Effects of Gd solutes on hardness and yield strength of Mg alloys

Relative contribution of individual strengthening mechanisms to the yield strength of Mg–0–15 wt%Gd alloys were investigated.Alloys with different grain size were prepared by adding Zr and hot extrusion.Hardness and tensile/compression yield strength were tested on the alloys after solid solution treatment and extrusion.HallPetch constants were calculated with hardness and tensile/compressive data.The results showed that the hardness of Mg–Gd alloys with similar Gd content and different grain size were almost the same,which indicates that grain size had little effect on hardness.The hardness linearly increased with rising Gd content(d H_v/dc≈25 kg mm~(-2)/at%Gd).The tensile and compressive yield strengths enhanced with the increase of Gd content for all alloys in different conditions.In addition,the tensile/compressive(t/c)yield asymmetry of extruded alloys decreased with increasing Gd content.Large t/c yield asymmetry ratio(1.77)was observed for pure Mg,and with increasing Gd content this value decreased to 1.With the increasing of tensile strength,the stress intensity factor,k_y,decreased from 0.27 MPa m~(1/2)for Mg–2 wt%Gd alloy to 0.19 MPa m~(1/2) for Mg–5 wt%Gd alloy,then increased to 0.29 MPa m~(1/2) for Mg–15 wt%Gd alloy.However,k_yincreased linearly form 0.16–0.31 MPa for compression test.The influence of grain size strengthening was eliminated,and the yield strength of tension and compression both linearly increased with c~n,where c is the atom concentration of Gd,and n=1/2 or 2/3.     

Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.     

Protective role of phospholipid oxidation products in endotoxin-induced tissue damage

Lipopolysaccharide (LPS), an outer-membrane component of Gram-negative bacteria, interacts with LPS-binding protein and CD14, which present LPS to toll-like receptor 4 (refs 1, 2), which activates inflammatory gene expression through nuclear factor kappa B (NF kappa B) and mitogen-activated protein-kinase signalling. Antibacterial defence involves activation of neutrophils that generate reactive oxygen species capable of killing bacteria; therefore host lipid peroxidation occurs, initiated by enzymes such as NADPH oxidase and myeloperoxidase. Oxidized phospholipids are pro-inflammatory agonists promoting chronic inflammation in atherosclerosis; however, recent data suggest that they can inhibit expression of inflammatory adhesion molecules. Here we show that oxidized phospholipids inhibit LPS-induced but not tumour-necrosis factor-alpha-induced or interleukin-1 beta-induced NF kappa B-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock. Thus, in severe Gram-negative bacterial infection, endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Furthermore, identified chemical structures capable of inhibiting the effects of endotoxins such as LPS could be used for the development of new drugs for treatment of sepsis.     

When the American sea sturgeon swam east

The two species of Atlantic sea sturgeon on either shore of the North Atlantic, Acipenser sturio in Europe and A. oxyrinchus in North America, probably diverged with the closure of the Tethys Sea and the onset of the North Atlantic Gyre 15-20 million years ago, and contact between them was then presumably precluded by geographic distance. Here we present genetic, morphological and archaeological evidence indicating that the North American sturgeon colonized the Baltic during the Middle Ages and replaced the native sturgeon there, before recently becoming extinct itself in Europe as a result of human activities. In addition to representing a unique transatlantic colonization event by a fish that swims upriver to spawn, our findings have important implications for projects aimed at restocking Baltic waters with the European sturgeon.     

Dynamics of ice ages on Mars

Unlike Earth, where astronomical climate forcing is comparatively small, Mars experiences dramatic changes in incident sunlight that are capable of redistributing ice on a global scale. The geographic extent of the subsurface ice found poleward of approximately +/-60 degrees latitude on both hemispheres of Mars coincides with the areas where ice is stable. However, the tilt of Mars' rotation axis (obliquity) changed considerably in the past several million years. Earlier work has shown that regions of ice stability, which are defined by temperature and atmospheric humidity, differed in the recent past from today's, and subsurface ice is expected to retreat quickly when unstable. Here I explain how the subsurface ice sheets could have evolved to the state in which we see them today. Simulations of the retreat and growth of ground ice as a result of sublimation loss and recharge reveal forty major ice ages over the past five million years. Today, this gives rise to pore ice at mid-latitudes and a three-layered depth distribution in the high latitudes of, from top to bottom, a dry layer, pore ice, and a massive ice sheet. Combined, these layers provide enough ice to be compatible with existing neutron and gamma-ray measurements.     

