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941.
942.
BACKGROUND: Macroorchidism in prepuberty is an uncommon condition which we hypothesised might reflect constitutive activation of the FSH receptor (FSHR). PATIENTS AND METHODS: Patient 1 was found to have macroorchidism (15 ml testicular volume) at the time of orchidopexy when 3.7 years of age. A gonadal biopsy was obtained at the time of surgery. Patient 2 developed macroorchidism (5 ml) when 8.8 years old. Despite a testicular volume >4 ml, morning testosterone levels were unrecordable with no measurable gonadotrophin production in either patient. Patient 2 had prepubertal gonadotrophin levels 3 years later despite a testicular volume that was 8 ml bilaterally. Inhibin B was measured and the FSHR sequenced in both patients. RESULTS: Inhibin B levels were age and pubertal stage appropriate. Gonadal biopsy (patient 1) demonstrated areas of Sertoli cell hyperplasia. Sequence analysis of all 10 exons of the FSHR was normal. There was significant, presumed gonadotrophin-dependent testosterone production in both boys by 15 years of age. CONCLUSIONS: The cause of prepubertal macroorchidism in our patients is unclear but the pronounced difference in phenotype suggests that there may be more than one underlying mechanism. This mechanism was not constitutive activation of a mutated FSHR. 相似文献
943.
Local anesthetics (LAs) are compounds that inhibit the propagation of action potentials in excitable tissues by blocking voltage-gated Na+ channels. Mutagenesis studies have demonstrated that several amino acid residues are important sites of LA interaction with the channel, but these studies provide little information regarding the molecular forces that govern drug-binding interactions, including the binding orientation of drugs. We used computational methods to construct a simple model of benzocaine analog binding with the D4S6 segment of rat skeletal muscle (NaV4.1) sodium channels. The model revealed that four hydrophobic residues form a binding cavity for neutral LAs, and docking studies indicated that increasing hydrophobicity among the benzocaine analogs allowed a better fit within the binding cavity. The similarities between our simple model and published experimental data suggested that modeling of LA interactions with sodium channels, along with experimental approaches, could further enhance our understanding of LA interactions with sodium channels. 相似文献
944.
Virulizin, a novel immunotherapy agent, activates NK cells through induction of IL-12 expression in macrophages 总被引:2,自引:0,他引:2
Li H Cao MY Lee Y Lee V Feng N Benatar T Jin H Wang M Der S Wright JA Young AH 《Cancer immunology, immunotherapy : CII》2005,54(11):1115-1126
Virulizin, a novel biological response modifier, has demonstrated significant antitumor efficacy in a variety of human tumor xenograft models including melanoma, pancreatic cancer, breast cancer, ovarian cancer and prostate cancer. The significant role of macrophages and NK (Natural killer) cells was implicated in the antitumor mechanism of Virulizin where expansion as well as increased activity of macrophages and NK cells were observed in mice treated with Virulizin. Depletion of macrophages compromised Virulizin-induced NK1.1+ cell infiltration into xenografted tumors and was accompanied by reduced antitumor efficacy. In the present study, involvement of macrophages in NK cell activation was investigated further. We found that depletion of NK cells in CD-1 nude mice by anti-ASGM1 antibody significantly compromised the antitumor activity of Virulizin. Cytotoxicity of NK cells isolated from Virulizin-treated mice was enhanced against NK-sensitive YAC-1 cells and C8161 human melanoma cells, but not against NK-insensitive P815 cells. An increased level of IL-12 was observed in the serum of mice treated with Virulizin. IL-12 mRNA and protein levels were also increased in peritoneal macrophages isolated from Virulizin-treated mice. Moreover, Virulizin-induced cytotoxic activity of NK cells isolated from the spleen was abolished when an IL-12 neutralizing antibody was co-administered. In addition, depletion of macrophages in mice significantly impaired Virulizin-induced NK cell cytotoxicty. Taken together, the results suggest that Virulizin induces macrophage IL-12 production, which in turn stimulates NK cell-mediated antitumor activity. 相似文献
945.
