The mutational landscape of head and neck squamous cell carcinoma     

Stransky N  Egloff AM  Tward AD  Kostic AD  Cibulskis K  Sivachenko A  Kryukov GV  Lawrence MS  Sougnez C  McKenna A  Shefler E  Ramos AH  Stojanov P  Carter SL  Voet D  Cortés ML  Auclair D  Berger MF  Saksena G  Guiducci C  Onofrio RC  Parkin M  Romkes M  Weissfeld JL  Seethala RR  Wang L  Rangel-Escareño C  Fernandez-Lopez JC  Hidalgo-Miranda A  Melendez-Zajgla J  Winckler W  Ardlie K  Gabriel SB  Meyerson M  Lander ES  Getz G  Golub TR  Garraway LA  Grandis JR 《Science (New York, N.Y.)》2011,333(6046):1157-1160

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.  相似文献   

AMPK is a direct adenylate charge-regulated protein kinase     

Oakhill JS  Steel R  Chen ZP  Scott JW  Ling N  Tam S  Kemp BE 《Science (New York, N.Y.)》2011,332(6036):1433-1435

The adenosine monophosphate (AMP)-activated protein kinase (AMPK) regulates whole-body and cellular energy balance in response to energy demand and supply. AMPK is an αβγ heterotrimer activated by decreasing concentrations of adenosine triphosphate (ATP) and increasing AMP concentrations. AMPK activation depends on phosphorylation of the α catalytic subunit on threonine-172 (Thr(172)) by kinases LKB1 or CaMKKβ, and this is promoted by AMP binding to the γ subunit. AMP sustains activity by inhibiting dephosphorylation of α-Thr(172), whereas ATP promotes dephosphorylation. Adenosine diphosphate (ADP), like AMP, bound to γ sites 1 and 3 and stimulated α-Thr(172) phosphorylation. However, in contrast to AMP, ADP did not directly activate phosphorylated AMPK. In this way, both ADP/ATP and AMP/ATP ratios contribute to AMPK regulation.  相似文献   

Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects     

Egan ME  Pearson M  Weiner SA  Rajendran V  Rubin D  Glöckner-Pagel J  Canny S  Du K  Lukacs GL  Caplan MJ 《Science (New York, N.Y.)》2004,304(5670):600-602

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, DeltaF508, results in the production of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degradation. Curcumin is a nontoxic Ca-adenosine triphosphatase pump inhibitor that can be administered to humans safely. Oral administration of curcumin to homozygous DeltaF508 CFTR mice in doses comparable, on a weight-per-weight basis, to those well tolerated by humans corrected these animals' characteristic nasal potential difference defect. These effects were not observed in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of DeltaF508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Thus, curcumin treatment may be able to correct defects associated with the homozygous expression of DeltaF508 CFTR.  相似文献   

HIV vaccine research: the way forward     

Fauci AS  Johnston MI  Dieffenbach CW  Burton DR  Hammer SM  Hoxie JA  Martin M  Overbaugh J  Watkins DI  Mahmoud A  Greene WC 《Science (New York, N.Y.)》2008,321(5888):530-532

The need to broaden research directed at answering fundamental questions in HIV vaccine discovery through laboratory, nonhuman primate (NHP), and clinical research has recently been emphasized. In addition, the importance of attracting and retaining young researchers, developing better NHP models, and more closely linking NHP and clinical research is being stressed. In an era of a level budget for biomedical research at the U.S. National Institutes of Health (NIH), HIV/AIDS vaccine research efforts will need to be carefully prioritized such that resources to energize HIV vaccine discovery can be identified. This article summarizes progress and challenges in HIV vaccine research, the priorities arising from a recent summit at NIAID, and the actions needed, some already under way, to address those priorities.  相似文献   

Relativistic spin precession in the double pulsar     

Breton RP  Kaspi VM  Kramer M  McLaughlin MA  Lyutikov M  Ransom SM  Stairs IH  Ferdman RD  Camilo F  Possenti A 《Science (New York, N.Y.)》2008,321(5885):104-107

