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PCSK9: an enigmatic protease   总被引:1,自引:0,他引:1  
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol metabolism by controlling the levels of low density lipoprotein (LDL) particles that circulate in the bloodstream. Several gain-of-function and loss-of-function mutations in the PCSK9 gene, that occur naturally, have been identified and linked to hypercholesterolemia and hypocholesterolemia, respectively. PCSK9 expression has been shown to be regulated by sterol regulatory element binding proteins (SREBPs) and statins similar to other genes involved in cholesterol homeostasis. The most critical finding concerning PCSK9 is that this protease is able to influence the number of LDL receptor molecules expressed on the cell surface. Studies have demonstrated that PCSK9 acts mainly by enhancing degradation of LDL receptor protein in the liver. Inactivation of PCSK9 in mice reduces plasma cholesterol levels primarily by increasing hepatic expression of LDL receptor protein and thereby accelerating clearance of circulating LDL cholesterol. The objective of this review is to summarize the current information related to the regulation and function of PCSK9 and to identify gaps in our present knowledge.  相似文献   

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Specific antibodies to laminin, type IV collagen, basement-membrane proteoglycan, and fibronectin have been used in immunofluorescence microscopy to study the development of basement membranes of the embryonic kidney. Kidney tubules are known to form from the nephrogenic mesenchyme as a result of an inductive tissue interaction. This involves a change in the composition of the extracellular matrix. The undifferentiated mesenchyme expresses in the composition of the extracellular matrix. The undifferentiated mesenchyme expresses fibronectin but no detectable laminin, type IV collagen, or basement-membrane proteoglycan. During the inductive interaction, basement-membrane specific components (laminin, type IV collagen, basement membrane proteoglycan) become detectable in the induced area, whereas fibronectin is lost. While the differentiation to epithelial cells of the kidney requires an inductive interaction, the development of the vasculature seems to involve an ingrowth of cells which throughout development deposits basement-membrane specific components, as well as fibronectin. These cells form the endothelium and possibly also the mesangium of the glomerulus, and contribute to the formation of the glomerular basement membrane. An analysis of differentiation of the kidney mesenchyme in vitro in the absence of circulation supports these conclusions. Because a continuity with vasculature is required for glomerular endothelial cell differentiation, it is possible that these cells are derived from outside vasculature.  相似文献   

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The concept of effective dose with its unit, the sievert, is frequently misunderstood. Originally conceived to simplify radiation protection management, this concept is also proposed for another and very ambitions objective: a quantitative evaluation of the risks of radio-induced diseases, whatever the dose, the dose rate, the nature of radiation.... However, using the sievert for the prediction of risks of cancer or hereditary diseases is hazardous, and errors of prediction have been observed these last decades, for example the lack of prediction of the number of thyroid cancer in the very young children after the Chernobyl accident, and the overestimation of the risks such as leukaemia, other cancer and hereditary diseases. What are one sievert and its subunits?  相似文献   

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Brefeldin A: deciphering an enigmatic inhibitor of secretion   总被引:25,自引:0,他引:25  
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The enigmatic urologic condition known as interstitial cystitis has an estimated prevalence of 0.01% to 0.50% of the female population. Its etiology is unknown but may involve microbiologic, immunologic, mucosal, neurogenic, and/or other, as yet undefined, agents. There is no gold standard for the diagnosis of interstitial cystitis; rather, it is a diagnosis of exclusion. It is impossible to provide a purely evidence-based treatment strategy, but review of available evidence suggests that conservative supportive therapy (including diet modification); oral treatment with pentosan polysulfate, amitriptyline, hydroxyzine, or cimetidine; and intravesical treatments with heparinoids, dimethyl sulfoxide, alkalized lidocaine, or bacille Calmette-Guérin may be effective in some patients.  相似文献   

