TY - JOUR T1 - Search for Higgs boson pair production in the b\(\overline{b}\)b\(\overline{b}\) final state from pp collisions at \(\sqrt {s}\) = 8 TeV with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - A search for Higgs boson pair production pp → hh is performed with 19.5 fb\(^{−1}\) of proton–proton collision data at \(\sqrt {s}\) = 8 TeV, which were recorded by the ATLAS detector at the Large Hadron Collider in 2012. The decay products of each Higgs boson are reconstructed as a high-momentum b\(\overline{b}\) system with either a pair of small-radius jets or a single large-radius jet, the latter exploiting jet substructure techniques and associated b-tagged track-jets. No evidence for resonant or non-resonant Higgs boson pair production is observed. The data are interpreted in the context of the Randall–Sundrum model with a warped extra dimension as well as the two-Higgs-doublet model. An upper limit on the cross-section for pp → G\(^{*}_{KK}\) → hh → b\(\overline{b}\)b\(\overline{b}\) of 3.2(2.3) fb is set for a Kaluza–Klein graviton G\(^{*}_{KK}\) mass of 1.0(1.5) TeV, at the 95 % confidence level. The search for non-resonant Standard Model hh production sets an observed 95 % confidence level upper limit on the production cross-section σ(pp → hh → b\(\overline{b}\)b\(\overline{b}\)) of 202 fb, compared to a Standard Model prediction of σ(pp → hh → b\(\overline{b}\)b\(\overline{b}\)) = 3.6±0.5 fb. KW - Higgs boson KW - proton-proton collision KW - ATLAS detector KW - pair production Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150119 VL - 75 IS - 9 ER - TY - JOUR T1 - Search for H→γγH→γγ produced in association with top quarks and constraints on the Yukawa coupling between the top quark and the Higgs boson using data taken at 7 TeV and 8 TeV with the ATLAS detector JF - Physics Letters B N2 - A search is performed for Higgs bosons produced in association with top quarks using the diphoton decay mode of the Higgs boson. Selection requirements are optimized separately for leptonic and fully hadronic final states from the top quark decays. The dataset used corresponds to an integrated luminosity of 4.5 fb\(^{−1}\) of proton–proton collisions at a center-of-mass energy of 7 TeV and 20.3 fb−120.3 fb\(^{−1}\) at 8 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. No significant excess over the background prediction is observed and upper limits are set on the \(t\overline{t}H\) production cross section. The observed exclusion upper limit at 95% confidence level is 6.7 times the predicted Standard Model cross section value. In addition, limits are set on the strength of the Yukawa coupling between the top quark and the Higgs boson, taking into account the dependence of the \(t\overline{t}H\) and tH   cross sections as well as the H→γγH→γγ branching fraction on the Yukawa coupling. Lower and upper limits at 95% confidence level are set at −1.3 and +8.0 times the Yukawa coupling strength in the Standard Model. KW - Higgs boson KW - diphoton decay KW - top quark KW - Yukawa coupling Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136100 VL - 740 ER - TY - JOUR T1 - Search for invisible decays of the Higgs boson produced in association with a hadronically decaying vector boson in pp collisions at \(\sqrt {s}\) = TeV with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - A search for Higgs boson decays to invisible particles is performed using 20.3 fb\(^{−1}\) of pp collision data at a centre-of-mass energy of 8 TeV recorded by the ATLAS detector at the Large Hadron Collider. The process considered is Higgs boson production in association with a vector boson (V = W or Z) that decays hadronically, resulting in events with two or more jets and large missing transverse momentum. No excess of candidates is observed in the data over the background expectation. The results are used to constrain VH production followed by H decaying to invisible particles for the Higgs boson mass range 115 < m\(_{H}\) < 300 GeV. The 95 % confidence-level observed upper limit on σ\(_{VH}\) × BR(H → inv.) varies from 1.6 pb at 115 GeV to 0.13 pb at 300 GeV. Assuming Standard Model production and including the gg → H contribution as signal, the results also lead to an observed upper limit of 78 % at 95 % confidence level on the branching ratio of Higgs bosons decays to invisible particles at a mass of 125 GeV. KW - Higgs boson KW - ATLAS detector KW - decays Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150126 VL - 75 IS - 7 ER - TY - JOUR T1 - Search for invisible particles produced in association with single-top-quarks in proton-proton collisions at \(\sqrt {s}\) = 8 TeV with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - A search for the production of single-top-quarks in association with missing energy is performed in proton–proton collisions at a centre-of-mass energy of \(\sqrt {s}\) =8 TeV with the ATLAS experiment at the large hadron collider using data collected in 2012, corresponding to an integrated luminosity of 20.3 fb\(^{−1}\). In this search, the W boson from the top quark is required to decay into an electron or a muon and a neutrino. No deviation from the standard model prediction is observed, and upper limits are set on the production cross-section for resonant and non-resonant production of an invisible exotic state in association with a right-handed top quark. In the case of resonant production, for a spin-0 resonance with a mass of 500 GeV, an effective coupling strength above 0.15 is excluded at 95 % confidence level for the top quark and an invisible spin-1/2 state with mass between 0 and 100 GeV. In the case of non-resonant production, an effective coupling strength above 0.2 is excluded at 95 % confidence level for the top quark and an invisible spin-1 state with mass between 0 and 657 GeV. KW - single-top-quarks KW - proton-proton collision KW - ATLAS detector Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150134 VL - 75 IS - 2 ER - TY - JOUR T1 - Search for metastable heavy charged particles with large ionisation energy loss in pp collisions at \(\sqrt {s}\) = 8 TeV using the ATLAS experiment JF - European Physical Journal C: Particles and Fields N2 - Many extensions of the Standard Model predict the existence of charged heavy long-lived particles, such as R-hadrons or charginos. These particles, if produced at the Large Hadron Collider, should be moving non-relativistically and are therefore identifiable through the measurement of an anomalously large specific energy loss in the ATLAS pixel detector. Measuring heavy long-lived particles through their track parameters in the vicinity of the interaction vertex provides sensitivity to metastable particles with lifetimes from 0.6 ns to 30 ns. A search for such particles with the ATLAS detector at the Large Hadron Collider is presented, based on a data sample corresponding to an integrated luminosity of 18.4 fb\(^{−1}\) of pp collisions at \(\sqrt {s}\) = 8 TeV. No significant deviation from the Standard Model background expectation is observed, and lifetime-dependent upper limits on R-hadrons and chargino production are set. Gluino R-hadrons with 10 ns lifetime and masses up to 1185 GeV are excluded at 95 % confidence level, and so are charginos with 15 ns lifetime and masses up to 482 GeV. KW - ATLAS detector KW - charged heavy long-lived particles KW - proton-proton collision Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150149 VL - 75 IS - 9 ER - TY - JOUR T1 - Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at \(\sqrt {s}\) = 8 TeV with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb\(^{−1}\) of \(\sqrt {s}\) = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between E\(^{miss}_{T}\) > 150 GeV and E\(^{miss}_{T}\) > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presented. KW - ATLAS detector KW - energetic jet KW - proton-proton collision Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150152 VL - 75 IS - 7 ER - TY - JOUR T1 - Search for pair-produced long-lived neutral particles decaying to jets in the ATLAS hadronic calorimeter in pp collisions at \(\sqrt{2}\)=8 TeV JF - Physics Letters B N2 - The ATLAS detector at the Large Hadron Collider at CERN is used to search for the decay of a scalar boson to a pair of long-lived particles, neutral under the Standard Model gauge group, in 20.3 fb−120.3 fb\(^{−1}\) of data collected in proton–proton collisions at \(\sqrt{2}\)=8 TeV. This search is sensitive to long-lived particles that decay to Standard Model particles producing jets at the outer edge of the ATLAS electromagnetic calorimeter or inside the hadronic calorimeter. No significant excess of events is observed. Limits are reported on the product of the scalar boson production cross section times branching ratio into long-lived neutral particles as a function of the proper lifetime of the particles. Limits are reported for boson masses from 100 GeV to 900 GeV, and a long-lived neutral particle mass from 10 GeV to 150 GeV. KW - new physics KW - long-lived neutral particle KW - high-energy collider experiment Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136099 VL - 743 ER - TY - JOUR T1 - Search for production of WW/WZ resonances decaying to a lepton, neutrino and jets in pp collisions at \(\sqrt {s}\)= 8 TeV with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - A search is presented for narrow diboson resonances decaying to WW or WZ in the final state where one W boson decays leptonically (to an electron or a muon plus a neutrino) and the other W/Z boson decays hadronically. The analysis is performed using an integrated luminosity of 20.3 fb\(^{−1}\) of pp collisions at \(\sqrt {s}\) = 8 TeV collected by the ATLAS detector at the large hadron collider. No evidence for resonant diboson production is observed, and resonance masses below 700 and 1490 GeV are excluded at 95 % confidence level for the spin-2 Randall–Sundrum bulk graviton G\(^{*}\) with coupling constant of 1.0 and the extended gauge model W′ boson respectively. KW - ATLAS detector KW - W boson KW - Z boson KW - proton-proton collision Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150164 VL - 75 IS - 5 ER - TY - JOUR T1 - Search for resonant diboson production in the ℓℓq\(\overline{q}\) final state in pp collisions at \(\sqrt {s}\) = 8 TeV with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - This paper reports on a search for narrow resonances in diboson production in the ℓℓq\(\overline{q}\) final state using pp collision data corresponding to an integrated luminosity of 20 fb\(^{−1}\) collected at \(\sqrt {s}\) = 8 TeV with the ATLAS detector at the Large Hadron Collider. No significant excess of data events over the Standard Model expectation is observed. Upper limits at the 95 % confidence level are set on the production cross section times branching ratio for Kaluza–Klein gravitons predicted by the Randall–Sundrum model and for Extended Gauge Model W′ bosons. These results lead to the exclusion of mass values below 740 and 1590 GeV for the graviton and W′ boson respectively. KW - ATLAS detector KW - proton-proton collision KW - diboson production KW - resonances Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150171 VL - 75 IS - 2 ER - TY - JOUR T1 - Search for s-channel single top-quark production in proton–proton collisions at \(\sqrt{s}\)=8 TeV with the ATLAS detector JF - Physics Letters B N2 - This Letter presents a search at the LHC for s-channel single top-quark production in proton–proton collisions at a centre-of-mass energy of 8 TeV. The analyzed data set was recorded by the ATLAS detector and corresponds to an integrated luminosity of 20.3 fb\(^{−1}\). Selected events contain one charged lepton, large missing transverse momentum and exactly two b-tagged jets. A multivariate event classifier based on boosted decision trees is developed to discriminate s-channel single top-quark events from the main background contributions. The signal extraction is based on a binned maximum-likelihood fit of the output classifier distribution. The analysis leads to an upper limit on the s-channel single top-quark production cross-section of 14.6 pb at the 95% confidence level. The fit gives a cross-section of σs=5.0±4.3 pb, consistent with the Standard Model expectation. KW - s-Channel KW - electroweak production KW - top-quark KW - ATLAS Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139869 VL - 740 ER - TY - JOUR T1 - Search for supersymmetry in events containing a same-flavour opposite-sign dilepton pair, jets, and large missing transverse momentum in \(\sqrt {s}\) = 8 TeV pp collisions with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - Two searches for supersymmetric particles in final states containing a same-flavour opposite-sign lepton pair, jets and large missing transverse momentum are presented. The proton–proton collision data used in these searches were collected at a centre-of-mass energy \(\sqrt {s}\) = 8 TeV by the ATLAS detector at the Large Hadron Collider and corresponds to an integrated luminosity of 20.3 fb\(^{−1}\). Two leptonic production mechanisms are considered: decays of squarks and gluinos with Z bosons in the final state, resulting in a peak in the dilepton invariant mass distribution around the Z-boson mass; and decays of neutralinos (e.g. \(\tilde{χ}\)\(^{0}_{2}\) → ℓ\(^{+}\)ℓ\(^{−}\)\(\tilde{χ}\)\(^{0}_{1}\)), resulting in a kinematic endpoint in the dilepton invariant mass distribution. For the former, an excess of events above the expected Standard Model background is observed, with a significance of three standard deviations. In the latter case, the data are well-described by the expected Standard Model background. The results from each channel are interpreted in the context of several supersymmetric models involving the production of squarks and gluinos. KW - ATLAS detector KW - supersymmetry KW - proton-proton collision Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150184 VL - 75 IS - 7 ER - TY - THES A1 - Schreyer, Manuel T1 - Search for supersymmetry in events containing light leptons, jets and missing transverse momentum in \(\sqrt{s}\) = 8 TeV pp collisions with the ATLAS detector T1 - Suche nach Supersymmetrie in Ereignissen mit leichten Leptonen, Jets und fehlendem Transversalimpuls in pp-Kollisionen bei \(\sqrt{s}\) = 8 TeV mit dem ATLAS-Detektor N2 - The results of two analyses searching for supersymmetry (SUSY) in data of the ATLAS experiment are presented in this thesis. The data were recorded in proton-proton collisions at the Large Hadron Collider in 2012 at a centre of mass energy of \(\sqrt{s}\)=8 TeV and correspond to an integrated luminosity of 20.3 fb\(^{−1}\). The first search is performed in signatures containing an opposite-sign electron or muon pair, which is compatible with originating from a Z boson decay, in addition to jets and large missing transverse momentum. The analysis targets the production of squarks and gluinos in R-parity conserving (RPC) models with SUSY breaking via General Gauge Mediation (GGM). The main Standard Model (SM) backgrounds are \(t\overline t\), WW, W+t and Z to \(\tau \tau\) processes which are entirely estimated from data using different-flavour events. Besides that, the SM production of Z bosons in association with jets and large fake missing momentum from mismeasurements plays a role and is predicted with the data-driven jet smearing method. Backgrounds from events with fake leptons are estimated with the data-driven matrix method. WZ/ZZ production as well as smaller background contributions are determined from Monte-Carlo simulations. The search observes an excess of data over the SM prediction with a local significance of 3.0 \(\sigma\) in the electron channel, 1.7 \(\sigma\) in the muon channel and 3.0 \(\sigma\) when the two channels are added together. The results are used to constrain the parameters of the GGM model. The second analysis uses the already published results of an ATLAS search for SUSY in events with one isolated electron or muon, jets and missing transverse momentum to reinterpret them in the context of squark and gluino production in SUSY models with R-parity violating (RPV) \(LQ\overline D\)-operators. In contrast to RPC models, the lightest SUSY particle (LSP) is not stable but decays into SM particles. "Standard" analyses often do not consider SUSY models with RPV although they are in principle sensitive to them. The exclusion limits on the squark and gluino mass obtained from the reinterpretation extend up to 1200 GeV. These are the first results by any ATLAS SUSY search which systematically cover a wide range of RPV couplings in the case of prompt LSP decays. However, the analysis is not sensitive to the full parameter space of the \(LQ\overline D\)-model and reveals gaps in the ATLAS SUSY program which have to be closed by dedicated search strategies in the future. N2 - In dieser Arbeit werden die Ergebnisse von zwei Suchen nach Supersymmetrie (SUSY) in Daten des ATLAS-Experiments präsentiert. Die Messdaten wurden im Jahr 2012 in Proton-Proton-Kollisionen am Large Hadron Collider bei einer Schwerpunktsenergie von \(\sqrt{s}\) = 8 TeV gewonnen und entsprechen einer integrierten Luminosität von 20,3 fb\(^{−1}\). Die erste Suche verwendet Signaturen mit Jets, großem fehlenden Transversalimpuls sowie einem Elektron- oder Myonpaar mit entgegengesetzter Ladung, dessen Eigenschaften mit einem Leptonpaar aus dem Zerfall eines Z-Bosons vereinbar sind. Die Analyse zielt auf die Untersuchung von Squark- und Gluinoproduktion im Rahmen R-paritätserhaltender (RPC) Modelle mit SUSY-Brechung durch General Gauge Mediation (GGM) ab. Die Hauptuntergründe des Standardmodells (SM) sind \(t\overline t\), WW, W+t und Z nach \(\tau \tau\) Prozesse. Diese werden komplett aus den Daten selbst unter Verwendung von Ereignissen mit Leptonpaaren unterschiedlichen Flavours abgeschätzt. Daneben spielt der Untergrund aus der SM-Produktion von Z-Bosonen in Verbindung mit Jets und großem fehlenden Impuls, der durch Fehlmessungen fälschlicherweise rekonstruiert wird, ein Rolle. Dieser wird mit der datengestützten Jet-Smearing-Methode abgeschätzt. Der Hintergrundbeitrag von Ereignissen mit fehlidentifizierten Leptonen wird mit der datengestützten Matrix-Methode bestimmt, während die Produktion von WZ/ZZ-Paaren sowie kleinere Untergrundprozesse mit Hilfe von Monte-Carlo-Simulationen abgeschätzt werden. Die Suche beobachtet einen Überschuss an Daten über der SM-Vorhersage mit einer lokalen Signifikanz von 3,0 \(\sigma\) im Elektronkanal, 1,7 \(\sigma\) im Myonkanal und 3,0 \(\sigma\), wenn beide Kanäle zusammengezählt werden. Mit den Ergebnissen lassen sich die Parameter des GGM-Modells einschränken. Die zweite Analyse interpretiert die bereits veröffentlichten Ergebnisse einer ATLAS SUSY-Suche in Ereignissen mit einem isolierten Elektron oder Myon, Jets und fehlendem Transversalimpuls im Rahmen von Squark- und Gluinoproduktion in SUSY-Modellen, in denen die R-Parität durch \(LQ\overline D\)-Operatoren verletzt wird. Im Gegensatz zu RPC-Modellen ist das leichteste SUSY-Teilchen (LSP) dort nicht stabil, sondern zerfällt in SM-Teilchen. R-paritätsverletzende (RPV) SUSY-Modelle werden von "Standardanalysen" oft vernachlässigt, obwohl diese prinzipiell sensitiv auf RPV SUSY sind. Die Ausschlussgrenzen auf die Squark- und Gluinomasse, die sich aus der Reinterpretation ergeben, reichen bis zu 1200 GeV. Dies sind die ersten derartigen Ergebnisse einer ATLAS SUSY-Suche, die einen großen Bereich möglicher RPV-Kopplungen für den Fall prompter LSP-Zerfälle auf systematische Art und Weise abdecken. Allerdings ist die Analyse nicht im gesamten Parameterraum des \(LQ\overline D\)-Modells sensitiv und deckt somit Lücken im ATLAS SUSY-Programm auf. Diese sollten in Zukunft durch speziell optimierte Suchstrategien geschlossen werden. KW - Supersymmetrie KW - Supersymmetry KW - Supersymmetrie KW - LHC KW - ATLAS-Detektor KW - Neue Physik KW - New physics KW - ATLAS KW - Proton-Proton-Streuung Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120863 ER - TY - JOUR T1 - Search for the associated production of the Higgs boson with a top quark pair in multilepton final states with the ATLAS detector JF - Physics Letters B N2 - A search for the associated production of the Higgs boson with a top quark pair is performed in multilepton final states using 20.3 fb\(^{−1}\) of proton–proton collision data recorded by the ATLAS experiment at \(\sqrt {s}\)=8 TeV at the Large Hadron Collider. Five final states, targeting the decays H→WW\(^{*}\), ττ, and ZZ\(^{*}\), are examined for the presence of the Standard Model (SM) Higgs boson: two same-charge light leptons (e or μ) without a hadronically decaying τ lepton; three light leptons; two same-charge light leptons with a hadronically decaying τ lepton; four light leptons; and one light lepton and two hadronically decaying τ leptons. No significant excess of events is observed above the background expectation. The best fit for the t\(\overline{t}\)H production cross section, assuming a Higgs boson mass of 125 GeV, is 2.1\(^{+1.4}_{-1.2}\) times the SM expectation, and the observed (expected) upper limit at the 95% confidence level is 4.7 (2.4) times the SM rate. The p-value for compatibility with the background-only hypothesis is 1.8σ; the expectation in the presence of a Standard Model signal is 0.9σ. KW - physics KW - associated production KW - Higgs boson Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144231 VL - 749 ER - TY - JOUR T1 - Search for the Standard Model Higgs boson produced in association with top quarks and decaying into b\(\overline{b}\) in pp collisions at \(\sqrt {s}\) = 8 TeV with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - A search for the Standard Model Higgs boson produced in association with a top-quark pair, t\(\overline{t}\)H, is presented. The analysis uses 20.3 fb\(^{−1}\) of pp collision data at \(\sqrt {s}\) = 8 TeV, collected with the ATLAS detector at the Large Hadron Collider during 2012. The search is designed for the H→b\(\overline{b}\) decay mode and uses events containing one or two electrons or muons. In order to improve the sensitivity of the search, events are categorised according to their jet and b-tagged jet multiplicities. A neural network is used to discriminate between signal and background events, the latter being dominated by t\(\overline{t}\)+jets production. In the single-lepton channel, variables calculated using a matrix element method are included as inputs to the neural network to improve discrimination of the irreducible t\(\overline{t}\)+b\(\overline{b}\) background. No significant excess of events above the background expectation is found and an observed (expected) limit of 3.4 (2.2) times the Standard Model cross section is obtained at 95 % confidence level. The ratio of the measured t\(\overline{t}\)H signal cross section to the Standard Model expectation is found to be μ = 1.5 ± 1.1 assuming a Higgs boson mass of 125 GeV. KW - Higgs boson KW - ATLAS detector KW - top quarks KW - proton-proton collision Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150197 VL - 75 IS - 7 ER - TY - JOUR T1 - Search for W' → tb → qqbb decays in pp collisions at \(\sqrt {s}\) = 8 TeV with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - A search for a massive W′ gauge boson decaying to a top quark and a bottom quark is performed with the ATLAS detector in pp collisions at the LHC. The dataset was taken at a centre-of-mass energy of \(\sqrt {s}\) = 8 TeV and corresponds to 20.3 fb\(^{−1}\) of integrated luminosity. This analysis is done in the hadronic decay mode of the top quark, where novel jet substructure techniques are used to identify jets from high-momentum top quarks. This allows for a search for high-mass W′ bosons in the range 1.5–3.0  TeV. b-tagging is used to identify jets originating from b-quarks. The data are consistent with Standard Model background-only expectations, and upper limits at 95 % confidence level are set on the W′ → tb cross section times branching ratio ranging from 0.16 pb to 0.33 pb for left-handed W′ bosons, and ranging from 0.10 pb to 0.21 pb for W′ bosons with purely right-handed couplings. Upper limits at 95 % confidence level are set on the W′-boson coupling to tb as a function of the W′ mass using an effective field theory approach, which is independent of details of particular models predicting a W′ boson. KW - ATLAS detector KW - proton-proton collision Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150068 VL - 75 IS - 4 ER - TY - JOUR A1 - Redelbach, Andreas T1 - Searches for prompt R-parity-violating supersymmetry at the LHC JF - Advances in High Energy Physics N2 - Searches for supersymmetry (SUSY) at the LHC frequently assume the conservation of R-parity in their design, optimization, and interpretation. In the case that R-parity is not conserved, constraints on SUSY particle masses tend to be weakened with respect to R-parity-conserving models. We review the current status of searches for R-parity-violating (RPV) supersymmetry models at the ATLAS and CMS experiments, limited to 8 TeV search results published or submitted for publication as of the end of March 2015. All forms of renormalisable RPV terms leading to prompt signatures have been considered in the set of analyses under review. Discussing results for searches for prompt R-parity-violating SUSY signatures summarizes the main constraints for various RPV models from LHC Run I and also defines the basis for promising signal regions to be optimized for Run II. In addition to identifying highly constrained regions from existing searches, also gaps in the coverage of the parameter space of RPV SUSY are outlined. KW - supergauge transformations KW - grand unification KW - proton-proton collisions KW - particle KW - breaking KW - standard model KW - hadron colliders KW - √s=8 TeV KW - local supersymmetry Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149149 VL - 2015 IS - 982167 ER - TY - JOUR A1 - Magg, Barbara A1 - Riegler, Christoph A1 - Wiedmann, Silke A1 - Heuschmann, Peter A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Self-administered version of the Fabry-associated pain questionnaire for adult patients JF - Orphanet Journal of Rare Diseases N2 - Background Fabry-associated pain may be the first symptom of Fabry disease (FD) and presents with a unique phenotype including mostly acral burning triggerable pain attacks, evoked pain, pain crises, and permanent pain. We recently developed and validated the first Fabry Pain Questionnaire (FPQ) for adult patients. Here we report on the validation of the self-administered version of the FPQ that no longer requires a face-to-face interview but can be filled in by the patients themselves allowing more flexible data collection. Methods At our Würzburg Fabry Center for Interdisciplinary Treatment, Germany, we have developed the self-administered version of the FPQ by adapting the questionnaire to a self-report version. To do this, consecutive Fabry patients with current or past pain history (n = 56) were first interviewed face-to-face. Two weeks later patients’ self-reported questionnaire results were collected by mail (n = 55). We validated the self-administered version of the FPQ by assessing the inter-rater reliability agreement of scores obtained by supervised administration and self-administration of the FPQ. Results The FPQ contains 15 questions on the different pain phenotypes, on pain development during life with and without therapy, and on impairment due to pain. Statistical analysis showed that the majority of questions were answered in high agreement in both sessions with a mean AC1-statistic of 0.857 for 55 nominal-scaled items and a mean ICC of 0.587 for 9 scores. Conclusions This self-administered version of the first pain questionnaire for adult Fabry patients is a useful tool to assess Fabry-associated pain without a time-consuming face-to-face interview but via a self-reporting survey allowing more flexible usage. KW - Fabry disease KW - Fabry-associated pain KW - pain questionnaire Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145294 VL - 10 IS - 113 ER - TY - THES A1 - Rest, Christina T1 - Self-assembly of amphiphilic oligo(phenylene ethynylene)-based (bi)pyridine ligands and their Pt(II) and Pd(II) complexes T1 - Selbstorganisation von amphiphilen oligo(phenylenethinylen)-basierten (Bi)pyridin-Liganden und ihrer Pt(II) und Pd(II) Komplexe N2 - The presented work in the field of supramolecular chemistry describes the synthesis and detailed investigation of (bi)pyridine-based oligo(phenylene ethynylene) (OPE) amphiphiles, decorated with terminal glycol chains. The metal-ligating property of these molecules could be exploited to coordinate to Pd(II) and Pt(II) metal ions, respectively, resulting in the creation of novel metallosupramolecular π-amphiphiles of square-planar geometry. The focus of the presented studies is on the self-assembly behaviour of the OPE ligands and their corresponding metal complexes in polar and aqueous environment. In this way, the underlying aggregation mechanism (isodesmic or cooperative) is revealed and the influence of various factors on the self-assembly process in supramolecular systems is elucidated. In this regard, the effect of the molecular design of the ligand, the coordination to a metal centre as well as the surrounding medium, the pH value and temperature is investigated. N2 - Die vorliegende Arbeit auf dem Gebiet der Supramolekularen Chemie beschäftigt sich mit der Synthese und detaillierten Untersuchung von (bi)pyridin-basierten Oligo(phenylenethinylen) (OPE)-Amphiphilen mit endständigen Glykolketten. Die komplexierende Eigenschaft dieser Moleküle wurde ausgenutzt um sie an Pd(II) bzw. Pt(II) Metallionen zu koordinieren, wobei neuartige metallosupramolekulare π-Amphiphile von quadratisch-planarer Geometrie entstehen. Das Hauptaugenmerk der beschriebenen Studien liegt auf der Selbstorganisation der OPE-Liganden und ihrer Metallkomplexe in polarer und wässriger Umgebung. Dabei wurde der zu Grunde liegende Aggregationsmechanismus (isodesmisch oder kooperativ) bestimmt und der Einfluss verschiedener Faktoren auf den Selbstorganisationsprozess in supramolekularen Systemen aufzeigt. Neben dem Effekt des Moleküldesigns des Liganden und dessen Koordination an ein Metallzentrum wird auch der des umgebenden Mediums, des pH-Wertes sowie der Temperatur erläutert. KW - Supramolekulare Chemie KW - Selbstorganisation KW - Kooperativität KW - Aggregat KW - Amphiphile Verbindungen KW - cooperativity KW - non-covalent interactions KW - (bi)pyridine-based ligand KW - oligo(phenylene ethynylene) (OPE) KW - self-assembly KW - metallosupramolecular π-amphiphiles KW - Aggregation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133248 ER - TY - JOUR A1 - Barteit, Sandra A1 - Hoepffner, Philip A1 - Huwendiek, Sören A1 - Karamagi, Angela A1 - Munthali, Charles A1 - Theurer, Antje A1 - Neuhann, Florian T1 - Self-directed e-learning at a tertiary hospital in Malawi - a qualitative evaluation and lessons learnt JF - GMS Journal for Medical Education N2 - Background: Malawi faces a severe lack of health workers. Despite initiatives to address this problem, a critical shortage of health care staff remains. This lack challenges the education and training of junior medical staff, especially medical interns in their final and crucial training year before they independently work as medical doctors. Project description: We have introduced an e-learning platform in the medical department of the Kamuzu Central Hospital (KCH) in Malawi. With the support of computer-assisted instruction, we aimed to improve the quality of medical training and education, as well as access to current medical materials, in particular for interns. Method: From March to April 2012, we conducted a qualitative evaluation to assess relevance and appropriateness of the e-learning platform. Data was collected via face-to-face interviews, a guided group discussion and a checklist based observation log. Evaluation data was recorded and coded using content analysis, interviewees were chosen via purposive sampling. Results: E-learning proved to be technically feasible in this setting. Users considered the e-learning platform to be relevant and appropriate. Concerns were raised about sustainability, accessibility and technical infrastructure, as well as limited involvement and responsibilities of Malawian partners. Interest in e-learning was high, yet, awareness of and knowledge about the e-learning platform among potential users was low. Evaluation results indicated that further adaptions to local needs are necessary to increase usage and accessibility. Conclusions: Interview results and our project experiences showed that, in the given setting, e-learning requires commitment from local stakeholders, adequate technical infrastructure, identification and assignation of responsibilities, as well as specific adaption to local needs. T2 - Selbstgesteuertes medizinisches Lernen via E-Learning an einem Lehrkrankenhaus in Malawi: Aufbau,Erkenntnisse und Erfahrungen KW - computer-assisted instruction KW - capacity KW - multimedia, KW - ICT KW - virtual patients KW - medical Education KW - understaffed KW - teaching hospital KW - Sub-saharan Africa Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150208 N1 - Deutschsprachige Version des Artikels ab Seite 8 des Dokuments. VL - 32 IS - 1 ER - TY - THES A1 - Wiese, Katrin Evelyn T1 - Sensing supraphysiological levels of MYC : mechanisms of MIZ1-dependent MYC-induced Apoptosis in Mammary Epithelial Cells T1 - Mechanismen der MIZ1-abhängigen MYC-induzierten Apoptose in Brustepithelzellen N2 - Deregulated MYC expression contributes to cellular transformation as well as progression and maintenance of human tumours. Interestingly, in the absence of additional genetic alterations, potentially oncogenic levels of MYC sensitise cells to a variety of apoptotic stimuli. Hence, MYC-induced apoptosis has long been recognised as a major barrier against cancer development. However, it is largely unknown how cells discriminate physiological from supraphysiological levels of MYC in order to execute an appropriate biological response. The experiments described in this thesis demonstrate that induction of apoptosis in mammary epithelial cells depends on the repressive actions of MYC/MIZ1 complexes. Analysis of gene expression profiles and ChIP-sequencing experiments reveals that high levels of MYC are required to invade low-affinity binding sites and repress target genes of the serum response factor SRF. These genes are involved in cytoskeletal dynamics as well as cell adhesion processes and are likely needed to transmit survival signals to the AKT kinase. Restoration of SRF activity rescues MIZ1- dependent gene repression and increases AKT phosphorylation and downstream function. Collectively, these results indicate that association with MIZ1 leads to an expansion of MYC’s transcriptional response that allows sensing of oncogenic levels, which points towards a tumour-suppressive role for the MYC/MIZ1 complex in epithelial cells. N2 - Eine Deregulation der MYC Expression trägt entscheidend zur malignen Transformation und Progression humaner Tumoren bei. In Abwesenheit von zusätzlichen genetischen Läsionen machen potentiell onkogene MYC Proteinmengen Zellen jedoch anfällig für eine Reihe Apoptoseauslösender Reize. Daher kann MYC-induzierte Apoptose als bedeutende tumorsuppressive Maßnahme und wichtige Barriere gegen die Entstehung von Krebs betrachtet werden. Mechanistisch unklar ist allerdings wie genau Zellen physiologische von supraphysiologischen MYC-Mengen unterscheiden um adäquat darauf reagieren zu können. Die Experimente in dieser Dissertation zeigen, dass die repressive Eigenschaft von MYC/MIZ1 Komplexen für die Induktion von Apoptose in Brustepithelzellen essentiell ist. Die Analyse von Genexpressions- und ChIP-Sequenzier-Experimenten verdeutlicht, dass hohe Level an MYC benötigt werden um niedrig-affine Bindestellen im Genom zu besetzen und Zielgene des SRF (serum response factor ) Transkriptionsfaktors zu reprimieren. Diese Gene haben eine wichtige Funktion in Prozessen wie Zytoskelettdynamik und Zelladhäsion und sind vermutlich daran beteiligt notwendige Überlebenssignale an die Kinase AKT weiterzuleiten. Eine Wiederherstellung der SRF Aktivität revertiert die MIZ1-abhängige Repression der Zielgene und führt zu einer vermehrten AKT Phosphorylierung und Funktion. Insgesamt deuten diese Resultate auf eine tumorsuppressive Rolle des MYC/MIZ1 Komplexes in epithelialen Zellen hin, da eine Veränderung der genregulatorischen Aktivität als Folge der Assoziation mit MIZ1 dazu beiträgen könnte onkogene Mengen an MYC zu erkennen. KW - Myc KW - Apoptosis KW - Myc KW - Miz1 KW - Apoptose KW - Repression KW - ChIP-sequencing KW - Repression Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132532 ER - TY - JOUR A1 - Loeffler, Claudia A1 - Loeffler, Jürgen A1 - Kobsar, Anna A1 - Speer, Christian P. A1 - Eigenthaler, Martin T1 - Septic Vs Colonizing Group B Streptococci Differentially Regulate Inflammation and Apoptosis in Human Coronary Artery Endothelial Cells - a Pilot Study JF - Journal of Pediatrics and Neonatal Care N2 - In this pilot study, we exemplify differences between a septic and a colonizing GBS strain during their interaction with Endothelial Cells by evaluating cytokine levels, surface and apoptosis-related molecules. These preliminary results indicate that in vitro infection using an exemplary septic GBS strain results in diminished activation of the innate immune response. KW - streptococci KW - apoptosis KW - inflammation KW - endothelial cells KW - innate immunity KW - early onset sepsis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125596 VL - 2 IS - 2 ER - TY - JOUR A1 - Wunsch, Marie A1 - Caspell, Richard A1 - Kuerten, Stefanie A1 - Lehmann, Paul V. A1 - Sundararaman, Srividya T1 - Serial measurements of apoptotic cell numbers provide better acceptance criterion for PBMC quality than a single measurement prior to the T cell assay JF - Cells N2 - As soon as Peripheral Blood Mononuclear Cells (PBMC) are isolated from whole blood, some cells begin dying. The rate of apoptotic cell death is increased when PBMC are shipped, cryopreserved, or stored under suboptimal conditions. Apoptotic cells secrete cytokines that suppress inflammation