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1.
The properties of [3H]dihydropyridine (DHP), nitrendipine and (+)-PN 200-110, binding to rat cerebral membranes were investigated. In normotensive Wistar-Kyoto (WKY) adult rats, the highest densities of [3H]DHP binding sites were found in the hippocampus. Frontal cerebral cortex and hypothalamus had intermediate levels and no specific binding of [3H]DHP and [125I]iodipine could be detected in the brainstem membranes and more precisely in the nucleus tractus solitarius and in the locus coeruleus. Changes in the maximal number of DHP binding sites (Bmax) were observed in spontaneously hypertensive rats (SHR) and in old Sprague-Dawley rats. In adult SHR, there was a significant increase in theBmax values of [3H](+)-PN 200-110 binding in the hippocampus when compared to the values obtained in WKY. There was no difference in theBmax values between young (3 weeks) prehypertensive SHR and age-matched WKY. In senescent (26 months) Sprague-Dawley rats, theBmax values of [3H](+)-PN 200-110 binding were significantly reduced (30%) in the frontal cerebral cortex and the hippocampus, as compared with the number of DHP binding sites found in mature Sprague-Dawley rats (15 weeks). 相似文献
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大量的研究证实多种人类实体肿瘤中存在着PIK3CA突变.PIK3CA是一种致癌基因,在肿瘤细胞中,其激酶活性增强,能持续刺激下游AKT,增加细胞侵袭和转移能力,因此在肿瘤的发生发展中起着至关重要的作用,同时对于临床诊断、治疗及预后有着重要意义.抑制PIK3CA突变将是一种新兴的分子靶向肿瘤治疗手段. 相似文献
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Huang Tien L. Székács András Uematsu Tamon Kuwano Eiichi Parkinson Andrew Hammock Bruce D. 《Pharmaceutical research》1993,10(5):639-648
Thirty carbonates, thiocarbonates, carbamates, and carboxylic esters of 110x57/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-naphthol, 110x57/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-naphthol, and p-nitrophenol were synthesized and tested as substrates for liver carboxylesterases from the crude microsomal fractions of human and mouse, and purified isozymes, hydrolases A and B, from rat liver microsomes. The carbonates, thiocarbonates, and carboxylic esters of 110x57/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-naphthol were cleaved more rapidly than the corresponding 110x57/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-naphthol isomers by the mammalian liver esterases. 110x57/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-Naphthyl esters of acetic, propionic, and butyric acids were among the best substrates tested for these enzymes. The majority of the substrates was consistently hydrolyzed at higher rates by hydrolase B compared with hydrolase A, although the Michaelis–Menten constant (K
m) values of selected substrates differed widely with these two isozymes. Malathion was a 15-fold better substrate for hydrolase B than for hydrolase A. Compared with the corresponding carboxylates, the carbonate moiety of 110x57/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">- and 110x57/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-naphthol and p-nitrophenol lowered the specific activities of the enzymes by about fivefold but improved stability under basic conditions. The optimum pH of mouse liver esterase with the acetate, methylcarbonate, and ethylthiocarbonate of 110x57/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-naphthol was between pH 7.0 and pH 7.6. Human and mouse liver microsomal esterase activities were about five orders of magnitude lower than the esterase activities of purified rat liver hydrolase B. A relationship between the catalytic activity of the enzymes and the lipophilicity of the naphthyl substrates indicated that (i) in the 110x57/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">- and 110x57/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-naphthyl carbonate series, an inverse relationship between enzyme activity and lipophilicity of the substrates was observed, whereas (ii) in the 110x57/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-naphthyl carboxylate series, an increase in enzyme activity with increasing lipophilicity of the substrates up to a log P value of about 4.0 was observed, after which the enzyme activity decreased. 相似文献
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STUDY OBJECTIVES: Despite the success of specialist cough clinics, there is increasing recognition of a subgroup of chronic coughers in whom a diagnosis cannot be made even after thorough, systematic investigation. We call this condition chronic idiopathic cough (CIC). The aim of this study is to compare the clinical characteristics of CIC patients with those of coughers in whom a diagnosis has been established (non-CIC) to see if there is a recognizable clinical pattern that distinguishes CIC from non-CIC. DESIGN: Retrospective analysis of the medical records of chronic cough patients. SETTING: The Royal Brompton Hospital Chronic Cough Clinic, London. PATIENTS: One hundred patients with chronic cough referred to the Royal Brompton Hospital Cough Clinic between October 2000 and February 2004. RESULTS: Seventy-one percent of all patients were female. Median age was 57 years (range, 19 to 81 years), with a median duration of symptoms of 48 months (range, 2 to 384 months). The primary diagnoses were CIC (42%), postnasal drip syndromes (22%), gastroesophageal reflux disease (16%), asthma (7%), and others (13%). In CIC patients, the median age at referral, age at onset of cough, and proportion of females did not differ significantly from non-CIC patients. CIC patients had a longer median duration of cough (72 months vs 24 months, p = 0.002), were more likely to report an upper respiratory tract infection (URTI) as the initial trigger of their cough (48% vs 24%, p = 0.0014), and had a significantly lower cough threshold in response to capsaicin (log concentration of capsaicin required to induce five or more coughs, - 0.009 vs 0.592, p = 0.032) than non-CIC patients. CONCLUSIONS: Patients with CIC commonly describe a URTI that initiates their cough, which then lasts for many years, and they demonstrate an exquisitely sensitive cough reflex. We believe that CIC may be a distinct clinical entity with an as-yet unidentified underlying pathology. 相似文献
9.
