RESUMEN
Angiogenesis is a crucial process in the progression of various pathologies, like solid tumors, wet age-related macular degeneration, and chronic inflammation. Current anti-angiogenic treatments still have major drawbacks like limited efficacy in diseases that also rely on inflammation. Therefore, new anti-angiogenic approaches are sorely needed, and simultaneous inhibition of angiogenesis and inflammation is desirable. Here, we show that 2-desaza-annomontine (C81), a derivative of the plant alkaloid annomontine previously shown to inhibit endothelial inflammation, impedes angiogenesis by inhibiting CDC2-like kinases (CLKs) and WNT/ß-catenin signaling. C81 reduced choroidal neovascularization in a laser-induced murine in vivo model, inhibited sprouting from vascular endothelial growth factor A (VEGF-A)-activated murine aortic rings ex vivo, and reduced angiogenesis-related activities of endothelial cells in multiple functional assays. This was largely phenocopied by CLK inhibitors and knockdowns, but not by inhibitors of the other known targets of C81. Mechanistically, CLK inhibition reduced VEGF receptor 2 (VEGFR2) mRNA and protein expression as well as downstream signaling. This was partly caused by a reduction of WNT/ß-catenin pathway activity, as activating the pathway induced, while ß-catenin knockdown impeded VEGFR2 expression. Surprisingly, alternative splicing of VEGFR2 was not detected. In summary, C81 and other CLK inhibitors could be promising compounds in the treatment of diseases that depend on angiogenesis and inflammation due to their impairment of both processes.
Asunto(s)
Carbolinas , Pirimidinas , Factor A de Crecimiento Endotelial Vascular , beta Catenina , Animales , Humanos , Ratones , Angiogénesis , Inhibidores de la Angiogénesis/farmacología , beta Catenina/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Inflamación , Neovascularización Patológica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Vía de Señalización WntRESUMEN
Since the properties of functional materials are highly dependent on their specific structure, and since the structural changes, for example during crystallization, induced by coating and annealing processes are significant, the study of structure and its formation is of interest for fundamental and applied science. However, structure analysis is often limited to ex situ determination of final states due to the lack of specialized sample cells that enable real-time investigations. The lack of such cells is mainly due to their fairly complex design and geometrical restrictions defined by the beamline setups. To overcome this obstacle, an advanced sample cell has been designed and constructed; it combines automated doctor blading, solvent vapor annealing and sample hydration with real-time grazing-incidence wide- and small-angle scattering (GIWAXS/GISAXS) and X-ray reflectivity (XRR). The sample cell has limited spatial requirements and is therefore widely usable at beamlines and laboratory-scale instruments. The cell is fully automatized and remains portable, including the necessary electronics. In addition, the cell can be used by interested scientists in cooperation with the Institute for Crystallography and Structural Physics and is expandable with regard to optical secondary probes. Exemplary research studies are presented, in the form of coating of P3HT:PC61PM thin films, solvent vapor annealing of DRCN5T:PC71BM thin films, and hydration of supported phospholipid multilayers, to demonstrate the capabilities of the in situ cell.
RESUMEN
BACKGROUND AND PURPOSE: 4D flow MR imaging is an emerging technique that allows visualization and quantification of 3D blood flow in vivo. However, representative studies evaluating its accuracy are lacking. Therefore, we compared blood flow quantification by using 4D flow MR imaging with US within the carotid bifurcation. MATERIALS AND METHODS: Thirty-two healthy volunteers (age 25.3 ± 3.4 years) and 20 patients with ≥50% ICA stenosis (age 67.7 ± 7.4 years) were examined preoperatively and postoperatively by use of 4D flow MR imaging, with complete coverage of the left and right carotid bifurcation. Blood flow velocities were assessed with standardized 2D analysis planes distributed along the CCA and the ICA and were compared with US at baseline and postoperatively in patients. In addition, we tested reproducibility and interobserver agreement of 4D MR imaging in 10 volunteers. RESULTS: Overall, 101 CCAs and 79 ICAs were available for comparison. MR imaging underestimated (P < .05) systolic CCA and ICA blood flow velocity by 26% (0.79 ± 0.29 m/s vs 1.06 ± 0.31 m/s) and 19% (0.72 ± 0.21 m/s vs 0.89 ± 0.27 m/s) compared with US. Diastolic blood flow velocities were similar for MR imaging and US (differences, 9% and 3%, respectively; not significant). Reproducibility and interobserver agreement of 4D flow MR imaging was excellent. CONCLUSIONS: 4D flow MR imaging allowed for an accurate measurement of blood flow velocities in the carotid bifurcation of both volunteers and patients with only moderate underestimation compared with US. Thus, 4D flow MR imaging seems promising for a future combination with MRA to comprehensively assess ICA stenosis and related hemodynamic changes.
