全文获取类型
收费全文 | 2668篇 |
免费 | 208篇 |
国内免费 | 96篇 |
专业分类
耳鼻咽喉 | 7篇 |
儿科学 | 14篇 |
妇产科学 | 15篇 |
基础医学 | 634篇 |
口腔科学 | 15篇 |
临床医学 | 84篇 |
内科学 | 533篇 |
皮肤病学 | 38篇 |
神经病学 | 551篇 |
特种医学 | 22篇 |
外国民族医学 | 1篇 |
外科学 | 96篇 |
综合类 | 207篇 |
现状与发展 | 1篇 |
预防医学 | 32篇 |
眼科学 | 40篇 |
药学 | 386篇 |
中国医学 | 37篇 |
肿瘤学 | 259篇 |
出版年
2023年 | 31篇 |
2022年 | 22篇 |
2021年 | 67篇 |
2020年 | 61篇 |
2019年 | 50篇 |
2018年 | 40篇 |
2017年 | 66篇 |
2016年 | 81篇 |
2015年 | 133篇 |
2014年 | 142篇 |
2013年 | 186篇 |
2012年 | 123篇 |
2011年 | 122篇 |
2010年 | 117篇 |
2009年 | 160篇 |
2008年 | 177篇 |
2007年 | 150篇 |
2006年 | 107篇 |
2005年 | 110篇 |
2004年 | 113篇 |
2003年 | 79篇 |
2002年 | 76篇 |
2001年 | 51篇 |
2000年 | 54篇 |
1999年 | 71篇 |
1998年 | 46篇 |
1997年 | 50篇 |
1996年 | 44篇 |
1995年 | 48篇 |
1994年 | 47篇 |
1993年 | 36篇 |
1992年 | 32篇 |
1991年 | 27篇 |
1990年 | 25篇 |
1989年 | 20篇 |
1988年 | 9篇 |
1987年 | 13篇 |
1986年 | 27篇 |
1985年 | 26篇 |
1984年 | 29篇 |
1983年 | 21篇 |
1982年 | 15篇 |
1981年 | 13篇 |
1980年 | 8篇 |
1979年 | 7篇 |
1978年 | 12篇 |
1977年 | 8篇 |
1976年 | 9篇 |
1975年 | 4篇 |
1974年 | 4篇 |
排序方式: 共有2972条查询结果,搜索用时 18 毫秒
1.
2.
《Clinical Lymphoma, Myeloma & Leukemia》2020,20(4):226-233.e1
BackgroundMidostaurin, a multikinase inhibitor, is approved for treatment of FLT3-mutant acute myeloid leukemia (AML). A phase I study established that midostaurin 75 mg orally twice daily for 14 days with standard dose azacitidine was safe and tolerable in elderly patients with AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients with AML.Patients and MethodsPrimary objectives were to further describe the toxicity profile and determine the response rate in untreated patients with AML. Patients received midostaurin 75 mg orally twice daily on days 8 to 21 in combination with intravenous azacitidine at 75 mg/m2 on days 1 to 7. Plasma inhibitory activity assay for FLT3 was performed pretreatment and on day 8 and day 15 of each cycle.ResultsTwenty-six patients (median age, 74 years; range, 59-85 years) with FLT3 wild-type AML were accrued. Patients received a median of 2 cycles of therapy (range, 1-10 cycles). Seven (29%) of 24 evaluable patients achieved a clinical response (4 complete response; 1 complete response with incomplete count recovery; and 2 partial response). The median overall survival was 244 days (95% confidence interval, 203-467 days). Hematologic, infectious, and gastrointestinal toxicities were comparable to similar studies. Peripheral blood FLT3 wild-type phosphorylation declined to 8% to 55% of pretreatment by day 15 of cycle 1 (7 patients) and declined with subsequent cycles (< 10% baseline) in 2 patients who were analyzed after cycle 3.ConclusionMultiple cycles of azacitidine and midostaurin were not well-tolerated, but persistent inhibition of FLT3 wild-type phosphorylation suggest intermittent dosing of midostaurin should be considered in future low-intensity regimens for FLT3-mutant AML. 相似文献
3.
