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Parkinson’s disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity.
Electronic supplementary material: The online version of this article (doi:10.1007/s00702-011-0717-3) contains supplementary material, which is available to authorized users.
Methodik
(2002)
Die vegetationskundliche und strukturelle Zuordnung der Lebensraumtypen erfolgt nach der vorrangig von Braun-Blanquet entwickelten Vegetationsklassifizierung, einer hierarchischen Gliederung der Vegetationstypen (Syntaxonomie), die die Ebenen der Assoziation, des Verbandes, der Ordnung und der Klasse umfasst. Hierbei ist die Assoziation die grundlegende Einheit, in der die Pflanzengesellschaften zusammengefasst werden, die sich durch gleiche charakteristische Arten(gruppen)kombinationen auszeichnen. Der Verband vereinigt ähnliche Assoziationen. Das sind bereits umfassendere, jedoch standörtlich noch recht einheitliche Vegetationseinheiten. In Ordnungen werden ähnliche Verbände zusammengefasst. Die Klasse vereinigt ähnliche Ordnungen.
FTY720 is a novel immunosuppressive drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. In its phosphorylated form FTY720 is a potent S1P receptor agonist. Recently it was also shown that FTY720 can reduce prostaglandin synthesis through the direct inhibition of the cytosolic phospholipase A2 (cPLA2). Since prostaglandins are important mediators of nociception, we studied the effects of FTY720 in different models of nociception. We found that intraperitoneal administration of FTY720 reduced dose-dependently the nociceptive behaviour of rats in the formalin assay. Although the antinociceptive doses of FTY720 were too low to alter the lymphocyte count, prostanoid concentrations in the plasma were dramatically reduced. Surprisingly, intrathecally administered FTY720 reduced the nociceptive behaviour in the formalin assay without altering spinal prostaglandin synthesis, indicating that additional antinociceptive mechanisms beside the inhibition of prostaglandin synthesis are involved. Accordingly, FTY720 reduced also the nociceptive behaviour in the spared nerve injury model for neuropathic pain which does not depend on prostaglandin synthesis. In this model the antinociceptive effect of FTY720 was similar to gabapentin, a commonly used drug to treat neuropathic pain. Taken together we show for the first time that FTY720 possesses antinociceptive properties and that FTY720 reduces nociceptive behaviour during neuropathic pain.
Consequences of altered eicosanoid patterns for nociceptive processing in mPGES-1-deficient mice
(2007)
Cyclooxygenase-2 (COX-2)-dependent prostaglandin (PG) E2 synthesis in the spinal cord plays a major role in the development of inflammatory hyperalgesia and allodynia. Microsomal PGE2 synthase-1 (mPGES-1) isomerizes COX-2-derived PGH2 to PGE2. Here, we evaluated the effect of mPGES-1-deficiency on the noci-ceptive behavior in various models of nociception that depend on PGE2 synthesis. Surprisingly, in the COX-2-dependent zymosan-evoked hyperalgesia model, the nociceptive behavior was not reduced in mPGES-1-deficient mice despite a marked decrease of the spinal PGE2 synthesis. Similarly, the nociceptive behavior was unaltered in mPGES-1-deficient mice in the formalin test. Importantly, spinal cords and primary spinal cord cells derived from mPGES-1-deficient mice showed a redirection of the PGE2 synthesis to PGD2, PGF2α and 6-keto-PGF1α (stable metabolite of PGI2). Since the latter prostaglandins serve also as mediators of noci-ception they may compensate the loss of PGE2 synthesis in mPGES-1-deficient mice.
We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(α,γ)16O fusion reaction and to reach lower center-ofmass energies than measured so far.
The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-to-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.
How long does it take to emit an electron from an atom? This question has intrigued scientists for decades. As such emission times are in the attosecond regime, the advent of attosecond metrology using ultrashort and intense lasers has re-triggered strong interest on the topic from an experimental standpoint. Here, we present an approach to measure such emission delays, which does not require attosecond light pulses, and works without the presence of superimposed infrared laser fields. We instead extract the emission delay from the interference pattern generated as the emitted photoelectron is diffracted by the parent ion’s potential. Targeting core electrons in CO, we measured a 2d map of photoelectron emission delays in the molecular frame over a wide range of electron energies. The emission times depend drastically on the photoelectrons’ emission directions in the molecular frame and exhibit characteristic changes along the shape resonance of the molecule.
During SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) we performed measurements of a wide range of trace gases with different lifetimes and sink/source characteristics in the northern hemispheric upper troposphere (UT) and lowermost stratosphere (LMS). A large number of in-situ instruments were deployed on board a Learjet 35A, flying at altitudes up to 13.7 km, at times reaching to nearly 380 K potential temperature. Eight measurement campaigns (consisting of a total of 36 flights), distributed over all seasons and typically covering latitudes between 35° N and 75° N in the European longitude sector (10° W–20° E), were performed. Here we present an overview of the project, describing the instrumentation, the encountered meteorological situations during the campaigns and the data set available from SPURT. Measurements were obtained for N2O, CH4, CO, CO2, CFC12, H2, SF6, NO, NOy, O3 and H2O. We illustrate the strength of this new data set by showing mean distributions of the mixing ratios of selected trace gases, using a potential temperature – equivalent latitude coordinate system. The observations reveal that the LMS is most stratospheric in character during spring, with the highest mixing ratios of O3 and NOy and the lowest mixing ratios of N2O and SF6. The lowest mixing ratios of NOy and O3 are observed during autumn, together with the highest mixing ratios of N2O and SF6 indicating a strong tropospheric influence. For H2O, however, the maximum concentrations in the LMS are found during summer, suggesting unique (temperature- and convection-controlled) conditions for this molecule during transport across the tropopause. The SPURT data set is presently the most accurate and complete data set for many trace species in the LMS, and its main value is the simultaneous measurement of a suite of trace gases having different lifetimes and physical-chemical histories. It is thus very well suited for studies of atmospheric transport, for model validation, and for investigations of seasonal changes in the UT/LMS, as demonstrated in accompanying and elsewhere published studies.
Bericht der Arbeitsgruppe Technik zur Vorbereitung des Programms "Retrospektive Digitalisierung von Bibliotheksbeständen" im Förderbereich "Verteilte Digitale Forschungsbibliothek" Arbeitssitzungen am 14. Mai 1996 (Frankfurt a. M.), 29.-30. Juli 1996 (München), 12.-13. Dezember 1996 (Göttingen) Mitglieder der Arbeitsgruppe: Prof. Dr. Rudolf Bayer, Technische Universität München, Fakultät für Informatik Dr. Jürgen Bunzel, Deutsche Forschungsgemeinschaft, Bonn Dr. Marianne Dörr, Bayerische Staatsbibliothek München Dr. Reinhard Ecker, Beilstein-Institut bzw. ABC Datenservice GmbH, Frankfurt/Main Dipl.-Math. Heinz-Werner Hoffmann, Hochschulbibliothekszentrum NRW, Köln (als Gast für die AG der Verbundsysteme) Dr. Norbert Lossau, Niedersächsische Staats- und Universitätsbibliothek Göttingen (DFG-Projekt ‘Verteilte Digitale Forschungsbibliothek’) Prof. Dr. Elmar Mittler, Niedersächsische Staats- und Universitätsbibliothek Göttingen Dipl.-Inf. Christian Mönch, FB Informatik der J.W. Goethe-Universität Frankfurt Dr. Wilhelm R. Schmidt, Stadt- und Universitätsbibliothek Frankfurt Dr. Hartmut Weber, Landesarchivdirektion, Stuttgart
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired antimicrobial activity in phagocytic cells. As a monogenic disease affecting the hematopoietic system, CGD is amenable to gene therapy. Indeed in a phase I/II clinical trial, we demonstrated a transient resolution of bacterial and fungal infections. However, the therapeutic benefit was compromised by the occurrence of clonal dominance and malignant transformation demanding alternative vectors with equal efficacy but safety-improved features. In this work we have developed and tested a self-inactivating (SIN) gammaretroviral vector (SINfes.gp91s) containing a codon-optimized transgene (gp91(phox)) under the transcriptional control of a myeloid promoter for the gene therapy of the X-linked form of CGD (X-CGD). Gene-corrected cells protected X-CGD mice from Aspergillus fumigatus challenge at low vector copy numbers. Moreover, the SINfes.gp91s vector generates substantial amounts of superoxide in human cells transplanted into immunodeficient mice. In vitro genotoxicity assays and longitudinal high-throughput integration site analysis in transplanted mice comprising primary and secondary animals for 11 months revealed a safe integration site profile with no signs of clonal dominance.
New neutron cross section measurements of minor actinides have been performed recently in order to reduce the uncertainties in the evaluated data, which is important for the design of advanced nuclear reactors and, in particular, for determining their performance in the transmutation of nuclear waste. We have measured the 241Am(n,γ) cross section at the n_TOF facility between 0.2 eV and 10 keV with a BaF2 Total Absorption Calorimeter, and the analysis of the measurement has been recently concluded. Our results are in reasonable agreement below 20 eV with the ones published by C. Lampoudis et al. in 2013, who reported a 22% larger capture cross section up to 110 eV compared to experimental and evaluated data published before. Our results also indicate that the 241Am(n,γ) cross section is underestimated in the present evaluated libraries between 20 eV and 2 keV by 25%, on average, and up to 35% for certain evaluations and energy ranges.
