@article{ZeinerPreusseGolebiewskaetal.2019, author = {Zeiner, Pia S. and Preusse, Corinna and Golebiewska, Anna and Zinke, Jenny and Iriondo, Ane and Muller, Arnaud and Kaoma, Tony and Filipski, Katharina and M{\"u}ller-Eschner, Monika and Bernatz, Simon and Blank, Anna-Eva and Baumgarten, Peter and Ilina, Elena and Grote, Anne and Hansmann, Martin L. and Verhoff, Marcel A. and Franz, Kea and Feuerhake, Friedrich and Steinbach, Joachim P. and Wischhusen, J{\"o}rg and Stenzel, Werner and Niclou, Simone P. and Harter, Patrick N. and Mittelbronn, Michel}, title = {Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas}, series = {Brain Pathology}, volume = {29}, journal = {Brain Pathology}, doi = {10.1111/bpa.12690}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233897}, pages = {513-529}, year = {2019}, abstract = {While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma-associated microglia/macrophages (GAMs), on patients' clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I-IV). Furthermore, we analyzed a cohort of 241 IDH1R132H-non-mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high-grade astrocytomas by CD11b-based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT-PCR and bioinformatic analyses. A higher amount of CD68-, CD163- and CD206-positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro-inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti-inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2-like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H-non-mutant GBMs.}, language = {en} } @article{JandkeGarzSchwankeetal.2018, author = {Jandke, Solveig and Garz, Cornelia and Schwanke, Daniel and Sendtner, Michael and Heinze, Hans-Jochen and Carare, Roxana O. and Schreiber, Stefanie}, title = {The association between hypertensive arteriopathy and cerebral amyloid angiopathy in spontaneously hypertensive stroke-prone rats}, series = {Brain Pathology}, volume = {28}, journal = {Brain Pathology}, doi = {10.1111/bpa.12629}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323279}, pages = {844-859}, year = {2018}, abstract = {We aimed to test the hypothesis that in spontaneously hypertensive stroke-prone rats (SHRSP), non-amyloid cerebral small vessel disease/hypertensive arteriopathy (HA) results in vessel wall injury that may promote cerebral amyloid angiopathy (CAA). Our study comprised 21 male SHRSP (age 17-44 weeks) and 10 age- and sex-matched Wistar control rats, that underwent two-photon (2PM) imaging of the arterioles in the parietal cortex using Methoxy-X04, Dextran and cerebral blood flow (CBF) measurements. Our data suggest that HA in SHRSP progresses in a temporal and age-dependent manner, starting from small vessel wall damage (stage 1A), proceeding to CBF reduction (stage 1B), non-occlusive (stage 2), and finally, occlusive thrombi (stage 3). Wistar animals also demonstrated small vessel wall damage, but were free of any of the later HA stages. Nearly half of all SHRSP additionally displayed vascular Methoxy-X04 positivity indicative of cortical CAA. Vascular β-amyloid deposits were found in small vessels characterized by thrombotic occlusions (stage 2 or 3). Post-mortem analysis of the rat brains confirmed the findings derived from intravital 2PM microscopy. Our data thus overall suggest that advanced HA may play a role in CAA development with the two small vessel disease entities might be related to the same pathological spectrum of the aging brain.}, language = {en} } @article{BahramAnslanHildebrandetal.2019, author = {Bahram, Mohammad and Anslan, Sten and Hildebrand, Falk and Bork, Peer and Tedersoo, Leho}, title = {Newly designed 16S rRNA metabarcoding primers amplify diverse and novel archaeal taxa from the environment}, series = {Environmental Microbiology Reports}, volume = {11}, journal = {Environmental Microbiology Reports}, doi = {10.1111/1758-2229.12684}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221380}, pages = {487-494}, year = {2019}, abstract = {High-throughput studies of microbial communities suggest that Archaea are a widespread component of microbial diversity in various ecosystems. However, proper quantification of archaeal diversity and community ecology remains limited, as sequence coverage of Archaea is usually low owing to the inability of available prokaryotic primers to efficiently amplify archaeal compared to bacterial rRNA genes. To improve identification and quantification of Archaea, we designed and validated the utility of several primer pairs to efficiently amplify archaeal 16S rRNA genes based on up-to-date reference genes. We demonstrate that several of these primer pairs amplify phylogenetically diverse Archaea with high sequencing coverage, outperforming commonly used primers. Based on comparing the resulting long 16S rRNA gene fragments with public databases from all habitats, we found several novel family- to phylum-level archaeal taxa from topsoil and surface water. Our results suggest that archaeal diversity has been largely overlooked due to the limitations of available primers, and that improved primer pairs enable to estimate archaeal diversity more accurately.