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This study indicates that embryonic stem cells [ESCs] cultured with retinoic acid and activin A significantly upregulate the miRNA let-7e. This specific miRNA modulates the Wnt pathway and the expression of early nephrogenic markers under these differentiation conditions. The differentiation markers WT1, Pax2 and Wnt4 were downregulated when miRNA let-7e was silenced, thus indicating the role of miRNA let-7e in the differentiation process. PKCβ, GSK3β phosphorylation (GSK3βP) and β-catenin expression was reduced in differentiated cells and reversed by miRNA let-7e silencing. Addition of a PKCβ inhibitor to the miRNA let-7e silenced cells abolished let-7e-derived effects in differentiation markers, and reversed the increase in GSK3βP and β-catenin, thus indicating that miRNA let-7e is involved in differentiation via the modulation of GSK3β phosphorylation and β-catenin production.
The role of the mRNA-binding protein human antigen R (HuR) in stabilization and translation of AU-rich elements (ARE) containing mRNAs is well established. However, the trafficking of HuR and bound mRNA cargo, which comprises a fundamental requirement for the aforementioned HuR functions is only poorly understood. By administering different cytoskeletal inhibitors, we found that the protein kinase Cδ (PKCδ)-triggered accumulation of cytoplasmic HuR by Angiotensin II (AngII) is an actin-myosin driven process functionally relevant for stabilization of ARE-bearing mRNAs. Furthermore, we show that the AngII-induced recruitment of HuR and its bound mRNA from ribonucleoprotein particles to free and cytoskeleton bound polysomes strongly depended on an intact actomyosin cytoskeleton. In addition, HuR allocation to free and cytoskeletal bound polysomes is highly sensitive toward RNase and PPtase and structurally depends on serine 318 (S318) located within the C-terminal RNA recognition motif (RRM3). Conversely, the trafficking of the phosphomimetic HuRS318D, mimicking HuR phosphorylation at S318 by the PKCδ remained PPtase resistant. Co-immunoprecipitation experiments with truncated HuR proteins revealed that the stimulus-induced association of HuR with myosin IIA is strictly RNA dependent and mediated via the RRM3. Our data implicate a microfilament dependent transport of HuR, which is relevant for stimulus-induced targeting of ARE-bearing mRNAs from translational inactive ribonucleoprotein particles to polysomes.
Peripheral sensitization during inflammatory pain is mediated by a variety of endogenous proalgesic mediators including a number of oxidized lipids, some of which serve endogenous modulators of sensory TRP-channels. These lipids are eicosanoids of the arachidonic acid and linoleic acid pathway, as well as lysophophatidic acids (LPAs). However, their regulation pattern during inflammatory pain and their contribution to peripheral sensitization is still unclear. Here, we used the UVB-model for inflammatory pain to investigate alterations of lipid concentrations at the site of inflammation, the dorsal root ganglia (DRGs) as well as the spinal dorsal horn and quantified 21 lipid species from five different lipid families at the peak of inflammation 48 hours post irradiation. We found that known proinflammatory lipids as well as lipids with unknown roles in inflammatory pain to be strongly increased in the skin, whereas surprisingly little changes of lipid levels were seen in DRGs or the dorsal horn. Importantly, although there are profound differences between the number of cytochrome (CYP) genes between mice and rats, CYP-derived lipids were regulated similarly in both species. Since TRPV1 agonists such as LPA 18:1, 9- and 13-HODE, 5- and 12-HETE were elevated in the skin, they may contribute to thermal hyperalgesia and mechanical allodynia during UVB-induced inflammatory pain. These results may explain why some studies show relatively weak analgesic effects of cyclooxygenase inhibitors in UVB-induced skin inflammation, as they do not inhibit synthesis of other proalgesic lipids such as LPA 18:1, 9-and 13-HODE and HETEs.
Interleukin (IL)-10 and IL-22 are key members of the IL-10 cytokine family that share characteristic properties such as defined structural features, usage of IL-10R2 as one receptor chain, and activation of signal transducer and activator of transcription (STAT)-3 as dominant signaling mode. IL-10, formerly known as cytokine synthesis inhibitory factor, is key to deactivation of monocytes/macrophages and dendritic cells. Accordingly, pre-clinical studies document its anti-inflammatory capacity. However, the outcome of clinical trials assessing the therapeutic potential of IL-10 in prototypic inflammatory disorders has been disappointing. In contrast to IL-10, IL-22 acts primarily on non-leukocytic cells, in particular epithelial cells of intestine, skin, liver, and lung. STAT3-driven proliferation, anti-apoptosis, and anti-microbial tissue protection is regarded a principal function of IL-22 at host/environment interfaces. In this hypothesis article, hidden/underappreciated pro-inflammatory characteristics of IL-10 and IL-22 are outlined and related to cellular priming by type I interferon. It is tempting to speculate that an inherent inflammatory potential of IL-10 and IL-22 confines their usage in tissue protective therapy and beyond that determines in some patients efficacy of type I interferon treatment.
Objective. To test the influence of personalized ultrasound (PersUS) on patient management in critical care. Design of the Study. Prospective, observational, and critical care setting. Four substudies compared PersUS and mobile ultrasound, work distribution, and diagnostic and procedural quality. Patients and Interventions. 640 patient ultrasound exams including 548 focused diagnostic exams and 92 interventional procedures. Main Outcome Measures. Number of studies, physician’s judgement of feasibility, time of usage per patient, and referrals to echo lab. Results. Randomized availability of PersUS increased its application in ICU work shifts more than twofold from 33 to 68 exams mainly for detection and therapy of effusions. Diagnostic and procedural quality was rated as excellent/very good in PersUS-guided puncture in 95% of cases. Integrating PersUS within an initial physical examination of 48 randomized cases in an emergency department, PersUS extended the examination time by 100 seconds. Interestingly, PersUS integration into 53 randomized regular ward rounds of 1007 patients significantly reduced average contact time per patient by 103 seconds from 8.9 to 7.2 minutes. Moreover, it lowered the patient referral rate to an echo lab from 20% to 2% within the study population. Conclusions. We propose the development of novel ultrasound-based clinical pathways by integration of PersUS.
Background: One of the most popular and versatile model of murine melanoma is by inoculating B16 cells in the syngeneic C57BL6J mouse strain. A characterization of different B16 modified cell sub-lines will be of real practical interest. For this aim, modern analytical tools like surface enhanced Raman spectroscopy/scattering (SERS) and MTT were employed to characterize both chemical composition and proliferation behavior of the selected cells.
Methods: High quality SERS signal was recorded from each of the four types of B16 cell sub-lines: B164A5, B16GMCSF, B16FLT3, B16F10, in order to observe the differences between a parent cell line (B164A5) and other derived B16 cell sub-lines. Cells were incubated with silver nanoparticles of 50–100 nm diameter and the nanoparticles uptake inside the cells cytoplasm was proved by transmission electron microscopy (TEM) investigations. In order to characterize proliferation, growth curves of the four B16 cell lines, using different cell numbers and FCS concentration were obtained employing the MTT proliferation assay. For correlations doubling time were calculated.
Results: SERS bands allowed the identification inside the cells of the main bio-molecular components such as: proteins, nucleic acids, and lipids. An "on and off" SERS effect was constantly present, which may be explained in terms of the employed laser power, as well as the possible different orientations of the adsorbed species in the cells in respect to the Ag nanoparticles. MTT results showed that among the four tested cell sub-lines B16 F10 is the most proliferative and B164A5 has the lower growth capacity. Regarding B16FLT3 cells and B16GMCSF cells, they present proliferation ability in between with slight slower potency for B16GMCSF cells.
Conclusion: Molecular fingerprint and proliferation behavior of four B16 melanoma cell sub-lines were elucidated by associating SERS investigations with MTT proliferation assay.
