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41.
Calcineurin B1 is essential for positive but not negative selection during thymocyte development 总被引:6,自引:0,他引:6
During development, discrete cell fates often result from variation in the intensity of a particular signal. The mechanisms underlying these seemingly analog-to-digital switches are not understood. In developing T lymphocytes, low-intensity signals through the antigen receptor result in positive selection while more intense signals give rise to negative selection. By deleting the genetic locus encoding the regulatory B1 subunit of calcineurin specifically in thymocytes, we found an absolute requirement for calcineurin in positive selection. In contrast, calcineurin activity was dispensable in several models of negative selection. Unexpectedly, we found that removal of calcineurin activity from thymocytes results in inefficient ERK activation at the double-positive stage of thymocyte development, when selection occurs. These studies clarify the mechanism by which graded signals are converted to discrete outcomes in T cell development and further indicate that the developmental roles of calcineurin likely contribute to immunosuppression by calcineurin inhibitors. 相似文献
42.
Thymus leukemia antigen (TL) is an MHC class Ib molecule that is highly conserved in rats and mice with no obvious human homolog. TL is expressed in mouse small intestinal epithelial cells and is known to interact with CD8alphaalpha homodimers, which are expressed by intraepithelial lymphocytes (IELs), some other T cell subsets and some non-T cells such as a subset of dendritic cells. We show here that TL is abundantly expressed on the basolateral surface of mouse small intestinal epithelial cells and that expression is abrogated in beta2m-/- mice but unaffected in TCR-/- mice or CD8alpha chain-/- mice. We demonstrate that the interaction between TL and CD8alphaalpha is not necessary for IEL survival in vitro or in vivo and does not modulate IEL trafficking in vivo. TL co-stimulation of alpha-CD3 antibody-activated IELs resulted in modestly enhanced production of IFN-gamma in one subset of IELs. The lack of effect on IEL survival and trafficking and the modest effect on IFN-gamma production suggest that the functional consequences of TL interaction with CD8alphaalpha as well as the more general biological role of TL in mucosal immunity remains to be discovered. 相似文献
43.
Growth factor-dependent activation of the MAPK pathway in human pancreatic cancer: MEK/ERK and p38 MAP kinase interaction in uPA synthesis 总被引:3,自引:0,他引:3
Increased expression of the hepatocyte growth factor (HGF) receptor (c-met) and urokinase type plasminogen (uPA) correlated
with the development and metastasis of cancers. To investigate the role of HGF/c-met signaling on metastasis in cancer cells
stimulated with HGF, we examined the effects of a specific MEK1 inhibitor (PD98059) and a p38 MAP kinase inhibitor (SB203580)
on HGF-induced uPA expression in pancreatic cancer cell lines, L3.6PL and IMIM-PC2. Pretreatment of PD98059 decreased HGF-mediated
phosphorylation of extracellular receptor kinase (ERK), uPA secretion and expression of matrix metalloproteinases (MMP-2 and
MMP-9) in a dose-dependent manner. In contrast, SB203580 pretreatment increased HGF-stimulated ERK phosphorylation, uPA secretion
and expression of MMPs. SB203580 also reversed the inhibition of HGF-mediated ERK activation and uPA secretion in the PD98059-pretreated
cells. These results suggest that ERK activation by HGF might play important roles in the metastasis of pancreatic cancer
and the p38 MAPK pathway also involved in the HGF-mediated uPA secretion and metastasis by regulation of ERK pathway.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
44.
