全文获取类型
收费全文 | 5302篇 |
免费 | 656篇 |
国内免费 | 2篇 |
出版年
2021年 | 62篇 |
2018年 | 53篇 |
2017年 | 55篇 |
2016年 | 97篇 |
2015年 | 160篇 |
2014年 | 167篇 |
2013年 | 214篇 |
2012年 | 221篇 |
2011年 | 221篇 |
2010年 | 145篇 |
2009年 | 133篇 |
2008年 | 214篇 |
2007年 | 185篇 |
2006年 | 164篇 |
2005年 | 178篇 |
2004年 | 172篇 |
2003年 | 154篇 |
2002年 | 160篇 |
2001年 | 161篇 |
2000年 | 149篇 |
1999年 | 141篇 |
1998年 | 71篇 |
1997年 | 60篇 |
1996年 | 67篇 |
1995年 | 63篇 |
1994年 | 65篇 |
1993年 | 70篇 |
1992年 | 138篇 |
1991年 | 136篇 |
1990年 | 113篇 |
1989年 | 119篇 |
1988年 | 108篇 |
1987年 | 93篇 |
1986年 | 96篇 |
1985年 | 90篇 |
1984年 | 82篇 |
1983年 | 81篇 |
1982年 | 64篇 |
1981年 | 79篇 |
1980年 | 53篇 |
1979年 | 67篇 |
1978年 | 62篇 |
1977年 | 64篇 |
1976年 | 53篇 |
1975年 | 56篇 |
1974年 | 68篇 |
1973年 | 65篇 |
1972年 | 63篇 |
1971年 | 59篇 |
1970年 | 55篇 |
排序方式: 共有5960条查询结果,搜索用时 15 毫秒
991.
Daly NL Chen YK Rosengren KJ Marx UC Phillips ML Waring AJ Wang W Lehrer RI Craik DJ 《Biochemistry》2007,46(35):9920-9928
Retrocyclins are circular mini-defensins with significant potential as agents against human immunodeficiency virus, influenza A, and herpes simplex virus. Retrocyclins bind carbohydrate-containing surface molecules such as gp120 and CD4 with high affinity (Kd, 10-100 nM), promoting their localization on cell membranes. The structural features important for activity have yet to be fully elucidated, but here, we have determined the first three-dimensional structure of a retrocyclin, namely, one of the most potent forms, retrocyclin-2. In the presence of SDS micelles, a well-defined beta-hairpin braced by three disulfide bonds that defines the cystine ladder motif is present. By contrast, a well-defined structure could not be determined in aqueous solution, suggesting that the presence of SDS micelles stabilizes the extended conformation of retrocyclin-2. Translational diffusion measurements indicate that retrocyclin-2 interacts with the SDS micelles, and such a membrane-like interaction may be an important feature in the mechanism of action of these antimicrobial peptides. Analytical ultracentrifugation and the NMR data indicated that retrocyclin-2 self-associates to form a trimer in a concentration-dependent manner. The ability to self-associate may contribute to the high-affinity binding of retrocyclins for glycoproteins by increasing the valency and enhancing the ability of retrocyclins to cross-link cell surface glycoproteins. 相似文献
992.
Since the discovery of the ancient eukaryotic process of RNA-mediated gene silencing, the reverse-genetics technique RNA interference (RNAi) has increasingly been used to examine gene function in vertebrate and invertebrate systems. In this study, we report on the use of RNAi, adapted from studies on animal model systems, to manipulate gene expression in a symbiotic marine cnidarian. We describe gene knockdown of actin and of acasp--a cysteine protease, or caspase--in the symbiotic sea anemone Aiptasia pallida. Knockdown was assessed qualitatively with in situ hybridizations for both genes. Quantitative PCR and caspase activity assays were used as a quantitative measure of knockdown for acasp. 相似文献
993.
