全文获取类型
收费全文 | 5872篇 |
免费 | 353篇 |
国内免费 | 11篇 |
出版年
2022年 | 28篇 |
2021年 | 77篇 |
2020年 | 38篇 |
2019年 | 49篇 |
2018年 | 75篇 |
2017年 | 55篇 |
2016年 | 111篇 |
2015年 | 174篇 |
2014年 | 228篇 |
2013年 | 362篇 |
2012年 | 383篇 |
2011年 | 366篇 |
2010年 | 217篇 |
2009年 | 211篇 |
2008年 | 373篇 |
2007年 | 336篇 |
2006年 | 366篇 |
2005年 | 356篇 |
2004年 | 415篇 |
2003年 | 330篇 |
2002年 | 298篇 |
2001年 | 115篇 |
2000年 | 111篇 |
1999年 | 114篇 |
1998年 | 77篇 |
1997年 | 48篇 |
1996年 | 32篇 |
1995年 | 48篇 |
1994年 | 43篇 |
1993年 | 46篇 |
1992年 | 59篇 |
1991年 | 61篇 |
1990年 | 52篇 |
1989年 | 67篇 |
1988年 | 57篇 |
1987年 | 48篇 |
1986年 | 51篇 |
1985年 | 45篇 |
1984年 | 38篇 |
1983年 | 17篇 |
1982年 | 40篇 |
1981年 | 24篇 |
1980年 | 17篇 |
1979年 | 20篇 |
1978年 | 23篇 |
1977年 | 14篇 |
1976年 | 11篇 |
1974年 | 16篇 |
1973年 | 13篇 |
1969年 | 18篇 |
排序方式: 共有6236条查询结果,搜索用时 593 毫秒
961.
Ayumu Niida Yoko Kanematsu-Yamaki Tomoko Asakawa Yoshimasa Ishimura Hisashi Fujita Kouta Matsumiya Naoki Nishizawa Yusuke Adachi Taisuke Mochida Kazue Tsuchimori Mariko Yoneyama-Hirozane Junichi Sakamoto Hideki Hirabayashi Hideo Fukui Shiro Takekawa Taiji Asami 《Bioorganic & medicinal chemistry》2018,26(3):566-572
Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23–36), 1) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet-induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (Cmax) and longer time at maximum concentration (Tmax). Compounds 5 and 10, modified with 20?kDa PEG at the N-terminus and eicosanedioic acid at the Lys30 side chain of 1, respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10, with their relatively low Cmax and long Tmax, partially attenuated emesis in dogs compared with 1. These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism. 相似文献
962.
Mitsunori Kono Tsuneo Oda Michiko Tawada Takashi Imada Yoshihiro Banno Naohiro Taya Tetsuji Kawamoto Hidekazu Tokuhara Yoshihide Tomata Naoki Ishii Atsuko Ochida Yoshiyuki Fukase Tomoya Yukawa Shoji Fukumoto Hiroyuki Watanabe Keiko Uga Akira Shibata Hideyuki Nakagawa Satoshi Yamamoto 《Bioorganic & medicinal chemistry》2018,26(2):470-482
A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay. 相似文献
963.
Fixed‐effect variance and the estimation of repeatabilities and heritabilities: issues and solutions 下载免费PDF全文
P. de Villemereuil M. B. Morrissey S. Nakagawa H. Schielzeth 《Journal of evolutionary biology》2018,31(4):621-632
Linear mixed‐effects models are frequently used for estimating quantitative genetic parameters, including the heritability, as well as the repeatability, of traits. Heritability acts as a filter that determines how efficiently phenotypic selection translates into evolutionary change, whereas repeatability informs us about the individual consistency of phenotypic traits. As quantities of biological interest, it is important that the denominator, the phenotypic variance in both cases, reflects the amount of phenotypic variance in the relevant ecological setting. The current practice of quantifying heritabilities and repeatabilities from mixed‐effects models frequently deprives their denominator of variance explained by fixed effects (often leading to upward bias of heritabilities and repeatabilities), and it has been suggested to omit fixed effects when estimating heritabilities in particular. We advocate an alternative option of fitting models incorporating all relevant effects, while including the variance explained by fixed effects into the estimation of the phenotypic variance. The approach is easily implemented and allows optimizing the estimation of phenotypic variance, for example by the exclusion of variance arising from experimental design effects while still including all biologically relevant sources of variation. We address the estimation and interpretation of heritabilities in situations in which potential covariates are themselves heritable traits of the organism. Furthermore, we discuss complications that arise in generalized and nonlinear mixed models with fixed effects. In these cases, the variance parameters on the data scale depend on the location of the intercept and hence on the scaling of the fixed effects. Integration over the biologically relevant range of fixed effects offers a preferred solution in those situations. 相似文献
964.
