全文获取类型
收费全文 | 1472篇 |
免费 | 85篇 |
国内免费 | 2篇 |
出版年
2021年 | 10篇 |
2020年 | 5篇 |
2018年 | 17篇 |
2017年 | 10篇 |
2016年 | 22篇 |
2015年 | 38篇 |
2014年 | 46篇 |
2013年 | 85篇 |
2012年 | 62篇 |
2011年 | 63篇 |
2010年 | 39篇 |
2009年 | 31篇 |
2008年 | 82篇 |
2007年 | 52篇 |
2006年 | 55篇 |
2005年 | 62篇 |
2004年 | 69篇 |
2003年 | 61篇 |
2002年 | 74篇 |
2001年 | 46篇 |
2000年 | 67篇 |
1999年 | 50篇 |
1998年 | 16篇 |
1997年 | 13篇 |
1996年 | 10篇 |
1995年 | 24篇 |
1994年 | 14篇 |
1993年 | 11篇 |
1992年 | 38篇 |
1991年 | 32篇 |
1990年 | 38篇 |
1989年 | 28篇 |
1988年 | 23篇 |
1987年 | 40篇 |
1986年 | 33篇 |
1985年 | 21篇 |
1984年 | 20篇 |
1983年 | 13篇 |
1982年 | 13篇 |
1981年 | 12篇 |
1980年 | 17篇 |
1979年 | 10篇 |
1978年 | 8篇 |
1977年 | 13篇 |
1976年 | 10篇 |
1975年 | 6篇 |
1974年 | 10篇 |
1973年 | 6篇 |
1970年 | 4篇 |
1969年 | 7篇 |
排序方式: 共有1559条查询结果,搜索用时 15 毫秒
151.
Yoshihisa Hirota Kimie Nakagawa Natsumi Sawada Naoko Okuda Yoshitomo Suhara Yuri Uchino Takashi Kimoto Nobuaki Funahashi Maya Kamao Naoko Tsugawa Toshio Okano 《PloS one》2015,10(4)
UbiA prenyltransferase domain-containing protein 1 (UBIAD1) plays a significant role in vitamin K2 (MK-4) synthesis. We investigated the enzymological properties of UBIAD1 using microsomal fractions from Sf9 cells expressing UBIAD1 by analysing MK-4 biosynthetic activity. With regard to UBIAD1 enzyme reaction conditions, highest MK-4 synthetic activity was demonstrated under basic conditions at a pH between 8.5 and 9.0, with a DTT ≥0.1 mM. In addition, we found that geranyl pyrophosphate and farnesyl pyrophosphate were also recognized as a side-chain source and served as a substrate for prenylation. Furthermore, lipophilic statins were found to directly inhibit the enzymatic activity of UBIAD1. We analysed the aminoacid sequences homologies across the menA and UbiA families to identify conserved structural features of UBIAD1 proteins and focused on four highly conserved domains. We prepared protein mutants deficient in the four conserved domains to evaluate enzyme activity. Because no enzyme activity was detected in the mutants deficient in the UBIAD1 conserved domains, these four domains were considered to play an essential role in enzymatic activity. We also measured enzyme activities using point mutants of the highly conserved aminoacids in these domains to elucidate their respective functions. We found that the conserved domain I is a substrate recognition site that undergoes a structural change after substrate binding. The conserved domain II is a redox domain site containing a CxxC motif. The conserved domain III is a hinge region important as a catalytic site for the UBIAD1 enzyme. The conserved domain IV is a binding site for Mg2+/isoprenyl side-chain. In this study, we provide a molecular mapping of the enzymological properties of UBIAD1. 相似文献
152.
Saranya Ravi Balu Chacko Hirotaka Sawada Philip A. Kramer Michelle S. Johnson Gloria A. Benavides Valerie O’Donnell Marisa B. Marques Victor M. Darley-Usmar 《PloS one》2015,10(4)
Platelet thrombus formation includes several integrated processes involving aggregation, secretion of granules, release of arachidonic acid and clot retraction, but it is not clear which metabolic fuels are required to support these events. We hypothesized that there is flexibility in the fuels that can be utilized to serve the energetic and metabolic needs for resting and thrombin-dependent platelet aggregation. Using platelets from healthy human donors, we found that there was a rapid thrombin-dependent increase in oxidative phosphorylation which required both glutamine and fatty acids but not glucose. Inhibition of fatty acid oxidation or glutamine utilization could be compensated for by increased glycolytic flux. No evidence for significant mitochondrial dysfunction was found, and ATP/ADP ratios were maintained following the addition of thrombin, indicating the presence of functional and active mitochondrial oxidative phosphorylation during the early stages of aggregation. Interestingly, inhibition of fatty acid oxidation and glutaminolysis alone or in combination is not sufficient to prevent platelet aggregation, due to compensation from glycolysis, whereas inhibitors of glycolysis inhibited aggregation approximately 50%. The combined effects of inhibitors of glycolysis and oxidative phosphorylation were synergistic in the inhibition of platelet aggregation. In summary, both glycolysis and oxidative phosphorylation contribute to platelet metabolism in the resting and activated state, with fatty acid oxidation and to a smaller extent glutaminolysis contributing to the increased energy demand. 相似文献
153.
