全文获取类型
收费全文 | 1596篇 |
免费 | 122篇 |
国内免费 | 2篇 |
专业分类
1720篇 |
出版年
2022年 | 14篇 |
2021年 | 18篇 |
2020年 | 16篇 |
2019年 | 17篇 |
2018年 | 18篇 |
2017年 | 22篇 |
2016年 | 35篇 |
2015年 | 53篇 |
2014年 | 48篇 |
2013年 | 88篇 |
2012年 | 101篇 |
2011年 | 96篇 |
2010年 | 63篇 |
2009年 | 71篇 |
2008年 | 75篇 |
2007年 | 91篇 |
2006年 | 76篇 |
2005年 | 76篇 |
2004年 | 80篇 |
2003年 | 78篇 |
2002年 | 62篇 |
2001年 | 44篇 |
2000年 | 50篇 |
1999年 | 36篇 |
1998年 | 16篇 |
1997年 | 18篇 |
1996年 | 17篇 |
1995年 | 15篇 |
1994年 | 6篇 |
1993年 | 5篇 |
1992年 | 25篇 |
1991年 | 26篇 |
1990年 | 25篇 |
1989年 | 23篇 |
1988年 | 19篇 |
1987年 | 22篇 |
1986年 | 15篇 |
1985年 | 17篇 |
1984年 | 21篇 |
1983年 | 17篇 |
1982年 | 16篇 |
1981年 | 20篇 |
1979年 | 4篇 |
1978年 | 6篇 |
1977年 | 7篇 |
1976年 | 4篇 |
1975年 | 6篇 |
1973年 | 7篇 |
1972年 | 6篇 |
1957年 | 3篇 |
排序方式: 共有1720条查询结果,搜索用时 15 毫秒
131.
Makoto Nakabayashi Naoki Shibata Emi Ishido-Nakai Mayumi Kanagawa Yota Iio Hirofumi Komori Yasufumi Ueda Noriko Nakagawa Seiki Kuramitsu Yoshiki Higuchi 《Extremophiles : life under extreme conditions》2016,20(3):275-282
TTHA0829 from Thermus thermophilus HB8 has a molecular mass of 22,754 Da and is composed of 210 amino acid residues. The expression of TTHA0829 is remarkably elevated in the latter half of logarithmic growth phase. TTHA0829 can form either a tetrameric or dimeric structure, and main-chain folding provides an N-terminal cystathionine-β-synthase (CBS) domain and a C-terminal aspartate-kinase chorismate-mutase tyrA (ACT) domain. Both CBS and ACT are regulatory domains to which a small ligand molecule can bind. The CBS domain is found in proteins from organisms belonging to all kingdoms and is observed frequently as two or four tandem copies. This domain is considered as a small intracellular module with a regulatory function and is typically found adjacent to the active (or functional) site of several enzymes and integral membrane proteins. The ACT domain comprises four β-strands and two α-helices in a βαββαβ motif typical of intracellular small molecule binding domains that help control metabolism, solute transport and signal transduction. We discuss the possible role of TTHA0829 based on its structure and expression pattern. The results imply that TTHA0829 acts as a cell-stress sensor or a metabolite acceptor. 相似文献
132.
Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage 总被引:6,自引:0,他引:6
Indo HP Davidson M Yen HC Suenaga S Tomita K Nishii T Higuchi M Koga Y Ozawa T Majima HJ 《Mitochondrion》2007,7(1-2):106-118
Mitochondrial damage is a well known cause of mitochondria-related diseases. A major mechanism underlying the development of mitochondria-related diseases is thought to be an increase in intracellular oxidative stress produced by impairment of the mitochondrial electron transport chain (ETC). However, clear evidence of intracellular free radical generation has not been clearly provided for mitochondrial DNA (mtDNA)-damaged cells. In this study, using the novel fluorescence dye, 2-[6-(4'-hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid (HPF), which was designed to detect hydroxyl radicals (*OH), intracellular free radical formation was examined in 143B cells (parental cells), 143B-rho(0) cells (mtDNA-lacking cells), 87 wt (cybrid), and cybrids of 4977-bp mtDNA deletion (common deletion) cells containing the deletion with 0%, 5%, 50% and >99% frequency (HeLacot, BH5, BH50 and BH3.12, respectively), using a laser confocal microscope detection method. ETC inhibitors (rotenone, 3-nitropropionic acid, thenoyltrifluoroacetone, antimycin A and sodium cyanide) were also tested to determine whether inhibitor treatment increased intracellular reactive oxygen species (ROS) generation. A significant increase in ROS for 143B-rho(0) cells was observed compared with 143B cells. However, for the 87 wt cybrid, no increase was observed. An increase was also observed in the mtDNA-deleted cells BH50 and BH3.12. The ETC inhibitors increased intracellular ROS in both 143B and 143B-rho(0) cells. Furthermore, in every fluorescence image, the fluorescence dye appeared localized around the nuclei. To clarify the localization, we double-stained cells with the dye and MitoTracker Red. The resulting fluorescence was consistently located in mitochondria. Furthermore, manganese superoxide dismutase (MnSOD) cDNA-transfected cells had decreased ROS. These results suggest that more ROS are generated from mitochondria in ETC-inhibited and mtDNA-damaged cells, which have impaired ETC. 相似文献
133.