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GIgantonoclea: an enigmatic Permian plant from North China   总被引:1,自引:0,他引:1  
Gigantonoclea is a distinctive and enigmatic plant from the Permian of North China proper, with an unusual frond architecture and a pollen organ and vascular structure which are unique; it demonstrates a sudden rise and a rapid extinction. This paper reviews previous work on Asian gigantopterids and describes new material from the Upper Permian of Shanxi Province, including a new type of pollen organ (Jiaochengia lagrelii) and two new species of frond (Gigantonoclea crenataG. pubescens). Jiaochengia shows opposite, dissected and rather modified microsporophylls, laxly aggregating into an independent organ, which is markedly different from ‘Gigantotheca’ from Fujian. This presents evidence of heterogeneity among Asian gigantopterids and partly supports a relationship with the Carboniferous Callistophytales. Jiaochengia sporangia have what may be the first record of a waxy covering on the outer surface of a fossil plant, which is interpreted to have functioned to repel water, to protect against fungal attack and to scatter light. According to Hickey's rule, the venation of true Gigantonoclea fronds consists of three orders of main veins (rachis, midvein and secondary veins) and two orders of anastomosing veins (tertiary veins and veinlets). Certain putative ‘Gigantonoclea’ species from South China and some peripheral areas of North China do not have this type of venation and are thus excluded from the genus. Frond dimorphism is common among gigantopterids in both North and South China and can be compared with the amphibious variation from submerged to emergent leaves in extant aquatic plants. G. pubescens has a thick, bi-layered adaxial cuticle with an indumentum covering with dense papillae and trichomes bases, and deeply sunken, papillate stomata, suggesting that it favoured more arid conditions. An observed gradient from pubescent to glabrate or even glabrous gigantopterid cuticle structures between North and South China suggests a change from xeric, mesic to humid habitats.  相似文献   

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In frozen sections of thyroid glands with Hashimoto's thyroiditis (HT) and Graves' disease (GD), infiltrating lymphocytes were tested for their expression of HLA-DR antigens as a marker of in situ activation. In a combination of indirect immunoperoxidase and direct immunofluorescence staining, most of the immunoglobulin D positive mature B cells were found to be DR positive (DR+) in both diseases. In HT, sizable portions of both helper/inducer T (Leu3+) and suppressor/cytotoxic T (Leu2+) cells were DR+ in interfollicular regions as well as in lymphocyte clusters and lymphoid follicles. In GD, the proportion of DR+ cells in the interfollicular Leu2+ population was significantly lower than that of HT. DR+ thyrocytes were seen in all 14 cases of HT and in 14 out of 16 cases of GD, especially in the vicinity of lymphocyte aggregates. The extent of their DR expression was not correlated with the percentage of DR+ cells in either T subset. These results indicate that a significant portion of infiltrating T cells are activated in autoimmune thyroid diseases, and there may be bidirectional interaction between DR+ thyrocytes and DR+ T cells. The difference in frequency of Leu2+ DR+ cells may account for the difference between the immunopathological features of HT and GD.  相似文献   

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The triosephosphate isomerase (TPI) functions at a metabolic cross-road ensuring the rapid equilibration of the triosephosphates produced by aldolase in glycolysis, which is interconnected to lipid metabolism, to glycerol-3-phosphate shuttle and to the pentose phosphate pathway. The enzyme is a stable homodimer, which is catalytically active only in its dimeric form. TPI deficiency is an autosomal recessive multisystem genetic disease coupled with hemolytic anemia and neurological disorder frequently leading to death in early childhood. Various genetic mutations of this enzyme have been identified; the mutations result in decrease in the catalytic activity and/or the dissociation of the dimers into inactive monomers. The impairment of TPI activity apparently does not affect the energy metabolism at system level; however, it results in accumulation of dihydroxyacetone phosphate followed by its chemical conversion into the toxic methylglyoxal, leading to the formation of advanced glycation end products. By now, the research on this disease seems to enter a progressive stage by adapting new model systems such as Drosophila, yeast strains and TPI-deficient mouse, which have complemented the results obtained by prediction and experiments with recombinant proteins or erythrocytes, and added novel data concerning the complexity of the intracellular behavior of mutant TPIs. This paper reviews the recent studies on the structural and catalytic changes caused by mutation and/or nitrotyrosination of the isomerase leading to the formation of an aggregation-prone protein, a characteristic of conformational disorders.  相似文献   

