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21.
22.
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
23.
Cloning and developmental expression analysis of the murine homolog of the spinocerebellar ataxia type 1 gene (Sca1) 总被引:2,自引:0,他引:2
Banfi S; Servadio A; Chung M; Capozzoli F; Duvick LA; Elde R; Zoghbi HY; Orr HT 《Human molecular genetics》1996,5(1):33-40
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant
neurodegenerative disorder caused by the expansion of a CAG trinucleotide
repeat which encodes glutamine in the novel protein ataxin-1. In order to
characterize the developmental expression pattern of SCA1 and to identify
putative functional domains in ataxin-1, the murine homolog (Sca1) was
isolated. Cloning and characterization of the murine Sca1 gene revealed
that the gene organization is similar to that of the human gene. The murine
and human ataxin-1 are highly homologous but the CAG repeat is virtually
absent in the mouse sequence suggesting that the polyglutamine stretch is
not essential for the normal function of ataxin-1 in mice. Cellular and
developmental expression of the murine homolog was examined using RNA in
situ hybridization. During cerebellar development, there is a transient
burst of Sca1 expression at postnatal day 14 when the murine cerebellar
cortex becomes physiologically functional. There is also marked expression
of Sca1 in mesenchymal cells of the intervertebral discs during development
of the spinal column. These results suggest that the normal Sca1 gene, has
a role at specific stages of both cerebellar and vertebral column
development.
相似文献
24.
JE Robb LA Rymaszewski HB Bentley PT Donnan 《Surgical and radiologic anatomy : SRA》1991,13(3):181-185
Summary This study investigated the effect of tilt and observer reliability on radiographic measurements of the position of a prosthetic acetabular cup in seven dry bone pelves using the teardrop as a landmark. Coronal or sagittal tilt of more than five degrees was easily recognisable and there was effectively no observer variation in the measurements up to this limit. In addition, 90 out of 100 randomly selected antero-posterior pelvic radiographs from an outpatient department were not significantly rotated and 93 demonstrated a clearly defined teardrop. Measurements about the teardrop on routine radiographs are therefore sufficiently accurate to allow assessment of prosthetic position.
La valeur du sourcil cotyloidien comme repère d'analyse radiologique
Résumé Cette étude, conduite sur 7 bassins secs, apprécie l'effet de l'inclinaison du bassin sur la qualité de l'analyse radiographique de la position d'une cupule prothétique de hanche en utilisant le sourcil cotyloïdien comme repère. Une inclinaison du bassin dans les plans coronal et sagittal est aisément détectable et il n'existe pas de variation d'analyse entre les différents observateurs en dessous de 5° d'inclinaison. De plus, sur 100 radiographies antéro-postérieures de bassin choisies au hasard dans les dossiers de consultation, 90 avaient été réalisées sans incidence particulièrement adaptée et l'on pouvait repérer facilement le sourcil sur 93% d'entre elles. Les mesures faites sur des radios de routine sont donc suffisamment précises pour permettre l'évaluation de la position d'une prothèse à partir du sourcil cotyloïdien.相似文献
25.
A. PIONA L. LA ROSA A. TINCANI D. FADEN† G. MAGRO‡ S. GRASSO‡ F. NICOLETTI G. BALESTRIERI P. L. MERONI 《Scandinavian journal of immunology》1995,41(5):427-432
In the present study we evaluated the effect of passive transfer of a mouse monoclonal (CAM) or a human polyclonal anti-cardiolipin IgG on pregnancy outcome in BALB/c mice. The mice were immunized through the tail vein immediately after mating with 10 μg of monoclonal or polyclonal anti-cardiolipin antibodies. Two other groups of mice were given a mouse irrelevant monoclonal antibody or normal human polyclonal IgG respectively, at the same dose. In mice immunized with monoclonal or polyclonal anti-cardiolipin antibody we observed a significant increase in the number of fetal resorptions and a significant reduction of the mean weights of the embryos and the placentas. In mice immunized with CAM we also found a significant decrease in the number of healthy pups, while mice infused with human aCL antibody expressed a significant reduction in the fecundity rate. The histological examination showed widespread thrombosis and necrosis in the placentas derived from the mice immunized with the anti-cardiolipin antibodies. The model supports a possible direct pathogenetic effect of anti-phospholipid antibodies in recurrent fetal loss and points out that thrombotic events at placental level can be instrumental in the pathogenesis of the obstetric complications. 相似文献
26.
