@article{RichertKoinzerTodeetal.2018, author = {Richert, Elisabeth and Koinzer, Stefan and Tode, Jan and Schlott, Kerstin and Brinkmann, Ralf and Hillenkamp, Jost and Klettner, Alexa and Roider, Johann}, title = {Release of Different Cell Mediators During Retinal Pigment Epithelium Regeneration Following Selective Retina Therapy}, series = {Investigative Ophthalmology \& Visual Science}, volume = {59}, journal = {Investigative Ophthalmology \& Visual Science}, number = {3}, doi = {10.1167/iovs.17-23163}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226161}, pages = {1323-1331}, year = {2018}, abstract = {PURPOSE. To investigate the effect of selective retina therapy (SRT) on the release of AMD-relevant cell mediators, such as matrix metalloproteinases (MMPs), VEGF, and pigment epithelium derived factor (PEDF) using different laser spot sizes and densities. METHODS. Porcine RPE-choroid explants were treated with a pulsed 532 nm Nd:YAG laser using (1) large spot sizes, (2) small spot sizes with a high-density (hd) treatment, and (3) small spot sizes with a low-density (1d) treatment. Explains were cultivated in modified Ussing chambers. RPE regeneration and RPE cell death were investigated by calcein-AM staining and immunofluorescence. The MMP release was examined via zymography and immunofluorescence. VEGF and PEDF secretion was analyzed by ELISA. RESULTS. During pigment epithelium regeneration (PER), mitosis and RPE cell migration were observed. Four days after SRT (large spot size) the content of active MMP2 increased significantly (P < 0.01). Hd treatment with small spot sizes resulted also in an increase of active MMP2 (P < 0.05). In immunofluorescence explants showed a localized expression of MMP2 within the healing lesions after irradiation. The PEDF level increased significantly (P = 0.01) after SRT with large spot sizes. VEGF secretion decreased significantly (P < 0.05) following SRT with large spot sizes and with hd treatment of small spot sizes. CONCLUSIONS. SRT induces a cytokine profile, which may improve the flux across Brach's membrane, slows down progression of early AMD by RPE regeneration, and inhibits the formation of choroidal neovascularization. The cytokine release depends on the size and density of applied laser spots.}, language = {en} } @article{ScheibBroserConstantinetal.2018, author = {Scheib, Ulrike and Broser, Matthias and Constantin, Oana M. and Yang, Shang and Gao, Shiqiang and Mukherjee, Shatanik and Stehfest, Katja and Nagel, Georg and Gee, Christine E. and Hegemann, Peter}, title = {Rhodopsin-cyclases for photocontrol of cGMP/cAMP and 2.3 {\AA} structure of the adenylyl cyclase domain}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-04428-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228517}, pages = {2046, 1-15}, year = {2018}, abstract = {The cyclic nucleotides cAMP and cGMP are important second messengers that orchestrate fundamental cellular responses. Here, we present the characterization of the rhodopsinguanylyl cyclase from Catenaria anguillulae (CaRhGC), which produces cGMP in response to green light with a light to dark activity ratio > 1000. After light excitation the putative signaling state forms with tau = 31 ms and decays with tau = 570 ms. Mutations (up to 6) within the nucleotide binding site generate rhodopsin-adenylyl cyclases (CaRhACs) of which the double mutated YFP-CaRhAC (E497K/C566D) is the most suitable for rapid cAMP production in neurons. Furthermore, the crystal structure of the ligand-bound AC domain (2.25 angstrom) reveals detailed information about the nucleotide binding mode within this recently discovered class of enzyme rhodopsin. Both YFP-CaRhGC and YFP-CaRhAC are favorable optogenetic tools for non-invasive, cell-selective, and spatio-temporally precise modulation of cAMP/cGMP with light.}, language = {en} } @article{ReidenbergWannerPolskyetal.2018, author = {Reidenberg, Bruce E. and Wanner, Christoph and Polsky, Bruce and Castanheira, Mariana and Shelip, Alla and Stalleicken, Dirk and Pfaffle, Antony E.}, title = {Postmarketing experience with Neutrolin® (taurolidine, heparin, calcium citrate) catheter lock solution in hemodialysis patients}, series = {European Journal of Clinical Microbiology \& Infectious Diseases}, volume = {37}, journal = {European Journal of Clinical Microbiology \& Infectious Diseases}, number = {4}, doi = {10.1007/s10096-017-3157-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225091}, pages = {661-663}, year = {2018}, abstract = {Catheter-related bloodstream infections (CRBSI) are major complications for patients with life-threatening conditions requiring chronic vascular catheterization. The wide range of etiologic microbes and the ongoing development of resistance to antimicrobials with specific mechanisms of action make this an appropriate target for applying a nonspecific antimicrobial therapeutic. Taurolidine hydrolyzes into two antimicrobial moieties, formaldehyde and methylene glycol, which react with microbial surfaces. NeutrolinA (R) (taurolidine, heparin, calcium citrate) was recently introduced in Germany as an antimicrobial catheter lock solution. This postmarketing experience collected data on 201 patients at 20 centers from January 2014 through September 2016. Likely CRBSI was observed in 13 episodes in 47,118 days (0.2759 per 1000 days [0.1468, 0.4718]). Thrombosed catheter was observed in seven catheters in 47,118 days (0.1486 per 1000 days [0.0595, 0.3061]). No adverse drug reactions that led to the discontinuation of NeutrolinA (R) use were reported. Two patients experienced occasional transient dysgeusia. NeutrolinA (R), when used in conjunction with guideline-based catheter care, showed reduction in the rate of both CRBSI and catheter thrombosis relative to recent historical controls.}, language = {en} } @article{RosenstockPerkovicAlexanderetal.2018, author = {Rosenstock, Julio and Perkovic, Vlado and Alexander, John H. and Cooper, Mark E. and Marx, Nikolaus and Pencina, Michael J. and Toto, Robert D. and Wanner, Christoph and Zinman, Bernard and Baanstra, David and Pfarr, Egon and Mattheus, Michaela and Broedl, Uli C. and Woerle, Hans-J{\"u}rgen and George, Jyothis T. and von Eynatten, Maximilian and McGuire, Darren K.}, title = {Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin - (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk}, series = {Cardiovascular Diabetology}, volume = {17}, journal = {Cardiovascular Diabetology}, doi = {10.1186/s12933-018-0682-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226996}, pages = {39, 1-15}, year = {2018}, abstract = {Background: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA (R) trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. Methods: CARMELINA (R) is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0\% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, >= 40\% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA (R) was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90\% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided a-level of 2.5\%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. Results: Between July 2013 and August 2016, 6980 patients were randomized and took >= 1 dose of study drug (40.6, 33.1, 16.9, and 9.4\% from Europe, South America, North America, and Asia, respectively). At baseline, mean +/- SD age was 65.8 +/- 9.1 years, HbA1c 7.9 +/- 1.0\%, BMI 31.3 +/- 5.3 kg/m(2), and eGFR 55 +/- 25 mL/min/1.73 m(2). A total of 5148 patients (73.8\%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m(2) or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2\%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5\%]) and macroalbuminuria (n = 2691 [38.6\%]) were common. Conclusions: CARMELINA (R) will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk.}, language = {en} } @article{RudovickBraunerEnglertetal.2018, author = {Rudovick, Ladius and Brauner, Jan M. and Englert, Johanna and Seemann, Carolina and Plugaru, Karina and Kidenya, Benson R. and Kalluvya, Samuel E. and Scheller, Carsten and Kasang, Christa}, title = {Prevalence of pretreatment HIV drug resistance in Mwanza, Tanzania}, series = {Journal of Antimicrobial Chemotherapy}, volume = {73}, journal = {Journal of Antimicrobial Chemotherapy}, number = {12}, doi = {10.1093/jac/dky332}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227124}, pages = {3476-3481}, year = {2018}, abstract = {Background: In a 2008-10 study, we found a pretreatment HIV drug resistance (PDR) prevalence of 18.2\% in patients at Bugando Medical Centre (BMC) in Mwanza, Tanzania. Objectives: To determine the prevalence of PDR and transmitted HIV drug resistance (TDR) in patients visiting the BMC from 2013 to 2015. Methods: Adult outpatients were sequentially enrolled into two groups, separated by whether they were initiating ART. Previous exposure to antiretroviral drugs, except for prevention of mother-to-child transmission, was an exclusion criterion. HIV pol sequences were analysed according to WHO guidelines for surveillance of PDR and TDR. Results: Two hundred and thirty-five sequences were analysed (138 ART initiators, 97 non-initiators). The prevalence of PDR was 4.7\% (95\% CI 2.6\%-8.2\%) overall, 3.1\% (95\% CI 1.1\%-8.7\%) for non-initiators and 5.8\% (95\% CI 3.0\%-11.0\%) for ART initiators. PDR to NNRTIs and nucleoside or nucelotide reverse transcriptase inhibitors was found in 3.0\% (95\% CI 1.5\%-6.0\%) and 1.7\% (95\% CI 0.7\%-4.3\%) of patients, respectively. Resistance to PIs was not observed. The prevalence of TDR was 6.0\% (95\% CI 3.6\%-9.8\%). Conclusions: Prevalence of PDR significantly decreased compared with 2008-10 and was below the WHO-defined threshold for triggering a public health response. National and systematic surveillance is needed to inform Tanzania's public health strategy.}, language = {en} } @article{ReinholdSchwabeLuxetal.2018, author = {Reinhold, Ann Kristin and Schwabe, Joachim and Lux, Thomas J. and Salvador, Ellaine and Rittner, Heike L.}, title = {Quantitative and Microstructural Changes of the Blood-Nerve Barrier in Peripheral Neuropathy}, series = {Frontiers in Neuroscience}, volume = {12}, journal = {Frontiers in Neuroscience}, doi = {10.3389/fnins.2018.00936}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225179}, pages = {936, 1-9}, year = {2018}, abstract = {Peripheral neuropathy is accompanied by changes in the neuronal environment. The blood-nerve barrier (BNB) is crucial in protecting the neural homeostasis: Tight junctions (TJ) seal paracellular spaces and thus prevent external stimuli from entering. In different models of neuropathic pain, the BNB is impaired, thus contributing to local damage, immune cell invasion and, ultimately, the development of neuropathy with its symptoms. In this study, we examined changes in expression and microstructural localization of two key tight junction proteins (TJP), claudin-1 and the cytoplasmic anchoring ZO-1, in the sciatic nerve of mice subjected to chronic constriction injury (CCI). Via qPCR and analysis of fluorescence immunohistochemistry, a marked downregulation of mRNA as well as decreased fluorescence intensity were observed in the nerve for both proteins. Moreover, a distinct zig-zag structure for both proteins located at cell-cell contacts, indicative of the localization of TJs, was observed in the perineurial compartment of sham-operated animals. This microstructural location in cell-cell-contacts was lost in neuropathy as semiquantified via computational analysis, based on a novel algorithm. In summary, we provide evidence that peripheral neuropathy is not only associated with decrease in relevant TJPs but also exhibits alterations in TJP arrangement and loss in barrier tightness, presumably due to internalization. Specifically, semiquantification of TJP in cell-cell-contacts of microcompartments could be used in the future for routine clinical samples of patients with neuropathy.