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51.
Burwinkel B; Maichele AJ; Aagenaes O; Bakker HD; Lerner A; Shin YS; Strachan JA; Kilimann MW 《Human molecular genetics》1997,6(7):1109-1115
Glycogen storage disease due to phosphorylase kinase deficiency occurs in
several variants that differ in mode of inheritance and tissue-
specificity. This heterogeneity is suspected to be largely due to mutations
affecting different subunits and isoforms of phosphorylase kinase. The gene
of the ubiquitously expressed beta subunit, PHKB, was a candidate for
involvement in autosomally transmitted phosphorylase kinase deficiency of
liver and muscle. To identify such mutations, the complete PHKB coding
sequence was amplified by RT-PCR of RNA isolated from blood samples of
patients and analyzed by direct sequencing of PCR products. The
characterization of mutations was complemented by PCR of genomic DNA. In
one female and four male patients, we identified five independent nonsense
mutations (Y418ter; R428ter; Y974H+E975ter; Q656ter in two cases), one
single-base insertion in codon N421, one splice-site mutation affecting
exon 31, and a large deletion involving the loss of exon 8. Although these
severe translation-disrupting mutations occur in constitutively expressed
sequences of the only known beta subunit gene of phosphorylase kinase,
PHKB, they are associated with a surprisingly mild clinical phenotype,
affecting virtually only the liver, and relatively high residual enzyme
activity of approximately 10%.
相似文献
52.
Delivery of a hammerhead ribozyme specifically down-regulates the production of fibrillin-1 by cultured dermal fibroblasts 总被引:4,自引:1,他引:4
Kilpatrick MW; Phylactou LA; Godfrey M; Wu CH; Wu GY; Tsipouras P 《Human molecular genetics》1996,5(12):1939-1944
The hammerhead ribozyme is a small catalytic RNA molecule. Potential
hammerhead ribozymes that possess a catalytic domain and flanking sequence
complementary to a target mRNA can cleave in trans at a putative cleavage
site within the target molecule. We have investigated the potential of
hammerhead ribozymes to down-regulate the product of the fibrillin-1 gene
(FBN1). Fibrillin is a 347 kDa glycoprotein that is a major constituent of
the elastin-associated microfibrils. Mutations in the FBN1 gene are
responsible for Marfan syndrome (MFS), a common systemic disorder of the
connective tissue. Many FBN1 mutations responsible for MFS appear to act in
a dominant-negative fashion, raising the possibility that reduction of the
amount of product from the mutant FBN1 allele might be a valid therapeutic
approach for MFS. A trans-acting hammerhead ribozyme (FBN1-RZ1) targeted to
the 5' end of the human FBN1 mRNA has been designed and synthesized, and
shown to cleave its target efficiently in vitro. FBN1-RZ1 cleavage is
magnesium dependent and efficient at both 37 and 50 degrees C. Delivery of
the FBN1-RZ1 ribozyme into cultured dermal fibroblasts, by receptor-
mediated endocytosis of a ribozyme-transferrin-polylysine complex,
specifically reduces both cellular FBN1 mRNA and the deposition of
fibrillin in the extracellular matrix. These results suggest that the use
of hammerhead ribozymes is a valid approach to the study of fibrillin gene
expression and possibly to the development of a therapeutic approach to
MFS.
相似文献
53.
Colonization by indigenous microorganisms of the mucosal epithelia of the large bowels of suckling mice was followed by microbial culture techniques and by light, fluorescence, and electron microscopy. Certain microbes colonize in distinctive patterns the cecal and colonic epithelia in these mice. Coliforms and enterococci colonize the large bowel 7 to 9 days after birth and reach high population levels during the second week. During that period, these facultative anaerobes can be detected by immunofluorescence techniques in microcolonies in the mucin on the epithelium. During the third week, however, after their populations decline to the low levels characteristic of adult mice, coliforms and enteroccoci can be observed only infrequently in the mucous layer. Anaerobic fusiform-shaped bacteria appear in the mucous layers along with the microcolonies of enterococci and coliforms during the second week after birth. These anaerobes increase in numbers in the mucin until they form thick layers on the mucosal epithelium by the end of the third week. They remain in the mucous layer throughout the life of the normal mouse. Anaerobic spiral-shaped microbes also colonize the mucous layer on the cecal and colonic epithelium. But these organisms can be detected by immunofluorescence in 1-week-old mice, well in advance of the time the fusiform-shaped bacteria can be found. In the second week, the latter microbes co-inhabit the mucous layer with the spiral-shaped organisms. The fusiform- and spiral-shaped microbes remain associated in the mucin on the cecal and colonic mucosal epithelia into the adult life of mice. 相似文献
54.
D D Savage W L Henry J R Mitchell A A Taylor J M Gardin J I Drayer J H Laragh 《Journal of the National Medical Association》1979,71(7):709-712
Echocardiography was used to compare cardiac structure and function in 35 pairs of hypertensive blacks and hypertensive whites matched for age, sex, level and known duration of hypertension, treatment status, and renin level. 相似文献
55.
Protective cytotoxic T lymphocyte responses against paramyxoviruses induced by epitope-based DNA vaccines: involvement of IFN-gamma 总被引:1,自引:0,他引:1
Hsu SC; Obeid OE; Collins M; Iqbal M; Chargelegue D; Steward MW 《International immunology》1998,10(10):1441-1447
Plasmid DNA vectors have been constructed with minigenes encoding a single
cytotoxic T lymphocyte (CTL) epitope from either the M2 protein of
respiratory syncytial virus (RSV) or from the nucleoprotein of measles
virus (MV) with or without a signal sequence (also called secretory or
leader sequence). Following intradermal immunization, plasmids in which the
CTL epitopes were expressed in-frame with the signal sequence were more
effective at inducing peptide- and virus- specific CTL responses than
plasmids expressing CTL epitopes without the signal sequence. This
immunization resulted in protection against MV-induced encephalitis and a
significant reduction in viral load following RSV challenge. The reduction
of viral load following RSV challenge was abrogated by prior injection with
anti-IFN-gamma antibodies. These results highlight the ability of
epitope-based DNA immunization to induce protective immune responses to
well-defined epitopes and indicate the potential of this approach for the
development of vaccines against infectious diseases.