Rodent models of rheumatoid arthritis (RA) are useful tools to study the pathogenic process of RA. Among the most widely used models of RA are the streptococcal cell wall (SCW) arthritis model and the collagen-induced arthritis (CIA). Both innate and adaptive immune mechanisms are involved in these rodent models. While no models perfectly duplicate the condition of human RA, they are easily reproducible, well defined and have proven useful for development of new therapies for arthritis, as exemplified by cytokine blockade therapies. Besides SCW and CIA models, there are numerous others including transgenic models such as K/BxN, induced models such as adjuvant-induced and pristane models, and spontaneous models in certain mouse strains, that have been used to help understand some of the underlying mechanisms. This review provides an update and analysis of RA models in mice and rats. The array of models has provided rheumatologists and immunologists a means to understand the multifactorial disease in humans, to identify new drug targets, and to test new therapies. 相似文献
27.
Debelenko LV; Brambilla E; Agarwal SK; Swalwell JI; Kester MB; Lubensky IA; Zhuang Z; Guru SC; Manickam P; Olufemi SE; Chandrasekharappa SC; Crabtree JS; Kim YS; Heppner C; Burns AL; Spiegel AM; Marx SJ; Liotta LA; Collins FS; Travis WD; Emmert-Buck MR 《Human molecular genetics》1997,6(13):2285-2290
Lung carcinoids occur sporadically and rarely in association with multiple
endocrine neoplasia type 1 (MEN1). There are no well defined genetic
abnormalities known to occur in these tumors. We studied 11 sporadic lung
carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene
on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy
fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was
studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene
were inactivated. All four tumors showed the presence of a MEN1 gene
mutation and loss of the other allele. Observed mutations included a 1 bp
insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide
substitution affecting a donor splice site. Each mutation predicts
truncation or potentially complete loss of menin. The remaining seven
tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH.
The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a
complex germline MEN1 gene mutation. The data implicate the MEN1 gene in
the pathogenesis of sporadic lung carcinoids, representing the first
defined genetic alteration in these tumors.
相似文献
28.
Long Evans rats were trained to discriminate 0.2 mg/kg IP (±)-rolipram from vehicle injection in a food-motivated two-lever operant task. Eight out of nine rats acquired the discrimination after an average of 91 sessions (min 65, max 137). The ED50 of (±)-rolipram was 0.06 mg/kg IP. Generalization tests with (–)- and (+)-rolipram showed that the (–)-isomer was 8 times more active than (+)-rolipram with an ED50 of 0.06 and 0.4 mg/kg IP respectively. The phosphodiesterase inhibitor RO 20-1724 partially (83%) generalized to (±)-rolipram in doses of 0.6 and 1.0 mg/kg IP. IBMX 5 mg/kg IP showed 63% generalization. Tests with imipramine and the (+)- and (–)-isomer of the noradrenaline uptake inhibitor oxaprotiline suggest that NA-uptake inhibiting drugs do not form an interoceptive cue which is (±)-rolipram-like. dbcAMP 12.5 mg/kg SC and 100 mg/kg SC dbcGMP did not generalize to the training drug. The nature of the discriminative stimulus produced by this dose of (±)-rolipram in rats remains to be elucidated.
Offprint requests to: R. Ortman 相似文献
29.
R. Ortmann M. Schaub A. Felner J. Lauber P. Christen P. C. Waldmeier 《Psychopharmacology》1984,84(1):22-27
Stereotyped sniffing behavior together with forepaw padding — defined as the -phenylethylamine (PEA) syndrome — is induced by MAO-B inhibitors in rats injected with 30 mg/kg IP PEA. The comparison of the abilities of the MAO-B inhibitors to induce the syndrome and to inhibit MAO-B in rat brain homogenates indicated that at least 75% of MAO-B activity in rat brain had to be inhibited to induce the PEA syndrome. A good correlation was found between the abilities of MAO-B inhibitors to induce the behavioral syndrome and to increase levels of PEA in rat brain. Specific MAO-A inhibitors potentiated the behavioral effect of the MAO-B inhibitor deprenyl, while they did not induce the syndrome themselves or only at very high doses. Inhibitors of the reuptake of 5-HT or noradrenaline were inactive under the described experimental conditions. This behavioral test system seems to be useful in vivo screening test in rats for detecting compounds with strong MAO-B inhibiting activity. 相似文献
30.
目的:应用微乳液反应法制备磺胺嘧啶银均匀微晶,均匀制得的微晶的粒径大小约为2~4um,均匀微晶的结晶性好,纯度高。用均匀设计方法优化条件,制备的均匀的微晶平均粒径大小为2.09um,实验结果达到预测结果要求。结论:用微乳液反应法能获得磺胺嘧啶银均匀微晶。 相似文献