while promoting phagocytosis. Increased numbers of apoptotic cells in PBMC may modulate T cell functions in antigen-triggered T cell assays. We assessed the effect of apoptotic bystander cells on a T cell ELISPOT assay by selectively inducing B cell apoptosis using α-CD20 mAbs. The presence of large numbers of apoptotic B cells did not affect T cell functionality. In contrast, when PBMC were stored under unfavorable conditions, leading to damage and apoptosis in the T cells as well as bystander cells, T cell functionality was greatly impaired. We observed that measuring the number of apoptotic cells before plating the PBMC into an ELISPOT assay did not reflect the extent of PBMC injury, but measuring apoptotic cell frequencies at the end of the assay did. Our data suggest that measuring the numbers of apoptotic cells prior to and post T cell assays may provide more stringent PBMC quality acceptance criteria than measurements done only prior to the start of the assay. KW - T cell assay KW - apoptosis KW - acceptance KW - viability KW - ELISPOT Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150213 VL - 4 IS - 1 ER - TY - JOUR A1 - Girschick, Hermann A1 - Wolf, Christine A1 - Morbach, Henner A1 - Hertzberg, Christoph A1 - Lee-Kirsch, Min Ae T1 - Severe immune dysregulation with neurological impairment and minor bone changes in a child with spondyloenchondrodysplasia due to two novel mutations in the ACP5 gene JF - Pediatric Rheumatology N2 - Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia, characterized by metaphyseal lesions, neurological impairment and immune dysregulation associated with lupus-like features. SPENCD is caused by biallelic mutations in the ACP5 gene encoding tartrate-resistant phosphatase. We report on a child, who presented with spasticity, multisystem inflammation, autoimmunity and immunodeficiency with minimal metaphyseal changes due to compound heterozygosity for two novel ACP5 mutations. These findings extend the phenotypic spectrum of SPENCD and indicate that ACP5 mutations can cause severe immune dysregulation and neurological impairment even in the absence of metaphyseal dysplasia. KW - resistant acid phosphatase KW - expression KW - systemic lupus erythematosus KW - cerebral calcification KW - deficiency KW - autoimmunity KW - dysplasia KW - trap KW - spondyloenchondrodysplasia KW - ACP5 KW - immunodeficiency KW - type I interferonopathy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149990 VL - 13 IS - 37 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Puskás, István A1 - Pápai, Katalin A1 - Salvador, Ellaine A1 - Roewer, Norbert A1 - Förster, Carola A1 - Broscheit, Jens-Albert T1 - Sevoflurane-sulfobutylether-\(\beta\)-cyclodextrin complex: preparation, characterization, cellular toxicity, molecular modeling and blood-brain barrier transport studies JF - Molecules N2 - The objective of the present investigation was to study the ability of sulfobutylether-\(\beta\)-cyclodextrin (SBECD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBE\(\beta\)CD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (P\(_{app}\)). In addition, SEV binding affinity to SBE\(\beta\)CD was confirmed by a minimal Gibbs free energy of binding (ΔG\(_{bind}\)) value of -1.727 ± 0.042 kcal・mol\(^{-1}\) and an average binding constant (K\(_{b}\)) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity. KW - pharmaceutical applications KW - in vitro KW - propranolol KW - water KW - primary microvascular endothelial cells KW - molecular liphophilicity potential KW - molecular docking KW - blood-brain barrier KW - ulfobutylether-\(\beta\)-cyclodextrin KW - sevoflurane KW - cyclodextrin formulations KW - safety KW - etomidate KW - formulations KW - hydrochloride KW - ether KW - intestinal absorption Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148543 VL - 20 ER - TY - JOUR A1 - Tuchscherr, Lorena A1 - Bischoff, Markus A1 - Lattar, Santiago M. A1 - Noto Llana, Mariangeles A1 - Pförtner, Henrike A1 - Niemann, Silke A1 - Geraci, Jennifer A1 - Van de Vyver, Hélène A1 - Fraunholz, Martin J. A1 - Cheung, Ambrose L. A1 - Herrmann, Mathias A1 - Völker, Uwe A1 - Sordelli, Daniel O. A1 - Peters, Georg A1 - Loeffler, Bettina T1 - Sigma factor SigB is crucial to mediate Staphylococcus aureus adaptation during chronic infections JF - PLoS Pathogens N2 - Staphylococcus aureus is a major human pathogen that causes a range of infections from acute invasive to chronic and difficult-to-treat. Infection strategies associated with persisting S. aureus infections are bacterial host cell invasion and the bacterial ability to dynamically change phenotypes from the aggressive wild-type to small colony variants (SCVs), which are adapted for intracellular long-term persistence. The underlying mechanisms of the bacterial switching and adaptation mechanisms appear to be very dynamic, but are largely unknown. Here, we analyzed the role and the crosstalk of the global S. aureus regulators agr, sarA and SigB by generating single, double and triple mutants, and testing them with proteome analysis and in different in vitro and in vivo infection models. We were able to demonstrate that SigB is the crucial factor for adaptation in chronic infections. During acute infection, the bacteria require the simultaneous action of the agr and sarA loci to defend against invading immune cells by causing inflammation and cytotoxicity and to escape from phagosomes in their host cells that enable them to settle an infection at high bacterial density. To persist intracellularly the bacteria subsequently need to silence agr and sarA. Indeed agr and sarA deletion mutants expressed a much lower number of virulence factors and could persist at high numbers intracellularly. SigB plays a crucial function to promote bacterial intracellular persistence. In fact, \(\Delta\)sigB-mutants did not generate SCVs and were completely cleared by the host cells within a few days. In this study we identified SigB as an essential factor that enables the bacteria to switch from the highly aggressive phenotype that settles an acute infection to a silent SCV-phenotype that allows for long-term intracellular persistence. Consequently, the SigB-operon represents a possible target to develop preventive and therapeutic strategies against chronic and therapy-refractory infections. KW - gene regulator agr KW - endothelial cells KW - modulates virulence KW - death pathway sar locus KW - factor B KW - small-colony variants KW - alpha-toxin KW - epithelial cells KW - in vitro Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143419 VL - 11 IS - 4 ER - TY - JOUR A1 - Okoro, Chinyere K. A1 - Barquist, Lars A1 - Connor, Thomas R. A1 - Harris, Simon R. A1 - Clare, Simon A1 - Stevens, Mark P. A1 - Arends, Mark J. A1 - Hale, Christine A1 - Kane, Leanne A1 - Pickard, Derek J. A1 - Hill, Jennifer A1 - Harcourt, Katherine A1 - Parkhill, Julian A1 - Dougan, Gordon A1 - Kingsley, Robert A. T1 - Signatures of adaptation in human invasive Salmonella Typhimurium ST313 populations from sub-Saharan Africa JF - PLoS Neglected Tropical Diseases N2 - Two lineages of Salmonella enterica serovar Typhimurium (S. Typhimurium) of multi-locus sequence type ST313 have been linked with the emergence of invasive Salmonella disease across sub-Saharan Africa. The expansion of these lineages has a temporal association with the HIV pandemic and antibiotic usage. We analysed the whole genome sequence of 129 ST313 isolates representative of the two lineages and found evidence of lineage-specific genome degradation, with some similarities to that observed in S. Typhi. Individual ST313 S. Typhimurium isolates exhibit a distinct metabolic signature and modified enteropathogenesis in both a murine and cattle model of colitis, compared to S. Typhimurium outside of the ST313 lineages. These data define phenotypes that distinguish ST313 isolates from other S. Typhimurium and may represent adaptation to a distinct pathogenesis and lifestyle linked to an-immuno-compromised human population. KW - genome sequence KW - infection KW - pathogenicity KW - children KW - disease KW - adults KW - identification KW - Escherichia coli KW - virulence Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143779 VL - 9 IS - 3 ER - TY - JOUR A1 - Eden, Lars A1 - Ziegler, Dirk A1 - Gilbert, Fabian A1 - Fehske, Kai A1 - Fenwick, Annabel A1 - Meffert, Rainer H. T1 - Significant pain reduction and improved functional outcome after surgery for displaced midshaft clavicular fractures JF - Journal of Orthopaedic Surgery and Research N2 - Purpose Displaced midshaft clavicular fractures can be treated conservatively as well as operatively by titan elastic nail (TEN) or plate fixation. This survey was performed to evaluate the clinical results of each treatment method and elaborate advantages or possible complications of each modality. Methods Between 2008 and 2013, 102 patients were prospectively included in our study—37 patients for conservative treatment with a rucksack bandage for 4 to 6 weeks, 41 patients for plate osteosynthesis, and 24 for intramedullary stabilization with TEN. Disabilities of the Arm, Shoulder and Hand (DASH), Constant Murley Score (CMS), and visual analog scale (VAS) for pain and function as well as time of invalidity were recorded over a 1-year period. Results The clinical data collected reveals that all three different therapies lead to good or excellent clinical results after 1 year. However, one can observe advantages of operative treatment in comparison to conservative therapy in some characteristics. Conclusion Our data shows that there are several indications where operative treatment has advantages compared to conservative treatment. In special fracture types (Robinson 2B1), TEN gives the best results. Plate fixation is extraordinarily sufficient in pain reduction within the first 5 weeks and indicated in more-part fractures (Robinson 2B2). Nevertheless, conservative treatment is always a good and promising way to treat clavicular fractures, so that individual indications and thorough patient informative talks are inevitable. KW - clavicular fracture KW - TEN KW - AS clavicle plate KW - LCP KW - reconstruction plates Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146357 VL - 10 IS - 190 ER - TY - JOUR A1 - Alizadehrad, Davod A1 - Krüger, Timothy A1 - Engstler, Markus A1 - Stark, Holger T1 - Simulating the complex cell design of Trypanosoma brucei and its motility JF - PLOS Computational Biology N2 - The flagellate Trypanosoma brucei, which causes the sleeping sickness when infecting a mammalian host, goes through an intricate life cycle. It has a rather complex propulsion mechanism and swims in diverse microenvironments. These continuously exert selective pressure, to which the trypanosome adjusts with its architecture and behavior. As a result, the trypanosome assumes a diversity of complex morphotypes during its life cycle. However, although cell biology has detailed form and function of most of them, experimental data on the dynamic behavior and development of most morphotypes is lacking. Here we show that simulation science can predict intermediate cell designs by conducting specific and controlled modifications of an accurate, nature-inspired cell model, which we developed using information from live cell analyses. The cell models account for several important characteristics of the real trypanosomal morphotypes, such as the geometry and elastic properties of the cell body, and their swimming mechanism using an eukaryotic flagellum. We introduce an elastic network model for the cell body, including bending rigidity and simulate swimming in a fluid environment, using the mesoscale simulation technique called multi-particle collision dynamics. The in silico trypanosome of the bloodstream form displays the characteristic in vivo rotational and translational motility pattern that is crucial for survival and virulence in the vertebrate host. Moreover, our model accurately simulates the trypanosome's tumbling and backward motion. We show that the distinctive course of the attached flagellum around the cell body is one important aspect to produce the observed swimming behavior in a viscous fluid, and also required to reach the maximal swimming velocity. Changing details of the flagellar attachment generates less efficient swimmers. We also simulate different morphotypes that occur during the parasite's development in the tsetse fly, and predict a flagellar course we have not been able to measure in experiments so far. KW - multiparticle collision dynamics KW - human african trypanosomiasis KW - biology KW - cytoskeleton KW - flow KW - flagellar motility KW - tsetse fly KW - propulsion KW - cytokinesis KW - parasites Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144610 VL - 11 IS - 1 ER - TY - JOUR A1 - Kurrek, Matt M. A1 - Morgan, Pamela A1 - Howard, Steven A1 - Kranke, Peter A1 - Calhoun, Aaron A1 - Hui, Joshua A1 - Kiss, Alex T1 - Simulation as a New Tool to Establish Benchmark Outcome Measures in Obstetrics JF - PLoS ONE N2 - Background There are not enough clinical data from rare critical events to calculate statistics to decide if the management of actual events might be below what could reasonably be expected (i.e. was an outlier). Objectives In this project we used simulation to describe the distribution of management times as an approach to decide if the management of a simulated obstetrical crisis scenario could be considered an outlier. Design Twelve obstetrical teams managed 4 scenarios that were previously developed. Relevant outcome variables were defined by expert consensus. The distribution of the response times from the teams who performed the respective intervention was graphically displayed and median and quartiles calculated using rank order statistics. Results Only 7 of the 12 teams performed chest compressions during the arrest following the 'cannot intubate/cannot ventilate' scenario. All other outcome measures were performed by at least 11 of the 12 teams. Calculation of medians and quartiles with 95% CI was possible for all outcomes. Confidence intervals, given the small sample size, were large. Conclusion We demonstrated the use of simulation to calculate quantiles for management times of critical event. This approach could assist in deciding if a given performance could be considered normal and also point to aspects of care that seem to pose particular challenges as evidenced by a large number of teams not performing the expected maneuver. However sufficiently large sample sizes (i.e. from a national data base) will be required to calculate acceptable confidence intervals and to establish actual tolerance limits. KW - performance KW - anesthesiologists Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151646 VL - 10 IS - 6 ER - TY - THES A1 - Kurrek, Matthias M. T1 - Simulation To Establish Benchmark Outcome Measures T1 - Simulation zur Erstellung von Benchmarks für Outcomes N2 - Following the early experiences in aviation, medical simulation has rapidly evolved into one of the most novel educational tools of the last three decades. In addition to its use in training individuals or teams in crisis resource management, simulation has been studied as a tool to evaluate technical and non-technical skills of individuals as well as, more recently, entire medical teams. It is usually fairly difficult to obtain clinical reference data from critical events to refute claims that the management of actual events fell below what could reasonably be expected and we demonstrated the use of rank order statistics to calculate quantiles with confidence limits for management times of critical obstetrical events using data from realistic simulation. This approach could be used to describe the distribution of treatment times in order to assist in deciding what performance may constitute an outlier. It can also identify particular challenges of clinical practice and allow the development of educational curricula. While the information derived from simulation has to be interpreted with a high degree of caution for a clinical context, it may represent a further ‘added value’ or important step in establishing simulation as a training tool and to provide information that could be used in an appropriate clinical context for adverse events. Large amounts of data (such as from a simulation registry) would allow the calculation of acceptable confidence intervals for the required outcome parameters as well as actual tolerance limits. N2 - Es ist auf Grund der Rarität von vielen Notfällen normalerweise nicht möglich genug klinische Daten zur Auswertung zur Verfügung zu haben, um sagen zu können, ob das Management eines bestimmten Falles innerhalb von ‚normalen’ Grenzwerten fällt. In dieser wissenschaftlichen Arbeit zeigten wir das ‚Rank Order Statistiks’ dafür benutzt werden könnten, die Resultate von simulierten Notfällen in der Geburtshilfe als Bandbreite von ‚normalen’ klinischen Leistungen darzustellen. Dieses Vorgehen würde es erlauben, eine klinische Leistung mit einer Datenbank von vergleichbaren simulierten Zwischenfällen abzugleichen, um entscheiden zu können, ob die klinische Leistung innerhalb von ‚normalen’ Werten ausgefallen ist. Dieses Vorgehen verschafft außerdem Einblick, welche Probleme besondere Schwierigkeiten bereiten sodass ggf. gezielte Fortbildungen vorbereitet werden könnten. Obwohl die Daten der Simulation mit gewisser Vorsicht zu interpretieren sind, repräsentiert dieses Vorgehen eine neue Anwendung von Simulation, die für die Auswertung von klinischen Notfällen von großer Bedeutung sein könnte. Es wird in diesem Zusammenhang allerdings notwendig sein, relativ große Datenbanken von vielen simulierten Notfällen zu erstellen und auszuwerten, um die gesuchten Werte mit genug Genauigkeit kalkulieren zu können. KW - Simulation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143882 ER - TY - JOUR A1 - Kuger, Sebastian A1 - Flentje, Michael A1 - Djuzenova, Cholpon S. T1 - Simultaneous perturbation of the MAPK and the PI3K/mTOR pathways does not lead to increased radiosensitization JF - Radiation Oncology N2 - Background The mitogen-activated protein kinases (MAPK) and the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are intertwined on various levels and simultaneous inhibition reduces tumorsize and prolonges survival synergistically. Furthermore, inhibiting these pathways radiosensitized cancer cells in various studies. To assess, if phenotypic changes after perturbations of this signaling network depend on the genetic background, we integrated a time series of the signaling data with phenotypic data after simultaneous MAPK/ERK kinase (MEK) and PI3K/mTOR inhibition and ionizing radiation (IR). Methods The MEK inhibitor AZD6244 and the dual PI3K/mTOR inhibitor NVP-BEZ235 were tested in glioblastoma and lung carcinoma cells, which differ in their mutational status in the MAPK and the PI3K/mTOR pathways. Effects of AZD6244 and NVP-BEZ235 on the proliferation were assessed using an ATP assay. Drug treatment and IR effects on the signaling network were analyzed in a time-dependent manner along with measurements of phenotypic changes in the colony forming ability, apoptosis, autophagy or cell cycle. Results Both inhibitors reduced the tumor cell proliferation in a dose-dependent manner, with NVP-BEZ235 revealing the higher anti-proliferative potential. Our Western blot data indicated that AZD6244 and NVP-BEZ235 perturbed the MAPK and PI3K/mTOR signaling cascades, respectively. Additionally, we confirmed crosstalks and feedback loops in the pathways. As shown by colony forming assay, the AZD6244 moderately radiosensitized cancer cells, whereas NVP-BEZ235 caused a stronger radiosensitization. Combining both drugs did not enhance the NVP-BEZ235-mediated radiosensitization. Both inhibitors caused a cell cycle arrest in the G1-phase, whereas concomitant IR and treatment with the inhibitors resulted in cell line- and drug-specific cell cycle alterations. Furthermore, combining both inhibitors synergistically enhanced a G1-phase arrest in sham-irradiated glioblastoma cells and induced apoptosis and autophagy in both cell lines. Conclusion Perturbations of the MEK and the PI3K pathway radiosensitized tumor cells of different origins and the combination of AZD6244 and NVP-BEZ235 yielded cytostatic effects in several tumor entities. However, this is the first study assessing, if the combination of both drugs also results in synergistic effects in terms of radiosensitivity. Our study demonstrates that simultaneous treatment with both pathway inhibitors does not lead to synergistic radiosensitization but causes cell line-specific effects. KW - autophagy KW - radiosensitivity KW - NVP-BEZ235 KW - AZD6244 KW - cell cycle arrest KW - apoptosis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126104 VL - 10 IS - 214 ER - TY - JOUR A1 - He, Tao A1 - Stolte, Matthias A1 - Burschka, Christian A1 - Hansen, Nis Hauke A1 - Musiol, Thomas A1 - Kälblein, Daniel A1 - Pflaum, Jens A1 - Tao, Xutang A1 - Brill, Jochen A1 - Würthner, Frank T1 - Single-crystal field-effect transistors of new Cl\(_{2}\)-NDI polymorph processed by sublimation in air JF - Nature Communications N2 - Physical properties of active materials built up from small molecules are dictated by their molecular packing in the solid state. Here we demonstrate for the first time the growth of n-channel single-crystal field-effect transistors and organic thin-film transistors by sublimation of 2,6-dichloro-naphthalene diimide in air. Under these conditions, a new polymorph with two-dimensional brick-wall packing mode (\(\beta\)-phase) is obtained that is distinguished from the previously reported herringbone packing motif obtained from solution (\(\alpha\)-phase). We are able to fabricate single-crystal field-effect transistors with electron mobilities in air of up to 8.6 cm\(^{2}\)V\(^{-1}\)s\(^{-1}\) (\(\alpha\)-phase) and up to 3.5 cm\(^{2}\)V\(^{-1}\)s\(^{-1}\) (\(\beta\)-phase) on n-octadecyltriethoxysilane-modified substrates. On silicon dioxide, thin-film devices based on \(\beta\)-phase can be manufactured in air giving rise to electron mobilities of 0.37 cm\(^{2}\)V\(^{-1}\)s\(^{-1}\). The simple crystal and thin-film growth procedures by sublimation under ambient conditions avoid elaborate substrate modifications and costly vacuum equipment-based fabrication steps. KW - thin-film transistors KW - carrier transport KW - \(\beta\)-phase KW - organic semiconductors KW - induced phase transition KW - charge transport KW - materials design KW - \(\alpha\)-phase KW - mobility KW - pentacene Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149255 VL - 6 IS - 5954 ER - TY - JOUR A1 - Boelch, S. P. A1 - Jansen, H. A1 - Meffert, R. H. A1 - Frey, S. P. T1 - Six Sesamoid Bones on Both Feet: Report of a Rare Case JF - Journal of Clinical and Diagnostic Research N2 - There is a variation of the total number of distinct bones in the human in the literature. This difference is mainly caused by the variable existence of sesamoid bones. Sesamoid bones at the first MTP are seen regularly. In contrast additional sesamoid bones at the divond to fifth MTP are rare. We report a case of additional sesamoid bones at every metatarsophalangeal joint (MTP) of both feet. A 22-year-old female Caucasian presented with weight-dependent pain of the divond MTP of the left foot. In the radiographs of both feet additional sesamoid bones at every MTP could be seen. This case reports a very rare variation in human anatomy. A similar case has not been displayed to the academic society and therefore should be acknowledged. KW - anatomy KW - genetics KW - variation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126073 VL - 9 IS - 8 ER - TY - JOUR A1 - Merget, Benjamin A1 - Sotriffer, Christoph A. T1 - Slow-Onset Inhibition of Mycobacterium tuberculosis InhA: Revealing Molecular Determinants of Residence Time by MD Simulations JF - PLoS One N2 - An important kinetic parameter for drug efficacy is the residence time of a compound at a drug target, which is related to the dissociation rate constant koff. For the essential antimycobacterial target InhA, this parameter is most likely governed by the ordering of the flexible substrate binding loop (SBL). Whereas the diphenyl ether inhibitors 6PP and triclosan (TCL) do not show loop ordering and thus, no slow-binding inhibition and high koff values, the slightly modified PT70 leads to an ordered loop and a residence time of 24 minutes. To assess the structural differences of the complexes from a dynamic point of view, molecular dynamics (MD) simulations with a total sampling time of 3.0 µs were performed for three ligand-bound and two ligand-free (perturbed) InhA systems. The individual simulations show comparable conformational features with respect to both the binding pocket and the SBL, allowing to define five recurring conformational families. Based on their different occurrence frequencies in the simulated systems, the conformational preferences could be linked to structural differences of the respective ligands to reveal important determinants of residence time. The most abundant conformation besides the stable EI* state is characterized by a shift of Ile202 and Val203 toward the hydrophobic pocket of InhA. The analyses revealed potential directions for avoiding this conformational change and, thus, hindering rapid dissociation: (1) an anchor group in 2'-position of the B-ring for scaffold stabilization, (2) proper occupation of the hydrophobic pocket, and (3) the introduction of a barricade substituent in 5'-position of the diphenyl ether B-ring. KW - crystal structure KW - ethers KW - oxygen KW - cofactors (biochemistry) KW - binding analysis KW - biochemical simulations KW - hydrogen bonding mycobacterium tuberculosis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125607 VL - 10 IS - 5 ER - TY - JOUR A1 - Herter, Eva K. A1 - Stauch, Maria A1 - Gallant, Maria A1 - Wolf, Elmar A1 - Raabe, Thomas A1 - Gallant, Peter T1 - snoRNAs are a novel class of biologically relevant Myc targets JF - BMC Biology N2 - Background Myc proteins are essential regulators of animal growth during normal development, and their deregulation is one of the main driving factors of human malignancies. They function as transcription factors that (in vertebrates) control many growth- and proliferation-associated genes, and in some contexts contribute to global gene regulation. Results We combine chromatin immunoprecipitation-sequencing (ChIPseq) and RNAseq approaches in Drosophila tissue culture cells to identify a core set of less than 500 Myc target genes, whose salient function resides in the control of ribosome biogenesis. Among these genes we find the non-coding snoRNA genes as a large novel class of Myc targets. All assayed snoRNAs are affected by Myc, and many of them are subject to direct transcriptional activation by Myc, both in Drosophila and in vertebrates. The loss of snoRNAs impairs growth during normal development, whereas their overexpression increases tumor mass in a model for neuronal tumors. Conclusions This work shows that Myc acts as a master regulator of snoRNP biogenesis. In addition, in combination with recent observations of snoRNA involvement in human cancer, it raises the possibility that Myc’s transforming effects are partially mediated by this class of non-coding transcripts. KW - Drosophila KW - ribosome KW - snoRNA KW - Myc Transcription KW - growth Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124956 VL - 13 IS - 25 ER - TY - THES A1 - Meyer, Frank T1 - Soft X-ray Spectroscopic Study of Amino Acid and Salt Solutions T1 - Weichröntgenspektroskopische Untersuchungen von Aminosäuren und Salzen in wässriger Lösung N2 - This thesis focuses on the investigation of the electronic structure of amino acids and salts in aqueous solution using X-ray spectroscopic methods. Both material groups are of fundamental importance with regards to many physiological reactions, especially for the Hofmeister effect which describes the solubility of proteins in salt solutions. Hence, the investigation of the electronic structure of amino acids and the influence of ions on the hydrogen bonding network of liquid water are important milestones to a deeper understanding of the Hofmeister series. Besides investigating the electronic structure of amino acids in aqueous solution, the spectra were used to develop a building block model of the spectral fingerprints of the functional groups and were compared to spectral signatures of suitable reference molecules. In the framework of this thesis, it is shown that the building block approach is a useful tool with allows the interpretation of spectral signatures of considerably more complex molecules In this work, the focus lies on the investigation of the occupied and unoccupied electronic states of molecules in solid state, as well as in aqueous solution. Hereby, different X-ray spectroscopic methods were applied. X-ray emission spectroscopy (XES) was used to probe the occupied electronic structure of the solution, while the unoccupied electronic structure was addressed by using X-ray absorption spectroscopy (XAS). Finally, resonant inelastic X-ray scattering (RIXS) as a combination of XAS and XES measurements provides the combined information about the unoccupied and occupied molecular levels. The element specific character of the three measurement methods is a feature which allows the investigation of the local electronic structure of a single functional group. With RIXS, also non-equivalent atoms of the same element can be addressed separately. Within this thesis firstly, a library of the XE spectra of all 20 proteinogenic amino acids in zwitterionic form is presented. From this sample-set XES fingerprints of the protonated alpha-amino group NH3+ and the deprotonated carboxylic group COO- were evaluated and used to identify the XES fingerprints of the nitrogen and oxygen containing functional groups of the side chains of the amino acids. The data is discussed based on a building block approach. Furthermore, the XE spectra of the functional groups of lysine and histidine, namely the NH2 group and the C3N2H4 ring structure, are both compared to XE spectra of suitable reference molecules (imidazole, ammonia and methylamine). It is found that the XE and RIXS spectra of the side chains of lysine and histidine show large similarities to the XE spectra of the reference molecules. This agreement in the XE and RIXS spectra allows a qualitative investigation of XE and RIXS spectra of more complex amino acids using the XE and RIXS spectra of suitable reference molecules. The chemical structure of histidine and proline is quite different from the structures of the other proteinogenic amino acids. Due to the unique chemical structure of the side chain which in both cases consists of a heterocyclic ring structure, these two amino acids were investigated in more detail. Zubavichus et al. [1] have shown that amino acids are decomposing while exposed to X-ray radiation of the experiment. The damage is irreversible and molecular fragments can adsorb on the membrane of the experimental setup. This contamination can also create a spectral signature which then overlaps with the signal of the solution and which complicates the interpretation of the data. To record spectra which are free from contributions of adsorbed molecular fragments on the membrane, the adsorption behavior was investigated. In contrast to the solid phase in which the amino acids are present as salts in one electronic conformation, the charge state of the amino acids can be manipulated in aqueous solution by tuning the pH-value. By doing this, all possible charge states are accessible (cation, anion, zwitterion). In this work it is shown that also the spectra of the different charge states can be modeled by the spectra of suitable reference molecules using the building block approach. The spectral changes occurring upon protonation and deprotonation of the functional groups are explored and verified by comparing them to theoretical calculations. The comparison with measurements of pyrrolidine show that the electronic structure which surrounds the nitrogen atom of proline is strongly influenced by the ring structure of the side chain. Furthermore, the proline, pyrrolidine, and histidine molecules are also degrading during the liquid sample measurements. This can be observed by the detection of a new spectral component which increases with the measurement time originating from the window membrane. In all cases, the speed of the agglomeration of molecular fragments at the membrane was observed to be highly sensitive to the pH value of the solution. To understand the Hofmeister series, also the impact of the salt ions have to be investigated. In this study the influence of potassium chloride (KCl) on the hydrogen bond network of water was studied by using non-resonantly excited XES as well as RIXS. A decreased dissociation of hydrogen molecules and changes in the molecular vibrations could be detected. These changes were interpreted with a molecular reorganization of the water molecules and a decreased number of hydrogen bonds. N2 - Im Rahmen dieser Arbeit werden Untersuchungen zur elektronischen Struktur von verschiedenen Aminosäuren sowohl in wässriger Lösung als auch als Festkörper präsentiert. Das Hauptaugenmerk liegt hierbei auf dem Erlangen eines fundamentalen Verständnisses über die elektronische Struktur der Aminosäuren in wässriger Lösung und der Entwicklung eines Baukastenprinzips für die qualitative Analyse der Röntgenemissions- und resonanten inelastischen Röntgenstreuungsspektren. In dieser Arbeit wird neben Aminosäuren auch der Einfluss von Salzionen auf das dynamische Wasserstoffbrückenbindungsnetzwerk des flüssigen Wassers untersucht. Beide Aspekte stellen wichtige Zwischenschritte auf dem Weg zu einem detaillierten Verständnis des Hofmeister-Effekts dar. In dieser Arbeit wurden röntgenspektroskopische Methoden verwendet, um die besetzten und unbesetzten Zustände der Moleküle sowohl im Festkörper als auch in wässriger Lösung zu untersuchen. Angewandt wurde dabei die Röntgenabsorptionsspektroskopie (XAS), welche die Untersuchung der unbesetzten Zustände erlaubt. Im Gegensatz dazu liefert die Röntgenemissionsspektroskopie (XES) Informationen über die besetzten Zustände. Die resonante inelastische Röntgenstreuung (RIXS) vereint diese beiden Techniken und enthält Informationen über die gesamte elektronische Struktur eines Systems. Der elementspezifische Charakter dieser Messmethoden muss dabei gesondert hervorgehoben werden, denn dadurch ist es möglich die lokale elektronische Struktur unterschiedlicher funktioneller Gruppen getrennt voneinander zu untersuchen. Im Rahmen dieser Arbeit wurde zunächst eine Bibliothek der XES-Spektren der zwanzig proteinogenen Aminosäuren angelegt. Daraus konnten spektrale Fingerabdrücke der einzelnen funktionellen Gruppen und der Stickstoff und Sauerstoff enthaltenden Seitenketten der Aminosäuren erstellt werden. Die Spektren der einzelnen funktionellen Gruppen von Lysin und Histidin wurden in einem zweiten Schritt mit den Spektren von kleineren Molekülen, welche die pure funktionelle Gruppe repräsentieren, verglichen. Durch die sehr gute Übereinstimmung konnte gezeigt werden, dass die Röntgenemissionsspektren der untersuchten Aminosäuren nach einem Baukastenprinzip durch die Spektren der kleineren und dadurch einfacheren Referenzmoleküle beschrieben werden können. Mit Hilfe dieses Baukastenprinzips wurde im weiteren Verlauf dieser Arbeit die detaillierte Untersuchung der elektronischen Struktur der Aminosäuren Prolin und Histidin möglich. Die Aminosäuren Histidin und Prolin wurden dabei wegen ihrer speziellen chemischen Struktur, welche sich durch eine Ringstruktur an der Seitenkette von der chemischen Struktur der restlichen Aminosäuren unterscheidet, für eine genauere Untersuchung ausgewählt. Sowohl Prolin als auch Histidin werden durch die starke Röntgenstrahlung während des Experiments irreparabel beschädigt, wodurch sich die spektrale Signatur der Moleküle sehr stark ändert. Um diese Beschädigungen zu erkennen und zu vermeiden wurden die Veränderungen der Spektren in Abhängigkeit der Belichtungszeit dokumentiert. Neben Festkörpermessungen, bei welchen die Aminosäuren nur in einer einzigen Konfiguration vorhanden sind (zwitterionisch), wurden die Aminosäuren auch in ihrer natürlichen Umgebung, der wässrigen Lösung, untersucht. Durch die Variation des pH-Wertes der Lösung kann die Konfiguration und damit die elektronische Struktur geändert werden (Kation, Anion, Zwitterion). Eine starke Veränderung in den Spektren in Abhängigkeit des pH-Wertes konnte festgestellt werden. Dabei fällt auf, dass die elektronische Struktur des Stickstoffs in der Aminosäure Prolin sehr stark durch die Ringstruktur der Seitenkette beeinflusst wird, was durch den Vergleich des Spektrums mit dem Spektrum des Pyrrolidin Moleküls gezeigt wurde. Des Weiteren konnte sowohl bei den Flüssigexperimenten mit Prolin als auch mit Histidin eine Kontamination der Membran festgestellt werden, welche durch Molekülfragmente entsteht. Dieser Kontaminierungsprozess konnte für Prolin und Histidin vor allem bei neutralem und hohem pH-Wert beobachtet werden. Dennoch konnten durch das Baukastenprinzip und die Untersuchungen der Referenzmoleküle Imidazol und Pyrrolidin Erkenntnisse über die elektronische Struktur von Histidin und Prolin gewonnen werden. Mit Hilfe der resonanten inelastischen Röntgenstreuung konnten die spektralen Fingerabdrücke der beiden nicht äquivalenten Stickstoffatome des Imidazols experimentell voneinander getrennt werden. Des Weiteren wurden innerhalb der RIXS-Spektren starke resonante Einflüsse beobachtet. Mit Hilfe von berechneten Spektren von isolierten Imidazol und Imidazolium Molekülen konnten die spektralen Signaturen sowohl im nicht resonanten Spektrum als auch im resonanten Spektrum erklärt werden und im Einzelnen auf die Struktur der Valenzorbitale zurückgeführt werden. Auf dem Weg zum Verständnis des Hofmeister-Effekts ist neben den Aminosäuren natürlich auch der Einfluss von Salzen auf die Lösung zu berücksichtigen. Im letzten Teil dieser Arbeit stehen daher die Auswirkungen der Ionen des Kaliumchlorids auf das Röntgenemissionsspektrum des Wassers im Fokus. Dazu wurden KCl Lösungen verschiedener