Shinya Kodani Hikaru Hemmi Yuto Miyake Issara Kaweewan Hiroyuki Nakagawa 《Journal of industrial microbiology & biotechnology》2018,45(11):983-992
A shuttle vector pHSG396Sp was constructed to perform gene expression using Sphingomonas subterranea as a host. A new lasso peptide biosynthetic gene cluster, derived from Brevundimonas diminuta, was amplified by PCR and integrated to afford a expression vector pHSG396Sp-12697L. The new lasso peptide brevunsin was successfully produced by S. subterranea, harboring the expression vector, with a high production yield (10.2 mg from 1 L culture). The chemical structure of brevunsin was established by NMR and MS/MS experiments. Based on the information obtained from the NOE experiment, the three-dimensional structure of brevunsin was determined, which indicated that brevunsin possessed a typical lasso structure. This expression vector system provides a new heterologous production method for unexplored lasso peptides that are encoded by bacterial genomes. 相似文献
965.
Yoichiro Fujioka Shinya Nishide Toyoyuki Ose Tadaki Suzuki Izumi Kato Hideo Fukuhara Mari Fujioka Kosui Horiuchi Aya O. Satoh Prabha Nepal Sayaka Kashiwagi Jing Wang Mika Horiguchi Yuko Sato Sarad Paudel Asuka Nanbo Tadaaki Miyazaki Hideki Hasegawa Yusuke Ohba 《Cell host & microbe》2018,23(6):809-818.e5
966.
Comparative analysis of microbial diversity and bacterial seedling disease‐suppressive activity in organic‐farmed and standardized commercial conventional soils for rice nursery cultivation 下载免费PDF全文
Hideki Takahashi Yuko Matsushita Toyoaki Ito Yutaka Nakai Masami Nanzyo Takashi Kobayashi Shinji Iwaishi Tomoyoshi Hashimoto Shuhei Miyashita Toshiyuki Morikawa Shigenobu Yoshida Seiya Tsushima Sugihiro Ando 《Journal of Phytopathology》2018,166(4):249-264
The outbreak of rice plant diseases can be effectively suppressed in organic farming systems. However, the mechanisms of disease suppression by organic farming systems are not well understood. When Burkholderia‐infected rice seeds were sown and cultivated on nine organic‐farmed soils which were supplied by nine independent organic rice farmers or standardized commercial conventional soils, the emergence of bacterial seedling diseases was suppressed to equivalent degrees in nine organic‐farmed soils, whereas the diseases occurred in two commercial conventional soils. In any organic or commercial conventional soil sown with healthy rice seeds as a control, the diseases did not appear. Upon physicochemical analysis of the nine organic‐farmed soils, component common to these organic‐farmed soils seemed to not be directly associated with disease‐suppressive activity. However, microbiome analyses indicated that the bacterial population in these nine organic‐farmed soils was more diverse than those in commercial conventional soils. Intriguingly, the diverse bacterial population structures of organic‐farmed soils were preserved after irrigating and sowing rice seeds, but that of commercial conventional soils was clearly changed by them. Thus, organic‐farmed soils seem to maintain robust bacterial populations despite the irrigation and seedling growth. Indeed, pathogenic Burkholderia in infected rice seeds also did not proliferate in the seedling grown on organic‐farmed soils. Taken together, the common feature of organic‐farmed soils might be the correlation between bacterial seedling disease‐suppressive activity and higher robustness of the diversified microbiome. 相似文献
967.
968.