CD69 is a transmembrane lectin that can be expressed on most hematopoietic cells. In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in which the leukotrienes, a class of highly potent inflammatory mediators, are produced. However, regarding CD69 gene expression and its regulatory mechanisms in monocytes, only scarce data are available. Here, we report that CD69 mRNA expression, analogous to that of 5-lipoxygenase, is induced by the physiologic stimuli transforming growth factor-β (TGF-β) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in monocytic cells. Comparison with T- and B-cell lines showed that the effect was specific for monocytes. CD69 expression levels were increased in a concentration-dependent manner, and kinetic analysis revealed a rapid onset of mRNA expression, indicating that CD69 is a primary TGF-β/1α,25(OH)2D3 target gene. PCR analysis of different regions of the CD69 mRNA revealed that de novo transcription was initiated and proximal and distal parts were induced concomitantly. In common with 5-lipoxygenase, no activation of 0.7 kb or ~2.3 kb promoter fragments by TGF-β and 1α,25(OH)2D3 could be observed in transient reporter assays for CD69. Analysis of mRNA stability using a transcription inhibitor and a 3′UTR reporter construct showed that TGF-β and 1α,25(OH)2D3 do not influence CD69 mRNA stability. Functional knockdown of Smad3 clearly demonstrated that upregulation of CD69 mRNA, in contrast to 5-LO, depends on Smad3. Comparative studies with different inhibitors for mitogen activated protein kinases (MAPKs) revealed that MAPK signalling is involved in CD69 gene regulation, whereas 5-lipoxygenase gene expression was only partly affected. Mechanistically, we found evidence that CD69 gene upregulation depends on TAK1-mediated p38 activation. In summary, our data indicate that CD69 gene expression, conforming with 5-lipoxygenase, is regulated monocyte-specifically by the physiologic stimuli TGF-β and 1α,25(OH)2D3 on mRNA level, although different mechanisms account for the upregulation of each gene.
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM–C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans.
The mitogen-activated protein kinase (MAPK) pathway is the canonical signaling pathway for many receptor tyrosine kinases, such as the Epidermal Growth Factor Receptor. Downstream of the receptors, this pathway involves the activation of a kinase cascade that culminates in a transcriptional response and affects processes, such as cell migration and adhesion. In addition, the strength and duration of the upstream signal also influence the mode of the cellular response that is switched on. Thus, the same components can in principle coordinate opposite responses, such as proliferation and differentiation. In recent years, it has become evident that MAPK signaling is regulated and fine-tuned by proteins that can bind to several MAPK signaling proteins simultaneously and, thereby, affect their function. These so-called MAPK scaffolding proteins are, thus, important coordinators of the signaling response in cells. In this review, we summarize the recent advances in the research on MAPK/extracellular signal-regulated kinase (ERK) pathway scaffolders. We will not only review the well-known members of the family, such as kinase suppressor of Ras (KSR), but also put a special focus on the function of the recently identified or less studied scaffolders, such as fibroblast growth factor receptor substrate 2, flotillin-1 and mitogen-activated protein kinase organizer.
Introduction: We aimed at dissociating the neural correlates of memory disorders in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD).
Methods: We included patients with AD (n = 19, 11 female, mean age 61 years) and FTLD (n = 11, 5 female, mean age 61 years) in early stages of their diseases. Memory performance was assessed by means of verbal and visual memory subtests from the Wechsler Memory Scale (WMS-R), including forgetting rates. Brain glucose utilization was measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and brain atrophy by voxel-based morphometry (VBM) of T1-weighted magnetic resonance imaging (MRI) scans. Using a whole brain approach, correlations between test performance and imaging data were computed separately in each dementia group, including a group of control subjects (n = 13, 6 female, mean age 54 years) in both analyses. The three groups did not differ with respect to education and gender.
Results: Patients in both dementia groups generally performed worse than controls, but AD and FTLD patients did not differ from each other in any of the test parameters. However, memory performance was associated with different brain regions in the patient groups, with respect to both hypometabolism and atrophy: Whereas in AD patients test performance was mainly correlated with changes in the parieto-mesial cortex, performance in FTLD patients was correlated with changes in frontal cortical as well as subcortical regions. There were practically no overlapping regions associated with memory disorders in AD and FTLD as revealed by a conjunction analysis.
Conclusion: Memory test performance may not distinguish between both dementia syndromes. In clinical practice, this may lead to misdiagnosis of FTLD patients with poor memory performance. Nevertheless, memory problems are associated with almost completely different neural correlates in both dementia syndromes. Obviously, memory functions are carried out by distributed networks which break down in brain degeneration.
We present a numerical investigation of energy and charge distributions during electron-beam-induced growth of tungsten nanostructures on SiO2 substrates by using a Monte Carlo simulation of the electron transport. This study gives a quantitative insight into the deposition of energy and charge in the substrate and in the already existing metallic nanostructures in the presence of the electron beam. We analyze electron trajectories, inelastic mean free paths, and the distribution of backscattered electrons in different compositions and at different depths of the deposit. We find that, while in the early stages of the nanostructure growth a significant fraction of electron trajectories still interacts with the substrate, when the nanostructure becomes thicker the transport takes place almost exclusively in the nanostructure. In particular, a larger deposit density leads to enhanced electron backscattering. This work shows how mesoscopic radiation-transport techniques can contribute to a model that addresses the multi-scale nature of the electron-beam-induced deposition (EBID) process. Furthermore, similar simulations can help to understand the role that is played by backscattered electrons and emitted secondary electrons in the change of structural properties of nanostructured materials during post-growth electron-beam treatments.
Despite advances in allogeneic stem cell transplantation, BCR-ABL-positive acute lymphoblastic leukaemia (ALL) remains a high-risk disease, necessitating the development of novel treatment strategies. As the known oncomir, miR-17~92, is regulated by BCR-ABL fusion in chronic myeloid leukaemia, we investigated its role in BCR-ABL translocated ALL. miR-17~92-encoded miRNAs were significantly less abundant in BCR-ABL-positive as compared to -negative ALL-cells and overexpression of miR-17~19b triggered apoptosis in a BCR-ABL-dependent manner. Stable isotope labelling of amino acids in culture (SILAC) followed by liquid chromatography and mass spectroscopy (LC-MS) identified several apoptosis-related proteins including Bcl2 as potential targets of miR-17~19b. We validated Bcl2 as a direct target of this miRNA cluster in mice and humans, and, similar to miR-17~19b overexpression, Bcl2-specific RNAi strongly induced apoptosis in BCR-ABL-positive cells. Furthermore, BCR-ABL-positive human ALL cell lines were more sensitive to pharmacological BCL2 inhibition than negative ones. Finally, in a xenograft model using patient-derived leukaemic blasts, real-time, in vivo imaging confirmed pharmacological inhibition of BCL2 as a new therapeutic strategy in BCR-ABL-positive ALL. These data demonstrate the role of miR-17~92 in regulation of apoptosis, and identify BCL2 as a therapeutic target of particular relevance in BCR-ABL-positive ALL.
During the height of the Second World War pressure from Great Britain resulted in the transfer of thousands of German prisoners of war (PoWs) from British to Canadian control. To house them, Canada built a system of PoW camps, including Riding Mountain Camp in southwestern Manitoba. The PoWs sent there soon realized their good fortune: they lived in warm barracks, ate abundant food, and were able to purchase goods from a mail order catalog. But while the PoWs were well treated, they were at the same time subjected to a concerted reeducation campaign organized by the Allies. This reveals that these Canadian camps were not merely warehouses for the PoWs, but in fact, classic reforming institutions.
Initially subjected to ideological training under Nazism, the PoWs were next subjected to another kind of education under the Canadians. Evidence collected from oral history interviewing, archival research, and three seasons of field archaeology combine to reveal that material culture was a key nexus in this competition for the minds of the PoWs. In addition to providing books and teaching courses on history and political science, the Canadians introduced the PoWs to a democratic, capitalistic way of life by familiarizing them with North American consumer goods and by allowing them to fraternize with Canadian civilians. The Nazi bureaucracy, in turn, used material things to try to keep the PoWs from turning to the other side. For example, by sending them crisp new Wehrmacht uniforms from Germany, heartening Christmas cards, and packages filled with German goods adorned with Nazi symbolism.
La investigación sobre el desarrollo y la vida del derecho canónico en la América hispánica se ha visto enriquecida por la edición de los documentos de trabajo del Tercer Concilio Provincial Mexicano, celebrado en 1585. Esta monografía presenta las líneas de investigación que el autor está llevando a cabo en su tesis doctoral, confrontando los decretos promulgados con su iter redaccional de acuerdo a la información suministrada por los manuscritos editados. Los pedidos y memoriales presentados al concilio provincial pueden ser analizados, junto con la misma tarea legislativa, como un modo de resolución de conflictos por parte de la autoridad eclesiástica y su potestad de acuerdo con el derecho canónico entonces vigente.
