@article{GeigerHirtlerGottfriedetal.2017, author = {Geiger, Julia and Hirtler, Daniel and Gottfried, Kristina and Rahman, Ozair and Bollache, Emilie and Barker, Alex J. and Markl, Michael and Stiller, Brigitte}, title = {Longitudinal Evaluation of Aortic Hemodynamics in Marfan Syndrome: New Insights from a 4D Flow Cardiovascular Magnetic Resonance Multi-Year Follow-Up Study}, series = {Journal of Cardiovascular Magnetic Resonance}, volume = {19}, journal = {Journal of Cardiovascular Magnetic Resonance}, number = {33}, doi = {10.1186/s12968-017-0347-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171119}, year = {2017}, abstract = {Background The aim of this 4D flow cardiovascular magnetic resonance (CMR) follow-up study was to investigate longitudinal changes in aortic hemodynamics in adolescent patients with Marfan syndrome (MFS). Methods 4D flow CMR for the assessment of in-vivo 3D blood flow with full coverage of the thoracic aorta was performed twice (baseline scan t1/follow-up scan t2) in 19 adolescent MFS patients (age at t1: 12.7 ± 3.6 years, t2: 16.2 ± 4.3 years) with a mean follow-up duration of 3.5 ± 1.2 years. Ten healthy volunteers (24 ± 3.8 years) served as a control group. Data analysis included aortic blood flow visualization by color-coded 3D pathlines, and grading of flow patterns (helices/vortices) on a 3-point scale (none, moderate, severe; blinded reading, 2 observers). Regional aortic peak systolic velocities and systolic 3D wall shear stress (WSS) along the entire aortic wall were quantified. Z-Scores of the aortic root and proximal descending aorta (DAo) were assessed. Results Regional systolic WSS was stable over the follow-up duration, except for a significant decrease in the proximal inner DAo segment (p = 0.02) between t1 and t2. MFS patients revealed significant lower mean systolic WSS in the proximal inner DAo compared with volunteers (0.78 ± 0.15 N/m\(^{2}\)) at baseline t1 (0.60 ± 0.18 N/m\(^{2}\); p = 0.01) and follow-up t2 (0.55 ± 0.16 N/m\(^{2}\); p = 0.001). There were significant relationships (p < 0.01) between the segmental WSS in the proximal inner DAo, DAo Z-scores (r = -0.64) and helix/vortex pattern grading (r = -0.55) at both t1 and t2. The interobserver agreement for secondary flow patterns assessment was excellent (Cohen's k = 0.71). Conclusions MFS patients have lower segmental WSS in the inner proximal DAo segment which correlates with increased localized aberrant vortex/helix flow patterns and an enlarged diameter at one of the most critical sites for aortic dissection. General aortic hemodynamics are stable but these subtle localized DAo changes are already present at young age and tend to be more pronounced in the course of time.}, language = {en} } @article{SalingerHuLiuetal.2017, author = {Salinger, Tim and Hu, Kai and Liu, Dan and Herrmann, Sebastian and Lorenz, Kristina and Ertl, Georg and Nordbeck, Peter}, title = {Cardiac amyloidosis mimicking severe aortic valve stenosis - a case report demonstrating diagnostic pitfalls and role of dobutamine stress echocardiography}, series = {BMC Cardiovascular Disorders}, volume = {17}, journal = {BMC Cardiovascular Disorders}, number = {86}, doi = {10.1186/s12872-017-0519-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171109}, year = {2017}, abstract = {Background Aortic valve stenosis is a common finding diagnosed with high sensitivity in transthoracic echocardiography, but the examiner often finds himself confronted with uncertain results in patients with moderate pressure gradients and concomitant systolic heart failure. While patients with true-severe low-gradient aortic valve stenosis with either reduced or preserved left ventricular systolic function are primarily candidates for valve replacement, there is a relevant proportion of patients with pseudo-severe aortic valve stenosis anticipated not to benefit but actually rather deteriorate by interventional therapy or surgery. Case presentation In this article we present a case report of a male patient with pseudo-severe aortic valve stenosis due to cardiac amyloidosis highlighting the diagnostic schedule. The patient underwent stress echocardiography because of discrepant findings in transthoracic echocardiography and cardiac catheterization regarding the severity of aortic valve stenosis. After evaluation of the results, it became clear that he had a need for optimum heart failure medication and implantation of a cardiac resynchronization therapy defibrillator. Conclusion Due to the pitfalls in conventional as well as invasive diagnostics at rest, Stress echocardiography should be considered part of the standard optimum diagnostic spectrum in all unclear or borderline cases in order to confirm the correct diagnosis and constitute optimal therapy.