全文获取类型
收费全文 | 3489篇 |
免费 | 546篇 |
专业分类
4035篇 |
出版年
2021年 | 54篇 |
2020年 | 24篇 |
2019年 | 23篇 |
2018年 | 24篇 |
2017年 | 34篇 |
2016年 | 49篇 |
2015年 | 105篇 |
2014年 | 97篇 |
2013年 | 135篇 |
2012年 | 160篇 |
2011年 | 152篇 |
2010年 | 106篇 |
2009年 | 94篇 |
2008年 | 135篇 |
2007年 | 158篇 |
2006年 | 139篇 |
2005年 | 119篇 |
2004年 | 120篇 |
2003年 | 122篇 |
2002年 | 125篇 |
2001年 | 129篇 |
2000年 | 120篇 |
1999年 | 90篇 |
1998年 | 56篇 |
1997年 | 56篇 |
1996年 | 41篇 |
1995年 | 38篇 |
1994年 | 44篇 |
1993年 | 46篇 |
1992年 | 69篇 |
1991年 | 77篇 |
1990年 | 83篇 |
1989年 | 74篇 |
1988年 | 67篇 |
1987年 | 81篇 |
1986年 | 49篇 |
1985年 | 73篇 |
1984年 | 53篇 |
1983年 | 59篇 |
1982年 | 48篇 |
1981年 | 35篇 |
1980年 | 32篇 |
1979年 | 46篇 |
1978年 | 52篇 |
1977年 | 48篇 |
1976年 | 35篇 |
1975年 | 42篇 |
1974年 | 50篇 |
1973年 | 46篇 |
1972年 | 42篇 |
排序方式: 共有4035条查询结果,搜索用时 15 毫秒
131.
Joseph J. Barchi Motoyoshi Nomizu Akira Otaka Peter P. Roller Terrence R. Burke 《Biopolymers》1996,38(2):191-208
The structures of the cyclic hexapeptide cyclo(-Gly-Tyr-Val-Pro-Met-Leu-) ( 1 ) and its phosphotyrosyl (pTyr) derivative cyclo[-Gly-Tyr(PO3H2)-Val-Pro-Met-Leu-] ( 2 ), designed as constrained models of a sequence that interacts with the src homology 2 (SH2) region of the p85 subunit of phosphatidylinositol-3-OH kinase (PI-3 kinase), were studied in methanol/water solutions by 500 MHz nmr spectroscopy. Compound 1 was found to exist as a 2:1 mixture of isomers about the Val-Pro bond (trans and cis prolyl) between 292–330 K in 75% CD3O (D,H)/(D,H)2O solutions. A third species of undetermined structure (ca. 5%) was also observed. Compound 2, a model of phosphorylated peptide ligand that binds to the PI-3 kinase SH2 domain, exhibited similar conformational isomerism. When either compound was dissolved in pure solvent [i.e., 100% CD3O(H,D) or (H,D)2O] the ratio of cis to trans isomers was ca 1:1. A battery of one- and two-dimensional nmr experiments at different temperatures and solvent compositions allowed a complete assignment of both the cis and trans forms of 1 and indicated the trans compound to be the major isomer. The spectral properties of the phosphorylated derivative 2 paralleled those of 1 , indicating like conformations for the two compounds. Analysis of rotating frame Overhauser spectroscopy data, coupling constants, amide proton temperature dependence, and amide proton exchange rates generated a set of constraints that were employed in energy minimization and molecular dynamics calculations using the CHARMM force field. The trans isomer exists with the tyrosine and C-terminal Tyr(+3) (Met) residues at opposite corners of the 18-membered ring separated by a distance of 16–18 Å, in contrast with the cis isomer where the side chains of these residues are much closer in space (7–14 Å). It was previously shown that the pTyr and the third amino acid C-terminal to this residue are the critical recognition elements for pTyr-peptide binding to the PI-3 kinase SH2 domain. Such cyclic structures may offer appropriate scaffolding for positioning important amino acid side chains of pTyr-containing peptides as a means of increasing their binding affinities to SH2 domains, and in turn provide a conceptual approach toward the design of SH2 domain directed peptidomimetics. © 1995 John Wiley & Sons, Inc. 相似文献
132.
