@article{WuPonsGoudetetal.2017, author = {Wu, Yu and Pons, Val{\´e}rie and Goudet, Am{\´e}lie and Panigai, Laetitia and Fischer, Annette and Herweg, Jo-Ana and Kali, Sabrina and Davey, Robert A. and Laporte, J{\´e}r{\^o}me and Bouclier, C{\´e}line and Yousfi, Rahima and Aubenque, C{\´e}line and Merer, Goulven and Gobbo, Emilie and Lopez, Roman and Gillet, Cynthia and Cojean, Sandrine and Popoff, Michel R. and Clayette, Pascal and Le Grand, Roger and Boulogne, Claire and Tordo, No{\"e}l and Lemichez, Emmanuel and Loiseau, Philippe M. and Rudel, Thomas and Sauvaire, Didier and Cintrat, Jean-Christophe and Gillet, Daniel and Barbier, Julien}, title = {ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-15466-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173170}, year = {2017}, abstract = {Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identifed the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity. This compound efciently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite. ABMA provokes Rab7-positive late endosomal compartment accumulation in mammalian cells without affecting other organelles (early endosomes, lysosomes, the Golgi apparatus, the endoplasmic reticulum or the nucleus). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. ABMA may represent a novel class of broad-spectrum compounds with therapeutic potential against diverse severe infectious diseases.}, language = {en} } @article{WangIpKlausKarikarietal.2017, author = {Wang Ip, Chi and Klaus, Laura-Christin and Karikari, Akua A. and Visanji, Naomi P. and Brotchie, Jonathan M. and Lang, Anthony E. and Volkmann, Jens and Koprich, James B.}, title = {AAV1/2-induced overexpression of A53T-α-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: a new mouse model for Parkinson's disease}, series = {Acta Neuropathologica Communications}, volume = {5}, journal = {Acta Neuropathologica Communications}, number = {11}, doi = {10.1186/s40478-017-0416-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159429}, year = {2017}, abstract = {α-Synuclein is a protein implicated in the etiopathogenesis of Parkinson's disease (PD). AAV1/2-driven overexpression of human mutated A53T-α-synuclein in rat and monkey substantia nigra (SN) induces degeneration of nigral dopaminergic neurons and decreases striatal dopamine and tyrosine hydroxylase (TH). Given certain advantages of the mouse, especially it being amendable to genetic manipulation, translating the AAV1/2-A53T α-synuclein model to mice would be of significant value. AAV1/2-A53T α-synuclein or AAV1/2 empty vector (EV) at a concentration of 5.16 x 10\(^{12}\) gp/ml were unilaterally injected into the right SN of male adult C57BL/6 mice. Post-mortem examinations included immunohistochemistry to analyze nigral α-synuclein, Ser129 phosphorylated α-synuclein and TH expression, striatal dopamine transporter (DAT) levels by autoradiography and dopamine levels by high performance liquid chromatography. At 10 weeks, in AAV1/2-A53T α-synuclein mice there was a 33\% reduction in TH+ dopaminergic nigral neurons (P < 0.001), 29\% deficit in striatal DAT binding (P < 0.05), 38\% and 33\% reductions in dopamine (P < 0.001) and DOPAC (P < 0.01) levels and a 60\% increase in dopamine turnover (homovanilic acid/dopamine ratio; P < 0.001). Immunofluorescence showed that the AAV1/2-A53T α-synuclein injected mice had widespread nigral and striatal expression of vector-delivered A53T-α-synuclein. Concurrent staining with human PD SN samples using gold standard histological methodology for Lewy pathology detection by proteinase K digestion and application of specific antibody raised against human Lewy body α-synuclein (LB509) and Ser129 phosphorylated α-synuclein (81A) revealed insoluble α-synuclein aggregates in AAV1/2-A53T α-synuclein mice resembling Lewy-like neurites and bodies. In the cylinder test, we observed significant paw use asymmetry in the AAV1/2-A53T α-synuclein group when compared to EV controls at 5 and 9 weeks post injection (P < 0.001; P < 0.05). These data show that unilateral injection of AAV1/2-A53T α-synuclein into the mouse SN leads to persistent motor deficits, neurodegeneration of the nigrostriatal dopaminergic system and development of Lewy-like pathology, thereby reflecting clinical and pathological hallmarks of human PD.}, language = {en} } @phdthesis{Sprengel2017, author = {Sprengel, Martin}, title = {A Theoretical and Numerical Analysis of a Kohn-Sham Equation and Related Control Problems}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-153545}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {In this work, multi-particle quantum optimal control problems are studied in the framework of time-dependent density functional theory (TDDFT). Quantum control problems are of great importance in both fundamental research and application of atomic and molecular systems. Typical applications are laser induced chemical reactions, nuclear magnetic resonance experiments, and quantum computing. Theoretically, the problem of how to describe a non-relativistic system of multiple particles is solved by the Schr{\"o}dinger equation (SE). However, due to the exponential increase in numerical complexity with the