EP4 receptor stimulation down-regulates human eosinophil function

Accumulation of eosinophils in tissue is a hallmark of allergic inflammation. Here we observed that a selective agonist of the PGE₂ receptor EP4, ONO AE1-329, potently attenuated the chemotaxis of human peripheral blood eosinophils, upregulation of the adhesion molecule CD11b and the production of reactive oxygen species. These effects were accompanied by the inhibition of cytoskeletal rearrangement and Ca²⁺ mobilization. The involvement of the EP4 receptor was substantiated by a selective EP4 antagonist, which reversed the inhibitory effects of PGE₂ and the EP4 agonist. Selective kinase inhibitors revealed that the inhibitory effect of EP4 stimulation on eosinophil migration depended upon activation of PI 3-kinase and PKC, but not cAMP. Finally, we found that EP4 receptors are expressed by human eosinophils, and are also present on infiltrating leukocytes in inflamed human nasal mucosa. These data indicate that EP4 agonists might be a novel therapeutic option in eosinophilic diseases.     

Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection

Experimental infection with mouse cytomegalovirus (MCMV) has been used to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F(2) progeny from MCMV-resistant MA/My (H2 (k)) and MCMV-susceptible BALB/c (H2 (d)) and BALB.K (H2 (k)) mouse strains indicated that only the combination of alleles encoded by a gene in the Klra (also called Ly49) cluster on chromosome 6, and one in the major histocompatibility complex (H2) on chromosome 17, is associated with virus resistance. We found that natural killer cell-activating receptor Ly49P specifically recognized MCMV-infected cells, dependent on the presence of the H2 (k) haplotype. This binding was blocked using antibodies to H-2D(k) but not antibodies to H-2K(k). These results are suggestive of a new natural killer cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Ly49P receptor and the major histocompatibility complex class I molecule H-2D(k) on MCMV-infected cells.     

Isolation of cell lines possessing functional and serological properties resembling those of thymocyte precursors

Thymocytes develop from a committed haematopoietic progenitor, referred to as a prothymocyte. They are uniquely capable of migrating to and restoring the thymus of a lethally irradiated host, a property which has been exploited as a specific assay for these cells. Like other committed haematopoietic progenitors, prothymocytes are found only in small numbers in even the richest sources (0.05-1.0% of the nucleated cells in bone marrow). Purification has proved difficult both in terms of finding a suitable starting material and in the degree of enrichment achieved. We now report the isolation of cloned lines of cells with some of the serological and functional properties of prothymocytes. One of these lines has been in continuous culture for almost 2 years. When injected into irradiated recipients, cells from this line migrate to the thymus and there develop into cells which resemble normal cortical thymocytes.     

CEACAM1 regulates insulin clearance in liver

We hypothesized that insulin stimulates phosphorylation of CEACAM1 which in turn leads to upregulation of receptor-mediated insulin endocytosis and degradation in the hepatocyte. We have generated transgenic mice over-expressing in liver a dominant-negative, phosphorylation-defective S503A-CEACAM1 mutant. Supporting our hypothesis, we found that S503A-CEACAM1 transgenic mice developed hyperinsulinemia resulting from impaired insulin clearance. The hyperinsulinemia caused secondary insulin resistance with impaired glucose tolerance and random, but not fasting, hyperglycemia. Transgenic mice developed visceral adiposity with increased amounts of plasma free fatty acids and plasma and hepatic triglycerides. These findings suggest a mechanism through which insulin signaling regulates insulin sensitivity by modulating hepatic insulin clearance.     

Modelling and forecasting time series sampled at different frequencies

This paper discusses how to specify an observable high‐frequency model for a vector of time series sampled at high and low frequencies. To this end we first study how aggregation over time affects both the dynamic components of a time series and their observability, in a multivariate linear framework. We find that the basic dynamic components remain unchanged but some of them, mainly those related to the seasonal structure, become unobservable. Building on these results, we propose a structured specification method built on the idea that the models relating the variables in high and low sampling frequencies should be mutually consistent. After specifying a consistent and observable high‐frequency model, standard state‐space techniques provide an adequate framework for estimation, diagnostic checking, data interpolation and forecasting. An example using national accounting data illustrates the practical application of this method. Copyright © 2008 John Wiley & Sons, Ltd.     

