全文获取类型
收费全文 | 1570篇 |
免费 | 155篇 |
国内免费 | 2篇 |
出版年
2023年 | 12篇 |
2022年 | 35篇 |
2021年 | 68篇 |
2020年 | 31篇 |
2019年 | 35篇 |
2018年 | 51篇 |
2017年 | 43篇 |
2016年 | 58篇 |
2015年 | 94篇 |
2014年 | 106篇 |
2013年 | 112篇 |
2012年 | 152篇 |
2011年 | 141篇 |
2010年 | 89篇 |
2009年 | 76篇 |
2008年 | 82篇 |
2007年 | 80篇 |
2006年 | 70篇 |
2005年 | 68篇 |
2004年 | 52篇 |
2003年 | 40篇 |
2002年 | 43篇 |
2001年 | 7篇 |
2000年 | 3篇 |
1999年 | 5篇 |
1998年 | 13篇 |
1997年 | 9篇 |
1994年 | 5篇 |
1993年 | 3篇 |
1992年 | 6篇 |
1988年 | 6篇 |
1987年 | 6篇 |
1985年 | 3篇 |
1984年 | 5篇 |
1982年 | 7篇 |
1981年 | 4篇 |
1980年 | 5篇 |
1979年 | 6篇 |
1978年 | 5篇 |
1977年 | 3篇 |
1976年 | 6篇 |
1974年 | 4篇 |
1973年 | 9篇 |
1972年 | 4篇 |
1965年 | 3篇 |
1964年 | 5篇 |
1961年 | 4篇 |
1960年 | 6篇 |
1902年 | 2篇 |
1899年 | 2篇 |
排序方式: 共有1727条查询结果,搜索用时 15 毫秒
91.
92.
93.
Malaria remains a major health burden especially for the developing countries. Despite concerted efforts at using the current control tools, such as bed nets, anti malarial drugs and vector control measures, the disease is accountable for close to a million deaths annually. Vaccines have been proposed as a necessary addition to the armamentarium that could work towards elimination and eventual eradication of malaria in view of their historical significance in combating infectious diseases. However, because malaria vaccines would work differently depending on the targeted parasite stage, this review addresses the potential impact various malaria vaccine types could have on transmission. Further, because of the wide variation in the epidemiology of malaria across the endemic regions, this paper proposes that the ideal approach to malaria control ought to be tailor-made depending on the specific context. Finally, it suggests that although it is highly desirable to anticipate and aim for malaria elimination and eventual eradication, many affected regions should prioritize reduction of mortality and morbidity before aspiring for elimination. 相似文献
94.
Krom BP Cohen JB McElhaney Feser GE Cihlar RL 《Journal of microbiological methods》2007,68(2):421-423
Microtiter based candidal biofilm formation is commonly being used. Here we describe the analysis of factors influencing the development of candidal biofilms such as the coating with serum, growth medium and pH. The data reported here show that optimal candidal biofilm formation is obtained when grown in unbuffered YNB at pH 7, in wells that have been coated with Fetal Calf Serum or Fetal Bovine Serum. 相似文献
95.
Unique mutational patterns in the envelope alpha 2 amphipathic helix and acquisition of length in gp120 hypervariable domains are associated with resistance to autologous neutralization of subtype C human immunodeficiency virus type 1 下载免费PDF全文
Rong R Gnanakaran S Decker JM Bibollet-Ruche F Taylor J Sfakianos JN Mokili JL Muldoon M Mulenga J Allen S Hahn BH Shaw GM Blackwell JL Korber BT Hunter E Derdeyn CA 《Journal of virology》2007,81(11):5658-5668
Autologous neutralizing antibodies (NAb) against human immunodeficiency virus type 1 generate viral escape variants; however, the mechanisms of escape are not clearly defined. In a previous study, we determined the susceptibilities of 48 donor and 25 recipient envelope (Env) glycoproteins from five subtype C heterosexual transmission pairs to NAb in donor plasma by using a virus pseudotyping assay, thereby providing an ideal setting to probe the determinants of susceptibility to neutralization. In the present study, acquisition of length in the Env gp120 hypervariable domains was shown to correlate with resistance to NAb in donor plasma (P = 0.01; Kendall's tau test) but not in heterologous plasma. Sequence divergence in the gp120 V1-to-V4 region also correlated with resistance to donor (P = 0.0002) and heterologous (P = 0.001) NAb. A mutual information analysis suggested possible associations of nine amino acid positions in V1 to V4 with NAb resistance to the donor's antibodies, and five of these were located within an 18-residue amphipathic helix (alpha2) located on the gp120 outer domain. High nonsynonymous-to-synonymous substitution (dN/dS) ratios, indicative of positive selection, were also found at these five positions in subtype C sequences in the database. Nevertheless, exchange of the entire alpha2 helix between resistant donor Envs and sensitive recipient Envs did not alter the NAb phenotype. The combined mutual information and dN/dS analyses suggest that unique mutational patterns in alpha2 and insertions in the V1-to-V4 region are associated with NAb resistance during subtype C infection but that the selected positions within the alpha2 helix must be linked to still other changes in Env to confer antibody escape. These findings suggest that subtype C viruses utilize mutations in the alpha2 helix for efficient viral replication and immune avoidance. 相似文献
96.