}, language = {en} } @article{BrodehlBelkeGarnettetal.2017, author = {Brodehl, Andreas and Belke, Darrell D. and Garnett, Lauren and Martens, Kristina and Abdelfatah, Nelly and Rodriguez, Marcela and Diao, Catherine and Chen, Yong-Xiang and Gordon, Paul M. K. and Nygren, Anders and Gerull, Brenda}, title = {Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0174019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171084}, pages = {e0174019}, year = {2017}, abstract = {Background Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology. Methods and results We generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D-echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age. Conclusion Cardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy.}, language = {en} } @article{FischerHarrisonRamirezetal.2017, author = {Fischer, Annette and Harrison, Kelly S and Ramirez, Yesid and Auer, Daniela and Chowdhury, Suvagata Roy and Prusty, Bhupesh K and Sauer, Florian and Dimond, Zoe and Kisker, Caroline and Hefty, P Scott and Rudel, Thomas}, title = {Chlamydia trachomatis-containing vacuole serves as deubiquitination platform to stabilize Mcl-1 and to interfere with host defense}, series = {eLife}, volume = {6}, journal = {eLife}, number = {e21465}, doi = {10.7554/eLife.21465}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171073}, year = {2017}, abstract = {Obligate intracellular Chlamydia trachomatis replicate in a membrane-bound vacuole called inclusion, which serves as a signaling interface with the host cell. Here, we show that the chlamydial deubiquitinating enzyme (Cdu) 1 localizes in the inclusion membrane and faces the cytosol with the active deubiquitinating enzyme domain. The structure of this domain revealed high similarity to mammalian deubiquitinases with a unique α-helix close to the substrate-binding pocket. We identified the apoptosis regulator Mcl-1 as a target that interacts with Cdu1 and is stabilized by deubiquitination at the chlamydial inclusion. A chlamydial transposon insertion mutant in the Cdu1-encoding gene exhibited increased Mcl-1 and inclusion ubiquitination and reduced Mcl-1 stabilization. Additionally, inactivation of Cdu1 led to increased sensitivity of C. trachomatis for IFNγ and impaired infection in mice. Thus, the chlamydial inclusion serves as an enriched site for a deubiquitinating activity exerting a function in selective stabilization of host proteins and protection from host defense.}, language = {en} } @article{WiegeringMatthesMuehlingetal.2017, author = {Wiegering, Armin and Matthes, Niels and M{\"u}hling, Bettina and Koospal, Monika and Quenzer, Anne and Peter, Stephanie and Germer, Christoph-Thomas and Linnebacher, Michael and Otto, Christoph}, title = {Reactivating p53 and Inducing Tumor Apoptosis (RITA) Enhances the Response of RITA-Sensitive Colorectal Cancer Cells to Chemotherapeutic Agents 5-Fluorouracil and Oxaliplatin}, series = {Neoplasia}, volume = {19}, journal = {Neoplasia}, number = {4}, doi = {10.1016/j.neo.2017.01.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171067}, pages = {301-309}, year = {2017}, abstract = {Colorectal carcinoma (CRC) is the most common cancer of the gastrointestinal tract with frequently dysregulated intracellular signaling pathways, including p53 signaling. The mainstay of chemotherapy treatment of CRC is 5-fluorouracil (5FU) and oxaliplatin. The two anticancer drugs mediate their therapeutic effect via DNA damage-triggered signaling. The small molecule reactivating p53 and inducing tumor apoptosis (RITA) is described as an activator of wild-type and reactivator of mutant p53 function, resulting in elevated levels of p53 protein, cell growth arrest, and cell death. Additionally, it has been shown that RITA can induce DNA damage signaling. It is expected that the therapeutic benefits of 5FU and oxaliplatin can be increased by enhancing DNA damage signaling pathways. Therefore, we highlighted the antiproliferative response of RITA alone and in combination with 5FU or oxaliplatin in human CRC cells. A panel of long-term established CRC cell lines (n = 9) including p53 wild-type, p53 mutant, and p53 null and primary patient-derived, low-passage cell lines (n = 5) with different p53 protein status were used for this study. A substantial number of CRC cells with pronounced sensitivity to RITA (IC\(_{50}\)< 3.0 μmol/l) were identified within established (4/9) and primary patient-derived (2/5) CRC cell lines harboring wild-type or mutant p53 protein. Sensitivity to RITA appeared independent of p53 status and was associated with an increase in antiproliferative response to 5FU and oxaliplatin, a transcriptional