New Zealand species of Iphimediidae, Amphipoda, are revised. Based on new material from the Chatham Rise, east of New Zealand, two new species are described in detail: Labriphimedia meikae sp. nov. and Labriphimedia martinae sp. nov. A key to the six species belonging to three genera of New Zealand Iphimediidae is provided.
Cytoprotective functions of amyloid precursor protein family members in stress signaling and aging
(2013)
Poster presentation: Molecular Neurodegeneration: Basic biology and disease pathways Cannes, France. 10-12 September 2013.
Background: The amyloid precursor protein (APP) is processed via two different metabolic pathways: the amyloidogenic and the non-amyloidogenic pathway, the latter of which leading to generation of the secreted N-terminal APP fragment sAPPα [1]. Previous studies from our group suggest that sAPPα exerts potent neuroprotective effects and inhibits stress-triggered cell death via modulation of gene expression, as well as by antagonizing different types of neurotoxic stress [2]. It was also observed that the biochemical processing of APP is downregulated during aging which in turn reduced the secretion of sAPPα [3]. Based on these observations, we have studied the potential physiological function of sAPPα/APP and APLPs (APP like proteins) on the regulation of age-associated, stress induced signaling pathways, apoptosis and senescence.
Materials and methods: SH-SY5Y, PC12, IMR90 cells were used as cellular models. Depletion of APP, APLP1 (APP like protein 1) and APLP2 (APP like protein 2) in SH-SY5Y cells was achieved by stable lentiviral knockdown. To analyze the protective function of sAPPα, we have used conditioned supernatants of wild type APP overexpressing HEK cells and recombinant His-tagged sAPPα purified from yeast. The cells were treated with sAPPα prior to the addition of different stress stimuli (MG132, epoxomicin, UV, H2O2) after which cell death, gene expression and senescence were analyzed by MTT assays, caspase activity assays, Western blots and X-Gal staining respectively.
Results: Our data show that sAPPα can antagonize premature senescence induced by repetitive short term induction of proteasomal stress in IMR-90 cells and apoptosis triggered by prolonged proteasomal stress and other death stimuli in PC12, SH-SY5Y and IMR90 cells which was accompanied by a sAPPα-dependent inhibition of the JNK stress signaling pathway. In contrast, no significant changes in cell viability and apoptosis were observed when APP knockdown cells were pretreated with sAPPα.
Conclusions: Our observations suggest that sAPPα can antagonize both apoptosis and cellular senescence and requires expression of holo-APP to mediate its cytoprotective effects. They also support the notion that the physiological function of APP is linked to modulation of neuronal and brain aging.
Artificial environments for the co-translational stabilization of cell-free expressed proteins
(2013)
An approach for designing individual expression environments that reduce or prevent protein aggregation and precipitation is described. Inefficient folding of difficult proteins in unfavorable translation environments can cause significant losses of overexpressed proteins as precipitates or inclusion bodies. A number of chemical chaperones including alcohols, polyols, polyions or polymers are known to have positive effects on protein stability. However, conventional expression approaches can use such stabilizing agents only post-translationally during protein extraction and purification. Proteins that already precipitate inside of the producer cells cannot be addressed. The open nature of cell-free protein expression systems offers the option to include single chemicals or cocktails of stabilizing compounds already into the expression environment. We report an approach for systematic screening of stabilizers in order to improve the solubility and quality of overexpressed proteins co-translationally. A comprehensive list of representative protein stabilizers from the major groups of naturally occurring chemical chaperones has been analyzed and their concentration ranges tolerated by cell-free expression systems have been determined. As a proof of concept, we have applied the method to improve the yield of proteins showing instability and partial precipitation during cell-free synthesis. Stabilizers that co-translationally improve the solubility and functional folding of human glucosamine 6-phosphate N-acetyltransferase have been identified and cumulative effects of stabilizers have been studied.
Liveblog München, 3. Februar
(2013)
Live von der Münchner Sicherheitskonferenz bloggen hier Christopher Daase, Tobias Bunde, Thomas Mohr und Ingo Henneberg und von der Friedenskonferenz Hans Georg Klee und das SiPoBlog–Team. Weitere Informationen gibt es hier. Die Kommentarfunktion ist natürlich zusätzlich geöffnet für alle.
Die Sicherheitskonferenz beginnt wieder um 9h mit einer Session zu aktuellen Krisen (Mali, Syrien). Bei der Friedenskonferenz ist um 11.30h das Friedensgebet angesetzt.
Liveblog München, 2. Februar
(2013)
Liveblog München, 1. Februar
(2013)
Live von der Münchner Sicherheitskonferenz bloggen hier Christopher Daase, Tobias Bunde, Thomas Mohr und Ingo Henneberg und von der Friedenskonferenz Hans Georg Klee und euer SiPo-Team. Weitere Informationen gibt es hier. Die Kommentarfunktion ist natürlich weiterhin offen.Die Sicherheitskonferenz wird um 15h eröffnet, erste Eindrücke unten.
Das Internet ist ja per definitionem ein eher unordentlicher Ort. Das finden alle genau dann gut, wenn sich 14jährige Mädchen in Pakistan dadurch ausdrücken und emanzipieren können (auch wenn sich hinter einer solchen internet persona gerne mal ein alter weißer Mann verbirgt). Eher schlecht findet man es dagagen, wenn sich auch Fundamentalisten jeglicher couleur diese Freiheit im Netz zunutze machen. Da wollen die Innen- und Familienminister dieser Welt gleich regulieren, überwachen und strafen, doch… siehe oben. Zwischen diesen beiden Extrempolen pendeln sich die meisten Debatten über das Für und Wider der Internetnutzung ein. Auch in der Geisteswissenschaft – und dies hieß im konkreten Fall überwiegend: der Geschichtswissenschaft, wie wir auf einer Tagung in München feststellen konnten...
Humanitäre Interventionen sind seit den neunziger Jahren wiederkehrend im Fokus öffentlicher wie wissenschaftlicher Debatten. Erklärungen, warum sich Staaten entschließen, unabhängig von geopolitischen Interessen humanitäre Interventionen zu fordern oder sich an ihnen zu beteiligen, bleiben nach wie vor umstritten. Geteilte Moralvorstellungen und die Bereitstellung eines Handlungsrahmens für die Umsetzungspraxis sind zwei zentrale Analysedimensionen einer internationalen, humanitäre Interventionen befördernden Sicherheitskultur. Eine Normentwicklung kann in diesem Sinne nur in der Kombination mit tatsächlicher Akteurspraxis und medial-öffentlicher Aufmerksamkeit verstanden und beurteilt werden.
Im Rahmen eines umfangreichen Projekts zu Übersetzungsmöglichkeiten der deutschen Modalverben ins Portugiesische – und nachdem wir schon den Fall sollen behandelt haben (siehe Hörster/Athayde/Carecho 2011) – stellen wir in dieser Studie einige wesentliche Ergebnisse unserer Untersuchung bezüglich des Modalverbs müssen dar. Ziel unserer Arbeit war nicht die semantische und pragmatische Beschreibung der einzelnen Modalverben, ein Thema, das immer wieder im Mittelpunkt der wissenschaftlichen Diskussion steht. Vielmehr war es unsere Absicht, einen Beitrag zur zweisprachigen Lexikografie, zur Fremdsprachendidaktik und vor allem zur Übersetzungsdidaktik zu leisten.
Objectives Tumour recurrence of glioblastoma multiforme (GBM) after initial treatment with surgical resection, radiotherapy and chemotherapy is an inevitable phenomenon. This retrospective cohort study compared the efficacy of interstitial high dose rate brachytherapy (HDR-BRT), re-resection and sole dose dense temozolomide chemotherapy (ddTMZ) in the treatment of recurrent glioblastoma after initial surgery and radiochemotherapy.
Design Retropective cohort study.
Setting Primary level of care with two participating centres. The geographical location was central Germany.
Participants From January 2005 to December 2010, a total of 111 patients developed recurrent GBM after initial surgery and radiotherapy with concomitant temozolomide. The inclusion criteria were as follows: (1) histology-proven diagnosis of primary GBM (WHO grade 4), (2) primary treatment with resection and radiochemotherapy, and (3) tumour recurrence/progression.