Ofir Moreno Todd Butler Vanessa Zann Ashley Willson Pui Leung Alyson Connor 《Clinical therapeutics》2018,40(11):1855-1867
Purpose
ME-401 is a novel selective inhibitor of phosphatidylinositol 3 kinase p110δ, an enzyme often found overexpressed and overactive in B-cell malignancies. The current study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses of ME-401 in healthy volunteers.Methods
This analysis was an open-label, nonrandomized study in healthy male volunteers. Three sequential groups were dosed. Each group received single doses of ME-401 on two occasions; the doses tested ranged from 10 to 150 mg. Blood was drawn at various time points to analyze plasma concentrations of ME-401 and inhibition of basophil activation, a marker of phosphatidylinositol 3 kinase p110δ inhibition.Findings
Fifteen subjects received a single dose of ME-401 on two occasions. Three adverse events that were considered possibly related to the study drug were reported: one event of pain, one event of headache, and one event of upper abdominal pain. ME-401 exhibited dose proportionality up to 60 mg, and supra-proportional increases in exposure were observed above doses of 60 mg. In addition, there was a dose-proportional increase in the inhibition of basophil activation up to 60 mg. Mean t1/2 ranged from 9.36 to 29.23 hours across the dose range. A 60 mg dose of ME-401 approached 90% inhibition of basophil activation, and thereafter no further increase to the percent inhibition of basophil activation was observed for higher doses. Once-daily dosing of 60 mg ME-401 was forecasted to result in trough plasma levels exceeding the concentration needed for 90% inhibition of basophil activation.Implications
This first-in-human study showed that ME-401 was well tolerated after single doses up to 150 mg. Pharmacologic activity was confirmed after administration of single ascending oral doses of 10 to 150 mg. ME-401 60 mg, administered once daily, was selected as the starting dose for patient studies. ClinicalTrials.gov identifier: NCT02521389. 相似文献10.
HSP60 overexpression increases the protein levels of the p110α subunit of phosphoinositide 3‐kinase and c‐Myc 下载免费PDF全文
Feng‐Qin Yan Jian‐Qiu Wang Ya‐Ping Tsai Kou‐Juey Wu 《Clinical and experimental pharmacology & physiology》2015,42(10):1092-1097
Heat shock protein 60 (HSP60) is a chaperone protein which plays an essential role in facilitating the folding of many newly synthesized proteins to reach their native forms. Increased HSP60 expression is observed in various types of human cancers. However, proteins induced by HSP60 to mediate transformation remain largely unknown. Here we show that HSP60 overexpression increases the protein levels of the p110α subunit of phosphoinositide 3‐kinase (PI3K). The amino acid domain 288‐383 of HSP60 is used to increase the protein levels. Overexpression of HSP60 also induces the levels of phosphorylated Akt. In addition, the amino acid domain 288‐383 of HSP60 is used to induce c‐Myc expression. Finally, a mono‐ubiquitinated form of β‐catenin has a higher activity to activate β‐catenin downstream targets compared to wild‐type β‐catenin. These results indicate that HSP60 overexpression induces the levels or activity of multiple oncogenic proteins to mediate transformation. 相似文献