Recent Submissions

  • Journal Article

    Glycoprotein NMB: a novel Alzheimer’s disease associated marker expressed in a subset of activated microglia 

    Hüttenrauch, Melanie; Ogorek, Isabella; Klafki, Hans; Otto, Markus; Stadelmann, Christine; Weggen, Sascha; Wiltfang, Jens; Wirths, Oliver
    Acta Neuropathologica Communications 2018; 6(1): Art. 108
    Alzheimer's disease (AD) is an irreversible, devastating neurodegenerative brain disorder characterized by the loss of neurons and subsequent cognitive decline. Despite considerable progress in the understanding of the pathophysiology of AD, the precise molecular mechanisms that cause the disease remain elusive. By now, there is ample evidence that activated microglia have a critical role in the initiation and progression of AD. The present study describes the identification of Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a novel AD-related factor in both transgenic mice and sporadic AD patients by expression profiling, immunohistochemistry and ELISA measurements. We show that GPNMB levels increase in an age-dependent manner in transgenic AD models showing profound cerebral neuron loss and demonstrate that GPNMB co-localizes with a distinct population of IBA1-positive microglia cells that cluster around amyloid plaques. Our data further indicate that GPNMB is part of a microglia activation state that is only present under neurodegenerative conditions and that is characterized by the up-regulation of a subset of genes including TREM2, APOE and CST7. In agreement, we provide in vitro evidence that soluble Aβ has a direct effect on GPNMB expression in an immortalized microglia cell line. Importantly, we show for the first time that GPNMB is elevated in brain samples and cerebrospinal fluid (CSF) of sporadic AD patients when compared to non-demented controls.The current findings indicate that GPNMB represents a novel disease-associated marker that appears to play a role in the neuroinflammatory response of AD.
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  • Journal Article

    TMJ pathomorphology in patients with JIA-radiographic parameters for early diagnosis- 

    Klenke, Daniela; Quast, Anja; Prelog, Martina; Holl-Wieden, Annette; Riekert, Maximilian; Stellzig-Eisenhauer, Angelika; Meyer-Marcotty, Philipp
    Head & Face Medicine 2018; 14(15)
    BACKGROUND: Juvenile idiopathic arthritis (JIA) is often accompanied by pathomorphological changes to the temporomandibular joint (TMJ). By analyzing orthodontical orthopantomograms of JIA patients the aims of the study were a) classification of condyle changes, b) quantification of bony asymmetries of condylar destruction and c) detection of relationships between disease duration and TMJ-involvement. PATIENTS/METHODS: 46 caucasian JIA-patients (28 female; 18 male; < 16.0 years) were enrolled, each joint (n = 92) was morphologically assessed by means of orthopantomogram, quantitatively analysed and compared with duration of general disease. Condyle morphology was assessed using the Billiau scale for severity of destruction [1]. The quantitative analysis was based on ratios of condyle, ramus and mandible height. RESULTS: Patients were divided into groups (Group I - slightly affected, n = 36; Billiau severity 0-2; condyle findings: X-ray normal, condyle erosions, condylar flattening; Group II - severely affected, N = 10; Billiau severity 3-4; condyle findings: condylar flattenings and erosions, unilateral/bilateral complete loss of condyles), based on morphological analysis of condylar destruction. Duration of disease was significantly longer in Group II (8.9 ± 5.2 years) than in Group I (4.6 ± 4.7 years). Asymmetries of condyle, ramus and mandible height, quantitatively analysed by contralateral comparison, were significantly more marked in patients of Group II than of Group I. CONCLUSIONS: Orthopantomogram imaging can be used in orthodontics clinical routine to detect TMJ-pathologies and is an important reference for monitoring progression of JIA. Classification into severe and slightly affected TMJ is possible by analysis of condylar pathomorphology. An association between degree of destruction, extent of lower jaw asymmetry and disease duration is suggested by the results.
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  • Journal Article

    The transducer-like protein Tlp12 of Campylobacter jejuni is involved in glutamate and pyruvate chemotaxis 