Interventions This study compared retrospectively the efficacy of interstitial HDR-BRT, re-resection and ddTMZ alone in the treatment of recurrent glioblastoma.
Primary and secondary outcome measures Median survival, progression free survival and complication rate.
Results Median survival after salvage therapy of the recurrence was 37, 30 and 26 weeks, respectively. The HDR-BRT group did significantly better than both the reoperation (p<0.05) and the ddTMZ groups (p<0.05). Moderate to severe complications in the HDR-BRT, reoperation and sole chemotherapy groups occurred in 5/50 (10%), 4/36 (11%) and 9/25 (36%) cases, respectively.
Conclusions CT-guided interstitial HDR-BRT attained higher survival benefits in the management of recurrent glioblastoma after initial surgery and radiotherapy with concurrent temozolomide in comparison with the other treatment modalities. The low risk of complications of the HDR-BRT and the fact that it can be delivered percutaneously in local anaesthesia render it a promissing treatment option for selected patients which should be further evaluated.
Persistent neuropathic pain is a frequent consequence of peripheral nerve injuries, particularly in the elderly. Using the IntelliCage we studied if sciatic nerve injury obstructed learning and memory in young and aged mice, each in wild type and progranulin deficient mice, which develop premature signs of brain aging. Both young and aged mice developed long-term nerve injury-evoked hyperalgesia and allodynia. In both genotypes, aged mice with neuropathic pain showed high error rates in place avoidance acquisition tasks. However, once learnt, these aged mice with neuropathic pain showed a significantly stronger maintenance of the aversive memory. Nerve injury did not affect place preference behavior in neither genotype, neither in young nor aged mice. However, nerve injury in progranulin deficient mice impaired the learning of spatial sequences of awarded places, particularly in the aged mice. This task required a discrimination of clockwise and anti-clockwise sequences. The chaining failure occurred only in progranulin deficient mice after nerve injury, but not in sham operated or wildtype mice, suggesting that progranulin was particularly important for compensatory adaptations after nerve injury. In contrast, all aged mice with neuropathic pain, irrespective of the genotype, had a long maintenance of aversive memory suggesting a negative alliance and possibly mutual aggravation of chronic neuropathic pain and aversive memory at old age.
The inner structural Gag proteins and the envelope (Env) glycoproteins of human immunodeficiency virus (HIV-1) traffic independently to the plasma membrane, where they assemble the nascent virion. HIV-1 carries a relatively low number of glycoproteins in its membrane, and the mechanism of Env recruitment and virus incorporation is incompletely understood. We employed dual-color super-resolution microscopy visualizing Gag assembly sites and HIV-1 Env proteins in virus-producing and in Env expressing cells. Distinctive HIV-1 Gag assembly sites were readily detected and were associated with Env clusters that always extended beyond the actual Gag assembly site and often showed enrichment at the periphery and surrounding the assembly site. Formation of these Env clusters depended on the presence of other HIV-1 proteins and on the long cytoplasmic tail (CT) of Env. CT deletion, a matrix mutation affecting Env incorporation or Env expression in the absence of other HIV-1 proteins led to much smaller Env clusters, which were not enriched at viral assembly sites. These results show that Env is recruited to HIV-1 assembly sites in a CT-dependent manner, while Env(ΔCT) appears to be randomly incorporated. The observed Env accumulation surrounding Gag assemblies, with a lower density on the actual bud, could facilitate viral spread . Keeping Env molecules on the nascent virus low may be important for escape from the humoral immune response, while cell-cell contacts mediated by surrounding Env molecules could promote HIV-1 transmission through the virological synapse.
Within the last 30 years the role of nitrogen in Central European forests has changed fundamentally from limiting resource to environmental problem. As the retrospective tracking of nutrient availability by soil chemical and biogeochemical measurements faces serious problems, bioindication based on understorey species composition is indispensable for monitoring broad-scale eutrophication. Based on a broad survey of more than 100,000 forest vegetation plots accessible in electronic data-bases from Germany and adjacent countries, we calculated unweighted average Ellenberg nutrient values (mN) as a proxy of plant-available macronutrients. Based on the quantiles of the frequency distribution of mN in a regionally stratified sample, we define five trophic classes, which can be used to compare dimensionless mN values. We studied spatial patterns of average nutrient values within 17 regions and compared the periods from 1899 to 1975 and 1976 to 2006. After 1975 eutrophic (mN > 5.67) and hypertrophic (mN > 6.28) conditions were common everywhere except in the Alps and Saxony-Anhalt, but very oligotrophic conditions (mN < 3.44) were still widespread in regions with nutrient-poor bedrock. Before 1975 mN of plots had been lower than after 1975 in all but the southeastern regions. Between the pre- and post-1975 data the proportion of hypertrophic plots increased from 5.7 to 11.8%, and that of very oligo-trophic plots decreased from 14.6 to 8.3%. To remove bias resulting from uneven distribution, the dataset was stratified by five tree layer dominance types, period and region and resampled. In pre-1975 plots medians of mN increased in the order Pinus sylvestris, Quercus spp., Picea abies, Fagus sylvatica and Alnus spp, whereas the increase of mN was highest in forest types with historically low nutrient values. Therefore, the widespread change in mN must be attributed to the pronounced vegetation changes in Quercus and Pinus stands, indicating the importance of land-use change, i.e. recovery of nutrient cycles after hundreds of years of exploitation through coppicing, grazing and litter use. The analysis confirms eutrophication as a megatrend of modern vegetation change and demonstrates the high research potential of linking vegetation plot databases across large regions.
Diabetes is characterized by a dysregulation of glucose homeostasis and platelets from patients with diabetes are known to be hyper-reactive and contribute to the accelerated development of vascular diseases. Since many of the deleterious effects of glucose have been attributed to its metabolite methylgyloxal (MG) rather than to hyperglycemia itself, the aim of the present study was to characterize the effects of MG on platelet function. Washed human platelets were pre-incubated for 15 min with MG and platelet aggregation, adhesion on matrix-coated slides and signaling (Western blot) were assessed ex vivo. In vivo, the effect of MG on thrombus formation was determined using the FeCl3-induced carotid artery injury model. MG potentiated thrombin-induced platelet aggregation and dense granule release, but inhibited platelet spreading on fibronectin and collagen. In vivo, MG accelerated thrombus formation but decreased thrombus stability. At the molecular level, MG increased intracellular Ca2+ and activated classical PKCs at the same time as inhibiting PI3K/Akt and the β3-integrin outside-in signaling. In conclusion, these findings indicate that the enhanced MG concentration measured in diabetic patients can directly contribute to the platelet dysfunction associated with diabetes characterized by hyperaggregability and reduced thrombus stability.
Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclin-dependent kinase (CDK) inhibitor SNS-032 in a panel of 109 neuroblastoma cell lines consisting of 19 parental cell lines and 90 sublines with acquired resistance to 14 different anticancer drugs. Seventy-three percent of the investigated neuroblastoma cell lines and all four investigated primary tumor samples displayed concentrations that reduce cell viability by 50% in the range of the therapeutic plasma levels reported for SNS-032 (<754 nM). Sixty-two percent of the cell lines and two of the primary samples displayed concentrations that reduce cell viability by 90% in this concentration range. SNS-032 also impaired the growth of the multidrug-resistant cisplatin-adapted UKF-NB-3 subline UKF-NB-3rCDDP1000 in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The antineuroblastoma effects of SNS-032 did not depend on functional p53. The antineuroblastoma mechanism of SNS-032 included CDK7 and CDK9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of antiapoptotic proteins with a fast turnover rate including X-linked inhibitor of apoptosis (XIAP), myeloid cell leukemia sequence 1 (Mcl-1), baculoviral IAP repeat containing 2 (BIRC2; cIAP-1), and survivin. In conclusion, CDK7 and CDK9 represent promising drug targets and SNS-032 represents a potential treatment option for neuroblastoma including therapy-refractory cases.