}, language = {en} } @article{MollKellnerLeonhardtetal.2018, author = {Moll, Julia and Kellner, Harald and Leonhardt, Sabrina and Stengel, Elisa and Dahl, Andreas and B{\"a}ssler, Claus and Buscot, Fran{\c{c}}ois and Hofrichter, Martin and Hoppe, Bj{\"o}rn}, title = {Bacteria inhabiting deadwood of 13 tree species are heterogeneously distributed between sapwood and heartwood}, series = {Environmental Microbiology}, volume = {20}, journal = {Environmental Microbiology}, doi = {10.1111/1462-2920.14376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224168}, pages = {3744-3756}, year = {2018}, abstract = {Deadwood represents an important structural component of forest ecosystems, where it provides diverse niches for saproxylic biota. Although wood-inhabiting prokaryotes are involved in its degradation, knowledge about their diversity and the drivers of community structure is scarce. To explore the effect of deadwood substrate on microbial distribution, the present study focuses on the microbial communities of deadwood logs from 13 different tree species investigated using an amplicon based deep-sequencing analysis. Sapwood and heartwood communities were analysed separately and linked to various relevant wood physico-chemical parameters. Overall, Proteobacteria, Acidobacteria and Actinobacteria represented the most dominant phyla. Microbial OTU richness and community structure differed significantly between tree species and between sapwood and heartwood. These differences were more pronounced for heartwood than for sapwood. The pH value and water content were the most important drivers in both wood compartments. Overall, investigating numerous tree species and two compartments provided a remarkably comprehensive view of microbial diversity in deadwood.}, language = {en} } @article{HilmersFriessBaessleretal.2018, author = {Hilmers, Torben and Friess, Nicolas and B{\"a}ssler, Claus and Heurich, Marco and Brandl, Roland and Pretzsch, Hans and Seidl, Rupert and M{\"u}ller, J{\"o}rg}, title = {Biodiversity along temperate forest succession}, series = {Journal of Applied Ecology}, volume = {55}, journal = {Journal of Applied Ecology}, doi = {10.1111/1365-2664.13238}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320632}, pages = {2756-2766}, year = {2018}, abstract = {1. The successional dynamics of forests—from canopy openings to regeneration, maturation, and decay—influence the amount and heterogeneity of resources available for forest-dwelling organisms. Conservation has largely focused only on selected stages of forest succession (e.g., late-seral stages). However, to develop comprehensive conservation strategies and to understand the impact of forest management on biodiversity, a quantitative understanding of how different trophic groups vary over the course of succession is needed. 2. We classified mixed mountain forests in Central Europe into nine successional stages using airborne LiDAR. We analysed α- and β-diversity of six trophic groups encompassing approximately 3,000 species from three kingdoms. We quantified the effect of successional stage on the number of species with and without controlling for species abundances and tested whether the data fit the more-individuals hypothesis or the habitat heterogeneity hypothesis. Furthermore, we analysed the similarity of assemblages along successional development. 3. The abundance of producers, first-order consumers, and saprotrophic species showed a U-shaped response to forest succession. The number of species of producer and consumer groups generally followed this U-shaped pattern. In contrast to our expectation, the number of saprotrophic species did not change along succession. When we controlled for the effect of abundance, the number of producer and saproxylic beetle species increased linearly with forest succession, whereas the U-shaped response of the number of consumer species persisted. The analysis of assemblages indicated a large contribution of succession-mediated β-diversity to regional γ-diversity. 