全文获取类型
收费全文 | 2037篇 |
免费 | 32篇 |
国内免费 | 61篇 |
出版年
2023年 | 12篇 |
2022年 | 29篇 |
2021年 | 35篇 |
2020年 | 19篇 |
2019年 | 20篇 |
2018年 | 40篇 |
2017年 | 27篇 |
2016年 | 22篇 |
2015年 | 72篇 |
2014年 | 182篇 |
2013年 | 221篇 |
2012年 | 206篇 |
2011年 | 236篇 |
2010年 | 205篇 |
2009年 | 41篇 |
2008年 | 84篇 |
2007年 | 51篇 |
2006年 | 46篇 |
2005年 | 54篇 |
2004年 | 40篇 |
2003年 | 31篇 |
2002年 | 38篇 |
2001年 | 19篇 |
2000年 | 15篇 |
1999年 | 27篇 |
1998年 | 23篇 |
1997年 | 13篇 |
1996年 | 24篇 |
1995年 | 23篇 |
1994年 | 17篇 |
1993年 | 21篇 |
1992年 | 9篇 |
1991年 | 9篇 |
1990年 | 14篇 |
1989年 | 12篇 |
1988年 | 11篇 |
1987年 | 12篇 |
1986年 | 15篇 |
1985年 | 19篇 |
1984年 | 26篇 |
1983年 | 26篇 |
1982年 | 26篇 |
1981年 | 10篇 |
1980年 | 9篇 |
1979年 | 11篇 |
1978年 | 7篇 |
1976年 | 3篇 |
1974年 | 2篇 |
1973年 | 7篇 |
1972年 | 3篇 |
排序方式: 共有2130条查询结果,搜索用时 15 毫秒
71.
3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the target of the statins, important drugs that lower blood cholesterol levels and treat cardiovascular disease. Consequently, the regulation of HMGCR has been investigated in detail. However, this enzyme acts very early in the cholesterol synthesis pathway, with ∼20 subsequent enzymes needed to produce cholesterol. How they are regulated is largely unexplored territory, but there is growing evidence that enzymes beyond HMGCR serve as flux-controlling points. Here, we introduce some of the known regulatory mechanisms affecting enzymes beyond HMGCR and highlight the need to further investigate their control. 相似文献
72.
Jessica L. Feldman Josue Baeza John M. Denu 《The Journal of biological chemistry》2013,288(43):31350-31356
Mammalian sirtuins (SIRT1 through SIRT7) are members of a highly conserved family of NAD+-dependent protein deacetylases that function in metabolism, genome maintenance, and stress responses. Emerging evidence suggests that some sirtuins display substrate specificity toward other acyl groups attached to the lysine ϵ-amine. SIRT6 was recently reported to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups. Here we investigated the catalytic ability of all sirtuins to hydrolyze 13 different acyl groups from histone H3 peptides, ranging in carbon length, saturation, and chemical diversity. We find that long-chain deacylation is a general feature of mammalian sirtuins, that SIRT1 and SIRT2 act as efficient decrotonylases, and that SIRT1, SIRT2, SIRT3, and SIRT4 can remove lipoic acid. These results provide new insight into sirtuin function and a means for cellular removal of an expanding list of endogenous lysine modifications. Given that SIRT6 is a poor deacetylase in vitro, but binds and prefers to hydrolyze long-chain acylated peptides, we hypothesize that binding of certain free fatty acids (FFAs) could stimulate deacetylation activity. Indeed, we demonstrate that several biologically relevant FFAs (including myristic, oleic, and linoleic acids) at physiological concentrations induce up to a 35-fold increase in catalytic efficiency of SIRT6 but not SIRT1. The activation mechanism is consistent with fatty acid inducing a conformation that binds acetylated H3 with greater affinity. Binding of long-chain FFA and myristoylated H3 peptide is mutually exclusive. We discuss the implications of discovering endogenous, small-molecule activators of SIRT6. 相似文献
73.