Suicide and Social Change in China 总被引:7,自引:0,他引:7
Using recently available data from China's Disease Surveillance Points system, we estimate that there are over 300,000 suicides in China per year; this makes suicide one of the most important causes of death in the country and makes the suicide rate in China one of the highest in the world. Moreover, the pattern of suicides in China is quite different than in other parts of the world – there are more completed suicides among females than males and rural rates are three-fold urban rates. The lack of reliable suicide data prior to 1987 makes it difficult to determine whether the rates are currently rising, falling, or staying constant. However, reports of suicides in the Chinese press and case studies conducted by the authors suggest (but do not prove) that the high rates of suicide currently experienced are related to the social changes that have occurred with the economic reforms (which started in 1978). Another possible explanation for the high rates of suicide is the large numbers of persons with depressive illness in China who remain untreated. Single-cause models of suicide (i.e., social factors or mental illness) do not do justice to the complexity of the processes involved and, therefore, do not provide useful information about the etiology and prevention of suicide in China or elsewhere. We describe our own dynamic model of suicide that includes five interacting factors which, we believe, collectively determine the suicide rates in a community. 相似文献
994.
Polycyclic aromatic hydrocarbons in the diet. 总被引:23,自引:0,他引:23
D H Phillips 《Mutation research》1999,443(1-2):139-147
Polycyclic aromatic hydrocarbons (PAHs), of which benzo[a]pyrene is the most commonly studied and measured, are formed by the incomplete combustion of organic matter. They are widely distributed in the environment and human exposure to them is unavoidable. A number of them, such as benzo[a]pyrene, are carcinogenic and mutagenic, and they are widely believed to make a substantial contribution to the overall burden of cancer in humans. Their presence in the environment is reflected in their presence at detectable levels in many types of uncooked food. In addition, cooking processes can generate PAHs in food. PAHs can also be formed during the curing and processing of raw food prior to cooking. Several studies have been carried out to determine the levels of exposure to PAHs from representative human diets, and the proportion of the overall burden of environmental exposure to PAHs that is attributable to the diet. In most cases, it is concluded that diet is the major source of human exposure to PAHs. The major dietary sources of PAHs are cereals and vegetables, rather than meat, except where there is high consumption of meat cooked over an open flame. More recently, biomonitoring procedures have been developed to assess human exposure to PAHs and these have also indicated that diet is a major source of exposure. Exposure to nitro-PAHs through food consumption appears to be very low. 相似文献
995.
We have found previously that the metabolically-competent human MCL-5 cell line did not appear to be usefully sensitive to the DNA-damaging effects of several carcinogens, as measured by the alkaline single-cell gel electrophoresis ('comet') assay. We therefore sought to increase its sensitivity by inhibiting DNA repair during exposure to test compounds, using 10 mM hydroxyurea (HU) and 1.8 mM cytosine arabinoside (ara-C), which inhibit DNA resynthesis during nucleotide excision repair. The following compounds were tested, using a 30-min exposure, in the absence or presence of HU/ara-C: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4, 8-DiMeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-9H-pyrido[2,3-b]indole (A[alpha]C), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA[alpha]C), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), benzo[a]pyrene (B[a]P), 3-methylcholanthrene (3-MCA), 7, 12-dimethylbenz[a]anthracene (DMBA), 1-nitropyrene (1-NP), 2-nitrofluorene (2-NF), aniline, o-toluidine, benzene, lindane, bleomycin, cisplatin, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), sodium chromate, chromic chloride, and diethylstilboestrol (DES). We made the following observations. The background level of comet formation was reasonably constant over several months and was increased only slightly, but significantly, in the presence of the DNA-repair inhibitors. All compounds that induced comet formation did so without appreciable cytotoxicity as assessed by trypan blue exclusion. Of the compounds tested, the heterocyclic amines and polycyclic aromatic hydrocarbons (with the exceptions of PhIP and B[a]P) failed to induce convincing levels of comet formation in the absence of repair inhibitors. In their presence the heterocyclic amines tested induced comet formation (with the exception of 8-MeIQx), with widely differing potencies. 1-NP failed to elicit marked comet formation even in the presence of HU/ara-C. Aniline and o-toluidine produced significant levels of comet formation in the absence of HU/ara-C, but in their presence comet formation was markedly increased. Benzene, lindane, bleomycin, cisplatin, MNNG, sodium chromate and chromic chloride induced comet formation in the absence of HU/ara-C, but, with the exception of cisplatin, their presence enhanced comet formation. Neither sucrose nor DES elicited comet formation under the conditions used in this study. Many more agents need to be tested in order to determine how well the comet assay using MCL-5 cells (or modified versions of it) can distinguish genotoxins from non-genotoxins. 相似文献
996.