Rodríguez-Niedenführ M Vázquez T Choi D Parkin I Sañudo JR 《Clinical anatomy (New York, N.Y.)》2003,16(3):197-203
Supernumerary humeral heads of the biceps brachii muscle were found in 27 (15.4%) of 175 cadavers. They were bilateral in five cadavers and unilateral in 22 (8 left, 14 right), giving a total of 32 examples in 350 arms (9.1%). Depending on their origin and location, the supernumerary heads were classified as superior, infero-medial, and infero-lateral humeral heads. Previous studies were reviewed using this classification. The infero-medial humeral head was observed in 31 of 350 (9%) arms and was therefore the most common variation. The superior humeral head was observed in five (1.5%). The infero-lateral humeral head was the least common variation, observed only in one (0.3%) of 350 arms. A biceps brachii with three heads was observed in 27 of 350 (7.7%) arms and with four heads in five (1.4%) arms. 相似文献
45.
Van QN Klose JR Lucas DA Prieto DA Luke B Collins J Burt SK Chmurny GN Issaq HJ Conrads TP Veenstra TD Keay SK 《Disease markers》2003,19(4-5):169-183
The advent of systems biology approaches that have stemmed from the sequencing of the human genome has led to the search for new methods to diagnose diseases. While much effort has been focused on the identification of disease-specific biomarkers, recent efforts are underway toward the use of proteomic and metabonomic patterns to indicate disease. We have developed and contrasted the use of both proteomic and metabonomic patterns in urine for the detection of interstitial cystitis (IC). The methodology relies on advanced bioinformatics to scrutinize information contained within mass spectrometry (MS) and high-resolution proton nuclear magnetic resonance (1H-NMR) spectral patterns to distinguish IC-affected from non-affected individuals as well as those suffering from bacterial cystitis (BC). We have applied a novel pattern recognition tool that employs an unsupervised system (self-organizing-type cluster mapping) as a fitness test for a supervised system (a genetic algorithm). With this approach, a training set comprised of mass spectra and 1H-NMR spectra from urine derived from either unaffected individuals or patients with IC is employed so that the most fit combination of relative, normalized intensity features defined at precise m/z or chemical shift values plotted in n-space can reliably distinguish the cohorts used in training. Using this bioinformatic approach, we were able to discriminate spectral patterns associated with IC-affected, BC-affected, and unaffected patients with a success rate of approximately 84%. 相似文献
46.
Dutta Roy T Simon JL Ricci JL Rekow ED Thompson VP Parsons JR 《Journal of biomedical materials research. Part A》2003,67(4):1228-1237
The current study analyzes the in vivo performance of porous sintered hydroxyapatite (HA) bone repair scaffolds fabricated using the TheriForm solid freeform fabrication process. Porous HA scaffolds with engineered macroscopic channels had a significantly higher percentage of new bone area compared with porous HA scaffolds without channels in a rabbit calvarial defect model at an 8-week time point. An unexpected finding was the unusually large amount of new bone within the base material structure, which contained pores less than 20 microm in size. Compared with composite scaffolds of 80% polylactic-co-glycolic acid and 20% beta-tricalcium phosphate with the same macroscopic architecture as evaluated in a previous study, the porous HA scaffolds with channels had a significantly higher percentage of new bone area. Therefore, the current study indicates that scaffold geometry, as determined by the fabrication process, can enhance the ability of a ceramic material to accelerate healing of calvarial defects. 相似文献
47.
A procedure for antibody detection and identification that utilizes affinity microcolumns to isolate IgG antibodies in a gel matrix containing Protein G and Protein A was commercially available in recent years. We evaluated this method (ReACT, Red Cell Affinity Column Technology, Immucor Co., Norcross, GA) as an alternative to standard tube agglutination testing, in an effort to minimize subjectivity and increase consistency of antibody identification in our hospital blood banks. Although the ReACT kit was withdrawn from the market soon after completion of our study, the advantages and limitations of the procedure warrant consideration should a similar product be reintroduced. The performance of the ReACT method was compared to conventional antibody detection by a standard tube agglutination technique that uses polyethylene glycol (PEG) potentiator (Dominion Biologicals Ltd., Dartmouth, Nova Scotia, Canada). Of 685 serum or plasma samples that were screened for antibodies, 96 samples were found by the PEG procedure to contain clinically significant (n = 70) and insignificant antibodies (n = 26). In contrast, 48 of the samples were found by the ReACT procedure to contain clinically significant (n = 39) and clinically insignificant antibodies (n = 9). For the ReACT method, the sensitivity was 48.8% (95% CI = 37.8%, 58.0%) and the specificity was 99.6% (95% CI = 97.5%, 99.9%), compared to the PEG procedure. While the ReACT microcolumn system was designed to limit detection of clinically insignificant antibodies, this study documents a loss of sensitivity for detection of clinically significant antibodies. 相似文献
48.
