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951.
Liancai Mu Jun Wang Hungxi Su Ira Sanders 《The journal of histochemistry and cytochemistry》2007,55(3):199-207
The functional upper esophageal sphincter (UES) is composed of the cricopharyngeus muscle (CP), the most inferior part of the inferior pharyngeal constrictor (iIPC), and the upper esophagus (UE). This sphincter is collapsed and exhibits sustained muscle activity in the resting state; it only relaxes and opens during swallowing, vomiting, and belching. The tonic contractile properties of the UES suggest that the skeletal muscle fibers in this sphincter differ from those in the limb and trunk muscles. In this study, myosin heavy chain (MHC) composition in the adult human UES muscles obtained from autopsies was investigated using immunocytochemical and immunoblotting techniques. Results showed that the adult human UES muscle fibers expressed unusual MHC isoforms such as slow-tonic (MHC-ton), alpha-cardiac (MHC-alpha), neonatal (MHC-neo), and embryonic (MHC-emb), which coexisted with the major MHCs (i.e., MHCI, IIa, and IIx). MHC-ton and MHC-alpha were coexpressed predominantly with slow-type I MHC isoform, whereas MHC-neo and MHC-emb coexisted mainly with fast-type IIa MHC. A slow inner layer (SIL) and a fast outer layer (FOL) in the iIPC and CP were identified immunocytochemically. MHC-ton- and MHC-alpha-containing fibers were concentrated mainly in the SIL, whereas MHC-neo- and MHC-emb-containing fibers were distributed primarily to the FOL. Identification of the specialized muscle fibers and their distribution patterns in the adult human UES is valuable for a better understanding of the physiological and pathophysiological behaviors of the sphincter. 相似文献
952.
Ira Verena Röder Valentina Lissandron Jessica Martin Yvonne Petersen Giulietta Di Benedetto Manuela Zaccolo Rüdiger Rudolf 《Cellular signalling》2009,21(5):819-826
Signalling through protein kinase A (PKA) triggers a multitude of intracellular effects in response to a variety of extracellular stimuli. To guarantee signal specificity, different PKA isoforms are compartmentalised by A-kinase anchoring proteins (AKAPs) into functional microdomains. By using genetically encoded fluorescent reporters of cAMP concentration that are targeted to the intracellular sites where PKA type I and PKA type II isoforms normally reside, we directly show for the first time spatially and functionally separate PKA microdomains in mouse skeletal muscle in vivo. The reporters localised into clearly distinct patterns within sarcomers, from where they could be displaced by means of AKAP disruptor peptides indicating the presence of disparate PKA type I and PKA type II anchor sites within skeletal muscle fibres. The functional relevance of such differential localisation was underscored by the finding of mutually exclusive and AKAP-dependent increases in [cAMP] in the PKA type I and PKA type II microdomains upon application of different cAMP agonists. Specifically, the sensors targeted to the PKA type II compartment responded only to norepinephrine, whereas those targeted to the PKA type I compartment responded only to α-calcitonin gene-related peptide. Notably, in dystrophic mdx mice the localisation pattern of the reporters was altered and the functional separation of the cAMP microdomains was abolished. In summary, our data indicate that an efficient organisation in microdomains of the cAMP/PKA pathway exists in the healthy skeletal muscle and that such organisation is subverted in dystrophic skeletal muscle. 相似文献
953.
The polarized distribution of functions in polarized cells requires the coordinated interaction of three machineries that modify the basic mechanisms of intracellular protein trafficking and distribution. First, intrinsic protein-sorting signals and cellular decoding machineries regulate protein trafficking to plasma membrane domains; second, intracellular signalling complexes define the plasma membrane domains to which proteins are delivered; and third, proteins that are involved in cell-cell and cell-substrate adhesion orientate the three-dimensional distribution of intracellular signalling complexes and, accordingly, the direction of membrane traffic. The integration of these mechanisms into a complex and dynamic network is crucial for normal tissue function and is often defective in disease states. 相似文献
954.
955.
Familial Danish Dementia (FDD) is an autosomal disease, which is distinguished by gradual loss of vision, deafness, progressive ataxia and dementia. Cataract is the first manifestation of the disease. In this article, we demonstrate a specific correlation between the poisoning of the chaperone activity of the rat eye lens alpha-crystallins, loss of lens transparency in organ culture by the pathogenic form of the Danish dementia peptide, i.e. the reduced Danish dementia peptide (redADan peptide), by a combination of ex vivo, in vitro, biophysical and biochemical techniques. The interaction of redADan peptide and lens crystallins are very specific when compared with another chaperone, HSP-70, underscoring the specificity of the pathogenic form of Danish dementia peptide, redADan, for the early onset of cataract in this disease. 相似文献
956.
OBJECTIVE: To compare data on the practices of molecular genetic testing (MGT) in laboratories in the United States with those in 18 other countries. METHODS: A Web-based survey of MGT laboratory directors (n = 827; response rate 63%) in 18 countries on three continents was carried out, and the response from U.S. laboratories compared to all others. Quality assurance and reporting indices were developed and calculated for each responding laboratory. RESULTS: A comparison of U.S. results with all other countries identified differences in laboratory setting, personnel qualifications, and the specific tests being offered, but similar rates of adherence to MGT quality standards and reporting practices were found. The survey also documented substantial transborder flow of specimens, most commonly due to the lack of availability of the test in the United States or because the test was available only through a research protocol, highlighting the need for common reporting and practice guidelines for the international MGT community. CONCLUSION: The findings presented here provide further support for the need to consider the application of the Organisation for Economic Cooperation and Development (OECD) Guidelines and the establishment of compatible accreditation programs or equivalent mechanisms across national borders to ensure the quality of laboratory services and the clinical usefulness of molecular genetic test reports for referred specimens. 相似文献
957.
