全文获取类型
收费全文 | 2626篇 |
免费 | 365篇 |
国内免费 | 2篇 |
出版年
2022年 | 25篇 |
2021年 | 36篇 |
2016年 | 42篇 |
2015年 | 77篇 |
2014年 | 77篇 |
2013年 | 95篇 |
2012年 | 154篇 |
2011年 | 115篇 |
2010年 | 94篇 |
2009年 | 69篇 |
2008年 | 121篇 |
2007年 | 104篇 |
2006年 | 115篇 |
2005年 | 91篇 |
2004年 | 113篇 |
2003年 | 83篇 |
2002年 | 86篇 |
2001年 | 81篇 |
2000年 | 78篇 |
1999年 | 71篇 |
1998年 | 21篇 |
1997年 | 29篇 |
1996年 | 21篇 |
1995年 | 26篇 |
1994年 | 21篇 |
1993年 | 25篇 |
1992年 | 39篇 |
1991年 | 42篇 |
1990年 | 58篇 |
1989年 | 51篇 |
1988年 | 44篇 |
1987年 | 47篇 |
1986年 | 60篇 |
1985年 | 45篇 |
1984年 | 34篇 |
1983年 | 36篇 |
1982年 | 25篇 |
1981年 | 32篇 |
1980年 | 20篇 |
1979年 | 41篇 |
1978年 | 26篇 |
1977年 | 24篇 |
1976年 | 21篇 |
1975年 | 23篇 |
1974年 | 21篇 |
1973年 | 25篇 |
1972年 | 21篇 |
1971年 | 23篇 |
1970年 | 21篇 |
1967年 | 20篇 |
排序方式: 共有2993条查询结果,搜索用时 31 毫秒
81.
82.
One of a cell biologist's favourite occupations is to discover the proteins that perform newly described functions in the cell. Very often lately, this has resulted in the identification of protein families whose related amino acid sequences reflect similar functions, but can proteins with totally unrelated sequences have similar structures and functions? In this review, Ken Holmes, Chris Sander and Alfonso Valencia describe the structural similarities between three well-known proteins that have no readily detectable primary sequence similarities but for which X-ray crystallography has revealed very similar structures. A comparison of their structures provides insights into their common mechanisms of action and into protein evolution, and has been used to detect related proteins in sequence data bases. 相似文献
83.
Strains of Escherichia coli have been produced which express very high levels of the tRNAleu1 isoacceptor. This was accomplished by transforming cells with plasmids containing the leuV operon which encodes three copies of the tRNALeu1 gene. Most transformants grew very slowly and exhibited a 15-fold increase in cellular concentrations of tRNALeu1 As a result, total cellular tRNA concentration was approximately doubled and 56% of the total was tRNALeu1. We examined a number of parameters which might be expected to be affected by imbalances in tRNA concentration: in vivo tRNA charging levels, misreading, ribosome step time, and tRNA modification. Surprisingly, no increase in intracellular ppGpp levels was detected even though only about 40% of total leucyl tRNA was found to be charged in vivo. Gross ribosomal misreading was not detected, and it was shown that ribosomal step times were reduced between two- and threefold. Analyses of leucyl tRNA isolated from these slow-growing strains showed that at least 90% of the detectable tRNALeu1 was hypomodified as judged by altered mobility on RPC-5 reverse-phase columns, and by specific modification assays using tRNA(m1G)-methyltransferase and pseudo-uridylate synthetase. Analysis of fast-growing revertants demonstrated that tRNA concentration per se may not explain growth inhibition because selected revertants which grew at wild-type growth rates displayed levels of tRNA comparable to that of control strains bearing the leuV operon. A synthetic tRNALeu1 operon under the control of the T7 promoter was prepared which, when induced, produced six- to sevenfold increases in tRNALeu1 levels. This level of tRNALeu1 titrated the modification system as judged by RPC-5 column chromatography. Overall, our results suggest that hypomodified tRNA may explain, in part, the observed effects on growth, and that the protein-synthesizing system can tolerate an enormous increase in the concentration of a single tRNA. 相似文献
84.