Influence of the intertropical convergence zone on the East Asian monsoon

The Asian-Australian monsoon is an important component of the Earth's climate system that influences the societal and economic activity of roughly half the world's population. The past strength of the rain-bearing East Asian summer monsoon can be reconstructed with archives such as cave deposits, but the winter monsoon has no such signature in the hydrological cycle and has thus proved difficult to reconstruct. Here we present high-resolution records of the magnetic properties and the titanium content of the sediments of Lake Huguang Maar in coastal southeast China over the past 16,000 years, which we use as proxies for the strength of the winter monsoon winds. We find evidence for stronger winter monsoon winds before the B?lling-Aller?d warming, during the Younger Dryas episode and during the middle and late Holocene, when cave stalagmites suggest weaker summer monsoons. We conclude that this anticorrelation is best explained by migrations in the intertropical convergence zone. Similar migrations of the intertropical convergence zone have been observed in Central America for the period ad 700 to 900 (refs 4-6), suggesting global climatic changes at that time. From the coincidence in timing, we suggest that these migrations in the tropical rain belt could have contributed to the declines of both the Tang dynasty in China and the Classic Maya in Central America.     

Low density lipoprotein receptor-related protein 1 couples β1 integrin activation to degradation

Low density lipoprotein receptor-related protein (LRP) 1 modulates cell adhesion and motility under normal and pathological conditions. Previous studies documented that LRP1 binds several integrin receptors and mediates their trafficking to the cell surface and endocytosis. However, the mechanism by which LRP1 may regulate integrin activation remains unknown. Here we report that LRP1 promotes the activation and subsequent degradation of β1 integrin and thus supports cell adhesion, spreading, migration and integrin signaling on fibronectin. LRP1 interacts with surface β1 integrin, binds the integrin activator kindlin2 and stimulates β1 integrin–kindlin2 complex formation. Specifically, serine 76 in the LRP1 cytoplasmic tail is crucial for the interaction with kindlin2, β1 integrin activation and cell adhesion. Interestingly, a loss of LRP1 induces the accumulation of several integrin receptors on the cell surface. Following internalization, intracellular trafficking of integrins is driven by LRP1 in a protein kinase C- and class II myosin-dependent manner. Ultimately, LRP1 dictates the fate of endocytosed β1 integrin by directing it down the pathway of lysosomal and proteasomal degradation. We propose that LRP1 mediates cell adhesion by orchestrating a multi-protein pathway to activate, traffic and degrade integrins. Thus, LRP1 may serve as a focal point in the integrin quality control system to ensure a firm connection to the extracellular matrix.     

A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling

Receptor tyrosine kinase (RTK) signalling through extracellular-signal-regulated kinases (ERKs) has pivotal roles during metazoan development, underlying processes as diverse as fate determination, differentiation, proliferation, survival, migration and growth. Abnormal RTK/ERK signalling has been extensively documented to contribute to developmental disorders and disease, most notably in oncogenic transformation by mutant RTKs or downstream pathway components such as Ras and Raf. Although the core RTK/ERK signalling cassette has been characterized by decades of research using mammalian cell culture and forward genetic screens in model organisms, signal propagation through this pathway is probably regulated by a larger network of moderate, context-specific proteins. The genes encoding these proteins may not have been discovered through traditional screens owing, in particular, to the requirement for visible phenotypes. To obtain a global view of RTK/ERK signalling, we performed an unbiased, RNA interference (RNAi), genome-wide, high-throughput screen in Drosophila cells using a novel, quantitative, cellular assay monitoring ERK activation. Here we show that ERK pathway output integrates a wide array of conserved cellular processes. Further analysis of selected components-in multiple cell types with different RTK ligands and oncogenic stimuli-validates and classifies 331 pathway regulators. The relevance of these genes is highlighted by our isolation of a Ste20-like kinase and a PPM-family phosphatase that seem to regulate RTK/ERK signalling in vivo and in mammalian cells. Novel regulators that modulate specific pathway outputs may be selective targets for drug discovery.     

Progress and prospects in rat genetics: a community view

The rat is an important system for modeling human disease. Four years ago, the rich 150-year history of rat research was transformed by the sequencing of the rat genome, ushering in an era of exceptional opportunity for identifying genes and pathways underlying disease phenotypes. Genome-wide association studies in human populations have recently provided a direct approach for finding robust genetic associations in common diseases, but identifying the precise genes and their mechanisms of action remains problematic. In the context of significant progress in rat genomic resources over the past decade, we outline achievements in rat gene discovery to date, show how these findings have been translated to human disease, and document an increasing pace of discovery of new disease genes, pathways and mechanisms. Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research.     

Distribution and functional impact of DNA copy number variation in the rat

The abundance and dynamics of copy number variants (CNVs) in mammalian genomes poses new challenges in the identification of their impact on natural and disease phenotypes. We used computational and experimental methods to catalog CNVs in rat and found that they share important functional characteristics with those in human. In addition, 113 one-to-one orthologous genes overlap CNVs in both human and rat, 80 of which are implicated in human disease. CNVs are nonrandomly distributed throughout the genome. Chromosome 18 is a cold spot for CNVs as well as evolutionary rearrangements and segmental duplications, suggesting stringent selective mechanisms underlying CNV genesis or maintenance. By exploiting gene expression data available for rat recombinant inbred lines, we established the functional relationship of CNVs underlying 22 expression quantitative trait loci. These characteristics make the rat an excellent model for studying phenotypic effects of structural variation in relation to human complex traits and disease.