    Lübke, Anastasia-Lisa; Minatelli, Sabrina; Riedel, Thomas; Lugert, Raimond; Schober, Isabel; Spröer, Cathrin; Overmann, Jörg; Groß, Uwe; Zautner, Andreas E.; Bohne, Wolfgang
    BMC Microbiology 2018; 18(111)
    BACKGROUND: Campylobacter jejuni is one of the most common bacterial causes of food-borne enteritis worldwide. Chemotaxis in C. jejuni is known to be critical for the successful colonization of the host and key for the adaptation of the microbial species to different host environments. In C. jejuni, chemotaxis is regulated by a complex interplay of 13 or even more different chemoreceptors, also known as transducer-like proteins (Tlps). Recently, a novel chemoreceptor gene, tlp12, was described and found to be present in 29.5% of the investigated C. jejuni strains. RESULTS: In this study, we present a functional analysis of Tlp12 with the aid of a tlp12 knockout mutant of the C. jejuni strain A17. Substrate specificity was investigated by capillary chemotaxis assays and revealed that Tlp12 plays an important role in chemotaxis towards glutamate and pyruvate. Moreover, the Δtlp12 mutant shows increased swarming motility in soft agar assays, an enhanced invasion rate into Caco-2 cells and an increased autoagglutination rate. The growth rate was slightly reduced in the Δtlp12 mutant. The identified phenotypes were in partial restored by complementation with the wild type gene. Tlp12-harboring C. jejuni strains display a strong association with chicken, whose excreta are known to contain high glutamate levels. CONCLUSIONS: TLP12 is a chemoreceptor for glutamate and pyruvate recognition. Deletion of tlp12 has an influence on distinct physiological features, such as growth rate, swarming motility, autoagglutination and invasiveness.
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  • Journal Article

    mully: An R Package to Create, Modify and Visualize Multilayered Graphs 

    Hammoud, Zaynab; Kramer, Frank
    Genes 2018; 9(11): Art. 519
    The modelling of complex biological networks such as pathways has been a necessity for scientists over the last decades. The study of these networks also imposes a need to investigate different aspects of nodes or edges within the networks, or other biomedical knowledge related to it. Our aim is to provide a generic modelling framework to integrate multiple pathway types and further knowledge sources influencing these networks. This framework is defined by a multi-layered model allowing automatic network transformations and documentation. By providing a tool that generates this model, we aim to facilitate the data integration, boost the reproducibility and increase the interoperability between different sources and databases in the field of pathways. We present mully R package that allows the user to create, modify and visualize graphs with multi-layers. The package is implemented with features to specifically handle multilayered graphs.
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  • Journal Article

    CA1 Neurons Acquire Rett Syndrome Phenotype After Brief Activation of Glutamatergic Receptors: Specific Role of mGluR1/5 

    Balakrishnan, Saju; Mironov, Sergej L.
    Frontiers in Cellular Neuroscience 2018; 12: Art. 363
    Rett syndrome (RTT) is a neurological disorder caused by the mutation of the X-linked MECP2 gene. The neurophysiological hallmark of the RTT phenotype is the hyperexcitability of neurons made responsible for frequent epileptic attacks in the patients. Increased excitability in RTT might stem from impaired glutamate handling in RTT and its long-term consequences that has not been examined quantitatively. We recently reported (Balakrishnan and Mironov, 2018a,b) that the RTT hippocampus consistently demonstrates repetitive glutamate transients that parallel the burst firing in the CA1 neurons. We aimed to examine how brief stimulation of specific types of ionotropic and metabotropic glutamate receptors (GluR) can modulate the neuronal phenotype. We imaged glutamate with a fluorescence sensor (iGluSnFr) expressed in CA1 neurons in hippocampal organotypic slices from wild-type (WT) and Mecp2-/y mice (RTT). The neuronal and synaptic activities were assessed by patch-clamp and calcium imaging. In both WT and RTT slices, activation of AMPA, kainate, and NMDA receptors for 30 s first enhanced neuronal activity that induced a global release of glutamate. After transient augmentation of excitability and ambient glutamate, they subsided. After wash out of the agonists for 10 min, WT slices recovered and demonstrated repetitive glutamate transients, whose pattern resembled those observed in naïve RTT slices. Hyperpolarization-activated (HCN) decreased and voltage-sensitive calcium channel (VSCC) currents increased. The effects were long-lasting and bigger in WT. We examined the role of mGluR1/5 in more detail. The effects of the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) were the same as AMPA and NMDA and occluded by mGluR1/5 antagonists. Further modifications were examined using a non-stationary noise analysis of postsynaptic currents. The mean single channel current and their number at postsynapse increased after DHPG. We identified new channels as calcium-permeable AMPARs (CP-AMPAR). We then examined back-propagating potentials (bAPs) as a measure of postsynaptic integration. After bAPs, spontaneous afterdischarges were observed that lasted for ∼2 min and were potentiated by DHPG. The effects were occluded by intracellular CP-AMPAR blocker and did not change after NMDAR blockade. We propose that brief elevations in ambient glutamate (through brief excitation with GluR agonists) specifically activate mGluR1/5. This modifies CP-AMPAR, HCN, and calcium conductances and makes neurons hyperexcitable. Induced changes can be further supported by repetitive glutamate transients established and serve to persistently maintain the aberrant neuronal RTT phenotype in the hippocampus.
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  • Journal Article

