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171.
Biodiversity: climate change and the ecologist 总被引:2,自引:0,他引:2
Thuiller W 《Nature》2007,448(7153):550-552
172.
Northen TR Yanes O Northen MT Marrinucci D Uritboonthai W Apon J Golledge SL Nordström A Siuzdak G 《Nature》2007,449(7165):1033-1036
The ability of mass spectrometry to generate intact biomolecular ions efficiently in the gas phase has led to its widespread application in metabolomics, proteomics, biological imaging, biomarker discovery and clinical assays (namely neonatal screens). Matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization have been at the forefront of these developments. However, matrix application complicates the use of MALDI for cellular, tissue, biofluid and microarray analysis and can limit the spatial resolution because of the matrix crystal size (typically more than 10 mum), sensitivity and detection of small compounds (less than 500 Da). Secondary-ion mass spectrometry has extremely high lateral resolution (100 nm) and has found biological applications although the energetic desorption/ionization is a limitation owing to molecular fragmentation. Here we introduce nanostructure-initiator mass spectrometry (NIMS), a tool for spatially defined mass analysis. NIMS uses 'initiator' molecules trapped in nanostructured surfaces or 'clathrates' to release and ionize intact molecules adsorbed on the surface. This surface responds to both ion and laser irradiation. The lateral resolution (ion-NIMS about 150 nm), sensitivity, matrix-free and reduced fragmentation of NIMS allows direct characterization of peptide microarrays, direct mass analysis of single cells, tissue imaging, and direct characterization of blood and urine. 相似文献
173.
Proteomic studies have yielded detailed lists of the proteins present in a cell. Comparatively little is known, however, about how these proteins interact and are spatially arranged within the 'functional modules' of the cell: that is, the 'molecular sociology' of the cell. This gap is now being bridged by using emerging experimental techniques, such as mass spectrometry of complexes and single-particle cryo-electron microscopy, to complement traditional biochemical and biophysical methods. With the development of integrative computational methods to exploit the data obtained, such hybrid approaches will uncover the molecular architectures, and perhaps even atomic models, of many protein complexes. With these structures in hand, researchers will be poised to use cryo-electron tomography to view protein complexes in action within cells, providing unprecedented insights into protein-interaction networks. 相似文献
174.
175.
Milne JC Lambert PD Schenk S Carney DP Smith JJ Gagne DJ Jin L Boss O Perni RB Vu CB Bemis JE Xie R Disch JS Ng PY Nunes JJ Lynch AV Yang H Galonek H Israelian K Choy W Iffland A Lavu S Medvedik O Sinclair DA Olefsky JM Jirousek MR Elliott PJ Westphal CH 《Nature》2007,450(7170):712-716
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes. 相似文献
176.
Koebel CM Vermi W Swann JB Zerafa N Rodig SJ Old LJ Smyth MJ Schreiber RD 《Nature》2007,450(7171):903-907
The capacity of immunity to control and shape cancer, that is, cancer immunoediting, is the result of three processes that function either independently or in sequence: elimination (cancer immunosurveillance, in which immunity functions as an extrinsic tumour suppressor in naive hosts); equilibrium (expansion of transformed cells is held in check by immunity); and escape (tumour cell variants with dampened immunogenicity or the capacity to attenuate immune responses grow into clinically apparent cancers). Extensive experimental support now exists for the elimination and escape processes because immunodeficient mice develop more carcinogen-induced and spontaneous cancers than wild-type mice, and tumour cells from immunodeficient mice are more immunogenic than those from immunocompetent mice. In contrast, the equilibrium process was inferred largely from clinical observations, including reports of transplantation of undetected (occult) cancer from organ donor into immunosuppressed recipients. Herein we use a mouse model of primary chemical carcinogenesis and demonstrate that equilibrium occurs, is mechanistically distinguishable from elimination and escape, and that neoplastic cells in equilibrium are transformed but proliferate poorly in vivo. We also show that tumour cells in equilibrium are unedited but become edited when they spontaneously escape immune control and grow into clinically apparent tumours. These results reveal that, in addition to destroying tumour cells and sculpting tumour immunogenicity, the immune system of a naive mouse can also restrain cancer growth for extended time periods. 相似文献
177.
Hughes ID Däne M Ernst A Hergert W Lüders M Poulter J Staunton JB Svane A Szotek Z Temmerman WM 《Nature》2007,446(7136):650-653
The heavy rare earth elements crystallize into hexagonally close packed (h.c.p.) structures and share a common outer electronic configuration, differing only in the number of 4f electrons they have. These chemically inert 4f electrons set up localized magnetic moments, which are coupled via an indirect exchange interaction involving the conduction electrons. This leads to the formation of a wide variety of magnetic structures, the periodicities of which are often incommensurate with the underlying crystal lattice. Such incommensurate ordering is associated with a 'webbed' topology of the momentum space surface separating the occupied and unoccupied electron states (the Fermi surface). The shape of this surface-and hence the magnetic structure-for the heavy rare earth elements is known to depend on the ratio of the interplanar spacing c and the interatomic, intraplanar spacing a of the h.c.p. lattice. A theoretical understanding of this problem is, however, far from complete. Here, using gadolinium as a prototype for all the heavy rare earth elements, we generate a unified magnetic phase diagram, which unequivocally links the magnetic structures of the heavy rare earths to their lattice parameters. In addition to verifying the importance of the c/a ratio, we find that the atomic unit cell volume plays a separate, distinct role in determining the magnetic properties: we show that the trend from ferromagnetism to incommensurate ordering as atomic number increases is connected to the concomitant decrease in unit cell volume. This volume decrease occurs because of the so-called lanthanide contraction, where the addition of electrons to the poorly shielding 4f orbitals leads to an increase in effective nuclear charge and, correspondingly, a decrease in ionic radii. 相似文献
178.
A second generation human haplotype map of over 3.1 million SNPs 总被引:2,自引:0,他引:2
International HapMap Consortium Frazer KA Ballinger DG Cox DR Hinds DA Stuve LL Gibbs RA Belmont JW Boudreau A Hardenbol P Leal SM Pasternak S Wheeler DA Willis TD Yu F Yang H Zeng C Gao Y Hu H Hu W Li C Lin W Liu S Pan H Tang X Wang J Wang W Yu J Zhang B Zhang Q Zhao H Zhao H Zhou J Gabriel SB Barry R Blumenstiel B Camargo A Defelice M Faggart M Goyette M Gupta S Moore J Nguyen H Onofrio RC Parkin M Roy J Stahl E Winchester E Ziaugra L Altshuler D Shen Y Yao Z Huang W Chu X He Y Jin L Liu Y 《Nature》2007,449(7164):851-861
We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations. 相似文献
179.
Genome-wide detection and characterization of positive selection in human populations 总被引:3,自引:0,他引:3
Sabeti PC Varilly P Fry B Lohmueller J Hostetter E Cotsapas C Xie X Byrne EH McCarroll SA Gaudet R Schaffner SF Lander ES;International HapMap Consortium Frazer KA Ballinger DG Cox DR Hinds DA Stuve LL Gibbs RA Belmont JW Boudreau A Hardenbol P Leal SM Pasternak S Wheeler DA Willis TD Yu F Yang H Zeng C Gao Y Hu H Hu W Li C Lin W Liu S Pan H Tang X Wang J Wang W Yu J Zhang B Zhang Q Zhao H Zhao H Zhou J Gabriel SB Barry R Blumenstiel B Camargo A Defelice M Faggart M Goyette M Gupta S Moore J 《Nature》2007,449(7164):913-918
With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia. 相似文献
180.