全文获取类型
收费全文 | 4040篇 |
免费 | 287篇 |
国内免费 | 11篇 |
专业分类
耳鼻咽喉 | 34篇 |
儿科学 | 141篇 |
妇产科学 | 81篇 |
基础医学 | 604篇 |
口腔科学 | 42篇 |
临床医学 | 511篇 |
内科学 | 742篇 |
皮肤病学 | 48篇 |
神经病学 | 392篇 |
特种医学 | 72篇 |
外科学 | 489篇 |
综合类 | 28篇 |
一般理论 | 6篇 |
预防医学 | 493篇 |
眼科学 | 106篇 |
药学 | 281篇 |
中国医学 | 12篇 |
肿瘤学 | 256篇 |
出版年
2024年 | 11篇 |
2023年 | 25篇 |
2022年 | 82篇 |
2021年 | 89篇 |
2020年 | 66篇 |
2019年 | 97篇 |
2018年 | 105篇 |
2017年 | 70篇 |
2016年 | 89篇 |
2015年 | 107篇 |
2014年 | 128篇 |
2013年 | 183篇 |
2012年 | 312篇 |
2011年 | 309篇 |
2010年 | 148篇 |
2009年 | 155篇 |
2008年 | 293篇 |
2007年 | 299篇 |
2006年 | 271篇 |
2005年 | 296篇 |
2004年 | 249篇 |
2003年 | 211篇 |
2002年 | 209篇 |
2001年 | 34篇 |
2000年 | 32篇 |
1999年 | 31篇 |
1998年 | 47篇 |
1997年 | 30篇 |
1996年 | 34篇 |
1995年 | 29篇 |
1994年 | 16篇 |
1993年 | 21篇 |
1992年 | 18篇 |
1991年 | 21篇 |
1990年 | 9篇 |
1989年 | 7篇 |
1987年 | 9篇 |
1986年 | 9篇 |
1984年 | 11篇 |
1982年 | 11篇 |
1981年 | 8篇 |
1978年 | 7篇 |
1977年 | 6篇 |
1971年 | 5篇 |
1970年 | 7篇 |
1969年 | 5篇 |
1968年 | 5篇 |
1966年 | 6篇 |
1965年 | 5篇 |
1961年 | 5篇 |
排序方式: 共有4338条查询结果,搜索用时 15 毫秒
101.
102.
103.
Ngiap Chuan Tan Su-Yen Goh Eric Yin-Hao Khoo Rinkoo Dalan Agnes Koong Chin Meng Khoo Teck Shi Tan Anand B Jain Arvind Vilas Gadekar Yong Mong Bee IO HAT Investigator group 《Singapore medical journal》2020,61(3):129
INTRODUCTIONHypoglycaemia constitutes a significant barrier to achieving glycaemic control with insulin in both Type 1 (T1DM) and Type 2 diabetes mellitus (T2DM). The International Operations Hypoglycaemia Assessment Tool (IO HAT) study was designed to determine the incidence of hypoglycaemia in insulin-treated patients with T1DM and T2DM.METHODSThe IO HAT study retrospectively and prospectively assessed the incidence of hypoglycaemia in patients with insulin-treated diabetes mellitus in nine countries. This sub-analysis included patients from Singapore with T1DM or T2DM who were aged ≥ 21 years and had completed two self-assessment questionnaires (SAQ1 and SAQ2).RESULTSOf the 50 T1DM and 320 T2DM patients who completed the SAQ1, 39 T1DM and 265 T2DM patients completed SAQ2; 100% and 90.9%, respectively, experienced at least one hypoglycaemic event prospectively. The incidence rates of any hypoglycaemia were 49.5 events per patient-year (EPPY) and 16.1 EPPY for T1DM and T2DM patients, respectively, in the four-week prospective period. Hypoglycaemia rate did not differ in terms of glycated haemoglobin level. The vast majority of T1DM or T2DM patients (92.0% and 90.7%, respectively) knew the overall definition of hypoglycaemia before study participation, although over half of the patients (T1DM 54.0%, T2DM 51.9%) defined hypoglycaemia based only on symptoms.CONCLUSIONHigh proportions of insulin-treated patients with diabetes mellitus in Singapore reported hypoglycaemic events prospectively, showing that they had underreported hypoglycaemic episodes retrospectively. Patient education can help in improving hypoglycaemia awareness and its management in the region. 相似文献
104.
