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81.
82.
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
83.
84.
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
85.
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
86.
Akt, an essential component of the insulin pathway, is a potent inducer of tissue growth. One of Akt''s phosphorylation targets is Tsc2, an inhibitor of the anabolic kinase TOR. This could account for part of Akt''s growth promoting activity. Although phosphorylation of Tsc2 by Akt does occur in vivo, and under certain circumstances can lead to reduced Tsc2 activity, the functional significance of this event is unclear since flies lacking Akt phosphorylation sites on Tsc2 are viable and normal in size and growth rate. Since Drosophila Tsc1, the obligate partner of Tsc2, has an Akt phosphorylation motif that is not conserved in mammals, we investigate here whether Akt redundantly phosphorylates the Tsc complex on Tsc1 and Tsc2. We provide evidence that Akt phosphorylates Tsc1 at Ser533. We show that flies lacking Akt phosphorylation sites on Tsc1 alone, or on both Tsc1 and Tsc2 concurrently, are viable and normal in size. This shows that phosphorylation of the Tsc1/2 complex by Akt is not required for Akt to activate TORC1 and to promote tissue growth in Drosophila. 相似文献
87.
Neasham D Gallo V Guarrera S Dunning A Overvad K Tjonneland A Clavel-Chapelon F Linseisen JP Malaveille C Ferrari P Boeing H Benetou V Trichopoulou A Palli D Crosignani P Tumino R Panico S Bueno-De-Mesquita HB Peeters PH van Gib CH Lund E Gonzalez CA Martinez C Dorronsoro M Barricarte A Navarro C Quiros JR Berglund G Jarvholm B Khaw KT Key TJ Bingham S Diaz TM Riboli E Matullo G Vineis P 《DNA Repair》2009,8(1):60-71
We followed-up for mortality and cancer incidence 1088 healthy non-smokers from a population-based study, who were characterized for 22 variants in 16 genes involved in DNA repair pathways. Follow-up was 100% complete. The association between polymorphism and mortality or cancer incidence was analyzed using Cox Proportional Hazard regression models. Ninety-five subjects had died in a median follow-up time of 78 months (inter-quartile range 59-93 months). None of the genotypes was clearly associated with total mortality, except variants for two Double-Strand Break DNA repair genes, XRCC3 18067 C>T (rs#861539) and XRCC2 31479 G>A (rs#3218536). Adjusted hazard ratios were 2.25 (1.32-3.83) for the XRCC3 C/T genotype and 2.04 (1.00-4.13) for the T/T genotype (reference C/C), and 2.12 (1.14-3.97) for the XRCC2 G/A genotype (reference G/G). For total cancer mortality, the adjusted hazard ratios were 3.29 (1.23-7.82) for XRCC3 C/T, 2.84 (0.81-9.90) for XRCC3 T/T and 3.17 (1.21-8.30) for XRCC2 G/A. With combinations of three or more adverse alleles, the adjusted hazard ratio for all cause mortality was 17.29 (95% C.I. 8.13-36.74), and for all incident cancers the HR was 5.28 (95% C.I. 2.17-12.85). Observations from this prospective study suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly influence the risk of cancer and non-cancer disease, and can influence mortality. 相似文献
88.
Caroline Mauvezin Meritxell Orpinell Víctor A Francis Francisco Mansilla Jordi Duran Vicent Ribas Manuel Palacín Patricia Boya Aurelio A Teleman Antonio Zorzano 《EMBO reports》2010,11(1):37-44
The regulation of autophagy in metazoans is only partly understood, and there is a need to identify the proteins that control this process. The diabetes‐ and obesity‐regulated gene (DOR), a recently reported nuclear cofactor of thyroid hormone receptors, is expressed abundantly in metabolically active tissues such as muscle. Here, we show that DOR shuttles between the nucleus and the cytoplasm, depending on cellular stress conditions, and re‐localizes to autophagosomes on autophagy activation. We demonstrate that DOR interacts physically with autophagic proteins Golgi‐associated ATPase enhancer of 16 kDa (GATE16) and microtubule‐associated protein 1A/1B‐light chain 3. Gain‐of‐function and loss‐of‐function studies indicate that DOR stimulates autophagosome formation and accelerates the degradation of stable proteins. CG11347, the DOR Drosophila homologue, has been predicted to interact with the Drosophila Atg8 homologues, which suggests functional conservation in autophagy. Flies lacking CG11347 show reduced autophagy in the fat body during pupal development. All together, our data indicate that DOR regulates autophagosome formation and protein degradation in mammalian and Drosophila cells. 相似文献
89.
Boto A Gallardo JA Hernández R Ledo F Muñoz A Murguía JR Menacho-Márquez M Orjales A Saavedra CJ 《Bioorganic & medicinal chemistry letters》2006,16(23):6073-6077
The discovery of genotoxic amino acids derived from phenylglycine, and possessing halogen substituents, is described. The utility of hypervalent iodine reagents in the synthesis of this class of compounds is highlighted. The mechanism of action of the (haloaryl)glycines was studied in Saccharomyces cerevisiae. 相似文献
90.
Aurelio A. de los Reyes V Eunok Jung Franz Kappel 《Bulletin of mathematical biology》2014,76(6):1306-1332
In this paper, we develop a pulsatile model for the cardiovascular system which describes the reaction of this system to a submaximal constant workload imposed on a person at a bicycle ergometer test after a period of rest. Furthermore, the model should allow to use measurements for the pulsatile pressure in fingertips which provide information on the diastolic and the systolic pressure for parameter estimation. Based on the assumption that the baroreceptor loop is the essential control loop in this case, we design a stabilizing feedback control for the pulsatile model which is obtained by solving a linear-quadratic regulator problem for the linearization of a non-pulsatile counterpart of the pulsatile model. We also investigate the behavior of the model with respect to changes in the weight of the term in the cost functional for the linear-quadratic regulator problem which penalizes the deviation of the momentary pressure in the aorta from the pressure at the stationary situation which should be obtained. 相似文献