@article{NickersonAtalagdeBonoetal.2016, author = {Nickerson, David and Atalag, Koray and de Bono, Bernard and Geiger, J{\"o}rg and Goble, Carole and Hollmann, Susanne and Lonien, Joachim and M{\"u}ller, Wolfgang and Regierer, Babette and Stanford, Natalie J. and Golebiewski, Martin and Hunter, Peter}, title = {The Human Physiome: how standards, software and innovative service infrastructures are providing the building blocks to make it achievable}, series = {Interface Focus}, volume = {6}, journal = {Interface Focus}, number = {2}, doi = {10.1098/rsfs.2015.0103}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189584}, pages = {13 Seiten}, year = {2016}, abstract = {Reconstructing and understanding the Human Physiome virtually is a complex mathematical problem, and a highly demanding computational challenge. Mathematical models spanning from the molecular level through to whole populations of individuals must be integrated, then personalized. This requires interoperability with multiple disparate and geographically separated data sources, and myriad computational software tools. Extracting and producing knowledge from such sources, even when the databases and software are readily available, is a challenging task. Despite the difficulties, researchers must frequently perform these tasks so that available knowledge can be continually integrated into the common framework required to realize the Human Physiome. Software and infrastructures that support the communities that generate these, together with their underlying standards to format, describe and interlink the corresponding data and computer models, are pivotal to the Human Physiome being realized. They provide the foundations for integrating, exchanging and re-using data and models efficiently, and correctly, while also supporting the dissemination of growing knowledge in these forms. In this paper, we explore the standards, software tooling, repositories and infrastructures that support this work, and detail what makes them vital to realizing the Human Physiome.}, language = {en} } @article{Kuemmel2016, author = {K{\"u}mmel, Reiner}, title = {The Impact of Entropy Production and Emission Mitigation on Economic Growth}, series = {Entropy}, volume = {18}, journal = {Entropy}, number = {3}, doi = {10.3390/e18030075}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-163185}, pages = {75}, year = {2016}, abstract = {Entropy production in industrial economies involves heat currents, driven by gradients of temperature, and particle currents, driven by specific external forces and gradients of temperature and chemical potentials. Pollution functions are constructed for the associated emissions. They reduce the output elasticities of the production factors capital, labor, and energy in the growth equation of the capital-labor-energy-creativity model, when the emissions approach their critical limits. These are drawn by, e.g., health hazards or threats to ecological and climate stability. By definition, the limits oblige the economic actors to dedicate shares of the available production factors to emission mitigation, or to adjustments to the emission-induced changes in the biosphere. Since these shares are missing for the production of the quantity of goods and services that would be available to consumers and investors without emission mitigation, the "conventional" output of the economy shrinks. The resulting losses of conventional output are estimated for two classes of scenarios: (1) energy conservation; and (2) nuclear exit and subsidies to photovoltaics. The data of the scenarios refer to Germany in the 1980s and after 11 March 2011. For the energy-conservation scenarios, a method of computing the reduction of output elasticities by emission abatement is proposed.}, language = {en} } @article{KurabiPakBernhardtetal.2016, author = {Kurabi, Arwa and Pak, Kwang K. and Bernhardt, Marlen and Baird, Andrew and Ryan, Allen F.