Dopaminergic signaling is a prerequisite for motor learning. Delayed degeneration of dopaminergic neurons after stroke is linked to motor learning deficits impairing motor rehabilitation. This study investigates safety and efficacy of substance P (SP) treatment on post-stroke rehabilitation, as this neuropeptide combines neuroprotective and plasticity-promoting properties. Male Sprague Dawley rats received a photothrombotic stroke within the primary motor cortex (M1) after which a previously acquired skilled reaching task was rehabilitated. Rats were treated with intraperitoneal saline (control group, n = 7) or SP-injections (250 µg/kg) 30 min before (SP-pre; n = 7) or 16 h (SP-post; n = 6) after rehabilitation training. Dopaminergic neurodegeneration, microglial activation and substance P-immunoreactivity (IR) were analyzed immunohistochemically. Systemic SP significantly facilitated motor rehabilitation. This effect was more pronounced in SP-pre compared to SP-post animals. SP prevented dopaminergic cell loss after stroke, particularly in the SP-pre condition. Despite its proinflammatory propensity, SP administration did not increase stroke volumes, post-stroke deficits or activation of microglia in the midbrain. Finally, SP administration prevented ipsilesional hypertrophy of striatal SPergic innervation, particularly in the SP-post condition. Mechanistically, SP-pre likely involved plasticity-promoting effects in the early phase of rehabilitation, whereas preservation of dopaminergic signaling may have ameliorated rehabilitative success in both SP groups during later stages of training. Our results demonstrate the facilitating effect of SP treatment on motor rehabilitation after stroke, especially if administered prior to training. SP furthermore prevented delayed dopaminergic degeneration and preserved physiological endogenous SPergic innervation. 相似文献
Brain metastases are the most severe tumorous spread during breast cancer disease. They are associated with a limited quality of life and a very poor overall survival. A subtype of extracellular vesicles, exosomes, are sequestered by all kinds of cells, including tumor cells, and play a role in cell-cell communication. Exosomes contain, among others, microRNAs (miRs). Exosomes can be taken up by other cells in the body, and their active molecules can affect the cellular process in target cells. Tumor-secreted exosomes can affect the integrity of the blood-brain barrier (BBB) and have an impact on brain metastases forming. Serum samples from healthy donors, breast cancer patients with primary tumors, or with brain, bone, or visceral metastases were used to isolate exosomes and exosomal miRs. Exosomes expressed exosomal markers CD63 and CD9, and their amount did not vary significantly between groups, as shown by Western blot and ELISA. The selected 48 miRs were detected using real-time PCR. Area under the receiver-operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified two miRs with the potential to serve as prognostic markers for brain metastases. Hsa-miR-576-3p was significantly upregulated, and hsa-miR-130a-3p was significantly downregulated in exosomes from breast cancer patients with cerebral metastases with AUC: 0.705 and 0.699, respectively. Furthermore, correlation of miR levels with tumor markers revealed that hsa-miR-340-5p levels were significantly correlated with the percentage of Ki67-positive tumor cells, while hsa-miR-342-3p levels were inversely correlated with tumor staging. Analysis of the expression levels of miRs in serum exosomes from breast cancer patients has the potential to identify new, non-invasive, blood-borne prognostic molecular markers to predict the potential for brain metastasis in breast cancer. Additional functional analyzes and careful validation of the identified markers are required before their potential future diagnostic use. 相似文献
Fracture features, residual stresses, and zirconia transformation are studied in indentation strength specimens of alumina-Y2O3-stabilized zirconia (3% mol of Y2O3, 3YTZP) ceramics in order to analyze the extension of the indentation damage in the bulk of the specimens. Two compositions, 5 vol% 3YTZP (A5) and 40 vol% 3YTZP (A40), have been prepared by stacking tape-casted tapes and sintering. After indentation with loads ranging from 50 to 300 N, samples were fractured in four-point bending and the fracture surfaces were characterized by scanning electron microscopy. Raman and piezospectroscopic techniques were used to determine the monoclinic zirconia fraction and the residual stresses through the fracture surfaces. In the A5 composition, the indentation damage morphology was clearly half-penny, whereas the A40 composition presented Palmqvist crack formation. Zirconia transformation was only observed in the plastically deformed zones underneath the imprints whereas there were significant residual compressive stresses outside the plastic zones due to the indentation damage. The intensity of this residual compressive field was dependent on the level of zirconia transformation due to indentation damage because zirconia transformation induced tensile stress fields superimposed on the compressive stresses. 相似文献
The crude cell-free medium from a culture of Kluyveromyces marxianus var. bulgaricus was immobilized in a gelatin-water support, with an immobilization yield of 82.60% for inulinase activity. The optimum pH for both free and immobilized inulinase was the same (3.5) and the optimum temperatures were 55 °C for the free and 60 °C for the immobilized enzyme. The Arrhenius plots were linear and activation energies were 56.20 (free enzyme) and 20.27 kJ/mol K (immobilized enzyme). The kinetic parameters were calculated by Lineweaver–Burk plots and the Vmax and Km were 37.60 IU/mg protein and 61.83 mM for the free inulinase and 31.45 IU/mg protein and 149.28 mM for the immobilized enzyme, respectively. The operational stability of the immobilized inulinase was studied in a continuous fixed-bed column reactor for 33 days, at the end of which the sucrose conversion was 58.12%. 相似文献
The use of user-interface design knowledge such as general guidelines and environment-specific style guides can be valuable, and is increasingly required in professional user-interface design. However, conventional guidelines and style guides (
and
) in the form of documents are consistently found hard to use. We have earlier demonstrated knowledge-based critiquing to be a technically feasible way of delivering relevant
and
knowledge. The purpose of this study was to investigate the need and acceptability of such techniques for professional user-interface designers.
An experiment was carried out where four professional designers developed user-interface prototypes to a functional specification. The designs were evaluated using our
and
-based critiquing system, which identified a total of 17 deviations from style-guide requirements or design recommendations. Interviews were conducted with the designers to find the reasons for the deviations and to identify important requirements for a critiquing design-support tool. The deviation analysis points to an existing need for better ways of accessing
and
knowledge. The interviews indicate that the designers would find a critiquing tool valuable, provided that it leaves them in control of their work and indicates the severity of the detected deviations. 相似文献
In ferritic steels a propagating cleavage microcrack changes its propagation direction as it advances from grain to grain.
This is due to differences in the orientation of the cleavage planes of two neighboring grains. In order to reach a cleavage
plane in a new grain, a microcrack must first penetrate the grain boundary. Grain boundaries therefore act as natural barriers
in cleavage fracture. The influence of a grain boundary and the associated misorientation in cleavage planes on crack arrest
is here examined using a 3D finite element model with axisymmetric periodicity, representing two grains whose cleavage planes
are tilted and twisted relative to each other. The temperature dependent mechanical properties of ferrite are modeled using
a temperature dependent viscoplastic response. The development of the crack front as the microcrack penetrates through a grain
boundary is here presented. The influence of the twist misorientation on the critical grain size, defined as the largest grain
size that can arrest a rapidly propagating microcrack, is examined in a temperature range corresponding to the ductile to
brittle transition (DBT) region. It is shown that when both tilt and twist misorientation are present, the influence of tilt
and twist, respectively, on crack growth resistance can be decoupled. 相似文献