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131.
设2*=2(N α)(N-2 β),N≥3,是极限Sobolev指数,ΩRN是RN中的开子集.在f(x)∈Hβ-1满足合适的条件且f(x)≠0下,讨论了一个带非齐次项和Sobolev-Hardy临界指数的含权的椭圆型问题:{-div(|x|β▽u)=|x|αup*-1 εf(x),x∈Ω,u>0,x∈Ω,u=0,x∈Ω,,存在两个解u和-u在H01,,βp(Ω)中,且有u≥0,u-≥0对所有的f(x)≥0.值得注意的是,当f(x)=0时一般不成立. 相似文献
132.
Gudbjartsson DF Arnar DO Helgadottir A Gretarsdottir S Holm H Sigurdsson A Jonasdottir A Baker A Thorleifsson G Kristjansson K Palsson A Blondal T Sulem P Backman VM Hardarson GA Palsdottir E Helgason A Sigurjonsdottir R Sverrisson JT Kostulas K Ng MC Baum L So WY Wong KS Chan JC Furie KL Greenberg SM Sale M Kelly P MacRae CA Smith EE Rosand J Hillert J Ma RC Ellinor PT Thorgeirsson G Gulcher JR Kong A Thorsteinsdottir U Stefansson K 《Nature》2007,448(7151):353-357
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart. 相似文献
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Yagoda N von Rechenberg M Zaganjor E Bauer AJ Yang WS Fridman DJ Wolpaw AJ Smukste I Peltier JM Boniface JJ Smith R Lessnick SL Sahasrabudhe S Stockwell BR 《Nature》2007,447(7146):864-868
Therapeutics that discriminate between the genetic makeup of normal cells and tumour cells are valuable for treating and understanding cancer. Small molecules with oncogene-selective lethality may reveal novel functions of oncoproteins and enable the creation of more selective drugs. Here we describe the mechanism of action of the selective anti-tumour agent erastin, involving the RAS-RAF-MEK signalling pathway functioning in cell proliferation, differentiation and survival. Erastin exhibits greater lethality in human tumour cells harbouring mutations in the oncogenes HRAS, KRAS or BRAF. Using affinity purification and mass spectrometry, we discovered that erastin acts through mitochondrial voltage-dependent anion channels (VDACs)--a novel target for anti-cancer drugs. We show that erastin treatment of cells harbouring oncogenic RAS causes the appearance of oxidative species and subsequent death through an oxidative, non-apoptotic mechanism. RNA-interference-mediated knockdown of VDAC2 or VDAC3 caused resistance to erastin, implicating these two VDAC isoforms in the mechanism of action of erastin. Moreover, using purified mitochondria expressing a single VDAC isoform, we found that erastin alters the permeability of the outer mitochondrial membrane. Finally, using a radiolabelled analogue and a filter-binding assay, we show that erastin binds directly to VDAC2. These results demonstrate that ligands to VDAC proteins can induce non-apoptotic cell death selectively in some tumour cells harbouring activating mutations in the RAS-RAF-MEK pathway. 相似文献
137.
Although directed migration is a feature of both individual cells and cell groups, guided migration has been studied most extensively for single cells in simple environments. Collective guidance of cell groups remains poorly understood, despite its relevance for development and metastasis. Neural crest cells and neuronal precursors migrate as loosely organized streams of individual cells, whereas cells of the fish lateral line, Drosophila tracheal tubes and border-cell clusters migrate as more coherent groups. Here we use Drosophila border cells to examine how collective guidance is performed. We report that border cells migrate in two phases using distinct mechanisms. Genetic analysis combined with live imaging shows that polarized cell behaviour is critical for the initial phase of migration, whereas dynamic collective behaviour dominates later. PDGF- and VEGF-related receptor and epidermal growth factor receptor act in both phases, but use different effector pathways in each. The myoblast city (Mbc, also known as DOCK180) and engulfment and cell motility (ELMO, also known as Ced-12) pathway is required for the early phase, in which guidance depends on subcellular localization of signalling within a leading cell. During the later phase, mitogen-activated protein kinase and phospholipase Cgamma are used redundantly, and we find that the cluster makes use of the difference in signal levels between cells to guide migration. Thus, information processing at the multicellular level is used to guide collective behaviour of a cell group. 相似文献
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A thermally grown oxide layer formed by hot corrosion was investigated as an interface between plasma-sprayed coatings and a nickel-based superalloy substrate. The hot corrosion mechanism of NiCr-Cr2O3 and Al2O3-40wt% TiO2 (A40T) plasma coated Inconel 617 was evaluated. The experiments were carried out at 1000℃ using a combination of Na2SO4, NaCl, and 2O5 salts to simulate the conditions of a gas turbine in a marine environment. The hot corrosion results revealed the spallation and dissolution of oxides upon prolonged exposure. Optical images and scanning electron micrographs of the exposed samples revealed the formation of oxide scale and provided details of its morphology in NiCr-Cr2O3 coated samples. Microstructure characterization of A40T coatings demonstrated a thermally grown oxide (TGO) layer at 1000℃. Increasing the thickness of the TGO layer decreased the corrosion resistance. The elemental analysis and image mapping revealed the migration of active elements from the substrate and coatings toward the corrosive environment. 相似文献
140.
Barretina J Caponigro G Stransky N Venkatesan K Margolin AA Kim S Wilson CJ Lehár J Kryukov GV Sonkin D Reddy A Liu M Murray L Berger MF Monahan JE Morais P Meltzer J Korejwa A Jané-Valbuena J Mapa FA Thibault J Bric-Furlong E Raman P Shipway A Engels IH Cheng J Yu GK Yu J Aspesi P de Silva M Jagtap K Jones MD Wang L Hatton C Palescandolo E Gupta S Mahan S Sougnez C Onofrio RC Liefeld T MacConaill L Winckler W Reich M Li N Mesirov JP Gabriel SB Getz G Ardlie K Chan V Myer VE Weber BL Porter J 《Nature》2012,483(7391):603-607
The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens. 相似文献