increase of p53 targets p21 and NOXA, and a decrease in MYC mRNA. The effect of RITA as an inducer of DNA damage was shown by a strong elevation of phosphorylated histone variant H2A.X, which was restricted to RITA-sensitive cells. Our data underline the primary effect of RITA, inducing DNA damage, and demonstrate the differential antiproliferative effect of RITA to CRC cells independent of p53 protein status. We found a substantial number of RITA-sensitive CRC cells within both panels of established CRC cell lines and primary patient-derived CRC cell lines (6/14) that provide a rationale for combining RITA with 5FU or oxaliplatin to enhance the antiproliferative response to both chemotherapeutic agents.}, language = {en} } @article{SchaeferBauerDonhauseretal.2017, author = {Sch{\"a}fer, Kristina and Bauer, Boris and Donhauser, Julian and Kerstan, Andreas and Hamm, Henning}, title = {Becker Naevus Syndrome of the Lower Body: A New Case and Review of the Literature}, series = {Acta Dermato-Venereologica}, volume = {97}, journal = {Acta Dermato-Venereologica}, number = {4}, doi = {10.2340/00015555-2589}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171057}, pages = {499-504}, year = {2017}, abstract = {Becker naevus syndrome is a rare epidermal naevus syndrome defined by the co-occurrence of a Becker naevus with various cutaneous, muscular and skeletal anomalies. In the majority of cases, abnormalities exclusively consist of ipsilateral hypoplasia of the breast, areola and/or nipple in addition to the naevus. Here, we report on a 42-year-old woman with an extensive Becker naevus reaching from the left buttock to the left calf verified on histological examination. In addition, there was marked hypoplasia of the fatty tissue of the left thigh confirmed by magnetic resonance imaging in contrast to hyperplasia of the fatty tissue of the left gluteal area. Underlying muscles and bones were not affected. There was no difference in leg lengths. In addition, we review and discuss the features of Becker naevus syndrome with emphasis on 10 reported cases with involvement of the lower body.}, language = {en} } @article{MeiningerBlumSchameletal.2017, author = {Meininger, Susanne and Blum, Carina and Schamel, Martha and Barralet, Jake E. and Ignatius, Anita and Gbureck, Uwe}, title = {Phytic acid as alternative setting retarder enhanced biological performance of dicalcium phosphate cement in vitro}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {558}, doi = {10.1038/s41598-017-00731-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171047}, year = {2017}, abstract = {Dicalcium phosphate cement preparation requires the addition of setting retarders to meet clinical requirements regarding handling time and processability. Previous studies have focused on the influence of different setting modifiers on material properties such as mechanical performance or injectability, while ignoring their influence on biological cement properties as they are used in low concentrations in the cement pastes and the occurrence of most compounds in human tissues. Here, analyses of both material and biological behavior were carried out on samples with common setting retardants (citric acid, sodium pyrophosphate, sulfuric acid) and novel (phytic acid). Cytocompatibility was evaluated by in vitro tests with osteoblastic (hFOB 1.19) and osteoclastic (RAW 264.7) cells. We found cytocompatibility was better for sodium pyrophosphate and phytic acid with a three-fold cell metabolic activity by WST-1 test, whereas samples set with citric acid showed reduced cell number as well as cell activity. The compressive strength (CS) of cements formed with phytic acid (CS = 13 MPa) were nearly equal to those formed with citric acid (CS = 15 MPa) and approximately threefold higher than for other setting retardants. Due to a proven cytocompatibility and high mechanical strength, phytic acid seems to be a candidate replacement setting retardant for dicalcium phosphate cements.}, language = {en} } @article{SperlichWallmannSperlichZinneretal.2017, author = {Sperlich, Billy and Wallmann-Sperlich, Birgit and Zinner, Christoph and Von Stauffenberg, Valerie and Losert, Helena and Holmberg, Hans-Christer}, title = {Functional High-intensity Circuit Training Improves Body Composition,Peak Oxygen Uptake, Strength, and Alters Certain Dimensions of Quality of Life in Overweight Women}, series = {Frontiers in Physiology}, volume = {8}, journal = {Frontiers in Physiology}, number = {172}, doi = {10.3389/fphys.2017.00172}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171015}, year = {2017}, abstract = {The effects of circuit-like functional high-intensity training (Circuit\(_{HIIT}\)) alone or in