}, title = {Discovery of a Biological Mechanism of Active Transport through the Tympanic Membrane to the Middle Ear}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {22663}, doi = {10.1038/srep22663}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167741}, year = {2016}, abstract = {Otitis media (OM) is a common pediatric disease for which systemic antibiotics are often prescribed. While local treatment would avoid the systemic treatment side-effects, the tympanic membrane (TM) represents an impenetrable barrier unless surgically breached. We hypothesized that the TM might harbor innate biological mechanisms that could mediate trans-TM transport. We used two M13-bacteriophage display biopanning strategies to search for mediators of trans-TM transport. First, aliquots of linear phage library displaying 10\(^{10th}\) 12mer peptides were applied on the TM of rats with active bacterial OM. The middle ear (ME) contents were then harvested, amplified and the preparation re-applied for additional rounds. Second, the same na{\"i}ve library was sequentially screened for phage exhibiting TM binding, internalization and then transit. Results revealed a novel set of peptides that transit across the TM to the ME in a time and temperature dependent manner. The peptides with highest transport capacities shared sequence similarities. Historically, the TM was viewed as an impermeable barrier. However, our studies reveal that it is possible to translocate peptide-linked small particles across the TM. This is the first comprehensive biopanning for the isolation of TM transiting peptidic ligands. The identified mechanism offers a new drug delivery platform into the ME.}, language = {en} } @article{KuntzenKuhnKuntzenetal.2016, author = {Kuntzen, Thomas and Kuhn, Sereina and Kuntzen, Daniela and Seifert, Burkhardt and M{\"u}llhaupt, Beat and Geier, Andreas}, title = {Influence of Ribavirin Serum Levels on Outcome of Antiviral Treatment and Anemia in Hepatitis C Virus Infection}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {7}, doi = {10.1371/journal.pone.0158512}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166888}, pages = {e0158512}, year = {2016}, abstract = {Background Ribavirin blood levels vary considerably between patients with standard weight-based dosing. Their impact on sustained virological response (SVR) with pegylated interferon and ribavirin is controversial, but has mostly been studied before the IL28b gene polymorphism as a possible confounder was discovered. Methods The impact of serum ribavirin trough levels at week 4, at the end of treatment and of mean levels across the entire antiviral treatment with pegylated interferon and ribavirin on relapse, SVR rates and anemia was retrospectively studied by univariate and multivariable logistic regression analyses in 214 patients with HCV genotype 1-4 infection, including 88 patients with available IL28b genotyping. Results Mean ribavirin levels varied between 0.68-5.65 mg/l and significantly differed between patients with or without SVR. By multivariable regression including age, sex, HCV viral load, HCV genotype, liver fibrosis stage, prior treatments, immunosuppression and IL28b genotype, ribavirin levels consistently displayed significant influence on SVR and relapse without indication for a specific importance of higher concentrations early or late in the treatment course. Although hemoglobin decline was on average more pronounced in patients with higher ribavirin levels, hemoglobin remained relatively stable in a significant proportion of these, indicating that ribavirin levels alone are insufficient to predict anemia. Conclusion While data are scarce to draw conclusions applicable for modern DAA therapies, these results support ribavirin treatment based on serum levels instead of purely weight-based dosing in combination with pegylated interferon.}, language = {en} } @article{LousadaSorokaYagodzinskyyetal.2016, author = {Lousada, Cl{\´a}udio M. and Soroka, Inna L. and Yagodzinskyy, Yuriy and Tarakina, Nadezda V. and Todoshchenko, Olga and H{\"a}nninen, Hannu and Korzhavyi, Pavel A. and Jonsson, Mats}, title = {Gamma radiation induces hydrogen absorption by copper in water}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {24234}, doi = {10.1038/srep24234}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167730}, year = {2016}, abstract = {One of the most intricate issues of nuclear power is the long-term safety of repositories for radioactive waste. These repositories can have an impact on future generations for a period of time orders of magnitude longer than any known civilization. Several countries have considered copper as an outer corrosion barrier for canisters containing spent nuclear fuel. Among the many processes that must be considered in the safety assessments, radiation induced processes constitute a key-component. Here we show that copper metal immersed in water uptakes considerable amounts of hydrogen when exposed to γ-radiation. Additionally we show that the amount of hydrogen absorbed by copper depends on the total dose of radiation. At a dose of 69 kGy the uptake of hydrogen by metallic copper is 7 orders of magnitude higher than when the absorption is driven by H\(_{2}\)(g) at a pressure of 1 atm in a non-irradiated dry system. Moreover, irradiation of copper in water causes corrosion of the metal and the formation of a variety of surface cavities, nanoparticle deposits, and islands of needle-shaped crystals. Hence, radiation enhanced uptake of hydrogen by spent nuclear fuel encapsulating materials should be taken into account in the safety assessments of nuclear waste repositories.