Sarah E. Antinone Ghanashyam D. Ghadge Tukiet T. Lam Lijun Wang Raymond P. Roos William N. Green 《The Journal of biological chemistry》2013,288(30):21606-21617
Mutations in Cu,Zn-superoxide dismutase (mtSOD1) cause familial amyotrophic lateral sclerosis (FALS), a neurodegenerative disease resulting from motor neuron degeneration. Here, we demonstrate that wild type SOD1 (wtSOD1) undergoes palmitoylation, a reversible post-translational modification that can regulate protein structure, function, and localization. SOD1 palmitoylation was confirmed by multiple techniques, including acyl-biotin exchange, click chemistry, cysteine mutagenesis, and mass spectrometry. Mass spectrometry and cysteine mutagenesis demonstrated that cysteine residue 6 was the primary site of palmitoylation. The palmitoylation of FALS-linked mtSOD1s (A4V and G93A) was significantly increased relative to that of wtSOD1 expressed in HEK cells and a motor neuron cell line. The palmitoylation of FALS-linked mtSOD1s (G93A and G85R) was also increased relative to that of wtSOD1 when assayed from transgenic mouse spinal cords. We found that the level of SOD1 palmitoylation correlated with the level of membrane-associated SOD1, suggesting a role for palmitoylation in targeting SOD1 to membranes. We further observed that palmitoylation occurred predominantly on disulfide-reduced as opposed to disulfide-bonded SOD1, suggesting that immature SOD1 is the primarily palmitoylated species. Increases in SOD1 disulfide bonding and maturation with increased copper chaperone for SOD1 expression caused a decrease in wtSOD1 palmitoylation. Copper chaperone for SOD1 overexpression decreased A4V palmitoylation less than wtSOD1 and had little effect on G93A mtSOD1 palmitoylation. These findings suggest that SOD1 palmitoylation occurs prior to disulfide bonding during SOD1 maturation and that palmitoylation is increased when disulfide bonding is delayed or decreased as observed for several mtSOD1s. 相似文献
74.
Zhao Shan Qinglin Han Jia Nie Xuezhi Cao Zuojia Chen Shuying Yin Yayi Gao Fang Lin Xiaohui Zhou Ke Xu Huimin Fan Zhikang Qian Bing Sun Jin Zhong Bin Li Andy Tsun 《The Journal of biological chemistry》2013,288(49):35093-35103
Although lysine methylation is classically known to regulate histone function, its role in modulating antiviral restriction factor activity remains uncharacterized. Interferon-induced transmembrane protein 3 (IFITM3) was found monomethylated on its lysine 88 residue (IFITM3-K88me1) to reduce its antiviral activity, mediated by the lysine methyltransferase SET7. Vesicular stomatitis virus and influenza A virus infection increased IFITM3-K88me1 levels by promoting the interaction between IFITM3 and SET7, suggesting that this pathway could be hijacked to support infection; conversely, IFN-α reduced IFITM3-K88me1 levels. These findings may have important implications in the design of therapeutics targeting protein methylation against infectious diseases. 相似文献
75.
Andreia F. Verissimo Mohamad A. Mohtar Fevzi Daldal 《The Journal of biological chemistry》2013,288(9):6272-6283
Cytochrome c maturation (Ccm) is a post-translational process that occurs after translocation of apocytochromes c to the positive (p) side of energy-transducing membranes. Ccm is responsible for the formation of covalent bonds between the thiol groups of two cysteines residues at the heme-binding sites of the apocytochromes and the vinyl groups of heme b (protoporphyrin IX-Fe). Among the proteins (CcmABCDEFGHI and CcdA) required for this process, CcmABCD are involved in loading heme b to apoCcmE. The holoCcmE thus formed provides heme b to the apocytochromes. Catalysis of the thioether bonds between the apocytochromes c and heme b is mediated by the heme ligation core complex, which in Rhodobacter capsulatus contains at least the CcmF, CcmH, and CcmI components. In this work we show that the heme chaperone apoCcmE binds to the apocytochrome c and the apocytochrome c chaperone CcmI to yield stable binary and ternary complexes in the absence of heme in vitro. We found that during these protein-protein interactions, apoCcmE favors the presence of a disulfide bond at the apocytochrome c heme-binding site. We also establish using detergent-dispersed membranes that apoCcmE interacts directly with CcmI and CcmH of the heme ligation core complex CcmFHI. Implications of these findings are discussed with respect to heme transfer from CcmE to the apocytochromes c during heme ligation assisted by the core complex CcmFHI. 相似文献
76.
77.
