全文获取类型
收费全文 | 340760篇 |
免费 | 35624篇 |
国内免费 | 118篇 |
出版年
2018年 | 2932篇 |
2017年 | 2793篇 |
2016年 | 4001篇 |
2015年 | 5530篇 |
2014年 | 6483篇 |
2013年 | 9321篇 |
2012年 | 10433篇 |
2011年 | 10370篇 |
2010年 | 7070篇 |
2009年 | 6398篇 |
2008年 | 9292篇 |
2007年 | 9705篇 |
2006年 | 8993篇 |
2005年 | 8655篇 |
2004年 | 8387篇 |
2003年 | 8173篇 |
2002年 | 8113篇 |
2001年 | 18322篇 |
2000年 | 18553篇 |
1999年 | 14206篇 |
1998年 | 4213篇 |
1997年 | 4459篇 |
1996年 | 4212篇 |
1995年 | 4060篇 |
1994年 | 3997篇 |
1993年 | 3842篇 |
1992年 | 11602篇 |
1991年 | 11240篇 |
1990年 | 10773篇 |
1989年 | 10329篇 |
1988年 | 9570篇 |
1987年 | 8923篇 |
1986年 | 8152篇 |
1985年 | 8022篇 |
1984年 | 6453篇 |
1983年 | 5620篇 |
1982年 | 4165篇 |
1981年 | 3630篇 |
1980年 | 3395篇 |
1979年 | 6169篇 |
1978年 | 4617篇 |
1977年 | 4153篇 |
1976年 | 3791篇 |
1975年 | 4362篇 |
1974年 | 4519篇 |
1973年 | 4420篇 |
1972年 | 4116篇 |
1971年 | 3517篇 |
1970年 | 3200篇 |
1969年 | 2992篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
1.
Shuichi Nagashima Hiroaki Yagyu Ryuichi Tozawa Fumiko Tazoe Manabu Takahashi Tetsuya Kitamine Daisuke Yamamuro Kent Sakai Motohiro Sekiya Hiroaki Okazaki Jun-ichi Osuga Akira Honda Shun Ishibashi 《Journal of lipid research》2015,56(5):998-1005
Squalene synthase (SS) catalyzes the biosynthesis of squalene, the first specific intermediate in the cholesterol biosynthetic pathway. To test the feasibility of lowering plasma cholesterol by inhibiting hepatic SS, we generated mice in which SS is specifically knocked out in the liver (L-SSKO) using Cre-loxP technology. Hepatic SS activity of L-SSKO mice was reduced by >90%. In addition, cholesterol biosynthesis in the liver slices was almost eliminated. Although the hepatic squalene contents were markedly reduced in L-SSKO mice, the hepatic contents of cholesterol and its precursors distal to squalene were indistinguishable from those of control mice, indicating the presence of sufficient centripetal flow of cholesterol and/or its precursors from the extrahepatic tissues. L-SSKO mice showed a transient liver dysfunction with moderate hepatomegaly presumably secondary to increased farnesol production. In a fed state, the plasma total cholesterol and triglyceride were significantly reduced in L-SSKO mice, primarily owing to reduced hepatic VLDL secretion. In a fasted state, the hypolipidemic effect was lost. mRNA expression of liver X receptor α target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specific ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing significant mortality. 相似文献
2.
3.
C. Lawrence Kien Dwight E. Matthews Matthew E. Poynter Janice Y. Bunn Naomi K. Fukagawa Karen I. Crain David B. Ebenstein Emily K. Tarleton Robert D. Stevens Timothy R. Koves Deborah M. Muoio 《Journal of lipid research》2015,56(9):1795-1807
Palmitic acid (PA) is associated with higher blood concentrations of medium-chain acylcarnitines (MCACs), and we hypothesized that PA may inhibit progression of FA β-oxidation. Using a cross-over design, 17 adults were fed high PA (HPA) and low PA/high oleic acid (HOA) diets, each for 3 weeks. The [1-13C]PA and [13-13C]PA tracers were administered with food in random order with each diet, and we assessed PA oxidation (PA OX) and serum AC concentration to determine whether a higher PA intake promoted incomplete PA OX. Dietary PA was completely oxidized during the HOA diet, but only about 40% was oxidized during the HPA diet. The [13-13C]PA/[1-13C]PA ratio of PA OX had an approximate value of 1.0 for either diet, but the ratio of the serum concentrations of MCACs to long-chain ACs (LCACs) was significantly higher during the HPA diet. Thus, direct measurement of PA OX did not confirm that the HPA diet caused incomplete PA OX, despite the modest, but statistically significant, increase in the ratio of MCACs to LCACs in blood. 相似文献
4.