The 2'-O-ribose methyltransferase for cap 1 of spliced leader RNA and U1 small nuclear RNA in Trypanosoma brucei 下载免费PDF全文
Zamudio JR Mittra B Foldynová-Trantírková S Zeiner GM Lukes J Bujnicki JM Sturm NR Campbell DA 《Molecular and cellular biology》2007,27(17):6084-6092
mRNA cap 1 2'-O-ribose methylation is a widespread modification that is implicated in processing, trafficking, and translational control in eukaryotic systems. The eukaryotic enzyme has yet to be identified. In kinetoplastid flagellates trans-splicing of spliced leader (SL) to polycistronic precursors conveys a hypermethylated cap 4, including a cap 0 m7G and seven additional methylations on the first 4 nucleotides, to all nuclear mRNAs. We report the first eukaryotic cap 1 2'-O-ribose methyltransferase, TbMTr1, a member of a conserved family of viral and eukaryotic enzymes. Recombinant TbMTr1 methylates the ribose of the first nucleotide of an m7G-capped substrate. Knockdowns and null mutants of TbMTr1 in Trypanosoma brucei grow normally, with loss of 2'-O-ribose methylation at cap 1 on substrate SL RNA and U1 small nuclear RNA. TbMTr1-null cells have an accumulation of cap 0 substrate without further methylation, while spliced mRNA is modified efficiently at position 4 in the absence of 2'-O-ribose methylation at position 1; downstream cap 4 methylations are independent of cap 1. Based on TbMTr1-green fluorescent protein localization, 2'-O-ribose methylation at position 1 occurs in the nucleus. Accumulation of 3'-extended SL RNA substrate indicates a delay in processing and suggests a synergistic role for cap 1 in maturation. 相似文献
97.
Feng Z Mohapatra S Klimko PG Hellberg MR May JA Kelly C Williams G McLaughlin MA Sharif NA 《Bioorganic & medicinal chemistry letters》2007,17(11):2998-3002
A series of 8-substituted benzodifuran analogs was prepared and evaluated for 5-HT(2A) receptor binding and activation. Several compounds containing ether and ester functionality were found to be potent agonists. Topical ocular administration of 5, 18, and 25 effectively reduced intra-ocular pressure in the hypertensive cynomolgus monkey eye in the range of 25-37%. 相似文献
98.
Herring PA Ingels J Palmieri G Hasty KA 《The Journal of steroid biochemistry and molecular biology》2007,103(3-5):737-741
1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) is known to inhibit prostate cancer cells in vitro. Its effects on proliferation in the presence of living bone have not been reported, but are especially relevant since much of the morbidity and mortality associated with prostate cancer is due to metastatic bone disease. We investigated the effect of 1alpha,25(OH)(2)D(3) on MatLyLu-beta(2) cells (MatLyLu cells), a rat prostate cancer line, co-cultured in transwells with living rat calvaria. Cultures of MatLyLu cells with living calvaria treated with 1alpha,25(OH)(2)D(3) exhibited a statistically significant increase in proliferation (range 1.4 to 1.7-fold; p<0.05). Cultures of MatLylu cells alone, with spleen cells, muscle tissue, or with living or inactivated calvarial bone showed no differences in proliferation. To investigate the mechanism for enhanced proliferation, Galardin, a matrix metalloproteinase (MMP) inhibitor, or pamidronate, an antiresorptive agent, was added. Enhanced proliferation was prevented by either agent, but not to an equal extent. The presence of 1alpha,25(OH)(2)D(3) may lead to proteolytic release or activation of growth factors from bone. These results may explain the variability in reports on the in vivo effects of Vitamin D and suggest a potential concern in using Vitamin D or its analogs alone in patients with metastatic prostate cancer. 相似文献
99.
