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191.
Effect of hormone replacement therapy on the production of bone-resorbing cytokines by peripheral blood cells in postmenopausal women. 总被引:4,自引:0,他引:4
H Uemura M Kamada M Maegawa Y Ohmoto K Murata A Kuwahara T Matsuzaki T Yasui T Takeji M Irahara 《Hormones et métabolisme》2005,37(4):226-230
We studied the effects of hormone replacement therapy (HRT) with estrogen on postmenopausal changes in the production of bone-resorbing cytokines interleukin 1 beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha). Both cytokines were measured in the supernatants of lipopolysaccharide (LPS)-stimulated whole-blood cells from 72 untreated and 44 HRT-treated women by ELISA. The levels of IL-1beta were significantly higher in women in their 40s and 50s and in postmenopausal women than in women in their teens, 20s and 30s, while the levels of TNFalpha did not show any changes related to age. Both levels in HRT-treated women were significantly lower than those in untreated women at almost every postmenopausal stage. In a prospective study, HRT induced significant declines in both levels. These results show that estrogen decreases the accelerated production of IL-1beta and reduces the production of TNFalpha in postmenopausal women at each postmenopausal stage, even in late-postmenopausal women. 相似文献
192.
Nakase Y Nakamura-Kubo M Ye Y Hirata A Shimoda C Nakamura T 《Molecular biology of the cell》2008,19(6):2476-2487
The spindle pole body (SPB) of Schizosaccharomyces pombe is required for assembly of the forespore membrane (FSM) during meiosis. Before de novo biogenesis of the FSM, the meiotic SPB forms outer plaques, an event referred to as SPB modification. A constitutive SPB component, Spo15, plays an indispensable role in SPB modification and sporulation. Here, we analyzed two sporulation-specific genes, spo13(+) and spo2(+), which are not required for progression of meiotic nuclear divisions, but are essential for sporulation. Spo13 is a 16-kDa coiled-coil protein, and Spo2 is a 15-kDa nonconserved protein. Both Spo13 and Spo2 specifically associated with the meiotic SPB. The respective deletion mutants are viable, but defective in SPB modification and in the onset of FSM formation. Spo13 and Spo2 localized on the cytoplasmic side of the SPB in close contact with the nascent FSM. Localization of Spo13 to the SPB was dependent on Spo15 and Spo2; that of Spo2 depended only on Spo15, suggesting that their recruitment to the SPB is strictly controlled. Spo2 physically associated with both Spo15 and Spo13, but Spo13 and Spo15 did not interact directly. Taken together, these observations indicate that Spo2 is recruited to the SPB during meiosis and then assists in the localization of Spo13 to the outer surface of the SPB. 相似文献
193.
Hidaka K Kimura T Ruben AJ Uemura T Kamiya M Kiso A Okamoto T Tsuchiya Y Hayashi Y Freire E Kiso Y 《Bioorganic & medicinal chemistry》2008,16(23):10049-10060
Plasmepsin (Plm) is a potential target for new antimalarial drugs, but most reported Plm inhibitors have relatively low antimalarial activities. We synthesized a series of dipeptide-type HIV protease inhibitors, which contain an allophenylnorstatine-dimethylthioproline scaffold to exhibit potent inhibitory activities against Plm II. Their activities against Plasmodium falciparum in the infected erythrocyte assay were largely different from those against the target enzyme. To improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity. These results suggest that auxiliary substituents on a specific basic group contribute to deliver the inhibitors to the target Plm. 相似文献
194.
Sato I Morihira K Inami H Kubota H Morokata T Suzuki K Iura Y Nitta A Imaoka T Takahashi T Takeuchi M Ohta M Tsukamoto S 《Bioorganic & medicinal chemistry》2008,16(18):8607-8618
In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using ClogD(7.4) values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC(50)=23 nM) with much reduced CYP2D6 inhibitory activity (IC(50)=29,000 nM) compared with 1. 相似文献
195.
Generation Characteristics of Highly Uniform Nonspherical Droplets of Soybean Oil Using Microchannel Array Devices 总被引:1,自引:0,他引:1
This paper investigated the generation characteristics of nonspherical oil-in-water (O/W) droplets consisting of food-grade components using microchannel (MC) array devices that have many rectangular MCs with shallow
wells. The well height was designed to be twice the MC height. Two hydrophilic MC array devices made of surface-oxidized single-crystal
silicon with equivalent MC diameters of 3.2 and 8.4 μm were used. Refined soybean oil was used as the to-be-dispersed phase,
and a Milli-Q water solution of 1.0 wt% polyoxyethylene (20) sorbitan monolaurate (Tween20) was used as the continuous phase.
Highly uniform discoid droplets with diameters of 9.0 and 21.5 μm, heights of 4.6 and 9.8 μm, and coefficients of variation
of less than 4% were generated by simply forcing a to-be-dispersed phase via rectangular MCs into a well filled with a continuous
phase. The to-be-dispersed phase pressures necessary for droplet generation were less than 8 kPa. The detailed generation
process of the discoid droplets was analyzed using movie clips taken by a high-speed camera. Key phenomena during the detachment
process were considered to be rapid flow of the to-be-dispersed phase into the well and instantaneous pinch-off of the neck.