Light-induced protein conformational changes in the photolysis of octopus rhodopsin. 总被引:1,自引:1,他引:0 下载免费PDF全文
Light-induced protein conformational changes in the photolysis of octopus rhodopsin were measured with a highly sensitive time-resolved transient UV absorption spectrophotometer with nanosecond time resolution. A negative band around 280 nm in the lumirhodopsin minus rhodopsin spectra suggests that alteration of the environment of some of the tryptophan residues has taken place before the formation of lumirhodopsin. A small recovery of the absorbance at 280 nm was observed in the transformation of lumirhodopsin to mesorhodopsin. Kinetic parameters suggest that major conformational changes have taken place in the transformation of mesorhodopsin to acid metarhodopsin. In this transformation, drastic changes of amplitude and a shift of a difference absorption band around 280 nm take place, which suggest that some of the tryptophan residues of rhodopsin become exposed to a hydrophilic environment. 相似文献
969.
Hideki Katow Yasuo Yamamoto Shosuke Sofuku 《Development, growth & differentiation》1997,39(2):207-219
A fibronectin-related synthetic cyclic H-Cys-Arg-Gly-Asp-Ser-Pro-Ala-Ser-Ser-Cys-OH (RGDSPASS) peptide (FR-1) binding site in the embryo of the sand dollar Clypeaster japonicus was specified using dansyl-labeled FR-1 (Dns-FR-1) and horseradish peroxidase-labeled FR-1, and an FR-1 receptor was isolated using FR-1-affinity column chromatography. The FR-1 introduced to the blastocoel of blastulae inhibited primary mesenchyme cell (PMC) migration in mesenchyme blastulae, and complete gastrulation and spicule differentiation in gastrulae. The Dns-FR-1 bound to the entire basal side of the ectoderm in mesenchyme blastulae, and then restricted to the basal side of the ectoderm at the apical tuft region and the vegetal hemisphere in early gastrulae. The cytoplasm of the archenteron also bound to Dns-FR-1. In PMC, Dns-FR-1 bound to the nucleus and cytoplasmic reticular features. In unfertilized eggs, Dns-FR-1 bound to the entire cytoplasm, particularly to the oval-shaped granules and the nuclear envelope, but only to the cytoplasm after fertilization. Relative molecular mass ( Mr ) of the FR-1 -binding protein was 240 kDa under non-reducing conditions and 57 kDa under reducing conditions. The FR-1 receptor protein bound anti-sea urchin integrin (Spl) βL subunit antibodies raised against the embryos of Strongylocentrotus purpuratus . Immunohistochemistry showed that the antibody binding site was similar to the histochemical distribution of Dns-FR-1. However, Mr of the FR-1 receptor is distinctively larger than that of the Spl βL subunit. 相似文献
970.
Phosphatidylinositol 4,5-bisphosphate stimulates phosphorylation of the adaptor protein Shc by c-Src 总被引:1,自引:0,他引:1
Ken-ichi Sato Hideki Yamamoto Tetsuji Otsuki Mamoru Aoto Alexander A. Tokmakov Fumio Hayashi Yasuo Fukami 《FEBS letters》1997,410(2-3)
The adaptor protein Shc was prepared as glutathione S-transferase fusion proteins (GST–Shc) and used as in vitro substrate for c-Src. Since phosphotyrosine-binding domain of Shc has been shown to bind phosphatidyl-inositol 4,5-bisphosphate (PtdIns(4,5)P2) [Zhou et al. (1995) Nature 378, 584–592], effect of PtdIns(4,5)P2 on the phosphorylation of GST–Shc by c-Src was examined. PtdIns(4,5)P2 stimulated the phosphorylation of GST–Shc without any effect on the c-Src activity as judged by both its autophosphorylation and phosphorylation of exogenous substrate, Cdc2 peptide. On the other hand, phosphatidylserine, phosphatidic acid, phosphatidylinositol, and phosphatidylinositol 4-phosphate but not phosphatidylcholine stimulated the c-Src activity itself. Km for GST–Shc in the presence of 1 μM PtdIns(4,5)P2 was calculated to be 90 nM. The PtdIns(4,5)P2-dependent phosphorylation of GST–Shc was inhibited by a GST–fusion protein containing the phosphotyrosine-binding domain of Shc. These results suggest that PtdIns(4,5)P2 can act as a regulator of phosphorylation of Shc by c-Src through its binding to Shc. 相似文献