Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5

Mitogen-activated protein (MAP) kinases are essential regulators in immune responses, and their activities are modulated by kinases and phosphatases. MAP kinase phosphatase (MKP) is a family of dual-specificity phosphatases whose function is evolutionarily conserved. A number of mammalian MKPs have been identified so far, but their specific physiological functions in negative regulation of MAP kinases have not been genetically defined. Here we examine innate and adaptive immune responses in the absence of MKP5. JNK activity was selectively increased in Mkp5 (also known as Dusp10)-deficient mouse cells. Mkp5-deficient cells produced greatly enhanced levels of pro-inflammatory cytokines during innate immune responses and exhibited greater T-cell activation than their wild-type counterparts. However, Mkp5-deficient T cells proliferated poorly upon activation, which resulted in increased resistance to experimental autoimmune encephalomyelitis. By contrast, Mkp5-deficient CD4(+) and CD8(+) effector T cells produced significantly increased levels of cytokines compared with wild-type cells, which led to much more robust and rapidly fatal immune responses to secondary infection with lymphocytic choriomeningitis virus. Therefore, MKP5 has a principal function in both innate and adaptive immune responses, and represents a novel target for therapeutic intervention of immune diseases.     

Structure of the fibronectin type 1 module

The rapid accumulation of sequence data has provided insight into the evolution of proteins and led to the identification of 'mosaic proteins'. These proteins have evolved by duplication, insertion and deletion of a common pool of structural units or modules, yet their biological functions are diverse. They are involved in cell adhesion and migration, embryogenesis and the pathways of blood clotting, fibrinolysis and complement. The modular units are defined by 'consensus sequences' which often include conserved disulphide bonds. Despite the available sequence information, little is known of the tertiary structure of mosaic proteins. If, however, the 'consensus structure' of the modules were known, valuable structural information could be inferred about a wide variety of proteins and biological systems. An important mosaic protein is fibronectin, an extracellular matrix protein that consists of three types of module (see refs 3, 7 for reviews). Here we describe the structure of the fibronectin type 1 module which appears twelve times in fibronectin and is also found in factor XII and tissue plasminogen activator. The module was produced using a yeast expression system and the structure was determined in solution using 1H NMR. This methodology promises to be extremely powerful in the investigation of modules from a wide range of mosaic proteins.     

Using the bootstrap for improved ARIMA model identification

This paper presents a new method of identifying ARIMA time-series models. We use the bootstrap technique in estimating the distribution of sample autocorrelations both separately and in a simultaneous inference setting. The bootstrap has the advantage of being nonparametric and thus free of reliance on asymptotic normality, which may not hold for short or medium-size series. The simultaneous procedure is unique, as it has no feasible parametric alternatives. An application to exchange rates illustrates our methodology. In the example chosen, we are able to produce better forecasts using the model identified via the bootstrap technique.     

In situ Os isotopes in abyssal peridotites bridge the isotopic gap between MORBs and their source mantle

Abyssal peridotites are assumed to represent the mantle residue of mid-ocean-ridge basalts (MORBs). However, the osmium isotopic compositions of abyssal peridotites and MORB do not appear to be in equilibrium, raising questions about the cogenetic relationship between those two reservoirs. However, the cause of this isotopic mismatch is mainly due to a drastic filtering of the data based on the possibility of osmium contamination by sea water. Here we present a detailed study of magmatic sulphides (the main carrier of osmium) in abyssal peridotites and show that the 187Os/188Os ratio of these sulphides is of primary mantle origin and can reach radiogenic values suggesting equilibrium with MORB. Thus, the effect of sea water on the osmium systematics of abyssal peridotites has been overestimated and consequently there is no true osmium isotopic gap between MORBs and abyssal peridotites.     

Some generalizations relative to lithium aluminum hydride reactions

Zusammenfassung Unter den gewöhnlichen Reaktionsbedingungen bleiben-O-{ie356-1}-O- und -S-{ie356-2}-O-Gruppen durch LiAlH₄ unverändert, während -{ie356-3}-{ie356-4}-O- und möglicherweise auch-{ie356-5}-{ie356-6}-S-Gruppen an der C-O- bzw. C-S-Bindung gespalten werden. Diese Verallgemeinerungen, die sich auf aliphatische und aromatische Verbindungen, Zucker und Steroide, anwenden lassen, werden zur Bestätigung kürzlich aufgestellter Steroid- und Alkaloidformeln herangezogen. Es wird ein Reaktionsmechanismus vorgeschlagen.

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Contribution No. 8 from the Yerkes Research Laboratory, E. I. du Pont de Nemours & Co., Inc., Buffalo 7, New York.