}, language = {en} } @article{AbdaliYounasMafakherietal.2018, author = {Abdali, Narges and Younas, Farhan and Mafakheri, Samaneh and Pothula, Karunakar R. and Kleinekath{\"o}fer, Ulrich and Tauch, Andreas and Benz, Roland}, title = {Identification and characterization of smallest pore-forming protein in the cell wall of pathogenic Corynebacterium urealyticum DSM 7109}, series = {BMC Biochemistry}, volume = {19}, journal = {BMC Biochemistry}, doi = {10.1186/s12858-018-0093-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226959}, year = {2018}, abstract = {Background: Corynebacterium urealyticum, a pathogenic, multidrug resistant member of the mycolata, is known as causative agent of urinary tract infections although it is a bacterium of the skin flora. This pathogenic bacterium shares with the mycolata the property of having an unusual cell envelope composition and architecture, typical for the genus Corynebacterium. The cell wall of members of the mycolata contains channel-forming proteins for the uptake of solutes. Results: In this study, we provide novel information on the identification and characterization of a pore-forming protein in the cell wall of C. urealyticum DSM 7109. Detergent extracts of whole C. urealyticum cultures formed in lipid bilayer membranes slightly cation-selective pores with a single-channel conductance of 1.75 nS in 1 M KCl. Experiments with different salts and non-electrolytes suggested that the cell wall pore of C. urealyticum is wide and water-filled and has a diameter of about 1.8 nm. Molecular modelling and dynamics has been performed to obtain a model of the pore. For the search of the gene coding for the cell wall pore of C. urealyticum we looked in the known genome of C. urealyticum for a similar chromosomal localization of the porin gene to known porH and porA genes of other Corynebacterium strains. Three genes are located between the genes coding for GroEL2 and polyphosphate kinase (PKK2). Two of the genes (cur_1714 and cur_1715) were expressed in different constructs in C. glutamicum Delta porA Delta porH and in porin-deficient BL21 DE3 Omp8 E. coli strains. The results suggested that the gene cur_1714 codes alone for the cell wall channel. The cell wall porin of C. urealyticum termed PorACur was purified to homogeneity using different biochemical methods and had an apparent molecular mass of about 4 kDa on tricine-containing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Conclusions: Biophysical characterization of the purified protein (PorACur) suggested indeed that cur_1714 is the gene coding for the pore-forming protein in C. urealyticum because the protein formed in lipid bilayer experiments the same pores as the detergent extract of whole cells. The study is the first report of a cell wall channel in the pathogenic C. urealyticum.}, language = {en} } @article{SchieleZieglerKollertetal.2018, author = {Schiele, Miriam A. and Ziegler, Christiane and Kollert, Leonie and Katzorke, Andrea and Schartner, Christoph and Busch, Yasmin and Gromer, Daniel and Reif, Andreas and Pauli, Paul and Deckert, J{\"u}rgen and Herrmann, Martin J. and Domschke, Katharina}, title = {Plasticity of Functional MAOA Gene Methylation in Acrophobia}, series = {International Journal of Neuropsychopharmacology}, volume = {21}, journal = {International Journal of Neuropsychopharmacology}, number = {9}, doi = {10.1093/ijnp/pyy050}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228571}, pages = {822-827}, year = {2018}, abstract = {Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.}, language = {en} } @article{SchaeffnerSchloemerkemper2018, author = {Sch{\"a}ffner, M. and Schl{\"o}merkemper, A.}, title = {On Lennard-Jones systems with finite range interactions and their asymptotic analysis}, series = {Networks and Heterogeneous Media}, volume = {13}, journal = {Networks and Heterogeneous Media}, number = {1}, doi = {10.3934/nhm.2018005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228428}, pages = {95-118}, year = {2018}, abstract = {The aim of this work is to provide further insight into the qualitative behavior of mechanical systems that are well described by Lennard-Jones type interactions on an atomistic scale. By means of Gamma-convergence techniques, we study the continuum limit of one-dimensional chains of atoms with finite range interactions of Lennard-Jones type, including the classical Lennard-Jones potentials. So far, explicit formula for the continuum limit were only available for the case of nearest and next-to-nearest neighbour interactions. In this work, we provide an explicit expression for the continuum limit in the case of finite range interactions. The obtained homogenization formula is given by the convexification of a Cauchy-Born energy density. Furthermore, we study rescaled energies in which bulk and surface contributions scale in the same way. The related discrete-to-continuum limit yields a rigorous derivation of a one-dimensional version of Griffith' fracture energy and thus generalizes earlier derivations for nearest and next-to-nearest neighbors to the case of finite range interactions. A crucial ingredient to our proofs is a novel decomposition of the energy that allows for re fined estimates.}, language = {en} } @article{SchenkMitesserHovestadtetal.2018, author = {Schenk, Mariela and Mitesser, Oliver and Hovestadt, Thomas and Holzschuh, Andrea}, title = {Overwintering temperature and body condition shift emergence dates of spring-emerging solitary bees}, series = {PeerJ}, volume = {6}, journal = {PeerJ}, doi = {10.7717/peerj.4721}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228544}, pages = {e4721, 1-17}, year = {2018}, abstract = {Solitary bees in seasonal environments must align their life-cycles with favorable environmental conditions and resources; the timing of their emergence is highly fitness relevant. In several bee species, overwintering temperature influences both emergence date and body weight at emergence. High variability in emergence dates among specimens overwintering at the same temperatures suggests that the timing of emergence also depends on individual body conditions. However, possible causes for this variability, such as individual differences in body size or weight, have been rarely studied. In a climate chamber experiment using two spring-emerging mason bees (Osmia cornuta and O. bicornis), we investigated the relationship between temperature, emergence date, body weight, and body size, the last of which is not affected by overwintering temperature. Our study showed that body weight declined during hibernation more strongly in warm than in cold overwintering temperatures. Although bees emerged earlier in warm than in cold overwintering temperatures, at the time of emergence, bees in warm overwintering temperatures had lower body weights than bees in cold overwintering temperatures (exception of male O. cornuta). Among specimens that experienced the same overwintering temperatures, small and light bees emerged later than their larger and heavier conspecifics. Using a simple mechanistic model we demonstrated that spring-emerging solitary bees use a strategic approach and emerge at a date that is most promising for their individual fitness expectations. Our results suggest that warmer overwintering temperatures reduce bee fitness by causing a decrease in body weight at emergence. We showed furthermore that in order to adjust their emergence dates, bees use not only temperature but also their individual body condition as triggers. This may explain differing responses to climate warming within and among bee populations and may have consequences for bee-plant interactions as well as for the persistence of bee populations under climate change.}, language = {en} } @article{SchmidtKnemeyerHeinsen2018, author = {Schmidt, Martin J. and Knemeyer, Carola and Heinsen, Helmut}, title = {Neuroanatomy of the equine brain as revealed by high-field (3Tesla) magnetic-resonance-imaging}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0213814}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228945}, pages = {e0213814, 1-49}, year = {2018}, abstract = {In this study, the morphology of the horse brain (Equus caballus) is decribed in detail using high field MRI. The study includes sagittal, dorsal, and transverse T2-weighted images at 0.25 mm resolution at 3 Tesla and 3D models of the brain presenting the external morphology of the brain. Representative gallocyanin stained histological slides of the same brain are presented. The images represent a useful tool for MR image interpretation in horses and may serve as a starting point for further research aiming at in vivo analysis in this species.}, language = {en} } @article{RuizHerediaSanchezVegaOnechaetal.2018, author = {Ruiz-Heredia, Yanira and S{\´a}nchez-Vega, Beatriz and Onecha, Esther and Barrio, Santiago and Alonso, Rafael and Carlos Mart{\´i}nez-Avila, Jose and Cuenca, Isabel and Agirre, Xabier and Braggio, Esteban and Hern{\´a}ndez, Miguel-T. and Mart{\´i}nez, Rafael and Rosi{\~n}ol, Laura and Gutierrez, Norma and Martin-Ramos, Marisa and Ocio, Enrique M. and Echeveste, Mar{\´i}a-Asunci{\´o}n and P{\´e}rez de Oteyza, Jaime and Oriol, Albert and Bargay, Joan and Gironella, Mercedes and Ayala, Rosa and Blad{\´e}, Joan and Mateos, Mar{\´i}a-Victoria and Kortum, Klaus M. and Stewart, Keith and Garc{\´i}a-Sanz, Ram{\´o}n and San Miguel, Jes{\´u}s and Jos{\´e} Lahuerta, Juan and Martinez-Lopez, Joaqu{\´i}n}, title = {Mutational screening of newly diagnosed multiple myeloma patients by deep targeted sequencing}, series = {Haematologica}, volume = {103}, journal = {Haematologica}, number = {11}, doi = {10.3324/haematol.2018.188839}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227151}, pages = {e544-e548}, year = {2018}, abstract = {no abstract available}, language = {en} } @article{RufBrantlWagener2018, author = {Ruf, Dominik and Brantl, Victor and Wagener, Johannes}, title = {Mitochondrial Fragmentation in \(Aspergillus\) \(fumigatus\) as Early Marker of Granulocyte Killing Activity}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {8}, journal = {Frontiers in Cellular and Infection Microbiology}, number = {128}, doi = {10.3389/fcimb.2018.00128}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227133}, year = {2018}, abstract = {The host's defense against invasive mold infections relies on diverse antimicrobial activities of innate immune cells. However, studying these mechanisms in vitro is complicated by the filamentous nature of such pathogens that typically form long, branched, multinucleated and compartmentalized hyphae. Here we describe a novel method that allows for the visualization and quantification of the antifungal killing activity exerted by human granulocytes against hyphae of the opportunistic pathogen Aspergillus fumigatus. The approach relies on the distinct impact of fungal cell death on the morphology of mitochondria that were visualized with green fluorescent protein (GFP). We show that oxidative stress induces complete fragmentation of the tubular mitochondrial network which correlates with cell death of affected hyphae. Live cell microscopy revealed a similar and non-reversible disruption of the mitochondrial morphology followed by fading of fluorescence in Aspergillus hyphae that were killed by human granulocytes. Quantitative microscopic analysis of fixed samples was subsequently used to estimate the antifungal activity. By utilizing this assay, we demonstrate that lipopolysaccharides as well as human serum significantly increase the killing efficacy of the granulocytes. Our results demonstrate that evaluation of the mitochondrial morphology can be utilized to assess the fungicidal activity of granulocytes against A. fumigatus hyphae.