全文获取类型
收费全文 | 22454篇 |
免费 | 57篇 |
国内免费 | 53篇 |
专业分类
系统科学 | 225篇 |
丛书文集 | 493篇 |
教育与普及 | 45篇 |
理论与方法论 | 60篇 |
现状及发展 | 9489篇 |
研究方法 | 878篇 |
综合类 | 11003篇 |
自然研究 | 371篇 |
出版年
2013年 | 129篇 |
2012年 | 276篇 |
2011年 | 665篇 |
2010年 | 101篇 |
2008年 | 325篇 |
2007年 | 377篇 |
2006年 | 400篇 |
2005年 | 393篇 |
2004年 | 375篇 |
2003年 | 385篇 |
2002年 | 306篇 |
2001年 | 708篇 |
2000年 | 707篇 |
1999年 | 414篇 |
1992年 | 410篇 |
1991年 | 363篇 |
1990年 | 387篇 |
1989年 | 326篇 |
1988年 | 368篇 |
1987年 | 366篇 |
1986年 | 342篇 |
1985年 | 485篇 |
1984年 | 363篇 |
1983年 | 303篇 |
1982年 | 238篇 |
1981年 | 256篇 |
1980年 | 343篇 |
1979年 | 688篇 |
1978年 | 580篇 |
1977年 | 551篇 |
1976年 | 473篇 |
1975年 | 531篇 |
1974年 | 663篇 |
1973年 | 579篇 |
1972年 | 588篇 |
1971年 | 703篇 |
1970年 | 925篇 |
1969年 | 726篇 |
1968年 | 626篇 |
1967年 | 653篇 |
1966年 | 596篇 |
1965年 | 433篇 |
1964年 | 113篇 |
1959年 | 264篇 |
1958年 | 400篇 |
1957年 | 303篇 |
1956年 | 269篇 |
1955年 | 238篇 |
1954年 | 263篇 |
1948年 | 176篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
221.
Aerosols implicated as a prime driver of twentieth-century North Atlantic climate variability 总被引:5,自引:0,他引:5
Systematic climate shifts have been linked to multidecadal variability in observed sea surface temperatures in the North Atlantic Ocean. These links are extensive, influencing a range of climate processes such as hurricane activity and African Sahel and Amazonian droughts. The variability is distinct from historical global-mean temperature changes and is commonly attributed to natural ocean oscillations. A number of studies have provided evidence that aerosols can influence long-term changes in sea surface temperatures, but climate models have so far failed to reproduce these interactions and the role of aerosols in decadal variability remains unclear. Here we use a state-of-the-art Earth system climate model to show that aerosol emissions and periods of volcanic activity explain 76 per cent of the simulated multidecadal variance in detrended 1860-2005 North Atlantic sea surface temperatures. After 1950, simulated variability is within observational estimates; our estimates for 1910-1940 capture twice the warming of previous generation models but do not explain the entire observed trend. Other processes, such as ocean circulation, may also have contributed to variability in the early twentieth century. Mechanistically, we find that inclusion of aerosol-cloud microphysical effects, which were included in few previous multimodel ensembles, dominates the magnitude (80 per cent) and the spatial pattern of the total surface aerosol forcing in the North Atlantic. Our findings suggest that anthropogenic aerosol emissions influenced a range of societally important historical climate events such as peaks in hurricane activity and Sahel drought. Decadal-scale model predictions of regional Atlantic climate will probably be improved by incorporating aerosol-cloud microphysical interactions and estimates of future concentrations of aerosols, emissions of which are directly addressable by policy actions. 相似文献
222.
1 Results The enantioselective addition of allylic organometallic reagents to aldehydes is a fundamental tool in organic synthesis.The high degree of both diastereo-and enantioselectivity gives the possibility to obtain a wide series of homoallylic alcohols,versatile intermediates in a great number of synthesis[1]. One of the most successful approaches is related to the discovery that organocatalytic activation of the nucleophilic allyltrichlorosilanes by means of neutral Lewis bases,such as formamides,... 相似文献
223.
Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells 总被引:102,自引:0,他引:102
R L Williams D J Hilton S Pease T A Willson C L Stewart D P Gearing E F Wagner D Metcalf N A Nicola N M Gough 《Nature》1988,336(6200):684-687
Embryonic stem (ES) cells, the totipotent outgrowths of blastocysts, can be cultured and manipulated in vitro and then returned to the embryonic environment where they develop normally and can contribute to all cell lineages. Maintenance of the stem-cell phenotype in vitro requires the presence of a feeder layer of fibroblasts or of a soluble factor, differentiation inhibitory activity (DIA) produced by a number of sources; in the absence of DIA the ES cells differentiate into a wide variety of cell types. We recently noted several similarities between partially purified DIA and a haemopoietic regulator, myeloid leukaemia inhibitory factor (LIF), a molecule which induces differentiation in M1 myeloid leukaemic cells and which we have recently purified, cloned and characterized. We demonstrate here that purified, recombinant LIF can substitute for DIA in the maintenance of totipotent ES cell lines that retain the potential to form chimaeric mice. 相似文献
224.
Is there a decline in marine phytoplankton? 总被引:1,自引:0,他引:1
McQuatters-Gollop A Reid PC Edwards M Burkill PH Castellani C Batten S Gieskes W Beare D Bidigare RR Head E Johnson R Kahru M Koslow JA Pena A 《Nature》2011,472(7342):E6-7; discussion E8-9
225.
226.
HIV preferentially infects HIV-specific CD4+ T cells 总被引:34,自引:0,他引:34
Douek DC Brenchley JM Betts MR Ambrozak DR Hill BJ Okamoto Y Casazza JP Kuruppu J Kunstman K Wolinsky S Grossman Z Dybul M Oxenius A Price DA Connors M Koup RA 《Nature》2002,417(6884):95-98
HIV infection is associated with the progressive loss of CD4(+) T cells through their destruction or decreased production. A central, yet unresolved issue of HIV disease is the mechanism for this loss, and in particular whether HIV-specific CD4(+) T cells are preferentially affected. Here we show that HIV-specific memory CD4(+) T cells in infected individuals contain more HIV viral DNA than other memory CD4(+) T cells, at all stages of HIV disease. Additionally, following viral rebound during interruption of antiretroviral therapy, the frequency of HIV viral DNA in the HIV-specific pool of memory CD4(+) T cells increases to a greater extent than in memory CD4(+) T cells of other specificities. These findings show that HIV-specific CD4(+) T cells are preferentially infected by HIV in vivo. This provides a potential mechanism to explain the loss of HIV-specific CD4(+) T-cell responses, and consequently the loss of immunological control of HIV replication. Furthermore, the phenomenon of HIV specifically infecting the very cells that respond to it adds a cautionary note to the practice of structured therapy interruption. 相似文献
227.
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
228.
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
229.
The spacecraft Voyager 1 is at a distance greater than 85 au from the Sun, in the vicinity of the termination shock that marks the abrupt slowing of the supersonic solar wind and the beginning of the extended and unexplored distant heliosphere. This shock is expected to accelerate 'anomalous cosmic rays', as well as to re-accelerate Galactic cosmic rays and low-energy particles from the inner Solar System. Here we report a significant increase in the numbers of energetic ions and electrons that persisted for seven months beginning in mid-2002. This increase differs from any previously observed in that there was a simultaneous increase in Galactic cosmic ray ions and electrons, anomalous cosmic rays and low-energy ions. The low-intensity level and spectral energy distribution of the anomalous cosmic rays, however, indicates that Voyager 1 still has not reached the termination shock. Rather, the observed increase is an expected precursor event. We argue that the radial anisotropy of the cosmic rays is expected to be small in the foreshock region, as is observed. 相似文献
230.
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