The inheritance of adiposity and related traits has been investigated in the obese, diabetes-prone KK/HlLt (KK) and the lean,
normoglycemic C57BL/6J (B6) mouse strains, their F1 hybrids, and a large intercross generation. Adiposity index (AI) was defined as the sum of four fat depot weights divided
by body weight. Both male and female KK mice were obese, but AI values averaged twofold higher in females than in males. In
contrast, B6 females were slightly more lean than males. A genome-wide search revealed several qualitative trait loci (QTLs)
affecting AI. The proximal region of Chromosome (Chr) 9 has a large effect on AI, with a much stronger effect in females (lod
= 6.3) than in males (lod = 2.7). The data for females fit a model in which a dominant allele from KK increases AI by 30%,
with the lod score peak falling between markers D9Mit66 and D9Mit328. This QTL has large effects on inguinal and mesenteric fat pad weights, with smaller effects on gonadal and retroperitoneal
fat pads. The region of Chr 9 containing this QTL has extensive homology to human Chr 11q. An X-linked QTL affecting AI was
evident in males (lod = 3.77), but not females (lod = 0.7). Exclusion of mesenteric fat from male AI resulted in an increased
lod score (lod = 5.0) at 8 cM distal to DXMit166. A suggestive AI QTL (lod = 4.2), differentially affecting males, was localized to Chr 18 near the glucocorticoid receptor
locus. A region of Chr 7 had a strong effect on body weight (lod = 6.9), a significant effect on inguinal fat% (lod = 4.4),
and a suggestive effect on AI in females (lod = 4.1). Plasma leptin levels were associated with genotypes on Chr 9 (lod =
5.9) and Chr 7 (lod = 4.2). A region of Chr 1 had a suggestive effect on fasted blood glucose (lod = 3.6).
Received: 23 March 1999 / Accepted: 2 June 1999 相似文献
997.
R. A. Phillips K. C. Hamer 《Proceedings. Biological sciences / The Royal Society》1999,266(1426):1329
Several alternative explanations have been proposed to account for the evolution of nestling obesity in a variety of avian groups. These predict quite different patterns of fat accumulation, storage and use by chicks of different ages. Yet surprisingly few studies have measured changes in body composition during chick development. We tested the applicability of these hypotheses for fulmars, Fulmarus glacialis, by direct measurement of changes in water, lipid and lean dry mass in growing chicks. Lipid and lean dry mass increased until ca. 70% of the way through chick rearing, but then levelled off. Total body water also increased until the same stage, but gradually declined thereafter, and it was this change rather than fat metabolism that resulted in mass recession. The observed pattern of a continued increase in stored lipid, and most importantly, its maintenance all the way through the mass-recession phase until chicks reach fledging, is incompatible with many of the proposed hypotheses. We suggest that the most likely ultimate explanation for large fat deposits is to fuel chicks during the initial critical period away from the nest site while they learn to forage 相似文献
998.
