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Juncal Fernández-Orth, Petra Ehling, Tobias Ruck, Susann Pankratz, Majella-Sophie Hofmann, Peter Landgraf, Daniela C Dieterich, Karl-Heinz Smalla, Thilo Kähne, Guiscard Seebohm, Thomas Budde, Heinz Wiendl, Stefan Bittner, Sven G Meuth
K2P 5.1 channels (also called TASK-2 or KCNK5) have already been shown to be relevant in the pathophysiology of autoimmune disease since they are known to be upregulated on peripheral and central T lymphocytes of multiple sclerosis (MS) patients. Moreover, overexpression of K2P 5.1 channels in vitro provokes enhanced T-cell effector functions. However, the molecular mechanisms regulating intracellular K2P 5.1 channel trafficking are unknown so far. Thus, the aim of the study is to elucidate the trafficking of K2P 5...
October 15, 2016: Traffic
Stefan Christen, Doriane Lorendeau, Roberta Schmieder, Dorien Broekaert, Kristine Metzger, Koen Veys, Ilaria Elia, Joerg Martin Buescher, Martin Franz Orth, Shawn Michael Davidson, Thomas Georg Philipp Grünewald, Katrien De Bock, Sarah-Maria Fendt
Cellular proliferation depends on refilling the tricarboxylic acid (TCA) cycle to support biomass production (anaplerosis). The two major anaplerotic pathways in cells are pyruvate conversion to oxaloacetate via pyruvate carboxylase (PC) and glutamine conversion to α-ketoglutarate. Cancers often show an organ-specific reliance on either pathway. However, it remains unknown whether they adapt their mode of anaplerosis when metastasizing to a distant organ. We measured PC-dependent anaplerosis in breast-cancer-derived lung metastases compared to their primary cancers using in vivo (13)C tracer analysis...
October 11, 2016: Cell Reports
Helen Grete Orth, Silke Schicktanz
Outsourcing clinical trials sponsored by pharmaceutical companies from industrialized countries to low- (middle)-income countries - summarized as transnational biomedical research (TBR) - has lead to many concerns about ethical standards. Whether study participants are particularly vulnerable is one of those concerns. However, the concept of vulnerability is still vague and varies in its definition. Despite the fact that important international ethical guidelines such as the Declaration of Helsinki by the World Medical Association or the Ethical Guidelines for Biomedical Research Involving Human Subjects by the Council of International Organizations of Medical Sciences refer to vulnerability as ethical principle, each of their approaches are different...
October 4, 2016: Developing World Bioethics
Paul J Groot-Kormelink, Sandrine Ferrand, Nicholas Kelley, Anke Bill, Felix Freuler, Pierre-Eloi Imbert, Anthony Marelli, Nicole Gerwin, Lucia G Sivilotti, Loren Miraglia, Anthony P Orth, Edward J Oakeley, Ulrich Schopfer, Sandra Siehler
High throughput random mutagenesis is a powerful tool to identify which residues are important for the function of a protein, and gain insight into its structure-function relation. The human muscle nicotinic acetylcholine receptor was used to test whether this technique previously used for monomeric receptors can be applied to a pentameric ligand-gated ion channel. A mutant library for the α1 subunit of the channel was generated by error-prone PCR, and full length sequences of all 2816 mutants were retrieved using single molecule real time sequencing...
2016: PloS One
Magali Cucchiarini, Laura de Girolamo, Giuseppe Filardo, J Miguel Oliveira, Patrick Orth, Dietrich Pape, Pascal Reboul
Osteoarthritis (OA) is a prevalent, disabling disorder of the joints that affects a large population worldwide and for which there is no definitive cure. This review provides critical insights into the basic knowledge on OA that may lead to innovative end efficient new therapeutic regimens. While degradation of the articular cartilage is the hallmark of OA, with altered interactions between chondrocytes and compounds of the extracellular matrix, the subchondral bone has been also described as a key component of the disease, involving specific pathomechanisms controlling its initiation and progression...
December 2016: Journal of Experimental Orthopaedics
Michael Berktold, Wolfgang Mutschlechner, Dorothea Orth-Höller
Rapid microbial diagnostics is important for septicemic patients. The current gold standard is blood culture with consecutive pathogen identification and antimicrobial susceptibility testing. However, these culture-based methods need at least 48 h.The aim of this study was to compare Verigene(®) (Nanosphere, Northbrook, IL, USA), a rapid hybridization-based method, with conventional culture-based methods for detection of pathogens and resistance markers from positive blood cultures of septic patients.In 85 of 100 tested blood culture samples (85 %), pathogen identification as well as resistance profile were identical in Verigene and conventional culture...
