全文获取类型
收费全文 | 325篇 |
免费 | 27篇 |
国内免费 | 4篇 |
专业分类
儿科学 | 10篇 |
妇产科学 | 1篇 |
基础医学 | 22篇 |
口腔科学 | 5篇 |
临床医学 | 18篇 |
内科学 | 85篇 |
皮肤病学 | 11篇 |
神经病学 | 5篇 |
特种医学 | 71篇 |
外科学 | 45篇 |
综合类 | 11篇 |
预防医学 | 14篇 |
药学 | 37篇 |
肿瘤学 | 21篇 |
出版年
2022年 | 2篇 |
2021年 | 5篇 |
2020年 | 2篇 |
2019年 | 1篇 |
2017年 | 1篇 |
2016年 | 2篇 |
2015年 | 7篇 |
2014年 | 7篇 |
2013年 | 7篇 |
2012年 | 7篇 |
2011年 | 11篇 |
2010年 | 19篇 |
2009年 | 22篇 |
2008年 | 9篇 |
2007年 | 9篇 |
2006年 | 17篇 |
2005年 | 7篇 |
2004年 | 18篇 |
2003年 | 5篇 |
2002年 | 10篇 |
2001年 | 8篇 |
2000年 | 9篇 |
1999年 | 7篇 |
1998年 | 24篇 |
1997年 | 18篇 |
1996年 | 14篇 |
1995年 | 8篇 |
1994年 | 9篇 |
1993年 | 11篇 |
1992年 | 6篇 |
1991年 | 4篇 |
1990年 | 10篇 |
1989年 | 14篇 |
1988年 | 9篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 5篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1976年 | 4篇 |
1975年 | 4篇 |
1966年 | 1篇 |
排序方式: 共有356条查询结果,搜索用时 15 毫秒
151.
Rudresh Acharya Vincenzo Carnevale Giacomo Fiorin Benjamin G. Levine Alexei L. Polishchuk Victoria Balannik Ilan Samish Robert A. Lamb Lawrence H. Pinto William F. DeGrado Michael L. Klein 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(34):15075-15080
The M2 proton channel from influenza A virus is an essential protein that mediates transport of protons across the viral envelope. This protein has a single transmembrane helix, which tetramerizes into the active channel. At the heart of the conduction mechanism is the exchange of protons between the His37 imidazole moieties of M2 and waters confined to the M2 bundle interior. Protons are conducted as the total charge of the four His37 side chains passes through 2+ and 3+ with a pKa near 6. A 1.65 Å resolution X-ray structure of the transmembrane protein (residues 25–46), crystallized at pH 6.5, reveals a pore that is lined by alternating layers of sidechains and well-ordered water clusters, which offer a pathway for proton conduction. The His37 residues form a box-like structure, bounded on either side by water clusters with well-ordered oxygen atoms at close distance. The conformation of the protein, which is intermediate between structures previously solved at higher and lower pH, suggests a mechanism by which conformational changes might facilitate asymmetric diffusion through the channel in the presence of a proton gradient. Moreover, protons diffusing through the channel need not be localized to a single His37 imidazole, but instead may be delocalized over the entire His-box and associated water clusters. Thus, the new crystal structure provides a possible unification of the discrete site versus continuum conduction models. 相似文献
152.
153.
Jun Wang Yibing Wu Chunlong Ma Giacomo Fiorin Jizhou Wang Lawrence H. Pinto Robert A. Lamb Michael L. Klein William F. DeGrado 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(4):1315-1320
The influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine, whose use has been discontinued due to widespread drug resistance. Among the handful of drug-resistant mutants, S31N is found in more than 95% of the currently circulating viruses and shows greatly decreased inhibition by amantadine. The discovery of inhibitors of S31N has been hampered by the limited size, polarity, and dynamic nature of its amantadine-binding site. Nevertheless, we have discovered small-molecule drugs that inhibit S31N with potencies greater than amantadine’s potency against WT M2. Drug binding locks the protein into a well-defined conformation, and the NMR structure of the complex shows the drug bound in the homotetrameric channel, threaded between the side chains of Asn31. Unrestrained molecular dynamics simulations predicted the same binding site. This S31N inhibitor, like other potent M2 inhibitors, contains a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These sites might stabilize hydronium-like species formed as protons diffuse through the outer channel to the proton-shuttling residue His37 near the cytoplasmic end of the channel. 相似文献
154.
