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131.
The enantioselective allylation of ketones is a problem of fundamental importance in asymmetric reaction design, especially given that only a very small number of methods can generate tertiary carbinols. Despite the vast amount of attention that synthetic chemists have given to this problem, success has generally been limited to just a few simple ketone types. A method for the selective allylation of functionally complex ketones would greatly increase the utility of ketone allylation methods in the chemical synthesis of important targets. Here we describe the operationally simple, direct, regioselective and enantioselective allylation of β-diketones. The strong tendency of β-diketones to act as nucleophilic species was overcome by using their enol form to provide the necessary Br?nsted-acid activation. This reaction significantly expands the pool of enantiomerically enriched and functionally complex tertiary carbinols that may be easily accessed. It also overturns more than a century of received wisdom regarding the reactivity of β-diketones. 相似文献
132.
Illing PT Vivian JP Dudek NL Kostenko L Chen Z Bharadwaj M Miles JJ Kjer-Nielsen L Gras S Williamson NA Burrows SR Purcell AW Rossjohn J McCluskey J 《Nature》2012,486(7404):554-558
Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T?cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs?6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs. 相似文献
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Seo MD Velamakanni S Ishiyama N Stathopulos PB Rossi AM Khan SA Dale P Li C Ames JB Ikura M Taylor CW 《Nature》2012,483(7387):108-112
Inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca(2+) channels. In each of these receptor families, the pore, which is formed by carboxy-terminal transmembrane domains, is regulated by signals that are detected by large cytosolic structures. InsP(3)R gating is initiated by InsP(3) binding to the InsP(3)-binding core (IBC, residues 224-604 of InsP(3)R1) and it requires the suppressor domain (SD, residues 1-223 of InsP(3)R1). Here we present structures of the amino-terminal region (NT, residues 1-604) of rat InsP(3)R1 with (3.6??) and without (3.0??) InsP(3) bound. The arrangement of the three NT domains, SD, IBC-β and IBC-α, identifies two discrete interfaces (α and β) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR1 (ref. 9). The orientations of the three domains when docked into a tetrameric structure of InsP(3)R and of the ABC domains docked into RyR are remarkably similar. The importance of the α-interface for activation of InsP(3)R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations. Binding of InsP(3) causes partial closure of the clam-like IBC, disrupting the β-interface and pulling the SD towards the IBC. This reorients an exposed SD loop ('hotspot' (HS) loop) that is essential for InsP(3)R activation. The loop is conserved in RyR and includes mutations that are associated with malignant hyperthermia and central core disease. The HS loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A domain of RyR functionally replaced the SD in full-length InsP(3)R, and an InsP(3)R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP(3) and blocked by ryanodine. Activation mechanisms are conserved between InsP(3)R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit reorients the first domain (SD or A domain), allowing it, through interactions of the second domain of an adjacent subunit (IBC-β or B domain), to gate the pore. 相似文献
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J Pross L Contreras PK Bijl DR Greenwood SM Bohaty S Schouten JA Bendle U Röhl L Tauxe JI Raine CE Huck T van de Flierdt SS Jamieson CE Stickley B van de Schootbrugge C Escutia H Brinkhuis;Integrated Ocean Drilling Program Expedition Scientists 《Nature》2012,488(7409):73-77
The warmest global climates of the past 65 million years occurred during the early Eocene epoch (about 55 to 48 million years ago), when the Equator-to-pole temperature gradients were much smaller than today and atmospheric carbon dioxide levels were in excess of one thousand parts per million by volume. Recently the early Eocene has received considerable interest because it may provide insight into the response of Earth's climate and biosphere to the high atmospheric carbon dioxide levels that are expected in the near future as a consequence of unabated anthropogenic carbon emissions. Climatic conditions of the early Eocene 'greenhouse world', however, are poorly constrained in critical regions, particularly Antarctica. Here we present a well-dated record of early Eocene climate on Antarctica from an ocean sediment core recovered off the Wilkes Land coast of East Antarctica. The information from biotic climate proxies (pollen and spores) and independent organic geochemical climate proxies (indices based on branched tetraether lipids) yields quantitative, seasonal temperature reconstructions for the early Eocene greenhouse world on Antarctica. We show that the climate in lowland settings along the Wilkes Land coast (at a palaeolatitude of about 70° south) supported the growth of highly diverse, near-tropical forests characterized by mesothermal to megathermal floral elements including palms and Bombacoideae. Notably, winters were extremely mild (warmer than 10?°C) and essentially frost-free despite polar darkness, which provides a critical new constraint for the validation of climate models and for understanding the response of high-latitude terrestrial ecosystems to increased carbon dioxide forcing. 相似文献
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139.
Zuber MT Head JW Smith DE Neumann GA Mazarico E Torrence MH Aharonson O Tye AR Fassett CI Rosenburg MA Melosh HJ 《Nature》2012,486(7403):378-381
Shackleton crater is nearly coincident with the Moon's south pole. Its interior receives almost no direct sunlight and is a perennial cold trap, making Shackleton a promising candidate location in which to seek sequestered volatiles. However, previous orbital and Earth-based radar mapping and orbital optical imaging have yielded conflicting interpretations about the existence of volatiles. Here we present observations from the Lunar Orbiter Laser Altimeter on board the Lunar Reconnaissance Orbiter, revealing Shackleton to be an ancient, unusually well-preserved simple crater whose interior walls are fresher than its floor and rim. Shackleton floor deposits are nearly the same age as the rim, suggesting that little floor deposition has occurred since the crater formed more than three billion years ago. At a wavelength of 1,064 nanometres, the floor of Shackleton is brighter than the surrounding terrain and the interiors of nearby craters, but not as bright as the interior walls. The combined observations are explicable primarily by downslope movement of regolith on the walls exposing fresher underlying material. The relatively brighter crater floor is most simply explained by decreased space weathering due to shadowing, but a one-micrometre-thick layer containing about 20 per cent surficial ice is an alternative possibility. 相似文献
140.
Iverson RM Dzurisin D Gardner CA Gerlach TM LaHusen RG Lisowski M Major JJ Malone SD Messerich JA Moran SC Pallister JS Qamar AI Schilling SP Vallance JW 《Nature》2006,444(7118):439-443
The 2004-05 eruption of Mount St Helens exhibited sustained, near-equilibrium behaviour characterized by relatively steady extrusion of a solid dacite plug and nearly periodic shallow earthquakes. Here we present a diverse data set to support our hypothesis that these earthquakes resulted from stick-slip motion along the margins of the plug as it was forced incrementally upwards by ascending, solidifying, gas-poor magma. We formalize this hypothesis with a dynamical model that reveals a strong analogy between behaviour of the magma-plug system and that of a variably damped oscillator. Modelled stick-slip oscillations have properties that help constrain the balance of forces governing the earthquakes and eruption, and they imply that magma pressure never deviated much from the steady equilibrium pressure. We infer that the volcano was probably poised in a near-eruptive equilibrium state long before the onset of the 2004-05 eruption. 相似文献