全文获取类型
收费全文 | 1704篇 |
免费 | 93篇 |
国内免费 | 8篇 |
专业分类
耳鼻咽喉 | 14篇 |
儿科学 | 49篇 |
妇产科学 | 50篇 |
基础医学 | 337篇 |
口腔科学 | 38篇 |
临床医学 | 189篇 |
内科学 | 315篇 |
皮肤病学 | 29篇 |
神经病学 | 122篇 |
特种医学 | 57篇 |
外科学 | 278篇 |
综合类 | 14篇 |
预防医学 | 111篇 |
眼科学 | 8篇 |
药学 | 129篇 |
中国医学 | 2篇 |
肿瘤学 | 63篇 |
出版年
2023年 | 8篇 |
2022年 | 20篇 |
2021年 | 27篇 |
2020年 | 18篇 |
2019年 | 22篇 |
2018年 | 23篇 |
2017年 | 28篇 |
2016年 | 31篇 |
2015年 | 37篇 |
2014年 | 33篇 |
2013年 | 60篇 |
2012年 | 102篇 |
2011年 | 79篇 |
2010年 | 60篇 |
2009年 | 59篇 |
2008年 | 102篇 |
2007年 | 104篇 |
2006年 | 125篇 |
2005年 | 113篇 |
2004年 | 113篇 |
2003年 | 85篇 |
2002年 | 103篇 |
2001年 | 19篇 |
2000年 | 10篇 |
1999年 | 18篇 |
1998年 | 25篇 |
1997年 | 15篇 |
1996年 | 27篇 |
1995年 | 13篇 |
1994年 | 18篇 |
1993年 | 14篇 |
1992年 | 8篇 |
1991年 | 12篇 |
1990年 | 9篇 |
1989年 | 8篇 |
1987年 | 12篇 |
1986年 | 7篇 |
1985年 | 8篇 |
1984年 | 11篇 |
1983年 | 7篇 |
1981年 | 7篇 |
1980年 | 11篇 |
1937年 | 9篇 |
1930年 | 6篇 |
1929年 | 7篇 |
1928年 | 11篇 |
1926年 | 8篇 |
1925年 | 7篇 |
1923年 | 6篇 |
1922年 | 6篇 |
排序方式: 共有1805条查询结果,搜索用时 15 毫秒
21.
Ad F. Roffel Willy G. in't Hout Rokus A. de Zeeuw Johan Zaagsma 《Naunyn-Schmiedeberg's archives of pharmacology》1987,335(5):593-595
Summary We have characterized the muscarine receptors in bovine tracheal and left ventricular membranes using 3H-dexetimide/pirenzepine and 3H-dexetimide/AF-DX 116 competition studies. Pirenzepinc exhibited low (M2) affinity binding to both preparations; K
d was 590 nM in left ventricle and 463 nM in trachea. AF-DX 116 exhibited high (M2) affinity binding to left ventricle (K
d = 95.6 nM); in tracheal membranes it bound with high (M2) affinity (K
d = 40.7 nM) to 74% of the receptors and with low (M3) affinity (K
d = 2.26 M) to 26% of the receptors. It is concluded that bovine tracheal muscle membranes contain a heterogeneous population of muscarine binding sites, the majority having M2 (heart) subtype characteristics and being located on the smooth muscle membranes; a minority having M3 (exocrine gland) subtype characteristics and presumed to be located in submucosal glands. This is the first report of high affinity binding of AF-DX 116 to non-cardiac peripheral muscarine receptors.
Send offprint requests to A. F. Roffel at the above address 相似文献
22.
Willy Palm Erin Webb Cristina Hernández-Quevedo Giada Scarpetti Suszy Lessof Luigi Siciliani Ewout van Ginneken 《Health policy (Amsterdam, Netherlands)》2021,125(3):341-350
This study identifies gaps in universal health coverage in the European Union, using a questionnaire sent to the Health Systems and Policy Monitor network of the European Observatory on Health Systems and Policies. The questionnaire was based on a conceptual framework with four access dimensions: population coverage, service coverage, cost coverage, and service access. With respect to population coverage, groups often excluded from statutory coverage include asylum seekers and irregular residents. Some countries exclude certain social-professional groups (e.g. civil servants) from statutory coverage but cover these groups under alternative schemes. In terms of service coverage, excluded or restricted services include optical treatments, dental care, physiotherapy, reproductive health services, and psychotherapy. Early access to new and expensive pharmaceuticals is a concern, especially for rare diseases and cancers. As to cost coverage, some countries introduced protective measures for vulnerable patients in the form of exemptions or ceilings from user chargers, especially for deprived groups or patients with accumulation of out-of-pocket spending. For service access, common issues are low perceived quality and long waiting times, which are exacerbated for rural residents who also face barriers from physical distance. Some groups may lack physical or mental ability to properly formulate their request for care. Currently, available indicators fail to capture the underlying causes of gaps in coverage and access. 相似文献
23.
