全文获取类型
收费全文 | 3332篇 |
免费 | 227篇 |
专业分类
3559篇 |
出版年
2022年 | 27篇 |
2021年 | 34篇 |
2020年 | 18篇 |
2019年 | 28篇 |
2018年 | 43篇 |
2017年 | 41篇 |
2016年 | 50篇 |
2015年 | 85篇 |
2014年 | 109篇 |
2013年 | 158篇 |
2012年 | 143篇 |
2011年 | 143篇 |
2010年 | 99篇 |
2009年 | 73篇 |
2008年 | 172篇 |
2007年 | 160篇 |
2006年 | 195篇 |
2005年 | 147篇 |
2004年 | 148篇 |
2003年 | 129篇 |
2002年 | 134篇 |
2001年 | 136篇 |
2000年 | 130篇 |
1999年 | 91篇 |
1998年 | 45篇 |
1997年 | 40篇 |
1996年 | 28篇 |
1995年 | 25篇 |
1994年 | 22篇 |
1993年 | 30篇 |
1992年 | 71篇 |
1991年 | 73篇 |
1990年 | 62篇 |
1989年 | 63篇 |
1988年 | 74篇 |
1987年 | 56篇 |
1986年 | 57篇 |
1985年 | 36篇 |
1984年 | 41篇 |
1983年 | 32篇 |
1982年 | 25篇 |
1981年 | 20篇 |
1980年 | 25篇 |
1979年 | 38篇 |
1978年 | 25篇 |
1977年 | 22篇 |
1976年 | 18篇 |
1975年 | 14篇 |
1974年 | 20篇 |
1973年 | 20篇 |
排序方式: 共有3559条查询结果,搜索用时 0 毫秒
91.
Hiroshi Saga Akira Ohhata Akio Hayashi Makoto Katoh Tatsuo Maeda Hirotaka Mizuno Yuka Takada Yuka Komichi Hiroto Ota Naoya Matsumura Masami Shibaya Tetsuya Sugiyama Shinji Nakade Katsuya Kishikawa 《PloS one》2014,9(4)
Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation.The IC50 values of ONO-8540506 for lysophospholipase D activity were 6.4–19 nM for recombinant autotaxin/ENPP2 proteins and 4.7–11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration.Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia. 相似文献
92.
Camilla Dornfeld Alexandra J. Weisberg Ritesh K C Natalia Dudareva John G. Jelesko Hiroshi A. Maeda 《The Plant cell》2014,26(7):3101-3114
The aromatic amino acid Phe is required for protein synthesis and serves as the
precursor of abundant phenylpropanoid plant natural products. While Phe is
synthesized from prephenate exclusively via a phenylpyruvate intermediate in model
microbes, the alternative pathway via arogenate is predominant in plant Phe
biosynthesis. However, the molecular and biochemical evolution of the plant arogenate
pathway is currently unknown. Here, we conducted phylogenetically informed
biochemical characterization of prephenate aminotransferases (PPA-ATs) that belong to class-Ib aspartate aminotransferases
(AspAT Ibs) and catalyze the first
committed step of the arogenate pathway in plants. Plant PPA-ATs and succeeding arogenate dehydratases (ADTs) were found to be most closely related to
homologs from Chlorobi/Bacteroidetes bacteria. The Chlorobium
tepidum
PPA-AT and ADT homologs indeed efficiently converted prephenate and arogenate into
arogenate and Phe, respectively. A subset of AspAT
Ib enzymes exhibiting PPA-AT
activity was further identified from both Plantae and prokaryotes and, together with
site-directed mutagenesis, showed that Thr-84 and Lys-169 play key roles in specific
recognition of dicarboxylic keto (prephenate) and amino (aspartate) acid substrates.
The results suggest that, along with ADT, a gene encoding
prephenate-specific PPA-AT was transferred
from a Chlorobi/Bacteroidetes ancestor to a eukaryotic ancestor of Plantae, allowing
efficient Phe and phenylpropanoid production via arogenate in plants today. 相似文献
93.
