Rationalization of the effects of mutations on peptide and protein aggregation rates

In order for any biological system to function effectively, it is essential to avoid the inherent tendency of proteins to aggregate and form potentially harmful deposits. In each of the various pathological conditions associated with protein deposition, such as Alzheimer's and Parkinson's diseases, a specific peptide or protein that is normally soluble is deposited as insoluble aggregates generally referred to as amyloid. It is clear that the aggregation process is generally initiated from partially or completely unfolded forms of the peptides and proteins associated with each disease. Here we show that the intrinsic effects of specific mutations on the rates of aggregation of unfolded polypeptide chains can be correlated to a remarkable extent with changes in simple physicochemical properties such as hydrophobicity, secondary structure propensity and charge. This approach allows the pathogenic effects of mutations associated with known familial forms of protein deposition diseases to be rationalized, and more generally enables prediction of the effects of mutations on the aggregation propensity of any polypeptide chain.     

Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases

A range of human degenerative conditions, including Alzheimer's disease, light-chain amyloidosis and the spongiform encephalopathies, is associated with the deposition in tissue of proteinaceous aggregates known as amyloid fibrils or plaques. It has been shown previously that fibrillar aggregates that are closely similar to those associated with clinical amyloidoses can be formed in vitro from proteins not connected with these diseases, including the SH3 domain from bovine phosphatidyl-inositol-3'-kinase and the amino-terminal domain of the Escherichia coli HypF protein. Here we show that species formed early in the aggregation of these non-disease-associated proteins can be inherently highly cytotoxic. This finding provides added evidence that avoidance of protein aggregation is crucial for the preservation of biological function and suggests common features in the origins of this family of protein deposition diseases.     

Mechanism of force generation by myosin heads in skeletal muscle

Muscles generate force and shortening in a cyclical interaction between the myosin head domains projecting from the myosin filaments and the adjacent actin filaments. Although many features of the dynamic performance of muscle are determined by the rates of attachment and detachment of myosin and actin, the primary event in force generation is thought to be a conformational change or 'working stroke' in the actin-bound myosin head. According to this hypothesis, the working stroke is much faster than attachment or detachment, but can be observed directly in the rapid force transients that follow step displacement of the filaments. Although many studies of the mechanism of muscle contraction have been based on this hypothesis, the alternative view-that the fast force transients are caused by fast components of attachment and detachment--has not been excluded definitively. Here we show that measurements of the axial motions of the myosin heads at ?ngstr?m resolution by a new X-ray interference technique rule out the rapid attachment/detachment hypothesis, and provide compelling support for the working stroke model of force generation.     

Laser synthesized nanoparticle alloys of metals with bulk miscibility gaps

The nanoscale alloying of metals with bulk miscibility gaps, Ag-Pt and Ag-Rh, has been investigated using pulsed laser ablation of solids in solution(PLASiS). The procedure was in two steps. In the first step, the suspensions of monometallic nanoparticles were prepared by ablation of a metal rod submerged in water. In the second step,the monometallic suspensions were mixed and alloying was induced by re-irradiation. For the Ag-Pt system, a surface plasmon resonance was observed in the monometallic silver suspension. The surface plasmon resonance vanished in re-irradiated Ag-Pt suspensions, indicating alloying. Selected Area Electron Diffraction(SAED)analysis showed that the nanoparticles had a fcc structure with a lattice constant intermediate between that of monometallic Ag and Pt nanoparticles. First principles theoretical investigations of the mixing energy of Ag-Pt clusters confirm that mixing is favored at around ～1 nm. The same procedure used for Ag-Pt was followed for Ag-Rh. In this system where the two metals present miscibility gaps even in the liquid phase, no evidence of alloying was observed. Correspondingly, theoretical investigations found that the mixing energy of Ag-Rh clusters did not favor alloying.     

Modeling and forecasting the oil volatility index

The increase in oil price volatility in recent years has raised the importance of forecasting it accurately for valuing and hedging investments. The paper models and forecasts the crude oil exchange‐traded funds (ETF) volatility index, which has been used in the last years as an important alternative measure to track and analyze the volatility of future oil prices. Analysis of the oil volatility index suggests that it presents features similar to those of the daily market volatility index, such as long memory, which is modeled using well‐known heterogeneous autoregressive (HAR) specifications and new extensions that are based on net and scaled measures of oil price changes. The aim is to improve the forecasting performance of the traditional HAR models by including predictors that capture the impact of oil price changes on the economy. The performance of the new proposals and benchmarks is evaluated with the model confidence set (MCS) and the Generalized‐AutoContouR (G‐ACR) tests in terms of point forecasts and density forecasting, respectively. We find that including the leverage in the conditional mean or variance of the basic HAR model increases its predictive ability. Furthermore, when considering density forecasting, the best models are a conditional heteroskedastic HAR model that includes a scaled measure of oil price changes, and a HAR model with errors following an exponential generalized autoregressive conditional heteroskedasticity specification. In both cases, we consider a flexible distribution for the errors of the conditional heteroskedastic process.     

Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis

Integrity of the blood vessel wall is essential for vascular homeostasis and organ function. A dynamic balance between endothelial cell survival and apoptosis contributes to this integrity during vascular development and pathological angiogenesis. The genetic and molecular mechanisms regulating these processes in vivo are still largely unknown. Here, we show that Birc2 (also known as cIap1) is essential for maintaining endothelial cell survival and blood vessel homeostasis during vascular development. Using a forward-genetic approach, we identified a zebrafish null mutant for birc2, which shows severe hemorrhage and vascular regression due to endothelial cell integrity defects and apoptosis. Using genetic and molecular approaches, we show that Birc2 positively regulates the formation of the TNF receptor complex I in endothelial cells, thereby promoting NF-kappaB activation and maintaining vessel integrity and stabilization. In the absence of Birc2, a caspase-8-dependent apoptotic program takes place that leads to vessel regression. Our findings identify Birc2 and TNF signaling components as critical regulators of vascular integrity and endothelial cell survival, thereby providing an additional target pathway for the control of angiogenesis and blood vessel homeostasis during embryogenesis, regeneration and tumorigenesis.     

MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion

The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral (OMIM 251880). Known mutant genes, including TK2, SUCLA2, DGUOK and POLG, account for only a fraction of MDDS cases. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17. We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17-/- mice.