30 research outputs found
Die Rolle des Transkriptionsfaktors HIF-1alpha für die Integrität murinen Gelenkknorpels
No full textBackground and Objectives: Articular cartilage is a unique tissue that is outstanding through its avascularity. The therefore prevalent hypoxia sets high demands on the metabolism of the chondrocytes, whereby the transcription factor HIF-1alpha plays an important role for the cellular adaptation process. HIF-1alpha also supports the expression of many cartilage specific genes. In this research work we determined whether the inhibition of HIF-1alpha-activity promotes the progress of osteoarthritis in knee joints of mice. Furthermore this study investigated if an increase in HIF-1alpha-activity could prevent or decelerate spontaneously occurring degenerative changes in STR/ORT-mice. Methods: HIF-1alpha activity was inhibited by application of 2ME2 (2-Methoxyestradiol) in the knee joints of Balb/C mice. The joints were examined and assessed three and twelve weeks after injection both histochemically and immunohistochemically regarding the degeneration in articular cartilage, osteophyte development and synovialitis. The increase of activity of HIF-1alpha was archieved by injection of DMOG (Dimethyloxalolglycine) once a week during a total period of twelve weeks into the knee joints of STR/ORT-mice prior to their histochemical analysis. The effect of DMOG on collagen synthesis was examined in cell culture experiments. Results: Cellular hypoxia could be attested in the articular cartilage and meniscal tissue of mice. By the treatment with 2ME2, a distinct reduction of HIF-1alpha-activity in articular cartilage was observed which correlated with a higher rate of cellular apoptosis. The injection of 2ME2 led to a notable degenerative changes in the treated knee joints typical for osteoarthritis. The first signs of osteophyte formation could bee seen after just three weeks. After twelve weeks, distinct destructive changes of the articular cartilage could be observed. However, cartilage degeneration was not associated with significant inflammatory reaction of the synovial membrane. The application of DMOG could not prevent the development of osteoarthritis which spontaneously occurs in the knee joints of these STR/ORT- mice. In cell culture the treatment with DMOG was associated with a distinct intracellular accumulation of collagen type-II, which was accompanied by an impaired extracellular collagen-network. Conclusions: The induction of osteoarthritis by 2ME2 underlines the importance of HIF-1alpha for the viability of chondrocytes in hypoxic articular cartilage and the maintenance of the integrity of the joint. The stabilization of HIF-1alpha by DMOG did not prove any therapeutical value since DMOG interferes, as a non-selective Prolyl-Hydroxylase-inhibitor, also with the physiological collagen metabolism. Furthermore, the absent positive effect of an increased HIf-1alpha-activity may also be a consequence of an increased expression of catabolic cytokines.Hintergrund und Ziele: Gelenkknorpel ist ein einzigartiges Gewebe, welches sich durch seine Avaskularität auszeichnet. Die dadurch vorherrschende Hypoxie stellt hohe Ansprüche an den Stoffwechsel der Chondrozyten, wobei der Transkriptionsfaktor HIF-1alpha eine wichtige Rolle für die zellulären Anpassungsprozesse spielt. Zudem unterstützt HIF-1alpha auch die Expression einiger knorpelspezifischer Gene. In dieser Arbeit sollte zum einen untersucht werden, ob eine Hemmung der HIF-1alpha-Aktivität die Entwicklung von Arthrose in Kniegelenken von Mäusen fördert. Zum anderen bestand die Fragestellung, ob durch eine Aktivitätser-höhung von HIF-1alpha durch dessen Stabilisation spontan auftretende degenerative Veränderungen in STR/ORT-Mäusen verhindert oder verzögert werden können. Methoden: Die Hemmung der HIF-1alpha-Aktivität erfolgte durch Applikation von 2ME2 (2-Methoxyöstradiol) in Kniegelenken von Balb/C-Mäusen. Die Gelenke wurden drei und zwölf Wochen nach den Injektionen histochemisch und immunohisto-chemisch hinsichtlich der