In vivo activation of the p53 pathway by small-molecule antagonists of MDM2     

Vassilev LT  Vu BT  Graves B  Carvajal D  Podlaski F  Filipovic Z  Kong N  Kammlott U  Lukacs C  Klein C  Fotouhi N  Liu EA 《Science (New York, N.Y.)》2004,303(5659):844-848

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Forced unfolding of proteins within cells     

Johnson CP  Tang HY  Carag C  Speicher DW  Discher DE 《Science (New York, N.Y.)》2007,317(5838):663-666

To identify cytoskeletal proteins that change conformation or assembly within stressed cells, in situ labeling of sterically shielded cysteines with fluorophores was analyzed by fluorescence imaging, quantitative mass spectrometry, and sequential two-dye labeling. Within red blood cells, shotgun labeling showed that shielded cysteines in the two isoforms of the cytoskeletal protein spectrin were increasingly labeled as a function of shear stress and time, indicative of forced unfolding of specific domains. Within mesenchymal stem cells-as a prototypical adherent cell-nonmuscle myosin IIA and vimentin are just two of the cytoskeletal proteins identified that show differential labeling in tensed versus drug-relaxed cells. Cysteine labeling of proteins within live cells can thus be used to fluorescently map out sites of molecular-scale deformation, and the results also suggest means to colocalize signaling events such as phosphorylation with forced unfolding.  相似文献   

Holocene deglaciation of Marie Byrd Land,West Antarctica     

Stone JO  Balco GA  Sugden DE  Caffee MW  Sass LC  Cowdery SG  Siddoway C 《Science (New York, N.Y.)》2003,299(5603):99-102

Surface exposure ages of glacial deposits in the Ford Ranges of western Marie Byrd Land indicate continuous thinning of the West Antarctic Ice Sheet by more than 700 meters near the coast throughout the past 10,000 years. Deglaciation lagged the disappearance of ice sheets in the Northern Hemisphere by thousands of years and may still be under way. These results provide further evidence that parts of the West Antarctic Ice Sheet are on a long-term trajectory of decline. West Antarctic melting contributed water to the oceans in the late Holocene and may continue to do so in the future.  相似文献   

Accelerated uplift and magmatic intrusion of the Yellowstone caldera, 2004 to 2006     

Chang WL  Smith RB  Wicks C  Farrell JM  Puskas CM 《Science (New York, N.Y.)》2007,318(5852):952-956

The Yellowstone caldera began a rapid episode of ground uplift in mid-2004, revealed by Global Positioning System and interferometric synthetic aperture radar measurements, at rates up to 7 centimeters per year, which is over three times faster than previously observed inflation rates. Source modeling of the deformation data suggests an expanding volcanic sill of approximately 1200 square kilometers at a 10-kilometer depth beneath the caldera, coincident with the top of a seismically imaged crustal magma chamber. The modeled rate of source volume increase is 0.1 cubic kilometer per year, similar to the amount of magma intrusion required to supply the observed high heat flow of the caldera. This evidence suggests magma recharge as the main mechanism for the accelerated uplift, although pressurization of magmatic fluids cannot be ruled out.  相似文献   

Crystal structure of the malaria vaccine candidate apical membrane antigen 1     

Pizarro JC  Vulliez-Le Normand B  Chesne-Seck ML  Collins CR  Withers-Martinez C  Hackett F  Blackman MJ  Faber BW  Remarque EJ  Kocken CH  Thomas AW  Bentley GA 《Science (New York, N.Y.)》2005,308(5720):408-411

Apical membrane antigen 1 from Plasmodium is a leading malaria vaccine candidate. The protein is essential for host-cell invasion, but its molecular function is unknown. The crystal structure of the three domains comprising the ectoplasmic region of the antigen from P. vivax, solved at 1.8 angstrom resolution, shows that domains I and II belong to the PAN motif, which defines a superfamily of protein folds implicated in receptor binding. We also mapped the epitope of an invasion-inhibitory monoclonal antibody specific for the P. falciparum ortholog and modeled this to the structure. The location of the epitope and current knowledge on structure-function correlations for PAN domains together suggest a receptor-binding role during invasion in which domain II plays a critical part. These results are likely to aid vaccine and drug design.  相似文献   

Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis     

Partridge EA  Le Roy C  Di Guglielmo GM  Pawling J  Cheung P  Granovsky M  Nabi IR  Wrana JL  Dennis JW 《Science (New York, N.Y.)》2004,306(5693):120-124

