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1.
We have investigated whether the greater ability of forskolin to activate adenylate cyclase (EC 4.6.1.1) from rat heart compared with rat lung is due to interactions between G-proteins and catalytic units, isoforms of catalytic units or membrane-protein interactions. Interactions between Gs and catalytic units were found to be similar in both tissues with 10 microM Gpp(NH)p increasing activity up to 5-fold. While MnCl2 increased the response of the lung enzyme to forskolin, it reduced the response of the cardiac enzyme and uncoupled Gs from the cardiac catalytic units indicating that Gs interactions potentiate the response to forskolin. After enzyme solubilisation with n-octyl-beta-D-glucopyranoside, the response to forskolin was identical in heart and lung whether assayed with magnesium or manganese chloride, and not significantly different from the heart membrane enzyme. Overall, the results show that the relatively poor response of lung adenylate cyclase to forskolin is due to specific inhibitory interactions between the enzyme and lung membrane constituents. 相似文献
2.
3.
The thymidylate synthase (TS) inhibitor ICI D1694 (N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N -methylamino]-2 - thenoyl)-S-glutamic acid) is a structural analogue of the substrate N5,N10-methylenetetrahydrofolate (5,10-CH2FH4) and is currently under clinical evaluation as a treatment for cancer. The compound is shown here to be a mixed non-competitive inhibitor of TS from murine leukemia (L1210) cells when 5,10-CH2FH4 is varied. This result suggests formation of an inactive complex between TS, 5,10-CH2FH4 and the inhibitor. Thus, binding to only one of the two active sites on the TS homodimer may be sufficient to prevent catalysis fully. Treatment of L1210 cells with ICI D1694 is known to cause intracellular accumulation of the tetraglutamate derivative which is shown here to have a 60-fold higher affinity for TS. The IC50 for inhibition of L1210 cell growth is below the Ki value of ICI D1694 for L1210 TS but above that of the tetraglutamate. The formation of polyglutamates and concentration of drug inside cells, therefore, seem to be responsible for biological activity. 相似文献
4.
J B Ball T L Nero D Iakovidis L Tung G Jackman W J Louis 《Journal of medicinal chemistry》1992,35(25):4676-4682
Anomalously low affinities for the beta-1-adrenoceptor are seen for members of a series of para-substituted N-isopropylphenoxypropanolamines in which the substituent is able to conjugate with the aromatic ring. The energy of conjugation was calculated using the AM1 semiempirical molecular orbital method and appears to correlate with the loss of binding energy, and hence affinity for the receptor. This suggests that binding is associated with movement of the substituent out of the plane of the aromatic ring due to steric interference with the receptor. A previously unrecognized binding site for aromatic groups off the para position is also identified. 相似文献
5.
6.
Investigation of an outbreak of Salmonella enteritidis gastroenteritis associated with consumption of eggs in a restaurant chain in Maryland 总被引:6,自引:0,他引:6
F Y Lin J G Morris D Trump D Tilghman P K Wood N Jackman E Israel J P Libonati 《American journal of epidemiology》1988,128(4):839-844
Salmonella enteritidis ser. enteritidis was isolated from patrons and employees of three restaurants in a restaurant chain in Maryland during August and September 1985. Isolates from all three restaurants had identical plasmid profiles; this profile was present in 13 of 40 randomly selected S. enteritidis isolates received by the Maryland state health department laboratory during a comparable time period. The outbreak in one restaurant resulted in at least 71 illnesses, with 17 persons known to have been hospitalized. Scrambled eggs served on a "breakfast bar" were implicated as the vehicle of transmission in this restaurant, with eggs a possible vehicle in another of the three restaurants. The data point out the risks associated with improper handling of eggs in food service establishments, provide further evidence for the observed association between S. enteritidis and eggs in the northeastern United States, and demonstrate the utility of plasmid analysis in investigation of outbreaks involving common Salmonella serotypes. 相似文献
7.
8.
Competitive control of the self-renewing T cell repertoire 总被引:1,自引:0,他引:1
We develop a mathematical model for the self-renewing part of the T cell
repertoire. Assuming that self-renewing T cells have to be stimulated by
immunogenic MHC-peptide complexes presented on the surfaces of
antigen-presenting cells, we derive a model of T cell growth in which
competition for MHC-peptide complexes limits T cell clone sizes and
regulates the total number of self-renewing T cells in the animal. We show
that for a sufficient diversity and/or degree of cross-reactivity, the
total T cell number hardly depends upon the diversity of the T cell
repertoire or the diversity of the set of presented peptides. Conversely,
for repertoires of lower diversity and/or cross-reactivity, steady-state
total T cell numbers may be limited by the diversity of the T cells. This
provides a possible explanation for the limited repertoire expansion in
some, but not all, mouse T cell re-constitution experiments. We suggest
that the competitive interactions described by our model underlie the
normal T cells numbers observed in transgenic mice, germ-free mice and
various knockout mice.
相似文献
9.
Localization of a gene for otosclerosis to chromosome 15q25-q26 总被引:5,自引:0,他引:5
Tomek MS; Brown MR; Mani SR; Ramesh A; Srisailapathy CR; Coucke P; Zbar RI; Bell AM; McGuirt WT; Fukushima K; Willems PJ; Van Camp G; Smith RJ 《Human molecular genetics》1998,7(2):285-290
Among white adults otosclerosis is the single most common cause of hearing
impairment. Although the genetics of this disease are controversial, the
majority of studies indicate autosomal dominant inheritance with reduced
penetrance. We studied a large multi- generational family in which
otosclerosis has been inherited in an autosomal dominant pattern. Five of16
affected persons have surgically confirmed otosclerosis; the remaining nine
have a conductive hearing loss but have not undergone corrective surgery.
To locate the disease- causing gene we completed genetic linkage analysis
using short tandem repeat polymorphisms (STRPs) distributed over the entire
genome. Multipoint linkage analysis showed that only one genomic region, on
chromosome 15q, generated a lod score >2.0. Additional STRPs were typed
in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and
D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis
gene.
相似文献
10.
IMPT1, an imprinted gene similar to polyspecific transporter and multi- drug resistance genes 总被引:5,自引:1,他引:5
Dao D; Frank D; Qian N; O'Keefe D; Vosatka RJ; Walsh CP; Tycko B 《Human molecular genetics》1998,7(4):597-608
Human chromosome 11p15.5 and distal mouse chromosome 7 include a
megabase-scale chromosomal domain with multiple genes subject to parental
imprinting. Here we describe mouse and human versions of a novel imprinted
gene, IMPT1 , which lies between IPL and p57 KIP2 and which encodes a
predicted multi-membrane-spanning protein similar to bacterial and
eukaryotic polyspecific metabolite transporter and multi- drug resistance
pumps. Mouse Impt1 and human IMPT1 mRNAs are highly expressed in tissues
with metabolite transport functions, including liver, kidney, intestine,
extra-embryonic membranes and placenta, and there is strongly preferential
expression of the maternal allele in various mouse tissues at fetal stages.
In post-natal tissues there is persistent expression, but the allelic bias
attenuates. An allelic expression bias is also observed in human fetal and
post-natal tissues, but there is significant interindividual variation and
rare somatic allele switching. The fact that Impt1 is relatively repressed
on the paternal allele, together with data from other imprinted genes,
allows a statistical conclusion that the primary effect of human chromosome
11p15.5/mouse distal chromosome 7 imprinting is domain-wide relative
repression of genes on the paternal homolog. Dosage regulation of the
metabolite transporter gene(s) by imprinting might regulate placental and
fetal growth.
相似文献