Recent Submissions

  • Journal Article

    Mechanic's hands in a patient with isolated anti‐Ro52 antibodies: antisynthetase syndrome without antisynthetase antibodies 

    Korsten, Peter; Schmidt, Jens; Larsen, Jörg; Seitz, Cornelia S.
    JDDG: Journal der Deutschen Dermatologischen Gesellschaft
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  • Journal Article

    The impact of SOCS1 mutations in diffuse large B‐cell lymphoma 

    Mellert, Kevin; Martin, Melanie; Lennerz, Jochen K.; Lüdeke, Manuel; Staiger, Annette M.; Kreuz, Markus; Löffler, Markus; Schmitz, Norbert; Trümper, Lorenz; Feller, Alfred C.; et al.
    Hartmann, SylviaHansmann, Martin‐LeoKlapper, WolframStein, HaraldRosenwald, AndreasOtt, GermanZiepert, MaritaMöller, Peter
    British Journal of Haematology 2019; 187(5) p.627-637
    Mutations in SOCS1 are frequent in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. In the latter, SOCS1 mutations affect the length of the encoded protein (major mutations) and are associated with shorter patient survival. Two independent studies examined the prognostic impact of SOCS1 mutations in diffuse large B-cell lymphoma (DLBCL) and showed differing results. This may be due to the small number of included patients, the heterogeneity of patients' demographics and the distinct treatment schemes in these studies. To overcome the size limitations of these previous studies, we assessed SOCS1 mutations in the RICOVER-60 cohort. The cohort uniformly consists of elderly patients (aged 61-80 years) treated with the CHOP-14 scheme (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone at 14-day intervals) with or without an additional rituximab treatment. Patient outcomes were analysed with regard to overall SOCS1 mutation frequency, major and minor mutations and a novel impact-based classifier - against the treatment modalities. Patients harbouring putative pathogenic SOCS1 mutations showed significant reduced overall survival within the CHOP plus rituximab group. Hence, putative pathogenic SOCS1 mutations seem to efface the beneficial effect of the therapeutic CD20 antibody. Comparing published data of whole exome and transcriptome sequencing of a large DLBCL cohort confirmed that predicted deleterious SOCS1 mutations forecast pre-eminent survival in early onset DLBCL.
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  • Journal Article

    Challenging a paradigm: skin sensitivity to sodium lauryl sulfate is independent of atopic diathesis 

    Heetfeld, A.B.; Schill, T.; Schröder, S.S.; Forkel, S.; Mahler, V.; Pfützner, W.; Schön, M.P.; Geier, J.; Buhl, T.
    British Journal of Dermatology
    BACKGROUND: Sodium lauryl sulfate (SLS) is the best-studied detergent in irritant contact dermatitis. In atopic dermatitis, the two major pathophysiological abnormalities concern skin barrier function and regulation of cutaneous immune responses. The probability of atopic skin diathesis can be assessed by comprehensive analysis of patient history, as well as clinical and laboratory findings, resulting in the Erlangen Atopy Score (EAS). OBJECTIVES: To investigate the impacts of (i) atopic skin diathesis according to the EAS and (ii) the physician-assessed diagnoses 'atopic dermatitis', 'allergic rhinitis' and 'allergic asthma' on SLS skin reactions. METHODS: This is a retrospective analysis of data from 2030 consecutive patients patch tested with SLS (0·25% aqueous) from two tertiary referral centres in Germany, from 2008 to 2014. RESULTS: Patients with a high probability of atopic skin diathesis showed no significant increase in positive SLS reactions compared with patients without atopic skin diathesis (14·2% vs. 16·8%). The grading of positive SLS skin reactions (1-4) revealed no differences in patients with or without atopic skin diathesis. Furthermore, diagnoses of atopic dermatitis, allergic rhinitis or allergic asthma had no impact on positive SLS skin reactions in multivariate logistic regression analysis. CONCLUSIONS: We found no association of increased skin irritability to SLS with atopic skin diathesis, atopic dermatitis, allergic rhinitis or allergic asthma in a large patient cohort. It therefore seems that the test of skin irritability with SLS, which is currently common practice in many centres, does not allow prediction of susceptibility to irritant eczematous inflammation in atopic vs. nonatopic individuals. What's already known about this topic? Irritant contact dermatitis and atopic skin diathesis share impaired skin barrier function as a pathophysiological pattern. Sodium lauryl sulfate (SLS) is tested at 0·25% aqueous as an irritant control in patch testing, and hence the results might be affected by atopic skin diathesis. What does this study add? Challenging a long-standing paradigm, we found no association of increased reactivity to SLS patch tests in individuals with atopic skin diathesis, atopic dermatitis, allergic rhinitis or allergic asthma in a large patient cohort. Thus, irritant control testing with SLS, which is useful in interpreting doubtful allergen patch test results, does not depend on individual atopy status.
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  • Journal Article