}, language = {en} } @article{RossowVeitlVorlovaetal.2018, author = {Rossow, Leonie and Veitl, Simona and Vorlov{\´a}, Sandra and Wax, Jacqueline K. and Kuhn, Anja E. and Maltzahn, Verena and Upcin, Berin and Karl, Franziska and Hoffmann, Helene and G{\"a}tzner, Sabine and Kallius, Matthias and Nandigama, Rajender and Scheld, Daniela and Irmak, Ster and Herterich, Sabine and Zernecke, Alma and Erg{\"u}n, S{\"u}leyman and Henke, Erik}, title = {LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy}, series = {Oncogene}, volume = {37}, journal = {Oncogene}, doi = {10.1038/s41388-018-0320-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227008}, pages = {4921-4940}, year = {2018}, abstract = {The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.}, language = {en} } @article{RuttenVermettenVinkersetal.2018, author = {Rutten, BPF and Vermetten, E and Vinkers, CH and Ursini, G and Daskalakis, NP and Pishva, E and de Nijs, L and Houtepen, LC and Eijssen, L and Jaffe, AE and Kenis, G and Viechtbauer, W and van den Hove, D and Schraut, KG and Lesch, K-P and Kleinman, JE and Hyde, TM and Weinberger, DR and Schalkwyk, L and Lunnon, K and Mill, J and Cohen, H and Yehuda, R and Baker, DG and Maihofer, AX and Nievergelt, CM and Geuze, E and Boks, MPM}, title = {Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder}, series = {Molecular Psychiatry}, volume = {23}, journal = {Molecular Psychiatry}, number = {5}, doi = {10.1038/mp.2017.120}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227171}, pages = {1145-11562}, year = {2018}, abstract = {In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n = 93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n = 98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.}, language = {en} } @article{RemelgadoLeutnerSafietal.2018, author = {Remelgado, Ruben and Leutner, Benjamin and Safi, Kamran and Sonnenschein, Ruth and Kuebert, Carina and Wegmann, Martin}, title = {Linking animal movement and remote sensing - mapping resource suitability from a remote sensing perspective}, series = {Remote Sensing in Ecology and Conservation}, volume = {4}, journal = {Remote Sensing in Ecology and Conservation}, number = {3}, doi = {10.1002/rse2.70}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225199}, pages = {211-224}, year = {2018}, abstract = {Optical remote sensing is an important tool in the study of animal behavior providing ecologists with the means to understand species-environment interactions in combination with animal movement data. However, differences in spatial and temporal resolution between movement and remote sensing data limit their direct assimilation. In this context, we built a data-driven framework to map resource suitability that addresses these differences as well as the limitations of satellite imagery. It combines seasonal composites of multiyear surface reflectances and optimized presence and absence samples acquired with animal movement data within a cross-validation modeling scheme. Moreover, it responds to dynamic, site-specific environmental conditions making it applicable to contrasting landscapes. We tested this framework using five populations of White Storks (Ciconia ciconia) to model resource suitability related to foraging achieving accuracies from 0.40 to 0.94 for presences and 0.66 to 0.93 for absences. These results were influenced by the temporal composition of the seasonal reflectances indicated by the lower accuracies associated with higher day differences in relation to the target dates. Additionally, population differences in resource selection influenced our results marked by the negative relationship between the model accuracies and the variability of the surface reflectances associated with the presence samples. Our modeling approach spatially splits presences between training and validation. As a result, when these represent different and unique resources, we face a negative bias during validation. Despite these inaccuracies, our framework offers an important basis to analyze species-environment interactions. As it standardizes site-dependent behavioral and environmental characteristics, it can be used in the comparison of intra- and interspecies environmental requirements and improves the analysis of resource selection along migratory paths. Moreover, due to its sensitivity to differences in resource selection, our approach can contribute toward a better understanding of species requirements.}, language = {en} } @article{SalzmannManriqueBremmHueneckeetal.2018, author = {Salzmann-Manrique, Emilia and Bremm, Melanie and Huenecke, Sabine and Stech, Milena and Orth, Andreas and Eyrich, Matthias and Schulz, Ansgar and Esser, Ruth and Klingebiel, Thomas and Bader, Peter and Herrmann, Eva and Koehl, Ulrike}, title = {Joint Modeling of Immune Reconstitution Post Haploidentical Stem Cell Transplantation in Pediatric Patients With Acute Leukemia Comparing CD34(+)-Selected to CD3/CD19-Depleted Grafts in a Retrospective Multicenter Study}, series = {frontiers in Immunology}, volume = {9}, journal = {frontiers in Immunology}, doi = {10.3389/fimmu.2018.01841}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227302}, pages = {1841, 1-12}, year = {2018}, abstract = {Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34(+)-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3(+), CD3(+) CD4(+), and CD3(+) CD8(+) T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34(+)-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3(+) CD4(+) helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34(+)-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.}, language = {en} } @article{SalgarellaZahoranovaŠramkovaetal.2018, author = {Salgarella, Alice Rita and Zahoranov{\´a}, Anna and Šr{\´a}mkov{\´a}, Petra and Majerč{\´i}kov{\´a}, Monika and Pavlova, Ewa and Luxenhofer, Robert and Kronek, Juraj and Lac{\´i}k, Igor and Ricotti, Leonardo}, title = {Investigation of drug release modulation from poly(2-oxazoline) micelles through ultrasound}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-28140-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227277}, pages = {9893, 1-13}, year = {2018}, abstract = {Among external stimuli used to trigger release of a drug from a polymeric carrier, ultrasound has gained increasing attention due to its non-invasive nature, safety and low cost. Despite this attention, there is only limited knowledge about how materials available for the preparation of drug carriers respond to ultrasound. This study investigates the effect of ultrasound on the release of a hydrophobic drug, dexamethasone, from poly(2-oxazoline)-based micelles. Spontaneous and ultrasound-mediated release of dexamethasone from five types of micelles made of poly(2-oxazoline) block copolymers, composed of hydrophilic poly(2-methyl-2-oxazoline) and hydrophobic poly(2-n-propyl-2-oxazoline) or poly(2-butyl-2-oxazoline-co-2-(3-butenyl)-2-oxazoline), was studied. The release profiles were fitted by zeroorder and Ritger-Peppas models. The ultrasound increased the amount of released dexamethasone by 6\% to 105\% depending on the type of copolymer, the amount of loaded dexamethasone, and the stimulation time point. This study investigates for the first time the interaction between different poly(2-oxazoline)-based micelle formulations and ultrasound waves, quantifying the efficacy of such stimulation in modulating dexamethasone release from these nanocarriers.}, language = {en} } @article{RoelligKramerGabrechtetal.2018, author = {R{\"o}llig, C. and Kramer, M. and Gabrecht, M. and H{\"a}nel, M. and Herbst, R. and Kaiser, U. and Schmitz, N. and Kullmer, J. and Fetscher, S. and Link, H. and Mantovani-L{\"o}ffler, L. and Kr{\"u}mpelmann, U. and Neuhaus, T. and Heits, F. and Einsele, H. and Ritter, B. and Bornh{\"a}user, M. and Schetelig, J. and Thiede, C. and Mohr, B. and Schaich, M. and Platzbecker, U. and Sch{\"a}fer-Eckart, K. and Kr{\"a}mer, A. and Berdel, W. E. and Serve, H. and Ehninger, G. and Schuler, U. S.}, title = {Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients}, series = {Annals of Oncology}, volume = {29}, journal = {Annals of Oncology}, number = {4}, doi = {doi:10.1093/annonc/mdy030}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226473}, pages = {973-978}, year = {2018}, abstract = {Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7+3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA). Patients and methods: Patients with newly diagnosed AML>60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m(2) twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m(2) days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m(2) continuously days 1-7) plus daunorubicin (45 mg/m(2) days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone. Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76\% of patients were >65 years. The complete response rate after DA was 39\% [95\% confidence interval (95\% CI): 33-45] versus 55\% (95\% CI: 49-61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14\% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29\% versus 14\% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513). Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.}, language = {en} } @article{SchmidTarauRossietal.2018, author = {Schmid, Richard and Tarau, Ioana-Sandra and Rossi, Angela and Leonhardt, Stefan and Schwarz, Thomas and Schuerlein, Sebastian and Lotz, Christian and Hansmann, Jan}, title = {In Vivo-Like Culture Conditions in a Bioreactor Facilitate Improved Tissue Quality in Corneal Storage}, series = {Biotechnology Journal}, volume = {13}, journal = {Biotechnology Journal}, number = {1,1700344}, doi = {10.1002/biot.201700344}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228620}, pages = {1-7}, year = {2018}, abstract = {The cornea is the most-transplanted tissue worldwide. However, the availability and quality of grafts are limited due to the current methods of corneal storage. In this study, a dynamic bioreactor system is employed to enable the control of intraocular pressure and the culture at the air-liquid interface. Thereby, in vivo-like storage conditions are achieved. Different media combinations for endothelium and epithelium are tested in standard and dynamic conditions to enhance the viability of the tissue. In contrast to culture conditions used in eye banks, the combination of the bioreactor and biochrom medium 1 allows to preserve the corneal endothelium and the epithelium. Assessment of transparency, swelling, and the trans-epithelial-electrical-resistance (TEER) strengthens the impact of the in vivo-like tissue culture. For example, compared to corneas stored under static conditions, significantly lower optical densities and significantly higher TEER values were measured (p-value <0.05). Furthermore, healing of epithelial defects is enabled in the bioreactor, characterized by re-epithelialization and initiated stromal regeneration. Based on the obtained results, an easy-to-use 3D-printed bioreactor composed of only two parts was derived to translate the technology from the laboratory to the eye banks. This optimized bioreactor facilitates noninvasive microscopic monitoring. The improved storage conditions ameliorate the quality of corneal grafts and the storage time in the eye banks to increase availability and reduce re-grafting.