全文获取类型
收费全文 | 245篇 |
免费 | 11篇 |
专业分类
耳鼻咽喉 | 1篇 |
儿科学 | 13篇 |
妇产科学 | 9篇 |
基础医学 | 26篇 |
口腔科学 | 6篇 |
临床医学 | 22篇 |
内科学 | 29篇 |
皮肤病学 | 8篇 |
神经病学 | 13篇 |
特种医学 | 69篇 |
外科学 | 13篇 |
综合类 | 8篇 |
预防医学 | 2篇 |
药学 | 28篇 |
中国医学 | 2篇 |
肿瘤学 | 7篇 |
出版年
2020年 | 1篇 |
2019年 | 2篇 |
2017年 | 2篇 |
2016年 | 4篇 |
2015年 | 2篇 |
2014年 | 3篇 |
2013年 | 12篇 |
2012年 | 7篇 |
2011年 | 3篇 |
2010年 | 14篇 |
2009年 | 15篇 |
2008年 | 1篇 |
2007年 | 5篇 |
2006年 | 10篇 |
2005年 | 5篇 |
2004年 | 1篇 |
2003年 | 3篇 |
2002年 | 2篇 |
2001年 | 2篇 |
2000年 | 7篇 |
1999年 | 10篇 |
1998年 | 16篇 |
1997年 | 13篇 |
1996年 | 11篇 |
1995年 | 9篇 |
1994年 | 6篇 |
1993年 | 7篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 7篇 |
1987年 | 8篇 |
1986年 | 6篇 |
1985年 | 9篇 |
1984年 | 4篇 |
1983年 | 5篇 |
1982年 | 4篇 |
1981年 | 7篇 |
1980年 | 10篇 |
1979年 | 1篇 |
1978年 | 2篇 |
1977年 | 6篇 |
1976年 | 5篇 |
1975年 | 2篇 |
1939年 | 1篇 |
排序方式: 共有256条查询结果,搜索用时 734 毫秒
111.
112.
Historically, the ability of a ligand to bind to its receptor and the ability to subsequently activate that receptor have been described as the properties of affinity and intrinsic efficacy, respectively. These properties were originally believed to be independent of one another; both are possessed by ligands classed as "agonists," and they have served as the quantitative foundation of the drug and receptor classification process. Although affinity has been interpreted readily in physicochemical terms, equivalent molecular models for efficacy remain elusive. In recent times, there has been a significant paradigm shift in our understanding of the interrelationship between affinity and intrinsic efficacy, particularly on theoretical grounds, yet the actual methods available to measure these parameters remain largely operational. Nevertheless, a number of approaches, based on both functional measurements and radioligand binding studies, are available to quantify agonist efficacy on a relative scale and, to date, these remain the most practical. This commentary discusses the most common of these methods, their advantages and limitations, the dependence of the expression of agonism on the chosen assay system, and the impact of recent biochemical and molecular biological advances on the study of efficacy. Additionally, some of the more contemporary theories regarding the molecular nature of efficacy are briefly discussed, as well as the caveats that always must be borne in mind when any determinations of relative agonist efficacy are made. 相似文献
113.
The effect of Buthus occitanus venom on the isolated hearts appears to be mediated largely through stimulation of the autonomic nervous system with predominance of sympathetic stimulation and release of tissue catecholamines, although a direct cardiac stimulant action was also found. The injection of the venom into rabbits caused initial short lasting bradycardia followed by tachycardia then a prolonged bradycardia. The initial bradycardia was due to the cholinergic effect of the venom, the tachycardia to sympathetic stimulation and release of tissue catecholamines, while the delayed bradycardia seemed due to changes in the ionic composition of blood; notably hyperkalemia and hypocalcemia. The most striking electrocardiographic effects of the venom seemed related to inferior wall infarction and right bundle branch block. The former was evidenced from elevation of the ST segment in II, III and AVF and its depression in I, aVR, aVL and V1. The latter was revealed from the RSR′ pattern in V1. The wide S wave in I and V5, the prolonged QRS complex, the ST depression in V1 and the wide rSr′ complex in aVR. Some of the electrocardiographic wave abnormalities appeared to be mediated through hyperkalemia as shown from the tall, peaked and slender T wave and the wide QRS complex. The sympathetic stimulation and release of tissue catecholamines caused by the venom mask, while vagal stimulation potentiates, the effects due to electrolyte changes. The venom decreased the respiration rate but caused an increase in depth. The effect was greatly attenuated by carotid sinus and body denervation. The venom caused marked hypertension in cats, rats and guinea pigs. In cats blocking the alpha adrenergic receptors with phenoxybenzamine reversed the hypertensive effect of the venom to a hypotensive action that was blocked by propranolol. B. occitanus venom is unique among scorpion venoms in stimulating β-adrenergic receptors of the vascular system. 相似文献
114.
115.
