Oxidative stress triggers neuronal caspase-independent death: Endonuclease G involvement in programmed cell death-type III

To characterize neuronal death, primary cortical neurons (C57/Black 6 J mice) were exposed to hydrogen peroxide (H₂O₂) and staurosporine. Both caused cell shrinkage, nuclear condensation, DNA fragmentation and loss of plasma membrane integrity. Neither treatment induced caspase-7 activity, but caspase-3 was activated by staurosporine but not H₂O₂. Each treatment caused redistribution from mitochondria of both endonuclease G (Endo G) and cytochrome c. Neurons knocked down for Endo G expression using siRNA showed reduction in both nuclear condensation and DNA fragmentation after treatment with H₂O₂, but not staurosporine. Endo G suppression protected cells against H₂O₂-induced cell death, while staurosporine-induced death was merely delayed. We conclude that staurosporine induces apoptosis in these neurons, but severe oxidative stress leads to Endo G-dependent death, in the absence of caspase activation (programmed cell death-type III). Therefore, oxidative stress triggers in neurons a form of necrosis that is a systematic cellular response subject to molecular regulation. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Periodically integrated subset autoregressions for dutch industrial production and money stock

The univariate quarterly Dutch series of industrial production and money stock are both modelled with a periodically integrated subset autoregression (PISA). This model for a non-stationary series allows the lag orders, the values of the parameters and the cyclical patterns to vary over the seasons. The PISA models are found by applying a general-to-simple specification strategy, which deals with non-stationarity and periodicity simultaneously. It is found that the two series show a common asymmetric cyclical behaviour. This paper further proposes a test for periodicity in the errors, with which it is argued that a non-periodic model for the industrial production and money stock is misspecified and that seasonal adjustment does not remove periodicity in the autocorrelation function.     

Context-dependent contributions of backbone hydrogen bonding to beta-sheet folding energetics

Backbone hydrogen bonds (H-bonds) are prominent features of protein structures; however, their role in protein folding remains controversial because they cannot be selectively perturbed by traditional methods of protein mutagenesis. Here we have assessed the contribution of backbone H-bonds to the folding kinetics and thermodynamics of the PIN WW domain, a small beta-sheet protein, by individually replacing its backbone amides with esters. Amide-to-ester mutations site-specifically perturb backbone H-bonds in two ways: a H-bond donor is eliminated by replacing an amide NH with an ester oxygen, and a H-bond acceptor is weakened by replacing an amide carbonyl with an ester carbonyl. We perturbed the 11 backbone H-bonds of the PIN WW domain by synthesizing 19 amide-to-ester mutants. Thermodynamic studies on these variants show that the protein is most destabilized when H-bonds that are enveloped by a hydrophobic cluster are perturbed. Kinetic studies indicate that native-like secondary structure forms in one of the protein's loops in the folding transition state, but the backbone is less ordered elsewhere in the sequence. Collectively, our results provide an unusually detailed picture of the folding of a beta-sheet protein.     

Discovery of five irregular moons of Neptune

Each giant planet of the Solar System has two main types of moons. 'Regular' moons are typically larger satellites with prograde, nearly circular orbits in the equatorial plane of their host planets at distances of several to tens of planetary radii. The 'irregular' satellites (which are typically smaller) have larger orbits with significant eccentricities and inclinations. Despite these common features, Neptune's irregular satellite system, hitherto thought to consist of Triton and Nereid, has appeared unusual. Triton is as large as Pluto and is postulated to have been captured from heliocentric orbit; it traces a circular but retrograde orbit at 14 planetary radii from Neptune. Nereid, which exhibits one of the largest satellite eccentricities, is believed to have been scattered from a regular satellite orbit to its present orbit during Triton's capture. Here we report the discovery of five irregular moons of Neptune, two with prograde and three with retrograde orbits. These exceedingly faint (apparent red magnitude m(R) = 24.2-25.4) moons, with diameters of 30 to 50 km, were presumably captured by Neptune.     

Gigantism and comparative life-history parameters of tyrannosaurid dinosaurs

How evolutionary changes in body size are brought about by variance in developmental timing and/or growth rates (also known as heterochrony) is a topic of considerable interest in evolutionary biology. In particular, extreme size change leading to gigantism occurred within the dinosaurs on multiple occasions. Whether this change was brought about by accelerated growth, delayed maturity or a combination of both processes is unknown. A better understanding of relationships between non-avian dinosaur groups and the newfound capacity to reconstruct their growth curves make it possible to address these questions quantitatively. Here we study growth patterns within the Tyrannosauridae, the best known group of large carnivorous dinosaurs, and determine the developmental means by which Tyrannosaurus rex, weighing 5,000 kg and more, grew to be one of the most enormous terrestrial carnivorous animals ever. T. rex had a maximal growth rate of 2.1 kg d(-1), reached skeletal maturity in two decades and lived for up to 28 years. T. rex's great stature was primarily attained by accelerating growth rates beyond that of its closest relatives.     

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.