    xial Tubule Junctions Activate Atrial Ca2+ Release Across Species 

    Brandenburg, Sören; Pawlowitz, Jan; Fakuade, Funsho E.; Kownatzki-Danger, Daniel; Kohl, Tobias; Mitronova, Gyuzel Y.; Scardigli, Marina; Neef, Jakob; Schmidt, Constanze; Wiedmann, Felix; et al.
    Pavone, Francesco S.Sacconi, LeonardoKutschka, IngoSossalla, SamuelMoser, TobiasVoigt, NielsLehnart, Stephan E.
    Frontiers in Physiology 2018; 9: Art. 1227
    Rationale: Recently, abundant axial tubule (AT) membrane structures were identified deep inside atrial myocytes (AMs). Upon excitation, ATs rapidly activate intracellular Ca2+ release and sarcomeric contraction through extensive AT junctions, a cell-specific atrial mechanism. While AT junctions with the sarcoplasmic reticulum contain unusually large clusters of ryanodine receptor 2 (RyR2) Ca2+ release channels in mouse AMs, it remains unclear if similar protein networks and membrane structures exist across species, particularly those relevant for atrial disease modeling. Objective: To examine and quantitatively analyze the architecture of AT membrane structures and associated Ca2+ signaling proteins across species from mouse to human. Methods and Results: We developed superresolution microscopy (nanoscopy) strategies for intact live AMs based on a new custom-made photostable cholesterol dye and immunofluorescence imaging of membraneous structures and membrane proteins in fixed tissue sections from human, porcine, and rodent atria. Consistently, in mouse, rat, and rabbit AMs, intact cell-wide tubule networks continuous with the surface membrane were observed, mainly composed of ATs. Moreover, co-immunofluorescence nanoscopy showed L-type Ca2+ channel clusters adjacent to extensive junctional RyR2 clusters at ATs. However, only junctional RyR2 clusters were highly phosphorylated and may thus prime Ca2+ release at ATs, locally for rapid signal amplification. While the density of the integrated L-type Ca2+ current was similar in human and mouse AMs, the intracellular Ca2+ transient showed quantitative differences. Importantly, local intracellular Ca2+ release from AT junctions occurred through instantaneous action potential propagation via transverse tubules (TTs) from the surface membrane. Hence, sparse TTs were sufficient as electrical conduits for rapid activation of Ca2+ release through ATs. Nanoscopy of atrial tissue sections confirmed abundant ATs as the major network component of AMs, particularly in human atrial tissue sections. Conclusion: AT junctions represent a conserved, cell-specific membrane structure for rapid excitation-contraction coupling throughout a representative spectrum of species including human. Since ATs provide the major excitable membrane network component in AMs, a new model of atrial "super-hub" Ca2+ signaling may apply across biomedically relevant species, opening avenues for future investigations about atrial disease mechanisms and therapeutic targeting.
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  • Journal Article