相似文献
56.
Wang D Alpard SK Savage C Yamani HN Deyo DJ Nemser S Zwischenberger JB 《ASAIO journal (American Society for Artificial Internal Organs : 1992)》2003,49(6):673-677
A new perfluorocopolymer coating for micropore hollow fiber gas exchangers was developed to improve gas exchange, reduce plasma leakage, and reduce blood-surface interactions. The present authors evaluated gas exchanger performance using this new coating in a prospective, randomized, controlled, unblinded, large animal model of CO2 retention. Adult sheep (30-40 kg), under general anesthesia, underwent cannulation of the carotid artery (12 F) and jugular vein (14 F). The perfluorocopolymer coated (n = 5) and uncoated (n = 5) gas exchangers were attached to an arteriovenous CO2 removal (AVCO2R) circuit. Blood gases, CO2 removal, and hemodynamics were monitored throughout the 6 hour study. Average CO2 removal was 107.6 +/- 15.6 ml/min (coated) vs. 93.0 +/- 13.9 ml/min (uncoated; p < 0.01). PaCO2 and CO2 removal for both coated and uncoated did not deteriorate significantly over the study. Average AVCO2R blood flow was 1,130 +/- 25 ml/min (coated) versus 1,101 +/- 79 ml/min (uncoated; p = not significant). Likewise, cardiac output and AVCO2R blood flow did not change over the duration of the study. No significant differences in the pressure gradient or resistance between devices (coated, 6.89 +/- 1.14 mm Hg/L/min; uncoated, 6.42 +/- 0.23 mm Hg/L/min) was noted. The authors concluded that the new perfluorocopolymer coated gas exchanger improved CO2 removal without compromising hemodynamics in an acute performance evaluation. 相似文献
57.
58.
Heckers S Rauch SL Goff D Savage CR Schacter DL Fischman AJ Alpert NM 《Nature neuroscience》1998,1(4):318-323
Poor attention and impaired memory are enduring and core features of schizophrenia. These impairments have been attributed either to global cortical dysfunction or to perturbations of specific components associated with the dorsolateral prefrontal cortex (DLPFC), hippocampus and cerebellum. Here, we used positron emission tomography (PET) to dissociate activations in DLPFC and hippocampus during verbal episodic memory retrieval. We found reduced hippocampal activation during conscious recollection of studied words, but robust activation of the DLPFC during the effort to retrieve poorly encoded material in schizophrenic patients. This finding provides the first evidence of hippocampal dysfunction during episodic memory retrieval in schizophrenia. 相似文献
59.
Microbial interference and colonization of the murine gastrointestinal tract by Listeria monocytogenes. 总被引:2,自引:0,他引:2
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Two strains of Listeria monocytogenes, one that formed smooth colonies on agar surfaces and a varient of it that formed rough colonies, colonized the gastrointestinal tracts of germfree mice. Within 24 h after mice were inoculated orally with about 100 bacteria, the population levels per gram (wet weight) of tissue of both strains were 10(5) to 10(7) in the stomach and ileum and 10(8) to 10(9) in the cecum and colon, respectively. As detected in Gram-stained histological sections, in such gnotobiotes, the bacteria colonized the lumen in all areas of the tract and much of the mucus layer on the epithelial surface in the proximal colon. The strain that formed smooth colonies did not colonize the tracts of specific-pathogen-free mice, but did colonize, to the same levels as in germfree mice, the stomachs and bowels of ex-germfree mice previously associated with two members of the indigenous flora (Bacteroides and Clostridium). In the latter animals, however, the listeria did not form layers on the colonic epithelium as efficiently as they did in monoassociated gnotobiotes. 相似文献
60.
Savage ND Harris SH Rossi AG De Silva B Howie SE Layton GT Lamb JR 《European journal of immunology》2002,32(10):2905-2914
The generation of a productive primary immune response is dependent on the ability of na?ve T lymphocytes to recirculate through peripheral lymph organs to encounter specific antigen. The process of na?ve CD4(+) T cell entry into lymph nodes correlates with cell surface expression of L-selectin (CD62L), which mediates early tethering and rolling events to endothelium prior to entry. Here, we demonstrate that surface expression of CD62L enhances CD4(+) T cell activation in vitro. The synthetic hydroxamate metalloproteinase inhibitor (BB-3103), specifically inhibits activation-induced shedding of CD62L from CD4(+) T cells by TCR cross-linking and lowers proliferation in part by reducing rapid tyrosine phosphorylation of zeta-associated protein 70 kDa (ZAP-70) and by increasing cytosolic free Ca(2+) concentration mobilization. BB-3103 also inhibited the proliferative response of both murine CD4(+) Th1 and Th2 subsets in vitro but the inhibitory effects were sustained only in Th2-type cells. Similarly, BB-3103 mediated prolonged inhibition of allergen-dependent peripheral T cell proliferation in atopic dermatitis patients but not in healthy controls. Analysis of CD62L expression on murine CD4(+) T cell subsets revealed that surface expression was maintained on Th1 cells but not Th2 cells. The differential effects of BB-3103 on primed effector CD4(+) T cells may provide new insights into generating therapeutic agents capable of redressing the Th2/Th1 imbalance in allergic diseases. 相似文献