全文获取类型
收费全文 | 727篇 |
免费 | 64篇 |
国内免费 | 3篇 |
专业分类
儿科学 | 2篇 |
妇产科学 | 11篇 |
基础医学 | 122篇 |
临床医学 | 64篇 |
内科学 | 210篇 |
皮肤病学 | 7篇 |
神经病学 | 49篇 |
特种医学 | 23篇 |
外科学 | 95篇 |
综合类 | 1篇 |
一般理论 | 2篇 |
预防医学 | 37篇 |
眼科学 | 2篇 |
药学 | 66篇 |
中国医学 | 1篇 |
肿瘤学 | 102篇 |
出版年
2023年 | 1篇 |
2022年 | 10篇 |
2021年 | 14篇 |
2020年 | 6篇 |
2019年 | 14篇 |
2018年 | 8篇 |
2017年 | 12篇 |
2016年 | 14篇 |
2015年 | 31篇 |
2014年 | 36篇 |
2013年 | 35篇 |
2012年 | 66篇 |
2011年 | 69篇 |
2010年 | 31篇 |
2009年 | 33篇 |
2008年 | 61篇 |
2007年 | 48篇 |
2006年 | 59篇 |
2005年 | 65篇 |
2004年 | 53篇 |
2003年 | 46篇 |
2002年 | 42篇 |
2001年 | 5篇 |
2000年 | 5篇 |
1999年 | 2篇 |
1998年 | 5篇 |
1997年 | 4篇 |
1996年 | 6篇 |
1995年 | 5篇 |
1994年 | 7篇 |
1993年 | 1篇 |
排序方式: 共有794条查询结果,搜索用时 15 毫秒
61.
Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus 总被引:5,自引:0,他引:5
下载免费PDF全文
![点击此处可从《Antimicrobial agents and chemotherapy》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Higgins DL Chang R Debabov DV Leung J Wu T Krause KM Sandvik E Hubbard JM Kaniga K Schmidt DE Gao Q Cass RT Karr DE Benton BM Humphrey PP 《Antimicrobial agents and chemotherapy》2005,49(3):1127-1134
The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N'-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K(+). The timing of these changes correlated with rapid , concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties. 相似文献
62.
Dmitri A. Petrov Daniel L. Hartl 《Proceedings of the National Academy of Sciences of the United States of America》1999,96(4):1475-1479
To estimate patterns of molecular evolution of unconstrained DNA sequences, we used maximum parsimony to separate phylogenetic trees of a non-long terminal repeat retrotransposable element into either internal branches, representing mainly the constrained evolution of active lineages, or into terminal branches, representing mainly nonfunctional “dead-on-arrival” copies that are unconstrained by selection and evolve as pseudogenes. The pattern of nucleotide substitutions in unconstrained sequences is expected to be congruent with the pattern of point mutation. We examined the retrotransposon Helena in the Drosophila virilis species group (subgenus Drosophila) and the Drosophila melanogaster species subgroup (subgenus Sophophora). The patterns of point mutation are indistinguishable, suggesting considerable stability over evolutionary time (40–60 million years). The relative frequencies of different point mutations are unequal, but the “transition bias” results largely from an ≈2-fold excess of GC to AT substitutions. Spontaneous mutation is biased toward AT base pairs, with an expected mutational equilibrium of ≈65% A + T (quite similar to that of long introns). These data also enable the first detailed comparison of patterns of point mutations in Drosophila and mammals. Although the patterns are different, all of the statistical significance comes from a much greater rate of GC to AT substitution in mammals, probably because of methylated cytosine “hotspots.” When the GC to AT substitutions are discounted, the remaining differences are considerably reduced and not statistically significant. 相似文献
63.
64.
Colin D White Hema Khurana Dmitri V Gnatenko Zhigang Li Robert D Odze David B Sacks Valentina A Schmidt 《BMC gastroenterology》2010,10(1):125
Background
IQGAP1 and IQGAP2 are homologous members of the IQGAP family of scaffold proteins. Accumulating evidence implicates IQGAPs in tumorigenesis. We recently reported that IQGAP2 deficiency leads to the development of hepatocellular carcinoma (HCC) in mice. In the current study we extend these findings, and investigate IQGAP1 and IQGAP2 expression in human HCC. 相似文献65.
66.
Tidow H Melero R Mylonas E Freund SM Grossmann JG Carazo JM Svergun DI Valle M Fersht AR 《Proceedings of the National Academy of Sciences of the United States of America》2007,104(30):12324-12329
The homotetrameric tumor suppressor p53 consists of folded core and tetramerization domains, linked and flanked by intrinsically disordered segments that impede structure analysis by x-ray crystallography and NMR. Here, we solved the quaternary structure of human p53 in solution by a combination of small-angle x-ray scattering, which defined its shape, and NMR, which identified the core domain interfaces and showed that the folded domains had the same structure in the intact protein as in fragments. We combined the solution data with electron microscopy on immobilized samples that provided medium resolution 3D maps. Ab initio and rigid body modeling of scattering data revealed an elongated cross-shaped structure with a pair of loosely coupled core domain dimers at the ends, which are accessible for binding to DNA and partner proteins. The core domains in that open conformation closed around a specific DNA response element to form a compact complex whose structure was independently determined by electron microscopy. The structure of the DNA complex is consistent with that of the complex of four separate core domains and response element fragments solved by x-ray crystallography and contacts identified by NMR. Electron microscopy on the conformationally mobile, unbound p53 selected a minor compact conformation, which resembled the closed conformation, from the ensemble of predominantly open conformations. A multipronged structural approach could be generally useful for the structural characterization of the rapidly growing number of multidomain proteins with intrinsically disordered regions. 相似文献
67.