    Drosophila Ror is a nervous system-specific co-receptor for Wnt ligands 

    Ripp, Caroline; Loth, Julia; Petrova, Iveta; Linnemannstöns, Karen; Ulepic, Monique; Fradkin, Lee; Noordermeer, Jasprien; Wodarz, Andreas
    Biology Open 2018; 7(11): Art. bio033001
    Wnt ligands are secreted glycoproteins that control many developmental processes and are crucial for homeostasis of numerous tissues in the adult organism. Signal transduction of Wnts involves the binding of Wnts to receptor complexes at the surface of target cells. These receptor complexes are commonly formed between a member of the Frizzled family of seven-pass transmembrane proteins and a co-receptor, which is usually a single-pass transmembrane protein. Among these co-receptors are several with structural homology to receptor tyrosine kinases, including Ror, PTK7, Ryk and MUSK. In vertebrates, Ror-2 and PTK7 are important regulators of planar cell polarity (PCP). By contrast, PCP phenotypes were not reported for mutations in off-track (otk) and off-track2 (otk2), encoding the Drosophila orthologs of PTK7. Here we show that Drosophila Ror is expressed in the nervous system and localizes to the plasma membrane of perikarya and neurites. A null allele of Ror is homozygous viable and fertile, does not display PCP phenotypes and interacts genetically with mutations in otk and otk2 We show that Ror binds specifically to Wingless (Wg), Wnt4 and Wnt5 and also to Frizzled2 (Fz2) and Otk. Our findings establish Drosophila Ror as a Wnt co-receptor expressed in the nervous system.
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  • Journal Article

    Adults who stutter lack the specialised pre-speech facilitation found in non-stutterers 

    Whillier, Alexander; Hommel, Sina; Neef, Nicole E.; Wolff von Gudenberg, Alexander; Paulus, Walter; Sommer, Martin
    PLOS ONE 2018; 13(10): Art. e0202634
    OBJECTIVES: Persistent developmental stuttering is a speech fluency disorder defined by its symptoms, where the underlying neurophysiological causes remain uncertain. This study examined the underlying neurophysiological mechanisms of the speech planning process, using facilitation in the motor cortex during speech preparation as an analogue. METHODS: transcranial magnetic stimulation (TMS) pulses induced motor evoked potentials (MEPs), which were recorded from the tongue. Eighteen adults who stutter (AWS) and 17 adults who do not stutter (ANS) completed three experiments, which involved reading a German prefix+verb utterance from a screen. Each experiment involved 120 trials with three distinct levels of speech production: immediate speech, delayed speech without pacing and delayed speech with predefined pacing. TMS was applied shortly before speech onset. Trial MEPs were normalised to average non-speech MEPs. MEP amplitude, MEP facilitation ratio (amplitude: pre-speech offset) and group difference were the outcomes of interest analysed by multiple regression, as well as speech reaction time analysed by correlation. RESULTS: MEP values were 11·1%-23·4% lower in AWS than ANS (by standardised Beta), across all three experiments. MEP facilitation ratio slopes were also 4·9%-18·3% flatter in AWS than ANS across all three experiments. Reaction times for AWS were only significantly slower than for ANS in immediate speech and predefined pacing experiments. No stuttering was detected during the trials. The group difference in immediate speech was 100% and 101% greater than the other two experiments respectively. DISCUSSION: While performance of both ANS and AWS worsens under disturbed speech conditions, greater disturbance conditions affected controls worse than AWS. Future research and therapy in stuttering should focus on non-disturbed speech.
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  • Journal Article

    Training of clinical reasoning with a Serious Game versus small-group problem-based learning: A prospective study 

