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101.
Wilkie SE Newbold RJ Deery E Walker CE Stinton I Ramamurthy V Hurley JB Bhattacharya SS Warren MJ Hunt DM 《Human molecular genetics》2000,9(20):3065-3073
Three different mutations in codon 838 of GUCY2D, the gene for retinal guanylate cyclase 1, have been linked to autosomal dominant cone-rod dystrophy at the CORD6 locus. To examine the relationship between enzyme activity and disease severity, the three disease-causing substitutions (R838C, R838H and R838S) and four artificial mutations (R838A, R838E, R838L and R838K) were generated. Assay of GCAP1-stimulated cyclase activity in vitro shows that, compared with wild-type, R838E, R838L and R838K possess only low activity, whereas R838A, R838C, R838H and R838S have activity equal or superior to wild-type at low Ca(2+) concentrations. These four latter mutants showed a higher apparent affinity for GCAP1 than did wild-type. The Ca(2+) sensitivity of the GCAP1 activation was also altered with marked residual activity at high Ca(2+), the effect increasing: wild-type < R838C < R838H < R838A < R838S. Within the photoreceptor, this would result in a failure to inactivate cyclase activity at high physiological Ca(2+ )concentrations. Amongst the three disease-associated mutations, the effect correlates directly with disease severity. The wild-type and R838H mutant displayed a difference in pH sensitivity, with the mutant showing a higher specific activity with pH > 6.0. Site 838 is in the dimerization domain that forms a coiled-coil in the active protein. A computer-aided structure prediction of this region indicates that R838 in the wild-type breaks the structure at four helical turns, and there is an increasing tendency for the structure to continue for further turns in the order R838C < R838H,S,K < R838E < R838A < R838L. 相似文献
102.
J B Little E P Radford H L McCombs V R Hunt 《The New England journal of medicine》1965,273(25):1343-1351
Concentrations of the alpha-particle-emitting radioactive element polonium was measured in various pulmonary tissues of smokers and nonsmokers in order to determine 1) whether this radiation exposure is associated with the development of bronchial cancer in smokers; and 2) how smoke is absorbed and excreted in human lungs. Lung specimens from 25 current cigarette smokers, 2 current pipe smokers, 1 former cigarette smoker, and 8 nonsmokers ere analyzed. The average concentration of polonium in the peripheral parenchyma of current smokers was .0074 picocurie/gm and in nonsmokers was .0016. For smokers, the average concentration was doubled in more centrally located parenchyma and was greater in the upper than in the lower lobes. Polonium concentrations correlated with daily cigarette consumption but not with total cigarettes smoked. The concentrations in peribronchial lymph nodes of smokers were also higher than in nonsmokers. These values show no correlation with total or daily cigarette consumption. Polonium concentration was similiar in bronchial wall parenchyma as in lung parenchyma but was greater in bronchial epithelium than in parenchymal or lymph nodes. The patterns of distribution of polonium throughout the lung suggest that most inhaled smoke particles are rapidly cleared from the lung, and polonium is primarily cleared by mucus sheet. Since the highest local concentrations of polonium were found in bronchial epithelium from segmental bifurcations, leading to a high cumulative local radiation dose, polonium may be implicated in the initiation of bronchial cancer in humans. 相似文献
103.
The cellular receptor of subgroup B avian leukosis virus (ALVB) is encoded by a gene at the tumour virus B (TVB) locus. TVB alleles encode specific receptors permitting infection by exogenous ALVB or avian leukosis virus subgroup D (ALVD) as well as endogenous avian leukosis virus subgroup E (ALVE), and thus susceptibility is dominant to resistance. Two single nucleotide polymorphisms at the TVB locus have been reported distinguishing three TVB alleles (TVB*S1, TVB*S3 and TVB*R). We have developed a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay using the two single nucleotide polymorphisms to define three observed allelic haplotypes and to identify the six possible TVB genotypes consisting of the three haplotypes in defined laboratory strains of chickens. One additional potential allelic haplotype and four genotypes were also briefly discussed. Chickens from parents heterozygous for different TVB alleles were challenged with Rous sarcoma viruses of subgroup ALVB and ALVE to induce wing-web tumours. Tumour incidences were evaluated between chickens of the genotypes determined with this newly developed PCR-RFLP assay. Importantly, chickens typed with this assay as TVB*S3/*S3 were resistant to infection by ALVE only, and those TVB*R/*R were resistant to both ALVE and ALVB. Furthermore, a vast majority of chickens with the susceptible TVB*S1/- genotypes developed a tumour. This PCR-RFLP assay enables a relatively rapid assessment of all six anticipated TVB genotypes in experimental strains of chickens undergoing segregation for TVB*S1, TVB*S3, and TVB*R alleles. This non-infectious assay should be further evaluated for the capacity to select and breed commercial chickens for genetic resistance to infections by ALVB, ALVD and ALVE. 相似文献
104.