Konzentrationen untersucht. Durch die Zugabe von Salz konnte eine Umorientierung der Wassermoleküle und des damit verbundenen Netzwerks von Wasserstoffbrückenbindungen beobachtet werden. KW - Aminosäuren KW - Elektronenstruktur KW - Röntgenspektroskopie KW - RIXS KW - resonant inelastic x-ray scattering KW - amino acids KW - aqueous solution KW - electronic structure KW - salt solutions KW - Elektronenstruktur KW - Röntgenspektroskopie KW - Salzlösung Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124295 ER - TY - THES A1 - Bruttel, Valentin Stefan T1 - Soluble HLA-G binds to dendritic cells which likely suppresses anti-tumour immune responses in regional lymph nodes in ovarian carcinoma T1 - Lösliches HLA-G wird von dendritischen Zellen gebunden, was beim Ovarialkarzinom zur Hemmung von Immunraktionen in regionalen Lymphknoten führen kann N2 - Zusammenfassung Einleitung HLA-G, ein nicht-klassisches HLA bzw. MHC Klasse Ib Molekül, kann sowohl als membrangebundenes als auch als lösliches Molekül verschiedenste Immunzellpopulationen effektiv inhibieren. Unter physiologischen Bedingungen wird HLA-G vor allem in der Plazenta exprimiert, wo es dazu beiträgt den semiallogenen Embryo vor einer Abstoßung durch das mütterliche Immunsystem zu beschützen. Außerdem wird HLA-G in einer Vielzahl von Tumoren wie zum Beispiel in Ovarialkarzinomen überexprimiert. Ziel dieser Arbeit war es besonders die Rolle von löslichem HLA-G im Ovarialkarzinom und die Expression von HLA-G in verschiedenen Subtypen des Ovarialkarzinoms genauer zu untersuchen. Ergebnisse Anhand eines Tissue Microarrays wurde bestätigt dass HLA-G unter physiologischen Bedingungen nur in sehr wenigen Geweben wie Plazenta oder Testes exprimiert wird. Außerdem wurden erstmals auch im Nebennierenmark hohe Expressionslevel detektiert. Im Gegensatz zur physiologischen Expression wurde HLA-G in serösen, muzinösen, endometrioiden und Klarzellkarzinomen und somit in Tumoren aller untersuchten Subtypen des Ovarialkarzinoms detektiert. Am häufigsten war HLA-G in hochgradigen serösen Karzinomen überexprimiert. Hier konnte gezeigt werden dass auf Genexpressionslevel in Ovarialkarzinomen die Expression des immunsuppressiven HLA-G mit der Expression von klassischen MHC Molekülen wie HLA-A, -B oder -C hochsignifikant korreliert. Außerdem konnte in Aszitesproben von Patientinnen mit Ovarialkarzinomen hohe Konzentrationen von löslichem HLA-G nachgewiesen werden. Auch auf metastasierten Tumorzellen in regionalen Lymphknoten war HLA-G nachweisbar. Überraschenderweise wurde aber besonders viel HLA-G auf Dendritischen Zellen in Lymphknoten detektiert. Da in Monozyten und Dendritischen Zellen von gesunden Spendern durch IL-4 oder IL-10 im Gegensatz zu Literatur keine Expression von HLA-G induzierbar war, untersuchten wir ob Dendritische Zellen lösliches HLA-G binden. Es konnte gezeigt werden, dass besonders Dendritische Zellen die in Gegenwart von IL-4, IL-10 und GM-CSF aus Monozyten generiert wurden (DC-10) effektiv lösliches HLA-G über ILT Rezeptoren binden. In Abhängigkeit von ihrer Beladung mit HLA-G hemmen auch fixierte DC-10 Zellen noch die Proliferation von zytotoxischen CD8+ T Zellen. Zudem wurden regulatorische T Zellen induziert. Schlussfolgerungen Besonders in den am häufigsten diagnostizierten hochgradigen serösen Ovarialkarzinomen ist HLA-G in den meisten Fällen überexprimiert. Durch die Expression immunsuppressiver MHC Klasse Ib Moleküle wie HLA-G können wahrscheinlich auch Tumore wachsen, die noch klassische MHC Moleküle exprimieren und aufgrund ihrer Mutationslast eigentlich vom Immunsystem erkannt und eliminiert werden müssten. Lösliches HLA-G könnte zudem lokal Immunantworten gegen Tumorantigene unterdrücken indem es an Dendritische Zellen in regionalen Lymphknoten bindet. Diese Zellen präsentieren nomalerweise zytotoxischen T Zellen Tumorantigene und spielen daher eine entscheidende Rolle in der Entstehung von protektiven Immunantworten. Mit löslichem HLA-G beladene Dendritische Zellen hemmen jedoch die Proliferation von CD8+ T Zellen und induzieren regulatorische T Zellen. Dadurch könnten Ovarialkarzinome “aus der Ferne” auch in metastasenfreien Lymphknoten die Entstehung von gegen den Tumor gerichteten Immunantworten unterdrücken. Dieser erstmals beschriebene Mechanismus könnte auch in anderen malignen Erkrankungen eine Rolle spielen, da lösliches HLA-G in einer Vielzahl von Tumorindikationen nachgewiesen wurde. N2 - Abstract Background HLA-G is a non-classical MHC class I molecule which exerts strong immunosuppressive effects on various immune cells. Several membrane-bound and soluble isoforms are known. Physiologically, HLA-G is predominantly expressed in the placenta, where it contributes to protecting the semi-allogeneic embryo from rejection by the maternal immune system. However, HLA-G is also often upregulated during tumourigenesis, such as in ovarian cancer. The aim of this thesis is to investigate how soluble HLA-G may contribute to local immunosuppression in ovarian carcinomas, and to characterize HLA-G expression in different ovarian carcinoma subtypes and metastases. Results As reported by others, physiological HLA-G expression is restricted to few tissues, such as placenta and testes. Here, HLA-G was also detected in the medulla of the adrenal gland. In contrast, HLA-G expression was frequently detected in tumours of all assessed subtypes of ovarian carcinomas (serous, mucinous, endometrioid and clear cell). Highest expression levels were detected in high-grade serous carcinomas. In primary tumours, expression of HLA-G correlated with expression of classical MHC class I molecules HLA-A, -B and -C. Surprisingly, high levels of HLA-G were also detected on dendritic cells in local lymph nodes. As no expression of HLA-G was inducible in monocytes or dendritic cells from healthy donors in response to IL-10 or IL-4, we speculated that tumour-derived soluble HLA-G might be transferred to dendritic cells via the lymphatic system. Accordingly, high levels of tumour-derived soluble HLA-G were detected in ovarian cancer ascites samples. In vitro, dendritic cells expanded in the presence of IL-4, IL-10 and GM-CSF (DC-10) were particularly prone to binding high amounts of soluble HLA-G via ILT receptors. Furthermore, HLA-G loaded DC-10 cells inhibited the proliferation of CD8 effector cells and induced regulatory T cells, even when the DC-10 cells had been fixed with paraformaldehyde. Conclusion The immunosuppressive molecule HLA-G is overexpressed in high-grade serous ovarian carcinomas, which account for the majority of ovarian cancers. In particular tumours with a high mutational burden and intact expression of classical, immunogenic MHC class Ia molecules may use HLA-G to escape from immunosurveillance. Additionally, tumour-derived soluble HLA-G may inhibit adaptive immune responses by binding to dendritic cells in local lymph nodes. Dendritic cells usually play a decisive role in the initiation of adaptive anti-tumour immune responses by presenting tumour antigens to cytotoxic T cells. In contrast, dendritic cells loaded with soluble HLA-G inhibit the proliferation of effector T cells and promote the induction of regulatory T cells. Thus, soluble HLA-G that is transferred to dendritic cells via lymphatic vessels may enable ovarian carcinomas to remotely suppress anti-tumour immune responses in local lymph nodes. This novel immune-escape mechanism may also exist in other solid tumours that express HLA-G. KW - HLA-G KW - HLA-G KW - Dendritische Zelle KW - Eierstocktumor KW - ovarian cancer KW - ovarian carcinoma KW - transfer KW - dendritic cells KW - immune escape Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127252 ER - TY - JOUR A1 - Schneider, Johannes A1 - Klein, Teresa A1 - Mielich-Süss, Benjamin A1 - Koch, Gudrun A1 - Franke, Christian A1 - Kuipers, Oskar P. A1 - Kovács, Ákos T. A1 - Sauer, Markus A1 - Lopez, Daniel T1 - Spatio-temporal Remodeling of Functional Membrane Microdomains Organizes the Signaling Networks of a Bacterium JF - PLoS Genetics N2 - Lipid rafts are membrane microdomains specialized in the regulation of numerous cellular processes related to membrane organization, as diverse as signal transduction, protein sorting, membrane trafficking or pathogen invasion. It has been proposed that this functional diversity would require a heterogeneous population of raft domains with varying compositions. However, a mechanism for such diversification is not known. We recently discovered that bacterial membranes organize their signal transduction pathways in functional membrane microdomains (FMMs) that are structurally and functionally similar to the eukaryotic lipid rafts. In this report, we took advantage of the tractability of the prokaryotic model Bacillus subtilis to provide evidence for the coexistence of two distinct families of FMMs in bacterial membranes, displaying a distinctive distribution of proteins specialized in different biological processes. One family of microdomains harbors the scaffolding flotillin protein FloA that selectively tethers proteins specialized in regulating cell envelope turnover and primary metabolism. A second population of microdomains containing the two scaffolding flotillins, FloA and FloT, arises exclusively at later stages of cell growth and specializes in adaptation of cells to stationary phase. Importantly, the diversification of membrane microdomains does not occur arbitrarily. We discovered that bacterial cells control the spatio-temporal remodeling of microdomains by restricting the activation of FloT expression to stationary phase. This regulation ensures a sequential assembly of functionally specialized membrane microdomains to strategically organize signaling networks at the right time during the lifespan of a bacterium. KW - membrane proteins KW - gene expression KW - bacillus subtilis KW - fluorescence microscopy KW - cell fusion KW - signal transduction KW - gene regulation KW - lipids Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125577 VL - 11 IS - 4 ER - TY - JOUR A1 - Paletta, Daniel A1 - Fichtner, Alina Suzann A1 - Starick, Lisa A1 - Porcelli, Steven A. A1 - Savage, Paul B. A1 - Herrmann, Thomas T1 - Species Specific Differences of CD1d Oligomer Loading In Vitro JF - PLoS One N2 - CD1d molecules are MHC class I-like molecules that present glycolipids to iNKT cells. The highly conserved interaction between CD1d:α-Galactosylceramide (αGC) complexes and the iNKT TCR not only defines this population of αβ T cells but can also be used for its direct identification. Therefore, CD1d oligomers are a widely used tool for iNKT cell related investigations. To this end, the lipid chains of the antigen have to be inserted into the hydrophobic pockets of the CD1d binding cleft, often with help of surfactants. In this study, we investigated the influence of different surfactants (Triton X-100, Tween 20, Tyloxapol) on in vitro loading of CD1d molecules derived from four different species (human, mouse, rat and cotton rat) with αGC and derivatives carrying modifications of the acyl-chain (DB01-1, PBS44) and a 6-acetamido-6-deoxy-addition at the galactosyl head group (PBS57). We also compared rat CD1d dimers with tetramers and staining of an iNKT TCR transductant was used as readout for loading efficacy. The results underlined the importance of CD1d loading efficacy for proper analysis of iNKT TCR binding and demonstrated the necessity to adjust loading conditions for each oligomer/glycolipid combination. The efficient usage of surfactants as a tool for CD1d loading was revealed to be species-specific and depending on the origin of the CD1d producing cells. Additional variation of surfactant-dependent loading efficacy between tested glycolipids was influenced by the acyl-chain length and the modification of the galactosyl head group with PBS57 showing the least dependence on surfactants and the lowest degree of species-dependent differences. KW - cell staining KW - major histocompatibility complex KW - binding analysis KW - oligomers KW - glycolipids KW - lipids KW - surfactants KW - T cells Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124879 VL - 10 IS - 11 ER - TY - THES A1 - Rehm, Stefanie T1 - Spermine-functionalized Perylene Bisimide Dyes: Synthesis and Self-assembly in Water T1 - Spermin-funktionalisierte Perylenbisimid Farbstoffe: Synthese und Selbstassemblierung in Wasser N2 - The main objective of this thesis was the design and synthesis of perylene bisimide dyes with sufficient water-solubility for the construction of self-assembled architectures in aqueous solutions. Beside these tasks another goal of this project was the control over the self-assembly process in terms of aggregate size and helicity, respectively. Within this thesis an appropriate synthesis for spermine-functionalized perylene bisimide dyes was developed and conducted successfully. The characterization of these building blocks and their course of self-assembly were investigated by NMR, UV/Vis and fluorescence spectroscopy as well as by atomic force and transmission electron microscopy. For the better understanding of the experimental results theoretical calculations were performed. N2 - Ziel dieser Dissertation war das Design und die Synthese von Perylenbisimiden mit hinreichender Wasserlöslichkeit, die für den Aufbau von selbständig assemblierten Strukturen in wässrigen Lösungen verwendet werden sollen. Ein weiteres Ziel dieses Projektes war die Kontrolle über den Prozess der Selbstanordnung hinsichtlich der Aggregatgröße beziehungsweise deren Helizität. Im Rahmen dieser Doktorarbeit wurde eine entsprechende Synthese für Spermin-funktionalisierte Perylenbisimide entworfen und erfolgreich durchgeführt. Die Charakterisierung dieser Bausteine und der Prozess deren Selbstanordnung wurde mit Hilfe von NMR-, UV/Vis- und Fluoreszenz-Spektroskopie aber auch mit Rasterkraft- und Elektronentransmissionsmikroskopie durchgeführt. Für das bessere Verständnis der experimentellen Ergebnisse wurden theoretische Berechnungen durchgeführt. KW - Perylenderivate KW - Selbstorganisation KW - perylene bisimide KW - spermine KW - polyamine KW - bola-amphiphile KW - fluorescence KW - Perylenbisimid KW - Spermin KW - Polyamin KW - Bola-Amphiphil KW - Fluoreszenz KW - Aggregation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123201 ER - TY - THES A1 - Rothe, Dietrich Gernot T1 - Spin Transport in Topological Insulators and Geometrical Spin Control T1 - Spintransport in topologischen Isolatoren und geometrische Spinkontrolle N2 - In the field of spintronics, spin manipulation and spin transport are the main principles that need to be implemented. The main focus of this thesis is to analyse semiconductor systems where high fidelity in these principles can be achieved. To this end, we use numerical methods for precise results, supplemented by simpler analytical models for interpretation. The material system of 2D topological insulators, HgTe/CdTe quantum wells, is interesting not only because it provides a topologically distinct phase of matter, physically manifested in its protected transport properties, but also since within this system, ballistic transport of high quality can be realized, with Rashba spin-orbit coupling and electron densities that are tunable by electrical gating. Extending the Bernvevig-Hughes-Zhang model for 2D topological insulators, we derive an effective four-band model including Rashba spin-orbit terms due to an applied potential that breaks the spatial inversion symmetry of the quantum well. Spin transport in this system shows interesting physics because the effects of Rashba spin-orbit terms and the intrinsic Dirac-like spin-orbit terms compete. We show that the resulting spin Hall signal can be dominated by the effect of Rashba spin-orbit coupling. Based on spin splitting due to the latter, we propose a beam splitter setup for all-electrical generation and detection of spin currents. Its working principle is similar to optical birefringence. In this setup, we analyse spin current and spin polarization signals of different spin vector components and show that large in-plane spin polarization of the current can be obtained. Since spin is not a conserved quantity of the model, we first analyse the transport of helicity, a conserved quantity even in presence of Rashba spin-orbit terms. The polarization defined in terms of helicity is related to in-plane polarization of the physical spin. Further, we analyse thermoelectric transport in a setup showing the spin Hall effect. Due to spin-orbit coupling, an applied temperature gradient generates a transverse spin current, i.e. a spin Nernst effect, which is related to the spin Hall effect by a Mott-like relation. In the metallic energy regimes, the signals are qualitatively explained by simple analytic models. In the insulating regime, we observe a spin Nernst signal that originates from the finite-size induced overlap of edge states. In the part on methods, we discuss two complementary methods for construction of effective semiconductor models, the envelope function theory and the method of invariants. Further, we present elements of transport theory, with some emphasis on spin-dependent signals. We show the connections of the adiabatic theorem of quantum mechanics to the semiclassical theory of electronic transport and to the characterization of topological phases. Further, as application of the adiabatic theorem to a control problem, we show that universal control of a single spin in a heavy-hole quantum dot is experimentally realizable without breaking time reversal invariance, but using a quadrupole field which is adiabatically changed as control knob. For experimental realization, we propose a GaAs/GaAlAs quantum well system. N2 - Manipulation und Transport von elektronischen Spins sind die wesentlichen Elemente, die für das Funktionieren einer zukünftigen Spin-basierten Elektronik implementiert werden müssen. Diese Arbeit befasst sich schwerpunktmäßig mit Halbleitersystemen, in denen diese Prinzipien mit hoher Zuverlässigkeit möglich sind. Dazu wurden sowohl numerische als auch analytische Berechnungsmethoden genutzt, letztere oft in der Form einfacher Modelle zur Interpretation der numerischen Ergebnisse. Das Halbleitersystem von HgTe/CdTe Quantentrögen, auch bekannt als zweidimensionaler topologischer Isolator, ist sowohl von fundamentalem wissenschaftlichen Interesse, da die topologisch nichttriviale Energiestruktur zu einem Schutz von Transporteigenschaften führt, als auch von angewandterem Interesse, da aus diesem Materialsystem Proben gefertigt werden können, die ballistischen Transport hoher Qualität zeigen, und da zudem die Rashba Spin-Bahn-Kopplung sowie die elektronische Dichte durch elektrische Steuerelektroden einstellbar sind. Wir erweitern das Bernevig-Hughes-Zhang Modell für zweidimensionale topologische Isolatoren, indem wir ein Vierbandmodell herleiten, das Rashba Spin-Bahn-Kopplungsterme enthält, die durch ein äußeres elektrisches Feld hervorgerufen werden, wenn dieses die Inversionssymmetrie des Quantentroges bricht. Der Transport von Spins in diesem System zeigt ein interessantes Wechselspiel zwischen Effekten der Rashba Spin-Bahn-Kopplung und Effekten der intrinsischen Dirac-artigen Spin-Bahn-Kopplung. Dabei dominiert die Rashba Spin-Bahn-Kopplung das Verhalten des Spin-Hall-Signals. Basierend auf der einstellbaren Rashba Spin-Bahn-Kopplung, schlagen wir einen spinselektiven Polarisator zur rein elektrischen Erzeugung und Detektion von Spinströmen vor. Das Funktionsprinzip ist vergleichbar mit demjenigen eines doppelbrechenden Kristalls. In der vorgeschlagenen Anordnung untersuchen wir die Spinpolarisation in verschieden Spinvektorkomponenten und zeigen die Realisierbarkeit von hoher Spinpolarisation in der Ebene. Da der Spin keine Erhaltungsgröße des Halbleitermodells ist, analysieren wir in einem ersten Schritt den Transport von der Erhaltungsgröße Helizität, und setzen die erzeugte Polarisation dann in Bezug zur Spinpolarisation. Des Weiteren analysieren wir thermoelektrischen Transport in einem System, das auch den Spin-Hall-Effekt zeigt. Aufgrund von Spin-Bahn-Kopplung kommt es beim Anlegen eines Temperaturgradienten zu einem transversalen Spinstrom, genannt Spin-Nernst-Effekt. Dieser ist über eine Mott-artige Beziehung mit dem Spin-Hall-Effekt verknüpft. Im metallischen Energiebereich können wir die Signale qualitativ anhand von einfachen analytischen Modellen verstehen. Im Energiebereich der elektronischen Bandlücke finden wir ein Spin-Nernst-Signal, das vom räumlichen Überlapp der Randzustände herrührt, die an gegenüberliegenden Kanten des Halbleitersystems lokalisiert sind. Im methodischen ersten Teil dieser Arbeit diskutieren wir zwei komplementäre Methoden zur Konstruktion von effektiven Halbleitermodellen, nämlich die Methode der Envelopefunktionen und die Methode der Invarianten. Außerdem präsentieren wir Elemente der elektronischen Transporttheorie, unter besonderer Beachtung von Spintransport. Wir diskutieren die Zusammenhänge zwischen dem adiabatischen Theorem in der Quantenmechanik einerseits, und semiklassischer Transporttheorie sowie der topologischen Klassifizierung von Phasen andererseits. Als weitere Anwendung des adiabatischen Theorems zeigen wir, wie universelle Kontrolle eines einzelnen Spins in einem Quantenpunkt aus Schwerlochzuständen experimentell realisiert werden kann, ohne dabei die Zeitumkehrsymmetrie zu brechen. Zu diesem Zweck führen wir ein elektrisches Quadrupolfeld ein, dessen Konfiguration als adiabatischer Kontrollparameter dient. Wir schlagen die experimentelle Realisierung des Quantenpunktes in einem QaAs/GaAlAs Quantentrogsystem vor. KW - Elektronischer Transport KW - Topologischer Isolator KW - Spintronik KW - topological insulators KW - topologische Isolatoren KW - mesoskopische Physik KW - mesoscopic physics KW - Halbleiterphysik KW - Thermoelektrizität KW - Quanteninformation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125628 ER - TY - JOUR A1 - Rottlaender, Andrea A1 - Kuerten, Stefanie T1 - Stepchild or prodigy? Neuroprotection in multiple sclerosis (MS) research JF - International Journal of Molecular Sciences N2 - Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) and characterized by the infiltration of immune cells, demyelination and axonal loss. Loss of axons and nerve fiber pathology are widely accepted as correlates of neurological disability. Hence, it is surprising that the development of neuroprotective therapies has been neglected for a long time. A reason for this could be the diversity of the underlying mechanisms, complex changes in nerve fiber pathology and the absence of biomarkers and tools to quantify neuroregenerative processes. Present therapeutic strategies are aimed at modulating or suppressing the immune response, but do not primarily attenuate axonal pathology. Yet, target-oriented neuroprotective strategies are essential for the treatment of MS, especially as severe damage of nerve fibers mostly occurs in the course of disease progression and cannot be impeded by immune modulatory drugs. This review shall depict the need for neuroprotective strategies and elucidate difficulties and opportunities. KW - experimental autoimmune encephalomyelitis KW - white matter KW - lesions KW - remyelination KW - multiple sclerosis KW - regeneration KW - neuroprotection KW - degeneration KW - axonal damage KW - neurodegeneration KW - pathology KW - sodium channels KW - axonal injury KW - central nervous system Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148416 VL - 16 ER - TY - JOUR A1 - El Majdoub, Faycal A1 - Hunsche, Stefan A1 - Igressa, Alhadi A1 - Kocher, Martin A1 - Sturm, Volker A1 - Maarouf, Mohammad T1 - Stereotactic LINAC-Radiosurgery for Glomus Jugulare Tumors: A Long-Term Follow-Up of 27 Patients JF - PLoS ONE N2 - Background The optimal treatment of glomus jugulare tumors (GJTs) remains controversial. Due to the critical location, microsurgery still provides high treatment-related morbidity and a decreased quality of life. Thus, we performed stereotactical radiosurgery (SRS) for the treatment of GJTs and evaluated the long-term outcome. Methods Between 1991 and 2011, 32 patients with GJTs underwent SRS using a linear accelerator (LINAC) either as primary or salvage therapy. Twenty-seven patients (median age 59.9 years, range 28.7-79.9 years) with a follow-up greater than five years (median 11 years, range 5.3-22.1 years) were selected for retrospective analysis. The median therapeutic single dose applied to the tumor surface was 15 Gy (range 11-20 Gy) and the median tumor volume was 9.5 ml (range 2.8-51 ml). Results Following LINAC-SRS, 10 of 27 patients showed a significant improvement of their previous neurological complaints, whereas 12 patients remained unchanged. Five patients died during follow-up due to old age or other, not treatment-related reasons. MR-imaging showed a partial remission in 12 and a stable disease in 15 patients. No tumor progression was observed. The actuarial overall survival rates after five, ten and 20 years were 100%, 95.2% and 79.4%, respectively. Conclusions Stereotactic LINAC-Radiosurgery can achieve an excellent long-term tumor control beside a low rate of morbidity in the treatment of GJTs. It should be considered as an alternative therapy regime to surgical resection or fractionated external beam radiation either as primary, adjuvant or salvage therapy. KW - gamma knife radiosurgery KW - accelerator based radiosurgery KW - radiation therapy KW - temporal bone KW - skull base KW - surgery KW - paragangliomas KW - management KW - radiotherapy KW - head Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151717 VL - 10 IS - 6 ER - TY - JOUR A1 - Hoffmann, Linda S. A1 - Etzrodt, Jennifer A1 - Willkomm, Lena A1 - Sanyal, Abhishek A1 - Scheja, Ludger A1 - Fischer, Alexander W. C. A1 - Stasch, Johannes-Peter A1 - Bloch, Wilhelm A1 - Friebe, Andreas A1 - Heeren, Joerg A1 - Pfeifer, Alexander T1 - Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue JF - Nature Communications N2 - Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41-8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing \(\beta\)\(_{1}\)-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces 'browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities. KW - decompensated heart failure KW - mitochondrial biogenesis KW - pulmonary hypertension KW - nitric oxide KW - erectile dysfunction KW - beige adipocytes KW - fat development KW - cGMP KW - riociguat KW - white Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143127 VL - 6 IS - 7235 ER - TY - JOUR A1 - Zinner, Christoph A1 - Sperlich, Billy A1 - Krueger, Malte A1 - Focke, Tim A1 - Reed, Jennifer A1 - Mester, Joachim T1 - Strength, Endurance, Throwing Velocity and in-Water Jump Performance of Elite German Water Polo Players JF - Journal of Human Kinetics N2 - The purpose of this study was threefold: 1) to assess the eggbeater kick and throwing performance using a number of water polo specific tests, 2) to explore the relation between the eggbeater kick and throwing performance, and 3) to investigate the relation between the eggbeater kick in the water and strength tests performed in a controlled laboratory setting in elite water polo players. Fifteen male water polo players of the German National Team completed dynamic and isometric strength tests for muscle groups (adductor, abductor, abdominal, pectoralis) frequently used during water polo. After these laboratory strength tests, six water polo specific in-water tests were conducted. The eggbeater kick assessed leg endurance and agility, maximal throwing velocity and jump height. A 400 m test and a sprint test examined aerobic and anaerobic performance. The strongest correlation was found between jump height and arm length (p < 0.001, r = 0.89). The laboratory diagnostics of important muscles showed positive correlations with the results of the in-water tests (p < 0.05, r = 0.52-0.70). Muscular strength of the adductor, abdominal and pectoralis muscles was positively related to in-water endurance agility as assessed by the eggbeater kick (p < 0.05; r = 0.53-0.66). Findings from the current study emphasize the need to assess indices of water polo performance both in and out of the water as well as the relation among these parameters to best assess the complex profile of water polo players. KW - physiological characteristics KW - cinematographic analysis KW - penalty throw KW - strength KW - jump height KW - team sports KW - diagnostics KW - anaerobic and aerobic testing Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148812 VL - 45 ER - TY - JOUR A1 - Lukasczik, Matthias A1 - Gerlich, Christian A1 - Schuler, Michael A1 - Neuderth, Silke A1 - Dlugosch, Gabriele A1 - Faller, Hermann T1 - Stress and resources in women attending an inpatient prevention/rehabilitation measure for parents: Secondary analysis of quality assurance data JF - Open Journal of Medical Psychology N2 - Questionnaire data from two projects on the development of quality assurance instruments for an inpatient rehabilitation/prevention program for parents were used for a secondary analysis. In this analysis, the associations of gains in a psychosocial resource (parenting self-efficacy) and two types of stressors experienced by mothers at the start of treatment (parenting hassles, depressive symptoms) with general life satisfaction and satisfaction with health at the end of treatment were explored. Structural equation modeling was applied to data from N = 1724 female patients. Potential resource-stressor interactions were tested using the Latent Moderated Structural Equations approach. Results showed that parenting hassles were negatively associated with general life satisfaction and satisfaction with health while self-efficacy gains were weakly positively correlated with both variables. No interaction of parenting hassles and self-efficacy gains was found. Depressive symptoms were negatively associated with both satisfaction measures. In these models, self-efficacy gains were not substantially correlated with life satisfaction, but showed a small association with satisfaction with health. There was no significant interaction of depressive symptoms and self-efficacy gains. The findings imply that interventions for distressed mothers—as exemplarily illustrated by this inpatient setting—should focus on identifying and reducing initial stressors as these may continue to impair mothers’ subjective health despite gains in parenting-related resources. KW - parenting stress KW - resource KW - self-efficacy KW - depression KW - mothers Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125316 VL - 4 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Burek, Malgorzata A1 - Förster, Carola Y. T1 - Stretch and/or oxygen glucose deprivation (OGD) in an in vitro traumatic brain injury (TBI) model induces calcium alteration and inflammatory cascade JF - Frontiers in Cellular Neuroscience N2 - The blood-brain barrier (BBB), made up of endothelial cells of capillaries in the brain, maintains the microenvironment of the central nervous system. During ischemia and traumatic brain injury (TBI), cellular disruption leading to mechanical insult results to the BBB being compromised. Oxygen glucose deprivation (OGD) is the most commonly used in vitro model for ischemia. On the other hand, stretch injury is currently being used to model TBI in vitro. In this paper, the two methods are used alone or in combination, to assess their effects on cerebrovascular endothelial cells cEND in the presence or absence of astrocytic factors. Applying severe stretch and/or OGD to cEND cells in our experiments resulted to cell swelling and distortion. Damage to the cells induced release of lactate dehydrogenase enzyme (LDH) and nitric oxide (NO) into the cell culture medium. In addition, mRNA expression of inflammatory markers interleukin (I L)-6, IL-1\(\alpha\) chemokine (C-C motif) ligand 2 (CCL2) and tumor necrosis factor (TNF)-\(\alpha\) also increased. These events could lead to the opening of calcium ion channels resulting to excitotoxicity. This could be demonstrated by increased calcium level in OGD-subjected cEND cells incubated with astrocyte-conditioned medium. Furthermore, reduction of cell membrane integrity decreased tight junction proteins claudin-5 and occludin expression. In addition, permeability of the endothelial cell monolayer increased. Also, since cell damage requires an increased uptake of glucose, expression of glucose transporter glut1 was found to increase at the mRNA level after OGD. Overall, the effects of OGD on cEND cells appear to be more prominent than that of stretch with regards to TJ proteins, NO, glutl expression, and calcium level. Astrocytes potentiate these effects on calcium level in cEND cells. Combining both methods to model TBI in vitro shows a promising improvement to currently available models. KW - receptor antagonist KW - cytokine expression KW - tight junctions KW - cell stretch KW - calcium level KW - nitric oxide KW - endothelial cells KW - necrosis factor alpha KW - barrier properties KW - cerebral ischemia KW - nervous system KW - CNS injury KW - blood brain barrier KW - cEND KW - astrocytes KW - traumatic brain injury KW - oxygen-glucose deprivation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148255 VL - 9 IS - 323 ER - TY - JOUR A1 - Laine, Romain F. A1 - Albecka, Anna A1 - van de Linde, Sebastian A1 - Rees, Eric J. A1 - Crump, Colin M. A1 - Kaminski, Clemens F. T1 - Structural analysis of herpes simplex virus by optical super-resolution imaging JF - Nature Communications N2 - Herpes simplex virus type-1 (HSV-1) is one of the most widespread pathogens among humans. Although the structure of HSV-1 has been extensively investigated, the precise organization of tegument and envelope proteins remains elusive. Here we use super-resolution imaging by direct stochastic optical reconstruction microscopy (dSTORM) in combination with a model-based analysis of single-molecule localization data, to determine the position of protein layers within virus particles. We resolve different protein layers within individual HSV-1 particles using multi-colour dSTORM imaging and discriminate envelope-anchored glycoproteins from tegument proteins, both in purified virions and in virions present in infected cells. Precise characterization of HSV-1 structure was achieved by particle averaging of purified viruses and model-based analysis of the radial distribution of the tegument proteins VP16, VP1/2 and pUL37, and envelope protein gD. From this data, we propose a model of the protein organization inside the tegument. KW - tegument protein pUL36 KW - fluorescence microscopy KW - monoclonal antibodies KW - 3-dimensional structure KW - type-1 KW - nuclear pore complex KW - reconstruction microscopy KW - localization microscopy KW - resolution KW - envelopment Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144623 VL - 6 IS - 5980 ER - TY - THES A1 - Delto, Carolyn Francesca T1 - Structural and Biochemical Characterization of the GABA(A) Receptor Interacting Protein Muskelin T1 - Strukturelle und Biochemische Charakterisierung des GABA(A) Rezeptor interagierenden Proteins Muskelin N2 - In a study from 2011, the protein muskelin was described as a central coordinator of the retrograde transport of GABA(A) receptors in neurons. As muskelin governs the transport along actin filaments as well as microtubules, it might be the first representative of a novel class of regulators, which coordinate cargo transport across the borders of these two independent systems of transport paths and their associated motorproteins. To establish a basis for understanding the mode of operation of muskelin, the aim of this thesis was an in-depth biochemical and structural characterization of muskelin and its interaction with the GABA(A) receptor. One focus of the work was the analysis of the oligomerization of muskelin. As could be demonstrated, the oligomerization is based on two independent interactions mediated by different domains of the protein: a known interaction of the N-terminal discoidin domain with the C-terminal portion, termed head-to-tail interaction, and a dimerization of the LisH motif in muskelin that was so far neglected in the literature. For the detailed studies of both binding events, the solution of a crystal structure of a fragment of muskelin, comprising the Discoidin domain and the LisH motif, was an important basis. The fragment crystallized as a dimer, with dimerization being mediated solely by the LisH motif. Biochemical analysis corroborated that the LisH motif in muskelin serves as a dimerization element, and, moreover, showed that the C-terminal domain of the protein substantially stabilizes this dimerization. In addition, the crystal structure revealed the molecular composition of the surface of the head in the head-to-tail interaction, namely the discoidin domain. This information enabled to map the amino acids contributing to binding, which showed that the binding site of the head-to-tail interaction coincides with the generic ligand binding site of the discoidin domain. As part of the analyses, residues that are critical for LisH-dimerization and the head-to-tail binding, respectively, were identified, whose mutation specifically interfered with each of the interactions separately. These mutations allowed to investigate the interplay of these interactions during oligomerization. It could be shown that recombinant muskelin assembles into a tetramer to which both interactions, the LisH-dimerization and the head-to-tail binding, contribute independently. When one of the two interactions was disturbed, only a dimer mediated via the respective other interaction could be formed; when both interactions were disturbed, the protein was present as monomer. Furthermore, Frank Heisler in the group of Matthias Kneussel was able to show the drastic impact of an impaired LisH-dimerization on muskelin in cells using these mutations. Disturbing the LisH-dimerization led to a complete redistribution of the originally cytoplasmic muskelin to the nucleus which was accompanied by a severe impairment of its function during GABA(A) receptor transport. Following up on these results in an analysis of muskelin variants, for which alterations of the subcellular localization had been