49.
Arterial endothelial function in a porcine model of early stage atherosclerotic vascular disease 总被引:2,自引:0,他引:2
Turk JR Henderson KK Vanvickle GD Watkins J Laughlin MH 《International journal of experimental pathology》2005,86(5):335-345
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and is projected to become the leading cause of mortality in the world. Atherosclerosis is the most important single factor contributing to this disease burden. In this study, we characterize relationships between endothelial dysfunction and vascular disease in an animal model of diet-induced, early-stage atherosclerotic vascular disease. We tested the hypothesis that hypercholesterolaemia induces vascular disease and impairs endothelium-dependent relaxation (EDR) in conduit arteries of adult male Yucatan pigs. Pigs were fed a normal fat (NF) or high fat cholesterol (HFC) diet for 20-24 weeks. Results indicate that, while the HFC diet did not alter EDR in femoral or brachial arteries, EDR was significantly decreased in both carotid and coronary arteries. Sudanophilic fatty streaks were significantly present in the abdominal aorta and common carotid artery. Histopathology revealed increased intima-media thickness (IMT) and foam cell accumulation in Stary Stage I-III lesions in the abdominal aorta, common carotid artery and femoral arteries. In the coronary arteries, the accumulation of foam cells in Stary Stage I and II lesions resulted in a trend for increased IMT. There was no evidence of vascular disease in the brachial arteries. These results indicate that early stages of CVD (Stary Stage I-III) precede decreases in EDR induced by HFC diet, because femoral arteries exhibited foam cell accumulation and an increased IMT but no change in endothelial function. 相似文献
50.
Meyer-Fernandes JR Saad-Nehme J Peres-Sampaio CE Belmont-Firpo R Bisaggio DF Do Couto LC Fonseca De Souza AL Lopes AH Souto-Padrón T 《Parasitology research》2004,93(1):41-50
In this work, we describe the ability of living epimastigotes of Trypanosoma cruzi to hydrolyze extracellular ATP. In these intact parasites, there was a low level of ATP hydrolysis in the absence of any divalent metal (2.42±0.31 nmol Pi/h×108 cells). ATP hydrolysis was stimulated by MgCl2, and the Mg-dependent ecto-ATPase activity was 27.15±2.91 nmol Pi/h×108 cells. The addition of MgCl2 to the extracellular medium increased the ecto-ATPase activity in a dose-dependent manner. This stimulatory activity was also observed when MgCl2 was replaced by MnCl2, but not by CaCl2 or SrCl2. The apparent Km for Mg-ATP2– was 0.61 mM, and free Mg2+ did not increase the ecto-ATPase activity. This ecto-ATPase activity was insensitive to the inhibitors of other ATPase and phosphatase activities. To confirm that this Mg-dependent ATPase was an ecto-ATPase, we used an impermeant inhibitor, DIDS (4, 4.diisothiocyanostylbene 2-2-disulfonic acid) as well as suramin, an antagonist of P2 purinoreceptors and inhibitor of some ecto-ATPases. These two reagents inhibited the Mg2+-dependent ATPase activity in a dose-dependent manner. A comparison among the Mg2+-ecto-ATPase activities of the three forms of T. cruzi showed that the noninfective epimastigotes were less efficient at hydrolyzing ATP than the infective trypomastigote and amastigote stages. 相似文献