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KAP1 protein: an enigmatic master regulator of the genome   总被引:1,自引:0,他引:1  
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Tissue microarray (TMA) is a high throughput analysis tool to identify new diagnostic and prognostic markers in human cancers. However, standard automated method in tumour detection on both routine histochemical and immunohistochemistry (IHC) images is under developed. This paper presents a robust automated tumour cell segmentation model which can be applied to both routine histochemical tissue slides and IHC slides and deal with finer pixel-based segmentation in comparison with blob or area based segmentation by existing approaches. The presented technique greatly improves the process of TMA construction and plays an important role in automated IHC quantification in biomarker analysis where excluding stroma areas is critical. With the finest pixel-based evaluation (instead of area-based or object-based), the experimental results show that the proposed method is able to achieve 80% accuracy and 78% accuracy in two different types of pathological virtual slides, i.e., routine histochemical H&E and IHC images, respectively. The presented technique greatly reduces labor-intensive workloads for pathologists and highly speeds up the process of TMA construction and provides a possibility for fully automated IHC quantification.  相似文献   

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The tribeDrypeteae, whose traditional assignment inPhyllanthoideae ofEuphorbiaceae is now doubtful, is studied embryologically on the basis of a literature survey and examination of six additional species in two of the four constituent genera.Drypeteae are characterized by having several embryological features that are unknown in otherPhyllanthoideae, such as a two- or three-celled ovule archesporium; a thin, two cell-layered parietal layer in the nucellus; no nucellar beak or cap; an early disintegrating nucellar tissue; thick, multiplicative, inner and outer integuments; an endothelium; a few discrete vascular bundles in the outer integument; and a fibrous exotegmen (or its derived state). EmbryologicallyDrypeteae do not fit within thePhyllanthoideae and, as available nucleotide sequence data from therbcL gene suggest, are rather placed nearErythroxylaceae, Rhizophoraceae, Chrysobalanaceae, andLinaceae. Drypeteae share with those families a combination of the fibrous exotegmen, the endothelium, and the thick, multiplicative inner integument.  相似文献   

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The hypochord of the axolotl embryo is first visible at an early tailbud stage, forming a rod-like structure, situated immediately under the notochord. A profusion of extracellular matrix fibrils is attached to the dorsolateral regions of the hypochord, linking it with the somites. A basal lamina develops around the hypochord, indicating an epithelial type of cell differentiation. Abundant rough endoplasmic reticula in the hypochord cells suggest lively synthetic activity. Prospective endoderm cells were vitally labeled with the lipophilic dye 1,1-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine perchlorate (DiD) at the gastrula stage. Cells labeled with the dye were later found in the hypochord as well as in the gut endoderm. This shows that the hypochord is of endodermal origin, contrary to recent suggestions that the hypochord is of mesodermal origin, but consistent with histological data. After about 8 days of existence, the hypochord disappears. Experimental results, using an apoptosis detection kit, indicate that the hypochord cells may disintegrate by a type of apoptotic cell death. The close association between the hypochord and developing dorsal aorta suggests that the hypochord could be involved in the positioning of the dorsal aorta, which forms under it. J Morphol 232:57–66, 1997. © 1997 Wiley-Liss, Inc.  相似文献   

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In the cerebellum, the isoenzyme II of carbonic anhydrase (CAII) appears to be a specific oligodendrocyte marker. Formation and maturation of oligodendrocytes during the postnatal development of rat cerebellum were followed by using specific immune serum directed against CAII for immunohistofluorescence and radioimmunoassay. Few oligodendrocytes are present in the cerebellum of the newborn rat. Their number increases rapidly between the fourth and the tenth days after birth and then more slowly until the end of the third week. Sequential changes in oligodendrocyte morphology have been observed. Determinations of CAII in cerebellar homogenate by radioimmunoassay show that the CAII level is low from birth to the end of the second week, the increase in the number of oligodendrocytes being accompanied by a small increase in the CAII level. Subsequent cell maturation is accompanied by significant accumulation of CAII.  相似文献   

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The distribution of cellulosomal cohesin domains among the sequences currently compiled in various sequence databases was investigated. Two cohesin domains were detected in two consecutive open reading frames (ORFs) of the recently sequenced genome of the archaeon Archaeoglobus fulgidus. Otherwise, no cohesin-like sequence could be detected in organisms other than those of the Eubacteria. One of the A. fulgidus cohesin-containing ORFs also harbored a dockerin domain, but the additional modular portions of both genes are undefined, both with respect to sequence homology and function. It is currently unclear what function(s) the putative cohesin and dockerin-containing proteins play in the life cycle of this organism. In particular, since A. fulgidus contains no known glycosyl hydrolase gene, the presence of a cellulosome can be excluded. The results suggest that cohesin and dockerin signature sequences cannot be used alone for the definitive identification of cellulosomes in genomes.  相似文献   

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