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951.
952.
David A. Garber Leigh A. O'Mara Sailaja Gangadhara Monica McQuoid Xiugen Zhang Rui Zheng Kiran Gill Meena Verma Tianwei Yu Brent Johnson Bing Li Cynthia A. Derdeyn Chris Ibegbu John D. Altman Eric Hunter Mark B. Feinberg 《Journal of virology》2012,86(23):12605-12615
Modified vaccinia virus Ankara (MVA) is a safe, attenuated orthopoxvirus that is being developed as a vaccine vector but has demonstrated limited immunogenicity in several early-phase clinical trials. Our objective was to rationally improve the immunogenicity of MVA-based HIV/AIDS vaccines via the targeted deletion of specific poxvirus immune-modulatory genes. Vaccines expressing codon-optimized HIV subtype C consensus Env and Gag antigens were generated from MVA vector backbones that (i) harbor simultaneous deletions of four viral immune-modulatory genes, encoding an interleukin-18 (IL-18) binding protein, an IL-1β receptor, a dominant negative Toll/IL-1 signaling adapter, and CC-chemokine binding protein (MVAΔ4-HIV); (ii) harbor a deletion of an additional (fifth) viral gene, encoding uracil-DNA glycosylase (MVAΔ5-HIV); or (iii) represent the parental MVA backbone as a control (MVA-HIV). We performed head-to-head comparisons of the cellular and humoral immune responses that were elicited by these vectors during homologous prime-boost immunization regimens utilizing either high-dose (2 × 108 PFU) or low-dose (1 × 107 PFU) intramuscular immunization of rhesus macaques. At all time points, a majority of the HIV-specific T cell responses, elicited by all vectors, were directed against Env, rather than Gag, determinants, as previously observed with other vector systems. Both modified vectors elicited up to 6-fold-higher frequencies of HIV-specific CD8 and CD4 T cell responses and up to 25-fold-higher titers of Env (gp120)-specific binding (nonneutralizing) antibody responses that were relatively transient in nature. While the correlates of protection against HIV infection remain incompletely defined, our results indicate that the rational deletion of specific genes from MVA vectors can positively alter their cellular and humoral immunogenicity profiles in nonhuman primates. 相似文献
953.
954.
In clinical practice, most patients with non small cell lung cancer (NSCLC) who respond to tyrosine kinase inhibitors eventually
progress because of an acquired resistance mutation, T790M, in epidermal growth factor receptor (EGFR). Thus, it is important
to identify a new drug to reduce resistance. The aim of this study was to test whether genistein combined with gefitinib is
effective against NSCLC in a cell line carrying T790M, and to clarify the underlying mechanisms. The human lung cancer cell
line H1975 was used as an in vitro and in vivo model. Cells were treated with gefitinib, genistein, or a combination at a
range of concentrations. Cell proliferation was calculated to assess the anticancer effects of the compounds in vitro. Flow
cytometry and Western blotting were employed to determine the inhibitory effects on proliferation and the induction of apoptosis.
The in vivo effects of the compounds were examined using a xenografted nude mouse model for validation. Gefitinib together
with genistein enhanced both growth inhibition and apoptosis; however, the greatest synergistic effect was observed at low
concentrations. p-EGFR, p-Akt, and p-mTOR expressions in vitro were reduced more by the combined use of the drugs, whereas
caspase-3 and PARP activities were increased. Significantly more tumor growth inhibition was detected following combination
treatment in the in vivo model. These findings suggest that genistein enhanced the antitumor effects of gefitinib in a NSCLC
cell line carrying the T790M mutation. This synergistic activity may be due to increased inhibition of the downstream molecular
and pro-apoptotic effects of EGFR. 相似文献
955.
Bing Li Yi Xie Zhe Cheng Jie Cheng Rengping Hu Suxin Gui Xuezi Sang Qingqing Sun Xiaoyang Zhao Lei Sheng Weide Shen Fashui Hong 《Biological trace element research》2012,150(1-3):221-228
Bombyx mori nucleopolyhedrovirus (BmNPV) causes infection in the silkworm that is often lethal. The infection is hard to prevent, partly because of the nature of the virus particles and partly because of the different strains of B. mori. Titanium dioxide nanoparticles (TiO2 NPs) have been demonstrated to have antimicrobial properties. The present study investigated whether TiO2 NPs added to an artificial diet can increase the resistance of B. mori larvae to BmNPV and examined the molecular mechanism behind any resistance shown. The results indicated that ingested TiO2 NPs decreased reactive oxygen species and NO accumulation in B. mori larvae under BmNPV infection, which in turn led to a decrease in their growth inhibition and mortality. In addition, the TiO2 NPs significantly promoted the expression of resistance-related genes, including those encoding superoxide dismutase, catalase, glutathione peroxidase, acetylcholine esterase, carboxylesterase, heat shock protein 21, glutathione S transferase o1, P53, and transferring and of genes encoding cytochrome p302 and nitric oxide synthase. These findings are a useful addition to the understanding of the mechanism of BmNPV resistance of B. mori larvae in response to TiO2 NPs addition. Such information also provides a theoretical basis for the use of TiO2 NPs in sericulture. 相似文献
956.