combination with high-volume low-intensity exercise (Circuit\(_{combined}\)) on selected cardio-respiratory and metabolic parameters, body composition, functional strength and the quality of life of overweight women were compared. In this single-center, two-armed randomized, controlled study, overweight women performed 9-weeks (3 sessions·wk\(^{-1}\)) of either Circuit\(_{HIIT}\) (n = 11), or Circuit\(_{combined}\) (n = 8). Peak oxygen uptake and perception of physical pain were increased to a greater extent (p < 0.05) by Circuit\(_{HIIT}\), whereas Circuit\(_{combined}\) improved perception of general health more (p < 0.05). Both interventions lowered body mass, body-mass-index, waist-to-hip ratio, fat mass, and enhanced fat-free mass; decreased ratings of perceived exertion during submaximal treadmill running; improved the numbers of push-ups, burpees, one-legged squats, and 30-s skipping performed, as well as the height of counter-movement jumps; and improved physical and social functioning, role of physical limitations, vitality, role of emotional limitations, and mental health to a similar extent (all p < 0.05). Either forms of these multi-stimulating, circuit-like, multiple-joint training can be employed to improve body composition, selected variables of functional strength, and certain dimensions of quality of life in overweight women. However, Circuit\(_{HIIT}\) improves peak oxygen uptake to a greater extent, but with more perception of pain, whereas Circuit\(_{Combined}\) results in better perception of general health.}, language = {en} } @article{PirothBoelmansAmtageetal.2017, author = {Piroth, Tobias and Boelmans, Kai and Amtage, Florian and Rijntjes, Michel and Wierciochin, Anna and Musacchio, Thomas and Weiller, Cornelius and Volkmann, Jens and Klebe, Stephan}, title = {Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult}, series = {Frontiers in Neurology}, volume = {8}, journal = {Frontiers in Neurology}, number = {108}, doi = {10.3389/fneur.2017.00108}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171001}, year = {2017}, abstract = {Niemann-Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty.}, language = {en} } @article{SanchoVandersmissenCrapsetal.2017, author = {Sancho, Ana and Vandersmissen, Ine and Craps, Sander and Luttun, Aernout and Groll, J{\"u}rgen}, title = {A new strategy to measure intercellular adhesion forces in mature cell-cell contacts}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {46152}, doi = {10.1038/srep46152}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170999}, year = {2017}, abstract = {Intercellular adhesion plays a major role in tissue development and homeostasis. Yet, technologies to measure mature cell-cell contacts are not available. We introduce a methodology based on fluidic probe force microscopy to assess cell-cell adhesion forces after formation of mature intercellular contacts in cell monolayers. With this method we quantify that L929 fibroblasts exhibit negligible cell-cell adhesion in monolayers whereas human endothelial cells from the umbilical artery (HUAECs) exert strong intercellular adhesion forces per cell. We use a new in vitro model based on the overexpression of Muscle Segment Homeobox 1 (MSX1) to induce Endothelial-to-Mesenchymal Transition (EndMT), a process involved in cardiovascular development and disease. We reveal how intercellular adhesion forces in monolayer decrease significantly at an early stage of EndMT and we show that cells undergo stiffening and flattening at this stage. This new biomechanical insight complements and expands the established standard biomolecular analyses. Our study thus introduces a novel tool for the assessment of mature intercellular adhesion forces in a physiological setting that will be of relevance to biological processes in developmental biology, tissue regeneration and diseases like cancer and fibrosis.}, language = {en} } @article{AppeltMenzelCubukovaGuentheretal.2017, author = {Appelt-Menzel, Antje and Cubukova, Alevtina and G{\"u}nther, Katharina and Edenhofer, Frank and Piontek, J{\"o}rg and Krause, Gerd and St{\"u}ber, Tanja and Walles, Heike and Neuhaus, Winfried and Metzger, Marco}, title = {Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells}, series = {Stem Cell Reports}, volume = {8}, journal = {Stem Cell Reports}, number = {4}, doi = {10.1016/j.stemcr.2017.02.021}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170982}, pages = {894-906}, year = {2017}, abstract = {In vitro models of the human blood-brain barrier (BBB) are highly desirable for drug development. This study aims to analyze a set of ten different BBB culture models based on primary cells, human induced pluripotent stem cells (hiPSCs), and