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921.
Wyatt PG Allen MJ Borthwick AD Davies DE Exall AM Hatley RJ Irving WR Livermore DG Miller ND Nerozzi F Sollis SL Szardenings AK 《Bioorganic & medicinal chemistry letters》2005,15(10):2579-2582
This paper covers efforts to discover orally active potent and selective oxytocin antagonists. Screening pooled libraries identified a novel series of 2,5-diketopiperazine derivatives with antagonist activity at the human oxytocin receptor. We report the initial structure-activity relationship investigations and the determination of the stereochemistry of the most potent compounds. 相似文献
922.
Allen JF 《Current biology : CB》2005,15(22):R929-R932
Recent work identifies two kinases required for phosphorylation of proteins of chloroplast thylakoid membranes. One kinase, STN7, is required for phosphorylation of light-harvesting complex II; another, STN8, is required for phosphorylation of photosystem II. How do these kinases interact, what do they do, and what are they for? 相似文献
923.
Insulin-like growth factor (IGF)-1 has been implicated in the development of occlusive vascular lesions. Although its role in vascular smooth muscle cell (VSMC) growth and migration are fairly well characterized, anti-apoptotic signals of IGF-1 in human VSMC remain largely unknown. In this study, we examined IGF-1 signals that protect human and rat VSMC from staurosporine (STAU)- and c-myc- induced apoptosis, respectively. Treatment with STAU resulted in apoptotic DNA fragmentation, phosphatidylserine externalization and cell shrinkage, but only occasional VSMC 'blebbing'. STAU-induced death and IGF-1-mediated survival were concentration dependent, while time-lapse video microscopy showed that IGF-1 inhibited c-myc-induced apoptosis by 90%. Pretreatment with mitogen-activated protein kinase/extracellular signal regulated kinase kinase (MEK) inhibitors UO126 and PD098059, or with the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin, reversed IGF-1-mediated human VSMC survival by 25-27% and 66%, respectively. Translocation studies showed that IGF-1 activated protein kinase C (PKC)-epsilon, but not PKC-alpha or PKC-delta, even in the presence of STAU, while pharmacological PKC inhibition (Ro-318220 or Go6976) implicated PKC-zeta or a novel PKC isozyme in IGF-1-mediated survival. Transient expression of activated PKC-epsilon but not activated PKC-zeta decreased myc-induced apoptosis in rat VSMC. In human VSMC, antisense oligodeoxynucleotides to PKC-epsilon partially reversed IGF-1-induced survival. In addition, IGF-1 elicited a mild but sustained activation of extracellular signal regulated kinase (ERK)1/2 in human VSMC that was abolished after 1 h in the presence of STAU. PKC downregulation reversed both IGF-1- and PMA-induced ERK activity, but platelet-derived growth factor (PDGF)-induced activity was unchanged. These results indicate for the first time that IGF-1 can protect human VSMC via multiple signals, including PKC-epsilon, PI3-K and mitogen-activated protein kinase pathways. 相似文献
924.
The human visual system can distinguish variations in image contrast over a much larger range than measurements of the static relationship between contrast and response in visual cortex would suggest. This discrepancy may be explained if adaptation serves to re-center contrast response functions around the ambient contrast, yet experiments on humans have yet to report such an effect. By using event-related fMRI and a data-driven analysis approach, we found that contrast response functions in V1, V2, and V3 shift to approximately center on the adapting contrast. Furthermore, we discovered that, unlike earlier areas, human V4 (hV4) responds positively to contrast changes, whether increments or decrements, suggesting that hV4 does not faithfully represent contrast, but instead responds to salient changes. These findings suggest that the visual system discounts slow uninformative changes in contrast with adaptation, yet remains exquisitely sensitive to changes that may signal important events in the environment. 相似文献
925.
James?A.?Allen Ken?W.?KraussEmail author Katherine?C.?Ewel Bobby?D.?Keeland Erick?E.?Waguk 《Wetlands Ecology and Management》2005,13(6):657-669
Forested wetlands dominated by Terminalia carolinensis are endemic to Micronesia but common only on the island of Kosrae, Federated States of Micronesia. On Kosrae, these forests
occur on Nansepsep, Inkosr, and Sonahnpil soil types, which differ in degree of flooding and soil saturation. We compared
forest structure, growth, nutrition, and regeneration on two sites each on Nansepsep and Inkosr soils and one site on the
much less common Sonahnpil soil type. Terminalia tree sizes were similar on all three soil types, but forests differed in total basal area, species of smaller trees, and
total plant species diversity. Terminalia regeneration was found only on the Inkosr soil type, which had the highest water table levels. Other Terminalia species are relatively light demanding, and T. carolinensis exhibited similar characteristics. It is therefore likely that Terminalia requires periodic, but perhaps naturally rare, stand-replacing disturbances (e.g., typhoons) in order to maintain its dominance,
except on the wettest sites, where competition from other species is reduced. Terminalia swamps in the Nansepsep soil type appeared to be at the greatest risk of conversion to other uses, but swamps on all three
types may face greater pressure as Kosrae's population increases and the island's infrastructure becomes more developed. 相似文献
926.
