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71.
Taiji Asami Naoki Nishizawa Yoshihiro Ishibashi Kimiko Nishibori Masaharu Nakayama Yasuko Horikoshi Shin-ichi Matsumoto Masashi Yamaguchi Hirokazu Matsumoto Naoki Tarui Tetsuya Ohtaki Chieko Kitada 《Bioorganic & medicinal chemistry letters》2012,22(20):6391-6396
Metastin/kisspeptin, a 54-amino acid peptide, is the ligand of the G-protein-coupled receptor KISS1R which plays a key role in pathways that regulate reproduction and cell migration in many endocrine and gonadal tissues. The N-terminally truncated decapeptide, metastin(45–54), has 3–10 times higher receptor affinity and intracellular calcium ion-mobilizing activity but is rapidly inactivated in serum. In this study we designed and synthesized stable KISS1R agonistic decapeptide analogs with selected substitutions at positions 47, 50, and 51. Replacement of glycine with azaglycine (azaGly) in which the α-carbon is replaced with a nitrogen atom at position 51 improved the stability of amide bonds between Phe50-Gly51 and Gly51-Leu52 as determined by in vitro mouse serum stability studies. Substitution for tryptophan at position 47 with other amino acids such as serine, threonine, β-(3-pyridyl)alanine, and d-tryptophan (d-Trp), produced analogs that were highly stable in mouse serum. d-Trp47 analog 13 showed not only high metabolic stability but also excellent KISS1R agonistic activity. Other labile peptides may have increased serum stability using amino acid substitution. 相似文献
72.
Y Ujiié T Asami T de Garidel-Thoron H Liu Y Ishitani C de Vargas 《Ecology and evolution》2012,2(7):1725-1737
Evolutionary processes in marine plankton have been assumed to be dependent on the oceanic circulation system, which transports plankton between populations in marine surface waters. Gene flow facilitated by oceanic currents along longitudinal gradients may efficiently impede genetic differentiation of pelagic populations in the absence of confounding marine environmental effects. However, how responsible oceanic currents are for the geographic distribution and dispersal of plankton is poorly understood. We examined the phylogeography of the planktic foraminifer Pulleniatina obliquiloculata in the Indo-Pacific Warm Pool (IPWP) by using partial small subunit ribosomal DNA (SSU rDNA) sequences. We found longitudinal clines in the frequencies of three distinct genetic types in the IPWP area. These frequencies were correlated with environmental factors that are characteristic of three water masses in the IPWP. Noteworthy, populations inhabiting longitudinally distant water masses at the Pacific and Indian sides of the IPWP were genetically different, despite transportation of individuals via oceanic currents. These results demonstrate that populations of pelagic plankton have diverged genetically among different water masses within a single climate zone. Changes of the oceanic circulation system could have impacted the geographic patterns of dispersal and divergence of pelagic plankton. 相似文献
73.
Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c 总被引:1,自引:0,他引:1
Hagiwara A Cornu M Cybulski N Polak P Betz C Trapani F Terracciano L Heim MH Rüegg MA Hall MN 《Cell metabolism》2012,15(5):725-738
Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2. 相似文献
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76.
In three behavioral experiments using depth-inverted visual stimuli, the factors that contribute to the 'reverse perspective' illusion were measured. The density of linear perspective grid lines was found to induce the illusion most strongly, followed by shading/shadows, and texture/color information. The relative contributions of such pictorial cues to depth perception are similar to those that facilitate the normal perception of 3D space in 2D paintings. 相似文献
77.
Katsumoto Y Hayashi Y Oshige I Omori S Kishii N Yasuda A Asami K 《Biophysical journal》2008,95(6):3043-3047
We have developed what we believe is an efficient method to determine the electric parameters (the specific membrane capacitance C(m) and the cytoplasm conductivity kappa(i)) of cells from their dielectric dispersion. First, a limited number of dispersion curves are numerically calculated for a three-dimensional cell model by changing C(m) and kappa(i), and their amplitudes Deltaepsilon and relaxation times tau are determined by assuming a Cole-Cole function. Second, regression formulas are obtained from the values of Deltaepsilon and tau and then used for the determination of C(m) and kappa(i) from the experimental Deltaepsilon and tau. This method was applied to the dielectric dispersion measured for rabbit erythrocytes (discocytes and echinocytes) and human erythrocytes (normocytes), and provided reasonable C(m) and kappa(i) of the erythrocytes and excellent agreement between the theoretical and experimental dispersion curves. 相似文献
78.
M Kushiro T Nakano K Sato K Yamagishi T Asami A Nakano S Takatsuto S Fujioka Y Ebizuka S Yoshida 《Biochemical and biophysical research communications》2001,285(1):98-104
Obtusifoliol 14alpha-demethylase is a plant orthologue of sterol 14alpha-demethylase (CYP51) essential in sterol biosynthesis. We have prepared CYP51 antisense Arabidopsis in order to shed light on the sterol and steroid hormone biosynthesis in plants. Arabidopsis putative CYP51 cDNA (AtCYP51) was obtained from Arabidopsis expressed sequence tag (EST) library and its function was examined in a yeast lanosterol 14alpha-demethylase (Erg11) deficient mutant. A recombinant AtCYP51 protein fused with a yeast Erg11 signal-anchor peptide was able to complement the erg11 mutation, which confirmed AtCYP51 to be a functional sterol 14alpha-demethylase. AtCYP51 was then used to generate transgenic Arabidopsis by transforming with pBI vector harboring AtCYP51 in the antisense direction under CaMV35S promoter. The resulting transgenic plants were decreased in accumulation of AtCYP51 mRNA and increased in the amount of endogenous obtusifoliol. They showed a semidwarf phenotype in the early growth stage and a longer life span than control plants. This newly found phenotype is different from previously characterized brassinosteroid (BR)-deficient campesterol biosynthesis mutants. 相似文献
79.
Nuclease B, which contains an additional flexible amino acid sequence of 19 amino acid residues bound to the NH2-terminus of nuclease A, an extracellular nuclease of Staphylococcus aureus, has been investigated in order to determine the influence of the extra residues on the refolding of the nuclease A portion from the acid denaturated state by monitoring the change in tryptophan fluorescence using a stopped-flow technique. It was found that the kinetic parameters of this refolding is similar within experimental error for nuclease A and nuclease B for the entire course (up to 40 s) studied. Therefore, the extra residues do not appear to have any detectable effect on the dynamic events involved in the refolding process. Thus, the folding of the nuclease A portion of nuclease B appears to be thermodynamically and kinetically independent of the 19 residues at the amino-terminus. 相似文献
80.
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