Xiaofei Wang Hongyu Wang Aodon-geril Yujing Shu Yuriko Momotani Reiko Nagata 《Animal biotechnology》2013,24(1):44-49
We investigated the gene expression of matrix metalloproteinases-9 (MMP-9) and tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) in peripheral blood cells from infected cattle with Mycobacterium avium subsp. paratuberculosis (Map) in the ELISA-negative subclinical stage compared with uninfected control cattle. Significant decreased MMP-9 expression and increased TIMP-1 expression were found in peripheral blood cells from Map-infected cattle after stimulation with Map lysate and Map purified protein derivative (PPD) than in control cattle by real-time RT-PCR analysis. In contrast to the uninfected controls, the activity of MMP-9 was also decreased in peripheral blood cell culture supernatants from Map-infected cattle at 24 hr after Map lysate and MapPPD stimulation by gelatin zymography analysis. As a result, the MMP-9 may play an important role in the development of Mycobacterium avium subsp. paratuberculosis disease. 相似文献
134.
Yujiro Higuchi Peter Ashwin Yvonne Roger Gero Steinberg 《The Journal of cell biology》2014,204(3):343-357
Early endosomes (EEs) mediate protein sorting, and their cytoskeleton-dependent motility supports long-distance signaling in neurons. Here, we report an unexpected role of EE motility in distributing the translation machinery in a fungal model system. We visualize ribosomal subunit proteins and show that the large subunits diffused slowly throughout the cytoplasm (Dc,60S = 0.311 µm2/s), whereas entire polysomes underwent long-range motility along microtubules. This movement was mediated by “hitchhiking” on kinesin-3 and dynein-driven EEs, where the polysomes appeared to translate EE-associated mRNA into proteins. Modeling indicates that this motor-driven transport is required for even cellular distribution of newly formed ribosomes. Indeed, impaired EE motility in motor mutants, or their inability to bind EEs in mutants lacking the RNA-binding protein Rrm4, reduced ribosome transport and induced ribosome aggregation near the nucleus. As a consequence, cell growth was severely restricted. Collectively, our results indicate that polysomes associate with moving EEs and that “off- and reloading” distributes the protein translation machinery. 相似文献
135.
Jean P. H. B. Ometto James R. Ehleringer Tomas F. Domingues Joseph A. Berry Françoise Y. Ishida Edmar Mazzi Niro Higuchi Lawrence B. Flanagan Gabriela B. Nardoto Luiz A. Martinelli 《Biogeochemistry》2006,79(1-2):251-274
Here we present the within-site, seasonal, and interannual variations of the carbon (δ13C) and nitrogen (δ15N) isotope ratios of leaves, wood, bark and litter from four sites in the Amazon region, Brazil. Samples were collected in Manaus (3° 06′07′′ S; 60°01′30′′ W), Ji-Paraná (10°53′07′′ S; 61°57′06′′ W), and Santarém (2°26′35′′ S; 54°42′30′′ W) with mean annual precipitation of 2207, 2040 and 1909 mm respectively. The overall average for all leaf samples was
for δ13C and
for δ15N (n=756). The leaf δ values at these sites were often but not always statistically distinct from each other. The δ13C values varied from
to
. Pronounced differences in δ13C values occurred with height associated with differences in forest structure. The δ13C of leaf dry matter showed seasonal variations associated with the length of the dry season, despite the fact that total annual precipitation was similar among the studied sites. Leaf δ15N values ranged from
to a maximum value of
, and the Santarém sites showed more enriched values than Manaus and Ji-Paraná sites. No seasonal variation was detected in the δ15N of leaves, but significant differences were observed among sites and with changes in canopy height. The isotope ratio data are consistent with our current understanding of the roles of light, water availability, and recycling of soil-respired CO2 influences on δ13C and consistent with our understanding that an open nitrogen cycle can lead to high δ15N values despite a significant number of legumes in the vegetation. 相似文献
136.