published earlier, the crucial influence of LisH-dimerization to the subcellular localization and thereby the role of muskelin in the cell was confirmed. The biochemical studies of the interaction of muskelin and the alpha1 subunit of the GABA(A) receptor demonstrated a direct binding with an affinity in the low micromolar range, which is mediated primarily by the kelch repeat domain in muskelin. For the binding site on the GABA(A) receptor, it was confirmed that the thirteen most C-terminal residues of the intracellular domain are critical for the binding of muskelin. In accordance with the strong conservation of these residues among the alpha subunits of the GABA(A) receptor, it could be shown that an interaction with muskelin in vitro is also possible for the alpha2 and alpha5 subunits. Based on the comparison of the binding sites between the homologous subunits, tentative conclusions can be drawn about the details of the binding, which may serve as a starting point for follow-up studies. This thesis thereby makes valuable contributions to the understanding of muskelin, in particular the significance of its oligomerization. It furthermore provides an experimental framework for future studies that address related topics, such as the characterization of other muskelin interaction partners, or the questions raised in this work. N2 - Das Protein Muskelin wurde in einer Studie aus dem Jahr 2011 als zentraler Koordinator des retrograden Transports von GABA(A)-Rezeptoren in Neuronen beschrieben. Da Muskelin den Transport des Rezeptors sowohl entlang von Aktinfilamenten als auch Mikrotubuli steuert, könnte es der erste bekannte Vertreter einer neuen Klasse von Regulatoren sein, die den Transport einer Fracht über die Grenzen dieser beiden unabhängigen Systeme von Transportwegen und der damit assoziierten Motorproteine hinweg koordinieren. Um Grundlagen für das Verständnis der Wirkungsweise von Muskelin zu schaffen, war das Ziel dieser Arbeit die biochemische und strukturelle Charakterisierung von Muskelin und seiner Interaktion mit dem GABA(A)-Rezeptor. Ein Schwerpunkt der Arbeit lag dabei auf der Analyse der Oligomerisierung von Muskelin. Wie gezeigt werden konnte, beruht die Oligomerisierung auf zwei unabhängigen, von verschiedenen Domänen des Proteins vermittelten Bindungen: zum Einen auf einer bereits bekannten Wechselwirkung der N-terminalen Discoidin-Domäne und des C-terminalen Teils (anschaulich als Head-to-tail, englisch für Kopf-an-Schwanz, bezeichnet), zum Anderen auf einer in der Literatur bisher außer Acht gelassenen Dimerisierung des LisH-Motivs in Muskelin. Für die detaillierten Studien beider Bindungen lieferte die Aufklärung der Kristallstruktur eines Teilstücks von Muskelin, das die Discoidin-Domäne und das LisH-Motiv umfasst, eine wichtige Grundlage. Das Teilstück kristallisierte als Dimer, wobei die Dimerisierung ausschließlich über das LisH-Motiv vermittelt wurde. Die biochemischen Analysen bestätigten, dass das LisH-Motiv in Muskelin als Dimerisierungselement wirkt, und zeigten darüber hinaus, dass die C-terminale Domäne des Proteins diese Dimerisierung wesentlich stabilisiert. Zudem offenbarte die Kristallstruktur den molekularen Aufbau der Oberfläche des Kopfes in der Head-to-tail-Bindung, der Discoidin-Domäne. Die Kartierung der zur Bindung beitragenden Aminosäuren belegte, dass die Bindungsstelle der Head-to-tail-Interaktion mit der generischen Ligandenbindungsstelle der Discoidin-Domäne zusammenfällt. Als Teil der Analysen wurden zur LisH-Dimerisierung oder zur Head-to-tail-Bindung kritisch beitragende Aminosäurenseitenketten identifiziert, durch deren Mutationen Ispezifisch jeweils eine der beiden Interaktionen unterbunden werden konnte. Diese Mutationen ermöglichten es, das Zusammenspiel der Bindungen in der Oligomerisierung zu untersuchen. Es konnte gezeigt werden, dass rekombinantes Muskelin ein Tetramer bildet, wozu beide Interaktionen, die LisH-Dimerisierung und die Head-to-tail-Bindung, unabhängig beitragen. Wurde jeweils eine der beiden Interaktionen durch Mutation gestört, konnte nur noch ein über die jeweils andere Interaktion vermitteltes Dimer gebildet werden, bei gleichzeitiger Störung beider Interaktionen lag das Protein als Monomer vor. Darüber hinaus konnte Frank Heisler in der Arbeitsgruppe von Matthias Kneussel mit Hilfe dieser Mutationen zeigen, dass eine Störung der LisH-Dimerisierung drastische Auswirkungen auf Muskelin in Zellen hat. Die Störung der LisH-Dimerisierung führte zu einer vollständigen Umverteilung des sonst im Zytoplasma lokalisierten Muskelins in den Kern, begleitet von einer starken Beeinträchtigung seiner Funktion im Transport des GABA(A)-Rezeptors. Auf diesen Ergebnissen aufbauend wurde durch Analysen der oligomeren Zustände von Muskelin-Varianten, für die in der Literatur eine veränderte Lokalisation beschrieben worden war, die entscheidende Bedeutung der LisH-Dimerisierung für die subzelluläre Verteilung und damit die Rolle von Muskelin in der Zelle bekräftigt. Die biochemischen Studien der Interaktion von Muskelin und der alpha1-Untereinheit des GABA(A)-Rezeptors demonstrierten eine direkte Bindung mit mikromolarer Affinität, die in Muskelin vorwiegend durch die Kelch-repeat-Domäne vermittelt wird. Für die Bindungsstelle auf Seite des GABA(A)-Rezeptors wurde bestätigt, dass die dreizehn C-terminalen Reste der intrazellulären Domäne entscheidend sind. In Übereinstimmung mit der starken Konservierung dieser Reste in verschiedenen alpha-Untereinheiten des GABA(A)-Rezeptors, konnte gezeigt werden, dass in vitro eine Bindung von Muskelin auch an die intrazelluläre Domäne der alpha2- und alpha5-Untereinheit möglich ist. Anhand des Vergleichs der Bindungsstelle zwischen den homologen Untereinheiten lassen sich erste Rückschlüsse auf die Details der Interaktion ziehen, die als Anknüpfungspunkt für kommende Studien dienen können. Diese Arbeit liefert damit wesentliche Beiträge zum Verständnis von Muskelin, insbesondere der Bedeutung seiner Oligomerisierung. Sie bietet zudem ein experimentelles Rahmenwerk für zukünftige Studien, die sich verwandten Themen, wie der Charakterisierung weiterer Interaktionen von Muskelin, oder den in dieser Arbeit aufgeworfenen Fragen widmen. KW - Oligomerisation KW - GABA-Rezeptor KW - Muskelin KW - Oligomerization KW - GABA(A) receptor KW - Interaction analysis KW - Strukturanalyse KW - Biochemie Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115922 ER - TY - JOUR A1 - Lee, Eun-Hye A1 - Song, Jin-Dong A1 - Han, Il-Ki A1 - Chang, Soo-Kyung A1 - Langer, Fabian A1 - Höfling, Sven A1 - Forchel, Alfred A1 - Kamp, Martin A1 - Kim, Jong-Su T1 - Structural and optical properties of position-retrievable low-density GaAs droplet epitaxial quantum dots for application to single photon sources with plasmonic optical coupling JF - Nanoscale Research Letters N2 - The position of a single GaAs quantum dot (QD), which is optically active, grown by low-density droplet epitaxy (DE) (approximately 4 QDs/μm\(^{2}\)), was directly observed on the surface of a 45-nm-thick Al\(_{0.3}\)Ga\(_{0.7}\)As capping layer. The thin thickness of AlGaAs capping layer is useful for single photon sources with plasmonic optical coupling. A micro-photoluminescence for GaAs DE QDs has shown exciton/biexciton behavior in the range of 1.654 to 1.657 eV. The direct observation of positions of low-density GaAs DE QDs would be advantageous for mass fabrication of devices that use a single QD, such as single photon sources. KW - quantum dot KW - droplet epitaxy KW - micro-photoluminescence KW - single photon KW - GaAs Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143692 VL - 10 IS - 114 ER - TY - JOUR A1 - Dyksik, Mateusz A1 - Motyka, Marcin A1 - Sęk, Grzegorz A1 - Misiewicz, Jan A1 - Dallner, Matthias A1 - Weih, Robert A1 - Kamp, Martin A1 - Höfling, Sven T1 - Submonolayer Uniformity of Type II InAs/GaInSb W-shaped Quantum Wells Probed by Full-Wafer Photoluminescence Mapping in the Mid-infrared Spectral Range JF - Nanoscale Research Letters N2 - The spatial uniformity of GaSb- and InAs substrate-based structures containing type II quantum wells was probed by means of large-scale photoluminescence (PL) mapping realized utilizing a Fourier transform infrared spectrometer. The active region was designed and grown in a form of a W-shaped structure with InAs and GaInSb layers for confinement of electrons and holes, respectively. The PL spectra were recorded over the entire 2-in. wafers, and the parameters extracted from each spectrum, such as PL peak energy position, its linewidth and integrated intensity, were collected in a form of two-dimensional spatial maps. Throughout the analysis of these maps, the wafers' homogeneity and precision of the growth procedure were investigated. A very small variation of PL peak energy over the wafer indicates InAs quantum well width fluctuation of only a fraction of a monolayer and hence extraordinary thickness accuracy, a conclusion further supported by high uniformity of both the emission intensity and PL linewidth. KW - interband cascade lasers KW - fourier transform spectroscopy KW - mid-infrared KW - type II quantum wells KW - spatially resolved photoluminescence Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139733 VL - 10 IS - 402 ER - TY - JOUR A1 - Drube, Sebastian A1 - Weber, Franziska A1 - Loschinski, Romy A1 - Beyer, Mandy A1 - Rothe, Mandy A1 - Rabenhorst, Anja A1 - Göpfert, Christiane A1 - Meininger, Isabel A1 - Diamanti, Michaela A. A1 - Stegner, David A1 - Häfner, Norman A1 - Böttcher, Martin A1 - Reinecke, Kirstin A1 - Herdegen, Thomas A1 - Greten, Florian R. A1 - Nieswandt, Bernhard A1 - Hartmann, Karin A1 - Krämer, Oliver H. A1 - Kamradt, Thomas T1 - Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells JF - Oncotarget N2 - Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2\(^{+}\)-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term "subthreshold IKK activation". This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33. We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo. Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure. KW - mast cells KW - subthreshold IKK activation KW - mitogenic signaling KW - NFκB-activation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143681 VL - 6 IS - 7 ER - TY - THES A1 - Kuhlmann, Matthias T1 - Sulfur-functional polymers for biomedical applications T1 - Schwefel-funktionale Polymere für biomedizinische Anwendungen N2 - Aim of this thesis was to combine the versatility of sulfur-chemistry, regarding redox-sensitivity as well as chemo- and site-specific conjugation, with multifunctionality of poly(glycidol)s as an alternative to poly(ethylene glycol). First the homo- and copolymerizations of EEGE and AGE were performed with respect to molar-mass distribution and reaction kinetics. A detailed study was given, varying the polymerization parameters such as DP, counter ion, solvent and monomer influence. It can be concluded that in general the rates for all polymerizations are higher using K+, in contrast to Cs+, as counter ion for the active alkoxide species. Unfortunately, K+ as counter ion commonly leads to a reduced control over polymer dispersity. In this thesis it was shown that the broad molar-mass distributions might be reduced by adding the monomer in a step-wise manner. In experiments with a syringe pump, for continuously adding the monomer, a significant reduction of the dispersities could be found using K+ as counter ion. In analogy to the oxyanionic polymerization of epoxides, the polymerization of episulfides via a thioanionic mechanism with various DPs was successful with thiols/DBU as initiator. In most experiments bimodality could be observed due to the dimerization, caused by oxidation processes by introduced oxygen during synthesis. Reducing this was successful by modifying the degassing procedure, e.g. repeated degassing cycles after each step, i.e. initiation, monomer addition and quenching. Unfortunately, it was not always possible to completely avoid the dimerization due to oxidation. Thiophenol, butanethiol, mercaptoethanol and dithiothreitol were used as thiol initiators, all being capable to initiate the polymerization. With the prediction and the narrow molar-mass distributions, the living character of the polymerization is therefore indicated. Homo- and copolymers of poly(glycidol) were used to functionalize these polymers with side-chains bearing amines, thiols, carboxylic acids and cysteines. The cysteine side-chains were obtained using a newly synthesized thiol-functional thiazolidine. For this, cysteine was protected using a condensation reaction with acetone yielding a dimethyl-substituted thiazolidine. Protection of the ring-amine was obtained via a mixed-anhydride route using formic acid and acetic anhydride. The carboxylic acid of 2,2-dimethylthiazolidine-4-carboxylic acid was activated with CDI and cysteamine attached. The obtained crystalline mercaptothiazolidine was subjected to thiol-ene click chemistry with allyl-functional poly(glycidol). A systematic comparison of thermal- versus photo-initiation showed a much higher yield and reaction rate for the UV-light mediated thiol-ene synthesis with DMPA as photo-initiator. Hydrolysis of the protected thiazolidine-functionalities was obtained upon heating the samples for 5 d at 70 °C in 0.1 M HCl. Dialysis against acetic acid lead to cysteine-functional poly(glycidol)s, storable as the acetate salt even under non-inert atmosphere. An oxidative TNBSA assay was developed to quantify the cysteine-content without the influence of the thiol-functionality. A cooperation partner coupled C-terminal thioester peptides with the cysteine-functional poly(glycidol)s and showed the good accessibility and reactivity of the cysteines along the backbone. SDS-PAGE, HPLC and MALDI-ToF measurements confirmed the successful coupling. N2 - Ziel der Arbeit war es die Vielseitigkeit der Schwefelchemie, hinsichtlich der Redoxsensitivität und chemo- und seitenspezifischer Konjugation, mit der Funktionalisierbarkeit von Poly(glycidol)en, als multifunktionale PEG-Alternative zu kombinieren. Zunächst wurden die Homo- und Copolymerisationen von EEGE und AGE hinsichtlich der Molmassenverteilung und der Reaktionskinetik untersucht. Durch die Variation der Polymerisationsparameter, wie angestrebter Polymerisationsgrad, Gegenion, Lösungsmittel und Monomer, wurde der Einfluss dieser untersucht. Allgemein konnte gezeigt werden, dass die Polymerisationen schneller ablaufen, wenn K+, im Gegensatz zu Cs+, als Gegenion zum aktiven Alkoxidkettenende verwendet wird. Nachteilig bei der Verwendung von K+ als Gegenion ist der Kontrollverlust der Polymerisation, welcher mit einer Erhöhung der Dispersität einhergeht. Es konnte gezeigt werden, dass die Breite der Molmassenverteilung durch die Geschwindigkeit der Monomerzugabe kontrolliert werden kann. Tatsächlich konnte die Dispersität durch die Verwendung einer Spritzenpumpe verbessert werden, da das Monomer mit einer konstanten angepassten Flussrate hinzugefügt wurde. Analog zur oxyanionischen Polymerisation von Epoxiden, war die Polymerisation von Episulfiden mittels thioanionischer Polymerisation ebenfalls möglich. Hierzu wurden verschiedene Polymerisationsgrade von EETGE und ATGE angestrebt und mittels Thiol/DBU als Initiator auch erreicht. In den meisten Fällen war jedoch eine Dimerisierung der Polymere zu beobachten, welche durch die Oxidation der aktiven Thiolatspezies verursacht wurde. Eine Möglichkeit zur Dimerisierungsunterdrückung war die wiederholte Durchführung von Entgasungszyklen nach jedem Arbeitsschritt, z.B. nach Zugabe des Initiators, des Monomers oder nach dem Quenchen. Trotz dieses experimentellen Aufwandes konnte nicht immer ein vollständiger Ausschluss der Dimerisierung erreicht werden. Thiophenol, Butanthiol, Mercaptoethanol und Dithiothreitol wurden als Thiolinitiatoren (in Kombination mit DBU) verwendet und waren alle in der Lage die Polymerisation zu starten. Die Kontrolle des Polymerisationsgrades und die enge Molmassenverteilung der Polymere verdeutlichen, dass die thioanionische Polymerisation ebenfalls lebend verläuft. Glycidol Homo- und Copolymere wurden verwendet und die Seitenketten mit Amin-, Thiol-, Carbonsäure- und Cysteingruppen funktionalisiert. Die Cysteinseitenketten wurden durch ein neues thiolfunktionales Thiazolidin erhalten. Ausgehend von Cystein und Aceton wurde zunächst das Dimethyl-substituierte Thiazolidin erhalten, welches daraufhin am Ring-Amin mit Essigsäureanhydrid und Ameisensäure formyliert wurde. Die Carbonsäurefunktion des Thiazolidins wurde mittels CDI aktiviert und anschließend mit Cysteamin umgesetzt. Hierbei bildete sich das niedermolekulare kristalline thiolfunktionale Thiazolidin, welches mittels Thiol-En-Click Chemie an allyl-funktionales Poly(glycidol) geknüpft werden konnte. Eine systematische Untersuchungen der thermischen und UV-induzierten Thiol-En-Click Chemie zeigte, dass wesentlich höhere Umsätze und Geschwindigkeiten bei der photoinduzierten Reaktion erhalten werden. Mittels 0.1 M HCl konnte bei 70 °C innerhalb von 5 d die Hydrolyse der Thiazolidine im Anschluss erreicht werden. Nach der anschließenden Dialyse der Polymere gegen 0.1 M Essigsäure wurde erfolgreich das Acetatsalz der cysteine-funktionalen Poly(glycidol)e erhalten. Diese waren hinsichtlich der Thioloxidation unter atmosphärischen Bedingungen stabil. Ein oxidativer TNSBA-Assay wurde entwickelt, um die Menge der Cysteine zu quantifizieren und gleichzeitig den störenden Einfluss der Thiole zu unterbinden. Ein Kooperationspartner setzte die cysteinfunktionalisierten Poly(glycidol)e mit C-terminalen Thioestern um und konnte die gute Zugänglichkeit und Aktivität der Cysteine entlang des Polymerrückgrats nachweisen. SDS-PAGE, HPLC und MALDI-ToF Messungen bestätigten die erfolgreiche Konjugation im Anschluss. KW - Polymer KW - Thiol-Ene-Click-Chemie KW - Cystein KW - Organische Sulfide KW - Native Chemical Ligation KW - Polyglycidol Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119832 ER - TY - JOUR A1 - Ehmann, Nadine A1 - Sauer, Markus A1 - Kittel, Robert J. T1 - Super-resolution microscopy of the synaptic active zone JF - Frontiers in Cellular Neuroscience N2 - Brain function relies on accurate information transfer at chemical synapses. At the presynaptic active zone (AZ) a variety of specialized proteins are assembled to complex architectures, which set the basis for speed, precision and plasticity of synaptic transmission. Calcium channels are pivotal for the initiation of excitation-secretion coupling and, correspondingly, capture a central position at the AZ. Combining quantitative functional studies with modeling approaches has provided predictions of channel properties, numbers and even positions on the nanometer scale. However, elucidating the nanoscopic organization of the surrounding protein network requires direct ultrastructural access. Without this information, knowledge of molecular synaptic structure-function relationships remains incomplete. Recently, super-resolution microscopy (SRM) techniques have begun to enter the neurosciences. These approaches combine high spatial resolution with the molecular specificity of fluorescence microscopy. Here, we discuss how SRM can be used to obtain information on the organization of AZ proteins KW - excitation-secretion coupling KW - Ca\(^{2+}\) channels KW - structure-function relationships KW - super-resolution microscopy KW - active zone KW - presynaptic calcium KW - neurotransmitter release Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148997 VL - 9 IS - 7 ER - TY - JOUR A1 - Görl, Daniel A1 - Zhang, Xin A1 - Stepanenko, Vladimir A1 - Würthner, Frank T1 - Supramolecular block copolymers by kinetically controlled co-self-assembly of planar and core-twisted perylene bisimides JF - Nature Communications N2 - New synthetic methodologies for the formation of block copolymers have revolutionized polymer science within the last two decades. However, the formation of supramolecular block copolymers composed of alternating sequences of larger block segments has not been realized yet. Here we show by transmission electron microscopy (TEM), 2D NMR and optical spectroscopy that two different perylene bisimide dyes bearing either a flat (A) or a twisted (B) core self-assemble in water into supramolecular block copolymers with an alternating sequence of (A\(_{m}\)BB)\(_{n}\). The highly defined ultralong nanowire structure of these supramolecular copolymers is entirely different from those formed upon self-assembly of the individual counterparts, that is, stiff nanorods (A) and irregular nanoworms (B), respectively. Our studies further reveal that the as-formed supramolecular block copolymer constitutes a kinetic self-assembly product that transforms into thermodynamically more stable self-sorted homopolymers upon heating. KW - cylindrical micelles KW - water KW - amplification KW - association KW - emission KW - organization KW - polymerization KW - dyes KW - fluorescent KW - aqueous medium Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148657 VL - 6 IS - 7009 ER - TY - THES A1 - Holz, Elisa Mira T1 - Systematic evaluation of non-invasive brain-computer interfaces as assistive devices for persons with severe motor impairment based on a user-centred approach – in controlled settings and independent use T1 - Systematische Evaluation nicht-invasiver Gehirn-Computer Schnittstellen als Hilfsmittel für Personen mit schweren motorischen Einschränkungen auf Basis eines nutzerzentrierten Ansatzes – im kontrollierten Setting und experten-unabhängigen Gebrauch N2 - Brain-computer interfaces (BCIs) are devices that translate signals from the brain into control commands for applications. Within the last twenty years, BCI applications have been developed for communication, environmental control, entertainment, and substitution of motor functions. Since BCIs provide muscle independent communication and control of the environment by circumventing motor pathways, they are considered as assistive technologies for persons with neurological and neurodegenerative diseases leading to motor paralysis, such as amyotrophic lateral sclerosis (ALS), muscular dystrophy, spinal muscular atrophy and stroke (Kübler, Kotchoubey, Kaiser, Wolpaw, & Birbaumer, 2001). Although most researcher mention persons with severe motor impairment as target group for their BCI systems, most studies include healthy participants and studies including potential BCI end-users are sparse. Thus, there is a substantial lack of studies that investigate whether results obtained in healthy participants can be transferred to patients with neurodegenerative diseases. This clearly shows that BCI research faces a translational gap between intense BCI research and bringing BCI applications to end-users outside the lab (Kübler, Mattia, Rupp, & Tangermann, 2013). Translational studies are needed that investigate whether BCIs can be successfully used by severely disabled end-users and whether those end-users would accept BCIs as assistive devices. Another obvious discrepancy exists between a plethora of short-term studies and a sparse number of long-term studies. BCI research thus also faces a reliability gap (Kübler, Mattia, et al., 2013). Most studies present only one BCI session, however the few studies that include several testing sessions indicate high inter- and intra-individual variance in the end-users’ performance due to non-stationarity of signals. Long-term studies, however, are needed to demonstrate whether a BCI can be reliably used as assistive device over a longer period of time in the daily-life of a person. Therefore there is also a great need for reliability studies. The purpose of the present thesis was to address these research gaps and to bring BCIs closer to end-users in need, especially into their daily-lives, following a user-centred design (UCD). The UCD was suggested as theoretical framework for bringing BCIs to end-users by Kübler and colleagues (Kübler et al., 2014; Zickler et al., 2011). This approach aims at the close and iterative interaction between BCI developers and end-users with the final goal to develop BCI systems that are accepted as assistive devices by end-users. The UCD focuses on usability, that is, how well a BCI technology matches the purpose and meets the needs and requirements of the targeted end-users and was standardized with the ISO 9241-210. Within the UCD framework, usability of a device can be defined with regard to its effectiveness, efficiency and satisfaction. These aspects were operationalized by Kübler and colleagues to evaluate BCI-controlled applications. As suggested by Vaughan and colleagues, the number of BCI sessions, the total usage duration and the impact of the BCI on the life of the person can be considered as indicators of usefulness of the BCI in long-term daily-life use (Vaughan, Sellers, & Wolpaw, 2012). These definitions and metrics for usability and usefulness were applied for evaluating BCI applications as assistive devices in controlled settings and independent use. Three different BCI applications were tested and evaluated by in total N=10 end-users: In study 1 a motor-imagery (MI) based BCI for gaming was tested by four end-users with severe motor impairment. In study 2, a hybrid P300 event-related (ERP) based BCI for communication was tested by four severely motor restricted end-users with severe motor impairment. Study 1 and 2 are short-term studies conducted in a controlled-setting. In study 3 a P300-ERP BCI for creative expression was installed for long-term independent use at the homes of two end-users in the locked-in state. Both end-users are artists who had gradually lost the ability to paint after being diagnosed with ALS. Results reveal that BCI controlled devices are accepted as assistive devices. Main obstacles for daily-life use were the not very aesthetic design of the EEG-cap and electrodes (cap is eye-catching and looks medical), low comfort (cables disturb, immobility, electrodes press against head if lying on a head cushion), complicated and time-consuming adjustment, low efficiency and low effectiveness, and not very high reliability (many influencing factors). While effectiveness and efficiency in the MI based BCI were lower compared to applications using the P300-ERP as input channel, the MI controlled gaming application was nevertheless better accepted by the end-users and end-users would rather like to use it compared to the communication applications. Thus, malfunctioning and errors, low speed, and the EEG cap are rather tolerated in gaming applications, compared to communication devices. Since communication is essential for daily-life, it has to be fast and reliable. BCIs for communication, at the current state of the art, are not considered competitive with other assistive devices, if other devices, such as eye-gaze, are still an option. However BCIs might be an option when controlling an application for entertainment in daily-life, if communication is still available. Results demonstrate that BCI is adopted in daily-life if it matches the end-users needs and requirements. Brain Painting serves as best representative, as it matches the artists’ need for creative expression. Caveats such as uncomfortable cap, dependence on others for set-up, and experienced low control are tolerated and do not prevent BCI use on a daily basis. Also end-users in real need of means for communication, such as persons in the locked-in state with unreliable eye-movement or no means for independent communication, do accept obstacles of the BCI, as it is the last or only solution to communicate or control devices. Thus, these aspects are “no real obstacles” but rather “challenges” that do not prevent end-users to use the BCI in their daily-lives. For instance, one end-user, who uses a BCI in her daily-life, stated: “I don’t care about aesthetic design of EEG cap and electrodes nor amplifier”. Thus, the question is not which system is superior to the other, but which system is best for an individual user with specific symptoms, needs, requirements, existing assistive solutions, support by caregivers/family etc.; it is thereby a question of indication. These factors seem to be better “predictors” for adoption of a BCI in daily-life, than common usability criterions such as effectiveness or efficiency. The face valid measures of daily-life demonstrate that BCI-controlled applications can be used in daily-life for more than 3 years, with high satisfaction for the end-users, without experts being present and despite a decrease in the amplitude of the P300 signal. Brain Painting re-enabled both artists to be creatively active in their home environment and thus improved their feelings of happiness, usefulness, self-esteem, well-being, and consequently quality of life and supports social inclusion. This thesis suggests that BCIs are valuable tools for people in the locked-in state. N2 - Gehirn-Computer Schnittstellen (engl. Brain-computer interfaces, Abk.: BCIs) sind technische Systeme, die Gehirnsignale in Kontrollbefehle für Computeranwendungen übersetzen. In den vergangenen zwanzig Jahren wurden verschiedenste BCI Anwendungen entwickelt, beispielsweise zur Kommunikation, Umweltsteuerung, Unterhaltung und Ersatz von Motorfunktionen. Da BCIs muskelunabhängige Kommunikation und Kontrolle ermöglichen, werden sie als mögliche Hilfsmittel für Personen mit neurologischen und neurodegenerativen Krankheiten, die zu motorischen Lähmungen führen, wie beispielsweise bei Amyotrophe Lateralsklerose (ALS), Muskeldystrophie, Spinale Muskelatrophie und Schlaganfall, in Betracht gezogen (Kübler, Kotchoubey, et al., 2001). Auch wenn die meisten BCI Forscher Personen mit starken motorischen Einschränkungen als Zielgruppe für ihre BCI Systeme angeben, so testen sie ihre Systeme nur in Stichproben von gesunden Probanden. BCI Studien, die Patienten einschließen, sind dagegen selten. Daher gibt es einen beträchtlichen Mangel an Studien, die untersuchen, ob die Forschungsergebnisse, die basierend auf einer gesunden Stichprobe verzeichnet wurden, auch auf Patienten mit neurodegenerativen Erkrankungen übertragen werden können. Das macht deutlich, dass es in der BCI Forschung eine erhebliche Translationslücke zwischen der intensiven BCI Grundlagenforschung und dem Transfer von BCI Anwendungen aus dem Labor zu den Patienten, den sogenannten BCI End-Nutzern, gibt (Kübler, Mattia, et al., 2013). Es werden deshalb Translationsstudien benötigt, die untersuchen, ob BCIs von stark motorisch eingeschränkten Patienten verwendet werden können und ob diese sogenannten End-Nutzer BCIs als Hilfsmittel akzeptieren. Zusätzlich ist eine deutliche Diskrepanz zwischen der Vielzahl an Kurzzeitstudien und der geringen Anzahl an Langzeitstudien zu verzeichnen. BCI Forschung ist daher auch mit einer Reliabilitätslücke konfrontiert (Kübler, Mattia, et al., 2013). Die meisten Studien basieren nur auf einer BCI Sitzung, jedoch zeigen die wenigen Studien, die auf mehreren Sitzungen beruhen, hohe inter- und intraindividuelle Varianz in der Performanz der Patienten. Langzeitzeitstudien werden daher benötigt, um aufzuzeigen, ob ein BCI reliabel als Hilfsmittel über einen längeren Zeitraum im Alltagsleben eines Patienten verwendet werden kann. Demzufolge gibt es einen starken Bedarf an Translations- und Reliabilitätsstudien. Das Anliegen der vorliegenden Dissertation war es, diesen Forschungslücken zu begegnen und, basierend auf einem nutzerzentrierten Vorgehen, BCIs näher zu den BCI End-Nutzern zu bringen, besonders in ihr Alltagsleben. Der nutzerzentrierte Ansatz wurde von Kübler und Kollegen (Kübler et al., 2014; Zickler et al., 2011) als theoretisches Gerüst nahegelegt, um BCIs näher zu Patienten zu bringen. Dieser Ansatz beabsichtigt eine enge und iterative Interaktion zwischen BCI Entwicklern und den End-Nutzern mit dem finalen Ziel BCI Systeme zu entwickeln, die von den End-Nutzern als Hilfsmittel akzeptiert werden. Der nutzerzentrierte Ansatz fokussiert auf die Benutzbarkeit, das heißt, wie gut eine BCI Technologie den Bedürfnissen und den Ansprüchen der Zielgruppe entspricht. Dieser Ansatz wurde standardisiert mit dem ISO 9241-210. Demnach ist die Benutzbarkeit eines Gerätes definiert hinsichtlich der Effektivität, Effizienz, und Zufriedenheit. Um BCI Systeme zu evaluieren, wurden diese Aspekte von Kübler und Kollegen operationalisiert. Nach Vaughan und Kollegen können die Anzahl der BCI Sitzungen, die Gesamtnutzungsdauer und der Einfluss eines BCIs auf die Lebensqualität einer Person als Indikatoren der Nützlichkeit eines BCI betrachtet werden (Vaughan et al., 2012). Diese Definitionen und entsprechenden Operationalisierungen wurden in dieser Dissertation verwendet, um BCI Anwendungen hinsichtlich ihrer Benutzbarkeit und Nützlichkeit als Hilfsmittel zu evaluieren. N=10 End-Nutzer testeten und evaluierten drei BCI Anwendungen: In Studie 1 wurde ein auf Bewegungsvorstellung basiertes BCI (engl. motor imagery, Abk: MI) zur Steuerung einer Spielanwendung von vier potentiellen End-Nutzern mit unterschiedlichen neurologischen Erkrankungen getestet. In Studie 2 wurde ein Hybrid BCI, das das P300 ereignis-korrelierte Potential (EKP) und Muskelaktivität als Inputkanäle zur Steuerung eines Kommunikationsprogramms verwendet, von vier potentiellen End-Nutzern getestet. Studie 1 und 2 sind Kurzzeitstudien, welche in einem kontrollierten Design durchgeführt wurden. In Studie 3 wurde ein P300-EKP basiertes BCI zum künstlerischen Ausdruck bei zwei End-Nutzern zuhause für einen experten-unabhängigen und längerfristigen Gebrauch implementiert. Beide End-Nutzer sind Künstler, die, aufgrund der Diagnose ALS und der damit verbundenen fast kompletten körperlichen Lähmung (Locked-in Zustand), nicht mehr in der Lage waren zu malen (Studie 3). Die Ergebnisse zeigen, dass BCI Systeme als Hilfsmittel akzeptiert werden. Das nicht sehr ästhetische Design der EEG-Kappe und der Elektroden (Kappe zu auffällig, sieht medizinisch aus), der geringe Komfort (Kabel stören, Immobilität, Elektroden drücken gegen den Kopf), die komplizierte und zeitaufwändige Einstellung und Anpassung, die geringe Effizienz und geringe Effektivität und die nicht sehr hohe Reliabilität (viele Einflussfaktoren), wurden jedoch für einen Alltagsgebrauch als problematisch angesehen. Obwohl die Effektivität und Effizienz beim MI BCI geringer, verglichen mit beiden P300-EKP BCI Systemen, waren, wurde das MI basierte BCI-Spiel von den End-Nutzern besser akzeptiert und die End-Nutzer konnten sich eher vorstellen es im Alltag zu verwenden, als das Kommunikationsprogramm. Das zeigt, dass Störungen und Fehler, eine geringe Geschwindigkeit, und die EEG Kappe bei BCI Systemen zur Unterhaltung eher toleriert werden, als bei Systemen zur Kommunikation. Da Kommunikation im Leben essentiell ist, muss sie schnell und zuverlässig sein. BCI Systeme zur Kommunikation sind daher zum aktuellen Stand der Technik nicht konkurrenzfähig mit anderen Hilfsmitteln, wenn andere Hilfsmittel zur Kommunikation, wie Augensteuerung, verwendet werden können. BCI Systeme sind aber eine Option im Bereich Unterhaltung, sofern Möglichkeiten zur Kommunikation (noch) bestehen. Die Ergebnisse zeigen, dass ein BCI für einen Alltagsgebrauch übernommen wird, wenn es den Bedürfnissen und Anforderungen des End-Nutzers entspricht. Brain Painting zeigt hierbei beispielhaft, wie negative Facetten, wie die wenig komfortable EEG Kappe, die Abhängigkeit von anderen aufgrund der komplexen Einstellung, und eine subjektiv empfundene geringe Kontrolle toleriert werden, da es genau den Bedürfnissen der Künstler sich kreativ auszudrücken entspricht. Ebenso Patienten, die Bedarf an Kommunikation haben, wie Patienten im Locked-in Zustand, die keine zuverlässigen Augen-Bewegungen aufweisen, oder Patienten, die keine Hilfsmittel zur unabhängigen Kommunikation haben, akzeptieren diese Umstände beim BCI Gebrauch. Das zeigt, dass diese Umstände keine richtigen „Hindernisse“, sondern vielmehr Herausforderungen sind, die eine Übernahme eines BCI im Alltag eines Patienten nicht verhindern. Es ist daher nicht die Frage, welches BCI System überlegen ist, sondern welches BCI System das Beste für ein Individuum mit spezifischen Symptomen, Bedürfnissen, Ansprüchen, vorhandenen Hilfsmitteln, Unterstützung durch Familie und Pflegern, ist; es ist deshalb eine Frage der Indikation. Eine End-Nutzerin, die ein BCI im Alltag verwendet, sagte beispielsweise: „Mir ist das ästhetische Design der EEG-Kappe und der Elektroden, oder des EEG-Verstärkers völlig egal“. Diese Faktoren können als die besten “Prädiktoren” für eine Übernahme eines BCI Systems im Alltag eines Patienten angesehen werden, weniger hingegen die üblichen Kriterien zur Bewertung der Benutzbarkeit, wie Effektivität und Effizienz. Die Ergebnisse hinsichtlich des Alltagsgebrauches belegen ferner, dass ein P300-EKP basiertes BCI mit hoher Zufriedenheit über einen Zeitraum von 3 Jahren, ohne die Hilfe eines BCI Experten, und trotz einer Abnahme der Amplitude des P300-Signales verwendet werden kann. Brain Painting ermöglichte beiden Künstlern sich wieder kreativ auszudrücken und beeinflusste somit positiv das Empfinden von Freude, das Gefühl von Nützlichkeit, das Selbstwertgefühl, das Wohlbefinden und folglich die Lebensqualität der Künstler und förderte ihre soziale Inklusion. Die vorliegende Dissertation zeigt, dass BCIs wertvolle Hilfsmittel für Personen im Locked-in Zustand sein können. KW - Gehirn-Computer-Schnittstelle KW - Benutzerfreundlichkeit KW - brain-computer interface KW - evaluation KW - Evaluation KW - usability KW - Benutzerfreundlichkeit/ Benutzbarkeit KW - assistive device KW - Hilfsmittel KW - user-centred design KW - nutzerzentrierter Ansatz Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126334 ER - TY - THES A1 - Richard, Annika T1 - Systematic Review of Measles, Mumps and Rubella Vaccination Programs in Selected European Countries and the Influence of Migration Movements T1 - Systematischer Review der Impfstrategien für Masern, Mumps und Röteln in ausgewählten europäischen Ländern und die Auswirkungen von Migrationsbewegungen N2 - Masern, Mumps und Röteln sind virale Infektionskrankheiten, die schwere und verheerenden Komplikationen bei den erkrankten Personen verursachen können. Die weltweite Krankheitslast dieser Infektionskrankheiten ist hoch und könnte durch erfolgreiche