全文获取类型
收费全文 | 2141篇 |
免费 | 112篇 |
国内免费 | 10篇 |
专业分类
耳鼻咽喉 | 47篇 |
儿科学 | 104篇 |
妇产科学 | 42篇 |
基础医学 | 295篇 |
口腔科学 | 51篇 |
临床医学 | 218篇 |
内科学 | 371篇 |
皮肤病学 | 93篇 |
神经病学 | 147篇 |
特种医学 | 82篇 |
外科学 | 198篇 |
综合类 | 18篇 |
一般理论 | 1篇 |
预防医学 | 189篇 |
眼科学 | 185篇 |
药学 | 127篇 |
肿瘤学 | 95篇 |
出版年
2023年 | 10篇 |
2022年 | 11篇 |
2021年 | 39篇 |
2020年 | 15篇 |
2019年 | 30篇 |
2018年 | 36篇 |
2017年 | 28篇 |
2016年 | 36篇 |
2015年 | 45篇 |
2014年 | 39篇 |
2013年 | 73篇 |
2012年 | 102篇 |
2011年 | 103篇 |
2010年 | 67篇 |
2009年 | 63篇 |
2008年 | 78篇 |
2007年 | 97篇 |
2006年 | 124篇 |
2005年 | 86篇 |
2004年 | 96篇 |
2003年 | 99篇 |
2002年 | 75篇 |
2001年 | 76篇 |
2000年 | 61篇 |
1999年 | 74篇 |
1998年 | 36篇 |
1997年 | 37篇 |
1996年 | 37篇 |
1995年 | 24篇 |
1994年 | 18篇 |
1993年 | 22篇 |
1992年 | 44篇 |
1991年 | 27篇 |
1990年 | 31篇 |
1989年 | 47篇 |
1988年 | 33篇 |
1987年 | 51篇 |
1986年 | 30篇 |
1985年 | 26篇 |
1984年 | 16篇 |
1983年 | 22篇 |
1982年 | 11篇 |
1981年 | 8篇 |
1979年 | 21篇 |
1977年 | 15篇 |
1976年 | 11篇 |
1975年 | 13篇 |
1974年 | 13篇 |
1969年 | 7篇 |
1967年 | 7篇 |
排序方式: 共有2263条查询结果,搜索用时 171 毫秒
91.
Dietmar Weichert Andrew C. Kruse Aashish Manglik Christine Hiller Cheng Zhang Harald Hübner Brian K. Kobilka Peter Gmeiner 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(29):10744-10748
Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating Gs-, Gi-, and Gq-coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the β2-adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis.One of the major obstacles to the investigation of the structural basis of G protein-coupled receptor (GPCR) activation is the flexibility of their seven-transmembrane core, particularly in the active state (1), and the resulting biochemical instability of the solubilized protein (2, 3). Protein crystallography, the most powerful tool for the study of GPCR structure, requires the formation of stable and conformationally homogeneous ligand-receptor complexes (4). High-affinity agonists with dissociation constants in the low to subnanomolar range and low off-rates facilitate stabilization of the protein throughout the process of expression, purification, and crystallogenesis (2); however, endogenous neurotransmitters usually show poor binding affinity. Low binding affinity with rapid association and dissociation rates leads to conformational heterogeneity that prevents the formation of diffraction-quality crystals. The rapid dissociation rate of agonists also makes it difficult to generate active-state stabilizing proteins, such as the camelid antibodies (nanobodies) that have been used to obtain active-state structures of the β2-adrenergic receptor (β2AR) (5) and M2 muscarinic receptor (6).To prevent ligand dissociation, irreversible ligation of electrophilic moieties like halomethylketones, isothiocyanates, Michael acceptors, or aziridinium groups of small-molecule ligands with a suitably positioned nucleophilic residue in the receptor has been used (7–16). However, irreversible ligands often suffer from incomplete cross-linking (15) and reduced receptor activation when covalent binding leads to loss of agonist efficacy (10, 16). Furthermore, their highly electrophilic nature and the abundance of nucleophilic groups in biological systems may lead to a low coupling selectivity (7, 8).Disulfide-based cross-linking approaches (17, 18) offer the advantage that the covalent binding of disulfide-containing compounds is chemoselective for cysteine and enforced by the affinity of the ligand-pharmacophore rather than by the electrophilicity of the cross-linking function (19). We refer to the described ligands as covalent rather than irreversible agonists because cleavage may be promoted by reducing agents and the disulfide transfer process is a reversible chemical reaction in general.Structural information on the target protein facilitates the development of covalent ligand-receptor pairs. Mutation of H932.64 in the β2AR to cysteine introduced an anchor for the disulfide-based covalent agonist FAUC50, which does not perturb ligand binding or the activation of the receptor, and thus enabled, to our knowledge, the first agonist-bound GPCR structure (20). Taking advantage of the high structural homology among aminergic GPCRs, we reasoned that the introduction of cysteine into position X2.64 should also result in a covalently binding receptor mutant for other aminergic GPCRs.We here report a methodology to generate disulfide-based covalent ligand-receptor pairs to promote structural and functional studies on GPCRs. We demonstrate that even the low-affinity endogenous agonists noradrenaline, dopamine, and serotonin can be converted into efficient covalently binding molecular tools for the β2AR, the dopamine D2 receptor (D2R), and the 5-hydroxytryptamine 2A (5-HT2A) serotonergic subtype representing Gs-, Gi-, and Gq-coupled GPCRs, respectively. Analogous studies were conducted starting from histamine and the receptor subtype H1. We applied this strategy to obtain an active-state crystal structure of the β2ARH93C and a covalent (nor)adrenaline analog. 相似文献
92.