Two new colourful species of direct-developing frogs of the genus Pristimantis are described from the summit of two isolated tepuis (sandstone table mountains) in the Eastern Pantepui District of the Guiana Shield highlands. Pristimantis jamescameroni sp. nov. is described from the summit of Aprada-tepui from 2557-2571 m elevation, and P. imthurni sp. nov. is described from the summit of Ptaritepui at 2471 m elevation. Both species share the absence of a differentiated tympanic membrane and external tympanic annulus (but presence of tiny pharyngeal ostia), the presence of nuptial pads in males, and the presence of lateral fringes on fingers and toes, a combination of characters that immediately distinguishes them from all other known Pantepui congeners. The two new species are morphologically similar to each other and are phylogenetically closely related, but they can be distinguished based on colour pattern and morphological characters such as head proportions, dorsal skin texture, and condition of the supratympanic fold. The IUCN conservation status of the new species is considered as Endangered (EN) owing to their apparent very restricted ranges. The number of described Pristimantis species occurring exclusively on tepui (and faunistically related granitic mountains) summits and upper slopes now reaches eleven.
Insurance guarantee schemes aim to protect policyholders from the costs of insurer insolvencies. However, guarantee schemes can also reduce insurers’ incentives to conduct appropriate risk management. We investigate stock insurers’ risk-shifting behavior for insurance guarantee schemes under the two different financing alternatives: a flat-rate premium assessment versus a risk-based premium assessment. We identify which guarantee scheme maximizes policyholders’ welfare, measured by their expected utility. We find that the risk-based insurance guarantee scheme can only mitigate the insurer’s risk-shifting behavior if a substantial premium loading is present. Furthermore, the risk-based guarantee scheme is superior for improving policyholders’ welfare compared to the flat-rate scheme when the mitigating effect occurs.
Es wird allgemein vermutet, dass Klassenfahrten bei den Schülern nachhaltige Veränderungen bewirken können und nur wenige empirische Befunde belegen die Wirksamkeit von Klassenfahrten. Diese defizitäre Forschungslage aufgreifend, beschäftigt sich die vorliegende Arbeit mit der sozial-integrativen Wirkung einer sportbezogenen Klassenfahrt (Skifahrt) auf empirischer Grundlage.
Mit Hilfe der Desintegrationstheorie von Anhut & Heitmeyer (2000) lässt sich das Konstrukt „Integration“ in allgemeinerer Form über das antinomische Begriffspaar „Anerkennung vs. Ablehnung“ operationalisieren, wobei zwischen positionaler, moralischer und emotionaler Anerkennung bzw. Ablehnung unterschieden werden kann. Neben individuellen Merkmalen erfolgt die Vergabe und Verweigerung von Anerkennung über kollektive Merkmale, die auf Zugehörigkeit zu einer Gruppe beruht. Im pädagogischen Kontext der Schulklasse ist daher von besonderem Interesse, wie sich die Anerkennungsverhältnisse zwischen Gruppen verändern, denen besondere Potenziale für heterogenitätsbedingte Ablehnung zugeschrieben wird (vgl. Gerecke, 2010). Hypothetisch sind dies Mädchen „vs.“ Jungen, Jugendliche mit „vs.“ Jugendliche ohne Migrationshintergrund und bezüglich Klassenfahrten die Gruppe der Schüler, die nicht teilnehmen konnten „vs.“ der Gruppe derer, die teilgenommen haben. Auf dieser Grundlage beschäftigt sich die vorliegende Arbeit mit den Effekten sportbezogenen Klassenfahrten auf die soziale Integration operationalisiert in Anerkennungsverhältnissen.
Mittels eines soziometrischen Wahlverfahrens wurden die Anerkennungs- und Ablehnungsverhältnisse von vier Schulklassen (N=95) zu drei Messzeitpunkten (Eingangs-, Ausgangs- und Behaltenstest nach sechs Wochen) computergestützt erhoben.
Die Betrachtung der Gesamtgruppe zeigt eine Steigerung der positiven Wahlen (eta²=0,210) bei einer gleichzeitigen Reduktion der negativen Wahlen (eta²=0,167). Diese Entwicklung ist über Post-hoc-Einzelvergleiche auf eine signifikante Veränderung innerhalb des Treatmentzeitraumes (ET AT) zurückzuführen. Das Intervall AT-BT nach Abschluss der Klassenfahrt ist nicht signifikant, so dass auf eine zeitliche Stabilität der Ergebnisse geschlossen werden kann. Allerdings sind große Unterschiede zwischen den einzelnen Klassen festzustellen, die nicht teilweise nicht mit dem Gesamtergebnis übereinstimmen. In der differenzierten Betrachtung der heterogenitätsbedingten Unterschiede ist in erster Linie ein Geschlechtereffekt zu erkennen. Insbesondere die positiven und negativen Wahlen zwischen Schülern verschiedenen Geschlechts verändern sich signifikant. Aber auch hier zeigen sie die bereits dargestellten klassenspezifischen Differenzen.
Während der Teilnahmestatus keinen Einfluss auf die Vergabe von negativen und positiven Wahlen besitzt, beeinflusst der Migrationsstatus hingegen die positiven Wahlen signifikant.
Mit Blick auf die theoretischen Grundlagen dieser Arbeit kann der Anstieg der positiven Wahlen als Zuwachs von Anerkennung und der Rückgang negativer Wahlen als eine Reduktion von Ablehnung interpretiert werden, wobei sich kein einheitliches Bild auf Klassenebene ergibt.
Anhut, R. & Heitmeyer, W. (2000). Desintegration, Konflikt und Ethnisierung. Eine Problemanalyse und theoretische Rahmenkonzeption. In W. Heitmeyer (Hrsg.), Bedrohte Stadtgesellschaft. Soziale Desintegrationsprozesse und ethnisch-kulturelle Konfliktkonstellationen (S. 17–73). Weinheim: Juventa-Verlag.
Gerecke, P. (2010). Heterogenitätsbedingte Unterschiede zwischen Ingroup- und Outgroup-Anerkennung bzw. -Ablehnung im Sportunterricht. Eine empirische Studie zum integrativen Einfluss des Kooperativen Lernens. Dissertation. Frankfurt am Main: Johann-Wolfgang Goethe Universität.
Durch RNAinterferenz (RNAi) läßt sich die Expression eines beliebigen Gens spezifisch unterdrücken. Dafür müssen in das Zytoplasma kurze, doppelsträngige RNA Moleküle (siRNA bzw. shRNA) eingebracht werden, die teilweise komplementäre Sequenzen zu dem Zielgen aufweisen. Um siRNAs mit einer hohen Effizienz und Kopienzahl in die Zielzelle einzubringen, wurden Transfersysteme unterschiedlicher Art entwickelt. Nicht-virale Transfersysteme können nur einen transienten Effekt auslösen - ein Umstand, der für Langzeitstudien eine mehrfache Transfektion bedingt. Zur Lösung dieses Problems wurden retrovirale Vektorsysteme entwickelt, die durch Integration der shRNA-Expressionskassette in das zelluläre Genom eine stabile Unterdrückung eines Zielgens erreichen können. Insbesondere für präklinische Studien in vivo ist jedoch ein System mit erhöhter Transferrate wünschenswert, um in möglichst vielen Zielzellen einen RNAi-Effekt zu bewirken. Sliva et al. konnten zeigen, dass das Murine Leukämie Virus (MLV) theoretisch diese Anforderung erfüllt. Dafür wurde eine shRNA-Expressionskassette in das Virusgenom eingefügt und in vitro ein RNAi-Effekt nachgewiesen. In der vorliegenden Arbeit wurde dieses System nun durch die Verwendung von microRNA-adaptierten shRNAs (shRNAmir) verbessert. In mehreren Publikationen wurde bestätigt, dass shRNAs, die endogenen microRNAs nachempfunden sind, eine höhere Effizienz und niedrigere Toxizität aufweisen. Zunächst wurde die für die genetische Stabilität optimale Orientierung der shRNAmir-Expressionskassette bestimmt. Das Konstrukt in reverser Orientierung wies eine Deletion in der shRNAmir Promotersequenz auf, die wahrscheinlich durch Interferenz mit dem 5’LTR Promoter entstanden ist. Mit dem genetisch stabilen Viruskonstrukt wurden Experimente zur Reduktion der Expression von Markergenen durchgeführt, um die Effizienz der RNAi-Aktivität leicht zu quantifizieren. Dafür wurden humane Fibrosarkom (HT1080) Zellen infiziert, die eGFP oder Luziferase stabil exprimieren.
