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排序方式: 共有170条查询结果,搜索用时 15 毫秒
71.
72.
Jain R Shaul PW Borok Z Willis BC 《American journal of respiratory cell and molecular biology》2007,37(1):38-47
Endothelin-1 (ET-1) is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), but the cellular mechanisms underlying the role it plays in this disease are not well characterized. Epithelial-mesenchymal transition (EMT), which was recently demonstrated in alveolar epithelial cells (AEC), may play an important role in the pathogenesis of IPF and other forms of pulmonary fibrosis. Whether ET-1 contributes to the induction of EMT in AEC is unknown. The aims of this study were to evaluate AEC production of ET-1 and to determine if ET-1 induces EMT in AEC. We demonstrate that ET-1 is produced at physiologically relevant levels by primary AEC and is secreted preferentially toward the basolateral surface. We also demonstrate that AEC express high levels of endothelin type A receptors (ET-A) and, to a lesser extent, type B receptors (ET-B), suggesting autocrine or paracrine function for alveolar ET-1. In addition, ET-1 induces EMT through ET-A activation. Furthermore, TGF-beta1 synthesis is increased by ET-1, ET-1 induces Smad3 phosphorylation, and ET-1-induced EMT is attenuated by a TGF-beta1-neutralizing antibody. Thus, ET-1 is an important mediator of EMT in AEC, acting through ET-A-mediated TGF-beta1 production. These findings increase our basic understanding of the role of ET-1 in pulmonary fibrosis and suggest potential roles for AEC-derived ET-1 in the pathogenesis of other alveolar epithelial-mediated lung diseases. 相似文献
73.
Li M Krishnaveni MS Li C Zhou B Xing Y Banfalvi A Li A Lombardi V Akbari O Borok Z Minoo P 《The Journal of clinical investigation》2011,121(1):277-287
Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments. Although the etiology of IPF is unknown, dysregulated TGF-β signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial TGF-β signaling via TGF-β receptor II (TβRII) and its contribution to fibrosis by generating mice in which TβRII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as TβRIINkx2.1-cre mice, were used to determine the impact of TβRII inactivation on (a) embryonic lung morphogenesis in vivo; and (b) the epithelial cell response to TGF-β signaling in vitro and in a bleomycin-induced, TGF-β-mediated mouse model of pulmonary fibrosis. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, TβRIINkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial TβRII in alveolar homeostasis. Absence of TβRII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic TGF-β. However, TβRIINkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced pulmonary fibrosis. To our knowledge, these findings are the first to demonstrate a specific role for TGF-β signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis. 相似文献
74.
Fujino T Leslie JH Eavri R Chen JL Lin WC Flanders GH Borok E Horvath TL Nedivi E 《Genes & development》2011,25(24):2674-2685
Use-dependent selection of optimal connections is a key feature of neural circuit development and, in the mature brain, underlies functional adaptation, such as is required for learning and memory. Activity patterns guide circuit refinement through selective stabilization or elimination of specific neuronal branches and synapses. The molecular signals that mediate activity-dependent synapse and arbor stabilization and maintenance remain elusive. We report that knockout of the activity-regulated gene cpg15 in mice delays developmental maturation of axonal and dendritic arbors visualized by anterograde tracing and diolistic labeling, respectively. Electrophysiology shows that synaptic maturation is also delayed, and electron microscopy confirms that many dendritic spines initially lack functional synaptic contacts. While circuits eventually develop, in vivo imaging reveals that spine maintenance is compromised in the adult, leading to a gradual attrition in spine numbers. Loss of cpg15 also results in poor learning. cpg15 knockout mice require more trails to learn, but once they learn, memories are retained. Our findings suggest that CPG15 acts to stabilize active synapses on dendritic spines, resulting in selective spine and arbor stabilization and synaptic maturation, and that synapse stabilization mediated by CPG15 is critical for efficient learning. 相似文献
75.
76.