    Real-Time Magnetic Resonance Imaging. Radial Gradient-Echo Sequences With Nonlinear Inverse Reconstruction 

    Frahm, Jens; Voit, Dirk; Uecker, Martin
    Investigative Radiology 2019; 54(12) p.757-766
    OBJECTIVE: The aim of this study is to evaluate a real-time magnetic resonance imaging (MRI) method that not only promises high spatiotemporal resolution but also practical robustness in a wide range of scientific and clinical applications. MATERIALS AND METHODS: The proposed method relies on highly undersampled gradient-echo sequences with radial encoding schemes. The serial image reconstruction process solves the true mathematical task that emerges as a nonlinear inverse problem with the complex image and all coil sensitivity maps as unknowns. Extensions to model-based reconstructions for quantitative parametric mapping further increase the number of unknowns, for example, by adding parameters for phase-contrast flow or T1 relaxation. In all cases, an iterative numerical solution that minimizes a respective cost function is achieved with use of the iteratively regularized Gauss-Newton method. Convergence is supported by regularization, for example, to the preceding frame, whereas temporal fidelity is ensured by downsizing the regularization strength in comparison to the data consistency term in each iterative step. Practical implementations of highly parallelized algorithms are realized on a computer with multiple graphical processing units. It is "invisibly" integrated into a commercial 3-T MRI system to allow for conventional usage and to provide online reconstruction, display, and storage of regular DICOM image series. RESULTS: Depending on the application, the proposed method offers serial imaging, that is, the recording of MRI movies, with variable spatial resolution and up to 100 frames per second (fps)-corresponding to 10 milliseconds image acquisition times. For example, movements of the temporomandibular joint during opening and closing of the mouth are visualized with use of simultaneous dual-slice movies of both joints at 2 × 10 fps (50 milliseconds per frame). Cardiac function may be studied at 30 to 50 fps (33.3 to 20 milliseconds), whereas articulation processes typically require 50 fps (20 milliseconds) or orthogonal dual-slice acquisitions at 2 × 25 fps (20 milliseconds). Methodological extensions to model-based reconstructions achieve improved quantitative mapping of flow velocities and T1 relaxation times in a variety of clinical scenarios. CONCLUSIONS: Real-time gradient-echo MRI with extreme radial undersampling and nonlinear inverse reconstruction allows for direct monitoring of arbitrary physiological processes and body functions. In many cases, pertinent applications offer hitherto impossible clinical studies (eg, of high-resolution swallowing dynamics) or bear the potential to replace existing MRI procedures (eg, electrocardiogram-gated cardiac examinations). As a consequence, many novel opportunities will require a change of paradigm in MRI-based radiology. At this stage, extended clinical trials are needed.
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  • Journal Article

    The hRPC62 subunit of human RNA polymerase III displays helicase activity 

    Ayoubi, Leyla El; Dumay-Odelot, Hélène; Chernev, Aleksandar; Boissier, Fanny; Minvielle-Sébastia, Lionel; Urlaub, Henning; Fribourg, Sébastien; Teichmann, Martin
    Nucleic Acids Research 2019; 47(19) p.10313-10326
    In Eukaryotes, tRNAs, 5S RNA and U6 RNA are transcribed by RNA polymerase (Pol) III. Human Pol III is composed of 17 subunits. Three specific Pol III subunits form a stable ternary subcomplex (RPC62-RPC39-RPC32α/β) being involved in pre-initiation complex formation. No paralogues for subunits of this subcomplex subunits have been found in Pols I or II, but hRPC62 was shown to be structurally related to the general Pol II transcription factor hTFIIEα. Here we show that these structural homologies extend to functional similarities. hRPC62 as well as hTFIIEα possess intrinsic ATP-dependent 3'-5' DNA unwinding activity. The ATPase activities of both proteins are stimulated by single-stranded DNA. Moreover, the eWH domain of hTFIIEα can replace the first eWH (eWH1) domain of hRPC62 in ATPase and DNA unwinding assays. Our results identify intrinsic enzymatic activities in hRPC62 and hTFIIEα.
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  • Journal Article

    Clinical safety of the ProMRI implantable cardioverter-defibrillator systems during head and lower lumbar magnetic resonance imaging at 3 T: results of the ProMRI 3T ENHANCED Master study 