}, language = {en} } @article{SchaeferRoemerJanzenetal.2018, author = {Schaefer, Natascha and Roemer, Vera and Janzen, Dieter and Villmann, Carmen}, title = {Impaired Glycine Receptor Trafficking in Neurological Diseases}, series = {Frontiers in Molecular Neuroscience}, volume = {11}, journal = {Frontiers in Molecular Neuroscience}, number = {291}, doi = {10.3389/fnmol.2018.00291}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227531}, pages = {1-24}, year = {2018}, abstract = {Ionotropic glycine receptors (GlyRs) enable fast synaptic neurotransmission in the adult spinal cord and brainstem. The inhibitory GlyR is a transmembrane glycinegated chloride channel. The immature GlyR protein undergoes various processing steps, e.g., folding, assembly, and maturation while traveling from the endoplasmic reticulum to and through the Golgi apparatus, where post-translational modifications, e.g., glycosylation occur. The mature receptors are forward transported via microtubules to the cellular surface and inserted into neuronal membranes followed by synaptic clustering. The normal life cycle of a receptor protein includes further processes like internalization, recycling, and degradation. Defects in GlyR life cycle, e.g., impaired protein maturation and degradation have been demonstrated to underlie pathological mechanisms of various neurological diseases. The neurological disorder startle disease is caused by glycinergic dysfunction mainly due to missense mutations in genes encoding GlyR subunits (GLRA1 and GLRB). In vitro studies have shown that most recessive forms of startle disease are associated with impaired receptor biogenesis. Another neurological disease with a phenotype similar to startle disease is a special form of stiff-person syndrome (SPS), which is most probably due to the development of GlyR autoantibodies. Binding of GlyR autoantibodies leads to enhanced receptor internalization. Here we focus on the normal life cycle of GlyRs concentrating on assembly and maturation, receptor trafficking, post-synaptic integration and clustering, and GlyR internalization/recycling/degradation. Furthermore, this review highlights findings on impairment of these processes under disease conditions such as disturbed neuronal ER-Golgi trafficking as the major pathomechanism for recessive forms of human startle disease. In SPS, enhanced receptor internalization upon autoantibody binding to the GlyR has been shown to underlie the human pathology. In addition, we discuss how the existing mouse models of startle disease increased our current knowledge of GlyR trafficking routes and function. This review further illuminates receptor trafficking of GlyR variants originally identified in startle disease patients and explains changes in the life cycle of GlyRs in patients with SPS with respect to structural and functional consequences at the receptor level.}, language = {en} } @article{RinaldiVarottoAsaetal.2018, author = {Rinaldi, Christian and Varotto, Sara and Asa, Marco and Slawinska, Jagoda and Fujii, Jun and Vinai, Giovanni and Cecchi, Stefano and Di Sante, Domenico and Calarco, Raffaella and Vobornik, Ivana and Panaccione, Giancarlo and Picozzi, Silvia and Bertacco, Riccardo}, title = {Ferroelectric Control of the Spin Texture in GeTe}, series = {Nano Letters}, volume = {18}, journal = {Nano Letters}, number = {5}, doi = {10.1021/acs.nanolett.7b04829}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226294}, pages = {2751-2758}, year = {2018}, abstract = {The electric and nonvolatile control of the spin texture in semiconductors would represent a fundamental step toward novel electronic devices combining memory and computing functionalities. Recently, GeTe has been theoretically proposed as the father compound of a new class of materials, namely ferroelectric Rashba semiconductors. They display bulk bands with giant Rashba-like splitting due to the inversion symmetry breaking arising from the ferroelectric polarization, thus allowing for the ferroelectric control of the spin. Here, we provide the experimental demonstration of the correlation between ferroelectricity and spin texture. A surface-engineering strategy is used to set two opposite predefined uniform ferroelectric polarizations, inward and outward, as monitored by piezoresponse force microscopy. Spin and angular resolved photoemission experiments show that these GeTe(111) surfaces display opposite sense of circulation of spin in bulk Rashba bands. Furthermore, we demonstrate the crafting of nonvolatile ferroelectric patterns in GeTe films at the nanoscale by using the conductive tip of an atomic force microscope. Based on the intimate link between ferroelectric polarization and spin in GeTe, ferroelectric patterning paves the way to the investigation of devices with engineered spin configurations.}, language = {en} } @article{SchiererOstaleckiZinseretal.2018, author = {Schierer, Stefan and Ostalecki, Christian and Zinser, Elisabeth and Lamprecht, Ricarda and Plosnita, Bianca and Stich, Lena and Doerrie, Jan and Lutz, Manfred B and Schuler, Gerold and Baur, Andreas S}, title = {Extracellular vesicles from mature dendritic cells (DC) differentiate monocytes into immature DC}, series = {Life Science Alliance}, volume = {1}, journal = {Life Science Alliance}, number = {6}, doi = {10.26508/lsa.201800093}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228587}, pages = {e201800093, 1-17}, year = {2018}, abstract = {During inflammation, murine and human monocytes can develop into dendritic cells (DC), but this process is not entirely understood. Here, we demonstrate that extracellular vesicles (EV) secreted by mature human DC (maDC) differentiate peripheral monocytes into immature DC, expressing a unique marker pattern, including 6-sulfo LacNAc (slan), Zbtb46, CD64, and CD14. While EV from both maDC and immature DC differentiated monocytes similar to GM-CSF/IL-4 stimulation, only maDC-EV produced precursors, which upon maturation stimulus developed into T-cell-activating and IL-12p70-secreting maDC. Mechanistically, maDC-EV induced cell signaling through GM-CSF, which was abundant in EV as were IL-4 and other cytokines and chemokines. When injected into the mouse skin, murine maDC-EV attracted immune cells including monocytes that developed activation markers typical for inflammatory cells. Skin-injected EV also reached lymph nodes, causing a similar immune cell infiltration. We conclude that DC-derived EV likely serve to perpetuate an immune reaction and may contribute to chronic inflammation.}, language = {en} } @article{RinaldettiPfirrmannManzetal.2018, author = {Rinaldetti, S{\´e}bastien and Pfirrmann, Markus and Manz, Kirsi and Guilhot, Joelle and Dietz, Christian and Panagiotidis, Panayiotidis and Spiess, Birgit and Seifarth, Wolfgang and Fabarius, Alice and M{\"u}ller, Martin and Pagoni, Maria and Dimou, Maria and Dengler, Jolanta and Waller, Cornelius F. and Br{\"u}mmendorf, Tim H. and Herbst, Regina and Burchert, Andreas and Janßen, Carsten and Goebeler, Maria Elisabeth and Jost, Philipp J. and Hanzel, Stefan and Schafhausen, Philippe and Prange-Krex, Gabriele and Illmer, Thomas and Janzen, Viktor and Klausmann, Martine and Eckert, Robert and B{\"u}schel, Gerd and Kiani, Alexander and Hofmann, Wolf-Karsten and Mahon, Fran{\c{c}}ois-Xavier and Saussele, Susanne}, title = {Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial}, series = {Clinical Lymphoma, Myeloma \& Leukemia}, volume = {18}, journal = {Clinical Lymphoma, Myeloma \& Leukemia}, number = {4}, doi = {10.1016/j.clml.2018.02.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226281}, pages = {266-271}, year = {2018}, abstract = {Within the EURO-SKI trial, 132 chronic phase CML patients discontinued imatinib treatment. RNA was isolated from peripheral blood in order to analyze the expression of MDR1, ABCG2 and OCT1. ABCG2 was predictive for treatment-free remission in Cox regression analysis. High transcript levels of the ABCG2 efflux transporter (>4.5 parts per thousand) were associated with a twofold higher risk of relapse. Introduction: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54\% (95\% confidence interval [CI], 46\%-62\%). ABCG2 expression (parts per thousand) was retained as the only significant variable (P=.02; hazard ratio, 1.04; 95\% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P=.04). Patients with an ABCG2/GUSB transcript level >4.5 parts per thousand (n=93) showed a 12-month TFR rate of 47\% (95\% CI, 37\%-57\%), whereas patients with low ABCG2 expression (<= 4.5 parts per thousand; n=39) had a 12-month TFR rate of 72\% (95\% CI, 55\%-82\%). Conclusion: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation. (C) 2018 The Authors. Published by Elsevier Inc.}, language = {en} } @article{RingLandesHotho2018, author = {Ring, Markus and Landes, Dieter and Hotho, Andreas}, title = {Detection of slow port scans in flow-based network traffic}, series = {PLoS ONE}, volume = {13}, journal = {PLoS ONE}, number = {9}, doi = {10.1371/journal.pone.0204507}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226305}, pages = {e0204507, 1-18}, year = {2018}, abstract = {Frequently, port scans are early indicators of more serious attacks. Unfortunately, the detection of slow port scans in company networks is challenging due to the massive amount of network data. This paper proposes an innovative approach for preprocessing flow-based data which is specifically tailored to the detection of slow port scans. The preprocessing chain generates new objects based on flow-based data aggregated over time windows while taking domain knowledge as well as additional knowledge about the network structure into account. The computed objects are used as input for the further analysis. Based on these objects, we propose two different approaches for detection of slow port scans. One approach is unsupervised and uses sequential hypothesis testing whereas the other approach is supervised and uses classification algorithms. We compare both approaches with existing port scan detection algorithms on the flow-based CIDDS-001 data set. Experiments indicate that the proposed approaches achieve better detection rates and exhibit less false alarms than similar algorithms.}, language = {en} } @article{SchenkKraussHolzschuh2018, author = {Schenk, Mariela and Krauss, Jochen and Holzschuh, Andrea}, title = {Desynchronizations in bee-plant interactions cause severe fitness losses in solitary bees}, series = {Journal of Animal Ecology}, volume = {87}, journal = {Journal of Animal Ecology}, number = {1}, doi = {10.1111/1365-2656.12694}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228533}, pages = {139-149}, year = {2018}, abstract = {1. Global warming can disrupt mutualistic interactions between solitary bees and plants when increasing temperature differentially changes the timing of interacting partners. One possible scenario is for insect phenology to advance more rapidly than plant phenology. 2. However, empirical evidence for fitness consequences due to temporal mismatches is lacking for pollinators and it remains unknown if bees have developed strategies to mitigate fitness losses following temporal mismatches. 3. We tested the effect of temporal mismatches on the fitness of three spring-emerging solitary bee species, including one pollen specialist. Using flight cages, we simulated (i) a perfect synchronization (from a bee perspective): bees and flowers occur simultaneously, (ii) a mismatch of 3days and (iii) a mismatch of 6days, with bees occurring earlier than flowers in the latter two cases. 4. A mismatch of 6days caused severe fitness losses in all three bee species, as few bees survived without flowers. Females showed strongly reduced activity and reproductive output compared to synchronized bees. Fitness consequences of a 3-day mismatch were species-specific. Both the early-spring species Osmia cornuta and the mid-spring species Osmia bicornis produced the same number of brood cells after a mismatch of 3days as under perfect synchronization. However, O.cornuta decreased the number of female offspring, whereas O.bicornis spread the brood cells over fewer nests, which may increase offspring mortality, e.g. due to parasitoids. The late-spring specialist Osmia brevicornis produced fewer brood cells even after a mismatch of 3days. Additionally, our results suggest that fitness losses after temporal mismatches are higher during warm than cold springs, as the naturally occurring temperature variability revealed that warm temperatures during starvation decreased the survival rate of O.bicornis. 