全文获取类型
收费全文 | 1006篇 |
免费 | 2篇 |
国内免费 | 2篇 |
专业分类
系统科学 | 13篇 |
理论与方法论 | 5篇 |
现状及发展 | 259篇 |
研究方法 | 100篇 |
综合类 | 567篇 |
自然研究 | 66篇 |
出版年
2018年 | 4篇 |
2016年 | 4篇 |
2014年 | 3篇 |
2013年 | 8篇 |
2012年 | 31篇 |
2011年 | 98篇 |
2010年 | 6篇 |
2008年 | 39篇 |
2007年 | 37篇 |
2006年 | 36篇 |
2005年 | 37篇 |
2004年 | 34篇 |
2003年 | 31篇 |
2002年 | 34篇 |
2001年 | 20篇 |
2000年 | 44篇 |
1999年 | 16篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 18篇 |
1991年 | 10篇 |
1990年 | 19篇 |
1989年 | 15篇 |
1988年 | 12篇 |
1987年 | 14篇 |
1986年 | 19篇 |
1985年 | 12篇 |
1984年 | 13篇 |
1983年 | 12篇 |
1982年 | 6篇 |
1981年 | 9篇 |
1980年 | 10篇 |
1979年 | 16篇 |
1978年 | 19篇 |
1977年 | 20篇 |
1976年 | 15篇 |
1975年 | 20篇 |
1974年 | 23篇 |
1973年 | 17篇 |
1972年 | 20篇 |
1971年 | 31篇 |
1970年 | 44篇 |
1969年 | 15篇 |
1968年 | 27篇 |
1967年 | 26篇 |
1966年 | 22篇 |
1965年 | 10篇 |
1964年 | 8篇 |
1963年 | 2篇 |
1961年 | 2篇 |
排序方式: 共有1010条查询结果,搜索用时 15 毫秒
991.
Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing 总被引:10,自引:0,他引:10
Smith AN Skaug J Choate KA Nayir A Bakkaloglu A Ozen S Hulton SA Sanjad SA Al-Sabban EA Lifton RP Scherer SW Karet FE 《Nature genetics》2000,26(1):71-75
The multi-subunit H+-ATPase pump is present at particularly high density on the apical (luminal) surface of -intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. The complete subunit composition of the apical ATPase, however, has not been fully agreed upon. Functional failure of -intercalated cells results in a group of disorders, the distal renal tubular acidoses (dRTA), whose features include metabolic acidosis accompanied by disturbances of potassium balance, urinary calcium solubility, bone physiology and growth. Mutations in the gene encoding the B-subunit of the apical pump (ATP6B1) cause dRTA accompanied by deafness. We previously localized a gene for dRTA with preserved hearing to 7q33-34 (ref. 4). We report here the identification of this gene, ATP6N1B, which encodes an 840 amino acid novel kidney-specific isoform of ATP6N1A, the 116-kD non-catalytic accessory subunit of the proton pump. Northern-blot analysis demonstrated ATP6N1B expression in kidney but not other main organs. Immunofluorescence studies in human kidney cortex revealed that ATP6N1B localizes almost exclusively to the apical surface of -intercalated cells. We screened nine dRTA kindreds with normal audiometry that linked to the ATP6N1B locus, and identified different homozygous mutations in ATP6N1B in eight. These include nonsense, deletion and splice-site changes, all of which will truncate the protein. Our findings identify a new kidney-specific proton pump 116-kD accessory subunit that is highly expressed in proton-secreting cells in the distal nephron, and illustrate its essential role in normal vectorial acid transport into the urine by the kidney. 相似文献
992.
Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling 总被引:12,自引:0,他引:12
993.
Role for the p53 homologue p73 in E2F-1-induced apoptosis 总被引:20,自引:0,他引:20
994.
Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors 总被引:25,自引:0,他引:25
Souslova V Cesare P Ding Y Akopian AN Stanfa L Suzuki R Carpenter K Dickenson A Boyce S Hill R Nebenuis-Oosthuizen D Smith AJ Kidd EJ Wood JN 《Nature》2000,407(6807):1015-1017
ATP activates damage-sensing neurons (nociceptors) and can evoke a sensation of pain. The ATP receptor P2X3 is selectively expressed by nociceptors and is one of seven ATP-gated, cation-selective ion channels. Here we demonstrate that ablation of the P2X3 gene results in the loss of rapidly desensitizing ATP-gated cation currents in dorsal root ganglion neurons, and that the responses of nodose ganglion neurons to ATP show altered kinetics and pharmacology resulting from the loss of expression of P2X(2/3) heteromultimers. Null mutants have normal sensorimotor function. Behavioural responses to noxious mechanical and thermal stimuli are also normal, although formalin-induced pain behaviour is reduced. In contrast, deletion of the P2X3 receptor causes enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application are normal, P2X3-null mice are unable to code the intensity of non-noxious 'warming' stimuli. 相似文献
995.