    Zbinden, Rainer; Wollmann, Christian; Brachmann, Johannes; Michaelsen, Jochen; Steinwender, Clemens; Kovoor, Pramesh; Kelle, Sebastian; McGavigan, Andrew D; Ching, Chi Keong; Figtree, Gemma A; et al.
    Schmidt, JanTimmel, TobiasLotz, Joachim
    EP Europace 2019; 21(11) p.1678-1685
    AIMS: There have been no published studies on the safety of magnetic resonance imaging (MRI) at 3 Tesla (3 T) in patients with MRI-conditional implantable cardioverter-defibrillators (ICDs). The aim of this study was to assess clinical safety of the Biotronik ProMRI ICD system during non-diagnostic head and lower lumbar scans under 3 T MRI conditions. METHODS AND RESULTS: The study enrolled 129 patients at 12 sites in Australia, Singapore, and Europe. Predefined head and lower lumbar MR scans (total duration ≈30 min) were performed in 112 patients. Three primary endpoints were evaluated from the pre-MRI to the 1-month post-MRI visit: (i) freedom from serious adverse device effects (SADEs) related to MRI (hypothesized to be >90%); (ii) pacing threshold invariance for all leads (geometric mean of the patient-wise ratios for 1 month vs. pre-MRI was hypothesized to be <1.07); and (iii) sensing amplitude invariance (geometric mean of the ratios was hypothesized to be >0.993). No MRI-related SADE occurred (SADE-free rate 100%, 95% confidence interval 95.98-100%). Pacing threshold and sensing amplitudes fulfilled the invariance hypotheses with high statistical significance (P < 0.0013). No threshold increase >0.5 V or sensing amplitude decrease by >50% was observed (secondary endpoints). Lead impedances, battery capacity, and detection and treatment of arrhythmias by ICDs were not affected by MRI scans. CONCLUSION: The head and lower lumbar scans under specific 3 T MRI conditions were safe in the investigated MR-conditional ICD systems. There was no evidence of harm to the patients or any negative influence of the MRI scan on the implanted systems.
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  • Journal Article

    Rethinking calcium profiles around single channels: the exponential and periodic calcium nanodomains 

    Mironov, Sergej L.
    Scientific Reports 2019; 9(1): Art. 17196
    Many fundamental calcium-dependent physiological processes are triggered by high local calcium levels that are established around the sites of calcium entry into the cell (channels). They are dubbed as calcium nanodomains but their exact profiles are still elusive. The concept of calcium nanodomains stems from a linear model of calcium diffusion and is only valid when calcium increases are smaller than the concentration of cytoplasmic buffers. Recent data indicates that much higher calcium levels cause buffer saturation. Therefore, I sought explicit solutions of a nonlinear reaction-diffusion model and found a dichotomous solution. For small fluxes, the steady state calcium profile is quasi-exponential, and when calcium exceeds buffer concentration a spatial periodicity appears. Analytical results are supported by Monte-Carlo simulations. I also imaged 1D- and radial calcium distributions around single α-synuclein channels in cell-free conditions. Measured Ca profiles are consistent with theoretical predictions. I propose that the periodic calcium patterns may well arise under certain conditions and their specific functional role has to be established.
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  • Journal Article

    Identification of candidate cancer drivers by integrative Epi-DNA and Gene Expression (iEDGE) data analysis 

    Li, Amy; Chapuy, Bjoern; Varelas, Xaralabos; Sebastiani, Paola; Monti, Stefano
    Scientific Reports 2019; 9(1): Art. 16904
    The emergence of large-scale multi-omics data warrants method development for data integration. Genomic studies from cancer patients have identified epigenetic and genetic regulators - such as methylation marks, somatic mutations, and somatic copy number alterations (SCNAs), among others - as predictive features of cancer outcome. However, identification of "driver genes" associated with a given alteration remains a challenge. To this end, we developed a computational tool, iEDGE, to model cis and trans effects of (epi-)DNA alterations and identify potential cis driver genes, where cis and trans genes denote those genes falling within and outside the genomic boundaries of a given (epi-)genetic alteration, respectively. iEDGE first identifies the cis and trans gene expression signatures associated with the presence/absence of a particular epi-DNA alteration across samples. It then applies tests of statistical mediation to determine the cis genes predictive of the trans gene expression. Finally, cis and trans effects are annotated by pathway enrichment analysis to gain insights into the underlying regulatory networks. We used iEDGE to perform integrative analysis of SCNAs and gene expression data from breast cancer and 18 additional cancer types included in The Cancer Genome Atlas (TCGA). Notably, cis gene drivers identified by iEDGE were found to be significantly enriched for known driver genes from multiple compendia of validated oncogenes and tumor suppressors, suggesting that the remainder are of equal importance. Furthermore, predicted drivers were enriched for functionally relevant cancer genes with amplification-driven dependencies, which are of potential prognostic and therapeutic value. All the analyses results are accessible at https://montilab.bu.edu/iEDGE. In summary, integrative analysis of SCNAs and gene expression using iEDGE successfully identified known cancer driver genes and putative cancer therapeutic targets across 19 cancer types in the TCGA. The proposed method can easily be applied to the integration of gene expression profiles with other epi-DNA assays in a variety of disease contexts.
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  • Journal Article