105.
Angelika Varga Agnes Jenes Timothy H. Marczylo Joao Sousa-Valente Jie Chen Jonothan Austin Srikumaran Selvarajah Fabiana Piscitelli Anna P. Andreou Anthony H. Taylor Fiona Kyle Mohammed Yaqoob Sue Brain John P. M. White Laszlo Csernoch Vincenzo Di Marzo Laki Buluwela Istvan Nagy 《Pflügers Archiv : European journal of physiology》2014,466(7):1421-1435
The endogenous lipid agent N-arachidonoylethanolamine (anandamide), among other effects, has been shown to be involved in nociceptive processing both in the central and peripheral nervous systems. Anandamide is thought to be synthesised by several enzymatic pathways both in a Ca2+-sensitive and Ca2+-insensitive manner, and rat primary sensory neurons produce anandamide. Here, we show for the first time, that cultured rat primary sensory neurons express at least four of the five known Ca2+-insensitive enzymes implicated in the synthesis of anandamide, and that application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl, the common substrate of the anandamide-synthesising pathways, results in anandamide production which is not changed by the removal of extracellular Ca2+. We also show that anandamide, which has been synthesised in primary sensory neurons following the application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl induces a transient receptor potential vanilloid type 1 ion channel-mediated excitatory effect that is not inhibited by concomitant activation of the cannabinoid type 1 receptor. Finally, we show that sub-populations of transient receptor potential vanilloid type 1 ion channel-expressing primary sensory neurons also express some of the putative Ca2+-insensitive anandamide-synthesising enzymes. Together, these findings indicate that anandamide synthesised by primary sensory neuron via a Ca2+-insensitive manner has an excitatory rather than an inhibitory role in primary sensory neurons and that excitation is mediated predominantly through autocrine signalling. Regulation of the activity of the Ca2+-insensitive anandamide-synthesising enzymes in these neurons may be capable of regulating the activity of these cells, with potential relevance to controlling nociceptive processing. 相似文献
106.
Alena Stsiapanava Ulrika Olsson Min Wan Thea Kleinschmidt Dorothea Rutishauser Roman A. Zubarev Bengt Samuelsson Agnes Rinaldo-Matthis Jesper Z. Haeggstr?m 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(11):4227-4232
Leukotriene (LT) A4 hydrolase/aminopeptidase (LTA4H) is a bifunctional zinc metalloenzyme that catalyzes the committed step in the formation of the proinflammatory mediator LTB4. Recently, the chemotactic tripeptide Pro-Gly-Pro was identified as an endogenous aminopeptidase substrate for LTA4 hydrolase. Here, we determined the crystal structure of LTA4 hydrolase in complex with a Pro-Gly-Pro analog at 1.72 Å. From the structure, which includes the catalytic water, and mass spectrometric analysis of enzymatic hydrolysis products of Pro-Gly-Pro, it could be inferred that LTA4 hydrolase cleaves at the N terminus of the palindromic tripeptide. Furthermore, we designed a small molecule, 4-(4-benzylphenyl)thiazol-2-amine, denoted ARM1, that inhibits LTB4 synthesis in human neutrophils (IC50 of ∼0.5 μM) and conversion of LTA4 into LTB4 by purified LTA4H with a Ki of 2.3 μM. In contrast, 50- to 100-fold higher concentrations of ARM1 did not significantly affect hydrolysis of Pro-Gly-Pro. A 1.62-Å crystal structure of LTA4 hydrolase in a dual complex with ARM1 and the Pro-Gly-Pro analog revealed that ARM1 binds in the hydrophobic pocket that accommodates the ω-end of LTA4, distant from the aminopeptidase active site, thus providing a molecular basis for its inhibitory profile. Hence, ARM1 selectively blocks conversion of LTA4 into LTB4, although sparing the enzyme’s anti-inflammatory aminopeptidase activity (i.e., degradation and inactivation of Pro-Gly-Pro). ARM1 represents a new class of LTA4 hydrolase inhibitor that holds promise for improved anti-inflammatory properties.Leukotriene (LT) A4 hydrolase/aminopeptidase (EC 3.3.2.6) is a bifunctional zinc metalloenzyme that catalyzes the formation of the potent chemotactic agent LTB4, a key lipid mediator in the