Carapace ontogeny of the bromeliad dwelling ostracod Elpidium bromeliarum Müller, 1880 (Crustacea: Ostracoda)

Ostracods have discontinuous development, marked by ecdyses, and determinate growth. Ontogenetic studies have suggested a pattern of nine postembryonic stages (eight juvenile phases and the adult) for the main freshwater ostracod superfamilies Cypridoidea, Cytheroidea and Darwinuloidea. However, cases of a supposed extra moult in the adult stage have been proposed for some ostracod species, which would amount to 10 postembryonic growth stages. One such example is Elpidium bromeliarum Müller, 1880, a cytheroidean that inhabits tank-bromeliads. The present study is aimed at investigating the ontogenetic development of E. bromeliarum using width and length measurements, as well as carapace and appendage morphology in order to test the existing hypothesis of an additional growth stage in adults of this species. Our results revealed nine postembryonic growth stages (eight juvenile and the adult), with sexual dimorphism beginning its expression in the last juvenile stage. Thus, the ontogenetic development of E. bromeliarum agrees with the overall pattern observed for podocopid ostracods and the hypothesis of 10 postembryonic growth stages was not corroborated. We argue that the inability to differentiate juveniles from adults, or different species from one another, may have misled to the assumption of an additional moult in E. bromeliarum.     

研发项目中“团队-产品-功能”多领域集成与组织聚类研究

研发项目是由产品、功能、组织和流程等多个领域中元素之间相互联系构成的复杂网络.为了便于同时分析三个领域元素之间存在的相互依赖关系,本文引入扩展的域映射矩阵EDMM分析"团队-产品-功能"之间的依赖关系,进一步,通过"扩展的多领域矩阵"(EMDM),即"团队-产品-功能"EMDM,本文构建了由部件设计结构矩阵(DSM)、功能DSM和EDMM推导组织DSM的模型.然后,为优化组织架构以降低管理的复杂性,构建了改进的两阶段组织DSM聚类准则,提出了最大化"增加的类内外依赖强度比"AIDER和最小化项目的总协调成本的聚类准则,以平衡类内和类外元素对聚类的影响.最后,通过案例,将本文提出的AIDER聚类准则与传统的聚类准则进行了比较,聚类结果表明本方法可明显降低总协调成本.     

Spatial vegetation patterns and imminent desertification in Mediterranean arid ecosystems

Humans and climate affect ecosystems and their services, which may involve continuous and discontinuous transitions from one stable state to another. Discontinuous transitions are abrupt, irreversible and among the most catastrophic changes of ecosystems identified. For terrestrial ecosystems, it has been hypothesized that vegetation patchiness could be used as a signature of imminent transitions. Here, we analyse how vegetation patchiness changes in arid ecosystems with different grazing pressures, using both field data and a modelling approach. In the modelling approach, we extrapolated our analysis to even higher grazing pressures to investigate the vegetation patchiness when desertification is imminent. In three arid Mediterranean ecosystems in Spain, Greece and Morocco, we found that the patch-size distribution of the vegetation follows a power law. Using a stochastic cellular automaton model, we show that local positive interactions among plants can explain such power-law distributions. Furthermore, with increasing grazing pressure, the field data revealed consistent deviations from power laws. Increased grazing pressure leads to similar deviations in the model. When grazing was further increased in the model, we found that these deviations always and only occurred close to transition to desert, independent of the type of transition, and regardless of the vegetation cover. Therefore, we propose that patch-size distributions may be a warning signal for the onset of desertification.     

Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma

Autotaxin is a secreted cell motility-stimulating exo-phosphodiesterase with lysophospholipase D activity that generates bioactive lysophosphatidic acid. Lysophosphatidic acid has been implicated in various neural cell functions such as neurite remodeling, demyelination, survival and inhibition of axon growth. Here, we report on the in vivo expression of autotaxin in the brain during development and following neurotrauma. We found that autotaxin is expressed in the proliferating subventricular and choroid plexus epithelium during embryonic development. After birth, autotaxin is mainly found in white matter areas in the central nervous system. In the adult brain, autotaxin is solely expressed in leptomeningeal cells and oligodendrocyte precursor cells. Following neurotrauma, autotaxin is strongly up-regulated in reactive astrocytes adjacent to the lesion. The present study revealed the cellular distribution of autotaxin in the developing and lesioned brain and implies a function of autotaxin in oligodendrocyte precursor cells and brain injuries. Received 18 September 2006; received after revision 30 October 2006; accepted 4 December 2006