Prion propagation and toxicity in vivo occur in two distinct mechanistic phases

Mammalian prions cause fatal neurodegenerative conditions including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. Prion infections are typically associated with remarkably prolonged but highly consistent incubation periods followed by a rapid clinical phase. The relationship between prion propagation, generation of neurotoxic species and clinical onset has remained obscure. Prion incubation periods in experimental animals are known to vary inversely with expression level of cellular prion protein. Here we demonstrate that prion propagation in brain proceeds via two distinct phases: a clinically silent exponential phase not rate-limited by prion protein concentration which rapidly reaches a maximal prion titre, followed by a distinct switch to a plateau phase. The latter determines time to clinical onset in a manner inversely proportional to prion protein concentration. These findings demonstrate an uncoupling of infectivity and toxicity. We suggest that prions themselves are not neurotoxic but catalyse the formation of such species from PrP(C). Production of neurotoxic species is triggered when prion propagation saturates, leading to a switch from autocatalytic production of infectivity (phase 1) to a toxic (phase 2) pathway.     

Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension

To identify renally expressed genes that influence risk for hypertension, we integrated expression quantitative trait locus (QTL) analysis of the kidney with genome-wide correlation analysis of renal expression profiles and blood pressure in recombinant inbred strains derived from the spontaneously hypertensive rat (SHR). This strategy, together with renal transplantation studies in SHR progenitor, transgenic and congenic strains, identified deficient renal expression of Cd36 encoding fatty acid translocase as a genetically determined risk factor for spontaneous hypertension.     

Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.

Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.     

A ranking method for DMUs with interval data based on dea cross-efficiency evaluation and TOPSIS

The traditional data envelopment analysis(DEA)model can evaluate the relative efficiencies of a set of decision making units(DMUs)with exact values of inputs and outputs,but it cannot handle imprecise data.Imprecise data,for example,can be expressed in the form of the interval data or mixtures of interval data and ordinal data.In this study,a cross-efficiency method is introduced into the DEA model to calculate the interval of cross-efficiency values,based on which a new TOPSIS method is proposed to rank the DMUs.Two examples are presented to illustrate and validate the proposed method.     

Composition and functional role of the mucus layers in the intestine

In discussions on intestinal protection, the protective capacity of mucus has not been very much considered. The progress in the last years in understanding the molecular nature of mucins, the main building blocks of mucus, has, however, changed this. The intestinal enterocytes have their apical surfaces covered by transmembrane mucins and the whole intestinal surface is further covered by mucus, built around the gel-forming mucin MUC2. The mucus of the small intestine has only one layer, whereas the large intestine has a two-layered mucus where the inner, attached layer has a protective function for the intestine, as it is impermeable to the luminal bacteria.     

Aeolian processes at the Mars Exploration Rover Meridiani Planum landing site

The martian surface is a natural laboratory for testing our understanding of the physics of aeolian (wind-related) processes in an environment different from that of Earth. Martian surface markings and atmospheric opacity are time-variable, indicating that fine particles at the surface are mobilized regularly by wind. Regolith (unconsolidated surface material) at the Mars Exploration Rover Opportunity's landing site has been affected greatly by wind, which has created and reoriented bedforms, sorted grains, and eroded bedrock. Aeolian features here preserve a unique record of changing wind direction and wind strength. Here we present an in situ examination of a martian bright wind streak, which provides evidence consistent with a previously proposed formational model for such features. We also show that a widely used criterion for distinguishing between aeolian saltation- and suspension-dominated grain behaviour is different on Mars, and that estimated wind friction speeds between 2 and 3 m s(-1), most recently from the northwest, are associated with recent global dust storms, providing ground truth for climate model predictions.     

Evidence for magmatic evolution and diversity on Mars from infrared observations

Compositional mapping of Mars at the 100-metre scale with the Mars Odyssey Thermal Emission Imaging System (THEMIS) has revealed a wide diversity of igneous materials. Volcanic evolution produced compositions from low-silica basalts to high-silica dacite in the Syrtis Major caldera. The existence of dacite demonstrates that highly evolved lavas have been produced, at least locally, by magma evolution through fractional crystallization. Olivine basalts are observed on crater floors and in layers exposed in canyon walls up to 4.5 km beneath the surface. This vertical distribution suggests that olivine-rich lavas were emplaced at various times throughout the formation of the upper crust, with their growing inventory suggesting that such ultramafic (picritic) basalts may be relatively common. Quartz-bearing granitoid rocks have also been discovered, demonstrating that extreme differentiation has occurred. These observations show that the martian crust, while dominated by basalt, contains a diversity of igneous materials whose range in composition from picritic basalts to granitoids rivals that found on the Earth.     

An extended aggregated ratio analysis in DEA

Data Envelopment Analysis (DEA) and Ratio Analysis (RA) are two widely used methods for measuring units' productivity and any other criteria that could be assessed based on the available input and output variables. A number of researchers have studied DEA and RA and noted the positive and negative differences between them. Aggregated ratio analysis (ARA) model, which provide an important linkage between DEA and RA theory, is equivalent to the CCR DEA model, and this equivalence property offers a great deal of opportunities for DEA to be interpreted and applied in different ways. This paper extends the results of ARA model and proposes an extended aggregated ratio analysis (EARA) model, similar as the development from CCR model to BCC model in DEA context. The proposed model can offer an insight into the characteristic of returns to scale, playing the corresponding role as BCC model does. The numerical example is revisited in the paper and the results are compared.