innate immune response (1, 2). Previous work has shown that LTA4 hydrolase (LTA4H) is an aminopeptidase with high affinity for N-terminal arginines of various synthetic tripeptides (3, 4). The two enzyme activities of LTA4H are exerted via distinct but overlapping active sites and depend on the catalytic zinc, bound within the signature HEXXH-(X)18-E, typical of M1 metallopeptidases (5–7). In LTA4H, His295, His299, and Glu318 are the zinc-binding ligands, whereas Glu296 is the general base catalyst for peptide hydrolysis (8, 9).LTA4H’s crystal structure has been determined (10). The enzyme folds into an N-terminal domain, a catalytic domain, and a C-terminal domain, each with ∼200 amino acids. The interface of the domains forms a cavity, where the active site is located (Fig. 1). The cavity narrows at the zinc-binding site, forming a tunnel into the catalytic domain. The opening and wider parts of the cavity are highly polar; the tunnel is more hydrophobic. The cavity is mostly defined by the catalytic and C-terminal domains; part of the tunnel is defined by the N-terminal domain. Bound substrate is in contact with all three domains.Open in a separate windowFig. 1.Position and extension of the active center in LTA4H. Cartoon representation of the structure of LTA4H with a tunnel for LTA4 (red mesh) and peptide substrates (blue mesh). The catalytic zinc (yellow sphere) is located in a wide section of the active site from which a narrow, L-shaped, hydrophobic tunnel protrudes ∼15 Å deeper into the protein. LTA4 is believed to bind with its ω-end at the end of the hydrophobic tunnel. The volume of the active center was calculated in CAVER (31).Recently, it was discovered that LTA4H cleaves and inactivates the chemotactic tripeptide Pro-Gly-Pro, thus identifying a previously unrecognized endogenous, physiologically significant aminopeptidase substrate (11). Inasmuch as Pro-Gly-Pro attracts neutrophils and promotes inflammation, these data also suggest that LTA4H plays dual and opposite roles during an inflammatory response (i.e., production of chemotactic LTB4, as well as inactivation of chemotactic Pro-Gly-Pro). Previous efforts to develop inhibitors of LTA4H have used the aminopeptidase activity for screening purposes, and these molecules therefore block both catalytic activities of LTA4H (12).Here, we used crystallography, MS, and a stable peptide analog to determine the binding mode of Pro-Gly-Pro at the active site of LTA4H, as well as the mechanism of peptide cleavage. Based on the structure, we also designed a lead compound that selectively blocks the conversion of LTA4 into LTB4, although sparing the hydrolysis of Pro-Gly-Pro. 相似文献
107.
The proteasomal subunit Rpn6 is a molecular clamp holding the core and regulatory subcomplexes together 总被引:2,自引:0,他引:2
Pathare GR Nagy I Bohn S Unverdorben P Hubert A Körner R Nickell S Lasker K Sali A Tamura T Nishioka T Förster F Baumeister W Bracher A 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(1):149-154
Proteasomes execute the degradation of most cellular proteins. Although the 20S core particle (CP) has been studied in great detail, the structure of the 19S regulatory particle (RP), which prepares ubiquitylated substrates for degradation, has remained elusive. Here, we report the crystal structure of one of the RP subunits, Rpn6, and we describe its integration into the cryo-EM density map of the 26S holocomplex at 9.1?? resolution. Rpn6 consists of an α-solenoid-like fold and a proteasome COP9/signalosome eIF3 (PCI) module in a right-handed suprahelical configuration. Highly conserved surface areas of Rpn6 interact with the conserved surfaces of the Pre8 (alpha2) and Rpt6 subunits from the alpha and ATPase rings, respectively. The structure suggests that Rpn6 has a pivotal role in stabilizing the otherwise weak interaction between the CP and the RP. 相似文献
108.
109.
110.
Tarnoki AD Tarnoki DL Stazi MA Medda E Cotichini R Nisticò L Fagnani C Lucatelli P Boatta E Zini C Fanelli F Baracchini C Meneghetti G Osztovits J Jermendy G Préda I Kiss RG Metneki J Horvath T Karlinger K Racz A Lannert A Molnar AA Littvay L Garami Z Berczi V Schillaci G 《Journal of hypertension》2012,30(8):1564-1571