number of particles, it is impossible to directly solve the Schr{\"o}dinger equation for large systems of interest. An efficient and successful approach to overcome this difficulty is the framework of TDDFT and the use of the time-dependent Kohn-Sham (TDKS) equations therein. This is done by replacing the multi-particle SE with a set of nonlinear single-particle Schr{\"o}dinger equations that are coupled through an additional potential. Despite the fact that TDDFT is widely used for physical and quantum chemical calculation and software packages for its use are readily available, its mathematical foundation is still under active development and even fundamental issues remain unproven today. The main purpose of this thesis is to provide a consistent and rigorous setting for the TDKS equations and of the related optimal control problems. In the first part of the thesis, the framework of density functional theory (DFT) and TDDFT are introduced. This includes a detailed presentation of the different functional sets forming DFT. Furthermore, the known equivalence of the TDKS system to the original SE problem is further discussed. To implement the TDDFT framework for multi-particle computations, the TDKS equations provide one of the most successful approaches nowadays. However, only few mathematical results concerning these equations are available and these results do not cover all issues that arise in the formulation of optimal control problems governed by the TDKS model. It is the purpose of the second part of this thesis to address these issues such as higher regularity of TDKS solutions and the case of weaker requirements on external (control) potentials that are instrumental for the formulation of well-posed TDKS control problems. For this purpose, in this work, existence and uniqueness of TDKS solutions are investigated in the Galerkin framework and using energy estimates for the nonlinear TDKS equations. In the third part of this thesis, optimal control problems governed by the TDKS model are formulated and investigated. For this purpose, relevant cost functionals that model the purpose of the control are discussed. Henceforth, TDKS control problems result from the requirement of optimising the given cost functionals subject to the differential constraint given by the TDKS equations. The analysis of these problems is novel and represents one of the main contributions of the present thesis. In particular, existence of minimizers is proved and their characterization by TDKS optimality systems is discussed in detail. To this end, Fr{\´e}chet differentiability of the TDKS model and of the cost functionals is addressed considering \(H^1\) cost of the control. This part is concluded by deriving the reduced gradient in the \(L^2\) and \(H^1\) inner product. While the \(L^2\) optimization is widespread in the literature, the choice of the \(H^1\) gradient is motivated in this work by theoretical consideration and by resulting numerical advantages. The last part of the thesis is devoted to the numerical approximation of the TDKS optimality systems and to their solution by gradient-based optimization techniques. For the former purpose, Strang time-splitting pseudo-spectral schemes are discussed including a review of some recent theoretical estimates for these schemes and a numerical validation of these estimates. For the latter purpose, nonlinear (projected) conjugate gradient methods are implemented and are used to validate the theoretical analysis of this thesis with results of numerical experiments with different cost functional settings.}, subject = {Optimale Kontrolle}, language = {en} } @article{TawkSharanEulalioetal.2017, author = {Tawk, Caroline and Sharan, Malvika and Eulalio, Ana and Vogel, J{\"o}rg}, title = {A systematic analysis of the RNA-targeting potential of secreted bacterial effector proteins}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-09527-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158815}, pages = {9328}, year = {2017}, abstract = {Many pathogenic bacteria utilize specialized secretion systems to deliver proteins called effectors into eukaryotic cells for manipulation of host pathways. The vast majority of known effector targets are host proteins, whereas a potential targeting of host nucleic acids remains little explored. There is only one family of effectors known to target DNA directly, and effectors binding host RNA are unknown. Here, we take a two-pronged approach to search for RNA-binding effectors, combining biocomputational prediction of RNA-binding domains (RBDs) in a newly assembled comprehensive dataset of bacterial secreted proteins, and experimental screening for RNA binding in mammalian cells. Only a small subset of effectors were predicted to carry an RBD, indicating that if RNA targeting was common, it would likely involve new types of RBDs. Our experimental evaluation of effectors with predicted RBDs further argues for a general paucity of RNA binding activities amongst bacterial effectors. We obtained evidence that PipB2 and Lpg2844, effector proteins of Salmonella and Legionella species, respectively, may harbor novel biochemical activities. Our study presenting the first systematic evaluation of the RNA-targeting potential of bacterial effectors offers a basis for discussion of whether or not host RNA is a prominent target of secreted bacterial proteins.