Gelenkknorpeldegeneration, Osteophytenbildung und Synovialitis untersucht und bewertet. Die Aktivitätserhöhung von HIF-1alpha erfolgte durch Injektion von DMOG (Dimethyloxaloylglycin) in Kniegelenke von STR/ORT-Mäusen einmal wöchentlich über einen Zeitraum von zwölf Wochen hinweg, bevor die Gelenke in analoger Weise histomorphologisch analysiert wurden. Der Effekt von DMOG auf die Kollagensynthese wurde zudem in Zellkulturversuchen untersucht. Ergebnisse: Selbst im dünnen Gelenkknorpel und Meniskusgewebe von Mäusen konnte eine zelluläre Hypoxie nachgewiesen werden. Durch Behandlung mit 2ME2 konnte eine deutliche Abnahme der HIF-1alpha-Aktivität in den Gelenkknorpelzellen nachgewiesen werden, die mit vermehrt auftretenden apoptotischen Prozessen korrelierte. Die Injektion von 2ME2 führte zu deutlichen arthrosetypischen Veränderungen der behandelten Kniegelenke. Die ersten Anzeichen von Osteo-phytenbildung konnten bereits nach drei Wochen beobachtet werden. Nach zwölf Wochen zeigten sich ausgeprägte destruktive Veränderungen des Gelenkknorpels, wobei dies nicht mit entzündlichen Reaktionen der Synovialmembran einherging. Die Applikation von DMOG verhinderte nicht die ausgeprägten arthrotischen Veränderungen, welche sich in Kniegelenken der STR/ORT–Mäusen spontan entwickeln. In Zellkulturversuchen führte die Behandlung mit DMOG zu einer ausgeprägten intrazellulären Akkumulation von Kollagen Typ-II, einhergehend mit einer gestörten Ausbildung des extrazellulären Kollagennetzwerkes. Praktische Schlussfolgerungen: Die Induktion von Arthrose durch 2ME2 unterstreicht die Bedeutung von HIF-1alpha für das Überleben der Chondrozyten im hypoxischen Gelenknorpel und die Aufrechterhaltung der Gelenkintegrität. Die Stabilisierung von HIF-1alpha durch DMOG stellte allerdings keinen therapeutischen Nutzen dar, da DMOG als nicht-selektiver Prolyl-Hydroxylase-Inhibitor ebenso auch in den physio-logischen Kollagenstoffwechsel eingreift. Zudem könnte der ausbleibende positive Effekt einer vermehrten HIF-1alpha-Aktivität auch auf eine vermehrte Expression katabol wirkender Zytokine zurückzuführen sein
FIRST REALIZATION AND PERFORMANCE STUDY OF A SINGLE-SHOT LONGITUDINAL BUNCH PROFILE MONITOR UTILIZING A TRANSVERSE DEFLECTING STRUCTURE
No full textAbstract For the control and optimization of electron beam parameters at modern free-electron lasers (FEL), transverse deflecting structures (TDS) in combination with imaging screens have been widely used as robust longitudinal diagnostics with single-shot capability, high resolution and large dynamic range. At the free electron laser in Hamburg (FLASH), a longitudinal bunch profile monitor utilizing a TDS has been realized. In combined use with a fast kicker magnet and an off-axis imaging screen, selection and measurement of a single bunch out of the bunch train with bunch spacing down to 1 µs can be achieved without affecting the remaining bunches which continue to generate FEL radiation during user operation. Technical obstacles have been overcome such as suppression of coherent transition radiation from the imaging screen, the continuous image acquisition and processing with the bunch train repetition rate of 10 Hz. The monitor, which provides the longitudinal bunch profile and length, has been used routinely at FLASH. In this paper, we present the setup and operation of the longitudinal bunch profile monitor as well as its performance during user operation
A crisis-oriented approach to the rehabilitation of myocardial infarction patients
No full textBibliography: leaf 111-124.Myocardial infarction is introduced as a medical syndrome in which psychosocial factors are thought to have significant bearing on the etiology and outcome of the disease. An outline of the epidemiology, pathophysiological process, etiology and prognosis is provided in order to highlight the many psychological implications in each of these areas. The study aims at proposing a model for psychological intervention with myocardial infarction patients that is both economical and effective. Crisis intervention has been chosen as the theoretical basis, as it is felt that many of its concepts apply in this case. Myocardial infarction is seen primarily as a "shock" type crisis as described by Korner (1973) followed by a succession of vulnerable points at which certain individuals descend into crisis