4. Synthesis and applications. Depending on the species group, our data supported both the more-individuals hypothesis and the habitat heterogeneity hypothesis. Our results highlight the strong influence of forest succession on biodiversity and underline the importance of controlling for successional dynamics when assessing biodiversity change in response to external drivers such as climate change. The successional stages with highest diversity (early and late successional stages) are currently strongly underrepresented in the forests of Central Europe. We thus recommend that conservation strategies aim at a more balanced representation of all successional stages.}, language = {en} } @article{KwokUedaKadarietal.2018, author = {Kwok, Chee Keong and Ueda, Yuichiro and Kadari, Asifiqbal and G{\"u}nther, Katharina and Erg{\"u}n, S{\"u}leyman and Heron, Antoine and Schnitzler, Aletta C. and Rook, Martha and Edenhofer, Frank}, title = {Scalable stirred suspension culture for the generation of billions of human induced pluripotent stem cells using single-use bioreactors}, series = {Journal of Tissue Engineering and Regenerative Medicine}, volume = {12}, journal = {Journal of Tissue Engineering and Regenerative Medicine}, doi = {10.1002/term.2435}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234545}, pages = {e1076-e1087}, year = {2018}, abstract = {The production of human induced pluripotent stem cells (hiPSCs) in quantities that are relevant for cell-based therapies and cell-loaded implants through standard adherent culture is hardly achievable and lacks process scalability. A promising approach to overcoming these hurdles is the culture of hiPSCs in suspension. In this study, stirred suspension culture vessels were investigated for their suitability in the expansion of two hiPSC lines inoculated as a single cell suspension, with a free scalability between volumes of 50 and 2400 ml. The simple and robust two-step process reported here first generates hiPSC aggregates of 324 ± 71 μm diameter in 7 days in 125 ml spinner flasks (100 ml volume). These are subsequently dissociated into a single cell suspension for inoculation in 3000 ml bioreactors (1000 ml volume), finally yielding hiPSC aggregates of 198 ± 58 μm after 7 additional days. In both spinner flasks and bioreactors, hiPSCs can be cultured as aggregates for more than 40 days in suspension, maintain an undifferentiated state as confirmed by the expression of pluripotency markers TRA-1-60, TRA-1-81, SSEA-4, OCT4, and SOX2, can differentiate into cells of all three germ layers, and can be directed to differentiate into specific lineages such as cardiomyocytes. Up to a 16-fold increase in hiPSC quantity at the 100 ml volume was achieved, corresponding to a fold increase per day of 2.28; at the 1000 ml scale, an additional 10-fold increase was achieved. Taken together, 16 × 106 hiPSCs were expanded into 2 × 109 hiPSCs in 14 days for a fold increase per day of 8.93. This quantity of hiPSCs readily meets the requirements of cell-based therapies and brings their clinical potential closer to fruition.}, language = {en} } @article{HrynevichElciHaighetal.2018, author = {Hrynevich, Andrei and El{\c{c}}i, Bilge Ş. and Haigh, Jodie N. and McMaster, Rebecca and Youssef, Almoatazbellah and Blum, Carina and Blunk, Torsten and Hochleitner, Gernot and Groll, J{\"u}rgen and Dalton, Paul D.}, title = {Dimension-Based Design of Melt Electrowritten Scaffolds}, series = {Small}, volume = {14}, journal = {Small}, doi = {10.1002/smll.201800232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322677}, year = {2018}, abstract = {The electrohydrodynamic stabilization of direct-written fluid jets is explored to design and manufacture tissue engineering scaffolds based on their desired fiber dimensions. It is demonstrated that melt electrowriting can fabricate a full spectrum of various fibers with discrete diameters (2-50 µm) using a single nozzle. This change in fiber diameter is digitally controlled by combining the mass flow rate to the nozzle with collector speed variations without changing the applied voltage. The greatest spectrum of fiber diameters was achieved by the simultaneous alteration of those parameters during printing. The highest placement accuracy could be achieved when maintaining the collector speed slightly above the critical translation speed. This permits the fabrication of medical-grade poly(ε-caprolactone) into complex multimodal and multiphasic scaffolds, using a single nozzle in a single print. This ability to control fiber diameter during printing opens new design opportunities for accurate scaffold fabrication for biomedical applications.