}, language = {en} } @article{SperlichDuekingHolmberg2017, author = {Sperlich, Billy and D{\"u}king, Peter and Holmberg, Hans-Christer}, title = {A SWOT analysis of the use and potential misuse of implantable monitoring devices by athletes}, series = {Frontiers in Physiology}, volume = {8}, journal = {Frontiers in Physiology}, number = {629}, doi = {10.3389/fphys.2017.00629}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158742}, year = {2017}, abstract = {Kein Abstract vorhanden.}, language = {en} } @article{JordanBittrichFehskeetal.2017, author = {Jordan, Martin C. and Bittrich, Leonie A. and Fehske, Kai and Meffert, Rainer H. and Jansen, Hendrik}, title = {A rare case of Hoffa fracture combined with lateral patellar dislocation}, series = {Trauma Case Reports}, volume = {9}, journal = {Trauma Case Reports}, doi = {10.1016/j.tcr.2017.05.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158315}, pages = {13-16}, year = {2017}, abstract = {The coronal unicondylar fracture of the distal femur (AO 33-B3) is a rare intraarticular injury within the weight bearing area of the knee, initially described by Albert Hoffa in 1904. We report an unusual combination of a Hoffa fracture with lateral patellar dislocation in a young adult. Our patient sustained the injury by a sudden twist of his leg during sports. He presented clinically with knee swelling, dislocation of the patella, and localized tenderness; unable to bare weight. After plane radiograph confirmed the injury, manual reduction of the patella was done by hyperextension of the knee and medialward pressure. Afterwards, a CT scan and MRI were conducted. The injury was surgically treated with lag-screws, locking-plate and MPFL-reconstruction.}, language = {en} } @article{ZimmermannSubotaBatrametal.2017, author = {Zimmermann, Henriette and Subota, Ines and Batram, Christopher and Kramer, Susanne and Janzen, Christian J. and Jones, Nicola G. and Engstler, Markus}, title = {A quorum sensing-independent path to stumpy development in Trypanosoma brucei}, series = {PLoS Pathogens}, volume = {13}, journal = {PLoS Pathogens}, number = {4}, doi = {10.1371/journal.ppat.1006324}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158230}, pages = {e1006324}, year = {2017}, abstract = {For persistent infections of the mammalian host, African trypanosomes limit their population size by quorum sensing of the parasite-excreted stumpy induction factor (SIF), which induces development to the tsetse-infective stumpy stage. We found that besides this cell density-dependent mechanism, there exists a second path to the stumpy stage that is linked to antigenic variation, the main instrument of parasite virulence. The expression of a second variant surface glycoprotein (VSG) leads to transcriptional attenuation of the VSG expression site (ES) and immediate development to tsetse fly infective stumpy parasites. This path is independent of SIF and solely controlled by the transcriptional status of the ES. In pleomorphic trypanosomes varying degrees of ES-attenuation result in phenotypic plasticity. While full ES-attenuation causes irreversible stumpy development, milder attenuation may open a time window for rescuing an unsuccessful antigenic switch, a scenario that so far has not been considered as important for parasite survival.}, language = {en} } @article{MoschallDenkErkelenzetal.2017, author = {Moschall, Rebecca and Denk, Sarah and Erkelenz, Steffen and Schenk, Christian and Schaal, Heiner and Bodem, Jochen}, title = {A purine-rich element in foamy virus pol regulates env splicing and gag/pol expression}, series = {Retrovirology}, volume = {14}, journal = {Retrovirology}, number = {10}, doi = {10.1186/s12977-017-0337-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157614}, year = {2017}, abstract = {Background: The foamy viral genome encodes four central purine-rich elements localized in the integrase-coding region of pol. Previously, we have shown that the first two of these RNA elements (A and B) are required for protease dimerization and activation. The D element functions as internal polypurine tract during reverse transcription. Peters et al., described the third element (C) as essential for gag expression suggesting that it might serve as an RNA export element for the unspliced genomic transcript. Results: Here, we analysed env splicing and demonstrate that the described C element composed of three GAA repeats known to bind SR proteins regulates env splicing, thus balancing the amount of gag/pol mRNAs. Deletion of the C element effectively promotes a splice site switch from a newly identified env splice acceptor to the intrinsically strong downstream localised env 3′ splice acceptor permitting complete splicing of almost all LTR derived transcripts. We provide evidence that repression of this env splice acceptor is a prerequisite for gag expression. This repression is achieved by the C element, resulting in impaired branch point recognition and SF1/mBBP binding. Separating the branch point from the overlapping purine-rich C element, by insertion of only 20 nucleotides, liberated repression and fully restored splicing to the intrinsically strong env 3′ splice site. This indicated that the cis-acting element might repress splicing by blocking the recognition of essential splice site signals. Conclusions: The foamy viral purine-rich C element regulates splicing by suppressing the branch point recognition of the strongest env splice acceptor. It is essential for the formation of unspliced gag and singly spliced pol transcripts.