The Golgi enzyme beta1,6 N-acetylglucosaminyltransferase V (Mgat5) is up-regulated in carcinomas and promotes the substitution of N-glycan with poly N-acetyllactosamine, the preferred ligand for galectin-3 (Gal-3). Here, we report that expression of Mgat5 sensitized mouse cells to multiple cytokines. Gal-3 cross-linked Mgat5-modified N-glycans on epidermal growth factor and transforming growth factor-beta receptors at the cell surface and delayed their removal by constitutive endocytosis. Mgat5 expression in mammary carcinoma was rate limiting for cytokine signaling and consequently for epithelial-mesenchymal transition, cell motility, and tumor metastasis. Mgat5 also promoted cytokine-mediated leukocyte signaling, phagocytosis, and extravasation in vivo. Thus, conditional regulation of N-glycan processing drives synchronous modification of cytokine receptors, which balances their surface retention against loss via endocytosis.  相似文献   

Resolving the urban nest predator paradox: The role of alternative foods for nest predators     

Christine M. Stracey 《Biological conservation》2011,(5):1545-1552

Urbanization is a leading cause of species endangerment in the United States; however, certain species thrive in urban habitats. The loss of key predators or the addition of new predators in urban areas could alter the structure of urban communities. A reduction in nest predation is hypothesized to explain the high density of urban birds, yet urban areas typically have increased populations of avian nest predators. The loss of important nest predators in urban habitats, prey switching of urban predators, or successful nest defense against avian nest predators could explain this urban nest predator paradox. To assess these hypotheses I compared nest predation rates of Northern mockingbirds (Mimus polyglottos) in parking lots and residential neighborhoods to populations in pastures and wildlife preserves during 2007–2009 in Florida, USA and placed video cameras on a subset of nests in 2008–2009. Data do not support the hypothesis that urban nest predation rates are consistently lower than non-urban nest predation rates. Of the 56 nest predation events recorded, cats were the dominant urban predator and Cooper’s hawks (Accipiter cooperii) were the dominant non-urban predator. There was no evidence for a loss of important nest predators in urban habitats; however, prey switching by Cooper’s hawks likely occurred. There was also indirect evidence for the importance of nest defense. Furthermore, some of the cats recorded as nest predators in residential neighborhoods were owned cats and all but one cat predation event occurred at night. To reduce nest predation rates, cat owners should keep their cats indoors at night.  相似文献   

Bioaccumulation of melamine in catfish muscle following continuous, low-dose, oral administration     

Andersen WC  Turnipseed SB  Karbiwnyk CM  Evans E  Hasbrouck N  Mayer TD  Gieseker CM  Nochetto C  Stine CB  Reimschuessel R 《Journal of agricultural and food chemistry》2011,59(7):3111-3117

In this study, catfish muscle was analyzed for melamine (MEL) and cyanuric acid (CYA) residues following experimental feeding with low doses of MEL and MEL and CYA (MEL+CYA) and with the insoluble melamine-cyanurate complex (MEL=CYA). Catfish were daily fed 0.1 mg/kg BW of MEL for 15, 28, or 42 days, 0.1 mg/kg BW of MEL+CYA for 28 days, 2.5 mg/kg BW of MEL+CYA for 14 days, or 400 mg/kg BW of MEL=CYA for 3 days. Residues in the tissue were determined by LC-MS/MS. MEL was extracted with acidic acetonitrile, followed by defatting with dichloromethane, and isolated with cation exchange solid phase extraction (SPE). For CYA analysis, fish were extracted with dilute acetic acid, defatted with hexane, and cleaned up with a graphitic carbon SPE. Catfish fed 0.1 mg/kg BW of MEL reached a maximum muscle residue concentration of 0.33 ± 0.04 mg/kg (ppm) after 28 days of continuous feeding. The same concentration was found for MEL+CYA feeding at the 0.1 mg/kg BW level for 28 days. Feeding at 2.5 mg/kg BW of MEL+CYA yielded muscle concentrations above the 2.5 mg/kg level of concern for most of the study fish. Finally, catfish fed high levels of the MEL=CYA complex (400 mg/kg BW) accumulated relatively little MEL in the muscle (0.14 ± 0.07 mg/kg) and, unlike treatment with MEL+CYA, did not form renal melamine-cyanurate crystals. Appreciable concentrations of CYA were not detected in any of the muscles tested. These studies provide data to model the bioaccumulation of triazine residues into edible fish tissue as a result of the continuous consumption of adulterated feed.  相似文献   

Denitrification potential of intermittently saturated floodplain soils from a subtropical perennial stream and an ephemeral tributary     

Christine S. Fellows  Heather M. Hunter  Claire E.A. Eccleston  David W. Rassam  Philip M. Bloesch 《Soil biology & biochemistry》2011,43(2):324-332

