全文获取类型
收费全文 | 10034篇 |
免费 | 730篇 |
国内免费 | 6篇 |
出版年
2021年 | 115篇 |
2020年 | 73篇 |
2019年 | 86篇 |
2018年 | 119篇 |
2017年 | 95篇 |
2016年 | 169篇 |
2015年 | 342篇 |
2014年 | 375篇 |
2013年 | 538篇 |
2012年 | 637篇 |
2011年 | 632篇 |
2010年 | 462篇 |
2009年 | 380篇 |
2008年 | 569篇 |
2007年 | 548篇 |
2006年 | 514篇 |
2005年 | 523篇 |
2004年 | 518篇 |
2003年 | 514篇 |
2002年 | 448篇 |
2001年 | 113篇 |
2000年 | 102篇 |
1999年 | 129篇 |
1998年 | 167篇 |
1997年 | 98篇 |
1996年 | 124篇 |
1995年 | 110篇 |
1994年 | 93篇 |
1993年 | 111篇 |
1992年 | 106篇 |
1991年 | 86篇 |
1990年 | 82篇 |
1989年 | 71篇 |
1988年 | 93篇 |
1987年 | 75篇 |
1986年 | 56篇 |
1985年 | 81篇 |
1984年 | 112篇 |
1983年 | 94篇 |
1982年 | 108篇 |
1981年 | 93篇 |
1980年 | 94篇 |
1979年 | 73篇 |
1978年 | 82篇 |
1977年 | 84篇 |
1976年 | 71篇 |
1975年 | 64篇 |
1974年 | 74篇 |
1973年 | 64篇 |
1972年 | 44篇 |
排序方式: 共有10000条查询结果,搜索用时 171 毫秒
971.
Tobback J Boerjan B Vandersmissen HP Huybrechts R 《Insect biochemistry and molecular biology》2011,41(5):313-321
The circadian clocks govern many metabolic and behavioral processes in an organism. In insects, these clocks and their molecular machinery have been found to influence reproduction in many different ways. Reproductive behavior including courtship, copulation and egg deposition, is under strong influence of the daily rhythm. At the molecular level, the individual clock components also have their role in normal progress of oogenesis and spermatogenesis. In this study on the desert locust Schistocerca gregaria, three circadian clock genes were identified and their expression profiles were determined. High expression was predominantly found in reproductive tissues. Similar daily expression profiles were found for period (per) and timeless (tim), while the clock (clk) mRNA level is higher 12 h before the first per and tim peak. A knockdown of either per or tim resulted in a significant decrease in the progeny produced by dsRNA treated females confirming the role of clock genes in reproduction and providing evidence that both PER and TIM are needed in the ovaries for egg development. Since the knockdown of clk is lethal for the desert locust, its function remains yet to be elucidated. 相似文献
972.
Ranyuk ER Cauchon N Ali H Lecomte R Guérin B van Lier JE 《Bioorganic & medicinal chemistry letters》2011,21(24):7470-7473
Sulfonated metallo phthalocyanines (MPcS(n)) are second generation photosensitizers advanced for photodynamic therapy of various medical applications. A series of ZnPcS(n) was demetallated and subsequently converted to the corresponding [(64)Cu]CuPcS(n) in 40-50% isolated yields and >98% radiochemical purities. Tumor-bearing mice were injected with the (64)Cu-labeled products and subjected to 3-h dynamic PET imaging studies. Biodistribution patterns showed characteristic differences between the various derivatives. Tumor uptake was detected only for the amphiphilic derivatives [(64)Cu]CuPcS(2) and [(64)Cu]CuPcS(3)C(6) (1-1.5%ID/g). The biological data suggest that PET imaging with [(64)Cu]CuPc can be used to establish structure-PDT efficacy relationships for Pc-based photosensitizers. 相似文献
973.
Miles TJ Barfoot C Brooks G Brown P Chen D Dabbs S Davies DT Downie DL Eyrisch S Giordano I Gwynn MN Hennessy A Hoover J Huang J Jones G Markwell R Rittenhouse S Xiang H Pearson N 《Bioorganic & medicinal chemistry letters》2011,21(24):7483-7488
As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties. 相似文献
974.
Miles TJ Axten JM Barfoot C Brooks G Brown P Chen D Dabbs S Davies DT Downie DL Eyrisch S Gallagher T Giordano I Gwynn MN Hennessy A Hoover J Huang J Jones G Markwell R Miller WH Minthorn EA Rittenhouse S Seefeld M Pearson N 《Bioorganic & medicinal chemistry letters》2011,21(24):7489-7495
We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model. 相似文献
975.
Spliceosomal introns are hallmarks of most eukaryotic genomes and are excised from premature mRNAs by a spliceosome that is among the largest, and most complex, molecular machine in cells. The divergent unicellular eukaryote Giardia intestinalis, the causative agent of giardiasis, also possesses spliceosomes, but only four canonical (cis-spliced) introns have been identified in its genome to date. We demonstrate that this organism has a novel form of spliceosome-mediated trans-splicing of split introns that is essential for generating mature mRNAs for at least two important genes: one encoding a heat shock protein 90 (HSP90), which controls the conformation of a suite of cellular proteins, and the other encoding a dynein molecular motor protein, involved in the motility of eukaryotic flagella. These split introns have properties that distinguish them from other trans-splicing systems known within eukaryotes, suggesting that Giardia independently evolved a unique system to splice split introns. 相似文献
976.