}, language = {en} } @article{MaaroufNeudorferElMajdoubetal.2016, author = {Maarouf, Mohammad and Neudorfer, Clemens and El Majdoub, Faycal and Lenartz, Doris and Kuhn, Jens and Sturm, Volker}, title = {Deep Brain Stimulation of Medial Dorsal and Ventral Anterior Nucleus of the Thalamus in OCD: A Retrospective Case Series}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0160750}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166830}, pages = {e0160750}, year = {2016}, abstract = {Background The current notion that cortico-striato-thalamo-cortical circuits are involved in the pathophysiology of obsessive-compulsive disorder (OCD) has instigated the search for the most suitable target for deep brain stimulation (DBS). However, despite extensive research, uncertainty about the ideal target remains with many structures being underexplored. The aim of this report is to address a new target for DBS, the medial dorsal (MD) and the ventral anterior (VA) nucleus of the thalamus, which has thus far received little attention in the treatment of OCD. Methods In this retrospective trial, four patients (three female, one male) aged 31-48 years, suffering from therapy-refractory OCD underwent high-frequency DBS of the MD and VA. In two patients (de novo group) the thalamus was chosen as a primary target for DBS, whereas in two patients (rescue DBS group) lead implantation was performed in a rescue DBS attempt following unsuccessful primary stimulation. Results Continuous thalamic stimulation yielded no significant improvement in OCD symptom severity. Over the course of thalamic DBS symptoms improved in only one patient who showed "partial response" on the Yale-Brown Obsessive Compulsive (Y-BOCS) Scale. Beck Depression Inventory scores dropped by around 46\% in the de novo group; anxiety symptoms improved by up to 34\%. In the de novo DBS group no effect of DBS on anxiety and mood was observable. Conclusion MD/VA-DBS yielded no adequate alleviation of therapy-refractory OCD, the overall strategy in targeting MD/VA as described in this paper can thus not be recommended in DBS for OCD. The magnocellular portion of MD (MDMC), however, might prove a promising target in the treatment of mood related and anxiety disorders.}, language = {en} } @article{HellenbrandClausSchinketal.2016, author = {Hellenbrand, Wiebke and Claus, Heike and Schink, Susanne and Marcus, Ulrich and Wichmann, Ole and Vogel, Ulrich}, title = {Risk of Invasive Meningococcal Disease in Men Who Have Sex with Men: Lessons Learned from an Outbreak in Germany, 2012-2013}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0160126}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166842}, pages = {e0160126}, year = {2016}, abstract = {Background We undertook investigations in response to an invasive meningococcal disease (IMD) outbreak in men who have sex with men (MSM) in Berlin 2012-2013 to better understand meningococcal transmission and IMD risk in MSM. Methods We retrospectively searched for further IMD cases in MSM in Germany through local health departments and undertook exploratory interviews. We performed antigen sequence typing, characterized fHbp and aniA genes of strains with the outbreak finetype and reviewed epidemiologically or spatiotemporally linked cases from 2002-2014. Results Among the 148 IMD-cases notified from 01.01.2012-30.09.2013 in 18-59 year-old men we identified 13 MSM in 6 federal states: 11 serogroup C (MenC, all finetype C:P1.5-1,10-8:F3-6), 2 MenB. Interviews with 7 MSM revealed frequent meeting of multiple partners online or via mobile apps and illicit drug use as potential risk factors. MenC incidence was 13-fold higher in MSM than non-MSM. MenC isolates from 9/11 MSM had a novel fHbp allele 766. All C:P1.5-1,10-8:F3-6 strains from MSM versus 16/23 from non-MSM had intact aniA genes (p = 0.04). Although definitive evidence for transmission among MSM in epidemiological or spatiotemporal clusters in 2002-2014 was lacking, clusters were more frequent in men aged 20-49 years. Molecular analysis of C:P1.5-1,10-8:F3-6 strains revealed cases with intact aniA since 2007, mainly associated with fHbp361, fHbp766 and fHbp813, all involving one or more MSM. Conclusions MenC incidence was elevated in MSM during the study period. Multiple casual sexual contacts and illicit drug use were common in affected MSM. In all strains from MSM we detected an intact aniA gene coding for a nitrite reductase, which permits survival in microanaerobic environments and could play a role in meningococcal transmission in MSM through urogenital colonization. Furthermore, meningococcal transmission among MSM may be sustained over large areas and thus require modified spatiotemporal scanning algorithms for timely detection and control.