Katsunori Takahashi Shin-ichiro Kanno Kensaku Mizuno 《Biochemical and biophysical research communications》2014
Slingshot-1 (SSH1) is a protein phosphatase that dephosphorylates and activates cofilin, an actin-severing and -disassembling protein. SSH1 is bound to and activated by F-actin, but not G-actin. SSH1 is accumulated in the F-actin-rich lamellipodium but is also diffusely distributed in the cytoplasm. It remains unknown whether SSH1 is activated by soluble (low-level polymerized) actin filaments in the cytoplasm. In this study, we show that SSH1 binds to gelsolin via actin filaments in the cytosolic fraction. Gelsolin promoted solubilization of actin filaments and SSH1 in cell-free assays and in cultured cells. SSH1 was activated by gelsolin-generated soluble actin filaments. Furthermore, gelsolin enhanced cofilin dephosphorylation in neuregulin-stimulated cells. Our results suggest that cytosolic SSH1 forms a complex with gelsolin via soluble actin filaments and is activated by gelsolin-generated soluble actin filaments and that gelsolin promotes stimulus-induced cofilin dephosphorylation through increasing soluble actin filaments, which support SSH1 activation in the cytoplasm. 相似文献
5.
O. I. Grabelnych O. A. Borovik E. L. Tauson T. P. Pobezhimova A. I. Katyshev N. S. Pavlovskaya N. A. Koroleva I. V. Lyubushkina V. Yu. Bashmakov V. N. Popov G. B. Borovskii V. K. Voinikov 《Biochemistry. Biokhimii?a》2014,79(6):506-519
Gene expression, protein synthesis, and activities of alternative oxidase (AOX), uncoupling proteins (UCP), adenine nucleotide translocator (ANT), and non-coupled NAD(P)H dehydrogenases (NDex, NDPex, and NDin) were studied in shoots of etiolated winter wheat (Triticum aestivum L.) seedlings after exposure to hardening low positive (2°C for 7 days) and freezing (?2°C for 2 days) temperatures. The cold hardening efficiently increased frost-resistance of the seedlings and decreased the generation of reactive oxygen species (ROS) during further cold shock. Functioning of mitochondrial energy-dissipating systems can represent a mechanism responsible for the decrease in ROS under these conditions. These systems are different in their response to the action of the hardening low positive and freezing temperatures. The functioning of the first system causes induction of AOX and UCP synthesis associated with an increase in electron transfer via AOX in the mitochondrial respiratory chain and also with an increase in the sensitivity of mitochondrial non-phosphorylating respiration to linoleic and palmitic acids. The increase in electron transfer via AOX upon exposure of seedlings to hardening freezing temperature is associated with retention of a high activity of NDex. It seems that NDex but not the NDPex and NDin can play an important role in maintaining the functional state of mitochondria in heterotrophic tissues of plants under the influence of freezing temperatures. The involvement of the mitochondrial energy-dissipating systems and their possible physiological role in the adaptation of winter crops to cold and frost are discussed. 相似文献
6.
Kazunari Kaizu Wiet de?Ronde Joris Paijmans Koichi Takahashi Filipe Tostevin Pieter?Rein ten?Wolde 《Biophysical journal》2014,106(4):976-985
Biological systems often have to measure extremely low concentrations of chemicals with high precision. When dealing with such small numbers of molecules, the inevitable randomness of physical transport processes and binding reactions will limit the precision with which measurements can be made. An important question is what the lower bound on the noise would be in such measurements. Using the theory of diffusion-influenced reactions, we derive an analytical expression for the precision of concentration estimates that are obtained by monitoring the state of a receptor to which a diffusing ligand can bind. The variance in the estimate consists of two terms, one resulting from the intrinsic binding kinetics and the other from the diffusive arrival of ligand at the receptor. The latter term is identical to the fundamental limit derived by Berg and Purcell (Biophys. J., 1977), but disagrees with a more recent expression by Bialek and Setayeshgar. Comparing the theoretical predictions against results from particle-based simulations confirms the accuracy of the resulting expression and reaffirms the fundamental limit established by Berg and Purcell. 相似文献
7.
8.