Xanomeline is a functionally selective M(1)/M(4) muscarinic acetylcholine receptor agonist that nevertheless binds with high affinity to all five subtypes of muscarinic receptors. A novel mode of interaction of this ligand with the muscarinic M(1) receptors characterized by persistent binding and receptor activation after extensive washout has been shown previously. In the present study, using human M(1) and M(2) receptors expressed in Chinese hamster ovary cells and [(3)H]N-methylscopolamine as a tracer, we show that persistent binding of xanomeline also occurs at the M(2) receptor with similar affinity as at the M(1) receptor (K(I) = 294 and 296 nM, respectively). However, kinetics of formation of xanomeline wash-resistant binding to M(2) receptors was markedly slower than to M(1) receptors. Xanomeline was a potent fast-acting full agonist in stimulating guanosine 5'-O-(3-[(35)S]thio)triphosphate binding at M(1) receptors, whereas at M(2) receptors it behaved as a potent partial agonist (40% of carbachol maximal response) only upon preincubation for 1 h. Development of xanomeline agonistic effects at the M(2) receptor was slower than its ability to attenuate carbachol responses. We also demonstrate that xanomeline discriminates better between G protein subtypes at M(1) than at M(2) receptors. Our data support the notion that xanomeline interacts with multiple sites on the muscarinic receptor, resulting in divergent conformations that exhibit differential effects on ligand binding and receptor activation. These conformations are both time- and concentration-dependent and vary between the M(1) and the M(2) receptor. 相似文献
116.
Francis MJ; Jones EE; Levy ER; Ponnambalam S; Chelly J; Monaco AP 《Human molecular genetics》1998,7(8):1245-1252
Menkes disease arises from a genetic impairment in copper transport. The
gene responsible for the phenotype has been identified as a copper
transporting ATPase ( ATP7A ). Recently, the protein encoded by the ATP7A
gene has been localized to the Golgi complex. In order to investigate the
role of the Menkes disease protein in copper transport, recombinant
constructs containing both the full-length open reading frame and an
alternatively spliced form have been successfully expressed and localized
in mammalian cells. Other studies of a patient with occipital horn
syndrome, an allelic variant of Menkes disease, have demonstrated that only
this alternatively spliced isoform and not the full-length form is
expressed in this patient. The milder form of this patient's phenotype
suggests that the alternatively spliced isoform has some functional role in
copper transport. In the present study the full-length recombinant Menkes
protein was shown by immunofluorescence to localize to the Golgi apparatus
and the alternatively spliced form, lacking sequences for transmembrane
domains 3 and 4 encoded by exon 10, was shown to localize to the
endoplasmic reticulum. Using sequences from exon 10 fused to a non-Golgi
reporter molecule, a 38 amino acid sequence containing transmembrane domain
3 of the Menkes protein was found to be sufficient for localization to the
Golgi complex. Therefore, the protein sequence encoded by exon 10 may be
responsible for this differential localization and both isoforms may be
required for comprehensive transport of copper within the cell.
相似文献
117.
Wanker EE; Rovira C; Scherzinger E; Hasenbank R; Walter S; Tait D; Colicelli J; Lehrach H 《Human molecular genetics》1997,6(3):487-495
We report the discovery of the huntingtin interacting protein I (HIP-I)
which binds specifically to the N-terminus of human huntingtin, both in the
two-hybrid screen and in in vitro binding experiments. For the interaction
in vivo, a protein region downstream of the polyglutamine stretch in
huntingtin is essential. The HIP1 cDNA isolated by the two- hybrid screen
encodes a 55 kDa fragment of a novel protein. Using an affinity-purified
polyclonal antibody raised against recombinant HIP-I, a protein of 116 kDa
was detected in brain extracts by Western blot analysis. The predicted
amino acid sequence of the HIP-I fragment exhibits significant similarity
to cytoskeleton proteins, suggesting that HIP-I and huntingtin play a
functional role in the cell filament networks. The HIP1 gene is
ubiquitously expressed in different brain regions at low level. HIP-I is
enriched in human brain but can also be detected in other human tissues as
well as in mouse brain. HIP-I and huntingtin behave almost identically
during subcellular fractionation and both proteins are enriched in the
membrane containing fractions.
相似文献
118.
119.
Duplication of a gene-rich cluster between 16p11.1 and Xq28: a novel pericentromeric-directed mechanism for paralogous genome evolution 总被引:15,自引:6,他引:15
120.
Bardet–Biedl syndrome (BBS) is a rare pediatric ciliopathy characterized by marked clinical variability and extensive genetic heterogeneity. Typical diagnosis of BBS is secured at a median of 9 years of age, and sometimes well into adolescence. Here, we report a patient in whom prenatal detection of increased nuchal fold, enlarged echogenic kidneys, and polydactyly prompted us to screen the most commonly mutated genes in BBS and the phenotypically and genetically overlapping ciliopathy, Meckel–Gruber syndrome (MKS). We identified the common Met390Arg mutation in BBS1 in compound heterozygosity with a novel intronic variant of unknown significance (VUS). Testing of mRNA harvested from primary foreskin fibroblasts obtained shortly after birth revealed the VUS to induce a cryptic splice site, which in turn led to a premature termination and mRNA degradation. To our knowledge, this is the earliest diagnosis of BBS in the absence of other affected individuals in the family, and exemplifies how combining clinical assessment with genetic and timely assays of variant pathogenicity can inform clinical diagnosis and assist with patient management in the prenatal and neonatal setting. 相似文献