    Middeke, Angélina; Anders, Sven; Schuelper, Madita; Raupach, Tobias; Schuelper, Nikolai
    PLOS ONE 2018; 13(9): Art. e0203851
    INTRODUCTION: Serious Games are increasingly being used in undergraduate medical education. They are usually intended to enhance learning with a focus on knowledge acquisition and skills development. According to the current literature, few studies have assessed their effectiveness regarding clinical reasoning (CR). The aim of this prospective study was to compare a Serious Game, the virtual Accident & Emergency department 'EMERGE' to small-group problem-based learning (PBL) regarding student learning outcome on clinical reasoning in the short term. METHODS: A total of 112 final-year medical students self-selected to participate in ten 90-minute sessions of either small-group PBL or playing EMERGE. CR was assessed in a formative examination consisting of six key feature cases and a final 45-minute EMERGE session. RESULTS: Overall, the EMERGE group (n = 78) scored significantly higher than the PBL group (n = 34) in the key feature examination (62.5 (IQR: 17.7)% vs. 54.2 (IQR: 21.9)%; p = 0.015). There was no significant difference in performance levels between groups regarding those cases which had been discussed in both instructional formats during the training phase. In the final EMERGE session, the EMERGE group achieved significantly better results than the PBL group in all four cases regarding the total score as well as in three of four cases regarding the final diagnosis and the correct therapeutic interventions. CONCLUSION: EMERGE can be used effectively for CR training in undergraduate medical education. The difference in key feature exam scores was driven by additional exposure to more cases in EMERGE compared to PBL despite identical learning time in both instructional formats. EMERGE is a potential alternative to intensive small-group teaching. Further work is needed to establish how Serious Games enhance CR most effectively.
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  • Journal Article

    Regenerative glutamate release in the hippocampus of Rett syndrome model mice 

    Balakrishnan, Saju; Mironov, Sergej L.
    PLOS ONE 2018; 13(9): Art. e0202802
    Excess glutamate during intense neuronal activity is not instantly cleared and may accumulate in the extracellular space. This has various long-term consequences such as ectopic signaling, modulation of synaptic efficacy and excitotoxicity; the latter implicated in various neurodevelopmental and neurodegenerative diseases. In this study, the quantitative imaging of glutamate homeostasis of hippocampal slices from methyl-CpG binding protein 2 knock-out (Mecp2-/y) mice, a model of Rett syndrome (RTT), revealed unusual repetitive glutamate transients. They appeared in phase with bursts of action potentials in the CA1 neurons. Both glutamate transients and bursting activity were suppressed by the blockade of sodium, AMPA and voltage-gated calcium channels (T- and R-type), and enhanced after the inhibition of HCN channels. HCN and calcium channels in RTT and wild-type (WT) CA1 neurons displayed different voltage-dependencies and kinetics. Both channels modulated postsynaptic integration and modified the pattern of glutamate spikes in the RTT hippocampus. Spontaneous glutamate transients were much less abundant in the WT preparations, and, when observed, had smaller amplitude and frequency. The basal ambient glutamate levels in RTT were higher and transient glutamate increases (spontaneous and evoked by stimulation of Schaffer collaterals) decayed slower. Both features indicate less efficient glutamate uptake in RTT. To explain the generation of repetitive glutamate spikes, we designed a novel model of glutamate-induced glutamate release. The simulations correctly predicted the patterns of spontaneous glutamate spikes observed under different experimental conditions. We propose that pervasive spontaneous glutamate release is a hallmark of Mecp2-/y hippocampus, stemming from and modulating the hyperexcitability of neurons.
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  • Journal Article

    Validation of collateral scoring on flat-detector multiphase CT angiography in patients with acute ischemic stroke 