    Polygenic burden associated to oligodendrocyte precursor cells and radial glia influences the hippocampal volume changes induced by aerobic exercise in schizophrenia patients 

    Papiol, Sergi; Keeser, Daniel; Hasan, Alkomiet; Schneider-Axmann, Thomas; Raabe, Florian; Degenhardt, Franziska; Rossner, Moritz J.; Bickeböller, Heike; Cantuti-Castelvetri, Ludovico; Simons, Mikael; et al.
    Wobrock, ThomasSchmitt, AndreaMalchow, BerendFalkai, Peter
    Translational Psychiatry 2019; 9(1)
    Hippocampal volume decrease is a structural hallmark of schizophrenia (SCZ), and convergent evidence from postmortem and imaging studies suggests that it may be explained by changes in the cytoarchitecture of the cornu ammonis 4 (CA4) and dentate gyrus (DG) subfields. Increasing evidence indicates that aerobic exercise increases hippocampal volume in CA subfields and improves cognition in SCZ patients. Previous studies showed that the effects of exercise on the hippocampus might be connected to the polygenic burden of SCZ risk variants. However, little is known about cell type-specific genetic contributions to these structural changes. In this secondary analysis, we evaluated the modulatory role of cell type-specific SCZ polygenic risk scores (PRS) on volume changes in the CA1, CA2/3, and CA4/DG subfields over time. We studied 20 multi-episode SCZ patients and 23 healthy controls who performed aerobic exercise, and 21 multi-episode SCZ patients allocated to a control intervention (table soccer) for 3 months. Magnetic resonance imaging-based assessments were performed with FreeSurfer at baseline and after 3 months. The analyses showed that the polygenic burden associated with oligodendrocyte precursor cells (OPC) and radial glia (RG) significantly influenced the volume changes between baseline and 3 months in the CA4/DG subfield in SCZ patients performing aerobic exercise. A higher OPC- or RG-associated genetic risk burden was associated with a less pronounced volume increase or even a decrease in CA4/DG during the exercise intervention. We hypothesize that SCZ cell type-specific polygenic risk modulates the aerobic exercise-induced neuroplastic processes in the hippocampus.
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  • Journal Article

    Attitudes toward the right to autonomous decision‐making in psychiatric genetic testing: Controversial and context‐dependent 

    Strohmaier, Jana; Witt, Stephanie H.; Frank, Josef; Lemme, Noemi; Flatau, Laura; Streit, Fabian; Foo, Jerome C.; Reitt, Markus; Rujescu, Dan; Schulze, Thomas G.; et al.
    Lanzerath, DirkIlles, FranciskaDegenhardt, FranziskaRietschel, Marcella
    American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2019; 180(8) p.555-565
    Recent breakthroughs in psychiatric genetics have identified genetic risk factors of yet unknown clinical value. A main ethical principal in the context of psychiatric research as well as future clinical genetic testing is the respect for a person's autonomy to decide whether to undergo genetic testing, and whom to grant access to genetic data. However, experience within the psychiatric genetic research setting has indicated controversies surrounding attitudes toward this ethical principal. This study aimed to explore attitudes concerning the right of individuals to self-determine testing and disclosure of results, and to determine whether these attitudes are context-dependent, that is, not directly related to the test result but rather to specific circumstances. N = 160 individuals with major depression or bipolar disorder and n = 29 relatives of individuals with either illness completed an online-questionnaire assessing attitudes toward genetic testing, genetic research, disclosure of results, incidental findings, and access to psychiatric genetic test results. Generally, the right of the person's autonomy was considered very important, but attitudes varied. For example, half of those who considered that children should have the right to refuse psychiatric genetic testing even against their parents' will, also state that they should be tested upon their parents' wishes. Also, the majority of respondents considered the physician entitled to disregard their stated wishes concerning the disclosure of incidental findings in case of good treatment options. Thus, researchers and clinicians must be aware that attitudes toward psychiatric genetic testing are often mutable and should discuss these prior to testing.
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  • Journal Article