The interaction of phenylbutazone with the enantiomers and racemic [
3
H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 g/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(–), and R, S (±) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained nearly unaffected by phenylbutazone. Thus there is no evidence for a stereoselective drug interaction between phenprocoumon and phenyl-butazone. For racemic [
3
H]phenprocoumon it was possible to follow the kinetics of free drug in plasma and liver along with the time course of anticoagulant activity. In these studies, free drug concentrations in plasma and liver increased during treatment with phenylbutazone, but the elimination rate constant of free racemic phenprocoumon in plasma and liver remained essentially unchanged. Phenylbutazone markedly decreased the volume of distribution referenced to free drug and the clearance of free phenprocoumon (i.e., intrinsic metabolic clearance). Whereas the total (bound and unbound) drug concentration-effect relationship in plasma and liver was shifted to the left in rats treated with phenylbutazone, such shift was not seen in the free drug concentration-response relationship. In conclusion, the increase in the free concentration of phenprocoumon in plasma and liver and the concomitant decrease in the clearance of free drug are the mechanisms responsible for the marked and sustained enhancement of the anticoagulant effect which follows treatment with phenbutazone.This work was supported by the Deutsche Forschungsgemeinschaft. 相似文献
24.
25.
26.
27.
Willy Carrasquel-Ursulaez Ignacio Segura Ignacio Díaz-Franulic Valeria Mrquez-Miranda Felipe Echeverría Yenisleidy Lorenzo-Ceballos Nicols Espinoza Maximiliano Rojas Jose Antonio Garate Eduardo Perozo Osvaldo Alvarez Fernando D. Gonzalez-Nilo Ramn Latorre 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(25)
In neurosecretion, allosteric communication between voltage sensors and Ca2+ binding in BK channels is crucially involved in damping excitatory stimuli. Nevertheless, the voltage-sensing mechanism of BK channels is still under debate. Here, based on gating current measurements, we demonstrate that two arginines in the transmembrane segment S4 (R210 and R213) function as the BK gating charges. Significantly, the energy landscape of the gating particles is electrostatically tuned by a network of salt bridges contained in the voltage sensor domain (VSD). Molecular dynamics simulations and proton transport experiments in the hyperpolarization-activated R210H mutant suggest that the electric field drops off within a narrow septum whose boundaries are defined by the gating charges. Unlike Kv channels, the charge movement in BK appears to be limited to a small displacement of the guanidinium moieties of R210 and R213, without significant movement of the S4.Excitable tissues accomplish their signaling functions thanks in part to the interplay of several voltage-sensitive ion channels (1–6). Hence, to understand these processes, it is crucial to establish how voltage-sensitive ion channels sense changes in the electric field across the membrane, an issue that has been a matter of extensive study and intense debate for decades. The most widely accepted mechanism proposes the existence of voltage-sensor domains (VSDs), modules that undergo two or more discrete conformational states in response to changes in the membrane voltage. The simplest model considers two states: active (), which promotes pore opening, and resting (), which promotes channel closing. To accomplish its function, VSDs contain voltage-sensitive particles, which move in response to changes in the electric field. This movement triggers the interconversion between the two discrete conformational states. These voltage-sensing particles are typically the guanidine groups of arginine residues within the S4 transmembrane segment, which undergo a combination of rotational, translational, and tilting movement in response to changes in membrane voltage (7–14).The large-conductance Ca2+- and voltage-activated K+ (BK) channels have a wide distribution in mammalian tissues (15–18), where they participate in a diversity of physiological processes. Their malfunction is often related to diverse pathological conditions (19, 20). BK channel open probability is independently regulated by membrane depolarization and intracellular Ca2+ concentration (21, 22), each stimulus being detected by specialized modules. Like other voltage-sensitive K+ (Kv) channels, BK is an homotetramer in which each of its subunits consists of a pore domain (PD; S5-S6 transmembrane segments), a voltage-sensing domain (VSD; S1–S4 transmembrane segments) containing a positively charged S4, and a cytosolic C-terminal regulatory domain, which contains