Structure of the Chlamydomonas reinhardtii cabII-1 gene encoding a chlorophyll-a/b-binding protein 总被引:4,自引:0,他引:4
Gene cabII-1 is a light regulated gene that encodes the precursor of a major chlorophyll-a/b-binding protein in Chlamydomonas reinhardtii. It is a member of a small gene family composed of about 3-7 members. Nucleotide sequencing data and S1 mapping reveal that the cabII-1 gene is interrupted by three introns. Except for the transit peptide and the N-terminus, the cabII-1 gene product is similar to cabII proteins in higher plants. The cabII-1 gene in C. reinhardtii appears to be an intermediate between type-I and type-II cabII genes described in higher plants. 相似文献
133.
Thyroid hormone-regulated enhancer blocking: cooperation of CTCF and thyroid hormone receptor 下载免费PDF全文
Lutz M Burke LJ LeFevre P Myers FA Thorne AW Crane-Robinson C Bonifer C Filippova GN Lobanenkov V Renkawitz R 《The EMBO journal》2003,22(7):1579-1587
The highly conserved, ubiquitously expressed, zinc finger protein CTCF is involved in enhancer blocking, a mechanism crucial for shielding genes from illegitimate enhancer effects. Interestingly, CTCF-binding sites are often flanked by thyroid hormone response elements (TREs), as at the chicken lysozyme upstream silencer. Here we identify a similar composite site positioned upstream of the human c-myc gene. For both elements, we demonstrate that thyroid hormone abrogates enhancer blocking. Relief of enhancer blocking occurs even though CTCF remains bound to the lysozyme chromatin. Furthermore, chromatin immunoprecipitation analysis of the lysozyme upstream region revealed that histone H4 is acetylated at the CTCF-binding site. Loss of enhancer blocking by the addition of T3 led to increased histone acetylation, not only at the CTCF site, but also at the enhancer and the promoter. Thus, when TREs are adjacent to CTCF-binding sites, thyroid hormone can regulate enhancer blocking, thereby providing a new property for what was previously thought to be constitutive enhancer shielding by CTCF. 相似文献
134.
Twelve years after reporting a novel chromosomal passenger protein, Mollinari et al. in this issue of Developmental Cell finally report its molecular identification, and the results are stunning. TD-60 is a member of the RCC1 family of guanine nucleotide exchange factors implicating small GTPases in chromosome congression and cytokinesis. 相似文献
135.
Argininosuccinate synthetase (AS) is the rate-limiting enzyme of both the urea and arginine-citrulline cycles. In mammals, deficiency of AS leads to citrullinemia, a debilitating and often fatal autosomal recessive urea cycle disorder, whereas its overexpression for sustained nitric oxide production via the arginine-citrulline cycle leads to the potentially fatal hypotension associated with septic and cytokine-induced circulatory shock. The crystal structures of Escherichia coli argininosuccinate synthetase (EAS) in complex with ATP and with ATP and citrulline have been determined at 2.0-A resolution. These are the first EAS structures to be solved in the presence of a nucleotide substrate and clearly identify the residues that interact with both ATP and citrulline. Two distinct conformations are revealed for ATP, both of which are believed to be catalytically relevant. In addition, comparisons of these EAS structures with those of the apoenzyme and EAS complexed with aspartate and citrulline (Lemke, C. T., and Howell, P. L. (2001) Structure (Lond.) 9, 1153-1164) provide structural evidence of ATP-induced conformational changes in the nucleotide binding domain. Combined, these structures also provide structural explanations of some of the observed kinetic properties of the enzyme and have enabled a detailed enzymatic mechanism of AS catalysis to be proposed. 相似文献
136.
Geranyl diphosphate synthase belongs to a subgroup of prenyltransferases, including farnesyl diphosphate synthase and geranylgeranyl diphosphate synthase, that catalyzes the specific formation, from C(5) units, of the respective C(10), C(15), and C(20) precursors of monoterpenes, sesquiterpenes, and diterpenes. Unlike farnesyl diphosphate synthase and geranylgeranyl diphosphate synthase, which are homodimers, geranyl diphosphate synthase from Mentha is a heterotetramer in which the large subunit shares functional motifs and a high level of amino acid sequence identity (56-75%) with geranylgeranyl diphosphate synthases of plant origin. The small subunit, however, shares little sequence identity with other isoprenyl diphosphate synthases; yet it is absolutely required for geranyl diphosphate synthase catalysis. Coexpression in Escherichia coli of the Mentha geranyl diphosphate synthase small subunit with the phylogenetically distant geranylgeranyl diphosphate synthases from Taxus canadensis and Abies grandis yielded a functional hybrid heterodimer that generated geranyl diphosphate as product in each case. These results indicate that the geranyl diphosphate synthase small subunit is capable of modifying the chain length specificity of geranylgeranyl diphosphate synthase (but not, apparently, farnesyl diphosphate synthase) to favor the production of C(10) chains. Comparison of the kinetic behavior of the parent prenyltransferases with that of the hybrid enzyme revealed that the hybrid possesses characteristics of both geranyl diphosphate synthase and geranylgeranyl diphosphate synthase. 相似文献
137.