}, language = {en} } @article{deRuijterHrynevichHaighetal.2018, author = {de Ruijter, Myl{\`e}ne and Hrynevich, Andrei and Haigh, Jodie N. and Hochleitner, Gernot and Castilho, Miguel and Groll, J{\"u}rgen and Malda, Jos and Dalton, Paul D.}, title = {Out-of-Plane 3D-Printed Microfibers Improve the Shear Properties of Hydrogel Composites}, series = {Small}, volume = {14}, journal = {Small}, doi = {10.1002/smll.201702773}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223666}, year = {2018}, abstract = {One challenge in biofabrication is to fabricate a matrix that is soft enough to elicit optimal cell behavior while possessing the strength required to withstand the mechanical load that the matrix is subjected to once implanted in the body. Here, melt electrowriting (MEW) is used to direct-write poly(ε-caprolactone) fibers "out-of-plane" by design. These out-of-plane fibers are specifically intended to stabilize an existing structure and subsequently improve the shear modulus of hydrogel-fiber composites. The stabilizing fibers (diameter = 13.3 ± 0.3 µm) are sinusoidally direct-written over an existing MEW wall-like structure (330 µm height). The printed constructs are embedded in different hydrogels (5, 10, and 15 wt\% polyacrylamide; 65\% poly(2-hydroxyethyl methacrylate) (pHEMA)) and a frequency sweep test (0.05-500 rad s-1, 0.01\% strain, n = 5) is performed to measure the complex shear modulus. For the rheological measurements, stabilizing fibers are deposited with a radial-architecture prior to embedding to correspond to the direction of the stabilizing fibers with the loading of the rheometer. Stabilizing fibers increase the complex shear modulus irrespective of the percentage of gel or crosslinking density. The capacity of MEW to produce well-defined out-of-plane fibers and the ability to increase the shear properties of fiber-reinforced hydrogel composites are highlighted.}, language = {en} } @article{GreberPolatFlentjeetal.2019, author = {Greber, Johannes and Polat, B{\"u}lent and Flentje, Michael and Bratengeier, Klaus}, title = {Properties of the anisotropy of dose contributions: A planning study on prostate cases}, series = {Medical Physics}, volume = {46}, journal = {Medical Physics}, doi = {10.1002/mp.13308}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228237}, pages = {419-425}, year = {2019}, abstract = {Purpose To characterize the static properties of the anisotropy of dose contributions for different treatment techniques on real patient data (prostate cases). From this, we aim to define a class of treatment techniques with invariant anisotropy distribution carrying information of target coverage and organ-at-risk (OAR) sparing. The anisotropy presumably is a helpful quantity for plan adaptation problems. Methods The anisotropy field is analyzed for different intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) techniques for a total of ten planning CTs of prostate cases. Primary irradiation directions ranged from 5 to 15. The uniqueness of anisotropy was explored: In particular, the anisotropy distribution inside the planning treatment volume (PTV) and in its vicinity was investigated. Furthermore, deviations of the anisotropy under beam rotations were explored by direct plan comparison as an indicating the susceptibility of each planned technique to changes in the geometric plan configuration. In addition, plan comparisons enabled the categorization of treatment techniques in terms of their anisotropy distribution. Results The anisotropy profile inside the PTV and in the transition between OAR and PTV is independent of the treatment technique as long as a sufficient number of beams contribute to the dose distribution. Techniques with multiple beams constitute a class of almost identical and technique-independent anisotropy distribution. For this class of techniques, substructures of the anisotropy are particularly pronounced in the PTV, thus offering good options for applying adaptation rules. Additionally, the techniques forming the mentioned class fortunately allow a better OAR sparing at constant PTV coverage. Besides the characterization of the distribution, a pairwise plan comparison reveals each technique's susceptibility to deviations which decreases for an increasing number of primary irradiation directions. Conclusions Techniques using many irradiation directions form a class of almost identical anisotropy distributions which are assumed to provide a basis for improved adaptation procedures. Encouragingly, these techniques deliver quite invariant anisotropy distributions with respect to rotations correlated with good plan qualities than techniques using few gantry angles. The following will be the next steps toward anisotropy-based adaptation: first, the quantification of anisotropy regarding organ deformations; and second, establishing the interrelation between the anisotropy and beam shaping.