Elevated CO2 increases productivity and invasive species success in an arid ecosystem 总被引:19,自引:0,他引:19
Smith SD Huxman TE Zitzer SF Charlet TN Housman DC Coleman JS Fenstermaker LK Seemann JR Nowak RS 《Nature》2000,408(6808):79-82
Arid ecosystems, which occupy about 20% of the earth's terrestrial surface area, have been predicted to be one of the most responsive ecosystem types to elevated atmospheric CO2 and associated global climate change. Here we show, using free-air CO2 enrichment (FACE) technology in an intact Mojave Desert ecosystem, that new shoot production of a dominant perennial shrub is doubled by a 50% increase in atmospheric CO2 concentration in a high rainfall year. However, elevated CO2 does not enhance production in a drought year. We also found that above-ground production and seed rain of an invasive annual grass increases more at elevated CO2 than in several species of native annuals. Consequently, elevated CO2 might enhance the long-term success and dominance of exotic annual grasses in the region. This shift in species composition in favour of exotic annual grasses, driven by global change, has the potential to accelerate the fire cycle, reduce biodiversity and alter ecosystem function in the deserts of western North America. 相似文献
996.
997.
The ion selectivity of pumps and channels is central to their ability to perform a multitude of functions. Here we investigate the mechanism of the extraordinary selectivity of the human voltage-gated proton channel, H(V)1 (also known as HVCN1). This selectivity is essential to its ability to regulate reactive oxygen species production by leukocytes, histamine secretion by basophils, sperm capacitation, and airway pH. The most selective ion channel known, H(V)1 shows no detectable permeability to other ions. Opposing classes of selectivity mechanisms postulate that (1) a titratable amino acid residue in the permeation pathway imparts proton selectivity, or (2) water molecules 'frozen' in a narrow pore conduct protons while excluding other ions. Here we identify aspartate 112 as a crucial component of the selectivity filter of H(V)1. When a neutral amino acid replaced Asp?112, the mutant channel lost proton specificity and became anion-selective or did not conduct. Only the glutamate mutant remained proton-specific. Mutation of the nearby Asp?185 did not impair proton selectivity, indicating that Asp?112 has a unique role. Although histidine shuttles protons in other proteins, when histidine or lysine replaced Asp?112, the mutant channel was still anion-permeable. Evidently, the proton specificity of H(V)1 requires an acidic group at the selectivity filter. 相似文献
998.
o aid the United States’ Nuclear Regulatory Commission, Sandia National Laboratories (SNL) was contracted to investigate the seismic behavior of typical dry cask storage systems. Parametric evaluations characterized the sensitivity of calculated cask response characteristics to input parameters. The parametric evaluation investigated two generic cask design (cylindrical and rectangular), three different foundation types (soft soil, hard soil, and rock), and three different cask to pad coefficients of friction (0.2, 0.55, 0.8) for earthquakes with peak ground accelerations of 0.25g, 0.6g, 1.0g and 1.25g. A total of 1 165 analyses were completed, with regression analyses being performed on the resulting cask response data to determine relationships relating the mean (and 16 % and 84 % confidence intervals on the mean) to peak ground acceleration, peak ground velocity, and pseudo-spectral acceleration at 1 Hz and 5 % damping. In general, the cylindrical casks experienced significantly larger responses in comparison to the rectangular cask. The cylindrical cask experienced larger top of cask displacements, larger cask rotations (rocking), and more occurrences of cask toppling (the rectangular cask never toppled over). The cylindrical cask was also susceptible to rolling once rocking had been initiated, a behavior not observed in the rectangular cask. Cask response was not overly sensitive to foundation type, but was significantly dependent on the response spectrum employed. 相似文献
999.
Ley TJ Mardis ER Ding L Fulton B McLellan MD Chen K Dooling D Dunford-Shore BH McGrath S Hickenbotham M Cook L Abbott R Larson DE Koboldt DC Pohl C Smith S Hawkins A Abbott S Locke D Hillier LW Miner T Fulton L Magrini V Wylie T Glasscock J Conyers J Sander N Shi X Osborne JR Minx P Gordon D Chinwalla A Zhao Y Ries RE Payton JE Westervelt P Tomasson MH Watson M Baty J Ivanovich J Heath S Shannon WD Nagarajan R Walter MJ Link DC Graubert TA DiPersio JF Wilson RK 《Nature》2008,456(7218):66-72
Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies. 相似文献
1000.