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81.
Orjales A Mosquera R López B Olivera R Labeaga L Núñez MT 《Bioorganic & medicinal chemistry》2008,16(5):2183-2199
New series of 2-(4-methylsulfonylphenyl) and 2-(4-sulfamoylphenyl)pyrimidines were synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). COX-1 and COX-2 inhibitory activity of these compounds was determined using purified enzyme (PE) and human whole blood (HWB) assays. Extensive structure-activity relationship (SAR) work was carried out within these series, and a wide number of potent and specific COX-2 inhibitors were identified (HWB COX-2 IC(50)=2.4-0.3nM and 80- to 780-fold more selective than rofecoxib). 相似文献
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Annacontini L Parisi D Portincasa A 《Plastic and reconstructive surgery》2008,121(2):681-2; author reply 682-3
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Bruce J. Ellis Aurelio José Figueredo Barbara H. Brumbach Gabriel L. Schlomer 《Human nature (Hawthorne, N.Y.)》2009,20(2):204-268
The current paper synthesizes theory and data from the field of life history (LH) evolution to advance a new developmental
theory of variation in human LH strategies. The theory posits that clusters of correlated LH traits (e.g., timing of puberty,
age at sexual debut and first birth, parental investment strategies) lie on a slow-to-fast continuum; that harshness (externally
caused levels of morbidity-mortality) and unpredictability (spatial-temporal variation in harshness) are the most fundamental
environmental influences on the evolution and development of LH strategies; and that these influences depend on population
densities and related levels of intraspecific competition and resource scarcity, on age schedules of mortality, on the sensitivity
of morbidity-mortality to the organism’s resource-allocation decisions, and on the extent to which environmental fluctuations
affect individuals versus populations over short versus long timescales. These interrelated factors operate at evolutionary
and developmental levels and should be distinguished because they exert distinctive effects on LH traits and are hierarchically
operative in terms of primacy of influence. Although converging lines of evidence support core assumptions of the theory,
many questions remain unanswered. This review demonstrates the value of applying a multilevel evolutionary-developmental approach
to the analysis of a central feature of human phenotypic variation: LH strategy. 相似文献
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Francesca Sacco Michele Tinti Anita Palma Emanuela Ferrari Aurelio P. Nardozza Rob Hooft van Huijsduijnen Takamune Takahashi Luisa Castagnoli Gianni Cesareni 《The Journal of biological chemistry》2009,284(33):22048-22058
Density-enhanced phosphatase-1 (DEP-1) is a trans-membrane receptor protein-tyrosine phosphatase that plays a recognized prominent role as a tumor suppressor. However, the mechanistic details underlying its function are poorly understood because its primary physiological substrate(s) have not been firmly established. To shed light on the mechanisms underlying the anti-proliferative role of this phosphatase, we set out to identify new DEP-1 substrates by a novel approach based on screening of high density peptide arrays. The results of the array experiment were combined with a bioinformatics filter to identify eight potential DEP-1 targets among the proteins annotated in the MAPK pathway. In this study we show that one of these potential targets, the ERK1/2, is indeed a direct DEP-1 substrate in vivo. Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2. After epidermal growth factor stimulation, the phosphorylation of the activation loop of ERK1/2 can be modulated by changing the concentration of DEP-1, without affecting the activity of the upstream kinase MEK. In addition, we show that DEP-1 contains a KIM-like motif to recruit ERK1/2 proteins by a docking mechanism mediated by the common docking domain in ERK1/2. ERK proteins that are mutated in the conserved docking domain become insensitive to DEP-1 de-phosphorylation. Overall this study provides novel insights into the anti-proliferative role of this phosphatase and proposes a new mechanism that may also be relevant for the regulation of density-dependent growth inhibition.DEP-14 (also known as CD148, HPTPη, and PTPRJ) is a class III receptor protein-tyrosine phosphatase, characterized by eight fibronectin type III repeats within the extracellular domain, a trans-membrane region, and a single cytosolic catalytic domain (1, 2). DEP-1 is expressed in all human hematopoietic cell lineages and was shown to negatively regulate T cell activation. In addition, several epithelial cell types display DEP-1 on their cell membranes (3). Homozygous DEP-1 mutant mice die before embryonic day 11.5, displaying severe defects in vascular organization (4). Interestingly, DEP-1 expression levels were found to augment with increased cell density (2), suggesting a role for this tyrosine phosphatase in sensing cell-cell contacts and in density-dependent growth inhibition (5). Moreover, accumulating evidence supports a prominent role for DEP-1 as a tumor suppressor as it negatively regulates cell proliferation and is poorly expressed in many cancer cell lines (6–10). The observed anti-proliferative effect may be accounted for by the ability of DEP-1 to down-regulate growth factor signaling through the dephosphorylation of various receptor tyrosine kinases, such as PDGFR, VEGFR2, and MET (11–13), resulting in quenching of the downstream RAS-MAPK pathway. However, given the complex pleiotropic functions of DEP-1, it is also possible that additional regulatory circuits mediated by yet unknown DEP-1 substrates may play a functional role in contact inhibition and control of cell proliferation.A variety of in vivo and in vitro approaches has led us to propose a number of DEP-1 substrates as mediators of its function. These include PDGFR, p120 catenin (CTND1), hepatocyte growth factor receptor, SRC kinase, VEGFR2, phosphatidylinositol 3-kinase regulatory subunit α (P85A), and RET receptor kinase (5, 11–16).Here we report a novel, unbiased strategy based on the screening of high density phosphopeptide arrays for their ability to bind phosphatase trapping mutants. A large portion of the phosphoproteome could be explored by this approach, thus unveiling a long list of potential substrates. A selected list of potentially relevant substrates has been obtained by applying a bioinformatics context filter. In this study we report the detailed characterization of one of these substrates, and we propose that DEP-1 modulates the RAS pathway by directly dephosphorylating Tyr-204 of ERK1/2. In addition, we show that the efficient removal of the phosphate group from Tyr-204 requires the integrity of a docking site on the ERK1/2 proteins. 相似文献
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Felipe Cava Aurelio Hidalgo José Berenguer 《Extremophiles : life under extreme conditions》2009,13(2):213-231
Thermus spp is one of the most wide spread genuses of thermophilic bacteria, with isolates found in natural as well as in man-made
thermal environments. The high growth rates, cell yields of the cultures, and the constitutive expression of an impressively
efficient natural competence apparatus, amongst other properties, make some strains of the genus excellent laboratory models
to study the molecular basis of thermophilia. These properties, together with the fact that enzymes and protein complexes
from extremophiles are easier to crystallize have led to the development of an ongoing structural biology program dedicated
to T. thermophilus HB8, making this organism probably the best so far known from a protein structure point view. Furthermore, the availability
of plasmids and up to four thermostable antibiotic selection markers allows its use in physiological studies as a model for
ancient bacteria. Regarding biotechnological applications this genus continues to be a source of thermophilic enzymes of great
biotechnological interest and, more recently, a tool for the over-expression of thermophilic enzymes or for the selection
of thermostable mutants from mesophilic proteins by directed evolution. In this article, we review the properties of this
organism as biological model and its biotechnological applications. 相似文献