}, language = {en} } @article{MirzaVainshteinDiRonzaetal.2019, author = {Mirza, Myriam and Vainshtein, Anna and DiRonza, Alberto and Chandrachud, Uma and Haslett, Luke J. and Palmieri, Michela and Storch, Stephan and Groh, Janos and Dobzinski, Niv and Napolitano, Gennaro and Schmidtke, Carolin and Kerkovich, Danielle M.}, title = {The CLN3 gene and protein: What we know}, series = {Molecular Genetics \& Genomic Medicine}, volume = {7}, journal = {Molecular Genetics \& Genomic Medicine}, doi = {10.1002/mgg3.859}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224138}, year = {2019}, abstract = {Background One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans. Objectives To present an unbiased comprehensive reference tool of the experimental understanding of the CLN3 gene and gene product of the same name. Methods BBDF compiled all of the available CLN3 gene and protein data from biological databases, repositories of federally and privately funded projects, patent and trademark offices, science and technology journals, industrial drug and pipeline reports as well as clinical trial reports and with painstaking precision, validated the information together with experts in Batten disease, lysosomal storage disease, lysosome/endosome biology. Results The finished product is an indexed review of the CLN3 gene and protein which is not limited in page size or number of references, references all available primary experiments, and does not draw conclusions for the reader. Conclusions Revisiting the experimental history of a target gene and its product ensures that inaccuracies and contradictions come to light, long-held beliefs and assumptions continue to be challenged, and information that was previously deemed inconsequential gets a second look. Compiling the information into one manuscript with all appropriate primary references provides quick clues to which studies have been completed under which conditions and what information has been reported. This compendium does not seek to replace original articles or subtopic reviews but provides an historical roadmap to completed works.}, language = {en} } @article{GermainBrandBurlinaetal.2018, author = {Germain, Dominique P. and Brand, Eva and Burlina, Alessandro and Cecchi, Franco and Garman, Scott C. and Kempf, Judy and Laney, Dawn A. and Linhart, Aleš and Mar{\´o}di, L{\´a}szl{\´o} and Nicholls, Kathy and Ortiz, Alberto and Pieruzzi, Federico and Shankar, Suma P. and Waldek, Stephen and Wanner, Christoph and Jovanovic, Ana}, title = {Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study}, series = {Molecular Genetics \& Genomic Medicine}, volume = {6}, journal = {Molecular Genetics \& Genomic Medicine}, doi = {10.1002/mgg3.389}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232976}, pages = {492-503}, year = {2018}, abstract = {Background The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. Methods To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. Results In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31\%, females 8\%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17\% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3\%). Conclusion p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.}, language = {en} } @article{ArlottiPalmisanoMinafraetal.2019, author = {Arlotti, Mattia and Palmisano, Chiara and Minafra, Brigida and Todisco, Massimiliano and Pacchetti, Claudio and Canessa, Andrea and Pozzi, Nicol{\´o} G. and Cilia, Roberto and Prenassi, Marco and Marceglia, Sara and Priori, Alberto and Rampini, Paolo and Barbieri, Sergio and Servello, Domenico and Volkmann, Jens and Pezzoli, Gianni and Isaias, Ioannis U.