Impfstrategien merkenswert reduziert werden. Die WHO hat daher das Ziel der globalen Eliminierung von Masern und Röteln sowie der Kontrolle der oft simultan geimpften Mumps Erkrankung gesetzt. Im Jahr 2010 einigten sich die WHO-Mitgliedstaaten der europäischen Region, gezielte Strategien zu verfolgen, um Masern und Röteln bis Ende des Jahres 2015 in Europa zu eliminieren. Analysen bezüglich des aktuellen Fortschrittes werden daher zunehmend relevanter. Als Teil dieser systematischen Literaturrecherche wurden die Immunisierungsstrategien, Impfraten und Krankheitsinzidenzen von elf europäischen Ländern untersucht und ihre Fortschritte im Hinblick auf die Krankheitseliminierung bewertet. Eine erfolgreiche Prävention der endemischen Übertragung von Masern, Mumps oder Röteln Viren konnte in mehreren Ländern erreicht werden, darunter Schweden, Kroatien, Griechenland und Spanien. Den Ländern Österreich, Frankreich, Deutschland, Italien, Polen, Türkei und dem Vereinigten Königreich von Großbritannien und Nordirland ist es trotz verbesserter Immunisierungsraten bisher nicht gelungen, die Eliminierungsziele zu erreichen. In der Türkei, Italien und Polen, kam es in den letzten Jahren zu starken Anstiegen der Fallzahlen, welche die Masern, Mumps und Röteln Kontrolle in Europa deutlich erschweren und das zeitnahe Erreichen der Eliminationsziele gefährden. Unzureichend immunisierte Bevölkerungsgruppen, die zu einer Aufrechterhaltung der Infektionserkrankungen im europäischen Raum beitragen können, wurden identifiziert. Dazu zählen Säuglinge und Kleinkinder, Jugendliche und junge Erwachsene, Männer, kürzlich eingewanderte Personen und Flüchtlinge, sowie reisende ethnischer Minderheiten. Die Gründe für das erhöhte Risiko einer Masern, Mumps oder Röteln Infektion unter diesen Personengruppen sind vielfältig und ein Ergebnis von verschiedenen historischen und aktuellen Impfstrategien, kulturellen, politischen und religiösen Unterschieden, sowie persönlichem Glauben und Ansichten. Das Reisen und die Migration von infizierten Personen nach und zwischen den verschiedenen europäischen Ländern spielt auch eine wesentliche Rolle bei der kontinuierlichen Übertragung der Erkrankungen in Europa. Nur durch eine ausreichend hohe Immunität der Bevölkerung kann das Auftreten von größeren Ausbrüchen trotz der Einfuhr viraler Erreger verhindert werden. Bestrebungen sollte daher die Immunisierung aller impffähigen Personen umfassen, sowie die Erweiterung spezifischer Impfstrategien für unzureichend immunisierte Bevölkerungsgruppen, die nur schwer durch Routineimpfungen zu erreichen sind. Europäische Länder, in denen die WHO Eliminierungsziele bisher nicht erreicht wurden, könnten möglicherweise von alternativen Impfstrategien profitieren. Ein einheitlicher, europaweiter MMR-Impfplan basierend auf den erfolgreichen Immunisierungsverfahren der Länder, die Masern, Mumps und Röteln erfolgreich bekämpft haben, stellt ein wirksames Instrument zur Verbesserung der allgemeinen Bevölkerungsimmunität und Kontrolle der drei Infektionskrankheiten dar. Ein Entwurf solch eines Impfplanes wurde im Rahmen dieser Dissertation erstellt und enthält Strategien für das Erreichen ungeschützter Bevölkerungsgruppen, unabhängig von Alter, Geschlecht oder Migrationshintergrund. Die Umsetzung einheitlicher Impfempfehlungen bringt mehrere Herausforderungen mit sich. Die vielen Vorteile im Hinblick auf die verbesserte Immunisierung, Überwachung und Bekämpfung der Erkrankungen lassen die Aufwände jedoch als berechtigt erscheinen. Die endemische Eliminierung von Masern, Mumps und Röteln Viren innerhalb der europäischen Region ist durchaus erzielbar. Die aktuelle epidemiologische Situation deutet jedoch darauf hin, dass das Ziel nicht bis zum Ende des Jahres 2015 erreicht wird, sondern weitere Bestrebungen auf internationaler Ebene notwendig sind, um eine wirksame Krankheitsbekämpfung in der näheren Zukunft zu erreichen. Durch nationale und internationale Verbesserungen der Immunisierungsstrategien und gezielten Impfkampagnen sowie Erkrankungs-Meldesystemen und laborchemischen Erregerbestätigungen kann eine weitgefächerte Bevölkerungsimmunität erzielt und Krankheitseliminierung unter adäquatem Monitoring des Fortschritts im gesamten europäischen Raum erreicht werden. N2 - Measles, mumps and rubella are viral infectious diseases that may cause severe and devastating complications among affected individuals. The disease burden of all three diseases is high, but could be reduced entirely through successful vaccination strategies. As such, the WHO has established the goal of globally eliminating measles and rubella and concomitantly controlling the frequently co-vaccinated mumps. In 2010, the WHO European Region member states agreed to strengthen efforts to eliminate measles and rubella from Europe by the end of 2015. As this date draws closer, progress analyses become increasingly relevant. In this systematic literature review, the immunization strategies, vaccination coverages and disease incidences of eleven European nations were assessed and their progress towards disease elimination evaluated. Successful prevention of the endemic transmission of measles, mumps, or rubella could be achieved in several nations, including Sweden, Croatia, Greece and Spain. Austria, France, Germany, Italy, Poland, Turkey and the United Kingdom of Great Britain and Northern Ireland, though having improved their overall immunization rates, have not yet been able to reach the elimination goals. In Turkey, Italy and Poland, sharp increases in case numbers during recent years are potentially threatening the successful measles, mumps and rubella control in Europe. Pockets of susceptible population groups that may contribute to the perpetuation of the diseases have been identified. They include infants and young children, adolescents and young adults, adolescent and adult males, recent immigrants and refugees,and traveling ethnic minority groups. Reasons for the increased risk of infection among these groups are manifold and a result of various historic and current vaccination practices, cultural, political and religious differences, as well as individual believes and concerns. Travel and migration of infected individuals to and between the various European nations also play an essential role in the continual transmission of measles, mumps and rubella in Europe. Only an adequate population-wide immunity can prevent the occurrence of major outbreaks due to viral importation. Efforts should therefore be made to immunize all population members able to receive vaccinations and to offer additional immunization opportunities to those susceptible population subgroups that are difficult to reach through routine vaccination programs. In countries struggling to meet the WHO elimination goals, alternative immunization practices may be necessary. A uniform, European-wide MMR vaccination schedule based on the successful immunization methods of countries that have eliminated measles, mumps and rubella may be an effective tool for improving the overall population-wide immunity and controlling the three diseases. A model for such a schedule was created and includes strategies for reaching population members regardless of age, gender or migratory background. The implementation of uniform immunization recommendations is challenging, but the advantages in terms of improved vaccination, surveillance and disease control methods may be worth at least considering such a strategy in Europe. Measles, mumps and rubella elimination may be attainable in the WHO European Region. The current epidemiological situation suggests that the goal is unlikely to be reached by the end of 2015, but through continued international efforts and collaboration, effective disease control could be achieved in the near future. In the meantime, improvements in immunization strategies, vaccination coverages, supplementary campaigns as well as disease notification systems and confirmations should be made on a national and international level, so that an adequate population-wide immunity can be established and the disease elimination progresses effectively monitored within the entire European region. KW - Masern KW - Mumps KW - Röteln KW - Impfung KW - systematic review KW - migration KW - Impfplan KW - vaccination program Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138033 ER - TY - JOUR A1 - Bahník, Štěpán A1 - Stuchlík, Aleš T1 - Temporal and spatial strategies in an active place avoidance task on Carousel: a study of effects of stability of arena rotation speed in rats JF - PeerJ N2 - The active place avoidance task is a dry-arena task used to assess spatial navigation and memory in rodents. In this task, a subject is put on a rotating circular arena and avoids an invisible sector that is stable in relation to the room. Rotation of the arena means that the subject's avoidancemust be active, otherwise the subject will be moved in the to-be-avoided sector by the rotation of the arena and a slight electric shock will be administered. The present experiment explored the effect of variable arena rotation speed on the ability to avoid the to-be-avoided sector. Subjects in a group with variable arena rotation speed learned to avoid the sector with the same speed and attained the same avoidance ability as rats in a group with a stable arena rotation speed. Only a slight difference in preferred position within the room was found between the two groups. No difference was found between the two groups in the dark phase, where subjects could not use orientation cues in the room. Only one rat was able to learn the avoidance of the to-be-avoided sector in this phase. The results of the experiment suggest that idiothetic orientation and interval timing are not crucial for learning avoidance of the to-be-avoided sector. However, idiothetic orientation might be sufficient for avoiding the sector in the dark. KW - navigation KW - interval timing KW - rats KW - morris water maze KW - hippocampal-neurons KW - D2 receptors KW - animal model KW - acute MK-801 KW - memory KW - behavior KW - dissociation KW - flexibility KW - spatial navigation KW - substratal idiothetic navigation KW - inertial idiothetic navigation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141931 VL - 3 IS - e1257 ER - TY - JOUR A1 - Hillmann, Steffi A1 - Wiedmann, Silke A1 - Fraser, Alec A1 - Baeza, Juan A1 - Rudd, Anthony A1 - Norrving, Bo A1 - Asplund, Kjell A1 - Niewada, Maciej A1 - Dennis, Martin A1 - Hermanek, Peter A1 - Wolfe, Charles D. A. A1 - Heuschmann, Peter U. T1 - Temporal changes in the quality of acute stroke care in five national audits across Europe JF - BioMed Research International N2 - Background. Data on potential variations in delivery of appropriate stroke care over time are scarce. We investigated temporal changes in the quality of acute hospital stroke care across five national audits in Europe over a period of six years. Methods. Data were derived from national stroke audits in Germany, Poland, Scotland, Sweden, and England/Wales/Northern Ireland participating within the European Implementation Score (EIS) collaboration. Temporal changes in predefined quality indicators with comparable information between the audits were investigated. Multivariable logistic regression analyses were performed to estimate adherence to quality indicators over time. Results. Between 2004 and 2009, individual data from 542,112 patients treated in 538 centers participating continuously over the study period were included. In most audits, the proportions of patients who were treated on a SU, were screened for dysphagia, and received thrombolytic treatment increased over time and ranged from 2-fold to almost 4-fold increase in patients receiving thrombolytic therapy in 2009 compared to 2004. Conclusions. A general trend towards a better quality of stroke care defined by standardized quality indicators was observed over time. The association between introducing a specific measure and higher adherence over time might indicate that monitoring of stroke care performance contributes to improving quality of care. KW - ischemic stroke KW - indicators KW - thrombolysis KW - registries KW - outcomes KW - mortality KW - implementation KW - German Stroke Registers Study Group Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149059 VL - 2015 IS - 432497 ER - TY - JOUR A1 - Scholz, Nicole A1 - Gehring, Jennifer A1 - Guan, Chonglin A1 - Ljaschenko, Dmitrij A1 - Fischer, Robin A1 - Lakshmanan, Vetrivel A1 - Kittel, Robert J. A1 - Langenhan, Tobias T1 - The adhesion GPCR Latrophilin/CIRL shapes mechanosensation JF - Cell Reports N2 - G-protein-coupled receptors (GPCRs) are typically regarded as chemosensors that control cellular states in response to soluble extracellular cues. However, the modality of stimuli recognized through adhesion GPCR (aGPCR), the second largest class of the GPCR superfamily, is unresolved. Our study characterizes the Drosophila aGPCR Latrophilin/dCirl, a prototype member of this enigmatic receptor class. We show that dCirl shapes the perception of tactile, proprioceptive, and auditory stimuli through chordotonal neurons, the principal mechanosensors of Drosophila. dCirl sensitizes these neurons for the detection of mechanical stimulation by amplifying their input-output function. Our results indicate that aGPCR may generally process and modulate the perception of mechanical signals, linking these important stimuli to the sensory canon of the GPCR superfamily. KW - \(\alpha\)-latrotoxin KW - chordotonal organs KW - Johnstons organ KW - ligand CD55 KW - hearing KW - binding KW - shear stress KW - protein-coupled receptors KW - drosophila larvae KW - domain Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148626 VL - 11 ER - TY - JOUR A1 - Rovituso, Damiano M. A1 - Duffy, Catharina E. A1 - Schroeter, Michael A1 - Kaiser, Claudia C. A1 - Kleinschnitz, Christoph A1 - Bayas, Antonios A1 - Elsner, Rebecca A1 - Kuerten, Stefanie T1 - The brain antigen-specific B cell response correlates with glatiramer acetate responsiveness in relapsing-remitting multiple sclerosis patients JF - Scientific Reports N2 - B cells have only recently begun to attract attention in the immunopathology of multiple sclerosis (MS). Suitable markers for the prediction of treatment success with immunomodulatory drugs are still missing. Here we evaluated the B cell response to brain antigens in n = 34 relapsing-remitting MS (RRMS) patients treated with glatiramer acetate (GA) using the enzyme-linked immunospot technique (ELISPOT). Our data demonstrate that patients can be subdivided into responders that show brain-specific B cell reactivity in the blood and patients without this reactivity. Only in patients that classified as B cell responders, there was a significant positive correlation between treatment duration and the time since last relapse in our study. This correlation was GA-specific because it was absent in a control group that consisted of interferon-\(\beta\) (IFN-\(\beta\))-treated RRMS patients (n = 23). These data suggest that GA has an effect on brain-reactive B cells in a subset of patients and that only this subset benefits from treatment. The detection of brain-reactive B cells is likely to be a suitable tool to identify drug responders. KW - cortical pathology KW - natural history KW - disability KW - expression KW - antibodies KW - disease KW - lesions KW - trial KW - multiple sclerosis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148172 VL - 5 IS - 14265 ER - TY - JOUR A1 - García-Martínez, Jorge A1 - Brunk, Michael A1 - Avalos, Javier A1 - Terpitz, Ulrich T1 - The CarO rhodopsin of the fungus Fusarium fujikuroi is a light-driven proton pump that retards spore germination JF - Scientific Reports N2 - Rhodopsins are membrane-embedded photoreceptors found in all major taxonomic kingdoms using retinal as their chromophore. They play well-known functions in different biological systems, but their roles in fungi remain unknown. The filamentous fungus Fusarium fujikuroi contains two putative rhodopsins, CarO and OpsA. The gene carO is light-regulated, and the predicted polypeptide contains all conserved residues required for proton pumping. We aimed to elucidate the expression and cellular location of the fungal rhodopsin CarO, its presumed proton-pumping activity and the possible effect of such function on F. fujikuroi growth. In electrophysiology experiments we confirmed that CarO is a green-light driven proton pump. Visualization of fluorescent CarO-YFP expressed in F. fujikuroi under control of its native promoter revealed higher accumulation in spores (conidia) produced by light-exposed mycelia. Germination analyses of conidia from carO\(^{-}\) mutant and carO\(^{+}\) control strains showed a faster development of light-exposed carO-germlings. In conclusion, CarO is an active proton pump, abundant in light-formed conidia, whose activity slows down early hyphal development under light. Interestingly, CarO-related rhodopsins are typically found in plant-associated fungi, where green light dominates the phyllosphere. Our data provide the first reliable clue on a possible biological role of a fungal rhodopsin. KW - microbial rhodopsins KW - intracellular pH KW - membrane proteins KW - mutants KW - virulence KW - channelrhodopsin-2 KW - growth KW - gene KW - expression KW - bacteriorhodopsin Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149049 VL - 5 IS - 7798 ER - TY - THES A1 - Zürn, Michael T1 - The Dual Nature of Utility - Categorical and Comparative Evaluations in Economic Decisions T1 - Die Dualität des Nutzens - kategoriale und komparative Bewertungen in ökonomischen Entscheidungen N2 - Utility is perhaps the most central concept in modern economic theorizing. However, the behaviorist reduction to Revealed Preference not only removed the psychological content of utility but experimental investigations also exposed numerous anomalies in this theory. This program of research focused on the psychological processes by which utility judgments are generated. For this purpose, the standard assumption of a homogeneous concept is substituted by the Utilitarian Duality Hypothesis. In particular, judgments concerning categorical utility (uCat) infer an object's category based on its attributes which may subsequently allow the transfer of evaluative information like feelings or attitudes. In contrast, comparative utility (uCom) depends on the distance to a reference value on a specific dimension of comparison. Importantly, dimensions of comparison are manifold and context dependent. In a series of experiments, we show that the resulting Dual Utility Model is able to explain several known anomalies in a parsimonious fashion. Moreover, we identify central factors determining the relative weight assigned to both utility components. Finally, we discuss the implications of the Utilitarian Duality for both, the experimental practice in economics as well as the consequences for economic theorizing. In sum, we propose that the Dual Utility Model can serve as an integrative framework for both the rational model and its anomalies. N2 - Der Nutzen ist wohl eines der meist beachteten Konzepte der ökonomischen Theorie. Allerdings entfernte die behavioristische Reduktion auf offenbarte Präferenzen nicht nur den psychologischen Inhalt des Nutzens, sondern zeigte darüber hinaus in experimentellen Untersuchungen auch zahlreiche Anomalien der Theorie auf. Das vorliegende Forschungsprogramm stellt die psychologischen Prozesse in den Vordergrund, mittels derer Nutzen beurteilt wird. Zu diesem Zweck wird die verbreitete Annahme eines homogenen Konzepts durch die Zwei-Nutzen-Hypothese ersetzt. Im Besonderen bestimmen Urteile über den kategorialen Nutzen (uCat) anhand der Attribute eines Objekts zunächst dessen Kategorie, wodurch daraufhin bewertende Informationen, wie z.B. Gefühle oder Einstellungen, auf das Objekt übertragen werden können. Demgegenüber bestimmt sich der komparative Nutzen (uCom) über die Abweichung von einem Referenzwert in einer bestimmten Vergleichsdimension, welche generell zahlreich und kontextabhängig sein können. In einer Serie von Experimenten wird gezeigt, dass das resultierende Zwei-Nutzen-Modell eine Reihe von bekannten Anomalien in einer sparsamen Weise erklären kann. Darüber hinaus werden zentrale Faktoren identifiziert, welche die relative Gewichtung beider Nutzenkomponenten bestimmen. Schließlich werden die Implikationen der Zwei-Nutzen-Hypothese für die experimentelle Praxis und die ökonomische Theorie diskutiert. Zusammenfassend wird ausgeführt, dass das entwickelte Zwei-Nutzen-Modell als integrativer Rahmen für sowohl das rationale Modell als auch für seine Anomalien dienen kann. KW - Nutzen KW - Psychologie KW - Ultimatum Game KW - transaction utility KW - preference construction KW - utility KW - revealed preference KW - Wert KW - Preisvergleich KW - Nutzenvergleich Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120141 ER - TY - JOUR A1 - Wieser, Matthias J. A1 - Moscovitch, David A. T1 - The effect of affective context on visuocortical processing of neutral faces in social anxiety - An ERP study JF - Frontiers in Psychology N2 - It has been demonstrated that verbal context information alters the neural processing of ambiguous faces such as faces with no apparent facial expression. In social anxiety, neutral faces may be implicitly threatening for socially anxious individuals due to their ambiguous nature, but even more so if these neutral faces are put in self-referential negative contexts. Therefore, we measured event-related brain potentials (ERPs) in response to neutral faces which were preceded by affective verbal information (negative, neutral, positive). Participants with low social anxiety (LSA; n = 23) and high social anxiety (HSA; n = 21) were asked to watch and rate valence and arousal of the respective faces while continuous EEG was recorded. ERP analysis revealed that HSA showed elevated P100 amplitudes in response to faces, but reduced structural encoding of faces as indexed by reduced N170 amplitudes. In general, affective context led to an enhanced early posterior negativity (EPN) for negative compared to neutral facial expressions. Moreover, HSA compared to LSA showed enhanced late positive potentials (LPP) to negatively contextualized faces, whereas in LSA this effect was found for faces in positive contexts. Also, HSA rated faces in negative contexts as more negative compared to LSA. These results point at enhanced vigilance for neutral faces regardless of context in HSA, while structural encoding seems to be diminished (avoidance). Interestingly, later components of sustained processing (LPP) indicate that LSA show enhanced visuocortical processing for faces in positive contexts (happy bias), whereas this seems to be the case for negatively contextualized faces in HSA (threat bias). Finally, our results add further new evidence that top-down information in interaction with individual anxiety levels can influence early-stage aspects of visual perception. KW - context effects KW - face processing KW - social anxiety KW - ERPs (Event-Related Potentials) KW - EEG/ERP Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125148 VL - 6 ER - TY - JOUR A1 - Zusan, Andreas A1 - Gieseking, Björn A1 - Zerson, Mario A1 - Dyakonov, Vladimir A1 - Magerle, Robert A1 - Deibel, Carsten T1 - The Effect of Diiodooctane on the Charge Carrier Generation in Organic Solar Cells Based on the Copolymer PBDTTT-C JF - Scientific Reports N2 - Microstructural changes and the understanding of their effect on photocurrent generation are key aspects for improving the efficiency of organic photovoltaic devices. We analyze the impact of a systematically increased amount of the solvent additive diiodooctane (DIO) on the morphology of PBDTTT-C:PC71BM blends and related changes in free carrier formation and recombination by combining surface imaging, photophysical and charge extraction techniques. We identify agglomerates visible in AFM images of the 0% DIO blend as PC71BM domains embedded in an intermixed matrix phase. With the addition of DIO, a decrease in the size of fullerene domains along with a demixing of the matrix phase appears for 0.6% and 1% DIO. Surprisingly, transient absorption spectroscopy reveals an efficient photogeneration already for the smallest amount of DIO, although the largest efficiency is found for 3% DIO. It is ascribed to a fine-tuning of the blend morphology in terms of the formation of interpenetrating donor and acceptor phases minimizing geminate and nongeminate recombination as indicated by charge extraction experiments. An increase in the DIO content to 10% adversely affects the photovoltaic performance, most probably due to an inefficient free carrier formation and trapping in a less interconnected donor-acceptor network. KW - electronic properties and materials KW - photonic devices Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125022 VL - 5 ER - TY - JOUR A1 - Neumann, Yvonne A1 - Ohlsen, Knut A1 - Donat, Stefanie A1 - Engelmann, Susanne A1 - Kusch, Harald A1 - Albrecht, Dirk A1 - Cartron, Michael A1 - Hurd, Alexander A1 - Foster, Simon J. T1 - The effect of skin fatty acids on Staphylococcus aureus JF - Archives of Microbiology N2 - Staphylococcus aureus is a commensal of the human nose and skin. Human skin fatty acids, in particular cis-6-hexadecenoic acid (C-6-H), have high antistaphylococcal activity and can inhibit virulence determinant production. Here, we show that sub-MIC levels of C-6-H result in induction of increased resistance. The mechanism(s) of C-6-H activity was investigated by combined transcriptome and proteome analyses. Proteome analysis demonstrated a pleiotropic effect of C-6-H on virulence determinant production. In response to C-6-H, transcriptomics revealed altered expression of over 500 genes, involved in many aspects of virulence and cellular physiology. The expression of toxins (hla, hlb, hlgBC) was reduced, whereas that of host defence evasion components (cap, sspAB, katA) was increased. In particular, members of the SaeRS regulon had highly reduced expression, and the use of specific mutants revealed that the effect on toxin production is likely mediated via SaeRS KW - S. aureus KW - skin fatty acid KW - C-6-H KW - resistance Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121657 VL - 197 ER - TY - THES A1 - Erlbeck, Helena T1 - The event-related potentials Mismatch Negativity, P300, and N400: Effects of attentional modulation and application in patients with disorders of consciousness T1 - Die ereigniskorrelierten Potentiale Mismatch Negativity, P300, und N400: Effekte von Aufmerksamkeitsmodulation und Anwendung in Patienten mit Störungen des Bewusstseins N2 - The present work comprises four studies dealing with the investigation of the auditory event-related potentials (ERP) Mismatch Negativity (MMN), P300, and N400 under different attentional instructions, and with their application in patients with disorders of consciousness (DOC) to assess residual cognitive functioning. In guided interviews (study 1), practitioners working with DOC patients stated their general interest in and an objective need for the complementation of current diagnostic procedures by reliable and valid ERP-based methods. Subsequently, in study 2, simple oddball and semantic paradigms were applied to 19 behaviorally non-responsive DOC patients revealing the presence of at least one ERP in eight patients investigated. In the third and fourth study, specific attentional effects on ERPs were investigated in healthy participants to define optimal instructions and stimulus parameters. In study 3, MMN and N400 amplitudes were assessed in 18 participants, and in study 4, MMN and P300 amplitudes were assessed in 32 participants. Both studies included an ignore task (attention on simultaneous visual stimuli), a passive task, and a focused task and revealed distinct attentional effects on P300 and N400 with largest amplitudes in the focused task, smaller ones in the passive task and no ERP in the ignore task. An MMN was elicited in all tasks, but still, amplitudes differed as a function of task. In addition, study 4 included oddball paradigms comprising several deviants in different dimensions. Higher amplitudes were found in this multifeature paradigm compared to traditional oddball paradigms and larger amplitudes were elicited by deviants highly different from standards. It is concluded that ERPs represent a promising tool to complement clinical assessment of DOC patients. Application of ERP paradigms should include focused instructions, especially when using semantic material. Furthermore, multifeature paradigms have been proven especially useful eliciting large amplitudes and allowing for the investigation of several dimensions of deviants at the same time. N2 - Die vorliegende Arbeit beinhaltet vier Studien, die die auditorischen ereigniskorrelierten Potentiale (EKP) Mismatch Negativität (MMN), P300, und N400 unter verschiedenen Instruktionen untersuchen, und deren Anwendung bei Patienten mit Bewusstseinsstörungen darstellen. In Studie 1 äußerten neurologische Fachärzte in Leitfadeninterviews ein generelles Interesse und eine objektive Notwendigkeit der Ergänzung bisheriger diagnostischer Vorgehensweisen durch EKP-basierte Methoden. In Studie 2 wurden 19 motorisch nicht-responsiven Patienten verschiedene Stimuli in Form einfacher Oddball-Paradigmen und semantischen Materials dargeboten und es konnte in acht Patienten mindestens ein EKP nachgewiesen wer-den. Studie 3 und 4 dienten der Untersuchung spezifischer Aufmerksamkeitseffekte auf EKPs in Gesunden, um optimale Instruktionen und Stimulusparameter zu definieren. Es wurden jeweils MMN und N400 in 18 Teilnehmern und MMN und P300 in 32 Teilnehmern untersucht. Beide Studien enthielten eine Ablenkungsaufgabe (simultane visuelle Reize), eine passive und eine fokussierte Aufgabe und zeigten deutliche Aufgabeneffekte auf P300 und N400. Die höchsten Amplituden wurden in der fokussierten Aufgabe ausgelöst, kleinere in der passiven und kein EKP in der Ablenkungsaufgabe. Eine MMN wurde in allen Aufgaben ausgelöst, aber auch hier unterschieden sich die Amplituden in Abhängigkeit der Aufgabe. Studie 4 ent-hielt außerdem ein Oddball mit mehreren abweichenden Tönen in vier Dimensionen. Dieses erzielte höhere Amplituden als das klassische Oddball mit nur einem abweichenden Ton. Hö-here Amplituden wurden von abweichenden Tönen ausgelöst, welche sich stark vom Standardton unterschieden. EKPs stellen ein vielversprechendes Instrument zur Ergänzung klini-scher Diagnosen bewusstseinsgestörter Patienten dar. Es sollte auf eindeutig zu differenzierende abweichende Reize und bei semantischen Material auf fokussierte Instruktionen zurückgegriffen werden. Paradigmen mit verschiedenen abweichenden Tönen können aufgrund höherer Amplituden und eines umfassenden Reizverarbeitungsprofils besonders nützlich sein. KW - event-related potentials KW - attention KW - ereigniskorrelierte Potentiale KW - Aufmerksamkeit KW - disorders of consciousness KW - Bewusstseinsstörungen KW - Bewusstseinsstörung KW - Ereigniskorreliertes Potenzial KW - Bewusstsein Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121041 ER - TY - JOUR A1 - Leonhardt, Ines A1 - Spielberg, Steffi A1 - Weber, Michael A1 - Albrecht-Eckardt, Daniela A1 - Bläss, Markus A1 - Claus, Ralf A1 - Barz, Dagmar A1 - Scherlach, Kirstin A1 - Hertweck, Christian A1 - Löffler, Jürgen A1 - Hünniger, Kerstin A1 - Kurzai, Oliver T1 - The fungal quorum-sensing molecule farnesol activates innate immune cells but suppresses cellular adaptive immunity JF - mBio N2 - Farnesol, produced by the polymorphic fungus Candida albicans, is the first quorum-sensing molecule discovered in eukaryotes. Its main function is control of C. albicans filamentation, a process closely linked to pathogenesis. In this study, we analyzed the effects of farnesol on innate immune cells known to be important for fungal clearance and protective immunity. Farnesol enhanced the expression of activation markers on monocytes (CD86 and HLA-DR) and neutrophils (CD66b and CD11b) and promoted oxidative burst and the release of proinflammatory cytokines (tumor necrosis factor alpha [TNF-\(\alpha\)] and macrophage inflammatory protein 1 alpha [MIP-1 \(\alpha\)]). However, this activation did not result in enhanced fungal uptake or killing. Furthermore, the differentiation of monocytes to immature dendritic cells (iDC) was significantly affected by farnesol. Several markers important for maturation and antigen presentation like CD1a, CD83, CD86, and CD80 were significantly reduced in the presence of farnesol. Furthermore, farnesol modulated migrational behavior and cytokine release and impaired the ability of DC to induce T cell proliferation. Of major importance was the absence of interleukin 12 (IL-12) induction in iDC generated in the presence of farnesol. Transcriptome analyses revealed a farnesol-induced shift in effector molecule expression and a down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor during monocytes to iDC differentiation. Taken together, our data unveil the ability of farnesol to act as a virulence factor of C. albicans by influencing innate immune cells to promote inflammation and mitigating the Th1 response, which is essential for fungal clearance. KW - human dendritic cells KW - Pseudomonas aeruginosa KW - induced apoptosis KW - cytokine production KW - biofilm formation KW - Candida albicans KW - mouse model KW - systemic candidiasis KW - oxidative stress KW - carcinoma cells Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143756 VL - 6 IS - 2 ER - TY - JOUR A1 - Wehrle, Esther A1 - Liedert, Astrid A1 - Heilmann, Aline A1 - Wehner, Tim A1 - Bindl, Ronny A1 - Fischer, Lena A1 - Haffner-Luntzer, Melanie A1 - Jakob, Franz A1 - Schinke, Thorsten A1 - Amling, Michael A1 - Ignatius, Anita T1 - The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice JF - Disease Models & Mechanisms N2 - Fracture healing is impaired in aged and osteoporotic individuals. Because adequate mechanical stimuli are able to increase bone formation, one therapeutical approach to treat poorly healing fractures could be the application of whole-body vibration, including low-magnitude high-frequency vibration (LMHFV). We investigated the effects of LMHFV on fracture healing in aged osteoporotic mice. Female C57BL/6NCrl mice (n=96) were either ovariectomised (OVX) or sham operated (non-OVX) at age 41 weeks. When aged to 49 weeks, all mice received a femur osteotomy that was stabilised using an external fixator. The mice received whole-body vibrations (20 minutes/day) with 0.3 g peak-to-peak acceleration and a frequency of 45 Hz. After 10 and 21 days, the osteotomised femurs and intact bones (contra-lateral femurs, lumbar spine) were evaluated using bending-testing, micro-computed tomography (mu CT), histology and gene expression analyses. LMHFV disturbed fracture healing in aged non-OVX mice, with significantly reduced flexural rigidity (-81%) and bone formation (-80%) in the callus. Gene expression analyses demonstrated increased oestrogen receptor β (ERβ, encoded by Esr2) and Sost expression in the callus of the vibrated animals, but decreased β-catenin, suggesting that ERβ might mediate these negative effects through inhibition of osteoanabolic Wnt/β-catenin signalling. In contrast, in OVX mice, LMHFV significantly improved callus properties, with increased flexural rigidity (+ 1398%) and bone formation (+637%), which could be abolished by subcutaneous oestrogen application (0.025 mg oestrogen administered in a 90-day-release pellet). On a molecular level, we found an upregulation of ER alpha in the callus of the vibrated OVX mice, whereas ERβ was unaffected, indicating that ERa might mediate the osteoanabolic response. Our results indicate a major role for oestrogen in the mechanostimulation of fracture healing and imply that LMHFV might only be safe and effective in confined target populations. KW - level mechanical vibrations KW - ovariectomized rats KW - bone formation KW - LMHFV KW - whole body vibration KW - receptor beta KW - replacement therapy KW - osteoblastic cells KW - early stage KW - alpha KW - Wnt KW - fracture healing KW - oestrogen receptor signalling KW - Wnt signalling Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144700 VL - 8 ER - TY - JOUR A1 - Wehrle, Esther A1 - Liedert, Astrid A1 - Heilmann, Aline A1 - Wehner, Tim A1 - Bindl, Ronny A1 - Fischer, Lena A1 - Haffner-Luntzer, Melanie A1 - Jakob, Franz A1 - Schinke, Thorsten A1 - Amling, Michael A1 - Ignatius, Anita T1 - The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice JF - Disease Models & Mechanisms N2 - Fracture healing is impaired in aged and osteoporotic individuals. Because adequate mechanical stimuli are able to increase bone formation, one therapeutical approach to treat poorly healing fractures could be the application of whole-body vibration, including low-magnitude high-frequency vibration (LMHFV). We investigated the effects of LMHFV on fracture healing in aged osteoporotic mice. Female C57BL/6NCrl mice (n=96) were either ovariectomised (OVX) or sham operated (non-OVX) at age 41 weeks. When aged to 49 weeks, all mice received a femur osteotomy that was stabilised using an external fixator. The mice received whole-body vibrations (20 minutes/day) with 0.3 G: peak-to-peak acceleration and a frequency of 45 Hz. After 10 and 21 days, the osteotomised femurs and intact bones (contra-lateral femurs, lumbar spine) were evaluated using bending-testing, micro-computed tomography (μCT), histology and gene expression analyses. LMHFV disturbed fracture healing in aged non-OVX mice, with significantly reduced flexural rigidity (-81%) and bone formation (-80%) in the callus. Gene expression analyses demonstrated increased oestrogen receptor β (ERβ, encoded by Esr2) and Sost expression in the callus of the vibrated animals, but decreased β-catenin, suggesting that ERβ might mediate these negative effects through inhibition of osteoanabolic Wnt/β-catenin signalling. In contrast, in OVX mice, LMHFV significantly improved callus properties, with increased flexural rigidity (+1398%) and bone formation (+637%), which could be abolished by subcutaneous oestrogen application (0.025 mg oestrogen administered in a 90-day-release