Huang C Jin H Song B Zhu X Zhao H Cai J Lu Y Chen B Lin Y 《Applied microbiology and biotechnology》2012,93(2):777-785
Alterporriol L, a new bianthraquinone derivative, was isolated from a marine fungus Alternaria sp. ZJ9-6B. The cytotoxic activity and anticancer mechanisms of alterporriol L towards breast cancer cells lines were detected
using MTT assay, immunofluorescence, and flow cytometry. Simultaneously, the changes in morphological properties of cells
were detected before and after treatment with alterporriol L by atomic force microscope (AFM) at a nanometer scale. MTT assay
showed that alterporriol L could effectively inhibit the growth and proliferation, and there was a dose-dependent manner of
cell death. Moreover, the alterporriol L could induce cancer cell apoptosis or necrosis. Furthermore, the reactive oxygen
species, mitochondrial membrane potential, and cytosolic free calcium level were changed after treatment with alterporriol
L, suggesting that alterporriol L played vital roles in breast cancer cells through destroying the mitochondrial. And all
these alterations are in accord with changes of morphology detected by AFM, which suggested that the AFM is a useful tool
to detect the morphological changes of the cancer cells. 相似文献
957.
958.
随着人类和黑猩猩全基因组测序工作宣布完成,以及其他灵长类基因组测序工作的逐步开展,目前已经积累了大量的灵长类基因组数据,一个崭新的研究领域——灵长类比较基因组学应运而生。该文主要通过对人类和其他非人灵长类系统关系和基因组结构的比较,从系统进化、基因组结构和基因表达调控等方面评述该领域的研究进展,阐述人类、黑猩猩与其他非人灵长类之间的主要生物学差异,揭示人类进化的生物学机制。 相似文献
959.
Four different bombesins (bombesin, His(6)-bombesin, Phe(13)-bombesin and Asp(2)-, Phe(4)-SAP-bombesin) have been identified by a systematic sequencing study of peptides in reverse phase HPLC fractions of the skin secretion of the European yellow-bellied toad, Bombina variegata, that had been solvated in 0.1% (v/v) aqueous trifluoroacetic acid (TFA) and stored frozen at -20°C for 12 years. By using a 3'- and 5'-RACE PCR strategy, the corresponding biosynthetic precursor-encoding cDNAs of all four peptides were cloned from a cDNA library made from the same long-term frozen, acid-solvated skin secretion sample following thawing and lyophilization. Canonical bombesin and His(6)-bombesin are classical bombesin sub-family members, whereas Phe(13)-bombesin and Asp(2)-, Phe(4)-SAP-bombesin, belong to the litorin/ranatensin sub-family of bombesin-like peptides (BLPs). Assignment of these peptides to respective sub-families, was based upon both their primary structural similarities and their comparative pharmacological activities. An interesting observation in this study, was that the nucleotide sequences of the open-reading frames of cloned cDNAs encoding bombesin and its His(6)-substituted analog, were identical except for a single base that was responsible for the change observed at the position 6 residue in the mature peptide from Asn to His. In contrast, the precursor cDNA nucleotide sequences encoding the Phe(13)-bombesins, exhibited 53 base differences. The pharmacological activities of synthetic replicates of each bombesin were compared using two different mammalian smooth muscle preparations and all four peptides were found to be active. However, there were significant differences in their relative potencies. 相似文献
960.
Cellular processes are governed and coordinated by a multitude of biopathways. A pathway can be viewed as a complex network of biochemical reactions. The dynamics of this network largely determines the functioning of the pathway. Hence the modeling and analysis of biochemical networks dynamics is an important problem and is an active area of research. Here we review quantitative models of biochemical networks based on ordinary differential equations (ODEs). We mainly focus on the parameter estimation and sensitivity analysis problems and survey the current methods for tackling them. In this context we also highlight a recently developed probabilistic approximation technique using which these two problems can be considerably simplified. 相似文献