}, title = {Monitoring subthalamic oscillations for 24 hours in a freely moving Parkinson's disease patient}, series = {Movement Disorders}, volume = {34}, journal = {Movement Disorders}, doi = {10.1002/mds.27657}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221249}, pages = {757-759}, year = {2019}, abstract = {No abstract available}, language = {en} } @article{SteigerwaldTimmermannKuehnetal.2018, author = {Steigerwald, Frank and Timmermann, Lars and K{\"u}hn, Andrea and Schnitzler, Alfons and Reich, Martin M. and Kirsch, Anna Dalal and Barbe, Michael Thomas and Visser-Vandewalle, Veerle and H{\"u}bl, Julius and van Riesen, Christoph and Groiss, Stefan Jun and Moldovan, Alexia-Sabine and Lin, Sherry and Carcieri, Stephen and Manola, Ljubomir and Volkmann, Jens}, title = {Pulse duration settings in subthalamic stimulation for Parkinson's disease}, series = {Movement Disorders}, volume = {33}, journal = {Movement Disorders}, doi = {10.1002/mds.27238}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239402}, pages = {165-169}, year = {2018}, abstract = {Background Stimulation parameters in deep brain stimulation (DBS) of the subthalamic nucleus for Parkinson's disease (PD) are rarely tested in double-blind conditions. Evidence-based recommendations on optimal stimulator settings are needed. Results from the CUSTOM-DBS study are reported, comparing 2 pulse durations. Methods A total of 15 patients were programmed using a pulse width of 30 µs (test) or 60 µs (control). Efficacy and side-effect thresholds and unified PD rating scale (UPDRS) III were measured in meds-off (primary outcome). The therapeutic window was the difference between patients' efficacy and side effect thresholds. Results The therapeutic window was significantly larger at 30 µs than 60 µs (P = ·0009) and the efficacy (UPDRS III score) was noninferior (P = .00008). Interpretation Subthalamic neurostimulation at 30 µs versus 60 µs pulse width is equally effective on PD motor signs, is more energy efficient, and has less likelihood of stimulation-related side effects. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.}, language = {en} } @article{CalderonPenaSuarezetal.2019, author = {Calderon, Dayana and Pe{\~n}a, Luis and Suarez, Ang{\´e}lica and Villamil, Carolina and Ramirez-Rojas, Adan and Anzola, Juan M. and Garc{\´i}a-Betancur, Juan C. and Cepeda, Martha L. and Uribe, Daniel and Del Portillo, Patricia and Mongui, Alvaro}, title = {Recovery and functional validation of hidden soil enzymes in metagenomic libraries}, series = {MicrobiologyOpen}, volume = {8}, journal = {MicrobiologyOpen}, doi = {10.1002/mbo3.572}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222016}, year = {2019}, abstract = {The vast microbial diversity on the planet represents an invaluable source for identifying novel activities with potential industrial and therapeutic application. In this regard, metagenomics has emerged as a group of strategies that have significantly facilitated the analysis of DNA from multiple environments and has expanded the limits of known microbial diversity. However, the functional characterization of enzymes, metabolites, and products encoded by diverse microbial genomes is limited by the inefficient heterologous expression of foreign genes. We have implemented a pipeline that combines NGS and Sanger sequencing as a way to identify fosmids within metagenomic libraries. This strategy facilitated the identification of putative proteins, subcloning of targeted genes and preliminary characterization of selected proteins. Overall, the in silico approach followed by the experimental validation allowed us to efficiently recover the activity of previously hidden enzymes derived from agricultural soil samples. Therefore, the methodology workflow described herein can be applied to recover activities encoded by environmental DNA from multiple sources.}, language = {en} } @article{HettichSchierjottRammetal.2019, author = {Hettich, Georg and Schierjott, Ronja A. and Ramm, Heiko and Graichen, Heiko and Jansson, Volkmar and Rudert, Maximilian and Traina, Francesco and Grupp, Thomas M.}, title = {Method for quantitative assessment of acetabular bone defects}, series = {Journal of Orthopaedic Research}, volume = {37}, journal = {Journal of Orthopaedic Research}, doi = {10.1002/jor.24165}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320226}, pages = {181-189}, year = {2019}, abstract = {The objective of the study was to suggest a novel quantitative assessment of acetabular bone defects based on a statistical shape model, validate the method, and present preliminary results. Two exemplary CT-data sets with acetabular bone defects were segmented to obtain a solid model of each defect pelvis. The pathological areas around the acetabulum were excluded and a statistical shape model was fitted to the remaining healthy bone structures. The excluded areas were extrapolated such that a solid model of the native pelvis per specimen resulted (i.e., each pelvis without defect). The validity of the reconstruction was tested by a leave-one-out study. Validation results showed median reconstruction errors of 3.0 mm for center of rotation, 1.7 mm for acetabulum diameter, 2.1° for inclination, 2.5° for anteversion, and 3.3 mm3 for bone volume around the acetabulum. By applying Boolean operations on the solid models of defect and native pelvis, bone loss and bone formation in four different sectors were assessed. For both analyzed specimens, bone loss and bone formation per sector were calculated and were consistent with the visual impression. In specimen_1 bone loss was predominant in the medial wall (10.8 ml; 79\%), in specimen_2 in the posterior column (15.6 ml; 46\%). This study showed the feasibility of a quantitative assessment of acetabular bone defects using a statistical shape model-based reconstruction method. Validation results showed acceptable reconstruction accuracy, also when less healthy bone remains. The method could potentially be used for implant development, pre-clinical testing, pre-operative planning, and intra-operative navigation. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 9999:1-9, 2018.}, language = {en} } @article{KasparOttHertigKasparetal.2019, author = {Kaspar-Ott, Irena and Hertig, Elke and Kaspar, Severin and Pollinger, Felix and Ring, Christoph and Paeth, Heiko and Jacobeit, Jucundus}, title = {Weights for general circulation models from CMIP3/CMIP5 in a statistical downscaling framework and the impact on future Mediterranean precipitation}, series = {The International Journal of Climatology}, volume = {39}, journal = {The International Journal of Climatology}, doi = {10.1002/joc.6045}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325628}, pages = {3639-3654}, year = {2019}, abstract = {This study investigates the projected precipitation changes of the 21st century in the Mediterranean area with a model ensemble of all available CMIP3 and CMIP5 data based on four different scenarios. The large spread of simulated precipitation change signals underlines the need of an evaluation of the individual general circulation models in order to give higher weights to better and lower weights to worse performing models. The models' spread comprises part of the internal climate variability, but is also due to the differing skills of the circulation models. The uncertainty resulting from the latter is the aim of our weighting approach. Each weight is based on the skill to simulate key predictor variables in context of large and medium scale atmospheric circulation patterns within a statistical downscaling framework for the Mediterranean precipitation. Therefore, geopotential heights, sea level pressure, atmospheric layer thickness, horizontal wind components and humidity data at several atmospheric levels are considered. The novelty of this metric consists in avoiding the use of the precipitation data by itself for the weighting process, as state-of-the-art models still have major deficits in simulating precipitation. The application of the weights on the downscaled precipitation changes leads to more reliable and precise change signals in some Mediterranean sub-regions and seasons. The model weights differ between sub-regions and seasons, however, a clear sequence from better to worse models for the representation of precipitation in the Mediterranean area becomes apparent.}, language = {en} } @article{MazonLaroucheStLouisetal.2018, author = {Mazon, Melody and Larouche, Val{\´e}rie and St-Louis, Maryse and Schindler, Detlev and Carreau, Madeleine}, title = {Elevated blood levels of Dickkopf-1 are associated with acute infections}, series = {Immunity, Inflammation and Disease}, volume = {6}, journal = {Immunity, Inflammation and Disease}, doi = {10.1002/iid3.232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222171}, pages = {428-434}, year = {2018}, abstract = {Introduction Dickkopf-1 (DKK1) is a soluble protein and antagonist of the Wnt/β-catenin signaling pathway. DKK1 is found elevated in serum from patients affected with various types of cancers and in some instances, it is considered a diagnostic and prognostic biomarker. Elevated serum levels of DKK1 have also been detected in animal models of chronic inflammatory diseases. Previous work from our laboratory has demonstrated upregulation of DKK1 in cells and mouse models of the bone marrow failure (BMF) and cancer-prone disease Fanconi anemia (FA). The present study aimed to investigate whether DKK1 blood levels in patients are associated with FA