93.
94.
Thomas Schneider Katharina Filo Michael C. Locher Thomas Gander Philipp Metzler Klaus W. Grätz Astrid L. Kruse Heinz-Theo Lübbers 《The British journal of oral & maxillofacial surgery》2014
Stafne bone cavities are usually found in men 50–70 years old. Typically they appear as lingual, open, ovoid lesions of the molar region of the lower jaw, and most contain parts of the submandibular gland. We have retrospectively examined panoramic radiographs acquired over a 5-year period. All lesions suspected of being Stafne bone cavities were included and analysed further to retrieve statistical information and derive a systematic diagnostic algorithm. We identified 21 Stafne bone cavities among 2928 patients (0.7%). Four of these were confirmed on cone-beam computed tomography (CT). One patient had magnetic resonance imaging (MRI) to confirm the diagnosis. The M:F ratio was 14:7 and the mean age 53 years (range 22–82). All cavities were located in the posterior mandible, 9 on the right and 12 on the left. The mean length was 10.9 (range 4.5–23) mm and height 5.7 (range 3.3–17.3) mm. All cavities were located in the posterior mandible. Sixteen panoramic radiographs (0.6%) were classified as possibly having a Stafne bone cavity but did not fulfil enough criteria to confirm the diagnosis. These 16 were not further analysed. It is rare to diagnose a Stafne bone cavity on a panoramic radiograph. Thorough investigation is essential to exclude differential diagnoses such as keratocystic odontogenic tumour, ameloblastoma, or a metastasis. 相似文献
95.
Alexia Stock Rachel A.Davidson Joseph E.Trainor Rachel Slotter Linda K.Nozick Jamie B.Kruse 《国际灾害风险科学学报(英文版)》2021,(3):312-325
We hypothesize that for disaster risk mitigation,many households,despite being aware of their risk and possible mitigation actions,never seriously consider doin... 相似文献
96.
97.
98.
C. Roux C. Gennari J. Farrerons J. P. Devogelaer H. Mulder H. P. Kruse C. Picot L. Titeux J. Y. Reginster M. Dougados 《Arthritis \u0026amp; Rheumatology》1995,38(6):851-858
Objective. To compare the efficacy and safety of tiludronate and etidronate at the same dosage (400 mg/day) for the treatment of active Paget's disease of bone. Methods. We studied 234 patients with radiologic lesions characteristic of Paget's disease of bone and serum alkaline phosphatase (AP) concentrations at least twice the upper limit of normal, in a prospective, randomized, double-blind, multicenter clinical trial lasting 6 months. Patients were randomly allocated into 1 of 3 treatment groups: tiludronate for 3 months followed by placebo for 3 months, tiludronate for 6 months, or etidronate for 6 months. Serum AP levels and urinary hydroxyproline excretion were measured at baseline and after 3 months and 6 months. Patients with a reduction of at least 50% in the serum AP concentration were considered to be responders. Results. After 3 months, the proportion of responders was higher in the tiludronate group (57.4%) than in the etidronate group (13.9%) (P < 0.0001). In the etidronate group, this percentage was lower among patients who had received previous treatment with a bisphosphonate (2.3%) than among those who had not (28.6%) (P < 0.01). Previous bisphosphonate treatment was not associated with response in the tiludronate group. After 6 months, the proportion of responders did not differ between the 2 tiludronate groups (60.3% and 70.1%), but was lower in the etidronate group (25.3%) (P < 0.0001). There was a higher proportion of patients with treatment-resistant disease ( < 25% reduction of serum AP) in the etidronate group (51.9%) than in the tiludronate 3-month group (17.9%) or the tiludronate 6-month group (19.5%) (P < 0.0001). Gastrointestinal disturbances were more common, and occurred earlier, with tiludronate, but they were mostly mild, requiring no treatment. Conclusion. Tiludronate at 400 mg/day for 3 months or 6 months is more effective than the same dosage of etidronate for 6 months in the treatment of Paget's disease. 相似文献
99.
Susanne Staehlke Philip Oster Susanne Seemann Fabian Kruse Jakob Brief Barbara Nebe 《Materials》2022,15(3)
Various approaches are being pursued to physico-chemically modify the zirconia neck region of dental implants to improve the integration into the surrounding soft tissue. In this study, polished zirconia discs were laser microstructured with periodic cavities and convex waves. These zirconia samples were additionally activated by argon plasma using the kINPen®09. The surface topography was characterized by scanning electron microscopy and the surface wettability by water contact angle. The in vitro study with human gingival fibroblasts (HGF-1) was focused on cell spreading, morphology, and actin cytoskeleton organization within the first 24 h. The laser-induced microstructures were originally hydrophobic (e.g., 60 µm cavities 138.4°), but after argon plasma activation, the surfaces switched to the hydrophilic state (60 µm cavities 13.7°). HGF-1 cells adhered flatly on the polished zirconia. Spreading is hampered on cavity structures, and cells avoid the holes. However, cells on laser-induced waves spread well. Interestingly, argon plasma activation for only 1 min promoted adhesion and spreading of HGF-1 cells even after 2 h cultivation. The cells crawl and grow into the depth of the cavities. Thus, a combination of both laser microstructuring and argon plasma activation of zirconia seems to be optimal for a strong gingival cell attachment. 相似文献