The leaf ultrastructure of NADP-malic enzyme type C4 species possessing different anatomical features in the Cyperaceae was examined: types were the Rhynchosporoid type, a normal
Kranz type in which mesophyll cells are adjacent to Kranz cells, and Fimbristyloid and Chlorocyperoid types, unusual Kranz
types in which nonchlorophyllous mestome sheath intervenes between the two types of green cells. They show structural characteristics
basically similar to the NADP-malic enzyme group of C4 grasses, that is, centrifugally located chloroplasts with reduced grana and no increase of mitochondrial frequency in the
Kranz cells. However, the Kranz cell chloroplasts of the Fimbristyloid and Chlorocyperoid types exhibit convoluted thylakoid
systems and a trend of extensive development of peripheral reticulum, although those of the Rhynchosporoid type do not possess
such particular membrane systems. The suberized lamella, probably a barrier for CO2 diffusion, is present in the Kranz cell walls of the Rhynchosporoid type and in the mestome sheath cell walls of the other
two types, and tightly surrounds the Kranz cells (sheaths) that are the sites of the decarboxylation of C4 acids. These ultrastructural features are discussed in relation to C4 photosynthetic function. 相似文献
94.
Characterization of Microtubule-Associated Protein 2 from Mouse Brain and Its Localization in the Cerebellar Cortex 总被引:1,自引:2,他引:1
Michio Niinobe Nobuaki Maeda Hidetoshi Ino Katsuhiko Mikoshiba 《Journal of neurochemistry》1988,51(4):1132-1139
Microtubule-associated protein (MAP) 2 was purified from the microtubule fraction of mouse brain by heat treatment and BioGel A-5m gel filtration. The purified preparation showed a single protein band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis using both a gradient gel (3.75-12.5%) and a low-percentage gel (5%), a finding indicating that MAP2B was absent under the conditions used. Amino acid analysis revealed that mouse MAP2 was an acidic protein with an isoelectric point (pI 4.5) and amino acid composition similar to those of porcine brain MAP2. Immunoblot analysis indicated that the antigens that reacted with MAP2 antiserum were present in large quantities in mouse brain. However, we also found a weak reaction in various tissues other than brain, and the major antigens involved were recognized to be common molecular species with the same molecular mass, 162 and 170 kilodaltons. Using antiserum against mouse brain MAP2, the developmental localization patterns of MAP2 in the mouse cerebellar cortex were studied by immunohistochemistry. MAP2 was mainly localized in the neuronal cells throughout development, with the expression in Purkinje cell dendrites being especially remarkable in the growth of arborization from postnatal day 3 to day 20. At the mature stage, the reaction was strong in the dendritic tree but very weak in the proximal dendrites and cell bodies. 相似文献
95.
The formation of the anulospiral ending of Ia fibers in muscle spindles was investigated in the masseter muscle of developing mice. Before 15 days after birth, the complete anulospiral ending was not observed in almost all of the muscle spindles examined. With the growth of mice, the Ia fiber began to construct the spiral ending, and by the 40th postnatal day after weaning, almost all of the Ia fibers of the muscle spindles had complete coiled endings, though the formation still continued in some spindles. The continuous formation of anulospiral endings for a long period after weaning indicates that muscle spindle morphogenesis may be affected by muscle tension in the masseter muscle due to the movement activated after weaning. 相似文献
96.
Miura Y Nishimura Y Katsuyama H Maeda M Hayashi H Dong M Hyodoh F Tomita M Matsuo Y Uesaka A Kuribayashi K Nakano T Kishimoto T Otsuki T 《Apoptosis : an international journal on programmed cell death》2006,11(10):1825-1835
To analyze the possibility that immunological alteration in asbestos-related diseases (ARDs) such as asbestosis (ASB) and
malignant mesothelioma (MM) may affect the progression of cancers, a human adult T cell leukemia virus-immortalized T cell
line (MT-2Org) was continuously exposed to 10 μg/ml of chrysotile-B (CB), an asbestos. After at least 8 months of exposure,
the rate of apoptosis in the cells became very low and the resultant subline was designated MT-2Rst. The MT-2Rst cells were
characterized by (i) enhanced expression of bcl-2, with regain of apoptosis-sensitivity by reduction of bcl-2 by siRNA, (ii) excess IL-10 secretion and expression, and (iii) activation of STAT3 that was inhibited by PP2, a specific
inhibitor of Src family kinases. These results suggested that the contact between cells and asbestos may affect the human
immune system and trigger a cascade of biological events such as activation of Src family kinases, enhancement of IL-10 expression,
STAT3 activation and Bcl-2 overexpression. This speculation was partially confirmed by the detection of elevated bcl-2 expression levels in CD4 + peripheral blood T cells from patients with MM compared with those from patients with ASB or healthy
donors. Further studies will be required to verify the role of T cells with enhanced bcl-2 expression in tumor progression induced by asbestos exposure. 相似文献
97.
