Premature ageing in mice expressing defective mitochondrial DNA polymerase

Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in a variety of tissues during ageing in humans, monkeys and rodents. These mutations are unevenly distributed and can accumulate clonally in certain cells, causing a mosaic pattern of respiratory chain deficiency in tissues such as heart, skeletal muscle and brain. In terms of the ageing process, their possible causative effects have been intensely debated because of their low abundance and purely correlative connection with ageing. We have now addressed this question experimentally by creating homozygous knock-in mice that express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase. Here we show that the knock-in mice develop an mtDNA mutator phenotype with a threefold to fivefold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced lifespan and premature onset of ageing-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia (hair loss), kyphosis (curvature of the spine), osteoporosis, anaemia, reduced fertility and heart enlargement. Our results thus provide a causative link between mtDNA mutations and ageing phenotypes in mammals.     

New Synthesis of Pt-Ru Nanoparticles on Surface Modified Carbon Vulcane XC-72 as an Effective Catalyst for Direct Methanol Fuel Cell

1 Results Pt-Ru nanoparticles are synthesised on the surface oxidized carbon Vulcane XC-72 as catalyst support by chemically anchoring Pt and Ru onto the surface of modified carbon vulcane XC-72 (by refluxing in 70% HNO3 at 120 ℃ for 12 h to introduce surface functional groups) .The nanoparticles of Pt and Ru are synthesized by reduction of H2PtCl6 and K4Ru(CN)6 with sodium borohydride in a 5.5 buffer solution of sodium citrate,the complexation of citrate with metal ions is beneficial to the formati...     

Robust Control of Robotic Manipulators in the Task-Space Using an Adaptive Observer Based on Chebyshev Polynomials

In this paper, an adaptive observer for robust control of robotic manipulators is proposed.The lumped uncertainty is estimated using Chebyshev polynomials. Usually, the uncertainty upper bound is required in designing observer-controller structures. However, obtaining this bound is a challenging task. To solve this problem, many uncertainty estimation techniques have been proposed in the literature based on neuro-fuzzy systems. As an alternative, in this paper, Chebyshev polynomials have been applied to uncertainty estimation due to their simpler structure and less computational load.Based on strictly-positive-real(SPR) Lyapunov theory, the stability of the closed-loop system can be verified. The Chebyshev coefficients are tuned based on the adaptation rules obtained in the stability analysis. Also, to compensate the truncation error of the Chebyshev polynomials, a continuous robust control term is designed while in previous related works, usually a discontinuous term is used. An SCARA manipulator actuated by permanent magnet DC motors is used for computer simulations.Simulation results reveal the superiority of the designed method.     

Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that causes substantial morbidity. As is typical for many other multifactorial disorders, much of the heritability of SLE remains unknown. We identified a rare autosomal recessive form of SLE, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene. The DNASE1L3-related SLE we describe was always pediatric in onset and correlated with a high frequency of lupus nephritis. Our findings confirm the critical role of impaired clearance of degraded DNA in SLE pathogenesis.     

Evolution and biology of supernumerary B chromosomes

B chromosomes (Bs) are dispensable components of the genome exhibiting non-Mendelian inheritance and have been widely reported on over several thousand eukaryotes, but still remain an evolutionary mystery ever since their first discovery over a century ago [1]. Recent advances in genome analysis have significantly improved our knowledge on the origin and composition of Bs in the last few years. In contrast to the prevalent view that Bs do not harbor genes, recent analysis revealed that Bs of sequenced species are rich in gene-derived sequences. We summarize the latest findings on supernumerary chromosomes with a special focus on the origin, DNA composition, and the non-Mendelian accumulation mechanism of Bs.     

The common fragile site FRA16D gene product WWOX: roles in tumor suppression and genomic stability

The fragile WWOX gene, encompassing the chromosomal fragile site FRA16D, is frequently altered in human cancers. While vulnerable to DNA damage itself, recent evidence has shown that the WWOX protein is essential for proper DNA damage response (DDR). Furthermore, the gene product, WWOX, has been associated with multiple protein networks, highlighting its critical functions in normal cell homeostasis. Targeted deletion of Wwox in murine models suggests its in vivo requirement for proper growth, metabolism, and survival. Recent molecular and biochemical analyses of WWOX functions highlighted its role in modulating aerobic glycolysis and genomic stability. Cumulatively, we propose that the gene product of FRA16D, WWOX, is a functionally essential protein that is required for cell homeostasis and that its deletion has important consequences that contribute to the neoplastic process. This review discusses the essential role of WWOX in tumor suppression and genomic stability and how its alteration contributes to cancer transformation.     

Fabrication,microstructure, and optical properties of nanocrystalline transparent LAST glass ceramics containing CeO2

In the present research, the effect of CeO2 dopant on the fabrication of transparent lithium aluminosilicate titanate （LAST） glass ceramics was investigated. Nanocrystallineβ-quartz solid solution （s.s.） was observed to be the main phase crystallized in this system. Com-parable refractive indices of the glassy matrix andβ-quartz s.s., as well as the incorporation of very fine grains size were determined as the main reasons for retaining the transparency of the glass ceramics. CeO2 was introduced as a suitable optical agent, playing a role as a network modifier in the glass ceramics, because it does not accelerate the growth process and retards the extended growth of crystals. Optical investi-gations indicate that the Fermi energy level, direct and indirect band gaps, and Urbach energy decrease with increasing nanocrystal content in the glassy matrix of specimens, which can be related to the expansion of conduction band, the enhancement of ionic bonds in the crystal lat-tice, and the enhancement of structural arrangement degree, respectively.     

Kinetic modeling of copper bioleaching from low-grade ore from the Shahrbabak Copper Complex

The copper recovery from low-grade copper sulfide ore was investigated using microbial leaching. Several parameters substantially affect the bioleaching of copper; among them, pulp density and nutrient media were selected for investigation. The optimum conditions for copper recovery were a pulp density of 5 g/mL, a mixed-mineral salt medium of Acidithiobacillus thiooxidans (70vol%) and Acidithiobacillus ferrooxidans (30vol%), and 10vol% of inoculum. Under these conditions, the maximum bioleaching capacity of the medium for copper recovery was determined to be approximately 99%. The effect of pulp density on the kinetics of the bioleaching process was surveyed using both da Silva's method and constrained multilinear regression analysis. The kinetics of copper dissolution followed the shrinking core model, and the process was diffusion controlled at a pulp density of 5 g/mL. Nevertheless, at higher pulp densities, the process was controlled by chemical reaction.     

Production planning problem with pricing under random yield: CVaR criterion

In this paper, we address a basic production planning problem with price dependent demand and stochastic yield of production. We use price and target quantity as decision variables to lower the risk of low yield. The value of risk control becomes more important especially for products with short life cycle. This is because, the profit implications of low yield might be unbearable in the short run. We apply Conditional Value at Risk （CVaR） to model the, risk. CVaR measure is a coherent risk measure and thereby having nice conceptual and mathematical underpinnings. It is also widely used in practice. We consider the problem under general demand function and general distribution function of yield and find sufficient conditions under which the problem has a unique local maximum. We also both analytically and numerically analyze the impact of parameter change on the optimal solution. Among our results, we analytically show that with increasing risk aversion, the optimal price increases. This relation is opposite to that of in Newsvendor problem where the uncertainty lies in demand side.     

RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.