Ghosh A Qiu J DeGrado WF Hochstrasser RM 《Proceedings of the National Academy of Sciences of the United States of America》2011,108(15):6115-6120
The M2 proton channel from influenza A virus transmits protons across membranes via a narrow aqueous pore lined by water and a proton sensor, His37. Near the center of the membrane, a water cluster is stabilized by the carbonyl of Gly34 and His37, the properties of which are modulated by protonation of His37. At low pH (5-6), where M2 conducts protons, this region undergoes exchange processes on the microsecond to second timescale. Here, we use 2D IR to examine the instantaneous conformational distribution and hydration of G34, and the evolution of the ensemble on the femtosecond to picosecond timescale. The channel water is strongly pH dependent as gauged by 2D IR which allows recording of the vibrational frequency autocorrelation function of a (13)C = (18)O Gly34 probe. At pH 8, where entry and exit of protons within the channel are very slow, the carbonyl groups appear to adopt a single conformation/environment. The high-pH conformer does not exhibit spectral dynamics near the Gly34, and water in the channel must form a relatively rigid ice-like structure. By contrast, two vibrational forms of G34 are seen at pH 6.2, neither of which is identical to the high-pH form. In at least one of these low-pH forms, the probe is immersed in a very mobile, bulk-like aqueous environment having a correlation time ca. 1.3 ps at pH 6.2. Thus, protonation of His37 at low pH causes liquid-like water molecules to flow into the neighborhood of the Gly34. 相似文献
155.
The choline transporter and choline kinase enzyme frequently are overexpressed in malignancy. Therefore, positron-emitter-labeled compounds derived from choline have the potential to serve as oncologic probes for positron emission tomography. The fluorine-18 ((18)F)-labeled choline derivative fluorocholine (FCH) in particular has demonstrated potential utility for imaging of a variety of neoplasms, including those of the breast, prostate, liver, and brain. The pharmacokinetics of FCH and other choline tracers allow for whole-body imaging within minutes of injection while still achieving high tumor-to-background contrast in most organs, including the brain. These features, along with the possibility of imaging malignancies that have proved elusive with the use of (18)F-fluorodeoxyglucose positron emission tomography support further clinical investigations of (18)F-labeled choline tracers. 相似文献
156.
157.
158.
TR EkmekcI† M Kendirci‡ O Kizilkaya§ A Koslu† 《Journal of the European Academy of Dermatology and Venereology》2005,19(5):603-604
We report a case of classical Kaposi's sarcoma involving multiple sites of the penis in a 62-year-old male who was treated with sildenafil citrate-aided electron beam therapy, resulting in complete resolution of the lesions. 相似文献
159.
Retrostructural analysis of metalloproteins: application to the design of a minimal model for diiron proteins
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Lombardi A Summa CM Geremia S Randaccio L Pavone V DeGrado WF 《Proceedings of the National Academy of Sciences of the United States of America》2000,97(12):6298-6305
De novo protein design provides an attractive approach for the construction of models to probe the features required for function of complex metalloproteins. The metal-binding sites of many metalloproteins lie between multiple elements of secondary structure, inviting a retrostructural approach to constructing minimal models of their active sites. The backbone geometries comprising the metal-binding sites of zinc fingers, diiron proteins, and rubredoxins may be described to within approximately 1 A rms deviation by using a simple geometric model with only six adjustable parameters. These geometric models provide excellent starting points for the design of metalloproteins, as illustrated in the construction of Due Ferro 1 (DF1), a minimal model for the Glu-Xxx-Xxx-His class of dinuclear metalloproteins. This protein was synthesized and structurally characterized as the di-Zn(II) complex by x-ray crystallography, by using data that extend to 2.5 A. This four-helix bundle protein is comprised of two noncovalently associated helix-loop-helix motifs. The dinuclear center is formed by two bridging Glu and two chelating Glu side chains, as well as two monodentate His ligands. The primary ligands are mostly buried in the protein interior, and their geometries are stabilized by a network of hydrogen bonds to second-shell ligands. In particular, a Tyr residue forms a hydrogen bond to a chelating Glu ligand, similar to a motif found in the diiron-containing R2 subunit of Escherichia coli ribonucleotide reductase and the ferritins. DF1 also binds cobalt and iron ions and should provide an attractive model for a variety of diiron proteins that use oxygen for processes including iron storage, radical formation, and hydrocarbon oxidation. 相似文献
160.
A functionally defined model for the M2 proton channel of influenza A virus suggests a mechanism for its ion selectivity
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Lawrence H. Pinto Gregg R. Dieckmann Chris S. Gandhi Carol G. Papworth Jeffrey Braman Margaret A. Shaughnessy James D. Lear Robert A. Lamb William F. DeGrado 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(21):11301-11306
The M2 protein from influenza A virus forms proton-selective channels that are essential to viral function and are the target of the drug amantadine. Cys scanning was used to generate a series of mutants with successive substitutions in the transmembrane segment of the protein, and the mutants were expressed in Xenopus laevis oocytes. The effect of the mutations on reversal potential, ion currents, and amantadine resistance were measured. Fourier analysis revealed a periodicity consistent with a four-stranded coiled coil or helical bundle. A three-dimensional model of this structure suggests a possible mechanism for the proton selectivity of the M2 channel of influenza virus. 相似文献