全文获取类型
收费全文 | 776篇 |
免费 | 61篇 |
国内免费 | 11篇 |
专业分类
耳鼻咽喉 | 3篇 |
儿科学 | 33篇 |
妇产科学 | 8篇 |
基础医学 | 61篇 |
口腔科学 | 12篇 |
临床医学 | 65篇 |
内科学 | 196篇 |
皮肤病学 | 12篇 |
神经病学 | 28篇 |
特种医学 | 159篇 |
外科学 | 75篇 |
综合类 | 34篇 |
预防医学 | 37篇 |
眼科学 | 4篇 |
药学 | 87篇 |
中国医学 | 6篇 |
肿瘤学 | 28篇 |
出版年
2023年 | 7篇 |
2022年 | 4篇 |
2021年 | 8篇 |
2020年 | 5篇 |
2019年 | 10篇 |
2018年 | 9篇 |
2016年 | 24篇 |
2015年 | 53篇 |
2014年 | 23篇 |
2013年 | 31篇 |
2012年 | 27篇 |
2011年 | 36篇 |
2010年 | 35篇 |
2009年 | 40篇 |
2008年 | 32篇 |
2007年 | 16篇 |
2006年 | 21篇 |
2005年 | 21篇 |
2004年 | 10篇 |
2003年 | 11篇 |
2002年 | 11篇 |
2001年 | 20篇 |
2000年 | 14篇 |
1999年 | 12篇 |
1998年 | 26篇 |
1997年 | 45篇 |
1996年 | 35篇 |
1995年 | 27篇 |
1994年 | 23篇 |
1993年 | 19篇 |
1992年 | 5篇 |
1991年 | 9篇 |
1990年 | 9篇 |
1989年 | 26篇 |
1988年 | 19篇 |
1987年 | 10篇 |
1986年 | 16篇 |
1985年 | 11篇 |
1984年 | 10篇 |
1983年 | 7篇 |
1982年 | 10篇 |
1981年 | 8篇 |
1980年 | 9篇 |
1979年 | 4篇 |
1978年 | 3篇 |
1977年 | 4篇 |
1976年 | 8篇 |
1972年 | 3篇 |
1971年 | 3篇 |
1967年 | 3篇 |
排序方式: 共有848条查询结果,搜索用时 144 毫秒
31.
Yu‐ming M. Huang Jason Munguia Yinglong Miao Victor Nizet J. Andrew McCammon 《Chemical biology & drug design》2019,93(4):647-652
To maintain the lipid asymmetry of the cell envelope in Gram‐negative bacteria, the MlaC protein serves as a lipid transfer factor and delivers phospholipids from the outer to the inner membrane. A strategy of antibiotic discovery is to design a proper compound that can tightly bind to the MlaC protein and inhibit the MlaC function. In this study, we performed virtual screening on multiple MlaC structures obtained from molecular dynamics simulations to identify potential MlaC binders. Our results suggested that clorobiocin is a compound that could bind to the MlaC protein. Through the comparison of the bound geometry between clorobiocin and novobiocin, we pointed out that the methyl‐pyrrole group of the noviose sugar in clorobiocin forms hydrophobic interactions with amino acids in the phospholipid binding pocket, which allows the compound to bind deep in the active site. This also explains why clorobiocin shows a tighter binding affinity than novobiocin. Our study highlights a practical path of antibiotic development against Gram‐negative bacteria. 相似文献
32.
33.
目的分析先天性肠闭锁病例的诊断及治疗,以提高治愈率及术后生活质量。方法回顾性分析166例先天性肠闭锁的临床资料。结果治愈142例,治愈率85.5%(142/166),其中包括18例二期手术治愈者;术中10例、术后8例放弃治疗;术后死亡6例。结论早期诊断和选择合理的术式是提高肠闭锁治愈率的关键,基础支持及手术技术改进能促进病情的恢复,改善预后。 相似文献
34.
35.
Aubé Mélanie Chua Michael DeLong Jessica McCammon Kurt Tonkin Jeremy Gilbert David Virasoro Ramón 《International urology and nephrology》2020,52(4):687-692
International Urology and Nephrology - To determine predictors for surgical complications and assess patient satisfaction after surgical treatment of Adult-Acquired Buried Penis (AABP). A... 相似文献
36.
Steffen Lindert Monica X. Li Brian D. Sykes J. Andrew McCammon 《Chemical biology & drug design》2015,85(2):99-106
In the fight against heart failure, therapeutics that have the ability to increase the contractile power of the heart are urgently needed. One possible route of action to improve heart contractile power is increasing the calcium sensitivity of the thin filament. From a pharmaceutical standpoint, calcium sensitizers have the distinct advantage of not altering cardiomyocyte calcium levels and thus have lower potential for side-effects. Small chemical molecules have been shown to bind to the interface between cTnC and the cTnI switch peptide and exhibit calcium-sensitizing properties, possibly by stabilizing cTnC in an open conformation. Building on existing structural data of a known calcium sensitizer bound to cardiac troponin, we combined computational structure-based virtual screening drug discovery methods and solution NMR titration assays to identify a novel calcium sensitizer 4-(4-(2,5-dimethylphenyl)-1-piperazinyl)-3-pyridinamine (NSC147866) which binds to cTnC and the cTnC-cTnI147–163 complex. Its presence increases the affinity of switch peptide to cTnC by approximately a factor of two. This action is comparable to that of known levosimendan analogues. 相似文献
37.