The accuracy on neutron capture cross section of fissile isotopes must be improved for the design of future nuclear systems such as Gen-IV reactors and Accelerator Driven Systems. The High Priority Request List of the Nuclear Energy Agency, which lists the most important nuclear data requirements, includes also the neutron capture cross sections of fissile isotopes such as 233,235U and 239,241Pu. A specific experimental setup has been used at the CERN n_TOF facility for the measurement of the neutron capture cross section of 235U by a set of micromegas fission detectors placed inside a segmented BaF2 Total Absorption Calorimeter.
A small electrostatic storage ring is the central machine of the Frankfurt Ion Storage Experiments (FIRE) which will be built at the new Stern-Gerlach Center of Frankfurt University. As a true multiuser, multipurpose facility with ion energies up to 50 keV, it will allow new methods to analyze complex many-particle systems from atoms to very large biomolecules. With envisaged storage times of some seconds and beam emittances in the order of a few mm mrad, measurements with up to 6 orders of magnitude better resolutions as compared to single-pass experiments become possible. In comparison to earlier designs, the ring lattice was modified in many details: Problems in earlier designs were related to, e.g., the detection of light particles and highly charged ions with different charge states. Therefore, the deflectors were redesigned completely, allowing a more flexible positioning of the diagnostics. Here, after an introduction to the concept of electrostatic machines, an overview of the planned FIRE is given and the ring lattice and elements are described in detail.
Hintergrund: Dehntrainings sind eine Maßnahme der betrieblichen Gesundheitsförderung (BGF) für Büroangestellte zur Prävention von muskuloskeletalen Erkrankungen (MSE). Sie können zu Beweglichkeitszuwächsen führen und auf psychischer Ebene entspannen. Ziel der Studie war es, ein standardisiertes und individualisiertes Dehntraining am Gerät, das „five-Business“, auf MSE, Lebensqualität und Beweglichkeit zu untersuchen. Dies ist eine Zusammenfassung der international publizierten Ergebnisse.
Methodik: In diese Untersuchung wurden 252 Proband(innen) eingeschlossen, 156 in die Interventionsgruppe (IG), 96 in die Kontrollgruppe (KG). Die IG absolvierte für 12 Wochen 22–24 Trainingseinheiten am „five-Business“, möglichst zweimal wöchentlich. Die Datenerhebung erfolgte mittels sportmotorischer bzw. Range-of-motion(ROM)-Tests, dem Nordic Questionnaire (NQ) und dem SF-36-Fragebogen in Form einer Prä-Post-Untersuchung.
Ergebnisse: Nach der Intervention gaben im NQ signifikant weniger Proband(innen) der IG Beschwerden im oberen Rücken (p < 0,001) im Vergleich zur KG an; keine signifikanten Unterschiede wurden bei Beschwerden im Nacken, Schultern, Hüfte und dem unteren Rücken gefunden. Der mit dem SF-36 erhobene allgemeine Gesundheitszustand und die gesundheitsbezogene Lebensqualität haben sich (nach subjektiven Angaben) signifikant verbessert (Summenscore IG: p = 0,005). In den ROM-Tests waren die Prä-Post-Differenzen bei IG-Proband(innen) in der Sagittalebene (Finger-Boden-Abstand und Retroflexion; p < 0,001) und im modifizierten Schultertest nach Janda auf der linken Seite (p = 0,003) signifikant größer.
Diskussion: Trotz des in Zeitdauer und Häufigkeit relativ geringen Trainingsaufwandes wurden sowohl auf körperlicher als auch auf psychischer Ebene relevante Verbesserungen erzielt, so dass das „five-Business“-Dehntraining als BGF-Maßnahme empfohlen werden kann.
In the context of workplace health promotion, physical activity programs have been shown to reduce musculoskeletal diseases and stress, and to improve the quality of life. The aim of this study was to examine the effects of using the “five-Business” stretch training device for office workers on their quality of life. A total of 313 office workers (173m/137f) participated voluntarily in this intervention–control study with an average age of 43.37 ± 11.24 (SD) years, 175.37 ± 9.35 cm in height and 75.76 ± 15.23 kg in weight, with an average BMI of 24.5 ± 3.81 kg/m2. The participants completed the stretch training twice a week for approximately 10 minutes for a duration of 12 weeks. The SF-36 questionnaire was used to evaluate the effectiveness of the intervention at baseline and after 12 weeks. Significantly improved outcomes in mental sum score (p = 0.008), physical functioning (p < 0.001), bodily pain (p = 0.01), vitality (p = 0.025), role limitations due to physical problems (p = 0.018) and mental health (p = 0.012) were shown after the stretching training. The results suggest that a 12-week stretching program for office desk workers is suitable to improve significantly their health-related quality of life.