Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.     

High 3He/4He ratios in picritic basalts from Baffin Island and the role of a mixed reservoir in mantle plumes

The high 3He/4He ratio of volcanic rocks thought to be derived from mantle plumes is taken as evidence for the existence of a mantle reservoir that has remained largely undegassed since the Earth's accretion. The helium isotope composition of this reservoir places constraints on the origin of volatiles within the Earth and on the evolution and structure of the Earth's mantle. Here we show that olivine phenocrysts in picritic basalts presumably derived from the proto-Iceland plume at Baffin Island, Canada, have the highest magmatic 3He/4He ratios yet recorded. A strong correlation between 3He/4He and 87Sr/86Sr, 143Nd/144Nd and trace element ratios demonstrate that the 3He-rich end-member is present in basalts that are derived from large-volume melts of depleted upper-mantle rocks. This reservoir is consistent with the recharging of depleted upper-mantle rocks by small volumes of primordial volatile-rich lower-mantle material at a thermal boundary layer between convectively isolated reservoirs. The highest 3He/4He basalts from Hawaii and Iceland plot on the observed mixing trend. This indicates that a 3He-recharged depleted mantle (HRDM) reservoir may be the principal source of high 3He/4He in mantle plumes, and may explain why the helium concentration of the 'plume' component in ocean island basalts is lower than that predicted for a two-layer, steady-state model of mantle structure.     

仿生水下机器人运动仿真技术研究

以哈尔滨工程大学仿生水下机器人“仿生-Ⅰ”为研究对象,建立了其运动仿真模型。采用水下机器人六自由度空间运动模型,对仿生水下机器人与传统水下机器人区别较大的推进系统、操纵系统以及附加质量的变化等进行了阐述。利用该模型进行的运动仿真结果和“仿生-Ⅰ”水池试验吻合的较好,表明该仿真模型是符合实际的。本研究也为仿生水下机器人运动控制研究提供了平台,对今后的工作有较大的现实意义。     

Methylmalonic acid — an endogenous toxin?

Methylmalonic acid was previously considered as major neurotoxin in methylmalonic acidurias. In contrast, recent studies support the notion that other metabolites deriving from propionyl-coenzyme A, inducing synergistic inhibition of mitochondrial energy metabolism, are more important than methylmalonic acid to understand the neuropathogenesis of this disease. However, it is not yet known whether methylmalonic acid is involved in the induction of other organ manifestations in this disease, such as chronic renal failure.Received 21 October 2004; received after revision 29 December 2004; accepted 4 January 2005     

A variant associated with nicotine dependence, lung cancer and peripheral arterial disease

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.     

The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans

Choanoflagellates are the closest known relatives of metazoans. To discover potential molecular mechanisms underlying the evolution of metazoan multicellularity, we sequenced and analysed the genome of the unicellular choanoflagellate Monosiga brevicollis. The genome contains approximately 9,200 intron-rich genes, including a number that encode cell adhesion and signalling protein domains that are otherwise restricted to metazoans. Here we show that the physical linkages among protein domains often differ between M. brevicollis and metazoans, suggesting that abundant domain shuffling followed the separation of the choanoflagellate and metazoan lineages. The completion of the M. brevicollis genome allows us to reconstruct with increasing resolution the genomic changes that accompanied the origin of metazoans.     

Domination of heliosheath pressure by shock-accelerated pickup ions from observations of neutral atoms

The solar wind blows an immense magnetic bubble, the heliosphere, in the local interstellar medium (mostly neutral gas) flowing by the Sun. Recent measurements by Voyager 2 across the termination shock, where the solar wind is slowed to subsonic speeds before entering the heliosheath, found that the shocked solar wind plasma contains only approximately 20 per cent of the energy released by the termination shock, whereas energetic particles above approximately 28 keV contain only approximately 10 per cent; approximately 70 per cent of the energy is unaccounted for, leading to speculation that the unmeasured pickup ions or energetic particles below 28 keV contain the missing energy. Here we report the detection and mapping of heliosheath energetic ( approximately 4-20 keV) neutral atoms produced by charge exchange of suprathermal ions with interstellar neutral atoms. The energetic neutral atoms come from a source approximately 60 degrees wide in longitude straddling the direction of the local interstellar medium. Their energy spectra resemble those of solar wind pickup ions, but with a knee at approximately 11 keV instead of approximately 4 keV, indicating that their parent ions are pickup ions energized by the termination shock. These termination-shock-energized pickup ions contain the missing approximately 70 per cent of the energy dissipated in the termination shock, and they dominate the pressure in the heliosheath.     

Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.