Analogues of oxytocin and deaminooxytocin with 4-glutamine replaced by 4-glutamic acid methyl ester readily lose their uterotonic activity when incubated with rat serum, presumably by hydrolysis to the much less active 4-glutamic acid derivatives. On the other hand, inactivation of the deaminooxytocin analogue in the rat uterus, as demonstrated by the 'oil-bath'technique, is only slightly more rapid than that of deaminooxytocin and distinctly slower than that of oxytocin. Its in situ/in vitro ratio of uterotonic activity is less than 0.1 whereas that for deaminooxytocin is about 3 and also the persistence of the uterotonic effect in situ is slightly less than that of deaminooxytocin. The results with these 'rapidly inactivated'analogues can be used as proof of some predictions of the three-compartment model for tissue distribution of neurohypophysial hormones and its influence upon the time course of a biological response published earlier. The potential use of analogues of neurohypophysial hormones as probes for inactivation mechanisms and the results thus far obtained are discussed. 相似文献
38.
Two patients with hairy cell leukemia with massive splenomegaly and severe pancytopenia were treated with recombinant alpha-A interferon (IFN-alpha-2a). There was no significant response to a trial of IFN- alpha-2a (11 and 20 weeks) with respect to blood counts or spleen size. Subsequent treatment with 2'-deoxycoformycin (dCF) for 8 consecutive weeks (4 mg/m2/wk) resulted in normalization of spleen size and a normalization of peripheral blood counts and bone marrow in one patient. The second patient demonstrated a reduction in spleen size and improved blood counts following 9 weeks of dCF therapy but eventually became refractory. This demonstrates that dCF is non-cross-resistant with interferon and confirms the efficacy of dCF in nonsplenectomized patients. 相似文献
39.
Auber ML; Horwitz LJ; Blaauw A; Khorana S; Tucker S; Woods T; Warmuth M; Dicke KA; McCredie KB; Spitzer G 《Blood》1988,71(1):166-172
Relatively nonmyelotoxic drugs and drug combinations were investigated for their ability to eliminate malignant cells from human bone marrow. In vitro 90% inhibitory concentration (IC90) doses were established on granulocyte macrophage colony-forming units (GM-CFU) in culture of bone marrow by using the GM-CFU assay for the following drugs: 4- hydroperoxycyclophosphamide (4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16, spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency of these drugs at IC90 doses was compared with that of 4-HC on acute lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay. Under these conditions, no single drug was superior to 4-HC. To increase the in vitro effect in leukemic cell kill, combinations of vincristine with hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine at 1 to 5 micrograms/mL increased the marrow cytotoxicity of hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive) with 4-HC. Vincristine and 4-HC in combination was additive to supraadditive on ALL cell lines, increased the leukemic cell kill by one to two logs above 4-HC alone at IC90 doses (P less than .05), and was not affected by the addition of excess marrow cells. The recommended doses for chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL, plus 4-HC, 5 micrograms/mL. 相似文献
40.
The factor V B-domain provides two functions to facilitate thrombin cleavage and release of the light chain 总被引:1,自引:1,他引:1
Blood coagulation factors V and VIII are homologous proteins that have the domain organization A1-A2-B-A3-C1-C2. Upon thrombin activation, the B-domains of both molecules are released. Previous studies on factor VIII showed that the B-domain was not required for thrombin cleavage or activity. In contrast, deletion of the factor V B-domain (residues 709 to 1545) yielded a molecule with sevenfold reduced procoagulant activity that was not cleaved by thrombin. However, this factor V B- domain deletion molecule was activated by factor Xa, although the fold- activation was 85% that of wild-type factor V. Thrombin cleavage of factor V occurs initially after residue 709 and subsequently after residues 1018 and 1545. The requirement for thrombin cleavage within the B-domain at residue 1018 was evaluated by mutagenesis of Arg1018 to Ile. In the resultant R1018I mutant, the rate of thrombin activation and appearance of maximal cofactor activity was delayed and was consistent with delayed cleavage of the light chain at residue 1545. In contrast, the rate of factor Xa activation in the R1018I mutant was not altered. This finding suggests that thrombin cleavage at 1018 facilitates subsequent thrombin cleavage at 1545. Further mutagenesis was used to study the requirement for sequences within the factor V B- domain for thrombin cleavage at residue 1545. Whereas the factor V deletion molecule removing residues 709 to 1545 was not cleaved by thrombin, a smaller B-domain deletion molecule (residues 709 to 1476) containing an acidic amino acid-rich region (residues 1490 to 1520) was effectively cleaved by thrombin. These results show that residues 1476 to 1545, which contain an acidic amino acid-rich region, were required for thrombin cleavage of the light chain. Introduction of an acidic amino acid-rich region from factor VIII (residues 337 to 372) into the factor V 709 to 1545 deletion also restored thrombin cleavage of the light chain. In contrast, similar replacement with the acidic region from the factor VIII light chain (residues 1649 to 1689) was significantly less effective in promoting thrombin cleavage of the light chain. This finding suggests that the different acidic regions in factors V and VIII are not functionally equivalent in their interaction with thrombin.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献