}, language = {en} } @article{MeierKruseButtlaretal.2016, author = {Meier, Doreen and Kruse, Janis and Buttlar, Jann and Friedrich, Michael and Zenk, Fides and Boesler, Benjamin and Forstner, Konrad U. and Hammann, Christian and Nellen, Wolfgang}, title = {Analysis of the Microprocessor in Dictyostelium: The Role of RbdB, a dsRNA Binding Protein}, series = {PLoS Genetics}, volume = {12}, journal = {PLoS Genetics}, number = {6}, doi = {10.1371/journal.pgen.1006057}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166687}, pages = {e1006057}, year = {2016}, abstract = {We identified the dsRNA binding protein RbdB as an essential component in miRNA processing in Dictyostelium discoideum. RbdB is a nuclear protein that accumulates, together with Dicer B, in nucleolar foci reminiscent of plant dicing bodies. Disruption of rbdB results in loss of miRNAs and accumulation of primary miRNAs. The phenotype can be rescued by ectopic expression of RbdB thus allowing for a detailed analysis of domain function. The lack of cytoplasmic dsRBD proteins involved in miRNA processing, suggests that both processing steps take place in the nucleus thus resembling the plant pathway. However, we also find features e.g. in the domain structure of Dicer which suggest similarities to animals. Reduction of miRNAs in the rbdB- strain and their increase in the Argonaute A knock out allowed the definition of new miRNAs one of which appears to belong to a new non-canonical class.}, language = {en} } @article{GoekbugetKelshChiaetal.2016, author = {G{\"o}kbuget, N. and Kelsh, M. and Chia, V. and Advani, A. and Bassan, R. and Dombret, H. and Doubek, M. and Fielding, A. K. and Giebel, S. and Haddad, V. and Hoelzer, D. and Holland, C. and Ifrah, N. and Katz, A. and Maniar, T. and Martinelli, G. and Morgades, M. and O'Brien, S. and Ribera, J.-M. and Rowe, J. M. and Stein, A. and Topp, M. and Wadleigh, M. and Kantarjian, H.}, title = {Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia}, series = {Blood Cancer Journal}, volume = {6}, journal = {Blood Cancer Journal}, doi = {10.1038/bcj.2016.84}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164495}, pages = {e473}, year = {2016}, abstract = {We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24\% (95\% CI: 20-27\%) and a median OS of 3.3 months (95\% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43\% (95\% CI: 36-50\%) and a median OS of 6.1 months (95\% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95\% CI: 1.67-4.31) and improved OS (HR=0.536, 95\% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.}, language = {en} } @article{KleberChenMichelsetal.2016, author = {Kleber, J{\"o}rg and Chen, Yi-Chun and Michels, Birgit and Saumweber, Timo and Schleyer, Michael and K{\"a}hne, Thilo and Buchner, Erich and Gerber, Bertram}, title = {Synapsin is required to "boost" memory strength for highly salient events}, series = {Learning and Memory}, volume = {23}, journal = {Learning and Memory}, number = {1}, doi = {10.1101/lm.039685.115}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191440}, pages = {9-20}, year = {2016}, abstract = {Synapsin is an evolutionarily conserved presynaptic phosphoprotein. It is encoded by only one gene in the Drosophila genome and is expressed throughout the nervous system. It regulates the balance between reserve and releasable vesicles, is required to maintain transmission upon heavy demand, and is essential for proper memory function at the behavioral level. Task-relevant sensorimotor functions, however, remain intact in the absence of Synapsin. Using an odor-sugar reward associative learning paradigm in larval Drosophila, we show that memory scores in mutants lacking Synapsin (syn\(^{97}\)) are lower than in wild-type animals only when more salient, higher concentrations of odor or of the sugar reward are used. Furthermore, we show that Synapsin is selectively required for larval short-term memory. Thus, without Synapsin Drosophila larvae can learn and remember, but Synapsin is required to form memories that match in strength to event salience-in particular to a high saliency of odors, of rewards, or the salient recency of an event. We further show that the residual memory scores upon a lack of Synapsin are not further decreased by an additional lack of the Sap47 protein. In combination with mass spectrometry data showing an up-regulated phosphorylation of Synapsin in the larval nervous system upon a lack of Sap47, this is suggestive of a functional interdependence of Synapsin and Sap47.