pellet). On a molecular level, we found an upregulation of ERα in the callus of the vibrated OVX mice, whereas ERβ was unaffected, indicating that ERα might mediate the osteoanabolic response. Our results indicate a major role for oestrogen in the mechanostimulation of fracture healing and imply that LMHFV might only be safe and effective in confined target populations. KW - fracture healing KW - LMHFV KW - oestrogen receptor signalling KW - whole-body vibration KW - Wnt-signalling Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121109 VL - 8 ER - TY - JOUR A1 - Diemer, Julia A1 - Alpers, Georg W. A1 - Peperkorn, Henrik M. A1 - Shiban, Youssef A1 - Mühlberger, Andreas T1 - The impact of perception and presence on emotional reactions: a review of research in virtual reality JF - Frontiers in Psychology N2 - Virtual reality (VR) has made its way into mainstream psychological research in the last two decades. This technology, with its unique ability to simulate complex, real situations and contexts, offers researchers unprecedented opportunities to investigate human behavior in well controlled designs in the laboratory. One important application of VR is the investigation of pathological processes in mental disorders, especially anxiety disorders. Research on the processes underlying threat perception, fear, and exposure therapy has shed light on more general aspects of the relation between perception and emotion. Being by its nature virtual, i.e., simulation of reality, VR strongly relies on the adequate selection of specific perceptual cues to activate emotions. Emotional experiences in turn are related to presence, another important concept in VR, which describes the user's sense of being in a VR environment. This paper summarizes current research into perception of fear cues, emotion, and presence, aiming at the identification of the most relevant aspects of emotional experience in VR and their mutual relations. A special focus lies on a series of recent experiments designed to test the relative contribution of perception and conceptual information on fear in VR. This strand of research capitalizes on the dissociation between perception (bottom up input) and conceptual information (top-down input) that is possible in VR. Further, we review the factors that have so far been recognized to influence presence, with emotions (e.g., fear) being the most relevant in the context of clinical psychology. Recent research has highlighted the mutual influence of presence and fear in VR, but has also traced the limits of our current understanding of this relationship. In this paper, the crucial role of perception on eliciting emotional reactions is highlighted, and the role of arousal as a basic dimension of emotional experience is discussed. An interoceptive attribution model of presence is suggested as a first step toward an integrative framework for emotion research in VR. Gaps in the current literature and future directions are outlined. KW - exposure therapy KW - flight phobics KW - environments KW - virtual reality KW - anxiety KW - presence KW - emotion KW - fear KW - perception KW - anxiety disorders KW - presence questionnaire KW - public speaking KW - spider phobia KW - social phobia KW - immersion Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144200 VL - 6 IS - 26 ER - TY - JOUR A1 - Federico, Stephanie A1 - Redenti, Sara A1 - Sturlese, Mattia A1 - Ciancetta, Antonella A1 - Kachler, Sonja A1 - Klotz, Karl-Norbert A1 - Cacciari, Barbara A1 - Moro, Stefano A1 - Spalluto, Giampiero T1 - The Influence of the 1-(3-Trifluoromethyl-Benzyl)-1H-Pyrazole-4-yl Moiety on the Adenosine Receptors Affinity Profile of Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine Derivatives JF - PLoS One N2 - A new series of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) derivatives has been developed in order to explore their affinity and selectivity profile at the four adenosine receptor subtypes. In particular, the PTP scaffold was conjugated at the C2 position with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole, a group believed to confer potency and selectivity toward the human (h) A\(_{2B}\) adenosine receptor (AR) to the xanthine ligand 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl-1H-purine-2,6(3H, 7H)-dione (CVT 6975). Interestingly, the synthesized compounds turned out to be inactive at the hA\(_{2B}\) AR but they displayed affinity at the hA\(_3\) AR in the nanomolar range. The best compound of the series (6) shows both high affinity (hA\(_3\) AR K\(_i\) = 11 nM) and selectivity (A\(_1\)/A\(_3\) and A\(_{2A}\)/A\(_3\) > 9090; A\(_{2B}\)/A\(_3\) > 909) at the hA\(_3\) AR. To better rationalize these results, a molecular docking study on the four AR subtypes was performed for all the synthesized compounds. In addition, CTV 6975 and two close analogues have been subjected to the same molecular docking protocol to investigate the role of the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole on the binding at the four ARs. KW - drug KW - human A(3) KW - protein-coupled receptors KW - classification KW - subtypes KW - potent KW - antagonists KW - mast cells KW - targets KW - A(2B) receptors KW - international union Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137133 VL - 10 IS - 12 ER - TY - JOUR A1 - Biernacka, J. M. A1 - Sangkuhl, K. A1 - Jenkins, G. A1 - Whaley, R. M. A1 - Barman, P. A1 - Batzler, A. A1 - Altman, R. B. A1 - Arolt, V. A1 - Brockmöller, J. A1 - Chen, C. H. A1 - Domschke, K. A1 - Hall-Flavin, D. K. A1 - Hong, C. J. A1 - Illi, A. A1 - Ji, Y. A1 - Kampman, O. A1 - Kinoshita, T. A1 - Leinonen, E. A1 - Liou, Y. J. A1 - Mushiroda, T. A1 - Nonen, S. A1 - Skime, M. K. A1 - Wang, L. A1 - Baune, B. T. A1 - Kato, M. A1 - Liu, Y. L. A1 - Praphanphoj, V. A1 - Stingl, J. C. A1 - Tsai, S. J. A1 - Kubo, M. A1 - Klein, T. E. A1 - Weinshilboum, R. T1 - The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response JF - Translational Psychiatry N2 - Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N = 2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P = 5.03E - 08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted. KW - major depressive disorder KW - genetic variation KW - schizophrenia KW - neuregulin-1 KW - population KW - microcephalin 1 KW - susceptibility KW - metaanalysis KW - MCPH1 KW - loci Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143223 VL - 5 IS - e553 ER - TY - JOUR A1 - Hopp, Sarah A1 - Albert-Weissenberger, Christiane T1 - The kallikrein-kinin system: a promising therapeutic target for traumatic brain injury JF - Neural Regeneration Research N2 - No abstract available. KW - kallikrein-kinin system KW - traumatic brain injury KW - therapy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149416 VL - 10 IS - 6 ER - TY - JOUR A1 - Pasch, Elisabeth A1 - Link, Jana A1 - Beck, Carolin A1 - Scheuerle, Stefanie A1 - Alsheimer, Manfred T1 - The LINC complex component Sun4 plays a crucial role in sperm head formation and fertility JF - Biology Open N2 - LINC complexes are evolutionarily conserved nuclear envelope bridges, physically connecting the nucleus to the peripheral cytoskeleton. They are pivotal for dynamic cellular and developmental processes, like nuclear migration, anchoring and positioning, meiotic chromosome movements and maintenance of cell polarity and nuclear shape. Active nuclear reshaping is a hallmark of mammalian sperm development and, by transducing cytoskeletal forces to the nuclear envelope, LINC complexes could be vital for sperm head formation as well. We here analyzed in detail the behavior and function of Sun4, a bona fide testis-specific LINC component. We demonstrate that Sun4 is solely expressed in spermatids and there localizes to the posterior nuclear envelope, likely interacting with Sun3/Nesprin1 LINC components. Our study revealed that Sun4 deficiency severely impacts the nucleocytoplasmic junction, leads to mislocalization of other LINC components and interferes with the formation of the microtubule manchette, which finally culminates in a globozoospermia-like phenotype. Together, our study provides direct evidence for a critical role of LINC complexes in mammalian sperm head formation and male fertility. KW - SUN domain proteins KW - sperm head formation KW - nuclear envelope KW - LINC complex KW - spermiogenesis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125212 VL - 4 ER - TY - RPRT A1 - Lauth, Hans-Joachim T1 - The Matrix of Democracy: A Three-Dimensional Approach to Measuring the Quality of Democracy and Regime Transformations T1 - Die Demokratiematrix: Ein dreidimensionaler Ansatz zur Messung der Qualität der Demokratie und von Regimetransformationen N2 - The article presents a proposal for the assessment of the quality of democracy. After elaborating on the methodological strategy, a definition of democracy is proposed, which entails the construction of the matrix of democracy based on three dimensions (political freedom, political equality, and political and judicial control) and five institutions. The methodological application of this measuring tool is then explained. This conception guarantees an appropriate measurement in different cultural contexts, enables the characterization of democratic profiles, and allows for the identification of deficiencies in democracies. Before the conclusion, three examples of the measurement (USA, Russia, and Italy) illustrate how the matrix works. N2 - Der Beitrag präsentiert einen Vorschlag zur Demokratiemessung. Auf der Grundlage einer vorgestellten methodologischen Strategie wird eine Demokratiedefinition vorgeschlagen. Diese ermöglicht die Konstruktion einer Demokratiematrix, die auf drei Dimensionen (politische Freiheit, politische Gleichheit sowie rechtliche und politischer Kontrolle) und fünf Institutionen beruht. Die methodische Anwendung der Demokratiematrix wird erläutert. Diese Messanlage ermöglicht eine kontextangemessene Messung in verschiedenen kulturellen Umwelten. Weiterhin erlaubt sie die Charakterisierung von demokratischen Profilen und die Identifizierung von demokratischen Defiziten. Neben dem Konzept und seiner methodischen Erläuterung werden drei Fallbeispiele (USA, Russland und Italien) vorgestellt, um die Arbeitsweise der Demokratiematrix zu illustrieren. T3 - Würzburger Arbeitspapiere zur Politikwissenschaft und Soziologie (WAPS) - 6 KW - Vergleichende politische Wissenschaft KW - Demokratie KW - Qualität KW - Democracy Measurement KW - Quality of Democracy KW - Matrix of Democracy KW - Defective Democracy KW - Political Freedom KW - Comparative politics KW - Political system KW - Politisches System KW - Freedom House KW - Politische Gleichheit Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-109665 ER - TY - JOUR A1 - Ruck, Tobias A1 - Bittner, Stefan A1 - Afzali, Ali Maisam A1 - Göbel, Kerstin A1 - Glumm, Sarah A1 - Kraft, Peter A1 - Sommer, Claudia A1 - Kleinschnitz, Christoph A1 - Preusse, Corinna A1 - Stenzel, Werner A1 - Wiendl, Heinz A1 - Meuth, Sven G. T1 - The NKG2D-IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies JF - Oncotarget N2 - NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. We here determined the involvement of the NKG2D - IL-15 signaling pathway. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, shedding of the soluble NKG2D ligand MICA (sMICA) decreased upon inflammation potentially diminishing inhibition of NKG2D signaling. Membrane-related expression of IL-15 by myoblasts induced differentiation of naive CD8\(^+\) T cells into highly activated, cytotoxic \(CD8^+NKG2D^{high}\) T cells demonstrating NKG2D-dependent lysis of myoblasts in vitro. \(CD8^+NKG2D^{high}\) T cell frequencies were increased in the peripheral blood of polymyositis (PM) patients and correlated with serum creatinine kinase concentrations, while serum sMICA levels were not significantly changed. In muscle biopsy specimens from PM patients expression of the NKG2D ligand MICA/B was upregulated, IL-15 was expressed by muscle cells, CD68\(^+\) macrophages as well as CD4\(^+\) T cells, and \(CD8^+NKG2D^+\) cells were frequently detected within inflammatory infiltrates arguing for a local signaling circuit in the inflammatory muscle milieu. In conclusion, the NKG2D - IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues. KW - MIC ligands KW - pathology section KW - T cell activation KW - idiopathic inflammatory myopathies KW - polymyositis KW - IL-15 KW - NKG2D KW - receptor KW - expression KW - lymphokine-activated killer KW - human muscle-cells KW - multiple sclerosis KW - celiac disease KW - tumor immunity KW - NKG2D ligands KW - cutting edge Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136047 VL - 6 IS - 41 ER - TY - JOUR A1 - Schulze, Daniel T1 - The Passive Gaze and Hyper-Immunised Spectators: The Politics of Theatrical Live-Broadcasting JF - Journal of Contemporary Drama in English N2 - No abstract available. KW - theatre Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195091 SN - 2195-0164 SN - 2195-0156 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 3 IS - 2 ER - TY - THES A1 - Klein, Dennis T1 - The pathogenic role of endogenous antibodies in a mouse model for Charcot-Marie-Tooth 1B neuropathy T1 - Die pathogenetische Funktion von endogenen Antikörpern in einem Maus-Modell der Charcot-Marie-Tooth 1B Neuropathie N2 - Charcot-Marie-Tooth (CMT) type 1 neuropathies are a genetically heterogeneous group of non-treatable inherited disorders affecting the peripheral nervous system that lead to sensory and motor dysfunction. Secondary low grade inflammation, implicating the innate and adaptive immune system, could previously be identified as a substantial disease modifier in two mouse models for CMT1, CMT1B and 1X, respectively. However, the exact mechanism how the adaptive immune system contributes to disease pathogenesis is not completely understood. Based on observations that the accumulation of endogenous antibodies to myelin components is important for rapid myelin clearance after nerve injury during Wallerian degeneration, a possibly similar mechanism was considered for endogenous antibodies as disease amplifier in mice heterozygously deficient for P0 (P0het), mimicking some typical features of CMT1B. In this study an increased antibody deposition was detected in the affected peripheral nerves of P0het myelin mutant mice. By crossbreeding P0het mutants with mice specifically lacking B-lymphocytes, and therefore antibodies (JHD-/-), a decline of endoneurial macrophages together with a substantially ameliorated demyelination could be demonstrated in 6-month-old mutant mice. Moreover, reconstitution with murine IgGs reverted the neuropathic phenotype, substantiating that endogenous antibodies are potentially pathogenic at this early stage of disease. Unexpectedly, in 12-months-old P0het mutants, JHD deficiency resulted in disease aggravation accompanied by an increased inflammatory reaction and M2-polarized macrophage response. These observations suggest that in a mouse model for CMT1B, the lack of endogenous antibodies has a dichotomous effect: ameliorating early macrophage-mediated demyelination, as opposed to increasing inflammatory reactions leading to disease aggravation at older ages. N2 - Als Charcot-Marie-Tooth (CMT) Typ 1 Erkrankungen bezeichnet man eine genetisch heterogene Gruppe von nicht behandelbaren, erblichen Neuropathien, die das periphere Nervensystem betreffen und letztendlich zu starken motorischen und sensorischen Defiziten führen. Anhand verschiedener Studien konnte gezeigt werden, dass sekundäre Entzündungsreaktionen, insbesondere des angeborenen und adaptiven Immunsystems, eine entscheidende Rolle bei der Pathogenese von zwei verschiedenen CMT1-Mausmodellen (CMT1B und CMT1X) spielen. Jedoch ist der genaue Mechanismus, in dem das adaptive Immunsystem zur Pathogenese beiträgt, nicht komplett bekannt. In einer veröffentlichten Studie wurden gebundenen endogenen Antiköpern eine wichtige Rolle beim raschen Myelinabbau nach Nervläsion während der Waller´schen Degeneration zugeschrieben. In Mäusen, die heterozygot defizient für P0 (P0het) sind und einige typische Merkmale der CMT1B Neuropathie aufweisen, sollte ein möglicherweise ähnlicher Mechanismus von endogenen Antikörpern untersucht werden, der zur Verstärkung der Krankheitsentwicklung führt. In dieser Studie konnte eine vermehrte Antikörperbindung in den betroffenen peripheren Nerven von P0het Myelinmutanten beobachtet werden. Anhand von Verkreuzungs-Experimenten von P0het Mutanten mit Mäusen, die keine B-Lymphozyten besitzen und daher keine Antikörper bilden können (JHD-/-), konnte zudem in den untersuchten 6 Monate alten Doppelmutanten eine verringerte Anzahl endoneuraler Makrophagen und eine deutliche Verbesserung der Demyelinisierung aufgezeigt werden. Zusätzlich konnte anhand von Rekonstitutions-Experimenten mit mausspezifischen-IgGs der neuropathische Phänotyp in peripheren Nerven wiederhergestellt werden, was die mögliche pathogenetische Rolle endogener Antikörper im frühen Stadium der Erkrankung bekräftigt. Unerwarteterweise führte die JHD-Defizienz jedoch in 12 Monate alten P0het Mausmutanten eher zu einer Verschlechterung der Neuropathie, zusammen mit einer verstärkten Entzündungsreaktion und M2-polarisierten Makrophagen-Aktivierung. Diese Beobachtungen deuten darauf hin, dass das Fehlen von Antikörpern in einem etablierten Mausmodell für CMT1B unterschiedliche Folgen hat, da dies zu einer verringerten Makrophagen-vermittelten Demyelinisierung im frühen Erkrankungsverlauf führt, gleichzeitig aber im späteren Alter in einer verstärkten Entzündungsreaktion und einem vermehrten Nervschaden resultiert. KW - Charcot-Marie-Tooth KW - Demyelinisierung KW - Adaptives Immunsystem KW - Antikörper KW - Makrophagen KW - B-Lymphocyten KW - Fc-Rezeptor KW - Komplement KW - demyelination KW - antibodies KW - macrophages KW - adaptive immune system KW - B-lymphocytes KW - Fc-receptor KW - complement KW - Maus KW - Charcot-Marie-Syndrom KW - Immunsystem KW - Antikörper Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121941 ER - TY - JOUR A1 - Phillips, Jane A. A1 - Chan, Angela A1 - Paeschke, Katrin A1 - Zakian, Virginia A. T1 - The Pif1 helicase, a negative regulator of telomerase, acts preferentially at long telomeres JF - PLoS Genetics N2 - Telomerase, the enzyme that maintains telomeres, preferentially lengthens short telomeres. The S. cerevisiae Pif1 DNA helicase inhibits both telomerase-mediated telomere lengthening and de novo telomere addition at double strand breaks (DSB). Here, we report that the association of the telomerase subunits Est2 and Est1 at a DSB was increased in the absence of Pif1, as it is at telomeres, suggesting that Pif1 suppresses de novo telomere addition by removing telomerase from the break. To determine how the absence of Pif1 results in telomere lengthening, we used the single telomere extension assay (STEX), which monitors lengthening of individual telomeres in a single cell cycle. In the absence of Pif1, telomerase added significantly more telomeric DNA, an average of 72 nucleotides per telomere compared to the 45 nucleotides in wild type cells, and the fraction of telomeres lengthened increased almost four-fold. Using an inducible short telomere assay, Est2 and Est1 no longer bound preferentially to a short telomere in pif1 mutant cells while binding of Yku80, a telomere structural protein, was unaffected by the status of the PIF1 locus. Two experiments demonstrate that Pif1 binding is affected by telomere length: Pif1 (but not Yku80) -associated telomeres were 70 bps longer than bulk telomeres, and in the inducible short telomere assay, Pif1 bound better to wild type length telomeres than to short telomeres. Thus, preferential lengthening of short yeast telomeres is achieved in part by targeting the negative regulator Pif1 to long telomeres. KW - Saccharomyces cerevisiae telomeres KW - DNA helicase KW - Pol II KW - in vitro KW - genome instability KW - yeast telomerase KW - G-quadruplex motifs KW - elongation KW - length KW - replication Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148722 VL - 11 IS - 4 ER - TY - THES A1 - Masís, Jethro T1 - The Primacy of Phenomenology Over Cognitivism. Towards a Critique of the Computational Theory of Mind T1 - Der Vorrang der Phänomenologie vor dem Kognitivismus. Zur Kritik an der computationalen Theorie des Geistes N2 - This investigation deals with the history of the reception of phenomenological philosophy in cognitive science and how this reception has altered and continues to shape the traditional view of cognition inspired by the computer metaphor of mind. The claim will be espoused that cognitive science is not devoid of a philosophical perspective and cognitivism will be characterized precisely as the philosophy behind much work in cognitive science. In conclusion, the irreducibility of philosophical questioning to cognitive science will be defended and reasons will be given as to why it matters to mount such defense. N2 - Vorliegende Arbeit befasst sich mit der Geschichte der Phänomenologie-Rezeption in der Kognitionswissenschaft und wie diese die Kritik an dem durch das Computermodell des Geistes inspirierten traditionellen Ansatz der Kognition umgestaltet hat und immer noch diesen Denkansatz mitprägt. In diesem Zusammenhang wird der Kognitivismus als ein Paradigma charakterisiert, welches allerdings eine solche Philosophie hinter der Kognitionswissenschaft spiegelt. Anschließend wird die Nichtreduzierbarkeit der philosophischen Fragestellung auf die Kognitionswissenschaft verteidigt und es werden Gründe angeführt, warum es wichtig ist, solche Verteidigungsstrategie wirksam zu machen. KW - Phenomenology KW - Philosophy of Cognitive Science KW - Philosophy of Mind KW - Contemporary Philosophy KW - Subjektive Theorie Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136404 ER - TY - JOUR A1 - Frank, Daniel O. A1 - Dengjel, Jörn A1 - Wilfling, Florian A1 - Kozjak-Pavlovic, Vera A1 - Häcker, Georg A1 - Weber, Arnim T1 - The Pro-Apoptotic BH3-Only Protein Bim Interacts with Components of the Translocase of the Outer Mitochondrial Membrane (TOM) JF - PLoS ONE N2 - The pro-apoptotic Bcl-2-family protein Bim belongs to the BH3-only proteins known as initiators of apoptosis. Recent data show that Bim is constitutively inserted in the outer mitochondrial membrane via a C-terminal transmembrane anchor from where it can activate the effector of cytochrome c-release, Bax. To identify regulators of Bim-activity, we conducted a search for proteins interacting with Bim at mitochondria. We found an interaction of Bim with Tom70, Tom20 and more weakly with Tom40, all components of the Translocase of the Outer Membrane (TOM). In vitro import assays performed on tryptically digested yeast mitochondria showed reduced Bim insertion into the outer mitochondrial membrane (OMM) indicating that protein receptors may be involved in the import process. However, RNAi against components of TOM (Tom40, Tom70, Tom22 or Tom20) by siRNA, individually or in combination, did not consistently change the amount of Bim on HeLa mitochondria, either at steady state or upon de novo-induction. In support of this, the individual or combined knockdowns of TOM receptors also failed to alter the susceptibility of HeLa cells to Bim-induced apoptosis. In isolated yeast mitochondria, lack of Tom70 or the TOM-components Tom20 or Tom22 alone did not affect the import of Bim into the outer mitochondrial membrane. In yeast, expression of Bim can sensitize the cells to Bax-dependent killing. This sensitization was unaffected by the absence of Tom70 or by an experimental reduction in Tom40. Although thus the physiological role of the Bim-TOM-interaction remains unclear, TOM complex components do not seem to be essential for Bim insertion into the OMM. Nevertheless, this association should be noted and considered when the regulation of Bim in other cells and situations is investigated. KW - bax KW - preproteins KW - phosphorylation KW - proteomics KW - degradation KW - cells KW - family KW - import KW - BH3 domains KW - Bcl-2 proteins Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143301 VL - 10 IS - 4 ER - TY - JOUR A1 - Wille, Michael A1 - Schümann, Antje A1 - Wree, Andreas A1 - Kreutzer, Michael A1 - Glocker, Michael O. A1 - Mutzbauer, Grit A1 - Schmitt, Oliver T1 - The Proteome Profiles of the Cerebellum of Juvenile, Adult and Aged Rats-An Ontogenetic Study JF - International Journal of Molecular Sciences N2 - In this study, we searched for proteins that change their expression in the cerebellum (Ce) of rats during ontogenesis. This study focuses on the question of whether specific proteins exist which are differentially expressed with regard to postnatal stages of development. A better characterization of the microenvironment and its development may result from these study findings. A differential two-dimensional polyacrylamide gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis of the samples revealed that the number of proteins of the functional classes differed depending on the developmental stages. Especially members of the functional classes of biosynthesis, regulatory proteins, chaperones and structural proteins show the highest differential expression within the analyzed stages of development. Therefore, members of these functional protein groups seem to be involved in the development and differentiation of the Ce within the analyzed development stages. In this study, changes in the expression of proteins in the Ce at different postnatal developmental stages (postnatal days (P) 7, 90, and 637) could be observed. At the same time, an identification of proteins which are involved in cell migration and differentiation was possible. Especially proteins involved in processes of the biosynthesis and regulation, the dynamic organization of the cytoskeleton as well as chaperones showed a high amount of differentially expressed proteins between the analyzed dates. KW - messenger RNA KW - brain KW - cerebellum KW - development KW - proteomics KW - rat KW - proteins KW - adenosine kinase KW - coated vesicles KW - phosphatase 2A KW - expression KW - neuronal differentiation KW - human brain KW - hnRNP K KW - postnatal development KW - binding Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151347 VL - 16 SP - 21454 EP - 21485 ER - TY - JOUR A1 - Wille, Michael A1 - Schümann, Antje A1 - Kreutzer, Michael A1 - Glocker, Michael O A1 - Wree, Andreas A1 - Mutzbauer, Grit A1 - Schmitt, Oliver T1 - The proteome profiles of the olfactory bulb of juvenile, adult and aged rats - an ontogenetic study JF - Proteome Science N2 - Background: In this study, we searched for proteins that change their expression in the olfactory bulb (oB) of rats during ontogenesis. Up to now, protein expression differences in the developing animal are not fully understood. Our investigation focused on the question whether specific proteins exist which are only expressed during different development stages. This might lead to a better characterization of the microenvironment and to a better determination of factors and candidates that influence the differentiation of neuronal progenitor cells. Results: After analyzing the samples by two-dimensional polyacrylamide gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), it could be shown that the number of expressed proteins differs depending on the developmental stages. Especially members of the functional classes, like proteins of biosynthesis, regulatory proteins and structural proteins, show the highest differential expression in the stages of development analyzed. Conclusion: In this study, quantitative changes in the expression of proteins in the oB at different developmental stages (postnatal days (P) 7, 90 and 637) could be observed. Furthermore, the expression of many proteins was found at specific developmental stages. It was possible to identify these proteins which are involved in processes like support of cell migration and differentiation. KW - axonally transported proteins KW - hippocampal stem cells KW - cerebral cortex KW - regional development KW - development KW - brain KW - olfactory bulb KW - proteomics KW - rat KW - growth-associated protein KW - messenger-RNA transport KW - goldfish optic nerve KW - postnatal development KW - subventricular zone KW - neuronal differentiation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144073 VL - 13 IS - 8 ER - TY - THES A1 - Bakhtiari, Giti T1 - The Role of Fluency in Oral Approach and Avoidance T1 - Die Rolle von Verarbeitungsflüssigkeit in oraler Annäherung und Vermeidung N2 - Names of, for instance, children or companies are often chosen very carefully. They should sound and feel good. Therefore, many companies try to choose artificially created names that can easily be pronounced in various languages. A wide range of psychological research has demonstrated that easy processing (high processing fluency) is intrinsically experienced as positive. Due to this positive feeling, easy processing can have profound influences on preferences for names. Topolinski, Maschmann, Pecher, and Winkielman (2014) have introduced a different mechanism that influences the perception of words. Across several experiments they found that words featuring consonantal inward wanderings (inward words) were preferred over words featuring consonantal outward wanderings (outward words). They argued that this was due to the fact that approach and avoidance motivations are activated by articulating inward and outward words, because the pronunciation resembles approach and avoidance behaviors of swallowing and spitting, respectively. They suggested this close link as an underlying mechanism for the so-called in-out effect, but did not test this assumption directly. In the current work, I tested an alternative fluency account of the in-out effect. Specifically, I hypothesized that processing fluency might play a critical role instead of motivational states of approach and avoidance being necessarily activated. In Chapter 1, I introduce the general topic of my dissertation, followed by a detailed introduction of the research area of approach and avoidance motivations in Chapter 2. In Chapter 3, I narrow the topic down to orally induced approach and avoidance motivations, which is the main topic of my dissertation. In Chapter 4, I introduce the research area of ecological influences on psychological processes. This chapter builds the base for the idea that human language might serve as a source of processing fluency in the in-out effect. In the following Chapter 5, I elaborate the research area of processing fluency, for which I examined whether it plays a role in the in-out effect. After an overview of my empirical work in Chapter 6, the empirical part starts with Study 1a and Study 1b (Chapter 7) that aimed to show that two languages (Eng. & Ger.) in which the in-out effect has originally been found might feature a source of higher processing fluency for inward over outward words. The results showed that higher frequencies of inward dynamics compared to outward dynamics were found in both languages. This can lead to higher pronunciation fluency for inward compared to outward words which might in turn lay the ground for higher preferences found for inward over outward words. In Chapter 8, the assumption that inward compared to outward dynamics might be more efficient to process was tested directly in experiments that examined objective as well as subjective processing fluency of artificially constructed non-words featuring pure inward or outward dynamics. Studies 2a-4b found an objective as well as subjective processing advantage for inward over outward words. In Chapter 9, the causal role of objective and subjective pronunciation fluency in the in-out effect was examined. In Study 5 mediational analyses on item-level and across studies were conducted using objective and subjective fluency as possible mediating variables. In Study 6 mediation analyses were conducted with data on subject- and trial-level from a within-subject design. Overall, the data of the item-based, subject-based and trial-based mediation analyses provide rather mixed results. Therefore, an experimental manipulation of fluency was implemented in the last two studies. In Chapter 10, Study 7 and Study 8 demonstrate that manipulating fluency experimentally does indeed modulate the attitudinal impact of consonantal articulation direction. Articulation ease was induced by letting participants train inward or outward kinematics before the actual evaluation phase. Additionally, the simulation training was intensified in Study 8 in order to examine whether a stronger modulation of the in-out effect could be found. Training outward words led to an attenuation and, after more extensive training, even to a reversal of the in-out effect, whereas training inward words led to an enhancement of the in-out effect. This hints at my overall hypothesis that the explicit preferences of inward and outward words are, at least partially, driven by processing fluency. Almost all studies of my dissertation, except for one analysis of the item-based mediation study, speak in favor of the hypothesis that inward words compared to outward words are objectively and subjectively easier to articulate. This possibly contributes partially to a higher preference of inward over outward words. The results are discussed in Chapter 11 with respect to processing fluency and to the role of language as an ecological factor. Finally, future research ideas are elaborated. N2 - Die Namensgebung von beispielsweise Kindern oder Firmen ist meist sehr sorgfältig bedacht. Ein Name sollte sich möglichst gut anfühlen und schön klingen. So wählen weltweit agierende Firmen oft künstlich kreierte Namen, die in mehreren Sprachen leicht aussprechbar sind. Psychologische Forschung hat vielfach gezeigt, dass eine leichte Verarbeitung (hohe fluency), beispielsweise von Wörtern, implizit als positiv wahrgenommen wird. Aufgrund dieses positiven Gefühls, kann eine leichte Verarbeitung starken Einfluss auf die Präferenzen für Namen haben. Topolinski und Kollegen (2014) stellten einen anderen Mechanismus vor, der die Wahrnehmung von Wörtern beeinflussen kann. In mehreren Experimenten konnten sie zeigen, dass Wörter mit einer konsonantischen rein-Wanderung (Reinwörter) gegenüber Wörtern mit einer raus-Wanderung (Rauswörter) präferiert wurden. Sie postulieren, dass dies durch Annäherungs- und Vermeidungsmotivationen zustände käme, die durch die Artikulation von Rein- und Rauswörtern ausgelöst wurden, da das Aussprechen von diesen jeweils dem Annäherungs- und Vermeidungsverhalten im Sinne von schlucken und spucken ähneln. Die Autoren nehmen an, dass diese enge Verknüpfung von Merkmalen der Aussprache mit Annäherungs-/Vermeidungsverhalten der Mechanismus dafür ist, dass wir Rein- gegenüber Rauswörtern präferieren (Rein-Rauseffekt). Jedoch wurde diese Annahme bislang nicht direkt empirisch überprüft. In der vorliegenden Arbeit untersuche ich eine alternative fluency-Darstellung des Rein-Rauseffekts. Genauer, stelle ich die Hypothese auf, dass fluency unabhängig davon, ob Annäherungs- und Vermeidungsmotivationen aktiviert werden, eine entscheidende Rolle für den Rein-Rauseffekt spielen könnte. In Kapitel 1 führe ich das Thema meiner Dissertation ein, gefolgt von einer Vorstellung des Forschungsbereichs der Annäherungs- und Vermeidungsmotivationen (Kapitel 2). In Kapitel 3 grenze ich das Thema auf oral induzierte Motivationen ein. In Kapitel 4 stelle ich den Forschungsbereich der ökologische Einflüsse auf psychologische Prozesse vor, welches die Grundlage für meine These bildet, dass Sprache als eine fluency-Quelle im Rein-Rauseffekt fungieren könnte. In Kapitel 5 führe ich den Forschungsbereich zur fluency näher aus, da dessen Rolle im Rein-Rauseffekt in meiner Arbeit untersucht wird. Nach einem Überblick (Kapitel 6), beginnt der empirische Teil mit den Studien 1a und 1b (Kapitel 7). Diese haben untersucht, ob die zwei Sprachen (En., Deu.), in denen der Rein-Rauseffekt gefunden wurde, eine höhere fluency-Quelle für Rein- im Vergleich zu Rauswörtern darstellen können. Die Ergebnisse zeigen in beiden Sprachen ein häufigeres Vorkommen von Rein- gegenüber Rausdynamiken. Diese Ungleichverteilung der Häufigkeiten könnte eine höhere Aussprechflüssigkeit von Reinwörtern gegenüber Rauswörtern zur Folge haben, was wiederum die Grundlage für den Rein-Rauseffekt sein könnte. In Kapitel 8 wurde überprüft, ob Rein- verglichen mit Rauswörtern eine höhere fluency haben. In mehreren Experimenten wurde die objektive und subjektive fluency von künstlich konstruierten Non-Wörtern (reine Rein- oder Rausdynamiken) untersucht. Die Studien 2a-4b zeigen, dass neben der objektiven auch die subjektive fluency von Reinwörtern höher ist als die von Rauswörtern. In Kapitel 9 wurde die mögliche kausale Rolle von objektiver und subjektiver fluency auf den Rein-Rauseffekt untersucht. In Studie 5 wurden Mediationsanalysen auf Item-Ebene mit objektiver und subjektiver fluency als mögliche mediierende Variablen berechnet. In Studie 6 wurden Mediationsanalysen für subjektive fluency auf Probanden- und Trial-Ebene mit Daten aus einem Within-Subjects Design durchgeführt. Insgesamt zeigen die Analysen keine eindeutigen Befunde. Daher wurde in den letzten Studien eine experimentelle fluency-Manipulation realisiert. In Kapitel 10 zeigen Studien 7 und 8, dass eine experimentelle fluency-Manipulation Auswirkungen von konsonantischen Rein- und Rausdynamiken auf Wortpräferenzen moduliert. Die fluency wurde vor der Evaluationsphase induziert. Zusätzlich wurde das Simulationstraining in Studie 8 intensiviert, um festzustellen, ob sich eine stärkere Modulation des Rein-Rauseffektes findet. Das Trainieren von Rausdynamiken führte zu einer Abschwächung des Rein-Rauseffektes (Studie 7) und nach intensiverem Training sogar zu einer Umkehrung des Effektes (Studie 8). Das Trainieren von Reindynamiken hingegen führte zu einer Verstärkung des Rein-Rauseffektes. Diese Ergebnisse deuten darauf hin, dass Präferenzen für Rein- und Rauswörter - zumindest partiell - durch die fluency von Rein- und Rauswörtern beeinflusst sind. Nahezu alle Studien meiner Arbeit, außer der item-basierten Mediation, sprechen für meine Hypothese, dass Reinwörter gegenüber Rauswörtern sowohl subjektiv als auch objektiv