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Velocidad del Flujo Sanguíneo/fisiología , Arterias Carótidas/fisiología , Procesamiento de Imagen Asistido por Computador/métodos , Angiografía por Resonancia Magnética/métodos , Adulto , Anciano , Arterias Carótidas/diagnóstico por imagen , Arteria Carótida Común/diagnóstico por imagen , Arteria Carótida Común/patología , Arteria Carótida Interna/diagnóstico por imagen , Arteria Carótida Interna/patología , Estenosis Carotídea/diagnóstico , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/cirugía , Medios de Contraste , Diástole/fisiología , Endarterectomía Carotidea/métodos , Procedimientos Endovasculares/métodos , Femenino , Estudios de Seguimiento , Frecuencia Cardíaca/fisiología , Humanos , Aumento de la Imagen/métodos , Masculino , Variaciones Dependientes del Observador , Oxígeno/sangre , Reproducibilidad de los Resultados , Stents , Sístole/fisiología , UltrasonografíaRESUMEN
OBJECTIVE: To investigate the impact of EEG frequency band biofeedback (neurofeedback) training on spectral EEG topography, which is presumed to mediate cognitive-behavioural training effects. In order to assess the effect of commonly applied neurofeedback protocols on spectral EEG composition, two studies involving healthy participants were carried out. METHODS: In Experiment 1, subjects were trained on low beta (12-15 Hz), beta1 (15-18 Hz), and alpha/theta (8-11 Hz/5-8 Hz) protocols, with spectral resting EEG assessed before and after training. The specific associations between learning indices of each individual training protocol and changes in absolute and relative spectral EEG topography was assessed by means of partial correlation analyses. Results of Experiment 1 served to generate hypotheses for Experiment 2, where subjects were randomly allocated to independent groups of low beta, beta1, and alpha/theta training. Spectral resting EEG measures were contrasted prior and subsequent to training within each group. RESULTS: Only few associations between particular protocols and spectral EEG changes were found to be consistent across the two studies, and these did not correspond to expectations based on the operant contingencies trained. Low-beta training was found to be somewhat associated with reduced post-training low-beta activity, while more reliably, alpha/theta training was associated with reduced relative frontal beta band activity. CONCLUSIONS: The results document that neurofeedback training of frequency components does affect spectral EEG topography in healthy subjects, but that these effects do not necessarily correspond to either the frequencies or the scalp locations addressed by the training contingencies. The association between alpha/theta training and replicable reductions in frontal beta activity constitutes novel empirical neurophysiological evidence supporting inter alia the training's purported role in reducing agitation and anxiety. SIGNIFICANCE: These results underline the complexity of the neural dynamics involved EEG self-regulation and emphasize the need for empirical validation of predictable neurophysiological outcomes of training EEG biofeedback protocols.
Asunto(s)
Biorretroalimentación Psicológica/fisiología , Encéfalo/fisiología , Electroencefalografía , Adulto , Ritmo alfa , Ritmo beta , Mapeo Encefálico , Femenino , Humanos , Masculino , Ritmo TetaRESUMEN
Viewing literature about aspects, goals and methods of school psychology a conceptual framework for the work of a school psychological counselling center is described. A broad perspective is intended through two guiding principles: Polarities like individual and system, single case counselling and school organisation development are connected; the role bearers--counsellors and the addressees of this counselling--take part as active and competent fashioners of the guidance process within the system of relationships growing from this process.