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61.
Gandhi DD Lane M Zhou Y Singh AP Nayak S Tisch U Eizenberg M Ramanath G 《Nature》2007,447(7142):299-302
Self-assembled molecular nanolayers (MNLs) composed of short organic chains and terminated with desired functional groups are attractive for modifying surface properties for a variety of applications. For example, organosilane MNLs are used as lubricants, in nanolithography, for corrosion protection and in the crystallization of biominerals. Recent work has explored uses of MNLs at thin-film interfaces, both as active components in molecular devices, and as passive layers, inhibiting interfacial diffusion, promoting adhesion and toughening brittle nanoporous structures. The relatively low stability of MNLs on surfaces at temperatures above 350-400 degrees C (refs 12, 13), as a result of desorption or degradation, limits the use of surface MNLs in high-temperature applications. Here we harness MNLs at thin-film interfaces at temperatures higher than the MNL desorption temperature to fortify copper-dielectric interfaces relevant to wiring in micro- and nano-electronic devices. Annealing Cu/MNL/SiO2 structures at 400-700 degrees C results in interfaces that are five times tougher than pristine Cu/SiO2 structures, yielding values exceeding approximately 20 J m(-2). Previously, similarly high toughness values have only been obtained using micrometre-thick interfacial layers. Electron spectroscopy of fracture surfaces and density functional theory modelling of molecular stretching and fracture show that toughening arises from thermally activated interfacial siloxane bridging that enables the MNL to be strongly linked to both the adjacent layers at the interface, and suppresses MNL desorption. We anticipate that our findings will open up opportunities for molecular-level tailoring of a variety of interfacial properties, at processing temperatures higher than previously envisaged, for applications where microlayers are not a viable option-such as in nanodevices or in thermally resistant molecular-inorganic hybrid devices. 相似文献
62.
63.
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
64.
65.
Identification of Tim4 as a phosphatidylserine receptor 总被引:1,自引:0,他引:1
In programmed cell death, a large number of cells undergo apoptosis, and are engulfed by macrophages to avoid the release of noxious materials from the dying cells. In definitive erythropoiesis, nuclei are expelled from erythroid precursor cells and are engulfed by macrophages. Phosphatidylserine is exposed on the surface of apoptotic cells and on the nuclei expelled from erythroid precursor cells; it works as an 'eat me' signal for phagocytes. Phosphatidylserine is also expressed on the surface of exosomes involved in intercellular signalling. Here we established a library of hamster monoclonal antibodies against mouse peritoneal macrophages, and found an antibody that strongly inhibited the phosphatidylserine-dependent engulfment of apoptotic cells. The antigen recognized by the antibody was identified by expression cloning as a type I transmembrane protein called Tim4 (T-cell immunoglobulin- and mucin-domain-containing molecule; also known as Timd4). Tim4 was expressed in Mac1+ cells in various mouse tissues, including spleen, lymph nodes and fetal liver. Tim4 bound apoptotic cells by recognizing phosphatidylserine via its immunoglobulin domain. The expression of Tim4 in fibroblasts enhanced their ability to engulf apoptotic cells. When the anti-Tim4 monoclonal antibody was administered into mice, the engulfment of apoptotic cells by thymic macrophages was significantly blocked, and the mice developed autoantibodies. Among the other Tim family members, Tim1, but neither Tim2 nor Tim3, specifically bound phosphatidylserine. Tim1- or Tim4-expressing Ba/F3 B cells were bound by exosomes via phosphatidylserine, and exosomes stimulated the interaction between Tim1 and Tim4. These results indicate that Tim4 and Tim1 are phosphatidylserine receptors for the engulfment of apoptotic cells, and may also be involved in intercellular signalling in which exosomes are involved. 相似文献
66.
Cdk1 is sufficient to drive the mammalian cell cycle 总被引:1,自引:0,他引:1
Santamaría D Barrière C Cerqueira A Hunt S Tardy C Newton K Cáceres JF Dubus P Malumbres M Barbacid M 《Nature》2007,448(7155):811-815
67.