927.
Wang X Zeng W Soyombo AA Tang W Ross EM Barnes AP Milgram SL Penninger JM Allen PB Greengard P Muallem S 《Nature cell biology》2005,7(4):405-411
Signalling by G proteins is controlled by the regulator of G-protein signalling (RGS) proteins that accelerate the GTPase activity of Galpha subunits and act in a G-protein-coupled receptor (GPCR)-specific manner. The conserved RGS domain accelerates the G subunit GTPase activity, whereas the variable amino-terminal domain participates in GPCR recognition. How receptor recognition is achieved is not known. Here, we show that the scaffold protein spinophilin (SPL), which binds the third intracellular loop (3iL) of several GPCRs, binds the N-terminal domain of RGS2. SPL also binds RGS1, RGS4, RGS16 and GAIP. When expressed in Xenopus laevis oocytes, SPL markedly increased inhibition of alpha-adrenergic receptor (alphaAR) Ca2+ signalling by RGS2. Notably, the constitutively active mutant alphaAR(A293E) (the mutation being in the 3iL) did not bind SPL and was relatively resistant to inhibition by RGS2. Use of betaAR-alphaAR chimaeras identified the 288REKKAA293 sequence as essential for the binding of SPL and inhibition of Ca2+ signalling by RGS2. Furthermore, alphaAR-evoked Ca2+ signalling is less sensitive to inhibition by SPL in rgs2-/- cells and less sensitive to inhibition by RGS2 in spl-/- cells. These findings provide a general mechanism by which RGS proteins recognize GPCRs to confer signalling specificity. 相似文献
928.
AB Chang NC Cox J Purcell JM Marchant PJ Lewindon GJ Cleghorn LC Ee GD Withers MK Patrick J Faoagali 《Respiratory research》2005,6(1):1-5
Background and methods
Human metapneumovirus (hMPV) is a recently discovered respiratory virus associated with bronchiolitis, pneumonia, croup and exacerbations of asthma. Since respiratory viruses are frequently detected in patients with acute exacerbations of COPD (AE-COPD) it was our aim to investigate the frequency of hMPV detection in a prospective cohort of hospitalized patients with AE-COPD compared to patients with stable COPD and to smokers without by means of quantitative real-time RT-PCR.Results
We analysed nasal lavage and induced sputum of 130 patients with AE-COPD, 65 patients with stable COPD and 34 smokers without COPD. HMPV was detected in 3/130 (2.3%) AE-COPD patients with a mean of 6.5 × 105 viral copies/ml in nasal lavage and 1.88 × 105 viral copies/ml in induced sputum. It was not found in patients with stable COPD or smokers without COPD.Conclusion
HMPV is only found in a very small number of patients with AE-COPD. However it should be considered as a further possible viral trigger of AE-COPD because asymptomatic carriage is unlikely. 相似文献929.
Association studies of quantitative traits have often relied on methods in which a normal distribution of the trait is assumed. However, quantitative phenotypes from complex human diseases are often censored, highly skewed, or contaminated with outlying values. We recently developed a rank-based association method that takes into account censoring and makes no distributional assumptions about the trait. In this study, we applied our new method to age-at-onset data on ALDX1 and ALDX2. Both traits are highly skewed (skewness > 1.9) and often censored. We performed a whole genome association study of age at onset of the ALDX1 trait using Illumina single-nucleotide polymorphisms. Only slightly more than 5% of markers were significant. However, we identified two regions on chromosomes 14 and 15, which each have at least four significant markers clustering together. These two regions may harbor genes that regulate age at onset of ALDX1 and ALDX2. Future fine mapping of these two regions with densely spaced markers is warranted. 相似文献
930.
Haplotypes, the combination of closely linked alleles that fall on the same chromosome, show great promise for studying the genetic components of complex diseases. However, when only multilocus genotype data are available, statistical approaches need to be employed to resolve haplotype phase ambiguity. Recently, we have proposed an approach to testing and estimating haplotype/disease association that is invariant to any existing genetic structure in the population. Here we evaluate this approach by applying it to the Genetic Analysis Workshop 14 simulated data. 相似文献