    Maier, Ilko L.; Scalzo, Fabien; Leyhe, Johanna R.; Schregel, Katharina; Behme, Daniel; Tsogkas, Ioannis; Psychogios, Marios-Nikos; Liebeskind, David S.
    PLOS ONE 2018; 13(8): Art. e0202592
    BACKGROUND: The pivotal impact of collateral circulation on outcomes in endovascular therapy has fueled the development of numerous CTA collateral scales, yet synchronized validation with conventional angiography has never occurred. We validated multiphase flat-detector CTA (mpFDCTA) for collateral imaging in patients undergoing endovascular stroke treatment. MATERIALS AND METHODS: Consecutive acute ischemic stroke patient data, including mpFDCTA shortly followed by digital subtraction angiography (DSA), in the setting of acute ICA- or MCA-occlusions were analyzed. An independent core lab scored mpFDCTA with an established collateral scale and separately graded American Society of Interventional and Therapeutic Neuroradiology (ASITN) collateral score on DSA, blind to all other data. RESULTS: 24 consecutive cases (age 76.7 ± 7.3 years; 58.3% women; baseline NIHSS median 17 (4-23)) of acute ICA- or MCA-occlusion were analyzed. Time from mpFDCTA to intracranial DSA was 23.04 ± 7.6 minutes. Median mpFDCTA collateral score was 3 (0-5) and median DSA ASITN collateral score was 2 (0-3), including the full range of potential collateral grades. mpFDCTA and ASITN collateral score were strongly correlated (r = 0.86, p<0.001). mpFDCTA provided more complete collateral data compared to selective DSA injections in cases of ICA-occlusion. ROC analyses for prediction of clinical outcomes revealed an AUC of 0.76 for mpFDCTA- and 0.70 for DSA ASITN collaterals. CONCLUSIONS: mpFDCTA in the angiography suite provides a validated measure of collaterals, offering distinct advantages over conventional angiography. Direct patient transfer to the angiography suite and mpFDCTA collateral grading provides a novel and reliable triage paradigm for acute ischemic stroke.
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  • Journal Article

    Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1α Expression in Hypoxia. 

    Chowdhury, Arpita; Aich, Abhishek; Jain, Gaurav; Wozny, Katharina; Lüchtenborg, Christian; Hartmann, Magnus; Bernhard, Olaf; Balleiniger, Martina; Alfar, Ezzaldin Ahmed; Zieseniss, Anke; et al.
    Toischer, KarlGuan, KaomeiRizzoli, Silvio OBrügger, BrittaFischer, AndrèKatschinski, Dörthe MRehling, PeterDudek, Jan
    Cell Reports 2018; 25(3) p.561-570
    Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs, integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin remodeling, upon loss of the cardiolipin acyl transferase tafazzin, decreases HIF-1α signaling in hypoxia. Tafazzin deficiency does not affect posttranslational HIF-1α regulation but rather HIF-1α gene expression, a dysfunction recapitulated in iPSC-derived cardiomyocytes from Barth syndrome patients with tafazzin deficiency. RNA-seq analyses confirmed drastically altered signaling in tafazzin mutant cells. In hypoxia, tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-κB activation and concomitantly HIF-1α gene expression. Tafazzin-deficient mice hearts display reduced HIF-1α levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin remodeling dampens HIF-1α signaling due to a lack of NF-κB activation through reduced mitochondrial ROS production, decreasing HIF-1α transcription.
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  • Journal Article

    Precisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions. 

    Fornasiero, Eugenio F.; Mandad, Sunit; Wildhagen, Hanna; Alevra, Mihai; Rammner, Burkhard; Keihani, Sarva; Opazo, Felipe; Urban, Inga; Ischebeck, Till; Sakib, M. Sadman; et al.
    Fard, Maryam K.Kirli, KorayCenteno, Tonatiuh PenaVidal, Ramon O.Rahman, Raza-UrBenito, EvaFischer, AndréDennerlein, SvenRehling, PeterFeussner, IvoBonn, StefanSimons, MikaelUrlaub, HenningRizzoli, Silvio O.
    Nature Communications 2018; 9(1): Art. 4230
    The turnover of brain proteins is critical for organism survival, and its perturbations are linked to pathology. Nevertheless, protein lifetimes have been difficult to obtain in vivo. They are readily measured in vitro by feeding cells with isotopically labeled amino acids, followed by mass spectrometry analyses. In vivo proteins are generated from at least two sources: labeled amino acids from the diet, and non-labeled amino acids from the degradation of pre-existing proteins. This renders measurements difficult. Here we solved this problem rigorously with a workflow that combines mouse in vivo isotopic labeling, mass spectrometry, and mathematical modeling. We also established several independent approaches to test and validate the results. This enabled us to measure the accurate lifetimes of ~3500 brain proteins. The high precision of our data provided a large set of biologically significant observations, including pathway-, organelle-, organ-, or cell-specific effects, along with a comprehensive catalog of extremely long-lived proteins (ELLPs).
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  • Journal Article

    Recent advances in methodology for clinical trials in small populations: the InSPiRe project. 