5. We conclude that short temporal mismatches can cause clear fitness losses in solitary bees. Although our results suggest that bees have evolved species-specific strategies to mitigate fitness losses after temporal mismatches, the bees were not able to completely compensate for impacts on their fitness after temporal mismatches with their food resources.}, subject = {pollination}, language = {en} } @article{ChristopherDUgelvigWiesenhoferetal.2018, author = {Christopher D., Pull and Ugelvig, Line V. and Wiesenhofer, Florian and Anna V., Grasse and Tragust, Simon and Schmitt, Thomas and Brown, Mark JF and Cremer, Sylvia}, title = {Destructive disinfection of infected brood prevents systemic disease spread in ant colonies}, series = {eLIFE}, volume = {7}, journal = {eLIFE}, doi = {10.7554/eLife.32073}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223728}, pages = {e 32073, 1-29}, year = {2018}, abstract = {In social groups, infections have the potential to spread rapidly and cause disease outbreaks. Here, we show that in a social insect, the ant Lasius neglectus, the negative consequences of fungal infections (Metarhizium brunneum) can be mitigated by employing an efficient multicomponent behaviour, termed destructive disinfection, which prevents further spread of the disease through the colony. Ants specifically target infected pupae during the pathogens non-contagious incubation period, utilising chemical 'sickness cues' emitted by pupae. They then remove the pupal cocoon, perforate its cuticle and administer antimicrobial poison, which enters the body and prevents pathogen replication from the inside out. Like the immune system of a metazoan body that specifically targets and eliminates infected cells, ants destroy infected brood to stop the pathogen completing its lifecycle, thus protecting the rest of the colony. Hence, in an analogous fashion, the same principles of disease defence apply at different levels of biological organisation.}, language = {en} } @article{ReineckeJuergensmeyerEngelbertzetal.2018, author = {Reinecke, Holger and J{\"u}rgensmeyer, Sabine and Engelbertz, Christiane and Gerss, Joachim and Kirchhof, Paulus and Breithardt, G{\"u}nter and Bauersachs, Rupert and Wanner, Christoph}, title = {Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study}, series = {BMJ open}, volume = {8}, journal = {BMJ open}, number = {9}, doi = {10.1136/bmjopen-2018-022690}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225156}, pages = {e022690, 1-10}, year = {2018}, abstract = {Introduction Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis. Methods and analysis A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017. Ethics and dissemination The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals. Trial registration numbers NCT02933697, Pre-results.}, language = {en} } @article{SausseleHehlmannFabariusetal.2018, author = {Saussele, Susanne and Hehlmann, Ruediger and Fabarius, Alice and Jeromin, Sabine and Proetel, Ulrike and Rinaldetti, Sebastien and Kohlbrenner, Katharina and Einsele, Hermann and Falge, Christine and Kanz, Lothar and Neubauer, Andreas and Kneba, Michael and Stegelmann, Frank and Pfreundschuh, Michael and Waller, Cornelius F. and Oppliger Leibundgut, Elisabeth and Heim, Dominik and Krause, Stefan W. and Hofmann, Wolf-Karsten and Hasford, Joerg and Pfirrmann, Markus and M{\"u}ller, Martin C. and Hochhaus, Andreas and Lauseker, Michael}, title = {Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV}, series = {Leukemia}, volume = {32}, journal = {Leukemia}, number = {5}, doi = {10.1038/s41375-018-0055-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227528}, pages = {1222-1228}, year = {2018}, abstract = {Major molecular remission (MMR) is an important therapy goal in chronic myeloid leukemia (CML). So far, MMR is not a failure criterion according to ELN management recommendation leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. At monthly landmarks, for different molecular remission status Hazard ratios (HR) were estimated for patients registered to CML study IV who were divided in a learning and a validation sample. The minimum HR for MMR was found at 2.5 years with 0.28 (compared to patients without remission). In the validation sample, a significant advantage for progression-free survival (PFS) for patients in MMR could be detected (p-value 0.007). The optimal time to predict PFS in patients with MMR could be validated in an independent sample at 2.5 years. With our model we provide a suggestion when to define lack of MMR as therapy failure and thus treatment change should be considered. The optimal response time for 1\% BCR-ABL at about 12-15 months was confirmed and for deep molecular remission no specific time point was detected. Nevertheless, it was demonstrated that the earlier the MMR is achieved the higher is the chance to attain deep molecular response later.}, language = {en} } @article{RosenbaumBlumSchweizeretal.2018, author = {Rosenbaum, David and Blum, Leonore and Schweizer, Paul and Fallgatter, Andreas J. and Herrmann, Martin J. and Ehlis, Ann-Christine and Metzger, Florian G.}, title = {Comparison of speed versus complexity effects on the hemodynamic response of the trail making test in block designs}, series = {Neurophotonics}, volume = {5}, journal = {Neurophotonics}, number = {4}, doi = {10.1117/1.NPh.5.4.045007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226982}, pages = {045007, 1-9}, year = {2018}, abstract = {The use of functional near-infrared spectroscopy (fNIRS) in block designs provides measures of cortical activity in ecologically valid environments. However, in some cases, the use of block designs may be problematic when data are not corrected for performance in a time-restricted block. We sought to investigate the effects of task complexity and processing speed on hemodynamic responses in an fNIRS block design. To differentiate the effects of task complexity and processing speed, 20 subjects completed the trail making test (TMT) in two versions (TMT-A versus TMT-B) and three different speed levels (slow versus moderate versus fast). During TMT-A, subjects are asked to connect encircled numbers in numerically ascending order (1-2-3 ... ). In the more complex TMT-B, subjects are instructed to connect encircled numbers and letters in alternating ascending order (1-A-2-B ... ). To illustrate the obscuring effects of processing speed on task complexity, we perform two different analyses. First, we analyze the classical measures of oxygenated blood, and second, we analyze the measures corrected for the number of processed items. Our results show large effects for processing speed within the bilateral inferior frontal gyrus, left dorsolateral prefrontal cortex, and superior parietal lobule (SPL). The TMT contrast did not show significant effects with classical measures, although trends are observed for higher activation during TMT-B. When corrected for processed items, higher activity for TMT-B in comparison to TMT-A is found within the SPL. The results are discussed in light of recent research designs, and simple to use correction methods are suggested. (c) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.}, language = {en} } @article{RoedingBrixner2018, author = {Roeding, Sebastian and Brixner, Tobias}, title = {Coherent two-dimensional electronic mass spectrometry}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, number = {2519}, doi = {10.1038/s41467-018-04927-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226458}, pages = {1-9}, year = {2018}, abstract = {Coherent two-dimensional (2D) optical spectroscopy has revolutionized our ability to probe many types of couplings and ultrafast dynamics in complex quantum systems. The dynamics and function of any quantum system strongly depend on couplings to the environment. Thus, studying coherent interactions for different environments remains a topic of tremendous interest. Here we introduce coherent 2D electronic mass spectrometry that allows 2D measurements on effusive molecular beams and thus on quantum systems with minimum system-bath interaction and employ this to identify the major ionization pathway of 3d Rydberg states in NO2. Furthermore, we present 2D spectra of multiphoton ionization, disclosing distinct differences in the nonlinear response functions leading to the ionization products. We also realize the equivalent of spectrally resolved transient-absorption measurements without the necessity for acquiring weak absorption changes. Using time-of-flight detection introduces cations as an observable, enabling the 2D spectroscopic study on isolated systems of photophysical and photochemical reactions.}, language = {en} } @article{RasaNoraKrukleHenningetal.2018, author = {Rasa, Santa and Nora-Krukle, Zaiga and Henning, Nina and Eliassen, Eva and Shikova, Evelina and Harrer, Thomas and Scheibenbogen, Carmen and Murovska, Modra and Prusty, Bhupesh K.}, title = {Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)}, series = {Journal of Translational Medicine}, volume = {16}, journal = {Journal of Translational Medicine}, number = {268}, doi = {10.1186/s12967-018-1644-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224960}, pages = {1-25}, year = {2018}, abstract = {Background and main text: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and controversial clinical condition without having established causative factors. Increasing numbers of cases during past decade have created awareness among patients as well as healthcare professionals. Chronic viral infection as a cause of ME/CFS has long been debated. However, lack of large studies involving well-designed patient groups and validated experimental set ups have hindered our knowledge about this disease. Moreover, recent developments regarding molecular mechanism of pathogenesis of various infectious agents cast doubts over validity of several of the past studies. Conclusions: This review aims to compile all the studies done so far to investigate various viral agents that could be associated with ME/CFS. Furthermore, we suggest strategies to better design future studies on the role of viral infections in ME/CFS.}, language = {en} } @article{ReilingKrohneFriedrichetal.2018, author = {Reiling, Sarah J. and Krohne, Georg and Friedrich, Oliver and Geary, Timothy G. and Rohrbach, Petra}, title = {Chloroquine exposure triggers distinct cellular responses in sensitive versus resistant Plasmodium falciparum parasites}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, number = {11137}, doi = {10.1038/s41598-018-29422-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225123}, pages = {1-11}, year = {2018}, abstract = {Chloroquine (CQ) treatment failure in Plasmodium falciparum parasites has been documented for decades, but the pharmacological explanation of this phenotype is not fully understood. Current concepts attribute CQ resistance to reduced accumulation of the drug at a given external CQ concentration ([CQ] ex) in resistant compared to sensitive parasites. The implication of this explanation is that the mechanisms of CQ-induced toxicity in resistant and sensitive strains are similar once lethal internal concentrations have been reached. To test this hypothesis, we investigated the mechanism of CQ-induced toxicity in CQ-sensitive (CQS) versus CQ-resistant (CQR) parasites by analyzing the time-course of cellular responses in these strains after exposure to varying [CQ] ex as determined in 72 h toxicity assays. Parasite killing was delayed in CQR parasites for up to 10 h compared to CQS parasites when exposed to equipotent [CQ] ex. In striking contrast, brief exposure (1 h) to lethal [CQ] ex in CQS but not CQR parasites caused the appearance of hitherto undescribed hemozoin (Hz)-containing compartments in the parasite cytosol. Hz-containing compartments were very rarely observed in CQR parasites even after CQ exposures sufficient to cause irreversible cell death. These findings challenge current concepts that CQ killing of malaria parasites is solely concentration-dependent, and instead suggest that CQS and CQR strains fundamentally differ in the consequences of CQ exposure.