or inflammatory responses to acute infections. Methods Plasma samples were collected from 58 children admitted to the Centre M{\`e}re-Enfant Soleil du Centre Hospitalier de Qu{\´e}bec-Universit{\´e} Laval with signs of acute infections. Blood plasma specimens were also collected from healthy blood donors at the H{\´e}ma-Qu{\´e}bec blood donor clinic. Plasmas from patients diagnosed with FA were also included in the study. DKK1 levels in blood plasmas were assessed by standard ELISA. Results Patients with acute infections showed dramatically high levels of DKK1 (6072 ± 518 pg/ml) in their blood compared to healthy blood donors (1726 ± 95 pg/ml). No correlations were found between DKK1 levels and C reactive protein (CRP) concentration, platelet numbers, or white blood cell counts. Patients with FA showed higher DKK1 plasma levels (3419 ± 147.5 pg/ml) than healthy blood donors (1726 ± 95 pg/ml) but significantly lower than patients with acute infections. Conclusion These findings suggest that blood DKK1 is elevated in response to infections and perhaps to inflammatory responses.}, language = {en} } @article{BavendiekBerlinerAguirreDavilaetal.2019, author = {Bavendiek, Udo and Berliner, Dominik and Aguirre D{\´a}vila, Lukas and Schwab, Johannes and Maier, Lars and Philipp, Sebastian A. and Rieth, Andreas and Westenfeld, Ralf and Piorkowski, Christopher and Weber, Kristina and H{\"a}nselmann, Anja and Oldhafer, Maximiliane and Schallhorn, Sven and von der Leyen, Heiko and Schr{\"o}der, Christoph and Veltmann, Christian and St{\"o}rk, Stefan and B{\"o}hm, Michael and Koch, Armin and Bauersachs, Johann}, title = {Rationale and design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double-blind, placebo-controlled study}, series = {European Journal of Heart Failure}, volume = {21}, journal = {European Journal of Heart Failure}, organization = {DIGIT-HF Investigators and Committees}, doi = {10.1002/ejhf.1452}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221548}, pages = {676-684}, year = {2019}, abstract = {Aims Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides - although regularly used for HF treatment - remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF). Methods Patients with chronic HF, New York Heart Association (NYHA) functional class III-IV and left ventricular ejection fraction (LVEF) ≤ 40\%, or patients in NYHA functional class II and LVEF ≤ 30\% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8-18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF. Conclusion The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.}, language = {en} } @article{deBoerDeKeulenaerBauersachsetal.2019, author = {de Boer, Rudolf A. and De Keulenaer, Gilles and Bauersachs, Johann and Brutsaert, Dirk and Cleland, John G. and Diez, Javier and Du, Xiao-Jun and Ford, Paul and Heinzel, Frank R. and Lipson, Kenneth E. and McDonagh, Theresa and Lopez-Andres, Natalia and Lunde, Ida G. and Lyon, Alexander R. and Pollesello, Piero and Prasad, Sanjay K. and Tocchetti, Carlo G. and Mayr, Manuel and Sluijter, Joost P. G. and Thum, Thomas and Tsch{\"o}pe, Carsten and Zannad, Faiez and Zimmermann, Wolfram-Hubertus and Ruschitzka, Frank and Filippatos, Gerasimos and Lindsey, Merry L. and Maack, Christoph and Heymans, Stephane}, title = {Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology}, series = {European Journal of Heart Failure}, volume = {21}, journal = {European Journal of Heart Failure}, doi = {10.1002/ejhf.1406}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223613}, pages = {272-285}, year = {2019}, abstract = {Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins — resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.}, language = {en} } @article{FrantzFalcaoPiresBalligandetal.2018, author = {Frantz, Stefan and Falcao-Pires, Ines and Balligand, Jean-Luc and Bauersachs, Johann and Brutsaert, Dirk and Ciccarelli, Michele and Dawson, Dana and de Windt, Leon J. and Giacca, Mauro and Hamdani, Nazha and Hilfiker-Kleiner, Denise and Hirsch, Emilio and Leite-Moreira, Adelino and Mayr, Manuel and Thum, Thomas and Tocchetti, Carlo G. and van der Velden, Jolanda and Varricchi, Gilda and Heymans, Stephane}, title = {The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC}, series = {European Journal of Heart Failure}, volume = {20}, journal = {European Journal of Heart Failure}, doi = {10.1002/ejhf.1138}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229091}, pages = {445-459}, year = {2018}, abstract = {Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.}, language = {en} }