leichter artikulierbar sind und möglicherweise aus diesem Grund auch präferiert werden. Die Ergebnisse werden in Kapitel 11 diskutiert. KW - Sozialpsychologie KW - Wahrnehmung KW - Präferenz KW - Wort KW - Stilles Lesen KW - Processing Fluency KW - Verarbeitungsflüssigkeit KW - Approach-Avoidance KW - Annäherung-Vermeidung KW - Wort-Präferenzen KW - Word-preferences Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118666 ER - TY - THES A1 - Subbarayal, Prema T1 - The role of human Ephrin receptor tyrosine kinase A2 (EphA2) in Chlamydia trachomatis infection T1 - Die Rolle der humanen Rezeptor-Tyrosinkinase EphrinA2 (EphA2) in der Chlamydia trachomatis Infektion N2 - Chlamydia trachomatis (Ctr), an obligate intracellular gram negative human pathogen, causes sexually transmitted diseases and acquired blindness in developing countries. The infectious elementary bodies (EB) of Ctr involved in adherence and invasion processes are critical for chlamydial infectivity and subsequent pathogenesis which requires cooperative interaction of several host cell factors. Few receptors have been known for this early event, yet the molecular mechanism of these receptors involvement throughout Ctr infection is not known. Chlamydial inclusion membrane serves as a signaling platform that coordinates Chlamydia-host cell interaction which encouraged me to look for host cell factors that associates with the inclusion membrane, using proteome analysis. The role of these factors in chlamydial replication was analyzed by RNA interference (RNAi) (in collaboration with AG Thomas Meyer). Interestingly, EphrinA2 receptor (EphA2), a cell surface tyrosine kinase receptor, implicated in many cancers, was identified as one of the potential candidates. Due to the presence of EphA2 in the Ctr inclusion proteome data, I investigated the role of EphA2 in Ctr infection. EphA2 was identified as a direct interacting receptor for adherence and entry of C. trachomatis. Pre-incubation of Ctr-EB with recombinant human EphA2, knockdown of EphA2 by siRNA, pretreatment of cells with anti-EphA2 antibodies or the tyrosine kinase inhibitor dasatinib significantly reduced Ctr infection. This marked reduction of Ctr infection was seen with both epithelial and endothelial cells used in this study. Ctr activates EphA2 upon infection and invades the cell together with the activated EphA2 receptor that interacts and activates PI3K survival signal, promoting chlamydial replication. EphA2 upregulation during infection is associated with Ctr inclusion membrane inside the cell and are prevented being translocated to the cell surface. Ephrins are natural ligands for Ephrin receptors that repress the activation of the PI3K/Akt pathway in a process called reverse signaling. Purified Ephrin-A1, a ligand of EphA2, strongly interferes with chlamydial infection and normal development, supporting the central role of these receptors in Chlamydia infection. Overexpression of full length EphA2, but not the mutant form lacking the intracellular cytoplasmic domain, enhanced PI3K activation and Ctr infection. Ctr infection induces EphA2 upregulation and is mediated by activation of ERK signaling pathway. Interfering with EphA2 upregulation sensitizes Ctr-infected cells to apoptosis induced by tumor necrosis factor-alpha (TNF-α) suggesting the importance of intracellular EphA2 signaling. Collectively, these results revealed the first Ephrin receptor “EphA2” that functions in promoting chlamydial infection. In addition, the engagement of a cell surface receptor at the inclusion membrane is a new mechanism how Chlamydia subverts the host cell and induces apoptosis resistance. By applying the natural ligand Ephrin-A1 and targeting EphA2 offers a promising new approach to interfere with Chlamydia infection. Thus, the work provides the evidence for a host cell surface tyrosine kinase receptor that is exploited for invasion as well as for receptor-mediated intracellular signaling to facilitate the chlamydial replication. N2 - Chlamydia trachomatis (Ctr) ist ein obligat intrazellulär lebendes Gram negatives Bakterium, das Geschlechtskrankheiten verursachen kann. In Entwicklungsländern führt es zudem häufig zu erworbener Blindheit. Die infektiösen Elementarkörper (EB) sind für die Anheftung an die Wirtszelle sowie die Aufnahme von Ctr in die Wirtzelle verantwortlich. Dies ist ein wichtiger Schritt, da nur so die sich anschließende Krankheitsentwicklung stattfinden kann. Diese ist auch abhängig vom engen Zusammenspiel der Ctr Proteine mit den Wirtszellfaktoren. Obgleich dieser Schritt so wichtig ist, wurden erst wenige Wirtszellrezeptoren gefunden und welche Rolle diese Rezeptoren im weiteren Verlauf der Infektion spielen, ist noch nicht richtig verstanden. Die chlamydiale Inklusionsmembran fungiert als Signalplattform, die das Zusammenspiel von Chlamydien und Wirtszelle koordiniert. In dieser Arbeit wurden die Wirtszellproteine, die an der Inklusionsmembran lokalisiert sind, mit Hilfe einer Proteomanalyse identifiziert. Anschließend wurde die Rolle dieser Proteine bei der Chlamydienvermehrung in einem RNAi screen untersucht (in Zusammenarbeit mit der AG Thomas Meyer). Hier wurde überraschenderweise der EphrinA2 Rezeptor, eine sich auf der Oberfläche der Zellen befindliche Rezeptor Tyrosin Kinase, die vor allem mit Krebs in Verbindung gebracht wird, als ein potentieller Kandidat identifiziert. Da die Proteomdaten gezeigt haben, dass EphrinA2 an der Inklusionsmembran lokalisiert ist, wurde die Rolle von EphrinA2 während der Ctr Infektion hier näher untersucht. Es konnte gezeigt werden, dass EphrinA2 ein direkter Rezeptor für Ctr ist, der sowohl die Adhärenz als auch die Aufnahme von Ctr in die Wirtszelle bewerkstelligt. Vorinkubation von Ctr- EB mit rekombinantem menschlichen EphrinA2, das herunterregulieren von EphrinA2 mit Hilfe einer siRNA oder das Vorinkubieren der menschlichen Zelle mit Antikörpern gegen EphrinA2 oder dem Tyrosinkinase Inhibitor Dasatinib, reduzierten die Ctr Infektion signifikant. Diese drastische Reduktion der Ctr Infektion wurde sowohl in Epithelzellen als auch in Endothelzellen beobachtet. Ctr aktiviert EphrinA2 während der Infektion und invadiert die Wirtszelle zusammen mit dem aktivierten Rezeptor, dieser interagiert mit dem aktivierten PI3K Überlebenssignal, was die Replikation der Chlamydien ermöglicht. An der Inklusionsmembran akkumuliert EphrinA2, da der Transport von neuem Rezeptor zur Zellmembran unterbunden ist. Ephrine sind die natürlichen Liganden der Ephrinrezeptoren, sie unterdrücken die Aktivierung des PI3K/Akt Signalweges in einem Prozess, der reverse Signalübertragung genannt wird. Aufgereinigtes Ephrin-A1, ein Ligand des EphrinA2 Rezeptors, verhindert eine normale Chlamydieninfektion, was eine zentrale Rolle dieses Rezeptors weiterhin bestätigt. Die Überexpression von EphrinA2, erhöhte die PI3K Aktivierung und Ctr Infektion. Dies war nicht der Fall, wenn eine Mutante, der die intrazelluläre Domäne fehlt, überexprimiert wurde. Eine Ctr Infektion induziert die Hochregulierung von EphrinA2, welche durch die Aktivierung des ERK Signalwegs bewerkstelligt wird. Wenn die Hochregulierung von EphrinA2 verhindert wird, werden Ctr infizierte Zellen sensitiver für Apoptose induziert durch tumor necrosis factor-alpha (TNF-α), was ein weiter Hinweis für die Bedeutung der intrazellulären EphrinA2 Signalübermittlung ist. Insgesamt haben diese Ergebnisse den ersten Ephrin Rezeptor "EphA2" offenbart, der in der Förderung chlamydialer Infektionen fungiert. Hinzu kommt, dass die Bindung eines Oberflächenrezeptors an die Inklusionsmembran ein neuer Mechanismus ist, die Wirtszelle zu verändern und eine Apoptoseresistenz in der Zelle zu induzieren. Die Zugabe des natürlichen Liganden Ephrin-A1 eröffnet eine neue vielversprechende Möglichkeit Chlamydieninfektionen zu bekämpfen. Daher liefert diese Arbeit erste Hinweise, das eine Wirtszelltyrosinkinase, die sich an der Zelloberfläche befindet, notwendig ist für die Invasion und die intrazelluläre Signalübermittlung, welche für die chlamydiale Replikation notwendig ist, essentiell ist. KW - Chlamydia trachomatis KW - ctr KW - Ephrine KW - Rezeptor KW - endocytosis KW - Ephrin ligand KW - chlamydia KW - signalling KW - PI3K KW - EphA2 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114778 ER - TY - JOUR A1 - Alavipanah, Sadroddin A1 - Wegmann, Martin A1 - Qureshi, Salman A1 - Weng, Qihao A1 - Koellner, Thomas T1 - The role of vegetation in mitigating urban land surface temperatures: a case study of Munich, Germany during the warm season JF - Sustainability N2 - The Urban Heat Island (UHI) is the phenomenon of altered increased temperatures in urban areas compared to their rural surroundings. UHIs grow and intensify under extreme hot periods, such as during heat waves, which can affect human health and also increase the demand for energy for cooling. This study applies remote sensing and land use/land cover (LULC) data to assess the cooling effect of varying urban vegetation cover, especially during extreme warm periods, in the city of Munich, Germany. To compute the relationship between Land Surface Temperature (LST) and Land Use Land Cover (LULC), MODIS eight-day interval LST data for the months of June, July and August from 2002 to 2012 and the Corine Land Cover (CLC) database were used. Due to similarities in the behavior of surface temperature of different CLCs, some classes were reclassified and combined to form two major, rather simplified, homogenized classes: one of built-up area and one of urban vegetation. The homogenized map was merged with the MODIS eight-day interval LST data to compute the relationship between them. The results revealed that (i) the cooling effect accrued from urban vegetation tended to be non-linear; and (ii) a remarkable and stronger cooling effect in terms of LST was identified in regions where the proportion of vegetation cover was between seventy and almost eighty percent per square kilometer. The results also demonstrated that LST within urban vegetation was affected by the temperature of the surrounding built-up and that during the well-known European 2003 heat wave, suburb areas were cooler from the core of the urbanized region. This study concluded that the optimum green space for obtaining the lowest temperature is a non-linear trend. This could support urban planning strategies to facilitate appropriate applications to mitigate heat-stress in urban area. KW - Surface Urban Heat Island (SUHI) KW - cities KW - buildings KW - Land Surface Temperature (LST) KW - urban vegetation KW - climate change KW - heat waves Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143447 VL - 7 ER - TY - JOUR A1 - Stöggl, Thomas L. A1 - Sperlich, Billy T1 - The training intensity distribution among well-trained and elite endurance athletes JF - Frontiers in Physiology N2 - Researchers have retrospectively analyzed the training intensity distribution (TID) of nationally and internationally competitive athletes in different endurance disciplines to determine the optimal volume and intensity for maximal adaptation. The majority of studies present a "pyramidal" TID with a high proportion of high volume, low intensity training (HVLIT). Some world-class athletes appear to adopt a so-called "polarized" TID (i.e., significant % of HVLIT and high intensity training) during certain phases of the season. However, emerging prospective randomized controlled studies have demonstrated superior responses of variables related to endurance when applying a polarized TID in well-trained and recreational individuals when compared with a TID that emphasizes HVLIT or threshold training. The aims of the present review are to: (1) summarize the main responses of retrospective and prospective studies exploring TID; (2) provide a systematic overview on TIDs during preparation, pre-competition, and competition phases in different endurance disciplines and performance levels; (3) address whether one TID has demonstrated greater efficacy than another; and (4) highlight research gaps in an effort to direct future scientific studies. KW - pyramidal retrospective KW - high volume KW - prospective KW - high intensity training KW - adaptations KW - cyclists KW - speed skaters KW - skeletal-muscle KW - polarized training KW - world championships KW - low intensity KW - optimize performance KW - blood lactate KW - cross-country skiers KW - aerobic performance KW - anaerobic threshold KW - threshold training Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138883 VL - 6 IS - 295 ER - TY - THES A1 - Pusch, Tobias T1 - The transcription factor NFATc1 mediates cytotoxic T cell function in vitro and in vivo T1 - Der Transkriptionsfaktor NFATc1 vermittelt die Funktion von zytotoxischen T Zellen in vitro und in vivo N2 - While numerous experiments on NFAT were already performed with CD4+ T cells showing defective cytokine release and a reduced T helper cell development, no detailed studies existed for CD8+ T cells. From this point, we wanted to examine the impact of NFATc1 and c2 on the physiological functions of CD8+ T cells in vitro and in vivo. Therefore, we used a murine infection model with the bacteria Listeria monocytogenes and mice in which NFATc1 was specifically depleted in the T cell compartment. Our first in vitro studies showed a typical NFATc1 and c2 nuclear translocation and changes on mRNA levels upon T cell activation similarly in CD4+ as well as in CD8+ T cells extracted from wild type mice. NFAT nuclear translocation is important for target gene activation and generation of effector functions. Stimulated T cell populations lacking NFATc1 and/or NFATc2 showed a markedly decreased expression of Th1/Tc1 cytokines, as e.g. IL 2 and IFNγ being important for the clearance of intracellular pathogens. From our in vitro model for the generation of allogenically reactive cytotoxic CD8+ T cells, we revealed a decreased killing and lytic granule-release capacity in Nfatc1 inactivated CD8+ T cells whereas NFATc2-/- cytotoxic T cells did not show an altered cytotoxic response compared to wild type cells. Interestingly, we found lytic granules accumulated and mitochondria not getting translocated to the immunological synapse upon re-stimulation in NFATc1-deficient CD8+ T cells. Together with results showing the CsA insensitivity of the CTL killing/degranulation capacities, we assume that some major cellular processes are affected by NFATc1 which are not directly linked to the TCR-induced signal transduction cascade. We also showed the importance of NFATc1 in T cells during intracellular infections with the bacteria Listeria monocytogenes in an in vivo mouse model. After five days, only few bacteria were detected in wt mice whereas high amounts of Listeria particles were extracted from livers of Nfatc1fl/fl x Cd4 cre mice. Although the reactivity towards the pathogen was similar in both groups, a decreased cytokine expression in NFATc1-/- CD8+ T cells was observed together with an altered memory cell generation. Our results show the importance of NFATc1 in CD8+ T cells and give some clue for a possible connection to other basal cellular functions, as e.g. the formation of an immunological synapse. N2 - Viele Experimente zur Rolle von NFAT wurden bereits anhand von CD4+ T Zellen durchgeführt und zeigten eine veränderte Zellphysiologie. Hingegen wurden CD8+ T Zellen diesbezüglich noch nicht intensiv studiert. Deshalb untersuchten wir den Einfluss von NFATc1 und NFATc2 auf die Funktion von CD8+ T Zellen in vitro und in vivo anhand des murinen Infektionsmodells mit dem Bakterium Listeria monocytogenes. Für die Versuche benutzen wir Mäuse, in denen das Protein NFATc1 spezifisch im T Zellkompartiment entfernt wurde. Erste Ergebnisse zeigten eine typische Translokation von NFATc1 und NFATc2 in den Zellkern. Eine Veränderung in der mRNA Expression nach Aktivierung, sowohl in CD4+ T Zellen als auch in CD8+ T Zellen, fand ebenfalls statt. NFATc defiziente CD4+ und CD8+ T Zellen wiesen eine verminderte Expression von Th1/Tc1 Zytokinen wie z.B. Interleukin-2 und Interferon γ auf, welche für die Bekämpfung intrazellulärer Pathogene wichtig sind. In unserem in vitro Modell fanden wir eine verminderte Abtötungsfähigkeit und eine Reduktion in der Freisetzung lytischer Granula in NFATc1-/- CD8+ T Zellen wohingegen eine NFATc2 Defizienz keine Auswirkungen auf die Zytotoxizität - verglichen mit wildtypischen Zellen - aufweist. Interessanterweise fanden wir eine Anhäufung von lytischen Granula und eine verminderte intrazelluläre Migration von Mitochondrien nach Ausbildung einer immunologischen Synapse in NFATc1-/- CD8+ T Zellen. Zusammen mit den Ergebnissen unserer CsA-Inhibierungsversuche nehmen wir an, dass einige allgemeine zelluläre Prozesse von NFATc1 beeinflusst werden, die nicht direkt von der T Zellrezeptor-induzierten Signalkaskade abhängen. Anhand eines in vivo Mausmodells zeigten wir auch die wichtige Rolle von NFATc1 in T Zellen während der Infektion mit Listeria monocytogenes. Fünf Tage nach Infektion konnten aus Nfatc1fl/fl x Cd4 cre Mäusen mehr Bakterienpartikel extrahiert werden als aus wt Mäusen. Wie in den in vitro Versuchen konnte auch hier eine geringere Zytokinproduktion der CD8+ T Zellen festgestellt werden allerdings wiesen die Mäuse auch eine geringere Bildung von Gedächniszellen auf. Unsere Ergebnisse zeigen, dass NFATc1 in CD8+ T Zellen eine wichtige Rolle spielt und auch Auswirkungen auf grundlegendere zelluläre Funktionen, wie die Ausbildung einer immunologischen Synapse, hat. KW - Transkriptionsfaktor KW - Killerzelle KW - Antigen CD8 KW - Cytotoxizität KW - NFAT KW - CTL function KW - CD8 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123690 ER - TY - JOUR A1 - Paschke, Ralf A1 - Lincke, Thomas A1 - Müller, Stefan P. A1 - Kreissl, Michael C. A1 - Dralle, Henning A1 - Fassnacht, Martin T1 - The Treatment of Well-Differentiated Thyroid Carcinoma JF - Deutsches Ärzteblatt International N2 - Background: Recent decades have seen a rise in the incidence of well-differentiated (mainly papillary) thyroid carcinoma around the world. In Germany, the age-adjusted incidence of well-differentiated thyroid carcinoma in 2010 was 3.5 per 100 000 men and 8.7 per 100 000 women per year. Method: This review is based on randomized, controlled trials and multicenter trials on the treatment of well-differentiated thyroid carcinoma that were retrieved by a selective literature search, as well as on three updated guidelines issued in the past two years. Results: The recommended extent of surgical resection depends on whether the tumor is classified as low-risk or high-risk, so that papillary microcar cinomas, which carry a highly favorable prognosis, will not be overtreated. More than 90% of localized, well-differentiated thyroid carcinomas can be cured with a combination of surgery and radioactive iodine therapy. Radio active iodine therapy is also effective in the treatment of well-differentiated thyroid carcinomas with distant metastases, yielding a 10-year survival rate of 90%, as long as there is good iodine uptake and the tumor goes into remission after treatment; otherwise, the 10-year survival rate is only 10%. In the past two years, better treatment options have become available for radioactive-iodine-resistant thyroid carcinoma. Phase 3 studies of two different tyrosine kinase inhibitors have shown that either one can markedly prolong progression-free survival, but not overall survival. Their more common clinically significant side effects are hand-foot syndrome, hypertension, diarrhea, proteinuria, and weight loss. Conclusion: Slow tumor growth, good resectability, and susceptibility to radioactive iodine therapy lend a favorable prognosis to most cases of well-differentiated thyroid carcinoma. The treatment should be risk-adjusted and interdisciplinary, in accordance with the current treatment guidelines. Even metastatic thyroid carcinoma has a favorable prognosis as long as there is good iodine uptake. The newly available medical treatment options for radioactive-iodine-resistant disease need to be further studied. KW - BRAF(V600E) mutation KW - distant metastases KW - papillary KW - guidelines KW - surgery KW - dissection KW - management KW - association KW - cancer KW - radioiodine therapy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151636 VL - 112 SP - 452 EP - 458 ER - TY - JOUR A1 - Rodriguez, Héctor A1 - Rico, Sergio A1 - Yepes, Ana A1 - Franco-Echevarría, Elsa A1 - Antoraz, Sergio A1 - Santamaría, Ramón I. A1 - Díaz, Margerita T1 - The two kinases, AbrC1 and AbrC2, of the atypical two-component system AbrC are needed to regulate antibiotic production and differentiation in Streptomyces coelicolor JF - Frontiers in Microbiology N2 - Two-component systems (TCSs) are the most important sensing mechanisms in bacteria. In Streptomyces, TCSs-mediated responses to environmental stimuli are involved in the regulation of antibiotic production. This study examines the individual role of two histidine kinases (HKs), AbrC1 and AbrC2, which form part of an atypical TCS in Streptomyces coelicolor. gRT-PCR analysis of the expression of both kinases demonstrated that both are expressed at similar levels in NB and NMMP media. Single deletion of abrC1 elicited a significant increase in antibiotic production, while deletion of abrC2 did not have any clear effect. The origin of this phenotype, probably related to the differential phosphorylation ability of the two kinases, was also explored indirectly, analyzing the toxic phenotypes associated with high levels of phosphorylated RR. The higher the AbrC3 regulator phosphorylation rate, the greater the cell toxicity. For the first time, the present work shows in Streptomyces the combined involvement of two different HKs in the response of a regulator to environmental signals. Regarding the possible applications of this research, the fact that an abrC1 deletion mutant overproduces three of the S. coelicolor antibiotics makes this strain an excellent candidate as a host for the heterologous production of secondary metabolites. KW - halstedii JM8 KW - biosynthesis KW - expression mutants KW - domain genes A3(2) KW - two-component systems KW - Streptomyces KW - antibiotic production KW - histidine kinases KW - heterologous production KW - activation KW - response regulator KW - PCR Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143048 VL - 6 IS - 450 ER - TY - JOUR A1 - Konrad, Franziska M. A1 - Bury, Annette A1 - Schick, Martin A. A1 - Ngamsri, Kristian-Christos A1 - Reutershan, Jörg T1 - The Unrecognized Effects of Phosphodiesterase 4 on Epithelial Cells in Pulmonary Inflammation JF - PLoS ONE N2 - Acute pulmonary inflammation is characterized by migration of polymorphonuclear neutrophils (PMNs) into the different compartments of the lung, passing an endothelial and epithelial barrier. Recent studies showed evidence that phosphodiesterase (PDE) 4-inhibitors stabilized endothelial cells. PDE4B and PDE4D subtypes play a pivotal role in inflammation, whereas blocking PDE4D is suspected to cause gastrointestinal side effects. We thought to investigate the particular role of the PDE4-inhibitors roflumilast and rolipram on lung epithelium. Acute pulmonary inflammation was induced by inhalation of LPS. PDE4-inhibitors were administered i.p. or nebulized after inflammation. The impact of PDE4-inhibitors on PMN migration was evaluated in vivo and in vitro. Microvascular permeability, cytokine levels, and PDE4B and PDE4D expression were analyzed. In vivo, both PDE4-inhibitors decreased transendothelial and transepithelial migration even when administered after inflammation, whereas roflumilast showed a superior effect compared to rolipram on the epithelium. Both inhibitors decreased TNF\(\alpha\), IL6, and CXCL2/3. CXCL1, the strong PMN chemoattractant secreted by the epithelium, was significantly more reduced by roflumilast. In vitro assays with human epithelium also emphasized the pivotal role of roflumilast on the epithelium. Additionally, LPS-induced stress fibers, an essential requirement for a direct migration of PMNs into the alveolar space, were predominantly reduced by roflumilast. Expression of PDE4B and PDE4D were both increased in the lungs by LPS, PDE4-inhibitors decreased mainly PDE4B. The topical administration of PDE4-inhibitors was also effective in curbing down PMN migration, further highlighting the clinical potential of these compounds. In pulmonary epithelial cells, both subtypes were found coexistent around the nucleus and the cytoplasm. In these epithelial cells, LPS increased PDE4B and, to a lesser extend, PDE4D, whereas the effect of the inhibitors was prominent on the PDE4B subtype. In conclusion, we determined the pivotal role of the PDE4-inhibitor roflumilast on lung epithelium and emphasized its main effect on PDE4B in hyperinflammation. KW - acute lung injury KW - PDE4-inhibitor roflumilast KW - GRO alpha KW - expression KW - 4D KW - respiratory distress syndrome KW - mice KW - infiltration KW - rolipram KW - disease Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143203 VL - 10 IS - 4 ER - TY - THES A1 - Ilko, David T1 - The use of charged aerosol detection for the analysis of excipients and active pharmaceutical ingredients T1 - Die Verwendung des "Charged Aerosol Detectors" zur Analytik von Hilfs- und Wirkstoffen N2 - The Corona® charged aerosol detector (CAD) is an aerosol-based detector first de-scribed by Dixon and Peterson in 2002. It is capable of detecting compounds inde-pendent from their physico-chemical properties presumed the analyte is sufficiently non-volatile. Consequently, the CAD is often applied to the analysis of substances that do not possess a suitable UV chromophore. Major drawbacks are however, the detector signal is non-linear and depending on the content of organic solvent in the mobile phase. This thesis tried to explore possible applications of the CAD for pharmaceutical analysis. Therefore, several substances from different compound classes were in-vestigated. Newly developed or existing methods were validated. Thus the perfor-mance of the CAD could be examined. Both assay and impurity determination were evaluated for their compliance with ICH Q2(R1) “Validation of Analytical Proce-dures” and the “Technical Guide for the Elaboration of Monographs”. In the course of the establishment of reference substances at the EDQM, a generic screening method for the identification of organic and inorganic pharmaceutical counterions was needed. An HPLC-CAD method developed by Zhang et al. was therefore investigated for its suitability for pharmacopoeial purpose. Method valida-tion was performed. It was found that 23 ions could be separated and detected. Iden-tification was achieved via retention time of an authentic standard of the corre-sponding ions. Alternatively, peak assignment was performed by determination of the exact mass using TOF-MS. Ions could be quantified as impurities or for stoichi-ometric purpose. For the impurity control in topiramate, the performance characterstics of the CAD were compared to that of an ELSD. CAD was superior to ELSD in terms of repeata-bility, sensitivity and linearity. However, impurities could be quantified with satisfac-tory accuracy with both detectors. The application of the ELSD was not feasible due to non-reproducible spike peaks eluting after the principle peak in the chromatogram of the test solution. One of the impurities, topiramate impurity A (diacetonide), gave no or a vastly diminished signal in the ELSD and the CAD, respectively. It is evapo-rated during the detection process due to its relatively high vapor pressure. The re-sponse could be enhanced by a factor of nine via post-column addition of acetoni-trile and a lower nebulizer temperature. As the response of topiramate impurity A was still about thousand-fold lower than the response of all other impurities, its quantification was not feasible. Additionally, the HPLC-CAD was successfully vali-dated as an assay procedure for topiramate. There seems to be a great potential in the application of the CAD to the analysis of excipients as most compounds do not possess a suitable UV chromophore. Here, a simple and rapid HPLC-CAD method for the determination of polidocanol (PD) was developed. The method was successfully validated as a potential assay procedure for the Ph. Eur. as none is described in either of the two PD monographs. The same method was applied to the determination of the PD release from a pharmaceutical polymer matrix. A method for the determination of the fatty acid (FA) composition of polysorbate 80 (PS80) was developed and validated. Using the CAD and mass spectrometry, we were able to identify two new FAs in 16 batches from four manufacturers. All batch-es complied with pharmacopoeial specification. Furthermore, the overall composi-tion of the different PS80 species (“fingerprinting”) and the peroxide content were determined. In addition to the chemical characterization, functionality related charac-teristics (FRCs) were determined. Correlations between chemical composition and FRCs were found. The validation data of the above mentioned methods suggests that the CAD repre-sents a viable detection technique for pharmaceutical analysis. The CAD was suffi-ciently sensitive for non-volatile analytes. Impurity control down to concentrations of 0.05 or 0.03%, as demanded by ICH Q3A (R2), is achievable. However, the response of semi-volatile compounds may be drastically diminished. It could be confirmed that the response of the CAD is linear when the range does not exceed two orders of magnitude. Exceptions may be observed depending on the actual method setup. When the measuring range is sufficiently narrow, quantification can be done using single-point calibration which is common practice in pharmaceutical anlysis. Impuri-ties may also be quantified against a single calibration solution. However, correction factors may be needed and the accuracy is considerably lower compared to an as-say method. If a compound is to be quantified over a large concentration range, log-log transformation of the calibration curve is needed and a decreased accuracy has to be accepted. N2 - Der “Corona® charged aerosol detector” (CAD) ist ein aerosol-basierter Detektor, welcher 2002 von Dixon und Peterson vorgestellt wurde. Damit lassen sich nicht-flüchtige Substanzen unabhängig von ihren physiko-chemischen Eigenschaften detektieren. Daraus folgt, dass der CAD oft zur Analyse von Substanzen ohne UV-Chromophor angewandt wird. Großes Manko ist jedoch, dass das Signal nicht linear und abhängig vom Anteil organischen Lösemittels in der mobilen Phase ist. Ziel dieser Arbeit war es, mögliche Anwendungen des CAD in der pharmazeuti-schen Analytik zu erschließen. Dies wurde anhand von Beispielen aus unter-schiedlichen Substanzklassen untersucht. Dabei wurden neu entwickelte oder be-stehende Methoden validiert um die Leistung des CAD beurteilen zu können. So-wohl Gehaltsbestimmungen als auch Methoden zur Erfassung von Verunreinigun-gen wurden hinsichtlich ihrer Konformität mit dem Europäischen Arzneibuch (Ph. Eur.) geprüft. Im Zuge der Charakterisierung von Referenzsubstanzen beim EDQM wurde eine Methode zur Identifikation von pharmazeutischen Gegenionen benötigt. Zu diesem Zweck wurde eine HPLC-CAD-Methode von Zhang et al. hinsichtlich ihrer Eignung für das Ph. Eur. überprüft. Mit dieser Methode ließen sich 23 pharmazeutisch rele-vante Ionen trennen und detektieren. Die Ionen wurden durch Vergleich der Re-tentionszeiten eines Standards erreicht. Zusätzlich wurde die Peakzuordnung mit-tels der Bestimmung der Präzisionsmasse des Gegenions oder des Arzneistoffes durch ein TOF-MS durchgeführt. Die Methode ließ die Quantifizierung von Ionen als Verunreinigung oder zur Bestimmung der Stöchiometrie eines Salzes zu. Bei der Bestimmung von Verunreinigungen von Topiramat wurde ein Vergleich zwischen CAD und ELSD angestellt. Es zeigte sich, dass der CAD in den Punkten Wiederholbarkeit, Empfindlichkeit und Linearität überlegen war. Mit beiden Detekto-ren wurde eine ähnlich gute Richtigkeit erzielt. Durch das Auftreten von nicht re-produzierbaren Peaks, welche nach dem Hauptpeak im Chromatogramm der Testlö-sung auftraten, war die Anwendung des ELSD hier auszuschließen. Eine der Ver-unreinigungen, Topiramat Verunreinigung A (Diacetonid) lieferte kein bzw. ein ver-ringertes Signal in ELSD und CAD. Aufgrund des relativ hohen Dampfdrucks der Substanz wurde sie während des Detektionsvorgangs verdampft. Das Signal konn-te durch Zugabe von Acetonitril nach der Säule und durch eine Verringerung der Temperatur des Vernebler um das neunfache vergrößert werden. Da aber die Emp-findlichkeit für alle anderen Verunreinigungen dennoch um das tausendfache hö-her war, war eine Quantifizierung von Topiramat Verunreinigung A nicht möglich. Die HPLC-CAD Methode wurde zusätzlich als Gehaltsbestimmungsmethode für Topiramat validiert. Die Anwendung des CAD zur Analyse von Hilfsstoffen birgt großes Potenzial, da viele Substanzen nicht über ein Chromophor verfügen. Im Zuge dieser Arbeit wurde eine einfache und schnelle Methode zur Gehaltsbestimmung von Polidocanol (PD) entwickelt. Diese wurde als mögliche Methode für das Ph. Eur. validiert. Zusätzlich wurde die Methode zur Bestimmung der Freisetzung von PD aus einer pharmazeu-tischen Matrix verwendet. Es wurde eine Methode zur Bestimmung der Fettsäurezusammensetzung von Poly-sorbat 80 (PS80) entwickelt und validiert. Mittels CAD und Massenspektrometrie war es möglich zwei neue Fettsäuren in 16 Chargen von vier verschiedenen Herstellern zu identifizieren. Alle Chargen entsprachen den Anforderungen des Ph. Eur. Wei-terhin wurde die Zusammensetzung der einzelnen PS80-Spezies („fingerprinting“) sowie der Peroxidgehalt untersucht. Neben dieser chemischen Charakterisierung wurden auch funktionalitätsbezogene Eigenschaften (FRCs) bestimmt. Korrelatio-nen zwischen chemischen Zusammensetzung und FRCs wurden gefunden. Die Validierungsdaten der genannten Methoden legen nahe, dass der CAD sinn-voll zur pharmazeutischen Analytik angewendet werden kann. Für nicht-flüchtige Substanzen wurde stets eine ausreichende Empfindlichkeit erreicht. Somit können Verunreinigungen bis zu einer Konzentration von 0.05 bzw. 0.03%, wie von der ICH Richtlinie Q3A (R2) gefordert, quantifiziert werden. Jedoch kann das Detektorsignal bei halb-flüchtigen Substanzen stark erniedrigt sein. Es konnte bestätigt werden, dass sich das Detektorsignal über zwei Größenordnungen linear verhält. Abwei-chungen davon sind in Abhängigkeit der jeweiligen Methode möglich. Ist der Mess-bereich genügen klein, so kann ein Stoff mittels Einpunkt-Kalibrierung quantifiziert werden. Dieses Vorgehen sollte bei Gehaltsbestimmungen angewandt werden. Ebenfalls mittels Einpunkt-Kalibrierung können Verunreinigungen erfasst werden. Jedoch kann es notwendig sein, Korrekturfaktoren zu bestimmen. Die Richtigkeit ist hier deutlich niedriger als bei einer Gehaltsbestimmungsmethode. Über einen gro-ßen Konzentrationsbereich muss eine Ausgleichskurve mit log-log-Transformation verwendet werden. Die Richtigkeit ist hierbei ebenfalls geringer als bei einer Ge-haltsbestimmung. KW - Analyse KW - Chemische Reinheit KW - Verunreinigung KW - Detektor KW - Pharmazie KW - charged aerosol detector KW - pharmaceutical analysis KW - Analytik Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118377 ER - TY - JOUR A1 - Nguyen, Minh Thu A1 - Kraft, Beatrice A1 - Yu, Wenqi A1 - Demicrioglu, Dogan Doruk A1 - Hertlein, Tobias A1 - Burian, Marc A1 - Schmaler, Mathias A1 - Boller, Klaus A1 - Bekeredjian-Ding, Isabelle A1 - Ohlsen, Knut A1 - Schittek, Birgit A1 - Götz, Friedrich T1 - The vSa\(\alpha\) Specific Lipoprotein Like Cluster (lpl) of S. aureus USA300 Contributes to Immune Stimulation and Invasion in Human Cells JF - PLoS Pathogens N2 - All Staphylococcus aureus genomes contain a genomic island, which is termed vSa\(\alpha\) and characterized by two clusters of tandem repeat sequences, i.e. the exotoxin (set) and 'lipoprotein-like' genes (lpl). Based on their structural similarities the vSa\(\alpha\) islands have been classified as type I to IV. The genomes of highly pathogenic and particularly epidemic S. aureus strains (USA300, N315, Mu50, NCTC8325, Newman, COL, JH1 or JH9) belonging to the clonal complexes CC5 and CC8 bear a type I vSa\(\alpha\) island. Since the contribution of the lpl gene cluster encoded in the vSa\(\alpha\) island to virulence is unclear to date, we deleted the entire lpl gene cluster in S. aureus USA300. The results showed that the mutant was deficient in the stimulation of pro-inflammatory cytokines in human monocytes, macrophages and keratinocytes. Purified lipoprotein Lpl1 was further shown to elicit a TLR2-dependent response. Furthermore, heterologous expression of the USA300 lpl cluster in other S. aureus strains enhanced their immune stimulatory activity. Most importantly, the lpl cluster contributed to invasion of S. aureus into human keratinocytes and mouse skin and the non-invasive S. carnosus expressing the lpl gene cluster became invasive. Additionally, in a murine kidney abscess model the bacterial burden in the kidneys was higher in wild type than in mutant mice. In this infection model the lpl cluster, thus, contributes to virulence. The present report is one of the first studies addressing the role of the vSa\(\alpha\) encoded lpl gene cluster in staphylococcal virulence. The finding that the lpl gene cluster contributes to internalization into non-professional antigen presenting cells such as keratinocytes high-lights the lpl as a new cell surface component that triggers host cell invasion by S. aureus. Increased invasion in murine skin and an increased bacterial burden in a murine kidney abscess model suggest that the lpl gene cluster serves as an important virulence factor. KW - resistant Staphylococcus-aureus KW - bacterial lipoproteins KW - internalization KW - evolution KW - fibronectin-binding protein KW - toll-like receptor 2 KW - epithelial cells KW - genome sequence KW - activation KW - mechanisms Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151856 VL - 11 IS - 6 ER - TY - JOUR A1 - Kleih, Sonja C. A1 - Herweg, Andreas A1 - Kaufmann, Tobias A1 - Staiger-Sälzer, Pit A1 - Gerstner, Natascha A1 - Kübler, Andrea T1 - The WIN-speller: a new intuitive auditory brain-computer interface spelling