}, language = {en} } @article{RauertWunderlichBerberichRosenwaldetal.2018, author = {Rauert-Wunderlich, Hilka and Berberich, Ingolf and Rosenwald, Andreas and Rudelius, Martina}, title = {CD40L mediated alternative NF kappa B-signaling induces resistance to BCR-inhibitors in patients with mantle cell lymphoma}, series = {Cell Death \& Disease}, journal = {Cell Death \& Disease}, number = {9}, doi = {10.1038/s41419-017-0157-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225027}, pages = {86, 1-9}, year = {2018}, abstract = {Drug resistance is a significant obstacle in cancer treatment and therefore a frequent subject of research. Developed or primary resistance limits the treatment success of inhibitors of the B cell receptor (BCR) pathway in mantle cell lymphoma (MCL) patients. Recent research has highlighted the role of the nuclear factor-kappa B (NF kappa B) pathway in the context of resistance to BCR inhibitors in MCL. In this study, we analyzed the dependency of MCL cell lines on NF kappa B signaling and illustrated the ability of CD40L to activate the alternative NF kappa B pathway in MCL. This activation leads to independency of classical NF kappa B signaling and results in resistance to BCR inhibitors. Therefore, ligands (such as CD40L) and their activation of the alternative NF kappa B pathway have a major impact on the drug response in MCL. Furthermore, this study indicates a protective role for cells expressing specific ligands as microenvironmental niches for MCL cells and underlines the significance of therapeutically targeting alternative NF kappa B signaling in MCL.}, language = {en} } @article{Scheer2018, author = {Scheer, Ulrich}, title = {Boveri's research at the Zoological Station Naples: Rediscovery of his original microscope slides at the University of W{\"u}rzburg}, series = {Marine Genomics}, volume = {40}, journal = {Marine Genomics}, doi = {10.1016/j.margen.2018.01.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228453}, pages = {1-8}, year = {2018}, abstract = {Eric Davidson once wrote about Theodor Boveri: "From his own researches, and perhaps most important, his generalized interpretations, derive the paradigms that underlie modern inquiries into the genomic basis of embryogenesis" (Davidson, 1985). As luck would have it, the "primary data" of Boveri's experimental work, namely the microscope slides prepared by him and his wife Marcella during several stays at the Zoological Station in Naples (1901/02, 1911/12 and 1914), have survived at the University of Wurzburg. More than 600 slides exist and despite their age they are in a surprisingly good condition. The slides are labelled and dated in Boveri's handwriting and thus can be assigned to his published experimental work on sea urchin development. The results allowed Boveri to unravel the role of the cell nucleus and its chromosomes in development and inheritance. Here, I present an overview of the slides in the context of Boveri's work along with photographic images of selected specimens taken from the original slides. It is planned to examine the slides in more detail, take high-resolution focal image series of significant specimens and make them online available.}, language = {en} } @article{RostasBollmannSavilleetal.2018, author = {Rost{\´a}s, Michael and Bollmann, Felix and Saville, David and Riedel, Michael}, title = {Ants contribute to pollination but not to reproduction in a rare calcareous grassland forb}, series = {PeerJ}, volume = {6}, journal = {PeerJ}, doi = {10.7717/peerj.4369}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227053}, pages = {e4369, 1-16}, year = {2018}, abstract = {The number of plants pollinated by ants is surprisingly low given the abundance of ants and the fact that they are common visitors of angiosperms. Generally ants are considered as nectar robbers that do not provide pollination service. We studied the pollination system of the endangered dry grassland forb Euphorbia seguieriana and found two ant species to be the most frequent visitors of its flowers. Workers of Formica cunicularia carried five times more pollen than smaller Tapinoma erraticum individuals, but significantly more viable pollen was recovered from the latter. Overall, the viability of pollen on ant cuticles was significantly lower (p < 0.001)-presumably an antibiotic effect of the metapleural gland secretion. A marking experiment suggested that ants were unlikely to facilitate outcrossing as workers repeatedly returned to the same individual plant. In open pollinated plants and when access was given exclusively to flying insects, fruit set was nearly 100\%. In plants visited by ants only, roughly one third of flowers set fruit, and almost none set fruit when all insects were excluded. The germination rate of seeds from flowers pollinated by flying insects was 31 +/- 7\% in contrast to 1 +/- 1\% resulting from ant pollination. We conclude that inbreeding depression may be responsible for the very low germination rate in ant pollinated flowers and that ants, although the most frequent visitors, play a negligible or even deleterious role in the reproduction of E. seguieriana. Our study reiterates the need to investigate plant fitness effects beyond seed set in order to confirm ant-plant mutualisms.}, language = {en} } @article{RiegerLissMellinghoffetal.2018, author = {Rieger, C. T. and Liss, B. and Mellinghoff, S. and Buchheidt, D. and Cornely, O. A. and Egerer, G. and Heinz, W. J. and Hentrich, M. and Maschmeyer, G. and Mayer, K. and Sandherr, M. and Silling, G. and Ullmann, A. and Vehreschild, M. J. G. T. and von Lilienfeld-Toal, M. and Wolf, H. H. and Lehners, N.}, title = {Anti-infective vaccination strategies in patients with hematologic malignancies or solid tumors-Guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO)}, series = {Annals of Oncology}, volume = {29}, journal = {Annals of Oncology}, number = {6}, doi = {10.1093/annonc/mdy117}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226196}, pages = {1354-1365}, year = {2018}, abstract = {Infectious complications are a significant cause of morbidity and mortality in patients with malignancies specifically when receiving anticancer treatments. Prevention of infection through vaccines is an important aspect of clinical care of cancer patients. Immunocompromising effects of the underlying disease as well as of antineoplastic therapies need to be considered when devising vaccination strategies. This guideline provides clinical recommendations on vaccine use in cancer patients including autologous stem cell transplant recipients, while allogeneic stem cell transplantation is subject of a separate guideline. The document was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) by reviewing currently available data and applying evidence-based medicine criteria.}, language = {en} } @article{SchihadaVandenabeeleZabeletal.2018, author = {Schihada, Hannes and Vandenabeele, Sylvie and Zabel, Ulrike and Frank, Monika and Lohse, Martin J. and Maiellaro, Isabella}, title = {A universal bioluminescence resonance energy transfer sensor design enables high-sensitivity screening of GPCR activation dynamics}, series = {Communications Biology}, volume = {1}, journal = {Communications Biology}, number = {105}, doi = {10.1038/s42003-018-0072-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228592}, pages = {1-8}, year = {2018}, abstract = {G-protein-coupled receptors (GPCRs) represent one of the most important classes of drug targets. The discovery of new GCPR therapeutics would greatly benefit from the development of a generalizable high-throughput assay to directly monitor their activation or de-activation. Here we screened a variety of labels inserted into the third intracellular loop and the C-terminus of the alpha(2 Lambda)-adrenergic receptor and used fluorescence (FRET) and bioluminescence resonance energy transfer (BRET) to monitor ligand-binding and activation dynamics. We then developed a universal intramolecular BRET receptor sensor design to quantify efficacy and potency of GPCR ligands in intact cells and real time. We demonstrate the transferability of the sensor design by cloning beta(2)-adrenergic and PTH1-receptor BRET sensors and monitored their efficacy and potency. For all biosensors, the Z factors were well above 0.5 showing the suitability of such design for microtiter plate assays. This technology will aid the identification of novel types of GPCR ligands.}, language = {en} } @article{RogowskiLehmannGeroulaPrejbiszetal.2018, author = {Rogowski-Lehmann, Natalie and Geroula, Aikaterini and Prejbisz, Aleksander and Timmers, Henri J. L. M. and Megerle, Felix and Robledo, Mercedes and Fassnacht, Martin and Fliedner, Stephanie M. J. and Reincke, Martin and Stell, Anthony and Januszewicz, Andrzej and Lenders, Jacques W. M. and Eisenhofer, Graeme and Beuschlein, Felix}, title = {Missed clinical clues in patients with pheochromocytoma/paraganglioma discovered by imaging}, series = {Endocrine Connections}, volume = {7}, journal = {Endocrine Connections}, number = {11}, doi = {10.1530/EC-18-0318}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226481}, pages = {1168-1177}, year = {2018}, abstract = {Background: Pheochromocytomas and paragangliomas (PPGLs) are rare but potentially harmful tumors that can vary in their clinical presentation. Tumors may be found due to signs and symptoms, as part of a hereditary syndrome or following an imaging procedure. Objective: To investigate potential differences in clinical presentation between PPGLs discovered by imaging (iPPGLs), symptomatic cases (sPPGLs) and those diagnosed during follow-up because of earlier disease/known hereditary mutations (fPPGL). Design: Prospective study protocol, which has enrolled patients from six European centers with confirmed PPGLs. Data were analyzed from 235 patients (37 iPPGLs, 36 sPPGLs, 27\% fPPGLs) and compared for tumor volume, biochemical profile, mutation status, presence of metastases and self-reported symptoms. iPPGL patients were diagnosed at a significantly higher age than fPPGLs (P<0.001), found to have larger tumors (P=0.003) and higher metanephrine and normetanephrine levels at diagnosis (P=0.021). Significantly lower than in sPPGL, there was a relevant number of self-reported symptoms in iPPGL (2.9 vs 4.3 symptoms, P< 0.001). In 16.2\% of iPPGL, mutations in susceptibility genes were detected, although this proportion was lower than that in fPPGL (60.9\%) and sPPGL (21.5\%). Patients with PPGLs detected by imaging were older, have higher tumor volume and more excessive hormonal secretion in comparison to those found as part of a surveillance program. Presence of typical symptoms indicates that in a relevant proportion of those patients, the PPGL diagnosis had been delayed. Precis: Pheochromocytoma/paraganglioma discovered by imaging are often symptomatic and carry a significant proportion of germline mutations in susceptibility genes.