Zhihong Cheng Kazuki Saito Andrey V. Pisarev Miki Wada Vera P. Pisareva Tatyana V. Pestova Michal Gajda Adam Round Chunguang Kong Mengkiat Lim Yoshikazu Nakamura Dmitri I. Svergun Koichi Ito Haiwei Song 《Genes & development》2009,23(9):1106-1118
Eukaryotic translation termination is mediated by two interacting release factors, eRF1 and eRF3, which act cooperatively to ensure efficient stop codon recognition and fast polypeptide release. The crystal structures of human and Schizosaccharomyces pombe full-length eRF1 in complex with eRF3 lacking the GTPase domain revealed details of the interaction between these two factors and marked conformational changes in eRF1 that occur upon binding to eRF3, leading eRF1 to resemble a tRNA molecule. Small-angle X-ray scattering analysis of the eRF1/eRF3/GTP complex suggested that eRF1''s M domain contacts eRF3''s GTPase domain. Consistently, mutation of Arg192, which is predicted to come in close contact with the switch regions of eRF3, revealed its important role for eRF1''s stimulatory effect on eRF3''s GTPase activity. An ATP molecule used as a crystallization additive was bound in eRF1''s putative decoding area. Mutational analysis of the ATP-binding site shed light on the mechanism of stop codon recognition by eRF1. 相似文献
68.
Serwer LP Noble CO Michaud K Drummond DC Kirpotin DB Ozawa T Prados MD Park JW James CD 《Neuro-oncology》2011,13(12):1288-1295
Achieving effective treatment outcomes for patients with glioblastoma (GBM) has been impeded by many obstacles, including the pharmacokinetic limitations of antitumor agents, such as topotecan (TPT). Here, we demonstrate that intravenous administration of a novel nanoliposomal formulation of TPT (nLS-TPT) extends the survival of mice with intracranial GBM xenografts, relative to administration of free TPT, because of improved biodistribution and pharmacokinetics of the liposome-formulated drug. In 3 distinct orthotopic GBM models, 3 weeks of biweekly intravenous therapy with nLS-TPT was sufficient to delay tumor growth and significantly extend animal survival, compared with treatment with free TPT (P ≤ .03 for each tumor tested). Analysis of intracranial tumors showed increased activation of cleaved caspase-3 and increased DNA fragmentation, both indicators of apoptotic response to treatment with nLS-TPT. These results demonstrate that intravenous delivery of nLS-TPT is a promising strategy in the treatment of GBM and support clinical investigation of this therapeutic approach. 相似文献
69.
Frank Reimann James J. Cox Inna Belfer Luda Diatchenko Dmitri V. Zaykin Duncan P. McHale Joost P. H. Drenth Feng Dai Jerry Wheeler Frances Sanders Linda Wood Tian-Xia Wu Jaro Karppinen Lone Nikolajsen Minna M?nnikk? Mitchell B. Max Carly Kiselycznyk Minakshi Poddar Rene H.M. te Morsche Shad Smith Dustin Gibson Anthi Kelempisioti William Maixner Fiona M. Gribble C. Geoffrey Woods 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(11):5148-5153
The gene SCN9A is responsible for three human pain disorders. Nonsense mutations cause a complete absence of pain, whereas activating mutations cause severe episodic pain in paroxysmal extreme pain disorder and primary erythermalgia. This led us to investigate whether single nucleotide polymorphisms (SNPs) in SCN9A were associated with differing pain perception in the general population. We first genotyped 27 SCN9A SNPs in 578 individuals with a radiographic diagnosis of osteoarthritis and a pain score assessment. A significant association was found between pain score and SNP rs6746030; the rarer A allele was associated with increased pain scores compared to the commoner G allele (P = 0.016). This SNP was then further genotyped in 195 pain-assessed people with sciatica, 100 amputees with phantom pain, 179 individuals after lumbar discectomy, and 205 individuals with pancreatitis. The combined P value for increased A allele pain was 0.0001 in the five cohorts tested (1277 people in total). The two alleles of the SNP rs6746030 alter the coding sequence of the sodium channel Nav1.7. Each was separately transfected into HEK293 cells and electrophysiologically assessed by patch-clamping. The two alleles showed a difference in the voltage-dependent slow inactivation (P = 0.042) where the A allele would be predicted to increase Nav1.7 activity. Finally, we genotyped 186 healthy females characterized by their responses to a diverse set of noxious stimuli. The A allele of rs6746030 was associated with an altered pain threshold and the effect mediated through C-fiber activation. We conclude that individuals experience differing amounts of pain, per nociceptive stimulus, on the basis of their SCN9A rs6746030 genotype. 相似文献
70.
Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice
下载免费PDF全文
![点击此处可从《The Journal of clinical investigation》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Harja E Bu DX Hudson BI Chang JS Shen X Hallam K Kalea AZ Lu Y Rosario RH Oruganti S Nikolla Z Belov D Lalla E Ramasamy R Yan SF Schmidt AM 《The Journal of clinical investigation》2008,118(1):183-194
Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE-/- mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall. 相似文献