Yoshiaki Tsuda Haruo Sawada Takafumi Ohsawa Katsuhiro Nakao Hiroki Nishikawa Yuji Ide 《Tree Genetics & Genomes》2010,6(3):377-387
We evaluated the genetic structure of 16 Betula maximowicziana populations in the Chichibu mountain range, central Japan, located within a 25-km radius; all but two populations were at
altitudes of 1,100–1,400 m. The results indicate the effects of geographic topology on the landscape genetic structure of
the populations and should facilitate the development of local-scale strategies to conserve and manage them. Analyses involving
11 nuclear simple sequence repeat loci showed that most populations had similar intrapopulation genetic diversity parameters.
Population differentiation (F
ST = 0.021, G′ST = 0.033) parameters for the populations examined were low but were relatively high compared to those obtained in a previous
study covering populations in a much larger area with a radius of approximately 1,000 km (F
ST = 0.062, G′ST = 0.102). Three populations (Iriyama, Kanayamasawa, and Nishizawa) were differentiated from the other populations by Monmonier’s
and spatial analysis of molecular variance algorithms or by STRUCTURE analysis. Since a high mountain ridge (nearly 2,000 m)
separates the Kanayamasawa and Nishizawa populations from the other 14 populations and the Kanayamasawa and Nishizawa populations
are themselves separated by another mountain ridge, the genetic structure appears to be partly due to mountain ridges acting
as genetic barriers and restricting gene flow. However, the Iriyama population is genetically different but not separated
by any clear geographic barrier. These results show that the landscape genetic structure is complex in the mountain range
and we need to pay attention, within landscape genetic studies and conservation programs, to geographic barriers and local
population differentiation. 相似文献
154.
Masato Nakatsukasa Emma Mbua Yoshihiro Sawada Tetsuya Sakai Hideo Nakaya Wataru Yano Yutaka Kunimatsu 《American journal of physical anthropology》2010,143(3):365-382
Old World monkeys represent one of the most successful adaptive radiations of modern primates, but a sparse fossil record has limited our knowledge about the early evolution of this clade. We report the discovery of two partial skeletons of an early colobine monkey (Microcolobus) from the Nakali Formation (9.8–9.9 Ma) in Kenya that share postcranial synapomorphies with extant colobines in relation to arboreality such as mediolaterally wide distal humeral joint, globular humeral capitulum, distinctly angled zona conoidea, reduced medial trochlear keel, long medial epicondyle with weak retroflexion, narrow and tall olecranon, posteriorly dislocated fovea on the radial head, low projection of the femoral greater trochanter, wide talar head with a greater rotation, and proximodistally short cuboid and ectocuneiform. Microcolobus in Nakali clearly differs from the stem cercopithecoid Victoriapithecus regarding these features, as Victoriapithecus is postcranially similar to extant small‐sized terrestrial cercopithecines. However, degeneration of the thumb, a hallmark of modern colobines, is not observed, suggesting that this was a late event in colobine evolution. This discovery contradicts the prevailing hypothesis that the forest invasion by cercopithecids first occurred in the Plio‐Pleistocene, and shows that this event occurred by the late Miocene at a time when ape diversity declined. Am J Phys Anthropol 143:365‐382, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
155.
Junichi Matsubara Masaya Ono Kazufumi Honda Ayako Negishi Hideki Ueno Takuji Okusaka Junji Furuse Koh Furuta Emiko Sugiyama Yoshiro Saito Nahoko Kaniwa Junichi Sawada Ayako Shoji Tomohiro Sakuma Tsutomu Chiba Nagahiro Saijo Setsuo Hirohashi Tesshi Yamada 《Molecular & cellular proteomics : MCP》2010,9(4):695-704
156.
Yoshida K Obata S Ono M Esaki M Maejima T Sawada H 《European journal of cell biology》2007,86(8):461-471
The 5F9A cell, which is a mesenchymal stem cell-like clone established from rat bone marrow substrate adherent cells, can differentiate into adipocytes and osteoblasts in vitro under the appropriate conditions. Multinucleated cells could be also induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) in 5F9A cells. This effect was mediated by protein kinase C. Possible mechanisms of multinucleation by TPA were hypothesized to be either karyokinesis without cytokinesis or cell-cell fusion. By observation using time-lapse phase-contrast microscopy, we determined that the multinucleated cells were generated mainly by karyokinesis without cytokinesis. Cell fusion was studied using time-lapse photography, and confocal laser scanning microscopy using two differentially labeled cells. These techniques demonstrated that multinucleated 5F9A cells could be produced by cell fusion, albeit at a low frequency. We conclude that multinucleated 5F9A cells are formed primarily by karyokinesis without cytokinesis, although some cells are also formed by cell-cell fusion. 相似文献
157.