Molybdenum is required for induction of nitrate reductase and of NAD-linked formate dehydrogenase activities in suspensions of wild type Paracoccus denitrificans; tungsten prevents the development of these enzyme activities. The wild type forms a membrane protein M
r150,000 when incubated with tungsten and inducers of nitrate reductase and this is presumed to represent an inactive form of the enzyme. Suspensions of mutant M-1 did not develop nitrate reductase or formate dehydrogenase activities but the membrane protein M
r150,000 was formed under all conditions tested, including without inducers and without molybdenum. Analysis of membranes, solubilized with deoxycholate, by polyacrylamide gel electrophoresis under nondenaturing conditions showed that the mutant protein had similar electrophoretic mobility to the active nitrate reductase formed by the wilde type. Autoradiography of preparations from cells incubated with 55Fe showed that the mutant and wild type proteins contained iron. However, in similar experiments with 99Mo, incorporation of molybdenum into the mutant protein was not detectable.We conclude that mutant M-1 is defective in one or more steps required to process molybdenum for incorporation into molybdoenzymes. This failure affects the normal regulation of nitrate reductase protein with respect to the role of inducers.Non-Standard Abbreviations DOC
deoxycholate
- PAGE
polyacrylamide gel electrophoresis
- SDS
sodium dodecyl sulfate 相似文献
138.
Proteolytic removal of the COOH terminus of the T4 gene 32 helix-destabilizing protein alters the T4 in vitro replication complex 总被引:7,自引:0,他引:7
The proteolytic removal of about 60 amino acids from the COOH terminus of the bacteriophage T4 helix-destabilizing protein (gene 32 protein) produces 32*I, a 27,000-dalton fragment which still binds tightly and cooperatively to single-stranded DNA. The substitution of 32*I protein for intact 32 protein in the seven-protein T4 replication complex results in dramatic changes in some of the reactions catalyzed by this in vitro DNA replication system, while leaving others largely unperturbed. 1. Like intact 32 protein, the 32*I protein promotes DNA synthesis by the DNA polymerase when the T4 polymerase accessory proteins (gene 44/62 and 45 proteins) are also present. The host helix-destabilizing protein (Escherichia coli ssb protein) cannot replace the 32I protein for this synthesis. 2. Unlike intact 32 protein, 32*I protein strongly inhibits DNA synthesis catalyzed by the T4 DNA polymerase alone on a primed single-stranded DNA template. 3. Unlike intact 32 protein, the 32*I protein strongly inhibits RNA primer synthesis catalyzed by the T4 gene 41 and 61 proteins and also reduces the efficiency of RNA primer utilization. As a result, de novo DNA chain starts are blocked completely in the complete T4 replication system, and no lagging strand DNA synthesis occurs. 4. The 32*I protein does not bind to either the T4 DNA polymerase or to the T4 gene 61 protein in the absence of DNA; these associations (detected with intact 32 protein) would therefore appear to be essential for the normal control of 32 protein activity, and to account at least in part for observations 2 and 3, above. We propose that the COOH-terminal domain of intact 32 protein functions to guide its interactions with the T4 DNA polymerase and the T4 gene 61 RNA-priming protein. When this domain is removed, as in 32*I protein, the helix destabilization induced by the protein is controlled inadequately, so that polymerizing enzymes tend to be displaced from the growing 3'-OH end of a polynucleotide chain and are thereby inhibited. Eukaryotic helix-destabilizing proteins may also have similar functional domains essential for the control of their activities. 相似文献
139.
140.
Genetic Analyses of the Polarity Alleles in Recombinants from Mitochondrial Genetic Crosses 总被引:2,自引:1,他引:2 下载免费PDF全文
Neil Howell Ruth M. Hall Anthony W. Linnane H. B. Lukins 《Journal of bacteriology》1974,119(3):1063-1065
A number of minority recombinant and parental types from a heterosexual cross were analyzed for the omega allele they carry. It was found that recombinant progeny can be omega(-), that minority parental types among the progeny can be omega(+) rather than omega(-), and, finally, that certain of the results suggest that the omega locus may not be at the proximal end of the mitochondrial genetic map (Bolotin et al., 1971; Grivell et al., 1973) but rather may lie between the [cap1-r/cap-s] and [ery1-r/ery-s] loci. 相似文献