Chie Tomikawa Takayuki Ohira Yasushi Inoue Takuya Kawamura Akihiko Yamagishi Tsutomu Suzuki Hiroyuki Hori 《FEBS letters》2013
Thermoplasma acidophilum is a thermo-acidophilic archaeon. We purified tRNALeu (UAG) from T. acidophilum using a solid-phase DNA probe method and determined the RNA sequence after determining via nucleoside analysis and m7G-specific aniline cleavage because it has been reported that T. acidophilum tRNA contains m7G, which is generally not found in archaeal tRNAs. RNA sequencing and liquid chromatography–mass spectrometry revealed that the m7G modification exists at a novel position 49. Furthermore, we found several distinct modifications, which have not previously been found in archaeal tRNA, such as 4-thiouridine9, archaeosine13 and 5-carbamoylmethyuridine34. The related tRNA modification enzymes and their genes are discussed. 相似文献
78.
Very little is known about how nucleic acids are translocated across membranes. The multi-subunit RNA Import Complex (RIC) from mitochondria of the kinetoplastid protozoon Leishmania tropica induces translocation of tRNAs across artificial or natural membranes, but the nature of the translocation pore remains unknown. We show that subunits RIC6 and RIC9 assemble on the membrane in presence of subunit RIC4A to form complex R3. Atomic Force Microscopy of R3 revealed particles with an asymmetric surface groove of ∼20 nm rim diameter and ∼1 nm depth. R3 induced translocation of tRNA into liposomes when the pH of the medium was lowered to ∼6 in the absence of ATP. R3-mediated tRNA translocation could also be induced at neutral pH by a K+ diffusion potential with an optimum of 60–70 mV. Point mutations in the Cys2–His2 Fe-binding motif of RIC6, which is homologous to the respiratory Complex III Fe–S protein, abrogated import induced by low pH but not by K+ diffusion potential. These results indicate that the R3 complex forms a pore that is gated by a proton-generated membrane potential and that the Fe–S binding region of RIC6 has a role in proton translocation. The tRNA import complex of L. tropica thus contains a novel macromolecular channel distinct from the mitochondrial protein import pore that is apparently involved in tRNA import in some species. 相似文献
79.
Oleksandr V. Savytskyi Semen O. Yesylevskyy Alexander I. Kornelyuk 《Journal of molecular recognition : JMR》2013,26(2):113-120
Human tyrosyl‐tRNA synthetase (HsTyrRS) is composed of two structural modules: N‐terminal catalytic core and an EMAP II‐like C‐terminal domain. The structures of these modules are known, but no crystal structure of the full‐length HsTyrRS is currently available. An all‐atom model of the full‐length HsTyrRS was developed in this work. The structure, dynamics, and domain binding interfaces of HsTyrRS were investigated by extensive molecular dynamics (MD) simulations. Our data suggest that HsTyrRS in solution consists of a number of compact asymmetric conformations, which differ significantly by their rigidity, internal mobility, orientation of C‐terminal modules, and the strength of interdomain binding. Interfaces of domain binding obtained in MD simulations are in perfect agreement with our previous coarse‐grained hierarchical rotations technique simulations. Formation of the hydrogen bonds between R93 residue of the ELR cytokine motif and the residues A340 and E479 in the C‐module was observed. This observation supports the idea that the lack of cytokine activity in the full‐length HsTyrRS is explained by interactions between N‐modules and C‐modules, which block the ELR motif. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
80.
Tomoyuki Numata 《Bioscience, biotechnology, and biochemistry》2013,77(3):347-353
Bacteria and archaea have 2-lysylcytidine (L or lysidine) and 2-agmatinylcytidine (agm2C or agmatidine), respectively, at the first (wobble) position of the anticodon of the AUA codon-specific tRNAIle. These lysine- or agmatine-conjugated cytidine derivatives are crucial for the precise decoding of the genetic code. L is synthesized by tRNAIle-lysidine synthetase (TilS), which uses l-lysine and ATP as substrates. Agm2C formation is catalyzed by tRNAIle-agm2C synthetase (TiaS), which uses agmatine and ATP for the reaction. Despite the fact that TilS and TiaS synthesize structurally similar cytidine derivatives, these enzymes belong to non-related protein families. Therefore, these enzymes modify the wobble cytidine by distinct catalytic mechanisms, in which TilS activates the C2 carbon of the wobble cytidine by adenylation, while TiaS activates it by phosphorylation. In contrast, TilS and TiaS share similar tRNA recognition mechanisms, in which the enzymes recognize the tRNA acceptor stem to discriminate tRNAIle and tRNAMet. 相似文献