About one woman in 1,000 has an extra X chromosome, but such women have no recognised characteristic somatic features and little is known about their long-term health and cancer risks. We conducted a cohort study of mortality and cancer incidence in 542 women diagnosed with X polysomy at 25 cytogenetic centres in Britain since 1959. Fifty-nine deaths occurred during follow-up to mid-2004. Mortality was significantly raised (standardised mortality ratio (SMR) = 2.5 (95% confidence interval (CI) 1.9–3.2)), with excess deaths due particularly to cardiovascular disease (SMR = 2.5 (95% CI 1.5–3.8)) and respiratory disease (SMR = 4.0 (95% CI 1.7–7.9)). Risks of cancer incidence and cancer mortality overall were not raised, but there was significantly raised mortality from non-Hodgkin’s lymphoma (NHL) (SMR = 10.4 (95% CI 1.3–37.6); based on 2 cases). The data indicate that mortality in women diagnosed with X polysomy is considerably raised. The raised risk of NHL is seen also in males with more than one X chromosome, and hence although unexpected and based on small numbers, it might indicate the action of a gene on the X chromosome, possibly in the pseudoautosomal region, that escapes X-inactivation.On behalf of the UK clinical cytogenetics group 相似文献
946.
Brown M McGuinness M Wright T Ren X Wang Y Boivin GP Hahn H Feldman AM Jones WK 《American journal of physiology. Heart and circulatory physiology》2005,289(1):H466-H476
The role of NF-kappaB in cardiac physiology and pathophysiology has been difficult to delineate due to the inability to specifically block NF-kappaB signaling in the heart. Cardiac-specific transgenic models have recently been developed that repress NF-kappaB activation by preventing phosphorylation at specific serine residues of the inhibitory kappaB (IkappaB) protein isoform IkappaBalpha. However, these models are unable to completely block NF-kappaB because of a second signaling pathway that regulates NF-kappaB function via Tyr42 phosphorylation of IkappaBalpha. We report the development of transgenic (3M) mouse lines that express the mutant IkappaBalpha(S32A,S36A,Y42F) in a cardiac-specific manner. NF-kappaB activation in cardiomyopathic TNF-1.6 mice is completely blocked by the 3M transgene but only partially blocked (70-80%) by the previously described double-mutant 2M [IkappaBalpha(S32A,S36A)] transgene, which demonstrates the action of two proximal pathways for NF-kappaB activation in TNF-alpha-induced cardiomyopathy. In contrast, after acute stimuli including administration of TNF-alpha and ischemia-reperfusion (I/R), NF-kappaB activation is blocked in both 2M and 3M transgenic mice. This result suggests that phosphorylation of the regulatory Ser32 and Ser36 predominantly mediates NF-kappaB activation in these situations. We show that infarct size after I/R is reduced by 70% in 3M transgenic mice, which conclusively demonstrates that NF-kappaB is involved in I/R injury. In summary, we have engineered novel transgenic mice that allow us to distinguish two major proximal pathways for NF-kappaB activation. Our results demonstrate that the serine and tyrosine phosphorylation pathways are differentially activated during different pathophysiological processes (cardiomyopathy and I/R injury) and that NF-kappaB contributes to infarct development after I/R. 相似文献
947.
Wright SJ 《Trends in ecology & evolution》2005,20(10):553-560
Understanding and mitigating the impact of an ever-increasing population and global economic activity on tropical forests is one of the great challenges currently facing biologists, conservationists and policy makers. Tropical forests currently face obvious regional changes, both negative and positive, and uncertain global changes. Although deforestation rates have increased to unprecedented levels, natural secondary succession has reclaimed approximately 15% of the area deforested during the 1990s. Governments have also protected 18% of the remaining tropical moist forest; however, unsustainable hunting continues to threaten many keystone mammal and bird species. The structure and dynamics of old-growth forests appear to be rapidly changing, suggesting that there is a pantropical response to global anthropogenic forcing, although the evidence comes almost exclusively from censuses of tree plots and is controversial. Here, I address ongoing anthropogenic change in tropical forests and suggest how these forests might respond to increasing anthropogenic pressure. 相似文献
948.