Mit eGFP- und Luziferase-spezifischen shRNAmir-Expressionskassetten konnte nach Infektion eine Herunterregulation von eGFP auf etwa 20 % und für Luziferase auf unter 10% beobachtet werden. Das Kontrollvirus, das eine unspezifische shRNAmir kodiert, hatte keinen Einfluss auf die Expression beider Markerproteine. Die Kinetik mit der die Markerproteine herrunterreguliert wurden, war abhängig von der Virusdosis. Die Virusdosis hatte aber keinen Einfluß auf die Stärke des RNAi-Effekts, der nach Infektion aller Zellen festgestellt werden konnte. Dieses Ergebnis entspricht der Erwartung an ein replikatives Transfersystems, das je nach applizierter Virusdosis unterschiedlich schnell RNAi in der Zellkultur ausbreitet und induziert. Die Anwendbarkeit dieses RNAi-Transfersystems auch für endogene Gene wurde mit MMP14-spezifischen shRNAmirs gezeigt. Nach Infektion von HT1080 Zellen mit den entsprechenden Viren in HT1080 Zellen konnte eine verringerte Menge an MMP14 mRNA und Protein nachgewiesen werden. Dies konnte funktionell durch eine verringerte Menge an intermediärem MMP2 und durch eine reduzierte Invasivität bestätigt werden. Zudem war die Fähigkeit dieser Zellen subkutane Tumore zu bilden stark eingeschränkt.
Um die Anwendbarkeit dieses Systems für in vivo Applikationen zu zeigen, wurde in Mäuse, die Luziferase-exprimierenden Tumoren trugen, MLV-shLuc oder das Kontrollvirus systemisch appliziert. 21 Tage nach Virusgabe konnte in den Tumoren von MLV-shLuc infizierten Mäusen eine Abnahme der Luziferaseaktivität auf 15 % nachgewiesen werden. Auch in Mäusen, die systemisch applizierte Tumorzellen erhielten, konnte eine Tendenz von RNAi-vermittelter Luziferase-Reduktion beobachtet werden.
Damit wurde in dieser Arbeit ein neuartiges RNAi-Transfersystem geschaffen, das in der Lage ist, auch in vivo einen starken und lang andauernden RNAi-Effekt auszulösen. Die Einzigartigkeit besteht in der Kombination von shRNAmir und Replikations-kompetenten Retroviren. Dadurch konnte eine erweiterte Transferrate von shRNAmir in Tumorzellen erreicht werden, so dass nun Genfunktionsstudien mit sehr hoher Aussagekraft möglich sind.
Weimarer Beiträge 59/2013
(2013)
Die Weimarer Beiträge sind eine Zeitschrift für Literaturwissenschaft, aktuelle ästhetische Theorie und Kulturwissenschaft. Zu Ihren Schwerpunkten gehören moderne Literatur im Rahmen anderer Künste und Medien, die Wechselbeziehungen von Literatur, philosophischer und ästhetischer Reflexion sowie die kritische Analyse der Gegenwartskultur.
Diese Arbeit entstand im Rahmen eines größeren Forschungsprojektes zum Thema Bewältigung von Lebensenttäuschungen, initiiert von Prof. Dr. Siegfried Preiser am Institut für Psychologie der Universität Frankfurt am Main. In diesem Kontext wurde die vorliegende Studie entwickelt.
Ausgehend von interpersonalem Engagement wurden mögliche Verknüpfungen von Einflussfaktoren im Umgang mit unterschiedlichen kritischen Lebenssituationen und der sich daraus ergebenden Konsequenzen auf psychische und physische Gesundheit, d.h. persönliches Wohlbefinden untersucht. Das Konstrukt Wohlbefinden wurde in dieser Studie als eine latente Variable gebildet, die sich aus einer Konstellation von bereichsspezifischen und allgemeinen Lebenszufriedenheitsfaktoren, dem seelischen Gesundheitsempfinden und – mit negativem Gewicht - dem aktuellen Belastungsempfinden zusammensetzt.
Außer der Erfassung der Partizipation an sozialen Gemeinschaften bzw. des sozialen Engagements wurden intrapsychische, motivationale, biographische und soziale Faktoren erfasst sowie religiöse Aspekte einbezogen. Zielgruppen der Untersuchung waren Gruppierungen vorwiegend aus dem Selbsthilfebereich.
Zur Beachtung der Zeitperspektive war die Befragung als Längsschnittstudie in Form einer Zweifachmessung konzipiert.
Erhoben und untersucht wurden im einzelnen Belastungs-, Persönlichkeits-, Gesundheits- und Zufriedenheitsfaktoren, des Weiteren die Aspekte des sozialen Kontextes mit Differenzierung der Ebenen von sozialer Unterstützung sowie religiöse Aspekte als angenommene Einflussfaktoren auf Lebenszufriedenheit und persönliches Wohlbefinden.
Zusammenfassend hatten die Persönlichkeitsfaktoren Flexibilität und Selbstwirksamkeit den größten positiven Einfluss auf Wohlbefinden. Bzgl. des sozialen Engagements zeigte sich dagegen kein signifikanter Einfluss.
Neben den Variablen Flexibilität und Selbstwirksamkeit stellte sich die wahrgenommene Unterstützung als bedeutsamster Einflussfaktor auf das Wohlbefinden heraus.
Religiöse Vorstellungen konnten nach ihrer persönlichen positiven oder negativen Grundhaltung gegenüber Gott bzw. einer höheren Wirklichkeit differenziert werden. Eine positive religiöse Grundhaltung ist geprägt von der Vorstellung eines schützenden, fürsorglichen und hilfreichen Gottes. Ein negatives Gottesbild beinhaltet die Vorstellung eines bedrohlichen und strafenden Gottes. Nur für diese Betrachtungsweise konnten eindeutige - und zwar negative - Einflüsse auf das Wohlbefinden ermittelt werden
Inhaltlich gliedert sich die Arbeit in vier Blöcke:
In Kapitel 1 werden theoretische Grundlagen und untersuchungsrelevante Konzepte näher erläutert und daraus die konkreten Fragestellungen einschließlich der Hypothesen entwickelt.
In Kapitel 2 schließt sich der methodische Teil mit den Beschreibungen der Stichprobe, der Erhebungsinstrumente und des Untersuchungsverlaufes an.
Kapitel 3 enthält die Ergebnisse und deren Diskussion. Kapitel 4 beinhaltet ein Resümee und Ausblick. In Kapitel 5 befindet sich die für diese Arbeit verwendete Literatur, woran sich der Anhang anschließt. Der Anhang besteht zum einen aus weitergehenden Informationen und Erläuterungen, die Durchführung und Auswertung betreffend (Anhang I). Anhang II, der der Druckversion als CD beiliegt, listet zum anderen die Originalantworten der Probanden in strukturierter Form auf.
In vier aufeinander aufbauenden Studien wird den Fragen nachgegangen „Was sind Nicht-Ereignisse?“ und „Welche Verarbeitungshilfen sind effektiv für den Bewältigungsprozess?“. Am Beispiel der ungewollten Kinderlosigkeit wird aus gesundheitspsychologischer Sicht nach zwei Aspekten von psychosozialem Wohlbefinden gefragt: „globaler Lebenszufriedenheit“ und „negativen Emotionen“ (z.B. Scham und Schmerz).
Es werden Bewältigungsstrategien und Bewältigungsstile unterschieden. Die Bewältigungsstile „religiöses Coping“ sowie „hartnäckige Zielverfolgung“ und „flexible Zielanpassung“ werden als andauernde Einflussfaktoren im Bewältigungsprozess betrachtet. Die entwickelten Bewältigungsstrategien „planendes Problemlösen“, „Unterstützung durch Freunde“, „regenerative Strategien“ und „kognitive Umdeutung zur Akzeptanz“ sind erlernbare Vorgehensweisen.
In der Pilotstudie 1 wurden 22 Menschen interviewt, die sich im Nicht-Ereignis-Prozess befinden. In Studie 2 wurden qualitativ und quantitativ 76 Männer und Frauen mit ungewollter Kinderlosigkeit befragt. Studie 3 erhob online mit 216 Teilnehmern die Häufigkeit und eingeschätzte Effektivität von Verarbeitungshilfen. Studie 4 erfasste zu zwei Messzeitpunkten (n = 732, n = 409) vier Bewältigungsstrategien, vier Bewältigungsstile, „globale Lebenszufriedenheit“, „negative Emotionen“ und kinderwunschspezifische Antworten von Menschen mit Kinderwunsch.