    Mapping Cellular Microenvironments: Proximity Labeling and Complexome Profiling (Seventh Symposium of the Göttingen Proteomics Forum) 

    Valerius, Oliver; Asif, Abdul R.; Beißbarth, Tim; Bohrer, Rainer; Dihazi, Hassan; Feussner, Kirstin; Jahn, Olaf; Majcherczyk, Andrzej; Schmidt, Bernhard; Schmitt, Kerstin; et al.
    Urlaub, HenningLenz, Christof
    Cells 2019; 8(10): Art. 1192
    Mass spectrometry-based proteomics methods are finding increasing use in structural biology research. Beyond simple interaction networks, information about stable protein-protein complexes or spatially proximal proteins helps to elucidate the biological functions of proteins in a wider cellular context. To shed light on new developments in this field, the Göttingen Proteomics Forum organized a one-day symposium focused on complexome profiling and proximity labeling, two emerging technologies that are gaining significant attention in biomolecular research. The symposium was held in Göttingen, Germany on 23 May, 2019, as part of a series of regular symposia organized by the Göttingen Proteomics Forum.
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  • Journal Article

    The Core Proteome of Biofilm-Grown Clinical Pseudomonas aeruginosa Isolates 

    Erdmann, Jelena; Thöming, Janne G.; Pohl, Sarah; Pich, Andreas; Lenz, Christof; Häussler, Susanne
    Cells 2019; 8(10): Art. 1129
    Comparative genomics has greatly facilitated the identification of shared as well as unique features among individual cells or tissues, and thus offers the potential to find disease markers. While proteomics is recognized for its potential to generate quantitative maps of protein expression, comparative proteomics in bacteria has been largely restricted to the comparison of single cell lines or mutant strains. In this study, we used a data independent acquisition (DIA) technique, which enables global protein quantification of large sample cohorts, to record the proteome profiles of overall 27 whole genome sequenced and transcriptionally profiled clinical isolates of the opportunistic pathogen Pseudomonas aeruginosa. Analysis of the proteome profiles across the 27 clinical isolates grown under planktonic and biofilm growth conditions led to the identification of a core biofilm-associated protein profile. Furthermore, we found that protein-to-mRNA ratios between different P. aeruginosa strains are well correlated, indicating conserved patterns of post-transcriptional regulation. Uncovering core regulatory pathways, which drive biofilm formation and associated antibiotic tolerance in bacterial pathogens, promise to give clues to interactions between bacterial species and their environment and could provide useful targets for new clinical interventions to combat biofilm-associated infections.
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  • Journal Article

    Patient-Reported Prevalence of Non-motor Symptoms Is Low in Adult Patients Suffering From 5q Spinal Muscular Atrophy 

    Günther, René; Wurster, Claudia Diana; Cordts, Isabell; Koch, Jan Christoph; Kamm, Christoph; Petzold, Daniel; Aust, Elisa; Deschauer, Marcus; Lingor, Paul; Ludolph, Albert Christian; et al.
    Hermann, Andreas
    Frontiers in Neurology 2019; 10: Art. 1098
    Background: 5q spinal muscular atrophy (SMA) is an autosomal recessive lower motoneuron disease caused by deletion or mutations in the survival motor neuron 1 gene (SMN1) which results in reduced expression of full-length SMN protein. The main symptoms are caused by spinal motor neuron demise leading to muscle atrophy, and medical care mostly refers to motor symptoms. However, new insights of recent studies in severe SMA type I revealed disease involvement of several non-motor regions, for example cardiac, vascular, sensory nerve involvement, and thalamic lesions. Non-motor symptoms (NMS) were previously described in many neurodegenerative diseases i.e., Parkinson's disease and, importantly, also amyotrophic lateral sclerosis. Methods: We screened for NMS in 70 adult patients with SMA type II (SMAII) and type III (SMAIII) and 59 age/sex-matched healthy controls (controls) in a multicenter cross-sectional study including 5 different centers with specialized expertise in medical health care of motoneuron diseases. We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is a validated tool in Parkinson's disease. Results: Total NMS burden was low in adult SMA (median: 3 items) and not significantly different compared to controls (median: 2 items). Total NMS of SMA patients did not correlate with disease severity scores. However, the items "swallowing difficulties," "falling," and particularly "swelling legs" were significantly more frequently reported in SMA. Neuropsychiatric symptoms were reported in a frequency comparable to controls and were not significantly increased in SMA. Conclusion: Patient-reported prevalence of NMS in adult SMA was low, which does not argue for a clinically relevant multisystemic disorder in SMAII/III. Importantly, adult SMA patients do not seem to suffer more frequently from symptoms of depression or adaptive disorders compared to controls. Our results yield novel information on previously underreported symptoms and will help to improve the medical guidance of these patients.
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  • Journal Article