Cytochrome c oxidase (CcO) is the terminal enzyme in the electron transfer chain. CcO catalyzes a four electron reduction of O2 to water at a catalytic site formed by high-spin heme (a3) and copper atoms (CuB). While it is recognized that proton movement is coupled to oxygen reduction, the proton channel(s) have not been well defined. Using computational methods developed to study protein topology, membrane channels and 3D packing arrangements within transmembrane (TM) helix arrays, we find that subunit-1 (COX-1), subunit-2 (COX-2) and subunit-3 (COX-3) contribute 139, 46 and 25 residues, respectively, to channel formation between the mitochondrial matrix and intermembrane space. Nine of 12 TM helices in COX-1, both helices in COX-2 and 5 of the 6 TM helices in COX-3 are pore-lining regions (possible channel formers). Heme a3 and the CuB sites (as well as the CuA center of COX-2) are located within the channel that includes TM-6, TM-7, TM-10 and TM-11 of COX-1 and are associated with multiple cholesterol and caveolin-binding (CB) motifs. Sequence analysis identifies five CB motifs within COX-1, two within COX-2 and four within COX-3; each caveolin containing a pore-lining helix C-terminal to a TM helix–turn–helix. Channel formation involves interaction between multiple pore-lining regions within protein subunits and/or dimers. PoreWalker analysis lends support to the D-channel model of proton translocation. Under physiological conditions, caveolins may introduce channel formers juxtaposed to those in COX-1, COX-2 and COX-3, which together with cholesterol may form channel(s) essential for proton translocation through the inner mitochondrial membrane. 相似文献
9.
The African lungfish, Protopterus annectens, can undergo aestivation during drought. Aestivation has three phases: induction, maintenance and arousal. The objective of this study was to examine the differential gene expression in the liver of P. annectens after 6 months (the maintenance phase) of aestivation as compared with the freshwater control, or after 1 day of arousal from 6 months aestivation as compared with 6 months of aestivation using suppression subtractive hybridization. During the maintenance phase of aestivation, the mRNA expression of argininosuccinate synthetase 1 and carbamoyl phosphate synthetase III were up-regulated, indicating an increase in the ornithine-urea cycle capacity to detoxify ammonia to urea. There was also an increase in the expression of betaine homocysteine-S-transferase 1 which could reduce and prevent the accumulation of hepatic homocysteine. On the other hand, the down-regulation of superoxide dismutase 1 expression could signify a decrease in ROS production during the maintenance phase of aestivation. In addition, the maintenance phase was marked by decreases in expressions of genes related to blood coagulation, complement fixation and iron and copper metabolism, which could be strategies used to prevent thrombosis and to conserve energy. Unlike the maintenance phase of aestivation, there were increases in expressions of genes related to nitrogen, carbohydrate and lipid metabolism and fatty acid transport after 1 day of arousal from 6 months aestivation. There were also up-regulation in expressions of genes that were involved in the electron transport system and ATP synthesis, indicating a greater demand for metabolic energy during arousal. Overall, our results signify the importance of sustaining a low rate of waste production and conservation of energy store during the maintenance phase, and the dependence on internal energy store for repair and structural modification during the arousal phase, of aestivation in the liver of P. annectens. 相似文献
10.
Saikat Boliar Supratik Das Manish Bansal Brihaspati N. Shukla Shilpa Patil Tripti Shrivastava Sweety Samal Sandeep Goswami C. Richter King Jayanta Bhattacharya Bimal K. Chakrabarti 《PloS one》2015,10(3)
An ideal HIV-1 Env immunogen is expected to mimic the native trimeric conformation for inducing broadly neutralizing antibody responses. The native conformation is dependent on efficient cleavage of HIV-1 Env. The clade B isolate, JRFL Env is efficiently cleaved when expressed on the cell surface. Here, for the first time, we report the identification of a native clade C Env, 4-2.J41 that is naturally and efficiently cleaved on the cell surface as confirmed by its biochemical and antigenic characteristics. In addition to binding to several conformation-dependent neutralizing antibodies, 4-2.J41 Env binds efficiently to the cleavage-dependent antibody PGT151; thus validating its native cleaved conformation. In contrast, 4-2.J41 Env occludes non-neutralizing epitopes. The cytoplasmic-tail of 4-2.J41 Env plays an important role in maintaining its conformation. Furthermore, codon optimization of 4-2.J41 Env sequence significantly increases its expression while retaining its native conformation. Since clade C of HIV-1 is the prevalent subtype, identification and characterization of this efficiently cleaved Env would provide a platform for rational immunogen design. 相似文献