Huse DM Song X Ozminkowski RJ Maguire J Williams SA Borok GM McDonough K 《Clinical therapeutics》2006,28(9):1425-1442
BACKGROUND: High blood cholesterol is a major modifiable risk factor for coronary heart disease (CHD) and stroke. OBJECTIVE: The aim of this study was to estimate the economic impact of rosuvastatin calcium use in patients at high risk for CHD and stroke, according to the National Cholesterol Education Program Adult Treatment Panel (ATP) III guidelines. METHODS: An economic simulation model was developed that used a Markov process to project the number of cardiovascular events and associated costs in a high-risk population in various treatment scenarios. According to the ATP III, high-risk patients are those with CHD, atherosclerosis of peripheral and/or cerebral arteries, diabetes, and/or multiple other risk factors conferring a risk of at least 20% within 10 years. Data on population characteristics and costs of cardiovascular disease (CVD) were obtained from claims data sets from employer-funded commercial and Medicare health plans in the United States. Treatment of lipid disorders was translated into CVD risk reduction based on results from the Heart Protection Study. The estimated efficacies of individual lipid-lowering drugs were based on data published in package inserts. The model generated costs at the health plan level of lipid-lowering therapy in high-risk patients and the number and total costs of cardiovascular events. Estimates were compared for scenarios representing the mix of treatments used before and after the introduction of rosuvastatin. Estimates were generated separately for commercial and Medicare health plans. RESULTS: For every 1 million members of a commercial health plan, an estimated 44,457 met ATP III criteria for high-risk status. Use of rosuvastatin in place of other 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") by 11 % of these patients over a period of 5 years was estimated to result in 36 fewer cardiovascular events and a net savings of US 4.03 million dollars. A Medicare plan of 1 million members with an estimated 433,268 high-risk patients and 7% rosuvastatin use was estimated to avoid 727 events and save US 34.32 million dollars. CONCLUSIONS: The results of this data analysis suggest that increasing the use of rosuvastatin can result in cardiovascular event reduction and cost savings. Because the impact of lipid-modifying therapy on cardiovascular risk has not been thoroughly documented in controlled clinical studies, our model assumed that incremental lipid changes had effects in proportion to the magnitude of change. 相似文献
77.
78.
目的:考察甲壳胺对不同性质药物的适应性。方法:选择了盐酸麻黄碱,盐酸心得安,卡马西平,磺胺嘧啶,阿司匹林,法莫替丁,朴热息痛,潘生丁,茶碱,炎痛喜康,水杨酸等不同性质的11种药物,以甲胺为阻滞剂,制备了缓释型骨架片溶出效果。结果:甲壳胺的缓释作用随药物碱性增强,分子量增大,溶解度降低而增强,结论:甲 胺对不同性质的药物均有一定缓释作用。 相似文献
79.
80.
Graczykowski JW; Francis MM; Paulson RJ; Sokol RZ 《Human reproduction (Oxford, England)》1998,13(3):670-675
The zona pellucida binding assay assesses the ability of spermatozoa to
bind to the zona pellucida. The present study investigated the influence
of: (i) prior oocyte exposure to spermatozoa on subsequent sperm-zona
pellucida binding in vitro; and (ii) cryopreservation of oocytes. Only
oocytes obtained from fertile donors were used and the binding capacity of
non-inseminated, cryopreserved oocytes was compared with both
inseminated/unfertilized, cryopreserved oocytes and
inseminated/unfertilized, non-cryopreserved oocytes recovered from in-
vitro fertilization cultures on sperm-zona pellucida binding using an
intact zona model. There was no statistically significant difference in
sperm-zona binding between non-inseminated, cryopreserved oocytes (range
9.6-23.2), inseminated/unfertilized, cryopreserved oocytes (range
15.0-16.0) and inseminated/ unfertilized, non-cryopreserved oocytes (range
3.3-23.0). The coefficient of variation for sperm binding to all oocyte
groups was very large (range 37-121%). We conclude that neither prior
exposure of human oocytes to human spermatozoa nor cryopreservation of
human oocytes influences the subsequent binding of a different population
of spermatozoa to the zona pellucida. However, large oocyte-to-oocyte
variation of sperm-zona binding may diminish the usefulness of this assay
in clinical practice and as a research tool.
相似文献