The effect of the to-be-dispersed phase velocity inside a rectangular MC (U
d,MC) on the resultant droplet diameter and the droplet-generation rate was also analyzed. Size-controlled discoid droplets were
stably generated via the rectangular MC below the critical U
d,MC, and the droplet-generation rate became maximum at the critical U
d,MC. 相似文献
196.
To understand the mechanistic basis of cold temperature stress and the role of the auxin response, we characterized root growth and gravity response of Arabidopsis thaliana after cold stress, finding that 8 to 12 h at 4°C inhibited root growth and gravity response by ∼50%. The auxin-signaling mutants axr1 and tir1, which show a reduced gravity response, responded to cold treatment like the wild type, suggesting that cold stress affects auxin transport rather than auxin signaling. Consistently, expression analyses of an auxin-responsive marker, IAA2-GUS, and a direct transport assay confirmed that cold inhibits root basipetal (shootward) auxin transport. Microscopy of living cells revealed that trafficking of the auxin efflux carrier PIN2, which acts in basipetal auxin transport, was dramatically reduced by cold. The lateral relocalization of PIN3, which has been suggested to mediate the early phase of root gravity response, was also inhibited by cold stress. Additionally, cold differentially affected various protein trafficking pathways. Furthermore, the inhibition of protein trafficking by cold is independent of cellular actin organization and membrane fluidity. Taken together, these results suggest that the effect of cold stress on auxin is linked to the inhibition of intracellular trafficking of auxin efflux carriers. 相似文献
197.
198.
Ippei Sato Koichiro Morihira Hiroshi Inami Hirokazu Kubota Tatsuaki Morokata Keiko Suzuki Kazuki Ohno Yosuke Iura Aiko Nitta Takayuki Imaoka Toshiya Takahashi Makoto Takeuchi Mitsuaki Ohta Shin-ichi Tsukamoto 《Bioorganic & medicinal chemistry》2009,17(16):5989-6002
Our laboratory has identified several acrylamide derivatives with potent CCR3 inhibitory activity. In the present study, we evaluated the in vitro metabolic stability (CLint; mL/min/kg) of these compounds in human liver microsomes (HLMs), and assessed the relationship between their structures and CLint values. Among the compounds identified, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-[1-(2-hydroxybenzoyl)piperidin-4-ylidene]acetamide (30j) was found to be a potent inhibitor (IC50 = 8.4 nM) with a high metabolic stability against HLMs. 相似文献
199.
Tomohiro Kabuta Aiko Kinugawa Chihana Kabuta Minako Tateno Keiji Wada 《Biochemical and biophysical research communications》2009,387(1):121-20136
Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause 20-25% of familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 causes motor neuron degeneration through toxic gain-of-function(s). However, the direct molecular targets of mutant SOD1, underlying its toxicity, are not fully understood. In this study, we found that α/β-tubulin is one of the major mutant SOD1-interacting proteins, but that wild-type SOD1 does not interact with it. The interaction between tubulin and mutant SOD1 was detected in the spinal cords of mutant G93A SOD1 transgenic mice before the onset of symptoms. Tubulin interacted with amino acid residues 1-23 and 116-153 of SOD1. Overexpression of mutant SOD1 resulted in the accumulation of tubulin in detergent-insoluble fractions. In a cell-free system, mutant SOD1 modulated tubulin polymerization, while wild-type SOD1 did not. Since tightly regulated microtubule dynamics is essential for neurons to remain viable, α/β-tubulin could be an important direct target of mutant SOD1. 相似文献
200.
Toshiaki Koda Satoshi Uemura Jin-ichi Inokuchi 《Biochemical and biophysical research communications》2009,387(4):729-40
Neu2 mRNA from the mouse thymus, as we have reported [K. Kotani, A. Kuroiwa, T. Saito, Y. Matsuda, T. Koda, S. Kijimoto-Ochiai, Cloning, chromosomal mapping, and characteristic 5′-UTR sequence of murine cytosolic sialidase, Biochem. Biophys. Res. Commun. 286 (2001) 250-258], has a novel sequence at the 5′ terminus that shows the ability to encode 6 extra amino acids in the N-terminus than that of the muscle. In this paper, we analyzed the cDNA and EST database and found the five types of alternative splicing of Neu2 mRNA: A, B, C, D and N. We studied the expression of these types in the immune tissues and found that the thymus expressed only type B. We constructed 2 types of plasmid that encode long (B) or short (C) form of Neu2 protein, and transfected them into COS7 cells to study them under the same conditions. We found that 30-40% of the both forms of Neu2 activity was located in the crude membrane-fraction, and hydrolyzed ganglioside effectively, while both soluble fraction showed particular behavior with substrate specificity. Microscopic study by active staining with X-NANA showed that they located not only in the cytoplasm but also in areas surrounding the nucleus and in the peripheral ruffled spot. 相似文献