GPRC5C drives branched-chain amino acid metabolism in leukemogenesis
No full textLeukemia stem cells (LSCs) share numerous features with healthy hematopoietic stem cells (HSCs). G-protein coupled receptor family C group 5 member C (GPRC5C) is a regulator of HSC dormancy. However, GPRC5C functionality in acute myeloid leukemia (AML) is yet to be determined. Within patient AML cohorts, high GPRC5C levels correlated with poorer survival. Ectopic Gprc5c expression increased AML aggression through the activation of NF-κB, which resulted in an altered metabolic state with increased levels of intracellular branched-chain amino acids (BCAAs). This onco-metabolic profile was reversed upon loss of Gprc5c, which also abrogated the leukemia-initiating potential. Targeting the BCAA transporter SLC7A5 with JPH203 inhibited oxidative phosphorylation and elicited strong antileukemia effects, specifically in mouse and patient AML samples while sparing healthy bone marrow cells. This antileukemia effect was strengthened in the presence of venetoclax and azacitidine. Our results indicate that the GPRC5C–NF-κB-SLC7A5–BCAAs axis is a therapeutic target that can compromise leukemia stem cell function in AML
Design and Test of a Fast Feedbacksystem for Orbit Correction at TTF and the TESLA Linear Collider
No full textTo achieve high luminosity in the TESLA Linear Collider feedback systems will be needed to provide orbit corrections within the bunch train. A prototype of the complete vertical feedback system has been installed in the TESLA Test Facility at DESY. The use of digital signal processing techniques led to a fast and highly flexible solution for the controller function. Additional features such as data logging and analysis allow easyadjustment of the feedback parameters to achieve the optimum performance of the system. An overview of the system will be presented as well as the results of first measurements
Recent upgrade of the PITZ facility
No full textThe Photo Injector Test facility at DESY, Zeuthen site (PITZ), is dedicated to develop and optimize high brightness electron sources for short wavelength Free-Electron Lasers (FELs) like FLASH and the European XFEL, both in Hamburg (Germany). Since October 2009 a major upgrade is ongoing with the goal to improve the accelerating components, the photocathode drive laser system and the beam diagnostics as well. The essential new feature in the running will be an in-vacuum 10 MW RF directional coupler to be used for the RF monitoring and control. In this context a significant improvement of the RF stability is expected. RF pulses of 800 microseconds with 10 Hz repetition rate will be used. The most important upgrade of the diagnostics system will be the implementation of a phase space tomography module (PST) consisting of three FODO cells each surrounded by two screen stations. The goal is an improved measurement of the transverse phase space at different charge levels. The upgraded facility will be described
Characteristics of chosen regions.
No full textConservation, chromatin events and TF binding events in chosen CREs (red) compared to all candidate CREs (blue). Left is the TF gene set, middle the TF cluster set and right all differentially expressed genes (DE set). (A) The log of the phylogenetic conservation scores (see Methods), (B) the chromatin events (H3K27Ac peaks and DHS), and (C) TF binding events. The p values were obtained using student t-test for conservation and Kolmogorov-Smirnoff test for chromatin and binding events. All the p values were less than 0.01 except for conservation distribution in TF set (p = 0.07).</p
Author Correction: A MHz-repetition-rate hard X-ray free-electron laser driven by a superconducting linear accelerator
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