}, language = {en} } @article{ZayatsJacobsenKleppeetal.2016, author = {Zayats, T and Jacobsen, KK and Kleppe, R and Jacob, CP and Kittel-Schneider, S and Ribas{\´e}s, M and Ramos-Quiroga, JA and Richarte, V and Casas, M and Mota, NR and Grevet, EH and Klein, M and Corominas, J and Bralten, J and Galesloot, T and Vasquez, AA and Herms, S and Forstner, AJ and Larsson, H and Breen, G and Asherson, P and Gross-Lesch, S and Lesch, KP and Cichon, S and Gabrielsen, MB and Holmen, OL and Bau, CHD and Buitelaar, J and Kiemeney, L and Faraone, SV and Cormand, B and Franke, B and Reif, A and Haavik, J and Johansson, S}, title = {Exome chip analyses in adult attention deficit hyperactivity disorder}, series = {Translational Psychiatry}, volume = {6}, journal = {Translational Psychiatry}, number = {e923}, doi = {10.1038/tp.2016.196}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168297}, year = {2016}, abstract = {Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1\%); (2) single marker association tests of common variants (MAF⩾1\%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.}, language = {en} } @article{JahnMarkertRyuetal.2016, author = {Jahn, Martin T. and Markert, Sebastian M. and Ryu, Taewoo and Ravasi, Timothy and Stigloher, Christian and Hentschel, Ute and Moitinho-Silva, Lucas}, title = {Shedding light on cell compartmentation in the candidate phylum Poribacteria by high resolution visualisation and transcriptional profiling}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {35860}, doi = {10.1038/srep35860}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167513}, year = {2016}, abstract = {Assigning functions to uncultivated environmental microorganisms continues to be a challenging endeavour. Here, we present a new microscopy protocol for fluorescence in situ hybridisation-correlative light and electron microscopy (FISH-CLEM) that enabled, to our knowledge for the first time, the identification of single cells within their complex microenvironment at electron microscopy resolution. Members of the candidate phylum Poribacteria, common and uncultivated symbionts of marine sponges, were used towards this goal. Cellular 3D reconstructions revealed bipolar, spherical granules of low electron density, which likely represent carbon reserves. Poribacterial activity profiles were retrieved from prokaryotic enriched sponge metatranscriptomes using simulation-based optimised mapping. We observed high transcriptional activity for proteins related to bacterial microcompartments (BMC) and we resolved their subcellular localisation by combining FISH-CLEM with immunohistochemistry (IHC) on ultra-thin sponge tissue sections. In terms of functional relevance, we propose that the BMC-A region may be involved in 1,2-propanediol degradation. The FISH-IHC-CLEM approach was proven an effective toolkit to combine -omics approaches with functional studies and it should be widely applicable in environmental microbiology.}, language = {en} } @article{PlumSteinbachAttemsetal.2016, author = {Plum, Sarah and Steinbach, Simone and Attems, Johannes and Keers, Sharon and Riederer, Peter and Gerlach, Manfred and May, Caroline and Marcus, Katrin}, title = {Proteomic characterization of neuromelanin granules isolated from human substantia nigra by laser-microdissection}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {37139}, doi = {10.1038/srep37139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167507}, year = {2016}, abstract = {Neuromelanin is a complex polymer pigment found primarily in the dopaminergic neurons of human substantia nigra. Neuromelanin pigment is stored in granules including a protein matrix and lipid droplets. Neuromelanin granules are yet only partially characterised regarding their structure and function. To clarify the exact function of neuromelanin granules in humans, their enrichment and in-depth characterization from human substantia nigra is necessary. Previously published global proteome studies of neuromelanin