    Multiple Functions of the Essential Gene PpV in Drosophila Early Development 

    Liu, Boyang; Sung, Hung-wei; Großhans, Jörg
    Genes|Genomes|Genetics 2019; 9(11) p.3583-3593
    Protein phosphatase V (PpV) encodes the Drosophila homolog of the evolutionarily conserved Protein Phosphatase 6 (PP6). The physiological and developmental functions of PpV/PP6 have not been well characterized due to lack of a genetically defined mutant. Here, we identified a PpV non-sense mutation and describe multiple mutant phenotypes in oogenesis and early embryogenesis. Specifically, we found that the defects in chromosome segregation during nuclear cycles are related to AuroraA function, which is consistent with the interaction of PP6 and AuroraA in mammalian cells. Surprisingly, we also identified a PpV function specifically in blastoderm cell cycle but not in cell proliferation in the follicle epithelium or larval wing imaginal discs. Embryos from PpV germline clones frequently undergo an extra nuclear division cycle. By epistasis analysis, we found that PpV functions in parallel with tribbles, but independently of auroraA for the remodeling of the nuclear cycles. Taken together, this study reports novel developmental functions of PpV and provides a framework for further genetic analysis under physiological conditions.
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  • Journal Article

    MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome–nascent chain complex 

    Wang, Cong; Richter‐Dennerlein, Ricarda; Pacheu‐Grau, David; Liu, Fan; Zhu, Ying; Dennerlein, Sven; Rehling, Peter
    EMBO reports: Art. e48833
    The mitochondrial genome encodes for thirteen core subunits of the oxidative phosphorylation system. These proteins assemble with imported proteins in a modular manner into stoichiometric enzyme complexes. Assembly factors assist in these biogenesis processes by providing co-factors or stabilizing transient assembly stages. However, how expression of the mitochondrial-encoded subunits is regulated to match the availability of nuclear-encoded subunits is still unresolved. Here, we address the function of MITRAC15/COA1, a protein that participates in complex I biogenesis and complex IV biogenesis. Our analyses of a MITRAC15 knockout mutant reveal that MITRAC15 is required for translation of the mitochondrial-encoded complex I subunit ND2. We find that MITRAC15 is a constituent of a ribosome-nascent chain complex during ND2 translation. Chemical crosslinking analyses demonstrate that binding of the ND2-specific assembly factor ACAD9 to the ND2 polypeptide occurs at the C-terminus and thus downstream of MITRAC15. Our analyses demonstrate that expression of the founder subunit ND2 of complex I undergoes regulation. Moreover, a ribosome-nascent chain complex with MITRAC15 is at the heart of this process.
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  • Journal Article

    Decreased plasma phospholipid concentrations and increased acid sphingomyelinase activity are accurate biomarkers for community-acquired pneumonia 

    Arshad, Haroon; Alfonso, Juan Carlos López; Franke, Raimo; Michaelis, Katina; Araujo, Leonardo; Habib, Aamna; Zboromyrska, Yuliya; Lücke, Eva; Strungaru, Emilia; Akmatov, Manas K.; et al.
    Hatzikirou, HaralamposMeyer-Hermann, MichaelPetersmann, AstridNauck, MatthiasBrönstrup, MarkBilitewski, UrsulaAbel, LaurentSievers, JorgVila, JordiIllig, ThomasSchreiber, JensPessler, Frank
    Journal of Translational Medicine 2019; 17(1): Art. 365
    BACKGROUND: There continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage. METHODS: We measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls. RESULTS: Phospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphatidylcholines, followed by lysophosphatidylcholines, sphingomyelins and ceramides (three of which were upregulated), and were least in acylcarnitines. Changes in COPD were less pronounced, but also differed qualitatively, e.g. by increases in selected sphingomyelins. We identified highly accurate biomarkers for CAP (AUC ≤ 0.97) and COPD (AUC ≤ 0.93) vs. Controls, and moderately accurate biomarkers for CAP vs. COPD (AUC ≤ 0.83), all of which were phospholipids. Phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins were also markedly decreased in S. aureus-infected human A549 and differentiated THP1 cells. Correlations with C-reactive protein and procalcitonin were predominantly negative but only of mild-to-moderate extent, suggesting that these markers reflect more than merely inflammation. Consistent with the increased ceramide concentrations, increased acid sphingomyelinase activity accurately distinguished CAP (fold change = 2.8, AUC = 0.94) and COPD (1.75, 0.88) from Controls and normalized with clinical resolution. CONCLUSIONS: The results underscore the high potential of plasma phospholipids as biomarkers for CAP, begin to reveal differences in lipid dysregulation between CAP and infection-associated COPD exacerbation, and suggest that the decreases in plasma concentrations are at least partially determined by changes in host target cells. Furthermore, they provide validation in clinical blood samples of acid sphingomyelinase as a potential treatment target to improve clinical outcome of CAP.
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  • Journal Article