}, subject = {Biochemical-Diagnosis}, language = {en} } @article{RefardtSailerWinzeleretal.2018, author = {Refardt, Julie and Sailer, Clara Odilia and Winzeler, Bettina and Betz, Matthias Johannes and Chifu, Irina and Schnyder, Ingeborg and Fassnacht, Martin and Fenske, Wiebke and Christ-Crain, Mirjam}, title = {FGF-21 levels in polyuria-polydipsia syndrome}, series = {Endocrine Connections}, volume = {7}, journal = {Endocrine Connections}, number = {12}, doi = {10.1530/EC-18-0469}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225085}, pages = {1501-1506}, year = {2018}, abstract = {The pathomechanism of primary polydipsia is poorly understood. Recent animal data reported a connection between fibroblast growth factor 21 (FGF-21) and elevated fluid intake independently of hormonal control by the hormone arginine-vasopressin (AVP) and osmotic stimulation. We therefore compared circulating FGF-21 levels in patients with primary polydipsia to patients with AVP deficiency (central diabetes insipidus) and healthy volunteers. In this prospective cohort study, we analyzed FGF-21 levels of 20 patients with primary polydipsia, 20 patients with central diabetes insipidus and 20 healthy volunteers before and after stimulation with hypertonic saline infusion targeting a plasma sodium level >= 150 mmol/L. The primary outcome was the difference in FGF-21 levels between the three groups. Baseline characteristics were similar between the groups except for patients with central diabetes insipidus being heavier. There was no difference in baseline FGF-21 levels between patients with primary polydipsia and healthy volunteers (122 pg/mL (52,277) vs 193 pg/mL (48,301), but higher levels in patients with central diabetes insipidus were observed (306 pg/mL (114,484); P=0.037). However, this was not confirmed in a multivariate linear regression analysis after adjusting for age, sex, BMI and smoking status. Osmotic stimulation did not affect FGF-21 levels in either group (difference to baseline: primary polydipsia -23 pg/mL (-43, 22); central diabetes insipidus 17 pg/mL (-76, 88); healthy volunteers -6 pg/mL (-68, 22); P=0.45). To conclude, FGF-21 levels are not increased in patients with primary polydipsia as compared to central diabetes insipidus or healthy volunteers. FGF-21 therefore does not seem to be causal of elevated fluid intake in these patients.}, subject = {Fibroblast Growth Factor-21}, language = {en} } @article{GrevingRichter2018, author = {Greving, Sven and Richter, Tobias}, title = {Examining the testing effect in university teaching: retrievability and question format matter}, series = {Frontiers in Psychology}, volume = {9}, journal = {Frontiers in Psychology}, issn = {1664-1078}, doi = {10.3389/fpsyg.2018.02412}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190802}, year = {2018}, abstract = {Review of learned material is crucial for the learning process. One approach that promises to increase the effectiveness of reviewing during learning is to answer questions about the learning content rather than restudying the material (testing effect). This effect is well established in lab experiments. However, existing research in educational contexts has often combined testing with additional didactical measures that hampers the interpretation of testing effects. We aimed to examine the testing effect in its pure form by implementing a minimal intervention design in a university lecture (N = 92). The last 10 min of each lecture session were used for reviewing the lecture content by either answering short-answer questions, multiple-choice questions, or reading summarizing statements about core lecture content. Three unannounced criterial tests measured the retention of learning content at different times (1, 12, and 23 weeks after the last lecture). A positive testing effect emerged for short-answer questions that targeted information that participants could retrieve from memory. This effect was independent of the time of test. The results indicated no testing effect for multiple-choice testing. These results suggest that short-answer testing but not multiple-choice testing may benefit learning in higher education contexts.}, language = {en} } @article{KrauseWeber2018, author = {Krause, Stefan and Weber, Silvana}, title = {Lift me up by looking down: social comparison effects of narratives}, series = {Frontiers in Psychology}, volume = {9}, journal = {Frontiers in Psychology}, issn = {1664-1078}, doi = {10.3389/fpsyg.2018.01889}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190624}, year = {2018}, abstract = {Stories are a powerful means to change recipients' views on themselves by being transported into the story world and by identifying with story characters. Previous studies showed that recipients temporarily change in line with a story and its characters (assimilation). Conversely, assimilation might be less likely when recipients are less identified with story protagonists or less transported into a story by comparing themselves with a story character. This may lead to changes, which are opposite to a story and its characters (contrast). In two experiments, we manipulated transportation and experience taking via two written reviews (Experiment 1; N = 164) and by varying the perspective of the story's narrator (Experiment 2; N = 79) of a short story about a negligent student. Recipients' self-ratings in comparison to others, motives, and problem-solving behavior served as dependent variables. However, neither the review nor the perspective manipulation affected transportation or experience taking while reading the story. Against our expectations, highly transported recipients (in Study 1) and recipients with high experience taking (in Study 2) showed more persistency working on an anagram-solving task, even when controlling for trait conscientiousness. Our findings are critically discussed in light of previous research.}, language = {en} } @article{FujiwaraHermannLuiblKatsuraetal.2018, author = {Fujiwara, Yuri and Hermann-Luibl, Christiane and Katsura, Maki and Sekiguchi, Manabu and Ida, Takanori and Helfrich-F{\"o}rster, Charlotte and Yoshii, Taishi}, title = {The CCHamide1 Neuropeptide Expressed in the Anterior Dorsal Neuron 1 Conveys a Circadian Signal to the Ventral Lateral Neurons in Drosophila melanogaster}, series = {Frontiers in Physiology}, volume = {09}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2018.01276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195940}, year = {2018}, abstract = {The fruit fly Drosophila melanogaster possesses approximately 150 brain clock neurons that control circadian behavioral rhythms. Even though individual clock neurons have self-sustaining oscillators, they interact and synchronize with each other through a network. However, little is known regarding the factors responsible for these network interactions. In this study, we investigated the role of CCHamide1 (CCHa1), a neuropeptide expressed in the anterior dorsal neuron 1 (DN1a), in intercellular communication of the clock neurons. We observed that CCHa1 connects the DN1a clock neurons to the ventral lateral clock neurons (LNv) via the CCHa1 receptor, which is a homolog of the gastrin-releasing peptide receptor playing a role in circadian intercellular communications in mammals. CCHa1 knockout or knockdown flies have a generally low activity level with a special reduction of morning activity. In addition, they exhibit advanced morning activity under light-dark cycles and delayed activity under constant dark conditions, which correlates with an advance/delay of PAR domain Protein 1 (PDP1) oscillations in the small-LNv (s-LNv) neurons that control morning activity. The terminals of the s-LNv neurons show rather high levels of Pigment-dispersing factor (PDF) in the evening, when PDF is low in control flies, suggesting that the knockdown of CCHa1 leads to increased PDF release; PDF signals the other clock neurons and evidently increases the amplitude of their PDP1 cycling. A previous study showed that high-amplitude PDP1 cycling increases the siesta of the flies, and indeed, CCHa1 knockout or knockdown flies exhibit a longer siesta than control flies. The DN1a neurons are known to be receptive to PDF signaling from the s-LNv neurons; thus, our results suggest that the DN1a and s-LNv clock neurons are reciprocally coupled via the neuropeptides CCHa1 and PDF, and this interaction fine-tunes the timing of activity and sleep.}, language = {en} } @article{BeckHovhanyanMenegazzietal.2018, author = {Beck, Katherina and Hovhanyan, Anna and Menegazzi, Pamela and Helfrich-F{\"o}rster, Charlotte and Raabe, Thomas}, title = {Drosophila RSK Influences the Pace of the Circadian Clock by Negative Regulation of Protein Kinase Shaggy Activity}, series = {Frontiers in Molecular Neuroscience}, volume = {11}, journal = {Frontiers in Molecular Neuroscience}, number = {122}, issn = {1662-5099}, doi = {10.3389/fnmol.2018.00122}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196034}, year = {2018}, abstract = {Endogenous molecular circadian clocks drive daily rhythmic changes at the cellular, physiological, and behavioral level for adaptation to and anticipation of environmental signals. The core molecular system consists of autoregulatory feedback loops, where clock proteins inhibit their own transcription. A complex and not fully understood interplay of regulatory proteins influences activity, localization and stability of clock proteins to set the pace of the clock. This study focuses on the molecular function of Ribosomal S6 Kinase (RSK) in the Drosophila melanogaster circadian clock. Mutations in the human rsk2 gene cause Coffin-Lowry syndrome, which is associated with severe mental disabilities. Knock-out studies with Drosophila ortholog rsk uncovered functions in synaptic processes, axonal transport and adult behavior including associative learning and circadian activity. However, the molecular targets of RSK remain elusive. Our experiments provide evidence that RSK acts in the key pace maker neurons as a negative regulator of Shaggy (SGG) kinase activity, which in turn determines timely nuclear entry of the clock proteins Period and Timeless to close the negative feedback loop. Phosphorylation of serine 9 in SGG is mediated by the C-terminal kinase domain of RSK, which is in agreement with previous genetic studies of RSK in the circadian clock but argues against the prevailing view that only the N-terminal kinase domain of RSK proteins carries the effector function. Our data provide a mechanistic explanation how RSK influences the molecular clock and imply SGG S9 phosphorylation by RSK and other kinases as a convergence point for diverse cellular and external stimuli.}, language = {en} } @article{LiDengXieetal.2018, author = {Li, Cong and Deng, Xiaobing and Xie, Xiaowen and Liu, Ying and Friedmann Angeli, Jos{\´e} Pedro and Lai, Luhua}, title = {Activation of Glutathione Peroxidase 4 as a Novel Anti-inflammatory Strategy}, series = {Frontiers in Pharmacology}, volume = {9}, journal = {Frontiers in Pharmacology}, number = {1120}, issn = {1663-9812}, doi = {10.3389/fphar.2018.01120}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195985}, year = {2018}, abstract = {The anti-oxidative enzyme, glutathione peroxidase 4 (GPX4), helps to promote inflammation resolution by eliminating oxidative species produced by the arachidonic acid (AA) metabolic network. Up-regulating its activity has been proposed as a promising strategy for inflammation intervention. In the present study, we aimed to study the effect of GPX4 activator on the AA metabolic network and inflammation related pathways. Using combined computational and experimental screen, we identified a novel compound that can activate the enzyme activity of GPX4 by more than two folds. We further assessed its potential in a series of cellular assays where GPX4 was demonstrated to play a regulatory role. We are able to show that GPX4 activation suppressed inflammatory conditions such as oxidation of AA and NF-κB pathway activation. We further demonstrated that this GPX4 activator can decrease the intracellular ROS level and suppress ferroptosis. Our study suggests that GPX4 activators can be developed as anti-inflammatory or cyto-protective agent in lipid-peroxidation-mediated diseases.