Für eine gewünschte Schwangerschaft kann geschlussfolgert werden, dass ein bedeutsamer Prädiktor für die Eintrittswahrscheinlichkeit im frühen Prozess fertility awareness ist. Das Alter der Frau dagegen leistet keinen Beitrag zur Vorhersage. Die Prädiktoren „negatives religiöses Coping“ und „planendes Problemlösen“ im fortgeschrittenen Nicht-Ereignis-Prozess stellen Risikofaktoren für das psychosoziale Wohlbefinden dar. Die Schutzfaktoren „Unterstützung durch Freunde“, „kognitive Umdeutung zur Akzeptanz“ und „flexible Zielanpassung“ sind signifikante Prädiktoren für psychosoziales Wohlbefinden. Interaktionseffekte von „Flexibler Zielanpassung“ und „Hartnäckiger Zielverfolgung“ konnten nicht identifiziert werden.
Numerous reactive volatile organic compounds (VOCs) are emitted into the atmosphere by vegetation. Most biogenic VOCs are highly reactive towards the atmosphere's most important oxidant, the hydroxyl (OH) radical. One way to investigate the chemical interplay between biosphere and atmosphere is through the measurement of total OH reactivity, the total loss rate of OH radicals. This study presents the first determination of total OH reactivity emission rates (measurements via the comparative reactivity method) based on a branch cuvette enclosure system mounted on a Norway spruce (Picea abies) throughout spring, summer and autumn 2011. In parallel VOC emission rates were monitored by a second proton-transfer-reaction mass spectrometer (PTR-MS), and total ozone (O3) loss rates were obtained inside the cuvette. Total OH reactivity emission rates were in general temperature and light dependent, showing strong diel cycles with highest values during daytime. Monoterpene emissions contributed most, accounting for 56–69% of the measured total OH reactivity flux in spring and early summer. However, during late summer and autumn the monoterpene contribution decreased to 11–16%. At this time, a large missing fraction of the total OH reactivity emission rate (70–84%) was found when compared to the VOC budget measured by PTR-MS. Total OH reactivity and missing total OH reactivity emission rates reached maximum values in late summer corresponding to the period of highest temperature. Total O3 loss rates within the closed cuvette showed similar diel profiles and comparable seasonality to the total OH reactivity fluxes.
Total OH reactivity fluxes were also compared to emissions from needle storage pools predicted by a temperature-only-dependent algorithm. Deviations of total OH reactivity fluxes from the temperature-only-dependent emission algorithm were observed for occasions of mechanical and heat stress. While for mechanical stress, induced by strong wind, measured VOCs could explain total OH reactivity emissions, during heat stress they could not. The temperature-driven algorithm matched the diel variation of total OH reactivity emission rates much better in spring than in summer, indicating a different production and emission scheme for summer and early autumn. During these times, unmeasured and possibly unknown primary biogenic emissions contributed significantly to the observed total OH reactivity flux.
Kompetenzen bezeichnen „erlernbare kontextspezifische Leistungsdispositionen, die sich funktional auf Situationen und Anforderungen in bestimmten Domänen beziehen“ (Klieme & Hartig, 2007, S. 17). Für den Bereich der Lehrerbildung wurden durch die Kultusministerkonferenz (2004) Standards für die Lehrerbildung: Bildungswissenschaften formuliert, die als Explikation professioneller pädagogischer Kompetenzen gelten können. Durch die Formulierung dieser Standards sieht sich die Lehrerbildung mit der Aufgabe konfrontiert, Studierende des Lehramts so auszubilden, dass die resultierenden Kompetenzen den genannten Standards genügen. Dies impliziert eine standard- und somit kompetenzorientierte Evaluation der Lehrerbildung. Bislang wird eine Evaluation der Lehrerbildung jedoch meist durch Selbsteinschätzungsverfahren umgesetzt – eine Methodik, die im Bereich der Kompetenzdiagnostik kritisch diskutiert wird (z. B. Nerdinger et al, 2008).
Der Situational Judgement Test als kompetenzdiagnostisches Instrumentarium weist die Vorteile situationsorientierter Verfahren auf und kann zusätzlich aufgrund der schriftlichen Darbietung problemlos auf große Stichproben angewandt werden. In der vorliegenden Studie wurde ein solcher Test entwickelt, um die professionelle pädagogische Kompetenz Lehramtsstudierender kontextnah und ökonomisch erfassen zu können. Die Studie hatte zum Ziel, den entwickelten standardorientierten Situational Judgement Test anhand verschiedener Außenkriterien konvergent und diskriminant zu validieren. Hierbei wurden konvergente Validitätsnachweise lediglich teilweise signifikant, wobei diskriminante Validitätsnachweise anhand des Studienfachs (Lehramtsstudium vs. Studium technisch-naturwissenschaftlicher Fächer) deutliche Signifikanzen und Effektstärken zeigten.
The creation of entirely synthetically derived bone substitute materials which are as effective as autologous bone grafts is desirable. Osteogenesis involves the concerted action of several proteins within a signaling cascade. Hedgehog proteins act upstream of this cascade, inducing the expression of various bone morphogenetic proteins (BMPs) and promoting physiological bone healing. Therefore, the hypothesis that hedgehog signaling in bone defects improves bone healing more than BMP signaling alone was tested. Recombinant N-terminal sonic hedgehog protein (N-SHh), BMP-2 or a combination of the two was added to β-tricalcium phosphate (β-TCP) and 5-mm femoral midshaft defects in nude rats were filled with these composites. The defects were stabilized with mini-plates. After eight weeks, the animals were sacrificed and the femora were explanted. The radiological evaluation was followed by a three-point bending test and histological examination. BMP-2/β-TCP composites showed a trend of increased stiffness compared with the controls (β-TCP without protein). N-SHh/β-TCP composites had lower stiffness compared with the control group and the N-SHh/BMP-2/β-TCP composites also had lower average stiffness compared with the controls (all not significant). Histomorphometry, however, revealed abundant cartilage and bone core formation in the N-SHh-composite groups. The sum of the new cartilage and bone was highest in the combination group N-SHh/BMP-2 (not significant). The addition of N-SHh to bone substitute materials appears to delay bone healing at the applied concentration and observation time but also showed a trend for higher amounts of ossifying cartilage.
The concept of focal epilepsies includes a seizure origin in brain regions with hyper synchronous activity (epileptogenic zone and seizure onset zone) and a complex epileptic network of different brain areas involved in the generation, propagation, and modulation of seizures. The purpose of this work was to study functional and effective connectivity between regions involved in networks of epileptic seizures. The beginning and middle part of focal seizures from ictal surface EEG data were analyzed using dynamic imaging of coherent sources (DICS), an inverse solution in the frequency domain which describes neuronal networks and coherences of oscillatory brain activities. The information flow (effective connectivity) between coherent sources was investigated using the renormalized partial directed coherence (RPDC) method. In 8/11 patients, the first and second source of epileptic activity as found by DICS were concordant with the operative resection site; these patients became seizure free after epilepsy surgery. In the remaining 3 patients, the results of DICS / RPDC calculations and the resection site were discordant; these patients had a poorer post-operative outcome. The first sources as found by DICS were located predominantly in cortical structures; subsequent sources included some subcortical structures: thalamus, Nucl. Subthalamicus and cerebellum. DICS seems to be a powerful tool to define the seizure onset zone and the epileptic networks involved. Seizure generation seems to be related to the propagation of epileptic activity from the primary source in the seizure onset zone, and maintenance of seizures is attributed to the perpetuation of epileptic activity between nodes in the epileptic network. Despite of these promising results, this proof of principle study needs further confirmation prior to the use of the described methods in the clinical praxis.