Verbout NG Lorton JK Jacoby DB Fryer AD 《American journal of physiology. Lung cellular and molecular physiology》2007,292(5):L1126-L1135
Airway hyperreactivity in antigen-challenged animals is mediated by eosinophil major basic protein (MBP) that blocks inhibitory M(2) muscarinic receptors on parasympathetic nerves, increasing acetylcholine release onto M(3) muscarinic receptors on airway smooth muscle. Acutely, anticholinergics block hyperreactivity in antigen-challenged animals and reverse asthma exacerbations in the human, but are less effective in chronic asthma. We tested whether atropine, given before antigen challenge, affected hyperreactivity, M(2) receptor function, eosinophil accumulation, and activation. Sensitized guinea pigs received atropine (1 mg/kg ip) 1 h before challenge and 6 h later. Twenty-four hours after challenge, animals were anesthetized, vagotomized, paralyzed, and ventilated. Airway reactivity to electrical stimulation of the vagi and to intravenous acetylcholine was not altered by atropine pretreatment in nonsensitized animals, indicating that atropine was no longer blocking postjunctional muscarinic receptors. Antigen challenge induced airway hyperreactivity to vagal stimulation that was significantly potentiated by atropine pretreatment. Bronchoconstriction induced by acetylcholine was not changed by antigen challenge or by atropine pretreatment. M(2) receptor function was lost in challenged animals but protected by atropine pretreatment. Eosinophils in bronchoalveolar lavage and within airway tissues were significantly increased by challenge but significantly reduced by atropine pretreatment. However, extracellular MBP in challenged airways was significantly increased by atropine pretreatment, which may account for reduced eosinophils. Depleting eosinophils with antibody to IL-5 before challenge prevented hyperreactivity and significantly reduced MBP in airways of atropine-pretreated animals. Thus atropine pretreatment potentiated airway hyperreactivity by increasing eosinophil activation and degranulation. These data suggest that anticholinergics enhance eosinophil interactions with airway nerves. 相似文献
100.
cGMP-dependent protein kinase I interacts with TRIM39R, a novel Rpp21 domain-containing TRIM protein
Roberts JD Chiche JD Kolpa EM Bloch DB Bloch KD 《American journal of physiology. Lung cellular and molecular physiology》2007,293(4):L903-L912
Nitric oxide modulates vascular smooth muscle cell (SMC) cytoskeletal kinetics and phenotype, in part, by stimulating cGMP-dependent protein kinase I (PKGI). To identify molecular targets of PKGI, an interaction trap screen in yeast was performed using a cDNA encoding the catalytic region of PKGI and a human lung cDNA library. We identified a cDNA that encodes a putative PKGI-interactor that is a novel variant of TRIM39, a member of the really interesting new gene (RING) finger family of proteins. Although this TRIM39 variant encodes the NH(2)-terminal RING finger (RF), B-box, and coiled-coil (RBBC) domains of TRIM39, instead of a complete COOH-terminal B30.2 domain, this TRIM39 isoform contains the COOH-terminal portion of Rpp21, a component of RNase P. RT-PCR demonstrated that the TRIM39 variant, which we refer to as TRIM39R, is transcribed in the human fetal lung and in rat pulmonary artery SMC. Indirect immunofluorescence using an antibody generated against the conserved domains of TRIM39 and TRIM39R revealed the proteins in speckled intranuclear structures in human acute monocytic leukemia (THP-1) and human epidermal carcinoma line (HEp-2) cells. PKGI phosphorylated a typical PKGI/PKA phosphorylation domain in a conserved region of TRIM39 and TRIM39R. Additional studies demonstrated that PKGI interacts with both isoforms of TRIM39 in yeast cells and phosphorylates both isoforms of TRIM39 in human cell lines. Although PKGI has been observed to interact with proteins that regulate cytoskeletal function and gene expression, this investigation shows for the first time that PKGI interacts with tripartite motif (TRIM) proteins, which, through diverse molecular pathways, are often observed to regulate important aspects of cellular homeostasis. 相似文献