}, language = {en} } @article{RueeggKriemlerZuercheretal.2017, author = {Rueegg, Corina S. and Kriemler, Susi and Zuercher, Simeon J. and Schindera, Christina and Renner, Andrea and Hebestreit, Helge and Meier, Christian and Eser, Prisca and von der Weid, Nicolas X.}, title = {A partially supervised physical activity program for adult and adolescent survivors of childhood cancer (SURfit): study design of a randomized controlled trial [NCT02730767]}, series = {BMC Cancer}, volume = {17}, journal = {BMC Cancer}, doi = {10.1186/s12885-017-3801-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172497}, year = {2017}, abstract = {Background: Beyond survival of nowadays >80\%, modern childhood cancer treatment strives to preserve long-term health and quality of life. However, the majority of today's survivors suffer from short- and long-term adverse effects such as cardiovascular and pulmonary diseases, obesity, osteoporosis, fatigue, depression, and reduced physical fitness and quality of life. Regular exercise can play a major role to mitigate or prevent such late-effects. Despite this, there are no data on the effects of regular exercise in childhood cancer survivors from randomized controlled trials (RCTs). \(Primary\) \(outcome\) of the current RCT is therefore the effect of a 12-months exercise program on a composite cardiovascular disease risk score in childhood cancer survivors. \(Secondary\) \(outcomes\) are single cardiovascular disease risk factors, glycaemic control, bone health, body composition, physical fitness, physical activity, quality of life, mental health, fatigue and adverse events (safety). Methods: A total of 150 childhood cancer survivors aged ≥16 years and diagnosed ≥5 years prior to the study are recruited from Swiss paediatric oncology clinics. Following the baseline assessments patients are randomized 1:1 into an intervention and control group. Thereafter, they are seen at month 3, 6 and 12 for follow-up assessments. The intervention group is asked to add ≥2.5 h of intense physical activity/week, including 30 min of strength building and 2 h of aerobic exercises. In addition, they are told to reduce screen time by 25\%. Regular consulting by physiotherapists, individual web-based activity diaries, and pedometer devices are used as motivational tools for the intervention group. The control group is asked to keep their physical activity levels constant. Discussion: The results of this study will show whether a partially supervised exercise intervention can improve cardiovascular disease risk factors, bone health, body composition, physical activity and fitness, fatigue, mental health and quality of life in childhood cancer survivors. If the program will be effective, all relevant information of the SURfit physical activity intervention will be made available to interested clinics that treat and follow-up childhood cancer patients to promote exercise in their patients.}, language = {en} } @article{SanchoVandersmissenCrapsetal.2017, author = {Sancho, Ana and Vandersmissen, Ine and Craps, Sander and Luttun, Aernout and Groll, J{\"u}rgen}, title = {A new strategy to measure intercellular adhesion forces in mature cell-cell contacts}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {46152}, doi = {10.1038/srep46152}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170999}, year = {2017}, abstract = {Intercellular adhesion plays a major role in tissue development and homeostasis. Yet, technologies to measure mature cell-cell contacts are not available. We introduce a methodology based on fluidic probe force microscopy to assess cell-cell adhesion forces after formation of mature intercellular contacts in cell monolayers. With this method we quantify that L929 fibroblasts exhibit negligible cell-cell adhesion in monolayers whereas human endothelial cells from the umbilical artery (HUAECs) exert strong intercellular adhesion forces per cell. We use a new in vitro model based on the overexpression of Muscle Segment Homeobox 1 (MSX1) to induce Endothelial-to-Mesenchymal Transition (EndMT), a process involved in cardiovascular development and disease. We reveal how intercellular adhesion forces in monolayer decrease significantly at an early stage of EndMT and we show that cells undergo stiffening and flattening at this stage. This new biomechanical insight complements and expands the established standard biomolecular analyses. Our study thus introduces a novel tool for the assessment of mature intercellular adhesion forces in a physiological setting that will be of relevance to biological processes in developmental biology, tissue regeneration and diseases like cancer and fibrosis.}, language = {en} }