    Friede, Tim; Posch, Martin; Zohar, Sarah; Alberti, Corinne; Benda, Norbert; Comets, Emmanuelle; Day, Simon; Dmitrienko, Alex; Graf, Alexandra; Günhan, Burak Kürsad; et al.
    Hee, Siew WanLentz, FrederikeMadan, JasonMiller, FrankOndra, ThomasPearce, MichaelRöver, ChristianToumazi, ArtemisUnkel, SteffenUrsino, MorenoWassmer, GernotStallard, Nigel
    Orphanet Journal of Rare Diseases 2018-10-25; 13: Art. 186
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  • Journal Article

    Viabahn stent graft compared with prosthetic surgical above-knee bypass in treatment of superficial femoral artery disease 

    Waezi, Narges; Saha, Shekhar; Bougioukas, Ioannis; Emmert, Alexander; Danner, Bernhard Christoph; Baraki, Hassina; Kutschka, Ingo; Zenker, Dieter; Stojanovic, Tomislav; Jebran, Ahmad Fawad
    Medicine 2018; 97(40): Art. e12449
    The prosthetic surgical above-knee bypass (pAKB) is a standard therapy in superficial femoral artery (SFA) occlusive disease in absence of suitable vein. Viabahn graft has been established as a promising alternative. Since limited comparative data are available, we conducted a retrospective study to compare long-term outcomes of these 2 therapies in a real-world setting.Records of 52 patients (60 limbs), who were treated by pAKB (29 limbs) or Viabahn (31 limbs) were reviewed. Patients were followed up by clinical assessment, physical examination, and resting ankle brachial index (ABI) after 3, 6, 12 months and yearly thereafter. Long-term data were available for 97% in the Viabahn and 93% for pAKB after 73 ± 3.7 months (mean ± standard error [SE]).Long-term primary and secondary patencies in Viabahn group were 40% and 70%, respectively, after 63 ± 2.8 months (mean ± SE). Total lesion length was 19 ± 11.06 cm (mean ± SE), graft size was 6 ± 0.72 mm (mean ± SE). Hospital stay was 4.8 ± 0.72 days (mean ± SE). Limb salvage was achieved in 90%. Patients in the pAKB group showed a total lesion length of 24.39 ± 1.97 cm (mean ± SE), graft size was 7 ± 0.99 mm (mean ± SE). Long-term analysis after 83 ± 6.8 months (mean ± SE) revealed a primary patency of 78% with a secondary patency of 94%. Hospital stay was 10.4 ± 1.27 days (mean ± SE). Limb salvage was ensured in 97%. Long-term primary patency was lower for Viabahn (P = .044), secondary patency (P = .245), and leg salvage (P = .389) were not significantly different. However, hospital stay was shorter (P = .0002) for Viabahn.Long-term analysis of Viabahn revealed a significantly lower primary patency, a similar secondary patency, limb salvage, and significantly shorter hospital stay when compared with pAKB. Our data suggest that pAKB is still a valuable option in patients suitable for an open operation. However, Viabahn can be used as a less invasive treatment in high risk patients.
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  • Journal Article

    Danger-Associated Molecular Patterns (DAMPs): Molecular Triggers for Sterile Inflammation in the Liver 