J Gordon T K Sengupta C A Phillips S M O'Malley K R Williams E K Spicer 《The Journal of biological chemistry》1999,274(45):32265-32273
The T4 translational repressor RegA protein folds into two structural domains, as revealed by the crystal structure (Kang, C.-H. , Chan, R., Berger, I., Lockshin, C., Green, L., Gold, L., and Rich, A. (1995) Science 268, 1170-1173). Domain I of the RegA protein contains a four-stranded beta-sheet and two alpha-helices. Domain II contains a four-stranded beta-sheet and an unusual 3/10 helix. Since beta-sheet residues play a role in a number of protein-RNA interactions, one or both of the beta-sheet regions in RegA protein may be involved in RNA binding. To test this possibility, mutagenesis of residues on both beta-sheets was performed, and the effects on the RNA binding affinities of RegA protein were measured. Additional sites for mutagenesis were selected from molecular modeling of RegA protein. The RNA binding affinities of three purified mutant RegA proteins were evaluated by fluorescence quenching equilibrium binding assays. The activities of the remainder of the mutant proteins were evaluated by quantitative RNA gel mobility shift assays using lysed cell supernatants. The results of this mutagenesis study ruled out the participation of beta-sheet residues. Instead, the RNA binding site was found to be a surface pocket formed by residues on two loops and an alpha-helix. Thus, RegA protein appears to use a unique structural motif in binding RNA, which may be related to its unusual RNA recognition properties. 相似文献
999.
Noncontact dipole effects on channel permeation. I. Experiments with (5F-indole)Trp13 gramicidin A channels. 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《Biophysical journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
D D Busath C D Thulin R W Hendershot L R Phillips P Maughan C D Cole N C Bingham S Morrison L C Baird R J Hendershot M Cotten T A Cross 《Biophysical journal》1998,75(6):2830-2844
Gramicidin A (gA), with four Trp residues per monomer, has an increased conductance compared to its Phe replacement analogs. When the dipole moment of the Trp13 side chain is increased by fluorination at indole position 5 (FgA), the conductance is expected to increase further. gA and FgA conductances to Na+, K+, and H+ were measured in planar diphytanoylphosphatidylcholine (DPhPC) or glycerylmonoolein (GMO) bilayers. In DPhPC bilayers, Na+ and K+ conductances increased upon fluorination, whereas in GMO they decreased. The low ratio in the monoglyceride bilayer was not reversed in GMO-ether bilayers, solvent-inflated or -deflated bilayers, or variable fatty acid chain monoglyceride bilayers. In both GMO and DPhPC bilayers, fluorination decreased conductance to H+ but increased conductance in the mixed solution, 1 M KCl at pH 2.0, where K+ dominates conduction. Eadie-Hofstee plot slopes suggest similar destabilization of K+ binding in both lipids. Channel lifetimes were not affected by fluorination in either lipid. These observations indicate that fluorination does not change the rotameric conformation of the side chain. The expected difference in the rate-limiting step for transport through channels in the two bilayers qualitatively explains all of the above trends. 相似文献
1000.
This report describes the genetic organization of a euchromatic region on the third chromosome of Drosophila melanogaster extending cytologically from 68A2 to C1, an interval comprising 10 or 11 polytene chromosome bands. The gene for cytoplasmic superoxide dismutase (cSOD) maps within this interval, as does low xanthine dehydrogenase (lxd).--Recessive lethal mutations were generated within the region by ethyl methanesulfonate mutagenesis and by hybrid dysgenesis. These lethals fall into 11 functional groups, which were partially ordered by complementation with deletions having breakpoints within the region. The distribution of dysgenesis-induced mutations in the region is highly nonrandom, the majority being within a single group. The mutability of this gene is comparable to that of singed (sn), a documented "hot-spot" for P-element insertion.--One of the EMS-induced lethals, l-108, fulfills biochemical criteria expected of a hypomorphic allele of cSOD. To our knowledge this is the first such allele recovered of this gene, and it should prove very useful in an analysis of the in vivo function of cytoplasmic SOD. Indeed, it has been demonstrated that cSOD is almost certainly a vital gene. 相似文献