    N-Terminally Truncated Aβ Peptide Variants in Alzheimer’s Disease 

    Wirths, Oliver; Zampar, Silvia; Weggen, Sascha
    Codon Publications, 2019
    The accumulation and aggregation of amyloid-β (Aβ) peptides in the brain is believed to be the initial trigger in the molecular pathology of Alzheimer’s disease (AD). In addition to the widely studied full-length Aβ peptides (mainly Aβ1–40 and Aβ1–42), a variety of amino-terminally truncated (N-truncated) peptides, such as AβpE3-x and Aβ4-x, have been detected in high abundance in autopsy samples from sporadic and familial AD patients. N-truncated Aβ species adopt specific physicochemical properties resulting in a higher aggregation propensity and increased peptide stability, which likely account for their neurotoxic potential. The presence of N-truncated Aβ peptides in transgenic mouse models of AD and the selective overexpression of specific N-truncated variants in the murine brain have facilitated their investigation in relevant in vivo settings. In this chapter, we address the pathological relevance of N-truncated Aβ peptide species and summarize the current knowledge about the enzymatic activities that might be involved in their generation.
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  • Journal Article

    sEVD—smartphone-navigated placement of external ventricular drains 

    Eisenring, Christian V.; Burn, Felice; Baumann, Michelle; Stieglitz, Lennart H.; Kockro, Ralf A.; Beck, Jürgen; Raabe, Andreas; Oertel, Markus F.
    Acta Neurochirurgica
    BACKGROUND: Currently, the trajectory for insertion of an external ventricular drain (EVD) is mainly determined using anatomical landmarks. However, non-assisted implantations frequently require multiple attempts and are associated with EVD malpositioning and complications. The authors evaluated the feasibility and accuracy of a novel smartphone-guided, angle-adjusted technique for assisted implantations of an EVD (sEVD) in both a human artificial head model and a cadaveric head. METHODS: After computed tomography (CT), optimal insertion angles and lengths of intracranial trajectories of the EVDs were determined. A smartphone was calibrated to the mid-cranial sagittal line. Twenty EVDs were placed using both the premeasured data and smartphone-adjusted insertion angles, targeting the center of the ipsilateral ventricular frontal horn. The EVD positions were verified with post-interventional CT. RESULTS: All 20 sEVDs (head model, 8/20; cadaveric head, 12/20) showed accurate placement in the ipsilateral ventricle. The sEVD tip locations showed a mean target deviation of 1.73° corresponding to 12 mm in the plastic head model, and 3.45° corresponding to 33 mm in the cadaveric head. The mean duration of preoperative measurements on CT data was 3 min, whereas sterile packing, smartphone calibration, drilling, and implantation required 9 min on average. CONCLUSIONS: By implementation of an innovative navigation technique, a conventional smartphone was used as a protractor for the insertion of EVDs. Our ex vivo data suggest that smartphone-guided EVD placement offers a precise, rapidly applicable, and patient-individualized freehand technique based on a standard procedure with a simple, cheap, and widely available multifunctional device.
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  • Journal Article