Whippo CW Khurana P Davis PA DeBlasio SL DeSloover D Staiger CJ Hangarter RP 《Current biology : CB》2011,21(1):59-64
Chloroplast movement in response to changing light conditions optimizes photosynthetic light absorption. This repositioning is stimulated by blue light perceived via the phototropin photoreceptors and is transduced to the actin cytoskeleton. Some actin-based motility systems use filament reorganizations rather than myosin-based translocations. Recent research favors the hypothesis that chloroplast movement is driven by actin reorganization at the plasma membrane, but no proteins affecting chloroplast movements have been shown to associate with both the plasma membrane and actin filaments in vivo. Here we identified THRUMIN1 as a critical link between phototropin photoreceptor activity at the plasma membrane and actin-dependent chloroplast movements. THRUMIN1 bundles filamentous actin in vitro, and it localizes to the plasma membrane and displays light- and phototropin-dependent localization to microfilaments in vivo. These results suggest that phototropin-induced actin bundling via THRUMIN1 is important for chloroplast movement. A mammalian homolog of THRUMIN1, GRXCR1, has been implicated in auditory responses and hair cell stereocilla development as a regulator of actin architecture. Studies of THRUMIN1 will help elucidate the function of this family of eukaryotic proteins. 相似文献
977.
Burke JE Vadas O Berndt A Finegan T Perisic O Williams RL 《Structure (London, England : 1993)》2011,19(8):1127-1137
Phosphoinositide 3-kinase δ is upregulated in lymphocytic leukemias. Because the p85-regulatory subunit binds to any class IA subunit, it was assumed there is a single universal p85-mediated regulatory mechanism; however, we find isozyme-specific inhibition by p85α. Using deuterium exchange mass spectrometry (DXMS), we mapped regulatory interactions of p110δ with p85α. Both nSH2 and cSH2 domains of p85α contribute to full inhibition of p110δ, the nSH2 by contacting the helical domain and the cSH2 via the C terminus of p110δ. The cSH2 inhibits p110β and p110δ, but not p110α, implying that p110α is uniquely poised for oncogenic mutations. Binding RTK phosphopeptides disengages the SH2 domains, resulting in exposure of the catalytic subunit. We find that phosphopeptides greatly increase the affinity of the heterodimer for PIP2-containing membranes measured by FRET. DXMS identified regions decreasing exposure at membranes and also regions gaining exposure, indicating loosening of interactions within the heterodimer at membranes. 相似文献
978.
Ruchelman AL Man HW Chen R Liu W Lu L Cedzik D Zhang L Leisten J Collette A Narla RK Raymon HK Muller GW 《Bioorganic & medicinal chemistry》2011,19(21):6356-6374
A series of 1,1-diarylalkene derivatives were prepared to optimize the properties of CC-5079 (1), a dual inhibitor of tubulin polymerization and phosphodiesterase 4 (PDE4). By using the 3-ethoxy-4-methoxyphenyl PDE4 pharmacophore as one of the aromatic rings, a significant improvement in PDE4 inhibition was achieved. Compound 28 was identified as a dual inhibitor with potent PDE4 (IC(50)=54 nM) and antitubulin activity (HCT-116 IC(50)=34 nM and tubulin polymerization IC(50) ~1 μM). While the nitrile group at the alkene terminus was generally required for potent antiproliferative activity, its replacement was tolerated if there was a hydroxyl or amino group on one of the aryl rings. Conveniently, this group could also serve as a handle for amino acid derivatization to improve the compounds' solubility. The glycinamide analog 45 showed significant efficacy in the HCT-116 xenograft model, with 64% inhibition of tumor growth upon dosing at 20 mg/kg qd. 相似文献
979.
本研究通过对新疆地区不明原因发热人群血清Tahyna病毒抗体进行检测,以了解Tahyna病毒在当地的感染状况及分布特征。通过间接免疫荧光方法对新疆维吾尔自治区南部喀什地区、北部伊犁地区742例不明原因发热患者急性期血清标本进行Tahyna病毒抗体检测,并对IgM抗体阳性标本平行进行Tahyna病毒、Snowshoe hare病毒和Inkoo病毒三种抗原性相似的布尼亚病毒的蚀斑减少中和试验。研究结果显示新疆南部喀什地区采集不明原因发热患者急性期血清中,IgM抗体阳性率5.3%,IgG抗体阳性率18.3%;新疆北部伊犁地区采集的急性期患者血清标本中并未发现TAHV IgM抗体阳性;蚀斑减少中和试验结果显示,TAHV IgM抗体阳性患者血清中Tahyna病毒中和抗体滴度较其它两种布尼亚病毒中和抗体滴度升高明显。本研究证实新疆南部地区不明原因发热人群存在Tahyna病毒的急性感染和既往感染,为相关疾病的进一步监测提供基础。 相似文献
980.