@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} }