The initial rates of phosphorylation of glucose catalysed by glucokinase from Bacillus stearothermophilus were measured over a wide range of glucose, MgATP2-, MgADP- and glucose 6-phosphate concentrations. The results of the effects of the inhibitors on the initial rates suggest that the reaction mechanism is essentially the ordered Bi Bi, in which glucose adds to the enzyme before MgATP2- and glucose 6-phosphate is released from the enzyme after the dissociation of MgADP-, and also suggest that the final step in which glucose 6-phosphate is released is irreversible. For many reaction schemes, the rate equations were derived on the basis of the pseudo-steady-state assumption and were used to correlate the experimental rate data. From this result, we concluded that the reaction obeys the ordered mechanism accompanied by the formation of a non-productive ternary complex, glucose-MgADP--enzyme. By using the experimental Dalziel coefficients phi i, some kinetic parameters were evaluated. The enzyme was characterized by the thermal stability and the low Michaelis constant, the values of which were 54 microM for glucose and 32 microM for MgATP2-. 相似文献
98.
Y Hakeda Y Nakatani T Yoshino N Kurihara K Fujita N Maeda M Kumegawa 《Journal of biochemistry》1987,101(6):1463-1469
The effect of forskolin on collagen production in osteoblasts was investigated by using clonal osteoblastic MC3T3-E1 cells cultured in a-minimum essential medium containing 0.1% bovine serum albumin. Forskolin increased the adenylate cyclase activity in membranes pelleted from homogenates of the cell line in a dose-dependent manner. The drug caused a 13-fold stimulation at 10(-4) M, indicating that the compound directly acts on adenylate cyclase, leading to an increase in the intracellular cAMP content of the cells. Collagen accumulation in the cultures was elevated by one-day treatment with 5 X 10(-5) M forskolin to about twice that in the controls. The stimulation was mainly due to an elevation in collagen synthesis but not to an inhibition of intracellular collagen degradation because forskolin dose-dependently increased collagen synthesis; it also significantly increased the amount of low-molecular-weight hydroxyproline found in the cultures. Cells treated with forskolin produced mainly type I collagen, as found in bone matrix in situ, with only small amounts of other types of collagen. Furthermore, forskolin time-dependently inhibited DNA synthesis in the cells, indicating that the increase in type I collagen synthesis by forskolin was not due to stimulated cell proliferation. These results suggest that cAMP is closely linked to the differentiation of osteoblasts in vitro. 相似文献
99.
Poly(binaphthyl salen manganese complex)es 3-Mn were synthesized from a 3,3'-diformylbinaphthol derivative, alpha,omega-diamines, and Mn(OAc)2. Their helical structures were well-supported by their IR, UV, and CD spectra. The catalysis of 3-Mn in an asymmetric epoxidation was investigated. 相似文献
100.
Isolation and characterization of nucleases from a clinical isolate of Serratia marcescens kums 3958 总被引:1,自引:0,他引:1
Two new extracellular nucleases, nucleases SM1 and SM2, were purified from the culture fluid of S. marcescens kums 3958, a fresh clinical isolate. The purification was carried out by the following steps; ammonium sulfate precipitation, and DEAE-cellulose and Sephadex G-100 column chromatography. At the final step, nucleases SM1 and SM2 were purified about 3,700- and 1,000-fold, respectively. They were free from phosphomonoesterase and phosphodiesterase activities. The pIs were 8.1 and 7.5 for nucleases SM1 and SM2, respectively. The molecular weight was estimated to be 35,000 for both enzymes by SDS-polyacrylamide disc gel electrophoresis. The results of amino acid analyses showed that both the threonine and serine contents were higher in nuclease SM2 than in SM1. Furthermore, nuclease SM1 was more stable than nuclease SM2 at 4 degrees C. The other properties of the two enzymes were similar; pH optimum (8.0), Mg2+ or Mn2+ for activation, and inhibition by chemical reagents such as EDTA and pyrophosphate. No significant difference was found in base specificity between nucleases SM1 and SM2. Both enzymes specifically degraded double-stranded homopolymers, especially poly(I). poly(C), as well as yeast RNA and calf thymus DNA. They hardly degraded, however, single-stranded homopolymers such as poly(dA), poly(G), and poly(U). 相似文献