Guimezanes A Barrett-Wilt GA Gulden-Thompson P Shabanowitz J Engelhard VH Hunt DF Schmitt-Verhulst AM Engelhardt VH 《European journal of immunology》2001,31(2):421-432
We studied the molecular basis for CD8 independence of in vivo generated (BM3.3) versus CD8 dependence of in vitro sensitized (KB5.C20/Des) alloreactive H-2K(b)-specific cytotoxic T lymphocytes (CTL). Using microcapillary high-performance liquid chromatography fractionation of H-2K(b) eluates, mass spectrometry and CTL reconstitution assays, we determined that BM3.3 and KB5.C20 recognize, respectively, a single peptide (pBM1) expressed on 8,000 H-2K(b) molecules per allogeneic cell, and three distinct peptides (pKB1, 2, 3), each expressed on around 200 H-2K(b) molecules per allogeneic cell. CD8 (in)dependence was intrinsic to the respective TCR/H-2K(b)-peptide interactions. KB5.C20 and BM3.3 TCR illustrate the correlation that appears to exist between CD8 dependence/low affinity and in vitro sensitization as opposed to low dependency on CD8 and high TCR affinity observed after in vivo sensitization. The results suggest that CD8-dependent alloreactive CTL obtained in vitro with high frequency correspond to low-affinity TCR from the MHC-biased TCR repertoire unpurged by negative selection and have implications for cellular immunotherapeutic approaches. 相似文献
105.
C M Thumwood N H Hunt W B Cowden I A Clark 《British journal of experimental pathology》1989,70(3):293-303
A/J and CBA/H mice infected with Plasmodium berghei ANKA, a murine model of cerebral malaria, were used to see whether antioxidants influenced the outcome of this disease. Untreated, infected mice died 7 to 9 days after infection, often with cerebral symptoms. Haemorrhages, mononuclear infiltration and oedema were present in the central nervous system (CNS). Feeding a diet containing 0.75% (w/w) butylated hydroxyanisole (BHA) greatly altered the course of this disease. Death was delayed by up to 2 weeks and mice appeared healthy at parasitaemias that would have caused cerebral symptoms and death had they been on a conventional diet. BHA-fed mice showed few or no cerebral symptoms at a time at which control mice were clearly affected, and greatly reduced haemorrhages, mononuclear infiltration and oedema when the CNS was examined. Similar, but more consistent, protective effects were seen after administration of BHA by repeated injections or in osmotic pumps. The combination of superoxide dismutase and catalase, coupled to polyethylene glycol, when administered intravenously also protected mice against death from cerebral complications. Permeability of the blood-brain barrier was monitored by the use of 125I-labelled bovine serum albumin, 51Cr-labelled erythrocytes and the dye Evans blue, all of which are normally excluded from the CNS. Infected mice on control diet showed an increase in Evans blue staining and 125I and 51Cr retention in the CNS tissue itself. Feeding the diet containing BHA reduced these indices of increased blood-brain barrier permeability. In view of the potent radical scavenging activity of BHA in many other systems it is likely, but unproven, that this is its main role here. The protective effect of superoxide dismutase and catalase lends support to the idea that reactive oxygen species are involved in the pathology of experimental cerebral malaria. 相似文献
106.