multipotent fetal neural stem cells (fNSCs). We systematically investigated the impact of astrocytes, pericytes, and NSCs on hiPSC-derived BBB endothelial cell function and gene expression. The quadruple culture models, based on these four cell types, achieved BBB characteristics including transendothelial electrical resistance (TEER) up to 2,500 Ω cm\(^{2}\) and distinct upregulation of typical BBB genes. A complex in vivo-like tight junction (TJ) network was detected by freeze-fracture and transmission electron microscopy. Treatment with claudin-specific TJ modulators caused TEER decrease, confirming the relevant role of claudin subtypes for paracellular tightness. Drug permeability tests with reference substances were performed and confirmed the suitability of the models for drug transport studies.}, language = {en} } @article{LohseBockMaiellaroetal.2017, author = {Lohse, Christian and Bock, Andreas and Maiellaro, Isabella and Hannawacker, Annette and Schad, Lothar R. and Lohse, Martin J. and Bauer, Wolfgang R.}, title = {Experimental and mathematical analysis of cAMP nanodomains}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0174856}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170972}, pages = {e0174856}, year = {2017}, abstract = {In their role as second messengers, cyclic nucleotides such as cAMP have a variety of intracellular effects. These complex tasks demand a highly organized orchestration of spatially and temporally confined cAMP action which should be best achieved by compartmentalization of the latter. A great body of evidence suggests that cAMP compartments may be established and maintained by cAMP degrading enzymes, e.g. phosphodiesterases (PDEs). However, the molecular and biophysical details of how PDEs can orchestrate cAMP gradients are entirely unclear. In this paper, using fusion proteins of cAMP FRET-sensors and PDEs in living cells, we provide direct experimental evidence that the cAMP concentration in the vicinity of an individual PDE molecule is below the detection limit of our FRET sensors (<100nM). This cAMP gradient persists in crude cytosol preparations. We developed mathematical models based on diffusion-reaction equations which describe the creation of nanocompartments around a single PDE molecule and more complex spatial PDE arrangements. The analytically solvable equations derived here explicitly determine how the capability of a single PDE, or PDE complexes, to create a nanocompartment depend on the cAMP degradation rate, the diffusive mobility of cAMP, and geometrical and topological parameters. We apply these generic models to our experimental data and determine the diffusive mobility and degradation rate of cAMP. The results obtained for these parameters differ by far from data in literature for free soluble cAMP interacting with PDE. Hence, restricted cAMP diffusion in the vincinity of PDE is necessary to create cAMP nanocompartments in cells.}, language = {en} } @article{DeaconWiedenmannBocquillonetal.2017, author = {Deacon, R. S. and Wiedenmann, J. and Bocquillon, E. and Dom{\´i}nguez, F. and Klapwijk, T. M. and Leubner, P. and Br{\"u}ne, C. and Hankiewicz, E. M. and Tarucha, S. and Ishibashi, K. and Buhmann, H. and Molenkamp, L. W.}, title = {Josephson Radiation from Gapless Andreev Bound States in HgTe-Based Topological Junctions}, series = {Physical Review X}, volume = {7}, journal = {Physical Review X}, number = {021011}, doi = {10.1103/PhysRevX.7.021011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170969}, year = {2017}, abstract = {Frequency analysis of the rf emission of oscillating Josephson supercurrent is a powerful passive way of probing properties of topological Josephson junctions. In particular, measurements of the Josephson emission enable the detection of topological gapless Andreev bound states that give rise to emission at half the Josephson frequency f\(_{J}\) rather than conventional emission at f\(_{J}\). Here, we report direct measurement of rf emission spectra on Josephson junctions made of HgTe-based gate-tunable topological weak links. The emission spectra exhibit a clear signal at half the Josephson frequency f\(_{J}\)/2. The linewidths of emission lines indicate a coherence time of 0.3-4 ns for the f\(_{J}\)/2 line, much shorter than for the f\(_{J}\) line (3-4 ns). These observations strongly point towards the presence of topological gapless Andreev bound states and pave the way for a future HgTe-based platform for topological quantum computation.