September 13, 2016: Wiener Klinische Wochenschrift
Liang Gao, Patrick Orth, Lars K H Goebel, Magali Cucchiarini, Henning Madry
Subchondral bone alterations are emerging as considerable clinical problems associated with articular cartilage repair. Their analysis exposes a pattern of variable changes, including intra-lesional osteophytes, residual microfracture holes, peri-hole bone resorption, and subchondral bone cysts. A precise distinction between them is becoming increasingly important. Here, we present a tailored algorithm based on continuous data to analyse subchondral bone changes using micro-CT images, allowing for a clear definition of each entity...
2016: Scientific Reports
Renan B Campos, Leociley R A Menezes, Andersson Barison, Dean J Tantillo, Elisa S Orth
Imidazole (IMZ) rings catalyze many biological dephosphorylation processes. The methyl positioning effect on IMZs reactivity has long intrigued scientists and its full understanding comprises a promising tool for designing highly efficient IMZ-based catalysts. We evaluated all monosubstituted methylimidazoles (xMEI) in the reaction with diethyl 2,4-dinitrophenyl phosphate by kinetics studies, NMR analysis and DFT calculations. All xMEI showed remarkable rate enhancements, up to 1.9×10(5) fold, compared with spontaneous hydrolysis...
October 17, 2016: Chemistry: a European Journal
Marcel Endres, Susanne Kneitz, Martin F Orth, Ruwan K Perera, Alma Zernecke, Elke Butt
The process of tumor invasion requires degradation of extracellular matrix by proteolytic enzymes. Cancer cells form protrusive invadopodia, which produce and release matrix metalloproteinases (MMPs) to degrade the basement membrane thereby enabling metastasis. We investigated the effect of LASP1, a newly identified protein in invadopodia, on expression, secretion and activation of MMPs in invasive breast tumor cell lines.By analyzing microarray data of in-house generated control and LASP1-depleted MDA-MB-231 breast cancer cells, we observed downregulation of MMP1, -3 and -9 upon LASP1 depletion...
August 31, 2016: Oncotarget
Janina Frisch, Patrick Orth, Jagadeesh Kumar Venkatesan, Ana Rey-Rico, Gertrud Schmitt, Dieter Kohn, Henning Madry, Magali Cucchiarini
: : Transplantation of genetically modified peripheral blood aspirates that carry chondrogenically competent progenitor cells may offer new, convenient tools to treat articular cartilage lesions compared with the more complex and invasive application of bone marrow concentrates or of bone marrow-derived mesenchymal stem cells. Here, we show that recombinant adeno-associated viral (rAAV) vectors are powerful gene vehicles capable of successfully targeting primary human peripheral blood aspirates in a stable and safe manner, allowing for an efficient and long-term transgene expression in such samples (up to 63 days with use of a lacZ reporter gene and for at least 21 days with application of the pleiotropic, chondrogenic factor transforming growth factor-β [TGF-β])...
August 29, 2016: Stem Cells Translational Medicine
Laura L Govers, Willem A Man In 't Veld, Johan P Meffert, Tjeerd J Bouma, Patricia C J van Rijswick, Jannes H T Heusinkveld, Robert J Orth, Marieke M van Katwijk, Tjisse van der Heide
Phytophthora species are potent pathogens that can devastate terrestrial plants, causing billions of dollars of damage yearly to agricultural crops and harming fragile ecosystems worldwide. Yet, virtually nothing is known about the distribution and pathogenicity of their marine relatives. This is surprising, as marine plants form vital habitats in coastal zones worldwide (i.e. mangrove forests, salt marshes, seagrass beds), and disease may be an important bottleneck for the conservation and restoration of these rapidly declining ecosystems...
August 31, 2016: Proceedings. Biological Sciences
Michael Orth, Sarah Gregory, Rachael I Scahill, Isabella Sm Mayer, Lora Minkova, Stefan Klöppel, Kiran K Seunarine, Lara Boyd, Beth Borowsky, Ralf Reilmann, G Bernhard Landwehrmeyer, Blair R Leavitt, Raymund Ac Roos, Alexandra Durr, Geraint Rees, John C Rothwell, Douglas Langbehn, Sarah J Tabrizi
While the HTT CAG-repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age-at-onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory-motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory-motor structural MRI, tractography, resting-state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory-motor performance were measured...
