } @article{BremGruenblattDrechsleretal.2014, author = {Brem, Silvia and Gr{\"u}nblatt, Edna and Drechsler, Renate and Riederer, Peter and Walitza, Susanne}, title = {The neurobiological link between OCD and ADHD}, series = {Attention Deficit and Hyperactivity Disorders}, volume = {6}, journal = {Attention Deficit and Hyperactivity Disorders}, number = {3}, doi = {10.1007/s12402-014-0146-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121312}, pages = {175-202}, year = {2014}, abstract = {Obsessive compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) are two of the most common neuropsychiatric diseases in paediatric populations. The high comorbidity of ADHD and OCD with each other, especially of ADHD in paediatric OCD, is well described. OCD and ADHD often follow a chronic course with persistent rates of at least 40-50 \%. Family studies showed high heritability in ADHD and OCD, and some genetic findings showed similar variants for both disorders of the same pathogenetic mechanisms, whereas other genetic findings may differentiate between ADHD and OCD. Neuropsychological and neuroimaging studies suggest that partly similar executive functions are affected in both disorders. The deficits in the corresponding brain networks may be responsible for the perseverative, compulsive symptoms in OCD but also for the disinhibited and impulsive symptoms characterizing ADHD. This article reviews the current literature of neuroimaging, neurochemical circuitry, neuropsychological and genetic findings considering similarities as well as differences between OCD and ADHD.}, language = {en} } @article{BoelchJansenMeffertetal.2015, author = {Boelch, S. P. and Jansen, H. and Meffert, R. H. and Frey, S. P.}, title = {Six Sesamoid Bones on Both Feet: Report of a Rare Case}, series = {Journal of Clinical and Diagnostic Research}, volume = {9}, journal = {Journal of Clinical and Diagnostic Research}, number = {8}, doi = {10.7860/JCDR/2015/12842.6394}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126073}, pages = {RD04-RD05}, year = {2015}, abstract = {There is a variation of the total number of distinct bones in the human in the literature. This difference is mainly caused by the variable existence of sesamoid bones. Sesamoid bones at the first MTP are seen regularly. In contrast additional sesamoid bones at the divond to fifth MTP are rare. We report a case of additional sesamoid bones at every metatarsophalangeal joint (MTP) of both feet. A 22-year-old female Caucasian presented with weight-dependent pain of the divond MTP of the left foot. In the radiographs of both feet additional sesamoid bones at every MTP could be seen. This case reports a very rare variation in human anatomy. A similar case has not been displayed to the academic society and therefore should be acknowledged.}, language = {en} } @article{MergetKoetschanHackletal.2012, author = {Merget, Benjamin and Koetschan, Christian and Hackl, Thomas and F{\"o}rster, Frank and Dandekar, Thomas and M{\"u}ller, Tobias and Schultz, J{\"o}rg and Wolf, Matthias}, title = {The ITS2 Database}, series = {Journal of Visual Expression}, volume = {61}, journal = {Journal of Visual Expression}, number = {e3806}, doi = {10.3791/3806}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124600}, year = {2012}, abstract = {The internal transcribed spacer 2 (ITS2) has been used as a phylogenetic marker for more than two decades. As ITS2 research mainly focused on the very variable ITS2 sequence, it confined this marker to low-level phylogenetics only. However, the combination of the ITS2 sequence and its highly conserved secondary structure improves the phylogenetic resolution1 and allows phylogenetic inference at multiple taxonomic ranks, including species delimitation. The ITS2 Database presents an exhaustive dataset of internal transcribed spacer 2 sequences from NCBI GenBank accurately reannotated. Following an annotation by profile Hidden Markov Models (HMMs), the secondary structure of each sequence is predicted. First, it is tested whether a minimum energy based fold (direct fold) results in a correct, four helix conformation. If this is not the case, the structure is predicted by homology modeling. In homology modeling, an already known secondary structure is transferred to another ITS2 sequence, whose secondary structure was not able to fold correctly in a direct fold. The ITS2 Database is not only a database for storage and retrieval of ITS2 sequence-structures. It also provides several tools to process your own ITS2 sequences, including annotation, structural prediction, motif detection and BLAST search on the combined sequence-structure information. Moreover, it integrates trimmed versions of 4SALE and ProfDistS for multiple sequence-structure alignment calculation and Neighbor Joining tree reconstruction. Together they form a coherent analysis pipeline from an initial set of sequences to a phylogeny based on sequence and secondary structure. In a nutshell, this workbench simplifies first phylogenetic analyses to only a few mouse-clicks, while additionally providing tools and data for comprehensive large-scale analyses.}, language = {en} } @article{PoethkePfenningHovestadt2007, author = {Poethke, Hans J. and Pfenning, Brenda and Hovestadt, Thomas}, title = {The relative contribution of individual and kin selection to the evolution of density-dependent dispersal rates}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-48225}, year = {2007}, abstract = {Questions: What are the relative contributions of kin selection and individual selection to the evolution of dispersal rates in fragmented landscapes? How do environmental parameters influence the relative contributions of both evolutionary forces? Features of the model: Individual-based simulation model of a metapopulation. Logistic local growth dynamics and density-dependent dispersal. An optional shuffling algorithm allows the continuous destruction of any genetic structure in the metapopulation. Ranges of key variables: Depending on dispersal mortality (0.05-0.4) and the strength of environmental fluctuations, mean dispersal probability varied between 0.05 and 0.5. Conclusions: For local population sizes of 100 individuals, kin selection alone could account for dispersal probabilities of up to 0.1. It may result in a ten-fold increase of optimal dispersal rates compared with those predicted on the basis of individual selection alone. Such a substantial contribution of kin selection to dispersal is restricted to cases where the overall dispersal probabilities are small (textless 0.1). In the latter case, as much as 30\% of the total fitness of dispersing individuals could arise from the increased reproduction of kin left in the natal patch.}, language = {en} }