}, language = {en} } @article{DegenHovestadtMitesseretal.2017, author = {Degen, Tobias and Hovestadt, Thomas and Mitesser, Oliver and H{\"o}lker, Franz}, title = {Altered sex-specific mortality and female mating success: ecological effects and evolutionary responses}, series = {Ecosphere}, volume = {8}, journal = {Ecosphere}, number = {5}, doi = {10.1002/ecs2.1820}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170953}, pages = {e01820}, year = {2017}, abstract = {Theory predicts that males and females should often join the mating pool at different times (sexual dimorphism in timing of emergence [SDT]) as the degree of SDT affects female mating success. We utilize an analytical model to explore (1) how important SDT is for female mating success, (2) how mating success might change if either sex's mortality (abruptly) increases, and (3) to what degree evolutionary responses in SDT may be able to mitigate the consequences of such mortality increase. Increasing male pre-mating mortality has a non-linear effect on the fraction of females mated: The effect is initially weak, but at some critical level a further increase in male mortality has a stronger effect than a similar increase in female mortality. Such a change is expected to impose selection for reduced SDT. Increasing mortality during the mating season has always a stronger effect on female mating success if the mortality affects the sex that emerges first. This bias results from the fact that enhancing mortality of the earlier emerging sex reduces female-male encounter rates. However, an evolutionary response in SDT may effectively mitigate such consequences. Further, if considered independently for females and males, the predicted evolutionary response in SDT could be quite dissimilar. The difference between female and male evolutionary response in SDT leads to marked differences in the fraction of fertilized females under certain conditions. Our model may provide general guidelines for improving harvesting of populations, conservation management of rare species under altered environmental conditions, or maintaining long-term efficiency of pest-control measures.}, language = {en} } @article{GiampaoloWojcikSerflingetal.2017, author = {Giampaolo, Sabrina and W{\´o}jcik, Gabriela and Serfling, Edgar and Patra, Amiya K.}, title = {Interleukin-2-regulatory T cell axis critically regulates maintenance of hematopoietic stem cells}, series = {Oncotarget}, volume = {8}, journal = {Oncotarget}, number = {18}, doi = {10.18632/oncotarget.16377}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170947}, pages = {29625-29642}, year = {2017}, abstract = {The role of IL-2 in HSC maintenance is unknown. Here we show that Il2\(^{-/-}\) mice develop severe anomalies in HSC maintenance leading to defective hematopoiesis. Whereas, lack of IL-2 signaling was detrimental for lympho- and erythropoiesis, myelopoiesis was enhanced in Il2\(^{-/-}\) mice. Investigation of the underlying mechanisms of dysregulated hematopoiesis in Il2\(^{-/-}\) mice shows that the IL-2-T\(_{reg}\) cell axis is indispensable for HSC maintenance and normal hematopoiesis. Lack of T\(_{reg}\) activity resulted in increased IFN-γ production by activated T cells and an expansion of the HSCs in the bone marrow (BM). Though, restoring T\(_{reg}\) population successfully rescued HSC maintenance in Il2\(^{-/-}\) mice, preventing IFN-γ activity could do the same even in the absence of T\(_{reg}\) cells. Our study suggests that equilibrium in IL-2 and IFN-γ activity is critical for steady state hematopoiesis, and in clinical conditions of BM failure, IL-2 or anti-IFN-γ treatment might help to restore hematopoiesis.}, language = {en} } @article{ShamimMahapatraScappuccietal.2017, author = {Shamim, Saquib and Mahapatra, S. and Scappucci, G. and Klesse, W. M. and Simmons, M. Y. and Ghosh, Arindam}, title = {Dephasing rates for weak localization and universal conductance fluctuations in two dimensional Si: P and Ge: P δ-layers}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {46670}, doi = {10.1038/srep46670}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170934}, year = {2017}, abstract = {We report quantum transport measurements on two dimensional (2D) Si:P and Ge:P δ-layers and compare the inelastic scattering rates relevant for weak localization (WL) and universal conductance fluctuations (UCF) for devices of various doping densities (0.3-2.5 × 10\(^{18}\)m\(^{-2}\)) at low temperatures (0.3-4.2 K). The phase breaking rate extracted experimentally from measurements of WL correction to conductivity and UCF agree well with each other within the entire temperature range. This establishes that WL and UCF, being the outcome of quantum interference phenomena, are governed by the same dephasing rate.