The live attenuated yellow fever (YF) vaccine has an excellent record of efficacy and one dose provides long-lasting immunity, which in many cases may last a lifetime. Vaccination stimulates strong innate and adaptive immune responses, and neutralizing antibodies are considered to be the major effectors that correlate with protection from disease. Similar to other flaviviruses, such antibodies are primarily induced by the viral envelope protein E, which consists of three distinct domains (DI, II, and III) and is presented at the surface of mature flavivirions in an icosahedral arrangement. In general, the dominance and individual variation of antibodies to different domains of viral surface proteins and their impact on neutralizing activity are aspects of humoral immunity that are not well understood. To gain insight into these phenomena, we established a platform of immunoassays using recombinant proteins and protein domains that allowed us to dissect and quantify fine specificities of the polyclonal antibody response after YF vaccination in a panel of 51 vaccinees as well as determine their contribution to virus neutralization by serum depletion analyses. Our data revealed a high degree of individual variation in antibody specificities present in post-vaccination sera and differences in the contribution of different antibody subsets to virus neutralization. Irrespective of individual variation, a substantial proportion of neutralizing activity appeared to be due to antibodies directed to complex quaternary epitopes displayed on the virion surface only but not on monomeric E. On the other hand, DIII-specific antibodies (presumed to have the highest neutralizing activity) as well as broadly flavivirus cross-reactive antibodies were absent or present at very low titers. These data provide new information on the fine specificity as well as variability of antibody responses after YF vaccination that are consistent with a strong influence of individual-specific factors on immunodominance in humoral immune responses.
Author Summary: The live-attenuated yellow fever vaccine has been administered to more than 600 million people worldwide and is considered to be one of the most successful viral vaccines ever produced. Following injection, the apathogenic vaccine virus replicates in the vaccinee and induces antibodies that mediate virus neutralization and subsequent protection from disease. In principle, many different antibodies are induced by viral antigens, but it is becoming increasingly clear that only a subset of them is capable of inactivating the virus, and some antibody populations appear to dominate the immune response. However, to date there has been very little information on individual-specific variations of immunodominance and how such variations can affect the functionality of antibody responses. In our study, we addressed these issues and analyzed the fine specificities of antibodies induced by YF vaccination as well as the contribution of different antibody subsets to virus neutralization in 51 vaccinees. We demonstrate an extensive degree of individual variation with respect to immunodominance of antibody populations and their contribution to virus neutralization. Such variations can have an impact on vaccine-mediated protection, and thus insight into this phenomenon can provide leads for novel strategies in modern vaccine design.
The elliptic, v2, triangular, v3, and quadrangular, v4, azimuthal anisotropic flow coefficients are measured for unidentified charged particles, pions, and (anti-)protons in Pb–Pb collisions at √sNN=2.76 TeV with the ALICE detector at the Large Hadron Collider. Results obtained with the event plane and four-particle cumulant methods are reported for the pseudo-rapidity range |η|<0.8 at different collision centralities and as a function of transverse momentum, pT, out to pT=20 GeV/c. The observed non-zero elliptic and triangular flow depends only weakly on transverse momentum for pT>8 GeV/c. The small pT dependence of the difference between elliptic flow results obtained from the event plane and four-particle cumulant methods suggests a common origin of flow fluctuations up to pT=8 GeV/c. The magnitude of the (anti-)proton elliptic and triangular flow is larger than that of pions out to at least pT=8 GeV/c indicating that the particle type dependence persists out to high pT.
The production cross section of electrons from semileptonic decays of beauty hadrons was measured at mid-rapidity (|y|<0.8) in the transverse momentum range 1<pT<8 GeV/c with the ALICE experiment at the CERN LHC in pp collisions at a center of mass energy √s=7 TeV using an integrated luminosity of 2.2 nb−1. Electrons from beauty hadron decays were selected based on the displacement of the decay vertex from the collision vertex. A perturbative QCD calculation agrees with the measurement within uncertainties. The data were extrapolated to the full phase space to determine the total cross section for the production of beauty quark–antiquark pairs.
The inclusive transverse momentum (pT) distributions of primary charged particles are measured in the pseudo-rapidity range |η|<0.8 as a function of event centrality in Pb–Pb collisions at √sNN=2.76 TeV with ALICE at the LHC. The data are presented in the pT range 0.15<pT<50 GeV/c for nine centrality intervals from 70–80% to 0–5%. The results in Pb–Pb are presented in terms of the nuclear modification factor RAA using a pp reference spectrum measured at the same collision energy. We observe that the suppression of high-pT particles strongly depends on event centrality. The yield is most suppressed in central collisions (0–5%) with RAA≈0.13 at pT=6–7 GeV/c. Above pT=7 GeV/c, there is a significant rise in the nuclear modification factor, which reaches RAA≈0.4 for pT>30 GeV/c. In peripheral collisions (70–80%), only moderate suppression (RAA=0.6–0.7) and a weak pT dependence is observed. The measured nuclear modification factors are compared to other measurements and model calculations.
The gauge principle is fundamental in formulating the Standard Model. Fermion–gauge-boson couplings are the inescapable consequence and the primary determining factor for observable phenomena. Vertices describing such couplings are simple in perturbation theory and yet the existence of strong-interaction bound-states guarantees that many phenomena within the Model are nonperturbative. It is therefore crucial to understand how dynamics dresses the vertices and thereby fundamentally alters the appearance of fermion–gauge-boson interactions. We consider the coupling of a dressed-fermion to an Abelian gauge boson, and describe a unified treatment and solution of the familiar longitudinal Ward–Green–Takahashi identity and its less well known transverse counterparts. Novel consequences for the dressed-fermion–gauge-boson vertex are exposed.
Cellular cytotoxicity is the hallmark of NK cells mediating both elimination of virus-infected or malignant cells, and modulation of immune responses. NK cytotoxicity is triggered upon ligation of various activating NK cell receptors. Among these is the C-type lectin-like receptor NKp80 which is encoded in the human Natural Killer Gene Complex (NKC) adjacent to its ligand, activation-induced C-type lectin (AICL). NKp80-AICL interaction promotes cytolysis of malignant myeloid cells, but also stimulates the mutual crosstalk between NK cells and monocytes.
While many activating NK cell receptors pair with ITAM-bearing adaptors, we recently reported that NKp80 signals via a hemITAM-like sequence in its cytoplasmic domain. Here we molecularly dissect the NKp80 hemITAM and demonstrate that two non-consensus amino acids, in particular arginine 6, critically impair both hemITAM phosphorylation and Syk recruitment. Impaired Syk recruitment results in a substantial attenuation of cytotoxic responses upon NKp80 ligation. Reconstituting the hemITAM consensus or Syk overexpression resulted in robust NKp80-mediated responsiveness. Collectively, our data provide a molecular rationale for the restrained activation potential of NKp80 and illustrate how subtle alterations in signaling motifs determine subsequent cellular responses. They also suggest that non-consensus alterations in the NKp80 hemITAM, as commonly present among mammalian NKp80 sequences, may have evolved to dampen NKp80-mediated cytotoxic responses toward AICL-expressing cells.
Background: The activating NK receptor NKp80 triggers cytotoxicity by human NK cells via a cytoplasmic hemITAM sequence.
Results: A non-consensus hemITAM residue impairs the capacity of NKp80 to recruit Syk kinase and to trigger cytotoxicity.
Conclusion: Unlike typical hemITAM receptors, NKp80 does not efficiently recruit Syk kinase resulting in attenuated effector responses.
Significance: An attenuated cytotoxic responsiveness critically impacts on the immunomodulatory function of NKp80.
In the stomach, neoplastic lesions often arise in the setting of precursor conditions such as gastritis, intestinal metaplasia, or adenomatous lesions. Biopsies may, therefore, underestimate disease severity or even miss the diagnosis (sampling error). Endomicroscopy is able to visualize typical features of such pathologies. It enables in vivo microscopy of gastritis with definition of enhanced vascularity and vascular leakage, but the typical cobblestone appearance of the gastric mucosa is preserved. The presence of intestinal metaplasia is confirmed by columnar absorptive cells with brush border and goblet cells within villiform foveolar epithelium. Gastric neoplasia is characterized by crowded glands with intraluminal folding and glandular budding and branching accompanied by increased density of dilated and distorted capillaries. Finally, in gastric cancer, gland and overall mucosal architecture is progressively lost. These features are shown side by side with white-light endoscopic findings. Endomicroscopy is used in such a setting to rapidly screen larger areas (optical biopsies) and subsequently target tissue sampling to areas with highly suspicious microscopic patterns. In experienced hands, it therefore constitutes an important part especially in the presence of neoplastic lesions within noncircumscript gastric premalignant conditions. This article is part of an expert video encyclopedia.
Dieulafoy's lesion (DL) is a rare source of gastrointestinal tract bleeding that may occur at any site in the gastrointestinal tract and may be difficult to detect by endoscopy. DL is characterized by a large, tortuous arteriole in the submucosa. This is a case of duodenal DL that is detected and treated by endoscopy. This article is part of an expert video encyclopedia.