The double pulsar PSR J0737-3039A/B consists of two neutron stars in a highly relativistic orbit that displays a roughly 30-second eclipse when pulsar A passes behind pulsar B. Describing this eclipse of pulsar A as due to absorption occurring in the magnetosphere of pulsar B, we successfully used a simple geometric model to characterize the observed changing eclipse morphology and to measure the relativistic precession of pulsar B's spin axis around the total orbital angular momentum. This provides a test of general relativity and alternative theories of gravity in the strong-field regime. Our measured relativistic spin precession rate of 4.77 degrees (-0 degrees .65)(+0 degrees .66) per year (68% confidence level) is consistent with that predicted by general relativity within an uncertainty of 13%.  相似文献   

The environs of viking 2 lander     

Shorthill RW  Moore HJ  Hutton RE  Scott RF  Spitzer CR 《Science (New York, N.Y.)》1976,194(4271):1309-1318

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Increased structure and active learning reduce the achievement gap in introductory biology     

Haak DC  HilleRisLambers J  Pitre E  Freeman S 《Science (New York, N.Y.)》2011,332(6034):1213-1216

Science, technology, engineering, and mathematics instructors have been charged with improving the performance and retention of students from diverse backgrounds. To date, programs that close the achievement gap between students from disadvantaged versus nondisadvantaged educational backgrounds have required extensive extramural funding. We show that a highly structured course design, based on daily and weekly practice with problem-solving, data analysis, and other higher-order cognitive skills, improved the performance of all students in a college-level introductory biology class and reduced the achievement gap between disadvantaged and nondisadvantaged students--without increased expenditures. These results support the Carnegie Hall hypothesis: Intensive practice, via active-learning exercises, has a disproportionate benefit for capable but poorly prepared students.  相似文献   

A Method for Silvering a Dewar Flask for Optical Experiments     

Haynes JS  Scott JF 《Science (New York, N.Y.)》1948,107(2777):301

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An astronomical 2175 angstrom feature in interplanetary dust particles     

Bradley J  Dai ZR  Erni R  Browning N  Graham G  Weber P  Smith J  Hutcheon I  Ishii H  Bajt S  Floss C  Stadermann F  Sandford S 《Science (New York, N.Y.)》2005,307(5707):244-247

The 2175 angstrom extinction feature is the strongest (visible-ultraviolet) spectral signature of dust in the interstellar medium. Forty years after its discovery, the origin of the feature and the nature of the carrier(s) remain controversial. Using a transmission electron microscope, we detected a 5.7-electron volt (2175 angstrom) feature in interstellar grains embedded within interplanetary dust particles (IDPs). The carriers are organic carbon and amorphous silicates that are abundant in IDPs and in the interstellar medium. These multiple carriers may explain the enigmatic invariant central wavelength and variable bandwidth of the astronomical 2175 angstrom feature.  相似文献   

Blood and bone marrow findings in two pups with mucopolysaccharidosis type VII     

Erica Corda  Cheryl L. Swenson  Michael A. Scott  Dodd G. Sledge  John C. Fyfe 《Veterinary clinical pathology / American Society for Veterinary Clinical Pathology》2021,50(1):164-169

Routine blood smear findings in two of four 11‐day‐old mixed‐breed dog littermates were suggestive of a lysosomal storage disease (LSD) that was documented to be mucopolysaccharidosis type VII (MPS VII) by molecular testing. In this condition, a functional β‐glucuronidase deficiency results in the accumulation of glycosaminoglycans (GAGs) in cells and tissues where β‐glucuronidase is important in GAG degradation. Most neutrophils and a moderate number of lymphocytes within the blood had atypical cytoplasmic magenta inclusions. The bone marrow assessment from one of the two affected pups at 24 days of age revealed similar magenta granulation in myeloid precursor cells that was most prominent in promyelocytes and myelocytes. Moreover, atypical magenta material was present within vacuoles as well as extracellularly in some osteoblasts and macrophages. Histologic bone marrow sections revealed prominent vacuolation of osteoblasts, and some osteoclasts appeared separated from the bone by layers of osteoblasts or hematopoietic cells. At 2 months of age, the second affected dog showed moderate growth retardation and had similar but more prominent hematologic findings that extended to monocytes, eosinophils, and eosinophil precursors. It had an increased number of bone marrow macrophages with many vacuoles that could be seen cytologically to contain magenta material, and there was mild nonselective phagocytosis of hemic cells. Of the hematologic cells, inclusions were most prominent in promyelocytes, myelocytes, and macrophages, cells with relatively high β‐glucuronidase activity, and GAG exposure within lysosomes or lysosome‐like primary granules of granulocyte precursors.  相似文献