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Brain metastases are the most common intracranial tumor in adults and are associated with poor patient prognosis and median survival of only a few months. Treatment options for brain metastasis patients remain limited and largely depend on surgical resection, radio- and/or chemotherapy. The development and pre-clinical testing of novel therapeutic strategies require reliable experimental models and diagnostic tools that closely mimic technologies that are used in the clinic and reflect histopathological and biochemical changes that distinguish tumor progression from therapeutic response. In this study, we sought to test the applicability of magnetic resonance (MR) spectroscopy in combination with MR imaging to closely monitor therapeutic efficacy in a breast-to-brain metastasis model. Given the importance of radiotherapy as the standard of care for the majority of brain metastases patients, we chose to monitor the post-irradiation response by magnetic resonance spectroscopy (MRS) in combination with MR imaging (MRI) using a 7 Tesla small animal scanner. Radiation was applied as whole brain radiotherapy (WBRT) using the image-guided Small Animal Radiation Research Platform (SARRP). Here we describe alterations in different metabolites, including creatine and N-acetylaspartate, that are characteristic for brain metastases progression and lactate, which indicates hypoxia, while choline levels remained stable. Radiotherapy resulted in normalization of metabolite levels indicating tumor stasis or regression in response to treatment. Our data indicate that the use of MR spectroscopy in addition to MRI represents a valuable tool to closely monitor not only volumetrical but also metabolic changes during tumor progression and to evaluate therapeutic efficacy of intervention strategies. Adapting the analytical technology in brain metastasis models to those used in clinical settings will increase the translational significance of experimental evaluation and thus contribute to the advancement of pre-clinical assessment of novel therapeutic strategies to improve treatment options for brain metastases patients.
Editorial
(2010)
Wohl jeder Jurist kennt Kants Satz, dass die einfache Frage "Was ist Recht?" den "Rechtsgelehrten […] in Verlegenheit" setze. Höchstens "[w]as Rechtens sei (quid sit iuris), d. i. was die Gesetze an einem gewissen Ort und zu einer gewissen Zeit sagen oder gesagt haben", schloss Kant an, könne dieser "noch wohl angeben". Selbst das ist, wie wir inzwischen wissen, mindestens sehr optimistisch formuliert: Denn "Rechtens" war eben nicht nur, "was die Gesetze" sagten. Und obwohl vor allem deutsche Gelehrte seit Jahrzehnten beträchtliche intellektuelle Energie auf die Erforschung "des Rechtsbegriffs" verschiedener historischer Situationen verwenden, erscheinen die Grundbegriffe von "Recht" einem geschulten Beobachter immer noch "viel weniger historisch durchgearbeitet als 'Staat'". ...
Music listening has become a highly individualized activity with smartphones and music streaming services providing listeners with absolute freedom to listen to any kind of music in any situation. Until now, little has been written about the processes underlying the selection of music in daily life. The present study aimed to disentangle some of the complex processes among the listener, situation, and functions of music listening involved in music selection. Utilizing the experience sampling method, data were collected from 119 participants using a smartphone application. For 10 consecutive days, participants received 14 prompts using stratified-random sampling throughout the day and reported on their music-listening behavior. Statistical learning procedures on multilevel regression models and multilevel structural equation modeling were used to determine the most important predictors and analyze mediation processes between person, situation, functions of listening, and music selection. Results revealed that the features of music selected in daily life were predominantly determined by situational characteristics, whereas consistent individual differences were of minor importance. Functions of music listening were found to act as a mediator between characteristics of the situation and music-selection behavior. We further observed several significant random effects, which indicated that individuals differed in how situational variables affected their music selection behavior. Our findings suggest a need to shift the focus of music-listening research from individual differences to situational influences, including potential person-situation interactions.
Zu den dunkelsten Kapiteln deutscher Rechtsgeschichte zählt die zivile Besatzungsjustiz Nazideutschlands in Osteuropa. "Dunkel" ist hier in zweifacher Hinsicht zu verstehen: Zum einen war die Justiz durch die Involvierung in die Besatzungspolitik an der Unterdrückung und Ausplünderung der besetzten Gebiete und ihrer Bevölkerung beteiligt und trug durch die Verfolgung des Widerstandes und der "normalen" (Kriegs-)Kriminalität maßgeblich zur Stabilisierung der deutschen Herrschaft bei. Zum anderen ist dieser Aspekt nationalsozialistischer Rechtsund Justizgeschichte in der deutschen Forschung bislang wenig beachtet worden, was vor allem den Sprachbarrieren, den lange Zeit nur schwer zugänglichen osteuropäischen Archiven und ideologischen Hemmnissen in der Zeit des Kalten Krieges geschuldet ist. ...