application JF - Frontiers in Neuroscience N2 - The objective of this study was to test the usability of a new auditory Brain-Computer Interface (BCI) application for communication. We introduce a word based, intuitive auditory spelling paradigm the WIN-speller. In the WIN-speller letters are grouped by words, such as the word KLANG representing the letters A, G, K, L, and N. Thereby, the decoding step between perceiving a code and translating it to the stimuli it represents becomes superfluous. We tested 11 healthy volunteers and four end-users with motor impairment in the copy spelling mode. Spelling was successful with an average accuracy of 84% in the healthy sample. Three of the end-users communicated with average accuracies of 80% or higher while one user was not able to communicate reliably. Even though further evaluation is required, the WIN-speller represents a potential alternative for BCI based communication in end-users. KW - Brain-Computer Interface (BCI) KW - communication KW - P300 KW - motor-impaired end-user KW - auditory Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125972 VL - 9 ER - TY - THES A1 - Schmidt, Thomas Christian T1 - Theoretical Investigations on the Interactions of Small Compounds with their Molecular Environments T1 - Theoretische Untersuchungen der Wechselwirkungen Kleiner Moleküle mit deren Molekularen Umgebungen N2 - Im ersten Teil dieser Arbeit wird eine Kombination theoretischer Methoden für die strukturbasierte Entwicklung neuer Wirkstoffe präsentiert. Ausgehend von der Kristallstruktur eines kovalenten Komplexes einer Modellverbindung mit dem Zielprotein wurde mit Hilfe von quantenmechanischen und QM/MM Rechnungen die genaue Geometrie des vorausgehenden nicht-kovalenten Komplexes betimmt. Letztere ist der bestimmende Faktor für die Reaktivität des Inhibitors gegenüber der katalytisch aktiven Aminosäure und damit für die Ausbildung einer kovalenten Bindung. Aus diesem Grund wurde diese Geometrie auch für die Optimierung der Substitutionsmusters des Ihnibitors verwendet, um dessen Affinität zum Zielenzyme zu verbessern ohne dass dieser seine Fähigkeit kovalent an das aktive Zentrum zu binden verliert. Die Optimierung des Substitutionsmuster wurde doch Methode des Molekularen Dockings unterstützt, das diese optimal dazu geeignet sind, Bindungsaffinitäten vorherzusagen, die durch eine Modifikation der chemischen Struktur entstehen. Eine Auswahl der besten Strukturen wurde anschließend verwendet, um zu überprüfen, ob die veränderten Moleküle noch genügen Reaktivität gegenüber dem Zielprotein aufweisen. Moleküldynamik Simulationen der neuen Verbindungen haben jedoch gezeigt, dass die veränderten Verbindungen nur so and das Protein binden, dass die Bilung eine kovalenten Bindung zum Enzym nicht mehr möglich ist. Daher wurden in einem weiteren Schritt die Modellverbindungen weiter modifiziert. Neben Änderungen im Substitutionsmuster wurde auch die chemische Struktur im Kern verändert. Die Bindungsaffinitäten wurde wieder mittels Docking überprüft. Für die besten Bindungsposen wurden wieder Simulationen zur Moleküldynamik durchgeführt, wobei diesmal die Ausbildung einer kovalenten Bindung zum Enzyme möglich erscheint. In einer abschließenden Serie von QM/MM Rechnungen unter Berücksichtigung verschiedener Protonierungszustände des Inhibitors und des Proteins konnten Reaktionspfade und zugehörige Reaktionsenergien bestimmt werden. Die Ergebnisse lassen darauf schließen, dass eines der neu entwickelten Moleküle sowohl eine stark verbesserte Bindungsaffinität wie auch die Möglichkeit der kovalenten Bindung an Enzyme aufweist. Der zweite Teil der Arbeit konzentriert sich auf die Umgebungseinflüsse auf die Elektronenverteilung eines Inhibitormodells. Als Grundlage dient ein vinylsulfon-basiertes Moekül, für das eine experimentell bestimmte Kristallstruktur sowie ein theoretisch berechneter Protein Komplex verfügbar sind. Ein Referendatensatz für diese Systeme wurde erstellt, indem der Konformationsraum des Inhibitors nach möglichen Minimumsstrukturen abgesucht wurde, welche später mit den Geometrien des Moleküls im Kristall und im Protein verglichen werden konnten. The Geometrie in der Kristallumgebung konnte direkt aus den experimentellen Daten übernommen werden. Rechnungen zum nicht-kovalenten Protein Komplex hingegen haben gezeigt, dass für das Modellsystem mehrere Geometrien des Inhibiors sowie zwei Protonierungszustände für die katalytisch aktiven Aminosäuren möglich sind. Für die Analyse wurden daher alle möglichen Proteinkomplexe mit der Kristallstruktur verglichen. Ebenso wurden Vergleiche mit der Geometrie des isolierten Moleküls im Vakuum sowie der Geometrie in wässriger Lösung angestellt. Für die Geometrie des Moleküls an sich ergab sich eine gute Übereinstimmung für alle Modellsysteme, für die Wechselwirkungen mit der Umgebung jedoch nicht. Die Ausbildung von Dimeren in der Kristallumgebung hat einen stark stablisierenden Effekt und ist einer der Gründe, warum dieser Kristall so gut wie keine Fehlordungen aufweist. In den Proteinkomplexen hingegen ergibt sich eine Abstoßung zwischen dem Inhibitor und einer der katalytisch aktiven Aminosäuren. Als Ursache für diese Abstoßung konnte die Einführung der Methylaminfunktion ausgemacht werden. Vermutlicherweise führt diese strukturelle Änderung auch dazu, dass der Modellinhibitor nicht in der Lage ist, so wie die Leitstruktur K11777 an das aktive Zentrum des Enzyms zu binden. N2 - In the first part of this work, a combination of theoretical methods for the rational design of covalent inhibitor is presented. Starting from the crystal structure of the covalent complex of a lead compound, quantum mechanical and QM/MM calculations were used to derive the exact geometry of the preceeding non-covalent enzyme inhibitor complex. The geometry of the latter mainly determines the reactivity of the inhibitor against its target enzyme concerning the formation of the covalent bond towards an active site residue. Therefore, this geometry was used as starting point for the optimization of the substitution pattern of the inhibitor such as to increase its binding affinity without loosing its ability to covalently bind to the target protein. The optimization of the chemical structure was supported by using docking procedures, which are best suited to estimate binding affinities that arise from the introduced changes. A screening of the novel substitution patterns resulted in a first generation of model compounds which were further tested for their reactivity against the target. Dynamic simulations on the novel compounds revealed that the orientation that compounds adopt within the active site are such that a covalent interaction with the enzyme is no longer possible. Hence, the chemical structure was further modified, including not only changes in the substituents but also within the core of the molecule. Docking experiments have been conducted to assure sufficiently high binding affinities and to obtain the most favored binding poses. Those have then again been used for dynamic simulations which resulted in structures, for which the bond formation process appeared feasible. A final series of QM/MM calculations considering various protonation states was computed to estimate the reaction energies for the covalent attachment of the inhibitor to the enzyme. The theoretical results indicate a reasonable high inhibition potency of the novel compounds. The second part concentrates on the environmental influences on the electron density of an inhibitor molecule. Therefore, a vinylsulfone-based model compound was selected for which an experimental crystal structure for the pure compound as well as a theoretically determined enzyme-inhibitor complex have been available. To provide reference data for the larger systems, the conformational space of the isolated molecule was screened for favorable geometries which were later compared to those within the crystal and protein surrounding. The geometry of the crystal structure could readily be taken from the experimental data whereas calculations on the protein complex revealed four potential non-covalent complexes exhibiting different arrangements of the molecule within the active site of the protein as well as two possible protonation states of the catalytic dyad. Hence, all four protein complexes have been compared to the crystal structure of the molecule as well as against the more favorable geometries of the isolated molecule being determined within vacuum or aqueous surrounding. Whereas the molecule itself was found to adopt comparable geometries within all investigated environments, the interactions pattern between the crystal surrounding and the protein differed largely from each other. The favorable formation of dimers within the crystal has a strong stabilizing effect and explains the extraordinarily good quality of the crystal. Within the protein however, repulsive forces have been found between the protein and the inhibitor. The origin of the repulsion could be traced back to effect of on of the substituents to the vinyl scaffold. The difference in the chemical structure in comparison to a well known inhibitor might also explain the experimentally found loss of activity for the model compound in comparison to K11777. KW - Theoretische Chemie KW - theoretical chemistry KW - electron density KW - inhibition KW - Elektronendichte KW - Inhibitor Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127860 ER - TY - THES A1 - Schultz, Isabel T1 - Therapeutic systems for Insulin-like growth factor-1 T1 - Therapeutische Systeme für Insulin-like growth factor-1 N2 - SUMMARY Insulin-like growth factor I (IGF-I) is a polypeptide with a molecular weight of 7.649 kDa and an anabolic potential. Thereby, IGF-I has a promising therapeutic value e.g. in muscle wasting diseases such as sarcopenia. IGF-I is mainly secreted by the liver in response to growth hormone (GH) stimulation and is rather ubiquitously found within all tissues. The effects of IGF-I are mediated by its respective IGF-I transmembrane tyrosine kinase receptor triggering the stimulation of protein synthesis, glucose uptake and the regulation of cell growth. The actions of IGF-I are modulated by six IGF binding proteins binding and transporting IGF-I in a binary or ternary complex to tissues and receptors and modulating the binding of IGF-I to its receptor. The nature of the formed complexes impacts IGF-I`s half-life, modulating the half-life between 10 minutes (free IGF-I) to 12 - 15 hours when presented in a ternary complex with IGF binding protein 3 and an acid labile subunit (ALS). Therefore, sustained drug delivery systems of free IGF-I are superficially seen as interesting for the development of controlled release profiles, as the rate of absorption is apparently and easily set slower by simple formulation as compared to the rapid rate of elimination. Thereby, one would conclude, the formulation scientist can rapidly develop systems for which the pharmacokinetics of IGF-I are dominated by the formulation release kinetics. However, the in vivo situation is more complex and as mentioned (vide supra), the half-life may easily be prolonged up to hours providing proper IGF-I complexation takes place upon systemic uptake. These and other aspects are reviewed in Chapter I, within which we introduce IGF-I as a promising therapeutic agent detailing its structure and involved receptors along with the resulting signaling pathways. We summarize the control of IGF-I pharmacokinetics in nature within the context of its complex system of 6 binding proteins to control half-life and tissue distribution. Furthermore, we describe IGF-I variants with modulated properties in vivo and originated from alternative splicing. These insights were translated into sophisticated IGF-I delivery systems for therapeutic use. Aside from safety aspects, the challenges and requirements of an effective IGF-I therapy are discussed. Localized and systemic IGF-I delivery strategies, different routes of administration as well as liquid and solid IGF-I formulations are reviewed. Effective targeting of IGF-I by protein decoration is outlined and consequently this chapter provides an interesting guidance for successful IGF-I-delivery. In Chapter II, we firstly outline the stability of IGF-I in liquid formulations with the intention to deliver the biologic through the lung and the impact of buffer type, sodium chloride concentration and pH value on IGF-I stability is presented. IGF-I integrity was preserved in histidine buffer over 4 months at room temperature, but methionine 59 oxidation (Met(o)) along with reducible dimer and trimer formation was observed in an acidic environment (pH 4.5) and using acetate buffer. Strong aggregation resulted in a complete loss of IGF-I bioactivity, whereas the potency was partly maintained in samples showing a slight aggregation and complete IGF-I oxidation. Atomization by air-jet or vibrating-mesh nebulizers yielded in limited Met(o) formation and no aggregation. The results of IGF-I nebulization experiments regarding aerosol output rate, mass median aerodynamic diameter and fine particle fraction were comparable with 0.9% sodium chloride reference, approving the applicability of liquid IGF-I formulations for pulmonary delivery. In Chapter III we escalated the development to solid delivery systems designed for alveolar landing upon inhalation and by deploying trehalose and the newly introduced for pulmonary application silk-fibroin as carriers. Microparticles were produced using nano spray drying following analyses including IGF-I integrity, IGF-I release profiles and aerodynamic properties. In vitro transport kinetics of IGF-I across pulmonary Calu-3 epithelia were suggesting similar permeability as compared to IGF-I’s cognate protein, insulin that has already been successfully administered pulmonary in clinical settings. These in vivo results were translated to an ex vivo human lung lobe model. This work showed the feasibility of pulmonary IGF-I delivery and the advantageous diversification of excipients for pulmonary formulations using silk-fibroin. Chapter IV focuses on an innovative strategy for safe and controllable IGF-I delivery. In that chapter we escalated the development to novel IGF-I analogues. The intention was to provide a versatile biologic into which galenical properties can be engineered through chemical synthesis, e.g. by site directed coupling of polymers to IGF-I. For this purpose we genetically engineered two IGF-I variants containing an unnatural amino acid at two positions, respectively, thereby integrating alkyne functions into the primary sequence of the protein. These allowed linking IGF-I with other molecules in a site specific manner, i.e. via a copper catalyzed azide-alkyne Huisgen cycloaddition (click reaction). In this chapter we mainly introduce the two IGF-I variants, detail the delivery concept and describe the optimization of the expression conditions of the IGF-I variants. In conclusion, we span from simple liquid formulations for aerolization through solid systems for tailored for maximal alveolar landing to novel engineered IGF-I analogues. Thereby, three strategies for advanced IGF-I delivery were addressed and opportunities and limitations of each were outlined. Evidence was provided that sufficiently stable and easy to manufacture formulations can be developed as typically required for first in man studies. Interestingly, solid systems – typically introduced in later stages of pharmaceutical development – were quite promising. By use of silk-fibroin as a new IGF-I carrier for pulmonary administration, a new application was established for this excipient. The demonstrated success using the ex vivo human lung lobe model provided substantial confidence that pulmonary IGF-I delivery is possible in man. Finally, this work describes the expression of two IGF-I variants containing two unnatural amino acids to implement an innovative strategy for IGF-I delivery. This genetic engineering approach was providing the fundament for novel IGF-I analogues. Ideally, the biologic is structurally modified by covalently linked moieties for the control of pharmacokinetics or for targeted delivery, e.g. into sarcopenic muscles. One future scenario is dicussed in the ‘conclusion and outlook’ section for which IGF-I is tagged to a protease sensitive linker peptide and this linker peptide in return is coupled to a polyethylenglykole (PEG) polymer (required to prolong the half-life). Some proteases may serve as proxy for sarcopenia such that protease upregulation in compromised muscle tissues drives cleavage of IGF-I from the PEG. Thereby, IGF-I is released at the seat of the disease while systemic side effects are minimized. N2 - ZUSAMMEMFASSUNG Insulin-like growth factor I (IGF-I) ist ein 7.6 kDa großes Polypeptid, das eine anabole Wirkung besitzt und dadurch ein vielversprechendes Therapeutikum in Muskelerkrankungen wie z.B. Sarkopenie darstellt. IGF-I wird hauptsächlich von der Leber gebildet und infolge der Stimulation des Wachstumshormons Somatropin sezerniert. In fast jedem Gewebe des Körpers kommt IGF-I vor. Die Wirkungen von IGF-I werden über eigene Rezeptoren, die an die Zellmembran gebunden sind, die Rezeptor-Tyrosinkinasen, ausgeführt. Zu den Wirkungen gehören unter anderem die Stimulation der Proteinsynthese, die Aufnahme von Glucose in die Zellen und die Regulierung des Zellwachstums. Die Effekte von IGF-I werden von 6 IGF- Bindungsproteinen (IGFBP 1-6) gesteuert, indem IGF-I in einem binären oder ternären Komplex zu den Geweben transportiert oder auch die Bindung von IGF-I an den Rezeptor verhindert werden kann. Die sich bildenden Komplexe haben auch einen Einfluss auf die Halbwertszeit (HWZ) von IGF-I, da für ungebundenes IGF-I eine HWZ von ca. 10 Minuten festgestellt werden konnte, aber IGF-I, gebunden in einem ternären Komplex mit dem Bindungsprotein 3 und der säurelabilen Untereinheit (ALS) eine erhöhte HWZ von 12 – 15 Stunden aufweist. Deswegen sind „sustained drug delivery“ Systeme von ungebundenem IGF-I auf den ersten Blick interessant für die Entwicklung von kontrollierten Freisetungsprofilen, da die Absorptionsgeschwindigkeit offensichtlich und problemlos durch triviale Formulierung verlangsamt werden kann im Vergleich zu der schnellen Eliminationsgeschwindigkeit. Deshalb könnte man daraus schließen, dass ein Formulierungsexperte recht schnell Systeme entwickeln kann, in denen die Freisetzungskinetik der Formulierung über die pharmakokinetischen Eigenschaften von IGF-I dominiert. Jedoch ist die in vivo Situation wesentlich komplexer und wie oben bereits erwähnt, könnte die Halbwertszeit problemlos bis zu mehreren Stunden verlängert werden, sofern geeignete Komplexbildung von IGF-I nach systemischer Aufnahme erfolgt. Diese und weitere Aspekte werden in Kapitel I beschrieben. Außerdem stellen wir IGF-I als wertvolles Therapeutikum vor, beschreiben dessen Struktur, die beteiligten Rezeptoren und die daraus resultierenden Signalwege. Wir fassen die Kontrolle der Pharmakokinetik von IGF-I in der Natur zusammen, im Rahmen von einem komplexen System aus 6 Bindungsproteinen, die die Halbwertszeit und die Gewebeverteilung steuern. Außerdem beschreiben wir IGF-I Varianten, die veränderte Eigenschaften in vivo aufweisen und durch alternatives Spleißen entstanden sind. Diese Erkenntnisse werden in hochentwickelte „IGF-I delivery“ Systeme für den therapeutischen Gebrauch umgesetzt. Neben Sicherheitsaspekten werden die Herausforderungen und Anforderungen einer effektiven IGF-I Therapie diskutiert. Darüber hinaus wird über lokale und systemische „IGF-I delivery“ Strategien, verschiedene Verabreichungswege sowie flüssige und feste IGF-I Formulierungen berichtet. Ebenso wird die wirkungsvolle IGF-I Freisetzung am Zielort durch Ausschmückung des Proteins beschrieben und dementsprechend liefert dieses Kapitel eine interessante Orientierungshilfe für eine erfolgreiche IGF-I Therapie. Im Kapitel II untersuchen wir die Stabilität von IGF-I in flüssigen Formulierungen zur pulmonalen Anwendung bezüglich Puffersystem, Natriumchlorid Konzentration und pH Wert. Die IGF-I Integrität wurde im Histidin Puffer über 4 Monate bei Raumtemperatur aufrechterhalten. Allerdings wurde bei Verwendung eines Acetat Puffers pH 4.5, Oxidation am Methionin 59 (Met(o)) sowie die Entstehung von reduzierbaren Dimeren und Trimeren beobachtet. Starke Aggregation führte zum vollständigen Verlust der IGF-I Bioaktivität, während die Wirkung in Proben aufrechterhalten werden konnte, in denen eine geringe Aggregation, aber deutliche Oxidation festgestellt wurde. Nach der Verneblung der flüssigen IGF-I Formulierung im Histidin-Puffer pH 6.5 mit einem Druckluftvernebler und einem Schwingmembranvernebler wurde jeweils eine leichte Bildung von Met(o), aber keine Aggregatbildung ermittelt. Die Ergebnisse der IGF-I Verneblungsexperimente waren vergleichbar mit den Referenzwerten einer isotonischen Kochsalzlösung bezüglich der Abgabeleistung, dem massenbezogenen medianen aerodynamischen Durchmesser und dem Feinpartikel Anteil. Hierdurch wurde gezeigt, dass sich flüssige IGF-I Formulierungen zur pulmonalen Anwendung eignen. Im Kapitel III berichten wir von einer Weiterentwicklung zu festen IGF-I Formulierungen für die pulmonale Route unter Verwendung von Trehalose und Seidenfibroin als neues Trägermaterial für die pulmonale Applikation. Mikropartikel wurden durch Nanosprühtrocknung hergestellt und anschließend auf IGF-I Integrität, IGF-I Freisetzung und dem aerodynamischen Durchmesser untersucht. Die Kinetik des in vitro Transportes von IGF-I durch Calu-3 Lungenepithelzellen war vergleichbar zur Durchgängigkeit von Insulin, das bereits erfolgreich pulmonal verabreicht wurde. Dieser Erfolg wurden auch ex vivo in einem menschlichen Lungenlappen Model bestätigt. In der Arbeit wird somit gezeigt, dass IGF-I zur pulmonalen Anwendung geeignet ist und die Verwendung von Seidenfibroin eine nützliche Erweiterung zu den bisher eingesetzten Trägermaterialien darstellt. Das Kapitel IV konzentriert sich auf eine innovative Strategie, um IGF-I sicher und kontrollierbar zu verabreichen. In diesem Kapitel erweitern wir die Entwicklung zu neuartigen IGF-I Varianten. Wir streben damit an ein vielseitiges Biologikum zu entwickeln, dessen Eigenschaften durch chemische Reaktionen verändert werden können wie zum Beispiel die spezifische Verknüpfung mit Polymeren. Zu diesem Zweck erzeugten wir gentechnisch zwei IGF-I Varianten, die jeweils an zwei Positionen eine unnatürliche Aminosäure aufweisen und führten dadurch Alkine Gruppen in die Primärstruktur der Proteine ein. Diese Vorgehensweise ermöglicht es nun IGF-I mit anderen Molekülen positionsspezifisch zu verbinden wie zum Beispiel durch die kupferkatalysierte Azid-Alkin-Cycloaddition (Click – Reaktion). In diesem Kapitel stellen wir hauptsächlich die zwei IGF-I Varianten vor, beschreiben ausführlich das Konzept der IGF-I Zustellung und erklären die Vorgehensweise zur Optimierung der Expressionsbedingungen der IGF-I Varianten. Abschließend lässt sich sagen, dass sich diese Arbeit über einfach flüssige Formulierungen zur Verneblung, feste Formulierung mit guten aerodynamischen Eigenschaften zur Erreichung der Alveolen und neuartig entwickelte IGF-I Varianten erstreckt. Hierzu werden drei Strategien zur modernen IGF-I Gabe thematisiert und sowohl die Möglichkeiten als auch die Grenzen der jeweiligen Therapie erörtert. Wir haben den Nachweis erbracht, dass ausreichend stabile und leicht herzustellende Formulierungen entwickelt werden können, die üblicherweise für „First-In-Man“ Studien benötigt werden. Interessanterweise stellten sich die festen Formulierungen, die eigentlich in den späteren Phasen der pharmazeutischen Entwicklung eingeführt werden, als sehr vielversprechend heraus. Durch den Einsatz von Seidenfibroin als neuen Träger zur pulmonalen Anwendung haben wir einen neuen Verwendungszweck für Seidenfibroin etabliert. Der erfolgreiche Versuch ex vivo am menschlichen Lungenlappen Model liefert die feste Überzeugung, dass es möglich ist, IGF-I im Menschen pulmonal anzuwenden. Letztendlich, beschreibt die Arbeit die Expression von zwei IGF-I Varianten, die zwei unnatürliche Aminosäuren aufweisen, um eine neuartige Strategie zur IGF-I Verabreichung umzusetzen. Dieser gentechnische Ansatz liefert die Grundlage für neue IGF-I Varianten. Idealerweise, wird das Biopharmazeutikum strukturell durch kovalent gebundene Reste verändert, um die pharmakokinetischen Eigenschaften zu steuern oder um zielgenaue Wirkstoffabgabe zu erreichen zum Beispiel in den sarkopenischen Muskeln. Ein Zukunftsszenarium wird im Abschnitt „Conclusion and Outlook“ diskutiert, in dem IGF-I mit einem Protease empfindlichen Linker versehen wird, der wiederum mit einem Polyethylenglykol (PEG) Polymer verknüpft ist. Der PEG Rest wird benötigt, um die Hablbwertszeit von IGF-I zu erhöhen. Einige Proteasen könnten als Stellvertreter für Sarkopenie dienen, so dass die Hochregulierung der Proteasen in gefährdeten Muskelgeweben zur Spaltung von IGF-I und dem PEG Rest führt. Dadurch wird IGF-I am Ursprung der Erkrankungen freigesetzt, während die systemischen Nebenwirkungen weitgehend vermindert sind. KW - Insulin-like Growth Factor I KW - Pulmonary delivery KW - Spray drying KW - Silk-Fibroin KW - Protein Expression KW - Pulmonale Applikation KW - Sprühtrocknung KW - Seiden-Fibroin Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119114 ER - TY - JOUR A1 - Thierschmann, H A1 - Arnold, F A1 - Mittermüller, M A1 - Maier, L A1 - Heyn, C A1 - Hansen, W A1 - Buhmann, H A1 - Molenkamp, L W T1 - Thermal gating of charge currents with Coulomb coupled quantum dots JF - New Journal of Physics N2 - We have observed thermal gating, i.e. electrostatic gating induced by hot electrons. The effect occurs in a device consisting of two capacitively coupled quantum dots. The double dot system is coupled to a hot electron reservoir on one side (QD1), while the conductance of the second dot (QD2) is monitored. When a bias across QD2 is applied we observe a current which is strongly dependent on the temperature of the heat reservoir. This current can be either enhanced or suppressed, depending on the relative energetic alignment of the QD levels. Thus, the system can be used to control a charge current by hot electrons. KW - oscillations KW - physics KW - quantum dot systems KW - Coulomb interaction KW - thermal gating KW - three terminal device KW - thermoelectrics KW - energy KW - thermopower Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145196 VL - 17 IS - 113003 ER - TY - THES A1 - Bieker, Steffen T1 - Time and Spatially Resolved Photoluminescence Spectroscopy of Hot Excitons in Gallium Arsenide T1 - Orts- und Zeitaufgelöste Photolumineszenzspektroskopie Heißer Exzitonen in Galliumarsenid N2 - The present thesis investigates the impact of hot exciton effects on the low-temperature time and spatially resolved photoluminescence (PL) response of free excitons in high-purity gallium arsenide (GaAs). The work at hand extends available studies of hot carrier effects, which in bulk GaAs have up to now focused on hot electron populations. In crucial distinction from previous work, we extensively study the free exciton second LO-phonon replica. The benefit of this approach is twofold. First, the two LO phonon-assisted radiative recombination allows to circumvent the inherent interpretation ambiguities of the previously investigated free exciton zero-phonon line. Second, the recombination line shape of the second LO-phonon replica provides direct experimental access to the exciton temperature, thereby enabling the quantitative assessment of hot exciton effects. In the first part of the thesis, we address the influence of transient cooling on the time evolution of an initially hot photocarrier ensemble. To this end, we investigate time-resolved photoluminescence (TRPL) signals detected on the free exciton second LO-phonon replica. Settling a long-standing question, we show by comparison with TRPL transients of the free exciton zero-phonon line that the slow free exciton photoluminescence rise following pulsed optical excitation is dominated by the slow buildup of a free exciton population and not by the relaxation of large K-vector excitons to the Brillouin zone center. To establish a quantitative picture of the delayed photoluminescence onset, we determine the cooling dynamics of the initially hot photocarrier cloud from a time-resolved line shape analysis of the second LO-phonon replica. We demonstrate that the Saha equation, which fundamentally describes the thermodynamic population balance between free excitons and the uncorrelated electron-hole plasma, directly translates the experimentally derived cooling curves into the time-dependent conversion of unbound electron-hole pairs into free excitons. In the second part of the thesis, we establish the impact of hot exciton effects on low-temperature spatially resolved photoluminescence (SRPL) studies. Such experiments are widely used to investigate charge carrier and free exciton diffusion in semiconductors and semiconductor nanostructures. By SRPL spectroscopy of the second LO-phonon replica, we show that above-band gap focused laser excitation inevitably causes local heating in the carrier system, which crucially affects the diffusive expansion of a locally excited exciton packet. Undistorted free exciton diffusion profiles, which are correctly described by the commonly used formulation of the photocarrier diffusion equation, are only observed in the absence of spatial temperature gradients. At low sample temperatures, the reliable determination of free exciton diffusion coefficients from both continuous-wave and time-resolved SRPL spectroscopy requires strictly resonant optical excitation. Using resonant laser excitation, we observe the dimensional crossover of free exciton diffusion in etched wire structures of a thin, effectively two-dimensional GaAs epilayer. When the lateral wire width falls below the diffusion length, the sample geometry becomes effectively one-dimensional. The exciton diffusion profile along the wire stripe is then consistently reproduced by the steady-state solution to the one-dimensional diffusion equation. Finally, we demonstrate the formation of macroscopic free and bound exciton photoluminescence rings in bulk GaAs around a focused laser excitation spot. Both ring formation effects are due to pump-induced local heating in the exciton system. For a quantitative assessment of the mechanism underlying the free exciton ring formation, we directly determine the exciton temperature gradient from a spatially resolved line shape analysis of the free exciton second LO-phonon replica. We demonstrate that a pump-induced hot spot locally modifies the thermodynamic population balance between free excitons and unbound electron-hole pairs described by the Saha equation, which naturally explains the emergence of macroscopic free exciton ring structures. In summary, we demonstrate that quantitative consideration of hot exciton effects provides a coherent picture both of the time-domain free exciton luminescence kinetics and of the distinct spatially resolved photoluminescence patterns developing under the influence of spatial photocarrier diffusion. N2 - Die vorliegende Arbeit untersucht den Einfluss von Überheizungseffekten aufgrund nichtresonanter optischer Anregung auf die orts- und zeitaufgelöste Photolumineszenz-Dynamik freier Exzitonen in hochreinem Galliumarsenid (GaAs). Die Arbeit baut damit vorhandene Studien von Überheizungseffekten aus, welche sich in Volumen-GaAs vornehmlich auf die Untersuchung heißer Elektronenpopulationen konzentriert haben. In Abgrenzung zu vorherigen Studien erfolgt eine umfängliche Untersuchung der zweiten LO-Phonon Replik des freien Exzitons. Dieser Ansatz bietet zweifachen Nutzen. Zum einen können durch die Betrachtung des strahlenden Zerfalls freier Exzitonen unter gleichzeitiger Emission zweier LO Phononen die inhärenten Mehrdeutigkeiten bei der Interpretation der direkten Lumineszenz freier Exzitonen umgangen werden. Des Weiteren gestattet eine Linienformanayse der zweiten LO-Phonon Replik die direkte experimentelle Bestimmung der Exzitonentemperatur und schafft damit die Voraussetzung zur quantitativen Untersuchung von Überheizungseffekten im Exzitonensystem. Im ersten Teil der Arbeit wird der Einfluss des transienten Kühlens auf die Zeitentwicklung eines anfänglich heißen Ladungsträgerensembles untersucht. Durch einen Vergleich des Signalverlaufs der direkten Exzitonenlumineszenz mit der zweiten LO-Phonon Replik kann zweifelsfrei gezeigt werden, dass der verzögerte Anstieg der Exzitonenlumineszenz durch den relativ langsamen Aufbau einer Exzitonenpopulation dominiert wird und nicht lediglich die Relaxation von Exzitonen mit großen K-Vektoren zum Zentrum der Brillouinzone widerspiegelt. Zum quantitativen Verständnis des verzögerten Lumineszenzanstiegs wird das Abkühlverhalten des anfänglich heißen Ladungsträgerensembles durch eine zeitaufgelöste Linienformanalyse der zweiten LO-Phonon Replik bestimmt. Es wird gezeigt, dass die Saha-Gleichung, welche das thermodynamische Populations-Gleichgewicht zwischen freien Exzitonen und dem unkorrelierten Elektron-Loch-Plasma beschreibt, die experimentell bestimmten Kühlkurven direkt in die zeitabhängige Umwandlung von ungebundenen Elektron-Loch-Paaren in freie Exzitonen übersetzt. Im zweiten Teil der Arbeit werden die Auswirkungen von Überheizungseffekten im Exzitonensystem auf ortsaufgelöste Photolumineszenzmessungen bei tiefen Gittertemperaturen untersucht. Experimente dieser Art werden häufig zur Bestimmung von Ladungsträger- und Exzitonen-Diffusionskoeffizienten in Halbleitern und Halbleiter-Nanostrukturen genutzt. Durch die ortsaufgelöste Auswertung der zweiten LO-Phonon Replik kann gezeigt werden, dass fokussierte nichtresonante Laseranregung unweigerlich zu einer lokalen Überheizung des Ladungsträgersystems führt. Solche optisch induzierten Temperaturgradienten beeinflussen entscheidend die diffusive Ausbreitung eines lokal erzeugten Exzitonen-Pakets. Unverfälschte Diffusionsprofile, die korrekt durch die üblicherweise herangezogene Formulierung der Diffusionsgleichung beschrieben werden, sind ausschließlich bei Nichtanwesenheit von räumlichen Temperaturgradienten beobachtbar. Die verlässliche Bestimmung von Exzitonen-Diffusionskoeffizienten sowohl mittels zeitaufgelöster als auch stationärer ortsaufgelöster Photolumineszenzspektroskopie erfordert daher scharf resonante optische Anregung. Unter resonanter Laseranregung kann der Übergang von einem effektiv zweidimensionalen zu einem effektiv eindimensionalen Diffusionsverhalten freier Exzitonen in geätzten GaAs-Strukturen beobachtet werden. Die untersuchten Streifenstrukturen werden in eine dünne, effektiv zweidimensionale GaAs-Epischicht geätzt. Der dimensionale Übergang vollzieht sich, wenn die laterale Abmessung der geätzten Struktur die Diffusionslänge unterschreitet. Das stationäre Exzitonen-Diffusionsprofil wird dann korrekt durch die Lösung der eindimensionalen Diffusionsgleichung beschrieben. Abschließend wird die Bildung makroskopischer Ringstrukturen freier und gebundener Exzitonen in Volumen-GaAs um einen fokussierten Laserspot demonstriert. Beide Ringstrukturen resultieren aus lokalen Überheizungen des Exzitonensystems, die durch nichtresonante optische Anregung hervorgerufen werden. Zum quantitativen Verständnis des zugrunde liegenden Mechanismus für die Entstehung der beobachteten Ringstrukturen wird der Temperaturgradient im Exzitonensystem durch eine ortsaufgelöste Linienformanalyse der zweiten LO-Phonon Replik bestimmt. Es wird gezeigt, dass die Ringstrukturen freier Exzitonen auf natürliche Weise durch das lokale thermodynamische Saha-Gleichgewicht zwischen Exzitonen und ungebundenen Elektron-Loch-Paaren entstehen. Zusammenfassend zeigt die vorliegende Arbeit, dass die quantitative Berücksichtigung von Überheizungseffekten im Exzitonensystem zu einem kohärenten Gesamtbild des Lumineszenzprozesses führt, welches sowohl die zeitaufgelöste Lumineszenzkinetik freier Exzitonen als auch das Auftreten exzitonischer Ringstrukturen unter dem Einfluss räumlicher Ladungsträgerdiffusion erklärt. KW - Exziton KW - Galliumarsenid KW - Photoanregung KW - Dimensional Crossover KW - Photolumineszenzspektroskopie KW - Exciton KW - Diffusion KW - Photoluminescence Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134419 ER - TY - JOUR A1 - Kolominsky-Rabas, Peter L. A1 - Wiedmann, Silke A1 - Weingärtner, Michael A1 - Liman, Thomas G. A1 - Endres, Matthias A1 - Schwab, Stefan A1 - Buchfelder, Michael A1 - Heuschmann, Peter U. T1 - Time Trends in Incidence of Pathological and Etiological Stroke Subtypes during 16 Years: The Erlangen Stroke Project JF - Neuroepidemiology N2 - Background: Population-based data, which continuously monitors time trends in stroke epidemiology are limited. We investigated the incidence of pathological and etiological stroke subtypes over a 16 year time period. Methods: Data were collected within the Erlangen Stroke Project (ESPro), a prospective, population-based stroke register in Germany covering a total study population of 105,164 inhabitants (2010). Etiology of ischemic stroke was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results: Between January 1995 and December 2010, 3,243 patients with first-ever stroke were documented. The median age was 75 and 55% were females. The total stroke incidence decreased over the 16 year study period in men (Incidence Rate Ratio 1995-1996 vs. 2009-2010 (IRR) 0.78; 95% CI 0.58-0.90) but not in women. Among stroke subtypes, a decrease in ischemic stroke incidence (IRR 0.73; 95% CI 0.57-0.93) and of large artery atherosclerotic stroke (IRR 0.27; 95% CI 0.12-0.59) was found in men and an increase of stroke due to small artery occlusion in women (IRR 2.33; 95% CI 1.39-3.90). Conclusions: Variations in time trends of pathological and etiological stroke subtypes were found between men and women that might be linked to gender differences in the development of major vascular risk factors in the study population. KW - stroke KW - epidemiology KW - incidence KW - time trends KW - register Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196503 SN - 0251-5350 SN - 1423-0208 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 44 IS - 1 ER -