Geiger PC Wright DC Han DH Holloszy JO 《American journal of physiology. Endocrinology and metabolism》2005,288(4):E782-E788
Muscle contractile activity is followed by an increase in the sensitivity of glucose transport to insulin. There is evidence suggesting that activation of p38 MAP kinase (p38) is involved in the stimulation of glucose transport by insulin and contractions. Exercise results in an increase in p38 phosphorylation that lasts for hours. In this context, we tested the hypothesis that activation of p38 results in an increase in insulin sensitivity. Muscles were exposed to anisomycin for 30 min to activate p38. Anisomycin increased p38 phosphorylation approximately 2.5-fold and glucose transport activity 2- to 3-fold. Three hours after anisomycin treatment, by which time the acute effect on glucose transport had partially worn off, sensitivity of muscle glucose transport to 60 microU/ml insulin was markedly increased. Both the activation of p38 and the increase in insulin sensitivity induced by anisomycin were completely prevented by pretreatment of muscles with the p38 inhibitor SB-202190. However, in contrast to the finding with anisomycin, inhibition of p38 activation did not prevent the contraction-induced increase in insulin sensitivity. Thus our results show that activation of p38 is followed by an increase in insulin sensitivity of muscle glucose transport. However, activation of p38 is not necessary for induction of an increase in muscle insulin sensitivity by contractions. This finding provides evidence that contractions have an additional effect that makes p38 activation unnecessary for enhancement of insulin sensitivity by contractile activity. 相似文献
949.
Normal human cells in culture enter replicative senescence after a finite number of population doublings. The exact molecular mechanisms triggering the growth arrest are poorly understood. A recent report on the disappearance of the G-rich 3' telomeric overhang in senescent cells led to the hypothesis that loss of the 3' G-rich overhang is the molecular signal that triggers senescence. Here, we describe a quantitative assay to measure the length of the G-rich 3' telomeric overhangs from cultured cells. Using both this assay and the conventional nondenaturing hybridization assay for measuring G-rich overhangs, we show that normal human fibroblasts can maintain their overhangs at senescence. Furthermore, cells do not lose their overhangs when they bypass senescence after the inactivation of p53 and Rb. We thus conclude that a global reduction in overhang length is not the molecular signal that triggers replicative senescence. 相似文献
950.
Musayev F Sachdeva S Scarsdale JN Reynolds KA Wright HT 《Journal of molecular biology》2005,346(5):1313-1321
Beta-ketoacyl-acyl carrier protein synthase III (FabH) catalyzes a two step reaction that initiates the pathway of fatty acid biosynthesis in plants and bacteria. In Mycobacterium tuberculosis, FabH catalyzes extension of lauroyl, myristoyl and palmitoyl groups from which cell wall mycolic acids of the bacterium are formed. The first step of the reaction is an acyl group transfer from acyl-coenzyme A to the active-site cysteine of the enzyme; the second step is acyl chain extension by two carbon atoms through Claisen condensation with malonyl-acyl carrier protein. We have previously determined the crystal structure of a type II, dissociated M.tuberculosis FabH, which catalyzes extension of lauroyl, myristoyl and palmitoyl groups. Here we describe the first long-chain Michaelis substrate complex of a FabH, that of lauroyl-coenzyme A with a catalytically disabled Cys-->Ala mutant of M.tuberculosis FabH. An elongated channel extending from the mutated active-site cysteine defines the acyl group binding locus that confers unique acyl substrate specificity on M.tuberculosis FabH. CoA lies in a second channel, bound primarily through interactions of its nucleotide group at the enzyme surface. The apparent weak association of CoA in this complex may play a role in the binding and dissociation of long chain acyl-CoA substrates and products and poses questions pertinent to the mechanism of this enzyme. 相似文献