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Eosinophils, through their ability to generate an array of potent mediators, are thought to be the major effector cells in a number of conditions, including parasitic infection, asthma, and other allergic diseases. The mechanism(s) by which eosinophils, as opposed to neutrophils, accumulate at inflammatory sites is unknown. One possible mechanism would be an eosinophil-specific pathway of adhesion to vascular endothelium. In this study we have demonstrated that human eosinophils, but not neutrophils, constitutively express alpha 4 beta 1 (CD49d/CD29). Expression was not increased on low density eosinophils or normal density cells stimulated with platelet-activating factor. Eosinophils, but not neutrophils, specifically adhered to COS cells transfected with vascular adhesion molecule-1 in a alpha 4 beta 1-dependent manner. Eosinophil, but not neutrophil, adhesion to IL-1 stimulated human umbilical vascular endothelial cells was significantly inhibited by alpha 4 beta 1 mAb at both 5 h (p less than 0.05) and 20 h (p less than 0.001). Inhibition of both resting and platelet-activating factor-(10(-7) M) stimulated eosinophil adhesion was observed. We conclude that the alpha 4 beta 1/vascular adhesion molecule-1 adhesion pathway may be involved in specific eosinophil, as opposed to neutrophil, migration into sites of eosinophilic inflammation.  相似文献   
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Pharmacological focal adhesion kinase (FAK) inhibition prevents tumor growth and metastasis, via actions on both tumor and stromal cells. In this paper, we show that vascular endothelial cadherin (VEC) tyrosine (Y) 658 is a target of FAK in tumor-associated endothelial cells (ECs). Conditional kinase-dead FAK knockin within ECs inhibited recombinant vascular endothelial growth factor (VEGF-A) and tumor-induced VEC-Y658 phosphorylation in vivo. Adherence of VEGF-expressing tumor cells to ECs triggered FAK-dependent VEC-Y658 phosphorylation. Both FAK inhibition and VEC-Y658F mutation within ECs prevented VEGF-initiated paracellular permeability and tumor cell transmigration across EC barriers. In mice, EC FAK inhibition prevented VEGF-dependent tumor cell extravasation and melanoma dermal to lung metastasis without affecting primary tumor growth. As pharmacological c-Src or FAK inhibition prevents VEGF-stimulated c-Src and FAK translocation to EC adherens junctions, but FAK inhibition does not alter c-Src activation, our experiments identify EC FAK as a key intermediate between c-Src and the regulation of EC barrier function controlling tumor metastasis.  相似文献   
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Full length cDNAs for a variety of human N-CAM isoforms have been transfected into mouse L-cells and/or 3T3 cells. Three independent clones of each cell line that were shown to express human N-CAM were tested for their ability to support the morphological differentiation of sensory neurons. The cell surface expression of N-CAM isoforms, linked to the membrane directly by an integral transmembrane spanning domain or indirectly via covalent attachment to a glycosyl-phosphatidylinositol moiety, were consistently found to be associated with a significant increase in the morphological differentiation of both human and rat dorsal root ganglion neurons. Modification of the extracellular structure of both classes of N-CAM, consequent to the expression of a glycosylated 37-amino acid sequence normally found expressed exclusively in muscle N-CAM isoforms did not obviously affect the ability of transfected cells to support increased neuronal differentiation. 3T3 cells that were transfected with a full length cDNA encoding a secreted N-CAM isoform, and that have previously been shown to secrete N-CAM into the growth media rather than link it to the membrane did not significantly differ from control cells in their ability to support neuronal differentiation. These data provide direct evidence for both transmembrane and lipid-linked N-CAM isoforms being components of the regulatory machinery that determines neuronal morphology and process outgrowth.  相似文献   
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Current MR methods use T2? relaxation time as a surrogate measure of ligament strength. Currently, a multi-echo voxel-wise least squares fit is the gold standard to create T2? maps; however, the post-processing is time-intensive and serves as a stopgap for clinical use. The study objective was to determine if an alternative method could improve post-processing time without sacrificing fidelity of T2? values for eventual translational use in the clinic. Using a 6 echo FLASH sequence, three different methods were used to determine intact posterior cruciate ligament (PCL) median T2? Two of these methods utilized a voxel-wise method to establish T2? maps: (1) a current “gold standard” method using a voxel-wise 6 echo least-squares fit (6LS) and (2) a voxel-wise 2 echo point T2? determination (2MM). The third method used median ligament signal intensity and a single nonlinear least-squares fit (6LSROI) instead of a voxel-wise basis. The resulting median T2? values of the PCL and computational time were compared. The median T2? values were 42% higher using the 2MM compared to the 6LS method (p<0.0001). However, a strong correlation was found for the median T2? values between the 2MM and 6LS methods (R2=0.80). The median T2? values were not significantly different between the 6LS and 6LSROI methods (p=0.519). Using the 2MM (which provides a regional map) and the 6LSROI (which efficiently provides the median T2? value) methods in tandem would take only minutes of post-processing computational time compared to the 6LS method (~540 min), and hence would facilitate clinical application of T2? maps to predict ligament structural properties as a patient outcome measure.  相似文献   
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Trypanosoma and Leishmania are parasitic protozoa that cause a variety of diseases, which include African sleeping sickness and oriental sore. Attempts to determine pharmaceutically exploitable differences between host and parasite biochemistry have identified the unique trypanothione pathway as a possible target. This pathway includes the enzyme trypanothione reductase, the parasite analogue of glutathione reductase.  相似文献   
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Bis‐(3′,5′) cyclic di‐guanylate (c‐di‐GMP) is a key bacterial second messenger that is implicated in the regulation of many crucial processes that include biofilm formation, motility and virulence. Cellular levels of c‐di‐GMP are controlled through synthesis by GGDEF domain diguanylate cyclases and degradation by two classes of phosphodiesterase with EAL or HD‐GYP domains. Here, we have determined the structure of an enzymatically active HD‐GYP domain protein from Persephonella marina (PmGH) alone, in complex with substrate (c‐di‐GMP) and final reaction product (GMP). The structures reveal a novel trinuclear iron binding site, which is implicated in catalysis and identify residues involved in recognition of c‐di‐GMP. This structure completes the picture of all domains involved in c‐di‐GMP metabolism and reveals that the HD‐GYP family splits into two distinct subgroups containing bi‐ and trinuclear metal centres.  相似文献   
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1. 1. In this short review, previous studies regarding the modeling of lactate (La) response to exercise and its application to endurance training have been summarized.

2. 2. Additionally the result of a recent study by the present authors are shown.

3. 3. Several models for La response to step and ramp exercise are already proposed and deductions derived from them are used for practical purposes such as the prediction of race performance in middle-and long-distance runners as well as for construction of their training regimens.

4. 4. Only a limited number of models however have tried to quantify whole body La kinetics to exercise in humans concomitantly with describing physiological mechanisms underlying the observed phenomenon.

5. 5. In a recent study described further in this paper a 2 compartment model was used for the purpose of clarifying the current “La production vs degradation” controversy during La adaptation to training.

6. 6. It was determined from this investigation that the La metabolic clearance rate during recovery is enhanced by the endurance training.

7. 7. This is in accordance with another recent observation of an increased La metabolic clearance rate at high absolute work rates and all relative work rates during exercise.

Author Keywords: Lactate kinetics; training; physiological modeling  相似文献   

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