granules in human substantia nigra required high tissue amounts. Due to the limited availability of human brain tissue we established a new method based on laser microdissection combined with mass spectrometry for the isolation and analysis of neuromelanin granules. With this method it is possible for the first time to isolate a sufficient amount of neuromelanin granules for global proteomics analysis from ten 10 μm tissue sections. In total 1,000 proteins were identified associated with neuromelanin granules. More than 68\% of those proteins were also identified in previously performed studies. Our results confirm and further extend previously described findings, supporting the connection of neuromelanin granules to iron homeostasis and lysosomes or endosomes. Hence, this method is suitable for the donor specific enrichment and proteomic analysis of neuromelanin granules.}, language = {en} } @article{CuiSchlesingerSchoenhalsetal.2016, author = {Cui, Huanhuan and Schlesinger, Jenny and Schoenhals, Sophia and Tonjes, Martje and Dunkel, Ilona and Meierhofer, David and Cano, Elena and Schulz, Kerstin and Berger, Michael F. and Haack, Timm and Abdelilah-Seyfried, Salim and Bulyk, Martha L. and Sauer, Sascha and Sperling, Silke R.}, title = {Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA}, series = {Nucleic Acids Research}, volume = {44}, journal = {Nucleic Acids Research}, number = {6}, doi = {10.1093/nar/gkv1244}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166391}, pages = {2538-2553}, year = {2016}, abstract = {DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure.}, language = {en} } @article{YadavSelvarajBenderetal.2016, author = {Yadav, Preeti and Selvaraj, Bhuvaneish T. and Bender, Florian L. P. and Behringer, Marcus and Moradi, Mehri and Sivadasan, Rajeeve and Dombert, Benjamin and Blum, Robert and Asan, Esther and Sauer, Markus and Julien, Jean-Pierre and Sendtner, Michael}, title = {Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling}, series = {Acta Neuropathologica}, volume = {132}, journal = {Acta Neuropathologica}, number = {1}, doi = {10.1007/s00401-016-1564-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188234}, pages = {93-110}, year = {2016}, abstract = {In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3-stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features.}, language = {en} } @article{OrtizAbioseBichetetal.2016, author = {Ortiz, Alberto and Abiose, Ademola and Bichet, Daniel G. and Cabrera, Gustavo and Charrow, Joel and Germain, Dominique P. and Hopkin, Robert J. and Jovanovic, Ana and Linhart, Aleš and Maruti, Sonia S. and Mauer, Michael and Oliveira, Jo{\~a}o P. and Patel, Manesh R. and Politei, Juan and Waldek, Stephen and Wanner, Christoph and Yoo, Han-Wook and Warnock, David G.}, title = {Time to treatment benefit for adult patients with Fabry disease receiving agalsidase beta: data from the Fabry Registry}, series = {Journal of Medical Genetics}, volume = {53}, journal = {Journal of Medical Genetics}, number = {7}, doi = {10.1136/jmedgenet-2015-103486}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188241}, pages = {495-502}, year = {2016}, abstract = {Background Agalsidase beta is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low alpha-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase beta cleared glycolipid deposits from endothelial cells within 6 months; clearance from other cell types required sustained treatment. We hypothesised that there might be a 'lag time' to clinical benefit after initiating agalsidase beta treatment, and analysed the incidence of severe clinical events over time in patients receiving agalsidase beta. Methods The incidence of severe clinical events (renal failure, cardiac events, stroke, death) was studied in 1044 adult patients (641 men, 403 women) enrolled in the Fabry Registry who received agalsidase beta (average dose 1 mg/kg every 2 weeks) for up to 5 years. Results The incidence of all severe clinical events was 111 per 1000 person-years (95\% CI 84 to 145) during the first 6 months. After 6 months, the incidence decreased and remained stable within the range of 40-58 events per 1000 patient-years. The largest decrease in incidence rates was among male patients and those aged >= 40 years when agalsidase beta was initiated. Conclusions Contrary to the expected increased incidence of severe clinical events with time, adult patients with Fabry disease had decreased incidence of severe clinical events after 6 months treatment with agalsidase beta 1 mg/kg every 2 weeks.}, language = {en} }