}, language = {en} } @article{VonaNandaShehataDieleretal.2017, author = {Vona, Barbara and Nanda, Indrajit and Shehata-Dieler, Wafaa and Haaf, Thomas}, title = {Genetics of Tinnitus: Still in its Infancy}, series = {Frontiers in Neuroscience}, volume = {11}, journal = {Frontiers in Neuroscience}, number = {236}, doi = {10.3389/fnins.2017.00236}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170926}, year = {2017}, abstract = {Tinnitus is the perception of a phantom sound that affects between 10 and 15\% of the general population. Despite this considerable prevalence, treatments for tinnitus are presently lacking. Tinnitus exhibits a diverse array of recognized risk factors and extreme clinical heterogeneity. Furthermore, it can involve an unknown number of auditory and non-auditory networks and molecular pathways. This complex combination has hampered advancements in the field. The identification of specific genetic factors has been at the forefront of several research investigations in the past decade. Nine studies have examined genes in a case-control association approach. Recently, a genome-wide association study has highlighted several potentially significant pathways that are implicated in tinnitus. Two twin studies have calculated a moderate heritability for tinnitus and disclosed a greater concordance rate in monozygotic twins compared to dizygotic twins. Despite the more recent data alluding to genetic factors in tinnitus, a strong association with any specific genetic locus is lacking and a genetic study with sufficient statistical power has yet to be designed. Future research endeavors must overcome the many inherent limitations in previous study designs. This review summarizes the previously embarked upon tinnitus genetic investigations and summarizes the hurdles that have been encountered. The identification of candidate genes responsible for tinnitus may afford gene based diagnostic approaches, effective therapy development, and personalized therapeutic intervention.}, language = {en} } @article{ArmbrusterKriegWeissenbergeretal.2017, author = {Armbruster, Nicole and Krieg, Jennifer and Weißenberger, Manuel and Scheller, Carsten and Steinert, Andre F.}, title = {Rescued Chondrogenesis of Mesenchymal Stem Cells under Interleukin 1 Challenge by Foamyviral Interleukin 1 Receptor Antagonist Gene Transfer}, series = {Frontiers in Pharmacology}, volume = {8}, journal = {Frontiers in Pharmacology}, number = {255}, doi = {10.3389/fphar.2017.00255}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170919}, year = {2017}, abstract = {Background: Mesenchymal stem cells (MSCs) and their chondrogenic differentiation have been extensively investigated in vitro as MSCs provide an attractive source besides chondrocytes for cartilage repair therapies. Here we established prototype foamyviral vectors (FVV) that are derived from apathogenic parent viruses and are characterized by a broad host range and a favorable integration pattern into the cellular genome. As the inflammatory cytokine interleukin 1 beta (IL1β) is frequently present in diseased joints, the protective effects of FVV expressing the human interleukin 1 receptor antagonist protein (IL1RA) were studied in an established in vitro model (aggregate culture system) of chondrogenesis in the presence of IL1β. Materials and Methods: We generated different recombinant FVVs encoding enhanced green fluorescent protein (EGFP) or IL1RA and examined their transduction efficiencies and transgene expression profiles using different cell lines and human primary MSCs derived from bone marrow-aspirates. Transgene expression was evaluated by fluorescence microscopy (EGFP), flow cytometry (EGFP), and ELISA (IL1RA). For evaluation of the functionality of the IL1RA transgene to block the inhibitory effects of IL1β on chondrogenesis of primary MSCs and an immortalized MSC cell line (TERT4 cells), the cells were maintained following transduction as aggregate cultures in standard chondrogenic media in the presence or absence of IL1β. After 3 weeks of culture, pellets were harvested and analyzed by histology and immunohistochemistry for chondrogenic phenotypes. Results: The different FVV efficiently transduced cell lines as well as primary MSCs, thereby reaching high transgene expression levels in 6-well plates with levels of around 100 ng/ml IL1RA. MSC aggregate cultures which were maintained in chondrogenic media without IL1β supplementation revealed a chondrogenic phenotype by means of strong positive staining for collagen type II and matrix proteoglycan (Alcian blue). Addition of IL1β was inhibitory to chondrogenesis in untreated control pellets. In contrast, foamyviral mediated IL1RA expression rescued the chondrogenesis in pellets cultured in the presence of IL1β. Transduced MSC pellets reached thereby very high IL1RA transgene expression levels with a peak of 1087 ng/ml after day 7, followed by a decrease to 194 ng/ml after day 21, while IL1RA concentrations of controls were permanently below 200 pg/ml. Conclusion: Our results indicate that FVV are capable of efficient gene transfer to MSCs, while reaching IL1RA transgene expression levels, that were able to efficiently block the impacts of IL1β in vitro. FVV merit further investigation as a means to study the potential as a gene transfer tool for MSC based therapies for cartilage repair.