    Mihm, Sabine
    International Journal of Molecular Sciences 2018; 19(10): Art. 3104
    Inflammatory liver diseases in the absence of pathogens such as intoxication by xenobiotics, cholestatic liver injury, hepatic ischemia-reperfusion injury (I/R), non-alcoholic steatohepatitis (NASH), or alcoholic liver disease (ALD) remain threatening conditions demanding specific therapeutic options. Caused by various different noxae, all these conditions have been recognized to be triggered by danger- or death-associated molecular patterns (DAMPs), discompartmentalized self-structures released by dying cells. These endogenous, ectopic molecules comprise proteins, nucleic acids, adenosine triphosphate (ATP), or mitochondrial compounds, among others. This review resumes the respective modes of their release-passively by necrotic hepatocytes or actively by viable or apoptotic parenchymal cells-and their particular roles in sterile liver pathology. It addresses their sensors and the initial inflammatory responses they provoke. It further addresses a resulting second wave of parenchymal death that might be of different mode, boosting the release of additional, second-line DAMPs. Thus, triggering a more complex and pronounced response. Initial and secondary inflammatory responses comprise the activation of Kupffer cells (KCs), the attraction and activation of monocytes and neutrophil granulocytes, and the induction of type I interferons (IFNs) and their effectors. A thorough understanding of pathophysiology is a prerequisite for identifying rational therapeutic targets.
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  • Journal Article

    The CTLA-4 rs231775 GG genotype is associated with favorable 90-day survival in Caucasian patients with sepsis 

    Mewes, Caspar; Büttner, Benedikt; Hinz, José; Alpert, Ayelet; Popov, Aron Frederik; Ghadimi, Michael; Beissbarth, Tim; Tzvetkov, Mladen; Shen-Orr, Shai; Bergmann, Ingo; et al.
    Mansur, Ashham
    Scientific Reports 2018; 8(1)
    Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a surface protein on T cells, that has an inhibitory effect on the host immune reaction and prevents overreaction of the immune system. Because the functional single-nucleotide polymorphism (SNP) rs231775 of the CTLA-4 gene is associated with autoimmune diseases and because of the critical role of the immune reaction in sepsis, we intended to examine the effect of this polymorphism on survival in patients with sepsis. 644 septic adult Caucasian patients were prospectively enrolled in this study. Patients were followed up for 90 days. Mortality risk within this period was defined as primary outcome parameter. Kaplan-Meier survival analysis revealed a significantly lower 90-day mortality risk among GG homozygous patients (n = 101) than among A allele carriers (n = 543; 22% and 32%, respectively; p = 0.03565). Furthermore, the CTLA-4 rs231775 GG genotype remained a significant covariate for 90-day mortality risk after controlling for confounders in the multivariate Cox regression analysis (hazard ratio: 0.624; 95% CI: 0.399–0.975; p = 0.03858). In conclusion, our study provides the first evidence for CTLA-4 rs231775 as a prognostic variable for the survival of patients with sepsis and emphasizes the need for further research to reveal potential functional associations between CTLA-4 and the immune pathophysiology of sepsis.
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  • Journal Article

    Degrees-of-freedom estimation in the Student-t noise model 

    Röver, Christian
    The Student-t noise model was introduced as a robust alternative to the commonly used stationary, Gaussian noise model that constitutes the basis for many signal processing procedures. This model may also be used to generalize the matched filter in order to make it less outlier-sensitive. The generalized Student-t model includes an additional set of degrees-of-freedom parameters nu_j along with the power spectral density S(f_j). These d.o.f. parameters effectively specify the degree of heavy-tailedness of the noise that is accounted for or expected through the model. While there are many off-the-shelf procedures available for estimating the PSD S(f_j), it is not so obvious how one would go about estimating the d.o.f. parameters. We decribe a first attempt at eliciting these parameters from empirical measurements using some LIGO data.
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  • Journal Article

    Model averaging for robust extrapolation in evidence synthesis 

    Röver, Christian; Wandel, Simon; Friede, Tim
    Statistics in Medicine
    Extrapolation from a source to a target, e.g., from adults to children, is a promising approach to utilizing external information when data are sparse. In the context of meta-analysis, one is commonly faced with a small number of studies, while potentially relevant additional information may also be available. Here we describe a simple extrapolation strategy using heavy-tailed mixture priors for effect estimation in meta-analysis, which effectively results in a model-averaging technique. The described method is robust in the sense that a potential prior-data conflict, i.e., a discrepancy between source and target data, is explicitly anticipated. The aim of this paper to develop a solution for this particular application, to showcase the ease of implementation by providing R code, and to demonstrate the robustness of the general approach in simulations.
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