}, language = {en} } @article{SchaeferZhengvanBrederodeetal.2018, author = {Schaefer, Natascha and Zheng, Fang and van Brederode, Johannes and Berger, Alexandra and Leacock, Sophie and Hirata, Hiromi and Paige, Christopher J. and Harvey, Robert J. and Alzheimer, Christian and Villmann, Carmen}, title = {Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor α1 Subunits in the Shaky Mouse Model of Startle Disease}, series = {Frontiers in Molecular Neuroscience}, volume = {11}, journal = {Frontiers in Molecular Neuroscience}, number = {167}, issn = {1662-5099}, doi = {10.3389/fnmol.2018.00167}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196056}, year = {2018}, abstract = {Mutations in GlyR α1 or β subunit genes in humans and rodents lead to severe startle disease characterized by rigidity, massive stiffness and excessive startle responses upon unexpected tactile or acoustic stimuli. The recently characterized startle disease mouse mutant shaky carries a missense mutation (Q177K) in the β8-β9 loop within the large extracellular N-terminal domain of the GlyR α1 subunit. This results in a disrupted hydrogen bond network around K177 and faster GlyR decay times. Symptoms in mice start at postnatal day 14 and increase until premature death of homozygous shaky mice around 4-6 weeks after birth. Here we investigate the in vivo functional effects of the Q177K mutation using behavioral analysis coupled to protein biochemistry and functional assays. Western blot analysis revealed GlyR α1 subunit expression in wild-type and shaky animals around postnatal day 7, a week before symptoms in mutant mice become obvious. Before 2 weeks of age, homozygous shaky mice appeared healthy and showed no changes in body weight. However, analysis of gait and hind-limb clasping revealed that motor coordination was already impaired. Motor coordination and the activity pattern at P28 improved significantly upon diazepam treatment, a pharmacotherapy used in human startle disease. To investigate whether functional deficits in glycinergic neurotransmission are present prior to phenotypic onset, we performed whole-cell recordings from hypoglossal motoneurons (HMs) in brain stem slices from wild-type and shaky mice at different postnatal stages. Shaky homozygotes showed a decline in mIPSC amplitude and frequency at P9-P13, progressing to significant reductions in mIPSC amplitude and decay time at P18-24 compared to wild-type littermates. Extrasynaptic GlyRs recorded by bath-application of glycine also revealed reduced current amplitudes in shaky mice compared to wild-type neurons, suggesting that presynaptic GlyR function is also impaired. Thus, a distinct, but behaviorally ineffective impairment of glycinergic synapses precedes the symptoms onset in shaky mice. These findings extend our current knowledge on startle disease in the shaky mouse model in that they demonstrate how the progression of GlyR dysfunction causes, with a delay of about 1 week, the appearance of disease symptoms.}, language = {en} } @article{BahmerGupta2018, author = {Bahmer, Andreas and Gupta, Daya Shankar}, title = {Role of Oscillations in Auditory Temporal Processing: A General Model for Temporal Processing of Sensory Information in the Brain?}, series = {Frontiers in Neuroscience}, volume = {12}, journal = {Frontiers in Neuroscience}, number = {793}, issn = {1662-453X}, doi = {10.3389/fnins.2018.00793}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196087}, year = {2018}, abstract = {We review the role of oscillations in the brain and in the auditory system showing that the ability of humans to distinguish changes in pitch can be explained as a precise analysis of temporal information in auditory signals by neural oscillations. The connections between auditory brain stem chopper neurons construct neural oscillators, which discharge spikes at various constant intervals that are integer multiples of 0.4 ms, contributing to the temporal processing of auditory cochlear output. This is subsequently spatially mapped in the inferior colliculus. Electrophysiological measurements of auditory chopper neurons in different species show oscillations with periods which are integer multiples of 0.4 ms. The constant intervals of 0.4 ms can be attributed to the smallest synaptic delay between interconnected simulated chopper neurons. We also note the patterns of similarities between microcircuits in the brain stem and other parts of the brain (e.g., the pallidum, reticular formation, locus coeruleus, oculomotor nuclei, limbic system, amygdala, hippocampus, basal ganglia and substantia nigra), dedicated to the processing of temporal information. Similarities in microcircuits across the brain reflect the importance of one of the key mechanisms in the information processing in the brain, namely the temporal coupling of different neural events via coincidence detection.}, language = {en} } @article{GromerMadeiraGastetal.2018, author = {Gromer, Daniel and Madeira, Oct{\´a}via and Gast, Philipp and Nehfischer, Markus and Jost, Michael and M{\"u}ller, Mathias and M{\"u}hlberger, Andreas and Pauli, Paul}, title = {Height Simulation in a Virtual Reality CAVE System: Validity of Fear Responses and Effects of an Immersion Manipulation}, series = {Frontiers in Human Neuroscience}, volume = {12}, journal = {Frontiers in Human Neuroscience}, number = {372}, issn = {1662-5161}, doi = {10.3389/fnhum.2018.00372}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196113}, year = {2018}, abstract = {Acrophobia is characterized by intense fear in height situations. Virtual reality (VR) can be used to trigger such phobic fear, and VR exposure therapy (VRET) has proven effective for treatment of phobias, although it remains important to further elucidate factors that modulate and mediate the fear responses triggered in VR. The present study assessed verbal and behavioral fear responses triggered by a height simulation in a 5-sided cave automatic virtual environment (CAVE) with visual and acoustic simulation and further investigated how fear responses are modulated by immersion, i.e., an additional wind simulation, and presence, i.e., the feeling to be present in the VE. Results revealed a high validity for the CAVE and VE in provoking height related self-reported fear and avoidance behavior in accordance with a trait measure of acrophobic fear. Increasing immersion significantly increased fear responses in high height anxious (HHA) participants, but did not affect presence. Nevertheless, presence was found to be an important predictor of fear responses. We conclude that a CAVE system can be used to elicit valid fear responses, which might be further enhanced by immersion manipulations independent from presence. These results may help to improve VRET efficacy and its transfer to real situations.}, language = {en} } @article{VenturaBortWirknerGenheimeretal.2018, author = {Ventura-Bort, Carlos and Wirkner, Janine and Genheimer, Hannah and Wendt, Julia and Hamm, Alfons O. and Weymar, Mathias}, title = {Effects of Transcutaneous Vagus Nerve Stimulation (tVNS) on the P300 and Alpha-Amylase Level: A Pilot Study}, series = {Frontiers in Human Neuroscience}, volume = {12}, journal = {Frontiers in Human Neuroscience}, number = {202}, issn = {1662-5161}, doi = {10.3389/fnhum.2018.00202}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196129}, year = {2018}, abstract = {Recent research suggests that the P3b may be closely related to the activation of the locus coeruleus-norepinephrine (LC-NE) system. To further study the potential association, we applied a novel technique, the non-invasive transcutaneous vagus nerve stimulation (tVNS), which is speculated to increase noradrenaline levels. Using a within-subject cross-over design, 20 healthy participants received continuous tVNS and sham stimulation on two consecutive days (stimulation counterbalanced across participants) while performing a visual oddball task. During stimulation, oval non-targets (standard), normal-head (easy) and rotated-head (difficult) targets, as well as novel stimuli (scenes) were presented. As an indirect marker of noradrenergic activation we also collected salivary alpha-amylase (sAA) before and after stimulation. Results showed larger P3b amplitudes for target, relative to standard stimuli, irrespective of stimulation condition. Exploratory post hoc analyses, however, revealed that, in comparison to standard stimuli, easy (but not difficult) targets produced larger P3b (but not P3a) amplitudes during active tVNS, compared to sham stimulation. For sAA levels, although main analyses did not show differential effects of stimulation, direct testing revealed that tVNS (but not sham stimulation) increased sAA levels after stimulation. Additionally, larger differences between tVNS and sham stimulation in P3b magnitudes for easy targets were associated with larger increase in sAA levels after tVNS, but not after sham stimulation. Despite preliminary evidence for a modulatory influence of tVNS on the P3b, which may be partly mediated by activation of the noradrenergic system, additional research in this field is clearly warranted. Future studies need to clarify whether tVNS also facilitates other processes, such as learning and memory, and whether tVNS can be used as therapeutic tool.}, language = {en} } @article{MahyeraSchneiderHalligerKelleretal.2018, author = {Mahyera, Alexis S. and Schneider, Tamara and Halliger-Keller, Birgit and Schrooten, Katja and H{\"o}rner, Eva-Maria and Rost, Simone and Kress, Wolfram}, title = {Distribution and Structure of DM2 Repeat Tract Alleles in the German Population}, series = {Frontiers in Neurology}, volume = {9}, journal = {Frontiers in Neurology}, number = {463}, issn = {1664-2295}, doi = {10.3389/fneur.2018.00463}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196252}, year = {2018}, abstract = {Autosomal dominant inherited Myotonic dystrophy type 1 and 2 (DM1 and DM2) are the most frequent muscle dystrophies in the European population and are caused by repeat expansion mutations. For Germany cumulative empiric evidence suggests an estimated prevalence of DM2 of roughly 9 in 100,000, therefore being as prevalent as DM1. In DM2, a (CCTG)n repeat tract located in the first intron of the CNBP gene is expanded. The CCTG repeat tract is part of a complex repeat structure comprising not only CCTG tetraplets but also repeated TG dinucleotides and TCTG tetraplet elements as well as NCTG interruptions. Here, we provide the distribution of normal sized alleles in the German population, which was found to be highly similar to the Slovak population. Sequencing of 34 unexpanded healthy range alleles in DM2 positive patients (heterozygous for a full expansion) revealed that the CCTG repeat tract is usually interrupted by at least three tetraplets which according to current opinion is supposed to render it stable against expansion. Interestingly, only the largest analyzed normal allele had 23 uninterrupted CCTGs and consequently could represent an instable early premutation allele. In our diagnostic history of DM2 cases, a total of 18 premutations were detected in 16 independent cases. Here, we describe two premutation families, one with an expansion from a premutation allele and the other with a contraction of a full expansion down to a premutation allele. Our diagnostic results support the general assumption that the premutation range of unstable CCTG stretches lies obviously between 25 and 75 CCTGs. However, the clinical significance of premutation alleles is still unclear. In the light of the two described families we suggest incomplete penetrance. Thus, as it was proposed for other repeat expansion diseases (e.g., Huntington's disease), a fluid transition of penetrance is more likely rather than a clear cut CCTG number threshold.}, language = {en} }