A drop assay for chemotaxis to cAMP confirms that both anterior-like cells (ALC) and prestalk cells (pst cells) respond to
cAMP gradients. We present evidence that the chemotactic response of both ALC and pst cells is suppressed by ammonia, but
a higher concentration of ammonia is required to suppress the response in pst cells. ALC show a chemotactic response to cAMP
when moving on a substratum of prespore cells in isolated slug posteriors incubated under oxygen. ALC chemotaxis on a prespore
cell substratum is suppressed by the same concentration of ammonia that suppresses ALC chemotaxis on the agar substratum in
drop assays. Chemotaxis suppression is mediated by the unprotonated (NH3) species of ammonia. The observed suppression, by ammonia, of ALC chemotaxis to cAMP supports our earlier hypothesis that
ammonia is the tip-produced suppressor of such chemotaxis. We discuss implications of ammonia sensitivity of pst cells and
ALC with regard to the movement and localization of ALC and pst cells in the slug and to the roles played by ALC in fruiting
body formation. In addition, we suggest that a progressive decrease in sensitivity to ammonia is an important part of the
maturation of ALC into pst cells. 相似文献
958.
Park TS Hu Y Noh HL Drosatos K Okajima K Buchanan J Tuinei J Homma S Jiang XC Abel ED Goldberg IJ 《Journal of lipid research》2008,49(10):2101-2112
Ceramide is among a number of potential lipotoxic molecules that are thought to modulate cellular energy metabolism. The heart is one of the tissues thought to become dysfunctional due to excess lipid accumulation. Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including animals with cardiac-specific overexpression of glycosylphosphatidylinositol (GPI)-anchored human lipoprotein lipase (LpL(GPI)). To test whether excess ceramide was implicated in cardiac lipotoxicity, de novo ceramide biosynthesis was inhibited pharmacologically by myriocin and genetically by heterozygous deletion of LCB1, a subunit of serine palmitoyltransferase (SPT). Inhibition of SPT, a rate-limiting enzyme in ceramide biosynthesis, reduced fatty acid and increased glucose oxidation in isolated perfused LpL(GPI) hearts, improved systolic function, and prolonged survival rates. Our results suggest a critical role for ceramide accumulation in the pathogenesis of lipotoxic cardiomyopathy. 相似文献
959.
Ackerman ME Chalouni C Schmidt MM Raman VV Ritter G Old LJ Mellman I Wittrup KD 《Cancer immunology, immunotherapy : CII》2008,57(7):1017-1027
The A33 antigen is a cell surface glycoprotein of the small intestine and colonic epithelium with homology to tight junction-associated
proteins of the immunoglobulin superfamily, including CAR and JAM. Its restricted tissue localization and high level of expression
have led to its use as a target in colon cancer immunotherapy. Although the antigen is also present in normal intestine, radiolabeled
antibodies against A33 are selectively retained by tumors in the gut as well as in metastatic lesions for as long as 6 weeks.
Accordingly, we have studied the trafficking and kinetic properties of the antigen to determine its promise in two-step, pretargeted
therapies. The localization, mobility, and persistence of the antigen were investigated, and this work has demonstrated that
the antigen is both highly immobile and extremely persistent—retaining its surface localization for a turnover halflife of
greater than 2 days. In order to explain these unusual properties, we explored the possibility that A33 is a component of
the tight junction. The simple property of surface persistence, described here, may contribute to the prolonged retention
of the clinically administered antibodies, and their uncommon ability to penetrate solid tumors. 相似文献
960.
Yamashita H Bharadwaj KG Ikeda S Park TS Goldberg IJ 《American journal of physiology. Endocrinology and metabolism》2008,295(3):E705-E713
Fatty acids (FAs) are acquired from free FA associated with albumin and lipoprotein triglyceride that is hydrolyzed by lipoprotein lipase (LpL). Hypertrophied hearts shift their substrate usage pattern to more glucose and less FA. However, FAs may still be an important source of energy in hypertrophied hearts. The aim of this study was to examine the importance of LpL-derived FAs in hypertensive hypertrophied hearts. We followed cardiac function and metabolic changes during 2 wk of angiotensin II (ANG II)-induced hypertension in control and heart-specific lipoprotein lipase knockout (hLpL0) mice. Glucose metabolism was increased in ANG II-treated control (control/ANG II) hearts, raising it to the same level as hLpL0 hearts. FA uptake-related genes, CD36 and FATP1, were reduced in control/ANG II hearts to levels found in hLpL0 hearts. ANG II did not alter these metabolic genes in hLpL0 mice. LpL activity was preserved, and mitochondrial FA oxidation-related genes were not altered in control/ANG II hearts. In control/ANG II hearts, triglyceride stores were consumed and reached the same levels as in hLpL0/ANG II hearts. Intracellular ATP content was reduced only in hLpL0/ANG II hearts. Both ANG II and deoxycorticosterone acetate-salt induced hypertension caused heart failure only in hLpL0 mice. Our data suggest that LpL activity is required for normal cardiac metabolic compensation to hypertensive stress. 相似文献