137.
Shimada Y Nishida H Nishiyama Y Kobayashi H Higuchi T Eto Y Ida H Ohashi T 《Biochemical and biophysical research communications》2011,(2):274-278
Pompe disease (glycogen storage disease type II) is an autosomal recessive myopathic disorder arising from the deficiency of lysosomal acid α-glucosidase (GAA). Recently, we found that mutant GAA in patient fibroblasts carrying c.546G>T mutation is stabilized by treatment with proteasome inhibitor as well as pharmacological chaperon N-butyl-deoxynojirimycin. In this study, we characterized the effect of two proteasome inhibitors, bortezomib and MG132, on maturation, subcellular localization and residual activity of mutant GAA in the patient fibroblasts carrying c.546G>T mutation. Each proteasome inhibitor promoted the stabilization of patient GAA and processing of them to mature forms without cytotoxic effect. Immunocytochemical analysis showed increased colocalization of GAA with the lysosomal marker LAMP2 in patient fibroblasts treated with proteasome inhibitors. Furthermore, bortezomib and MG132 also increased enzyme activity in the patient fibroblasts (about 4-fold and 2-fold, respectively). These findings indicate that proteasome inhibitor may be a novel drug as potential pharmacological chaperone therapy for Pompe disease patient carrying chaperon-responsive mutation. 相似文献
138.
139.
To determine the direct effect of prolactin on adrenal androgen secretion, the daily secretions of dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione and cortisol were determined in monolayer culture of bovine adrenal cells in the presence or absence of adrenocorticotropic hormone (ACTH) and/or prolactin. In the absence of ACTH ovine prolactin alone had no effect on steroid secretion during seven-day culture. Ovine prolactin, when administered in combination with ACTH, significantly potentiated the stimulatory effect of ACTH on DHEA-S and DHEA but not androstenedione secretion on the seventh day in culture. On the first day in culture prolactin showed no synergistic effect with ACTH on DHEA and DHEA-S secretion, although ACTH significantly increased DHEA and cortisol secretion. DHEA-S secretion increased as a function of prolactin concentration in the presence of ACTH. These results indicated that long-term treatment by ovine prolactin with ACTH caused the increase in adrenal androgen secretion from bovine adrenal cells. The site of action of prolactin was suggested to be the partial inhibition of adrenal 3 beta-hydroxysteroid dehydrogenase by the result of increases in DHEA-S and DHEA but not androstenedione secretion. 相似文献
140.
Masanori Tachikawa Go Ozeki Takanori Higuchi Shin‐ichi Akanuma Kazuhiro Tsuji Ken‐ichi Hosoya 《Journal of neurochemistry》2012,123(5):750-760
An increasing level of prostaglandin (PG) E2 is involved in the progression of neuroinflammation induced by ischemia and bacterial infection. Although an imbalance in the rates of production and clearance of PGE2 under these pathological conditions appears to affect the concentration of PGE2 in the cerebrospinal fluid (CSF), the regulatory system remains incompletely understood. The purpose of this study was to investigate the cellular system of PGE2 production via microsomal PGE synthetase‐1 (mPGES‐1), the inducible PGE2‐generating enzyme, and PGE2 elimination from the CSF via the blood–CSF barrier (BCSFB). Immunohistochemical analysis revealed that mPGES‐1 was expressed in the soma and perivascular sheets of astrocytes, pia mater, and brain blood vessel endothelial cells, suggesting that these cells are local production sites of PGE2 in the CSF. The in vivo PGE2 elimination clearance from the CSF was eightfold greater than that of d ‐mannitol, which is considered to reflect CSF bulk flow. This process was inhibited by the simultaneous injection of unlabeled PGE2 and β‐lactam antibiotics, such as benzylpenicillin, cefazolin, and ceftriaxone, which are substrates and/or inhibitors of organic anion transporter 3 (OAT3). The characteristics of PGE2 uptake by the isolated choroid plexus were at least partially consistent with those of OAT3. OAT3 was able to mediate PGE2 transport with a Michaelis–Menten constant of 4.24 μM. These findings indicate that a system regulating the PGE2 level in the CSF involves OAT3‐mediated PGE2 uptake by choroid plexus epithelial cells, acting as a cerebral clearance pathway via the BCSFB of locally produced PGE2. 相似文献