}, language = {en} } @article{JannaschGaetznerWeigeletal.2017, author = {Jannasch, Maren and Gaetzner, Sabine and Weigel, Tobias and Walles, Heike and Schmitz, Tobias and Hansmann, Jan}, title = {A comparative multi-parametric in vitro model identifies the power of test conditions to predict the fibrotic tendency of a biomaterial}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {1689}, doi = {10.1038/s41598-017-01584-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170908}, year = {2017}, abstract = {Despite growing effort to advance materials towards a low fibrotic progression, all implants elicit adverse tissue responses. Pre-clinical biomaterial assessment relies on animals testing, which can be complemented by in vitro tests to address the Russell and Burch's 3R aspect of reducing animal burden. However, a poor correlation between in vitro and in vivo biomaterial assessments confirms a need for suitable in vitro biomaterial tests. The aim of the study was to identify a test setting, which is predictive and might be time- and cost-efficient. We demonstrated how sensitive in vitro biomaterial assessment based on human primary macrophages depends on test conditions. Moreover, possible clinical scenarios such as lipopolysaccharide contamination, contact to autologous blood plasma, and presence of IL-4 in an immune niche influence the outcome of a biomaterial ranking. Nevertheless, by using glass, titanium, polytetrafluorethylene, silicone, and polyethylene representing a specific material-induced fibrotic response and by comparison to literature data, we were able to identify a test condition that provides a high correlation to state-of-the-art in vivo studies. Most important, biomaterial ranking obtained under native plasma test conditions showed a high predictive accuracy compared to in vivo assessments, strengthening a biomimetic three-dimensional in vitro test platform.}, language = {en} } @article{MaierhoferFlunkertDittrichetal.2017, author = {Maierhofer, Anna and Flunkert, Julia and Dittrich, Marcus and M{\"u}ller, Tobias and Schindler, Detlev and Nanda, Indrajit and Haaf, Thomas}, title = {Analysis of global DNA methylation changes in primary human fibroblasts in the early phase following X-ray irradiation}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0177442}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170895}, pages = {e0177442}, year = {2017}, abstract = {Epigenetic alterations may contribute to the generation of cancer cells in a multi-step process of tumorigenesis following irradiation of normal body cells. Primary human fibroblasts with intact cell cycle checkpoints were used as a model to test whether X-ray irradiation with 2 and 4 Gray induces direct epigenetic effects (within the first cell cycle) in the exposed cells. ELISA-based fluorometric assays were consistent with slightly reduced global DNA methylation and hydroxymethylation, however the observed between-group differences were usually not significant. Similarly, bisulfite pyrosequencing of interspersed LINE-1 repeats and centromeric α-satellite DNA did not detect significant methylation differences between irradiated and non-irradiated cultures. Methylation of interspersed ALU repeats appeared to be slightly increased (one percentage point; p = 0.01) at 6 h after irradiation with 4 Gy. Single-cell analysis showed comparable variations in repeat methylation among individual cells in both irradiated and control cultures. Radiation-induced changes in global repeat methylation, if any, were much smaller than methylation variation between different fibroblast strains. Interestingly, α-satellite DNA methylation positively correlated with gestational age. Finally, 450K methylation arrays mainly targeting genes and CpG islands were used for global DNA methylation analysis. There were no detectable methylation differences in genic (promoter, 5' UTR, first exon, gene body, 3' UTR) and intergenic regions between irradiated and control fibroblast cultures. Although we cannot exclude minor effects, i.e. on individual CpG sites, collectively our data suggest that global DNA methylation remains rather stable in irradiated normal body cells in the early phase of DNA damage response.}, language = {en} }