Koizumi J Kojima T Kamekura R Kurose M Harimaya A Murata M Osanai M Chiba H Himi T Sawada N 《The Journal of membrane biology》2007,218(1-3):1-7
The epithelium of upper respiratory tissues such as nasal mucosa forms a continuous barrier to a wide variety of exogenous
antigens. The epithelial barrier function is regulated in large part by the intercellular junctions, referred to as gap and
tight junctions. However, changes of gap and tight junctions during differentiation of human nasal epithelial (HNE) cells
are still unclear. In the present study, to investigate changes of gap and tight junctions during differentiation of HNE cells
in vitro, we used primary human HNE cells cocultured with primary human nasal fibroblast (HNF) cells in a noncontact system. In HNE
cells cocultured with HNF cells for 2 weeks, numerous elongated cilia-like structures were observed compared to those without
HNF cells. In the coculture, downregulation of Cx26 and upregulation of Cx30.3 and Cx31 were observed together with extensive
gap junctional intercellular communication. Furthermore, expression of the tight junction proteins claudin-1, claudin-4, occludin
and ZO-2 was increased. These results suggest that switching in expression of connexins and induction of tight junction proteins
may be closely associated with differentiation of HNE cells in
vitro and that differentiation of HNE cells requires unknown soluble factors secreted from HNF cells. 相似文献
158.
The surface structures of the cells of Pasteurella pneumotropica from mice and Pasteurella multocida from rabbits were examined by transmission electron microscopy after ruthenium red staining and polycationic ferritin labelling. P. pneumotropica strains ATCC 35149 and K 79114 had slight extracellular fibrous materials associated with cell walls with ruthenium red staining. Ferritin labelling method revealed thick strands or sparsely ferritin-labelled materials on the cell surface of the strains. P. multocida strains Pm-78 and P-2440 had ferritin-labelled capsules surrounded with the cell wall. Strain Pm-78, which was serotyped as A:12, had a thick capsule, whereas serotype -:3 strain P-2440 had a thin and irregular capsule. 相似文献
159.
An Inhibitory Role of Nitric Oxide in the Dynamic Regulation of the Blood-Brain Barrier Function 总被引:1,自引:0,他引:1
Yamauchi A Dohgu S Nishioku T Shuto H Naito M Tsuruo T Sawada Y Kataoka Y 《Cellular and molecular neurobiology》2007,27(3):263-270
1. The present study aimed at elucidating the effect of nitric oxide (NO) on blood-brain barrier (BBB) function with mouse
brain capillary endothelial (MBEC4) cells.
2. Histamine (20–100 μM) evoked NO production (1.6–7 μM) in MBEC4 cells in a dose-dependent manner.
3. The permeability coefficient of sodium fluorescein for MBEC4 cells and the cellular accumulation of rhodamine 123 in MBEC4
cells were increased dose-dependently by the addition of NO solutions (14 and 28 μM) every 10 min during a 30-min period.
4. The present study demonstrated that NO increased the permeability and inhibited the P-glycoprotein efflux pump of brain
capillary endothelial cells, suggesting that NO plays an inhibitory role in the dynamic regulation of the BBB function. 相似文献
160.
Yoshida M Nishikawa Y Omori Y Yoshioka T Tokairin T McCourt P Enomoto K 《Cell and tissue research》2007,329(2):273-282
Embryonic development of the liver is closely associated with vascular organization. However, little is known about the mechanisms
of vascular differentiation during liver development. Our previous study showed that the maturation of sinusoidal endothelial
cells (SECs) occurred during embryonic day 13.0 (E13.0) to E15.0. To improve our understanding of SEC differentiation, we
examined here the expression of maturation markers, SE-1 and stabilin-2, in fetal livers and also attempted to establish an
in vitro SEC differentiation system by culturing E13.5 fetal liver cells. Immunohistochemical examination of SE-1 and stabilin-2
expression during fetal rat liver development revealed that these differentiation markers were co-expressed in SECs in the
late stage of liver development, although stabilin-2 was expressed in almost all vascular endothelial cells in the early stage.
Liver cells from the E13.5 rat fetus were cultured in EBM-2 medium containing vascular endothelial growth factor (VEGF), transforming
growth factor β1 (TGF-β1) and VEGF plus SB-431542 (an inhibitor of the TGF-β1 receptor, activin receptor-like kinase 5 [ALK-5]).
In vitro SEC differentiation, as indicated by the appearance of cells co-expressing SE-1 and stabilin-2 and of cells with
cytoplasmic fenestrae in endothelial sheets, was induced by the addition of both VEGF and SB-431542, an inhibitor of the phosphorylation
of Smad2/3 but not that of Smad1/5/8 in the cultured cells. These results indicate for the first time that both VEGF signaling
and the blocking of the ALK-5-Smad2/3 signal pathway are important for the fetal differentiation of SECs. 相似文献