全文获取类型
收费全文 | 8575篇 |
免费 | 79篇 |
国内免费 | 55篇 |
专业分类
系统科学 | 54篇 |
丛书文集 | 90篇 |
教育与普及 | 13篇 |
理论与方法论 | 22篇 |
现状及发展 | 3587篇 |
研究方法 | 483篇 |
综合类 | 4318篇 |
自然研究 | 142篇 |
出版年
2016年 | 52篇 |
2012年 | 134篇 |
2011年 | 298篇 |
2010年 | 61篇 |
2009年 | 54篇 |
2008年 | 183篇 |
2007年 | 207篇 |
2006年 | 166篇 |
2005年 | 172篇 |
2004年 | 268篇 |
2003年 | 151篇 |
2002年 | 161篇 |
2001年 | 311篇 |
2000年 | 326篇 |
1999年 | 224篇 |
1992年 | 133篇 |
1991年 | 129篇 |
1990年 | 124篇 |
1989年 | 113篇 |
1988年 | 118篇 |
1987年 | 131篇 |
1986年 | 128篇 |
1985年 | 170篇 |
1984年 | 132篇 |
1983年 | 110篇 |
1982年 | 90篇 |
1981年 | 125篇 |
1980年 | 119篇 |
1979年 | 263篇 |
1978年 | 214篇 |
1977年 | 203篇 |
1976年 | 151篇 |
1975年 | 178篇 |
1974年 | 229篇 |
1973年 | 188篇 |
1972年 | 212篇 |
1971年 | 242篇 |
1970年 | 316篇 |
1969年 | 223篇 |
1968年 | 214篇 |
1967年 | 233篇 |
1966年 | 203篇 |
1965年 | 154篇 |
1959年 | 54篇 |
1958年 | 105篇 |
1957年 | 76篇 |
1956年 | 74篇 |
1955年 | 52篇 |
1954年 | 75篇 |
1948年 | 50篇 |
排序方式: 共有8709条查询结果,搜索用时 0 毫秒
91.
92.
A dipole mode in the tropical Indian Ocean 总被引:203,自引:0,他引:203
For the tropical Pacific and Atlantic oceans, internal modes of variability that lead to climatic oscillations have been recognized, but in the Indian Ocean region a similar ocean-atmosphere interaction causing interannual climate variability has not yet been found. Here we report an analysis of observational data over the past 40 years, showing a dipole mode in the Indian Ocean: a pattern of internal variability with anomalously low sea surface temperatures off Sumatra and high sea surface temperatures in the western Indian Ocean, with accompanying wind and precipitation anomalies. The spatio-temporal links between sea surface temperatures and winds reveal a strong coupling through the precipitation field and ocean dynamics. This air-sea interaction process is unique and inherent in the Indian Ocean, and is shown to be independent of the El Ni?o/Southern Oscillation. The discovery of this dipole mode that accounts for about 12% of the sea surface temperature variability in the Indian Ocean--and, in its active years, also causes severe rainfall in eastern Africa and droughts in Indonesia--brightens the prospects for a long-term forecast of rainfall anomalies in the affected countries. 相似文献
93.
Vitamin B12 (cobalamin) was identified nearly 80 years ago as the anti-pernicious anaemia factor in liver, and its importance in human health and disease has resulted in much work on its uptake, cellular transport and utilization. Plants do not contain cobalamin because they have no cobalamin-dependent enzymes. Deficiencies are therefore common in strict vegetarians, and in the elderly, who are susceptible to an autoimmune disorder that prevents its efficient uptake. In contrast, many algae are rich in vitamin B12, with some species, such as Porphyra yezoensis (Nori), containing as much cobalamin as liver. Despite this, the role of the cofactor in algal metabolism remains unknown, as does the source of the vitamin for these organisms. A survey of 326 algal species revealed that 171 species require exogenous vitamin B12 for growth, implying that more than half of the algal kingdom are cobalamin auxotrophs. Here we show that the role of vitamin B12 in algal metabolism is primarily as a cofactor for vitamin B12-dependent methionine synthase, and that cobalamin auxotrophy has arisen numerous times throughout evolution, probably owing to the loss of the vitamin B12-independent form of the enzyme. The source of cobalamin seems to be bacteria, indicating an important and unsuspected symbiosis. 相似文献
94.
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
95.
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
96.
In this study, plasma nitriding was used to fabricate a hard protective layer on AISI P20 steel, at three process temperatures (450°C, 500°C, and 550°C) and over a range of time periods (2.5, 5, 7.5, and 10 h), and at a fixed gas N2:H2 ratio of 75vol%:25vol%. The morphology of samples was studied using optical microscopy and scanning electron microscopy, and the formed phase of each sample was determined by X-ray diffraction. The elemental depth profile was measured by energy dispersive X-ray spectroscopy, wavelength dispersive spectroscopy, and glow dispersive spectroscopy. The hardness profile of the samples was identified, and the microhardness profile from the surface to the sample center was recorded. The results show that ε-nitride is the dominant species after carrying out plasma nitriding in all strategies and that the plasma nitriding process improves the hardness up to more than three times. It is found that as the time and temperature of the process increase, the hardness and hardness depth of the diffusion zone considerably increase. Furthermore, artificial neural networks were used to predict the effects of operational parameters on the mechanical properties of plastic mold steel. The plasma temperature, running time of imposition, and target distance to the sample surface were all used as network inputs; Vickers hardness measurements were given as the output of the model. The model accurately reproduced the experimental outcomes under different operational conditions; therefore, it can be used in the effective simulation of the plasma nitriding process in AISI P20 steel. 相似文献
97.
98.
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
99.
Male development of chromosomally female mice transgenic for Sry 总被引:117,自引:0,他引:117
The initiation of male development in mammals requires one or more genes on the Y chromosome. A recently isolated gene, termed SRY in humans and Sry in mouse, has many of the genetic and biological properties expected of a Y-located testis-determining gene. It is now shown that Sry on a 14-kilobase genomic DNA fragment is sufficient to induce testis differentiation and subsequent male development when introduced into chromosomally female mouse embryos. 相似文献
100.
Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. 总被引:165,自引:0,他引:165
A Goate M C Chartier-Harlin M Mullan J Brown F Crawford L Fidani L Giuffra A Haynes N Irving L James 《Nature》1991,349(6311):704-706
A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene. 相似文献