    Temporal stability of fMRI in medetomidine-anesthetized rats 

    Sirmpilatze, Nikoloz; Baudewig, Jürgen; Boretius, Susann
    Scientific Reports 2019; 9(1)
    Medetomidine has become a popular choice for anesthetizing rats during long-lasting sessions of blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI). Despite this, it has not yet been thoroughly established how commonly reported fMRI readouts evolve over several hours of medetomidine anesthesia and how they are affected by the precise timing, dose, and route of administration. We used four different protocols of medetomidine administration to anesthetize rats for up to six hours and repeatedly evaluated somatosensory stimulus-evoked BOLD responses and resting state functional connectivity. We found that the temporal evolution of fMRI readouts strongly depended on the method of administration. Intravenous administration of a medetomidine bolus (0.05 mg/kg), combined with a subsequent continuous infusion (0.1 mg/kg/h), led to temporally stable measures of stimulus-evoked activity and functional connectivity throughout the anesthesia. Deviating from the above protocol-by omitting the bolus, lowering the medetomidine dose, or using the subcutaneous route-compromised the stability of these measures in the initial two-hour period. We conclude that both an appropriate protocol of medetomidine administration and a suitable timing of fMRI experiments are crucial for obtaining consistent results. These factors should be considered for the design and interpretation of future rat fMRI studies.
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  • Journal Article

    Range Variability in CMR Feature Tracking Multilayer Strain across Different Stages of Heart Failure 

    Tanacli, Radu; Hashemi, Djawid; Lapinskas, Tomas; Edelmann, Frank; Gebker, Rolf; Pedrizzetti, Gianni; Schuster, Andreas; Nagel, Eike; Pieske, Burkert; Düngen, Hans-Dirk; et al.
    Kelle, Sebastian
    Scientific Reports 2019; 9(1): Art. 16478
    Heart failure (HF) is associated with progressive ventricular remodeling and impaired contraction that affects distinctly various regions of the myocardium. Our study applied cardiac magnetic resonance (CMR) feature tracking (FT) to assess comparatively myocardial strain at 3 distinct levels: subendocardial (Endo-), mid (Myo-) and subepicardial (Epi-) myocardium across an extended spectrum of patients with HF. 59 patients with HF, divided into 3 subgroups as follows: preserved ejection fraction (HFpEF, N = 18), HF with mid-range ejection fraction (HFmrEF, N = 21), HF with reduced ejection fraction (HFrEF, N = 20) and a group of age- gender- matched volunteers (N = 17) were included. Using CMR FT we assessed systolic longitudinal and circumferential strain and strain-rate at Endo-, Myo- and Epi- levels. Strain values were the highest in the Endo- layer and progressively lower in the Myo- and Epi- layers respectively, this gradient was present in all the patients groups analyzed but decreased progressively in HFmrEF and further on in HFrEF groups. GLS decreased with the severity of the disease in all 3 layers: Normal > HFpEF > HFmrEF > HFrEF (Endo-: -23.0 ± 3.5 > -20.0 ± 3.3 > -16.4 ± 2.2 > -11.0 ± 3.2, p < 0.001, Myo-: -20.7 ± 2.4 > -17.5.0 ± 2.6 > -14.5 ± 2.1 > -9.6 ± 2.7, p < 0.001; Epi-: -15.7 ± 1.9 > -12.2 ± 2.1 > -10.6 ± 2.3 > -7.7 ± 2.3, p < 0.001). In contrast, GCS was not different between the Normal and HFpEF (Endo-: -34.5 ± 6.2 vs -33.9 ± 5.7, p = 0.51; Myo-: -21.9 ± 3.8 vs -21.3 ± 2.2, p = 0.39, Epi-: -11.4 ± 2.0 vs -10.9 ± 2.3, p = 0.54) but was, as well, markedly lower in the systolic heart failure groups: Normal > HFmrEF > HFrEF (Endo-: -34.5 ± 6.2 > -20.0 ± 4.2 > 12.3 ± 4.2, p < 0.001; Myo-: -21.9 ± 3.8 > -13.0 ± 3.4 > -8.0 ± 2.7. p < 0.001; Epi-: -11.4 ± 2.0 > -7.9 ± 2.3 > -4.5 ± 1.9. p < 0.001). CMR feature tracking multilayer strain assessment identifies large range differences between distinct myocardial regions. Our data emphasizes the importance of sub-endocardial myocardium for cardiac contraction and thus, its predilect role in imaging detection of functional impairment. CMR feature tracking offers a convenient, readily available, platform to evaluate myocardial contraction with excellent spatial resolution, rendering further details about discrete areas of the myocardium. Using this technique across distinct groups of patients with heart failure (HF), we demonstrate that subendocardial regions of the myocardium exhibit much higher strain values than mid-myocardium or subepicardial and are more sensitive to detect contractile impairment. We also show comparatively higher values of circumferential strain compared with longitudinal and a higher sensitivity to detect contractile impairment. A newly characterized group of patients, HF with mid-range ejection fraction (EF), shows similar traits of decompensation but has relatively higher strain values as patients with HF with reduced EF.
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