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61.
The genome sequence of the rice blast fungus Magnaporthe grisea 总被引:8,自引:0,他引:8
Dean RA Talbot NJ Ebbole DJ Farman ML Mitchell TK Orbach MJ Thon M Kulkarni R Xu JR Pan H Read ND Lee YH Carbone I Brown D Oh YY Donofrio N Jeong JS Soanes DM Djonovic S Kolomiets E Rehmeyer C Li W Harding M Kim S Lebrun MH Bohnert H Coughlan S Butler J Calvo S Ma LJ Nicol R Purcell S Nusbaum C Galagan JE Birren BW 《Nature》2005,434(7036):980-986
Magnaporthe grisea is the most destructive pathogen of rice worldwide and the principal model organism for elucidating the molecular basis of fungal disease of plants. Here, we report the draft sequence of the M. grisea genome. Analysis of the gene set provides an insight into the adaptations required by a fungus to cause disease. The genome encodes a large and diverse set of secreted proteins, including those defined by unusual carbohydrate-binding domains. This fungus also possesses an expanded family of G-protein-coupled receptors, several new virulence-associated genes and large suites of enzymes involved in secondary metabolism. Consistent with a role in fungal pathogenesis, the expression of several of these genes is upregulated during the early stages of infection-related development. The M. grisea genome has been subject to invasion and proliferation of active transposable elements, reflecting the clonal nature of this fungus imposed by widespread rice cultivation. 相似文献
62.
Ngo VN Davis RE Lamy L Yu X Zhao H Lenz G Lam LT Dave S Yang L Powell J Staudt LM 《Nature》2006,441(7089):106-110
The pursuit of novel therapeutic agents in cancer relies on the identification and validation of molecular targets. Hallmarks of cancer include self-sufficiency in growth signals and evasion from apoptosis; genes that regulate these processes may be optimal for therapeutic attack. Here we describe a loss-of-function screen for genes required for the proliferation and survival of cancer cells using an RNA interference library. We used a doxycycline-inducible retroviral vector for the expression of small hairpin RNAs (shRNAs) to construct a library targeting 2,500 human genes. We used retroviral pools from this library to infect cell lines representing two distinct molecular subgroups of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like DLBCL and germinal centre B-cell-like DLBCL. Each vector was engineered to contain a unique 60-base-pair 'bar code', allowing the abundance of an individual shRNA vector within a population of transduced cells to be measured using microarrays of the bar-code sequences. We observed that a subset of shRNA vectors was depleted from the transduced cells after three weeks in culture only if shRNA expression was induced. In activated B-cell-like DLBCL cells, but not germinal centre B-cell-like DLBCL cells, shRNAs targeting the NF-kappaB pathway were depleted, in keeping with the essential role of this pathway in the survival of activated B-cell-like DLBCL. This screen uncovered CARD11 as a key upstream signalling component responsible for the constitutive IkappaB kinase activity in activated B-cell-like DLBCL. The methodology that we describe can be used to establish a functional taxonomy of cancer and help reveal new classes of therapeutic targets distinct from known oncogenes. 相似文献
63.
Jonker JW Suh JM Atkins AR Ahmadian M Li P Whyte J He M Juguilon H Yin YQ Phillips CT Yu RT Olefsky JM Henry RR Downes M Evans RM 《Nature》2012,485(7398):391-394
Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ–FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization. 相似文献
64.
RNAi-mediated gene silencing in non-human primates 总被引:2,自引:0,他引:2
Zimmermann TS Lee AC Akinc A Bramlage B Bumcrot D Fedoruk MN Harborth J Heyes JA Jeffs LB John M Judge AD Lam K McClintock K Nechev LV Palmer LR Racie T Röhl I Seiffert S Shanmugam S Sood V Soutschek J Toudjarska I Wheat AJ Yaworski E Zedalis W Koteliansky V Manoharan M Vornlocher HP MacLachlan I 《Nature》2006,441(7089):111-114
The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs. 相似文献
65.
Inactivation of the apoptosis effector Apaf-1 in malignant melanoma 总被引:47,自引:0,他引:47
Soengas MS Capodieci P Polsky D Mora J Esteller M Opitz-Araya X McCombie R Herman JG Gerald WL Lazebnik YA Cordón-Cardó C Lowe SW 《Nature》2001,409(6817):207-211
Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type. 相似文献
66.
67.
【目的】分析泡桐黄化突变体的生理特性,为泡桐新品种的研究及应用提供理论参考。【方法】将新发现的泡桐黄化突变体(PFE)与白花泡桐(PF)、建始泡桐(PJ)、楸叶泡桐(PC)的生理特征进行比较,分析了其光合色素的含量、光合日变化、抗氧化酶活性及丙二醛含量。【结果】黄化突变体的叶绿素a、叶绿素b、总叶绿素、类胡萝卜素含量减少,其中叶绿素b显著减少; 黄化突变体的净光合速率和蒸腾速率总体小于其他种,气孔导度值与其他种相比总体降低,但差异较小,胞间CO2浓度日变化值均高于其他种; 泡桐黄化突变体的SOD、POD、CAT活性和丙二醛(MDA)含量均高于其他种。【结论】光合色素的减少是导致叶色黄化的主要原因; 它影响了植株捕光能力,致使净光合速率下降,抗氧化酶活性增强,植株抗性增加,可减少活性氧对植株的伤害,维持植物正常生长。 相似文献
68.
69.
采用实验探究与程序模拟的双重方法考察地下水中含Cr(Ⅵ)的亚铁还原去除过程,考察pH、原料投量与共存阴离子对反应进程的影响,并运用PHREEQC 程序对实验结果的内在机制进行解释.结果表明:Fe(Ⅱ)还原去除Cr(Ⅵ)在碱性条件下可以获得较好的去除效果;同时投加的FeSO4·7H2O 与Cr的质量比在80∶1时,去除过程达到较经济有效的处理效果.其原因是不同的反应条件影响铬化合物形成的种类与饱和指数(SI),从而影响其去除效果.地下水中存在大量的共存阴离子,其中Cl-易与Cr(Ⅲ)形成不稳定复合物从而对反应进程产生抑制作用;SiO23- 因其在不同pH 条件下存在形式不同而对反应进程影响不同,在酸性与中性条件下产生抑制作用,在碱性条件下呈现促进作用. 相似文献
70.
Shutao Li Jrg Isele Georg Bretthauer Institute for Applied Computer Science Forschungszentrum Karlsruhe P.O. Box Karlsruhe Germany 《清华大学学报》2008,13(Z1):138-144
For refurbishment and state review of an existing old building, a new model reflecting the current state is often required especially when the original plans are no longer accessible. Laser scanners are used more and more as surveying instruments for various applications because of their high-precision scanning abilities. For buildings, the most notable and widely accepted product data model is the IFC product data model. It is designed to cover the whole lifecycle and supported by various software vendors and enables applications to efficiently share and exchange project information. The models obtained with the laser scanner, normally sets of points ("point cloud"), have to be transferred to an IFC compatible building information model to serve the needs of different planning states. This paper presents an approach designed by the German Research Center in Karlsruhe (Forschungszentrum Karlsruhe) to create an IFC compatible building information model from laser range images. The methodology through the entire process from data acquisition to the IFC compatible product model was proposed in this paper. In addition, IFC-Models with different level of detail (LoDs) were introduced and discussed within the work. 相似文献