August 1, 2016: Human Brain Mapping
Ann Ray, Lisa N Kinch, Marcela de Souza Santos, Nick V Grishin, Kim Orth, Dor Salomon
UNLABELLED: Members of the genus Vibrio include many pathogens of humans and marine animals that share genetic information via horizontal gene transfer. Hence, the Vibrio pan-genome carries the potential to establish new pathogenic strains by sharing virulence determinants, many of which have yet to be characterized. Here, we investigated the virulence properties of Vibrio proteolyticus, a Gram-negative marine bacterium previously identified as part of the Vibrio consortium isolated from diseased corals...
2016: MBio
Clara Cosgaya, Marta Marí-Almirall, Ado Van Assche, Dietmar Fernández-Orth, Noraida Mosqueda, Murat Telli, Geert Huys, Paul G Higgins, Harald Seifert, Bart Lievens, Ignasi Roca, Jordi Vila
The recent advances in bacterial species identification methods have led to the rapid taxonomic diversification of the genus Acinetobacter. In the present study, phenotypic and molecular methods have been used to determine the taxonomic position of a group of 12 genotypically distinct strains belonging to the Acinetobacter calcoaceticus-Acinetobacter baumannii (ACB) complex, initially described by Gerner-Smidt and Tjernberg in 1993, that are closely related to A. pittii. Strains characterized in this study originated mostly from human samples obtained in different countries over a period of 15 years...
July 15, 2016: International Journal of Systematic and Evolutionary Microbiology
Stephanie Hucke, Martin Herold, Marie Liebmann, Nicole Freise, Maren Lindner, Ann-Katrin Fleck, Stefanie Zenker, Stephanie Thiebes, Juncal Fernandez-Orth, Dorothea Buck, Felix Luessi, Sven G Meuth, Frauke Zipp, Bernhard Hemmer, Daniel Robert Engel, Johannes Roth, Tanja Kuhlmann, Heinz Wiendl, Luisa Klotz
Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity...
September 2016: Acta Neuropathologica
Eva C Luciano, Ulrich Orth
Research suggests that self-esteem increases during late adolescence and young adulthood, but that there is large interindividual variability in this development. However, little is known about the factors accounting for these findings. Using propensity score matching, we tested whether important transitions in the domain of romantic relationships (i.e., beginning a relationship, marrying, and breaking up) explain why individuals differ in the particular self-esteem trajectory they follow. Data came from a longitudinal German study with a large sample of 3 nationally representative cohorts of late adolescents and young adults (total N = 9,069)...
July 4, 2016: Journal of Personality and Social Psychology
Peng Li, Giomar Rivera-Cancel, Lisa N Kinch, Dor Salomon, Diana R Tomchick, Nick V Grishin, Kim Orth
Bile is an important component of the human gastrointestinal tract with an essential role in food absorption and antimicrobial activities. Enteric bacterial pathogens have developed strategies to sense bile as an environmental cue to regulate virulence genes during infection. We discovered that Vibrio parahaemolyticus VtrC, along with VtrA and VtrB, are required for activating the virulence type III secretion system 2 in response to bile salts. The VtrA/VtrC complex activates VtrB in the presence of bile salts...
2016: ELife
Jason C Lenzo, Neil M O'Brien-Simpson, Rebecca K Orth, Helen L Mitchell, Stuart G Dashper, Eric C Reynolds
Periodontitis is a significant problem in companion animals, and yet little is known about the disease-associated microbiota. A major virulence factor for the human periodontal pathogen Porphyromonas gingivalis is the lysyl- and arginyl-specific proteolytic activity of the gingipains. We screened several Porphyromonas species isolated from companion animals-P. asaccharolytica, P. circumdentaria, P. endodontalis, P. levii, P. gulae, P. macacae, P. catoniae, and P. salivosa-for Lys- and Arg-specific proteolytic activity and compared the epithelial and macrophage responses and induction of alveolar bone resorption of the protease active species to that of Porphyromonas gingivalis Only P...
September 2016: Infection and Immunity
René Orth, Jakob Zscheischler, Sonia I Seneviratne
Central Europe was characterized by a humid-temperate climate in the 20(th) century. Climate change projections suggest that climate in this area will shift towards warmer temperatures by the end of the 21(st) century, while projected precipitation changes are highly uncertain. Here we show that the 2015 summer rainfall was the lowest on record since 1901 in Central Europe, and that climate models that perform best in the three driest years of the historical time period 1901-2015 project stronger drying trends in the 21(st) century than models that perform best in the remaining years...
2016: Scientific Reports
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