Kobayakawa K Kobayakawa R Matsumoto H Oka Y Imai T Ikawa M Okabe M Ikeda T Itohara S Kikusui T Mori K Sakano H 《Nature》2007,450(7169):503-508
The mammalian olfactory system mediates various responses, including aversive behaviours to spoiled foods and fear responses to predator odours. In the olfactory bulb, each glomerulus represents a single species of odorant receptor. Because a single odorant can interact with several different receptor species, the odour information received in the olfactory epithelium is converted to a topographical map of multiple glomeruli activated in distinct areas in the olfactory bulb. To study how the odour map is interpreted in the brain, we generated mutant mice in which olfactory sensory neurons in a specific area of the olfactory epithelium are ablated by targeted expression of the diphtheria toxin gene. Here we show that, in dorsal-zone-depleted mice, the dorsal domain of the olfactory bulb was devoid of glomerular structures, although second-order neurons were present in the vacant areas. The mutant mice lacked innate responses to aversive odorants, even though they were capable of detecting them and could be conditioned for aversion with the remaining glomeruli. These results indicate that, in mice, aversive information is received in the olfactory bulb by separate sets of glomeruli, those dedicated for innate and those for learned responses. 相似文献
68.
PTC124 targets genetic disorders caused by nonsense mutations 总被引:1,自引:0,他引:1
Welch EM Barton ER Zhuo J Tomizawa Y Friesen WJ Trifillis P Paushkin S Patel M Trotta CR Hwang S Wilde RG Karp G Takasugi J Chen G Jones S Ren H Moon YC Corson D Turpoff AA Campbell JA Conn MM Khan A Almstead NG Hedrick J Mollin A Risher N Weetall M Yeh S Branstrom AA Colacino JM Babiak J Ju WD Hirawat S Northcutt VJ Miller LL Spatrick P He F Kawana M Feng H Jacobson A Peltz SW Sweeney HL 《Nature》2007,447(7140):87-91
Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options. 相似文献
69.
Stark A Lin MF Kheradpour P Pedersen JS Parts L Carlson JW Crosby MA Rasmussen MD Roy S Deoras AN Ruby JG Brennecke J;Harvard FlyBase curators;Berkeley Drosophila Genome Project Hodges E Hinrichs AS Caspi A Paten B Park SW Han MV Maeder ML Polansky BJ Robson BE Aerts S van Helden J Hassan B Gilbert DG Eastman DA Rice M Weir M Hahn MW Park Y Dewey CN Pachter L Kent WJ Haussler D Lai EC Bartel DP Hannon GJ Kaufman TC Eisen MB Clark AG Smith D Celniker SE Gelbart WM Kellis M 《Nature》2007,450(7167):219-232
70.
Sluijs A Brinkhuis H Schouten S Bohaty SM John CM Zachos JC Reichart GJ Sinninghe Damsté JS Crouch EM Dickens GR 《Nature》2007,450(7173):1218-1221
The start of the Palaeocene/Eocene thermal maximum--a period of exceptional global warming about 55 million years ago--is marked by a prominent negative carbon isotope excursion that reflects a massive input of 13C-depleted ('light') carbon to the ocean-atmosphere system. It is often assumed that this carbon injection initiated the rapid increase in global surface temperatures and environmental change that characterize the climate perturbation, but the exact sequence of events remains uncertain. Here we present chemical and biotic records of environmental change across the Palaeocene/Eocene boundary from two sediment sections in New Jersey that have high sediment accumulation rates. We show that the onsets of environmental change (as recorded by the abundant occurrence ('acme') of the dinoflagellate cyst Apectodinium) and of surface-ocean warming (as evidenced by the palaeothermometer TEX86) preceded the light carbon injection by several thousand years. The onset of the Apectodinium acme also precedes the carbon isotope excursion in sections from the southwest Pacific Ocean and the North Sea, indicating that the early onset of environmental change was not confined to the New Jersey shelf. The lag of approximately 3,000 years between the onset of warming in New Jersey shelf waters and the carbon isotope excursion is consistent with the hypothesis that bottom water warming caused the injection of 13C-depleted carbon by triggering the dissociation of submarine methane hydrates, but the cause of the early warming remains uncertain. 相似文献