Familial correlations from genes and shared environment for urine, plasma, and intraerythrocytic sodium 总被引:1,自引:0,他引:1
S C Hunt M M Dadone R R Williams L L Wu J B Smith H Kuida K O Ash 《American journal of medical genetics》1987,27(2):249-255
Spouse-spouse, sib-sib, and parent-offspring correlations were calculated for urinary, plasma, and intracellular sodium levels on over 1,900 persons aged 3-86 years in 98 Utah kindreds. For 36 hours prior to their clinic visit, 31% of the sample was salt-loaded with salt tablets, while the rest followed their normal diet. For those on their normal diet, urine creatine-, age-, and sex-adjusted urinary sodium excretion from a timed 12-hour overnight sample showed similar and significant correlations between spouses (r = .29), sibs less than 20 years old (r = .38), and parent-offspring pairs for offspring less than 20 years old (r = .29). This contrasted with the lower correlations between sibs 20 years of age and older (r = .10) and parent-offspring pairs for offspring 20 years of age and older (r = .13), presumed to live in different households. Adult plasma sodium sib-sib (r = .13) and parent-offspring (r = .15) correlations were similar to the urinary sodium correlations, while the spouse-spouse (r = .48), the sib-sib (r = .64), and the parent-offspring (r = .63) correlations for those presumed to live in the same household nearly doubled. Intracellular sodium correlations for the adult sibs (r = .32) and offspring (r = .36) were over twice as large as for urinary or plasma sodium, although the spouse-spouse correlation (r = .37) remained large also.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
107.
Genetic analysis of sodium-lithium countertransport in 10 hypertension-prone kindreds 总被引:5,自引:0,他引:5
M M Dadone S J Hasstedt S C Hunt J B Smith K O Ash R R Williams 《American journal of medical genetics》1984,17(3):565-577
The rate of sodium-lithium countertransport (SLC flux) across red cell membranes has been reported to be elevated in hypertensive persons and their relatives as compared to normotensive individuals without family histories of hypertension. We have investigated the inheritance of this trait in 434 persons from 10 kindreds. Relatives show positive correlation of SLC flux values, but there is no spouse-spouse correlation. Pedigree analysis favors a model of polygenic inheritance over models of major-gene inheritance. Major-gene index statistics and offspring-between-parent statistics provide similar results. The proportion of total phenotypic variance that is attributable to polygenic differences between persons is estimated at 71%. The SLC flux values of hypertensive persons in this study population are lower than those reported from Boston, but are similar to those reported from Europe. We found a broad overlap of SLC flux values for hypertensive and normotensive persons. We conclude that SLC flux probably is not useful as a preclinical marker for essential hypertension. 相似文献
108.
109.
D R Hunt A Maslovitz B J Rowlands B Brooks 《Journal of the American Dietetic Association》1985,85(3):332-335
Nutrition screening is the process of identifying hospital patients with a high risk for nutrition problems who may require comprehensive nutrition assessment. Dietitians at a 700-bed teaching hospital recently implemented a nutrition screening program remarkable for efficient use of existing personnel resources. The three-step procedure includes a nutrition questionnaire completed by the patient in the hospital admissions office, measurement of each patient's height and weight by an admissions nurse, and addition of the patient's serum albumin concentration plus summary and recommendations for nutrition intervention by a registered dietitian. The procedure reduces the time needed for individual evaluation from 25 to 5 minutes and results in 1 1/2-hour time saving per day per clinical dietitian. Patients designated as "high risk" by this method appear to be more seriously ill, as shown by significantly longer hospitalization. The nutrition screening procedure described is simple, efficient, and applicable to a wide variety of institutional settings. 相似文献
110.
Dylan M. Jones Elizabeth M. Allen Andrew N. Griffiths Roger W. Marshall Alan Richens 《Psychopharmacology》1986,90(2):198-202
Rats were made diazepam dependent by chronic treatment with daily injections of the drug, 20 mg/kg, IP, for 3 weeks. On abrupt termination of the drug, the animals showed withdrawal hyperactivity which was indicated by increased horizontal locomotion and vertical activity, and diarrhoea. The peak effect was seen 3 days after the withdrawal of diazepam. Effects of various alpha2 agonists, clonidine, guanfacine and B-HT 920, were studied on the diazepam withdrawal phenomena. Clonidine (100 g/kg, IP) given twice a day at an interval of 12 h prevented both withdrawal-induced hyperactivity and diarrhoea. On the contrary, equimolar doses of guanfacine and B-HT 920 failed to reverse withdrawal-induced hyperactivity but attenuated the effect of diarrhoea. However, higher doses (500 g/kg, IP) of guanfacine and B-HT 920 given twice a day at 12-h intervals were found to be effective. Pretreatment with yohimbine (1.5 mg/kg, IP) reversed the protective effect of clonidine, indicating the involvement of alpha2 receptors in the action of clonidine. 相似文献