Denitrification has the potential to remove excess nitrogen from groundwater passing through riparian buffers, thus improving water quality downstream. In regions with markedly seasonal precipitation, transient stream flow events may be important in saturating adjacent floodplain soils and intermittently providing the anaerobic conditions necessary for denitrification to occur. In two experiments we characterised the denitrification potential of soils from two contrasting floodplains that experience intermittent saturation. We quantified under controlled laboratory conditions: 1) potential rates of denitrification in these soils with depth and over time, for a typical period of saturation; and 2) the influences on rates of nitrate and organic carbon. Treatments differed between experiments, but in each case soil-water slurries were incubated anaerobically with differing amendments of organic carbon and nitrate; denitrification rates were measured at selected time intervals by the acetylene-block technique; and slurry filtrates were analysed for various chemical constituents. In the first experiment (ephemeral tributary), denitrification was evident in soils from both depths (0-0.3 m; 0.3-1.1 m) within hours of saturation. Before Day 2, mean denitrification rates at each depth were generally comparable, irrespective of added substrates; mean rates (Days 0 and 1) were 5.2 ± 0.3 mg N kg dry soil⁻¹ day⁻¹ (0-0.3 m) and 1.6 ± 0.2 mg N kg dry soil⁻¹ day⁻¹ (0.3-1.1 m). Rates generally peaked on Days 2 or 3. The availability of labile organic carbon was a major constraint on denitrification in these soils. Acetate addition greatly increased rates, reaching a maximum in ephemeral floodplain soils of 17.4 ± 1.8 mg N kg dry soil⁻¹ day⁻¹ on Day 2: in one deep-soil treatment (low nitrate) this overcame differences in rates observed with depth when acetate was not added, although the rate increase in the other deep-soil treatment (high nitrate) was significantly less (P ≤ 0.01). Without acetate, peak denitrification rates in this experiment were 6.9 ± 0.4 and 2.8 ± 0.2 mg N kg dry soil⁻¹ day⁻¹ in surface and deep soils, respectively. Differences in rates were observed with depth on all occasions, despite similar initial concentrations of dissolved organic carbon (DOC) at both depths. Levels of substrate addition in the second experiment (perennial stream) more closely reflected natural conditions at the site. Mean denitrification rates were consistently much higher in surface soil (P ≤ 0.001), while the source of water used in the slurries (surface water or groundwater from the site) had little effect on rates at any depth. Mean rates when all treatments retained nitrate were: 4.5 ± 0.3 mg N kg dry soil⁻¹ day⁻¹ (0-0.3 m depth); 0.8 ± 0.3 mg N kg dry soil⁻¹ day⁻¹ (0.3-1.0 m); and 0.6 ± 0.1 mg N kg dry soil⁻¹ day⁻¹ (1.8-3.5 m). For comparable treatments and soil depths, denitrification potentials at both sites were similar, apart from higher initial rates in the ephemeral floodplain soils, probably associated with their higher DOC content and possibly also their history of more frequent saturation. The rapid onset of denitrification and the rates measured in these soils suggest there may be considerable potential for nitrate removal from groundwater in these floodplain environments during relatively short periods of saturation.  相似文献   

Formation of Maillard reaction products during heat treatment of carrots     

Wellner A  Huettl C  Henle T 《Journal of agricultural and food chemistry》2011,59(14):7992-7998

As indicators of the early stage of the Maillard reaction in carrots, N-(furoylmethyl) amino acids (FMAAs) formed during acid hydrolysis of the corresponding Amadori products were analyzed using RP-HPLC with UV detection. N(ε)-FM-Lys (furosine), FM-Gly, FM-Ala, FM-Val, FM-Ile, FM-Leu, and FM-GABA were identified using synthesized standard material by means of mass spectrometry. Furthermore, N(ε)-carboxymethyllysine (CML) and pyrraline were analyzed as indicators for advanced stages of glycation. For commercial samples with high water content, the formation of Amadori compounds predominates, whereas the advanced stage of Maillard reaction plays only a minor part. Carrot juices, baby food, and tinned carrots showed quite low rates of amino acid modification up to 5%. For dehydrated carrots, significantly higher values for Amadori products were measured, corresponding to a lysine derivatization of up to 58% and nearly 100% derivatization of GABA. Drying experiments revealed great differences in reactivity between the amino acids studied. Whereas furosine reached constant values quite quickly, some FMAAs showed a continuous increase with heating time, indicating that selected FMAAs can be used as a hallmark for the early Maillard reaction to control processing conditions.  相似文献