One of the major challenges of allogeneic stem cell transplantation (allo-SCT) is to reduce the risk of graft-versus-host disease (GVHD) while boosting the graft-versus-leukemia (GVL) effect. The reconstitution of natural killer (NK) cells following allo-SCT is of notable interest due to their known capability to induce GVL without GVHD. Here, in this study, we investigate the association between the incidence and severity of acute graft-versus-host disease (aGVHD) and the early reconstitution of NK cell subsets following allo-SCT. We analyzed 342 samples from 107 patients using flow cytometry, with a focus on immature CD56high and mature cytotoxic CD56dim NK cells. Longitudinal analysis of immune reconstitution after allo-SCT showed that the incidence of aGVHD was associated with a delayed expansion of the entire NK cell population, in particular the CD56high subset. Notably, the disturbed reconstitution of the CD56high NK cells also correlated with the severity of aGVHD.
Alterations in the autophagosomal–lysosomal pathway are a major pathophysiological feature of CLN3 disease, which is the most common form of childhood-onset neurodegeneration. Accumulating autofluorescent lysosomal storage material in CLN3 disease, consisting of dolichols, lipids, biometals, and a protein that normally resides in the mitochondria, subunit c of the mitochondrial ATPase, provides evidence that autophagosomal–lysosomal turnover of cellular components is disrupted upon loss of CLN3 protein function. Using a murine neuronal cell model of the disease, which accurately mimics the major gene defect and the hallmark features of CLN3 disease, we conducted an unbiased search for modifiers of autophagy, extending previous work by further optimizing a GFP-LC3 based assay and performing a high-content screen on a library of ~2000 bioactive compounds. Here we corroborate our earlier screening results and identify expanded, independent sets of autophagy modifiers that increase or decrease the accumulation of autophagosomes in the CLN3 disease cells, highlighting several pathways of interest, including the regulation of calcium signaling, microtubule dynamics, and the mevalonate pathway. Follow-up analysis on fluspirilene, nicardipine, and verapamil, in particular, confirmed activity in reducing GFP-LC3 vesicle burden, while also demonstrating activity in normalizing lysosomal positioning and, for verapamil, in promoting storage material clearance in CLN3 disease neuronal cells. This study demonstrates the potential for cell-based screening studies to identify candidate molecules and pathways for further work to understand CLN3 disease pathogenesis and in drug development efforts.
Von 9.–13. November 2009 kamen die 141 Vertragsstaaten der Anti-Korruptionskonvention der Vereinten Nationen in Doha (Katar) zusammen und nahmen die wichtigste Resolution seit Inkrafttreten der Konvention an. In Zukunft wird die Umsetzung der Konvention in jedem Vertragsstaat von jeweils zwei anderen Vertragsstaaten überprüft, die einen Bericht mit Empfehlungen abgeben. Dies soll nicht nur die Umsetzung des ersten globalen Abkommens gegen Korruption garantieren, sondern auch den internationalen Dialog und die Leistung technischer Hilfe fördern. Viele Delegierte wiesen darauf hin, dass Bestechung nur im Zusammenwirken von aktivem und passivem Part möglich sei und dass Korruption in ihren vielfältigen Formen nur in der geteilten Verantwortung von Industrie- und Entwicklungsländern effektiv bekämpft werden könne. Dies entspricht dem Geist der Konvention, die die internationale Zusammenarbeit erleichtert und durch umfassende Bestimmungen über die Strafbarkeit unter anderem von Bestechung gleiche Bedingungen unter den Staaten schafft. ...
Numbers and space are two semantic primitives that interact with each other. Both recruit brain regions along the dorsal pathway, notably parietal cortex. This makes parietal cortex a candidate for the origin of numerical–spatial interaction. The underlying cognitive architecture of the interaction is still under scrutiny. Two classes of explanations can be distinguished. The early interaction approach assumes that numerical and spatial information are integrated into a single representation at a semantic level. A second approach postulates independent semantic representations. Only at the stage of response selection and preparation these two streams interact. In this study we used a numerical landmark task to identify the locus of the interaction between numbers and space. While lying in an MR scanner participants decided on the smaller of two numerical intervals in a visually presented number triplet. The spatial position of the middle number was varied; hence spatial intervals were congruent or incongruent with the numerical intervals. Responses in incongruent trials were slower and less accurate than in congruent trials. By combining across-vertex correlations (micro pattern) with a cluster analysis (macro pattern) we identified large-scale networks that were devoted to number processing, eye movements, and sensory–motor functions. Using support vector classification in different regions of interest along the intraparietal sulcus, the frontal eye fields, and supplementary motor area we were able to distinguish between congruent and incongruent trials in each of the networks. We suggest that the identified networks participate in the integration of numerical and spatial information and that the exclusive assumption of either an early or a late interaction between numerical and spatial information does not do justice to the complex interaction between both dimensions.
The focus of this work, the debate about a body of law dealing with aristocratic issues, is not easy to summarize. This problem stems in part from a topic that historians who do not work on law might be forgiven for considering nonexistent; in part, it has to do with the indirect way in which Dorothee Gottwald engages with current trends in the historiography of nineteenth-century Germany. ...