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961.
Hongwu Liu Jianwei Wu Ying Ge Aibo Li Jia Li Zhengshi Liu Yungen Xu Qingxiang Xu Yuyan Li 《Bioorganic & medicinal chemistry》2018,26(5):1050-1061
A novel series of non-peptide proteasome inhibitors (PIs) that act on chymotrypsin-like (ChT-L) of the proteasome were developed. These PIs bearing 4-aromatic sulfonyl naphthalene-based scaffold and Leu-boronic moiety as covalent bonding group displayed far better activity than PI-8182 for inhibiting ChT-L in preliminary biological activity test. The results showed that 2a (IC50?=?6.942?μM, MCF-7) and 2c (IC50?=?6.905?μM, MCF-7) displayed higher anti-proliferative activities than Bortezomib (IC50?=?18.37?μM, MCF-7) under our experimental conditions. Furthermore, in the microsomal stability assay, 2a demonstrated excellent metabolic stability profiles with 56% remaining after 40?min, as compared to Bortezomib of which approximately 30% was remaining. The compounds 2a, 2c emerged as promising lead compounds for the development of novel non-peptide boronate PIs. 相似文献
962.
Katarzyna Szczepańska Tadeusz Karcz Magdalena Kotańska Agata Siwek Kamil J. Kuder Gniewomir Latacz Szczepan Mogilski Stefanie Hagenow Annamaria Lubelska Michał Sobolewski Holger Stark Katarzyna Kieć-Kononowicz 《Bioorganic & medicinal chemistry》2018,26(23-24):6056-6066
As a continuation of our search for novel histamine H3 receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2–25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H3 receptors (hH3R). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hH3R affinity (hH3R Ki?=?5.2–115?nM). Moreover introduction of carbonyl group containing residues in the lipophilic part of molecules instead of branched alkyl substituents resulted in increased affinity in correlation to previously described series, whereas propionyl derivatives showed slightly higher affinities than those of acetyl (16 and 22vs.4 and 10; hH3R Ki?=?5.2 and 15.4?nM vs. 10.2 and 115?nM, respectively). These findings were confirmed by molecular modelling studies, demonstrating multiple ligand-receptor interactions. Furthermore, pharmacological in vivo test results of compound 4 clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. Likewise, its protective action against hyperglycemia and the development of overweight has been shown. In order to estimate drug-likeness of compound 4, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. 相似文献
963.
In vitro and in vivo characterization of an interleukin‐15 antagonist peptide by metabolic stability, 99mTc‐labeling,and biological activity assays 下载免费PDF全文
Yunier Rodríguez‐Álvarez Ania Cabrales‐Rico Alejandro Perera‐Pintado Anais Prats‐Capote Hilda E. Garay‐Pérez Osvaldo Reyes‐Acosta Erik Pérez‐García Araceli Chico‐Capote Alicia Santos‐Savio 《Journal of peptide science》2018,24(4-5)
Interleukin (IL)–15 is an inflammatory cytokine that constitutes a validated therapeutic target in some immunopathologies, including rheumatoid arthritis (RA). Previously, we identified an IL‐15 antagonist peptide named [K6T]P8, with potential therapeutic application in RA. In the current work, the metabolic stability of this peptide in synovial fluids from RA patients was studied. Moreover, [K6T]P8 peptide was labeled with 99mTc to investigate its stability in human plasma and its biodistribution pattern in healthy rats. The biological activity of [K6T]P8 peptide and its dimer was evaluated in CTLL‐2 cells, using 3 different additives to improve the solubility of these peptides. The half‐life of [K6T]P8 in human synovial fluid was 5.88 ± 1.73 minutes, and the major chemical modifications included peptide dimerization, cysteinylation, and methionine oxidation. Radiolabeling of [K6T]P8 with 99mTc showed a yield of approximately 99.8%. The 99mTc‐labeled peptide was stable in a 30‐fold molar excess of cysteine and in human plasma, displaying a low affinity to plasma proteins. Preliminary biodistribution studies in healthy Wistar rats suggested a slow elimination of the peptide through the renal and hepatic pathways. Although citric acid, sucrose, and Tween 80 enhanced the solubility of [K6T]P8 peptide and its dimer, only the sucrose did not interfere with the in vitro proliferation assay used to assess their biological activity. The results here presented, reinforce nonclinical characterization of the [K6T]P8 peptide, a potential agent for the treatment of RA and other diseases associated with IL‐15 overexpression. 相似文献
964.
Michał Bijok Ewelina Gruszczynska Adam Kowalczyk Katarzyna Sikorska Agnieszka Walewska Pawel F. Kukolowicz 《Reports of Practical Oncology and Radiotherapy》2018,23(5):341-345
Aim
The aim of the study was to analyze the long-term stability of electron beams generated by the Novac11? IORT accelerator.Background
Novac11? (NRT®) is a mobile electron accelerator designed to irradiate small areas of tissue, up to 10?cm in diameter, with electron beams during surgical procedures. It is characterized by a great mobility guaranteed by a number of degrees of freedom enabling irradiation in the conditions of an operating theatre.Materials and methods
Over the period of January 2013 and September 2016, the measurement sessions of the output of clinically used beam qualities (6, 8 and 10?MeV) were carried out 41 times. Because of the unsatisfactory long-term stability, an extra procedure of tuning of the magnetron, suggested by the manufacturer, was introduced in October 2015, 15 measurements were performed since then. The output of the Novac11? accelerator was measured in the reference conditions recommended by the IAEA Report 398, the measurements of the charge in the ionization chamber at the reference depth were carried out with a Dose1? electrometer and a plane-parallel chamber PPC05? from IBA®.Results
The introduction of the tuning of the magnetron procedure resulted in satisfactory long-term stability of the measured outputs below 2%.Conclusions
After the introduction of the STV parameter tuning procedure, the long-term stability of the Novac11? output increased considerably and is within the values declared by the manufacturer. 相似文献965.
966.
967.
Daisuke Yamane-Koshizawa Sotaro Fujii Takahiro Maruno Yuji Kobayashi Masaru Yamanaka Satoshi Wakai 《Bioscience, biotechnology, and biochemistry》2018,82(2):304-311
AVCP cytochrome c′ from mesophilic Allochromatium vinosum exhibits lower stability than a thermophilic counterpart, Hydrogenophilus thermoluteolus cytochrome c′ (PHCP), in which the six specific amino acid residues that are not conserved in AVCP are responsible for its stability. Here we measured the stability of AVCP variants carrying these specific residues instead of the original AVCP ones. Among the six single AVCP variants, all of which formed a dimeric structure similar to that of the wild-type, three were successfully stabilized compared with the wild-type, while one showed lower stability than the wild-type. In addition, the most stabilized and destabilized AVCP variants could bind CO, similar to the wild-type. These results indicated that mesophilic AVCP could be stabilized through specific three mutations modeled by the thermophilic counterpart, PHCP, without changing the CO binding ability. 相似文献
968.
Mark Bell David Foley Claire Naylor Colin Robinson Jennifer Riley Ola Epemolu Paul Scullion Yoko Shishikura Elad Katz W.H. Irwin McLean Paul Wyatt Kevin D. Read Andrew Woodland 《Bioorganic & medicinal chemistry letters》2018,28(19):3255-3259
The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma. 相似文献
969.
970.