the Ca2+-binding sites (23, 24). Also, like some members of other K+ channel families (25, 26), the VSD and PD of BK are non–domain swapped (23, 24). BK channels display some distinctive structural and functional features: Despite sharing the selectivity filter sequence with Kv channels, BK unitary conductance and selectivity are exquisitely high (27–30). The BK subunit has an additional transmembrane segment S0 [therefore, its N terminus faces the extracellular medium (31)], and the voltage sensitivity in BK channels is significantly lower than that of Kv channels, presumably because of their lower number of gating charges (32).Although thoroughly studied, research into BK VSD and its voltage dependence has faced several technical obstacles. The relatively small gating charge per channel (32) and the large conductance of the BK pore makes isolating of the gating currents from the ionic currents a tough experimental challenge. In addition, because mutations of VSD residues can produce very large shifts in both the gating charge-voltage ( and the conductance-voltage relationships (33), it is necessary to use extreme voltages to accurately measure the voltage dependence of some mutants. Consequently, the identification of BK gating charges has been addressed by using indirect approaches (33, 34). The combination of electrophysiology measurements and kinetic modeling suggests a decentralized VSD in the BK channel, where four charged residues (D153 and R167 in S2, D186 in S3, and R213 in S4) act as voltage sensor particles (33). A recent report of the atomistic cryo-electron microscopy (cryo-EM) structures of the human BK channel and its homolog in Aplysia californica (AcSlo) revealed minor structural differences between the VSD in both the Ca2+-bound (open pore) and the Ca2+-unbound (closed pore) conformations (23, 24, 35). This result can be explained if the conformational changes of the BK VSD upon activation are small compared to those that occur during the activation of other channels, such as HCN channels (12–14).In this study, we identified voltage-sensing particles in the BK channel by using a direct functional approach, involving gating of current measurements and analysis of the curves spanning 800 mV in the voltage axis. Systematic neutralization of the individual charged residues in the VSD (S1–S4) revealed that only the neutralization of two arginines in S4 (R210 and R213) changed the voltage dependence of the curves. Neutralization of other VSD charges point to roles in tuning of the half-activation voltage of the VSD and its allosteric coupling with the PD. Molecular dynamics (MD) simulations based on the cryo-EM structures of the human BK channel (35) as templates suggested that R210 and R213 lie in a very narrow septum separating intra- and extracellular water-filled vestibules. This interpretation is consistent with the robust hyperpolarization-activated proton currents generated when R210 is mutated to the protonable amino acid histidine. Overall, our results point to a unique and distinctive mode of activation in BK: In contrast to Kv channels, where positive charges move one by one through a charge transfer center (absent in BK channels) that spans the entire electric field (36, 37), charge movement in BK channels is limited to the small displacement of R210 and R213, which itself constitutes a narrow septum where the electric field drops. 相似文献
28.
Dozent Dr. med. habil. Willy Maassen 《Medical microbiology and immunology》1948,128(1-2):148-151
Ohne Zusammenfassung 相似文献
29.
Dozent Dr. med. habil. Willy Maassen 《Medical microbiology and immunology》1948,127(6-8):630-634
Zusammenfassung Es wird über unspezifische Luesreaktionen, die bei 285 Rindern 219 Pferden, 25 Hammeln und 34 Schweinen angestellt wurden, berichtet. Ausgeführt wurde die Citocholreaktion, die M.K.R. II und die Trockenblutreaktion nachChediak (T.B.R.) nach der vonDahr angegebenen Technik. Die Citocholreaktion war bei fast allen Rindern und allen Kälbern positiv oder stark positiv. Bis auf die Blutproben von 52 Fohlen, bei denen sie sich nur dreimal positiv oder stark positiv erwies, reagierte sie in den übrigen Seren bis zur Hälfte der Fälle positiv oder stark positiv. Bei den untersuchten Tierarten fiel die M.K.R. II höchstens bei einem Viertel positiv oder stark positiv aus, während die T.B.R. nur vereinzelt positive oder stark positive Ergebnisse zeigte.Die andersartige Ernährung der Rinder im Sommer und im Winter hat keinen Einfluß auf den Ausfall der Reaktionen bei diesen Tieren.Akute Infektionskrankheiten sind wahrscheinlich nicht für den positiven Ausfall der serologischen Luesreaktionen bei Pferden verantwortlich zu machen. Vermutlich spielen erscheinungsfreie, chronisch einwirkende Reize eine Rolle. 相似文献
30.