E. A. Merritt S. Sarfaty M. G. Jobling T. Chang R. K. Holmes T. R. Hirst W. G. Hol 《Protein science : a publication of the Protein Society》1997,6(7):1516-1528
The wide range of receptor binding affinities reported to result from mutations at residue Gly 33 of the cholera toxin B-pentamer (CTB) has been most puzzling. For instance, introduction of an aspartate at this position abolishes receptor binding, whereas substitution by arginine retains receptor affinity despite the larger side chain. We now report the structure determination and 2.3-A refinement of the CTB mutant Gly 33-->Arg complexed with the GM1 oligosaccharide, as well as the 2.2-A refinement of a Gly 33-->Asp mutant of the closely related Escherichia coli heat-labile enterotoxin B-pentamer (LTB). Two of the five receptor binding sites in the Gly 33-->Arg CTB mutant are occupied by bound GM1 oligosaccharide; two other sites are involved in a reciprocal toxin:toxin interaction; one site is unoccupied. We further report a higher resolution (2.0 A) determination and refinement of the wild-type CTB:GM1 oligosaccharide complex in which all five oligosaccharides are seen to be bound in essentially identical conformations. Saccharide conformation and binding interactions are very similar in both the CTB wild-type and Gly 33-->Arg mutant complexes. The protein conformation observed for the binding-deficient Gly 33-->Asp mutant of LTB does not differ substantially from that seen in the toxin:saccharide complexes. The critical nature of the side chain of residue 33 is apparently due to a limited range of subtle rearrangements available to both the toxin and the saccharide to accommodate receptor binding. The intermolecular interactions seen in the CTB (Gly 33-->Arg) complex with oligosaccharide suggest that the affinity of this mutant for the receptor is close to the self-affinity corresponding to the toxin:toxin binding interaction that has now been observed in crystal structures of three CTB mutants. 相似文献
85.
Frequent intragenic deletion of the P gene in Tanzanian patients with type II oculocutaneous albinism (OCA2).
下载免费PDF全文
![点击此处可从《American journal of human genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Type II oculocutaneous albinism (OCA2) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in the skin, hair, and eyes. OCA2, which results from mutations of the P gene, is the most frequent type of albinism in African and African-American patients. OCA2 is especially frequent in Tanzania, where it occurs with an incidence of approximately 1/1,400. We have identified abnormalities of the P gene in each of 13 unrelated patients with OCA2 from Tanzania. One of these, a deletion of exon 7, is strongly predominant, accounting for approximately 77% of mutant alleles in this group of patients. 相似文献
86.
Tyson H. Holmes 《American journal of botany》1995,82(11):1432-1442
I investigated competition for light between canopy plants and juvenile valley oaks (Quercus lobata Nee) in a mixed-broadleaf woodland of California's northern Coast Ranges. Canopy effects on understory light supply were separated among the overlying adult valley oak, the adult's woody understory, and neighboring trees and shrubs through a series of light sampling surveys and measurements of the number, size, and spatial distribution of neighboring plants. Light supply in the understory was primarily influenced by neighboring plants, with no detectable effect of the overlying adult valley oak. Light supply in the understory averaged 25% full sun due to a high frequency of canopy gaps and a typically open understory. Seedling response to understory light supply was investigated in an experimental sunfleck gradient (10%, 19%, and 100% full sun). Between 10% and 100% full sun, seedling growth increased by 90% and the shoot:∗∗∗root ratio changed from 1.561 to 0.607. Shade seedlings were also taller and produced fewer, larger, and thinner leaves than seedlings grown in full sun. A field survey of the spatial distribution and crown morphology of saplings and young adults found 1) the distance between young valley oaks and neighboring overstory trees to increase with neighbor size, and 2) crowns of the young oaks to be skewed away from neighbors. Although shading by the canopy was only moderate, canopy effects on understory light supply may restrict juvenile recruitment of valley oak in this woodland. 相似文献
87.
Energy-dispersive X-ray analysis of the extracellular cadmium sulfide crystallites of Klebsiella aerogenes 总被引:4,自引:0,他引:4
Justin D. Holmes Peter R. Smith Richard Evans-Gowing David J. Richardson David A. Russell John R. Sodeau 《Archives of microbiology》1995,163(2):143-147
Klebsiella aerogenes forms electron-dense partieles on the cell surface in response to the presence of cadmium ions in the growth medium. These particles ranged from 20 to 200 nm in size, and quantitative energy dispersive X-ray analysis established that they comprise cadmium and sulfur in a 1:1 ratio. This observation leads to the conclusion that the particles are cadmium sulfide crystallites. A combination of atomic absorption spectroscopy, inductively coupled plasma mass spectrometry, and acid-labile sulfide analysis revealed that the total intracellular and bound extracellular cadmium:sulfur ratio is also 1:1, which suggests that the bulk of the cadmium is fixed as extracellular cadmium sulfide. The tolerance of K. acrogenes to cadmium ions and the formation of the cadmium sulfide crystallites were dependent on the buffer composition of the growth medium. The addition of cadmium ions to phosphate-buffered media resulted in cadmium phosphate precipitates that remove the potentially toxic cadmium ions from the growth medium. Electrondense particles formed on the surfaces of bacteria grown under these conditions were a combination of cadmium sulfide and cadmium phosphates. The specific bacterial growth rate in the exponential phase of batch cultures was not affected by up to 2mM cadmium in Tricine-buffered medium, but formation of cadmium sulfide crystallites was maximal during the stationary phase of batch culture. Cadmium tolerance was much lower (10 to 150 M) in growth media buffered with Tris, Bistris propane, Bes, Tes, or Hepes. These results illustrate the importance of considering medium composition when comparing levels of bacterial cadmium tolerance.Abbreviations
EDXA
Energy dispersive X-ray analysis
-
AAS
Atomic absorption spectroscopy
-
TEM
Transmission electron microscopy
-
SEM
Scanning electron microscopy
-
ICP-MS
Inductively coupled plasma mass spectrometry
-
ALSA
Acid-labile sulfide analysis 相似文献
88.
Specific receptors for corticotropin releasing factor (CRF) were identified in two functionally distinct systems within the brain, the cortex and the limbic system. Autoradiographic mapping of the CRF receptors in the brain revealed high binding density throughout the neocortex and cerebellar cortex, subiculum, lateral septum, olfactory tract, bed nucleus of the stria terminalis, interpeduncular nucleus and superior colliculus. Moderate to low binding was found in the hippocampus, nucleus accumbens, claustrum, nucleus periventricularis thalamus, mammillary bodies, subthalamic nucleus, periaqueductal grey, locus coeruleus and nucleus of the spinal trigeminal tract. As in the anterior pituitary gland, CRF receptors in the brain were shown to be coupled to adenylate cyclase. However, in contrast to the marked decrease in CRF receptors observed after adrenalectomy in the anterior pituitary gland, CRF receptor concentration in the brain and pars intermedia of the pituitary was unchanged. The presence of CRF receptors in areas involved in the control of hypothalamic and autonomic nervous system functions is consistent with the major role of CRF in the integrated response to stress. 相似文献
89.
T.J. Holmes Jr. V. John J. Vennerstrom Richard J. Kulmacz William E.M. Lands 《Prostaglandins & other lipid mediators》1984,28(5)
Two novel salicylate-derived quinhydrones were evaluated for their effect on the kinetics of cyclooxygenase activity of sheep seminal vesicle prostaglandin H synthase. These quinhydrones, which form semiquinone radicals in solution, were designed to resemble oxidized intermediates of salicylic acid metabolism. Although initially investigated for their potential role in irreversible inactivation of cyclooxygenase, these derivatives were found to give three-fold stimulation of this activity. In the absence of arachidonic acid, preincubation of the enzyme with these quinhydrones did not lead to inactivation of the cyclooxygenase activity. These compounds thus resemble the phenolic antioxidants in their effects on the cyclooxygenase activity of the synthase. 相似文献
90.
Electrophoretic and activity variants have been observed for stomach and testis aldehyde dehydrogenases, respectively, among inbred strains of the house mouse (Mus musculus). Genetic evidence was obtained for two new loci encoding these isozymes (designated Ahd-4 and Ahd-6, respectively, for the stomach and testis isozymes) which segregated independently of a number of mouse gene markers, including Ahd-1 (encoding mitochondrial aldehyde dehydrogenase) on chromosome 4, ep (pale ears), a marker for chromosome 19, on which Ahd-2 (encoding liver cytosolic aldehyde dehydrogenase) has been previously localized, and Adh-3 (encoding the stomach-specific isozyme of alcohol dehydrogenase) on chromosome 3. Recombination studies have indicated, however, that Ahd-4 and Ahd-6 are distinct but closely linked loci on the mouse genome. An extensive survey of the distribution of Ahd-1, Ahd-2, Ahd-4, and Ahd-6 alleles among 56 strains of mice is reported. No variants have been observed, so far, for the microsomal (AHD-3) and mitochondrial/cytosolic (AHD-5) isozymes previously described. This study, in combination with previous investigations on mouse aldehyde dehydrogenases, provides evidence for six genetic loci for this enzyme. 相似文献