John F. Allen 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(33):10231-10238
Chloroplasts and mitochondria are subcellular bioenergetic organelles with their own genomes and genetic systems. DNA replication and transmission to daughter organelles produces cytoplasmic inheritance of characters associated with primary events in photosynthesis and respiration. The prokaryotic ancestors of chloroplasts and mitochondria were endosymbionts whose genes became copied to the genomes of their cellular hosts. These copies gave rise to nuclear chromosomal genes that encode cytosolic proteins and precursor proteins that are synthesized in the cytosol for import into the organelle into which the endosymbiont evolved. What accounts for the retention of genes for the complete synthesis within chloroplasts and mitochondria of a tiny minority of their protein subunits? One hypothesis is that expression of genes for protein subunits of energy-transducing enzymes must respond to physical environmental change by means of a direct and unconditional regulatory control—control exerted by change in the redox state of the corresponding gene product. This hypothesis proposes that, to preserve function, an entire redox regulatory system has to be retained within its original membrane-bound compartment. Colocation of gene and gene product for redox regulation of gene expression (CoRR) is a hypothesis in agreement with the results of a variety of experiments designed to test it and which seem to have no other satisfactory explanation. Here, I review evidence relating to CoRR and discuss its development, conclusions, and implications. This overview also identifies predictions concerning the results of experiments that may yet prove the hypothesis to be incorrect. 相似文献
4.
目的 探讨负荷渐增式训练对老年小鼠骨骼肌卫星细胞腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)磷酸化的影响。方法 实验小鼠分为 3 组:青年对照组(YC组,n=12)、老年对照组(OC组,n=12)与老年运动组(OT组,n=12)。OT组进行负荷渐增式训练,流式细胞分选技术分离CD45-/CD31-/Sca1-/VCAM(CD106)+细胞群体,分选细胞通过desmin、Myod肌原性染色以及成肌分化诱导培养进行肌卫星细胞鉴定,免疫组化结合Western blotting方法检测肌卫星细胞p-AMPK水平。结果 YC组骨骼肌卫星细胞AMPK及p-AMPK表达水平显著高于OC组(P<0.05);OT组与OC组AMPK表达无明显变化(P>0.05),而OT组p-AMPK表达水平显著高于OC组(P<0.05)。结论 负荷渐增式训练可促进老年小鼠骨骼肌卫星细胞AMPK磷酸化,改善老年小鼠骨骼肌能量代谢。 相似文献
5.
6.
Stefan S du Plessis Ashok Agarwal Gayatri Mohanty Michelle van der Linde 《Asian journal of andrology》2015,17(2):230-235
Spermatozoa are highly specialized cells. Adenosine triphosphate (ATP), which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation (OXPHOS). It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy production in human spermatozoa during fertilization. 相似文献
7.
Insulin/IGF-1 signaling involves phosphorylation/dephosphorylation of serine/threonine or tyrosine residues of the insulin receptor substrate (IRS) proteins and is associated with hormonal control of longevity determination of certain long-lived mice. The stimulation of serine phosphorylations by IGF-1 suggests there is insulin/IGF-1 crosstalk that involves the phosphorylation of the same serine residues. By this mechanism, insulin and IGF-1 mediated phosphorylation of specific IRS-1 serines could play a role in longevity determination.We used fibroblasts from WT and Ames dwarf mice to examine whether: (a) IGF-1 stimulates phosphorylation of IRS-1 serines targeted by insulin; (b) the levels of serine phosphorylation differ in WT vs. Ames fibroblasts; and (c) aging affects the levels of these serine phosphorylations which are altered in the Ames dwarf mutant. We have shown that IRS-1 is a substrate for IGF-1 induced phosphorylation of Ser307, Ser612, Ser636/639, and Ser1101; that the levels of phosphorylation of these serines are significantly lower in Ames vs. WT cells; that IGF-1 mediated phosphorylation of these serines increases with age in WT cells. We propose that insulin/IGF-1 cross talk and level of phosphorylation of specific IRS-1 serines may promote the Ames dwarf longevity phenotype. 相似文献
8.
Baicalein increases keratin 1 and 10 expression in HaCaT keratinocytes via TRPV4 receptor activation 下载免费PDF全文
In this study, we characterized the effect of baicalein on the regulation of keratinocyte differentiation and proliferation, which are abnormal in atopic dermatitis or psoriasis. Treatment of HaCaT keratinocytes with 10 μm baicalein slightly inhibited cell growth, caused morphological differentiation and increased expression of keratins 1 and 10 (K1/K10) without affecting ROS generation, cytochrome c release or apoptosis. Baicalein treatment caused growth arrest in G0/G1 phase and also induced Ca2+ influx via TRPV4 receptor activation. Phosphorylation of ERK, Akt and p38 MAPK, but not JNK, was increased by baicalein, and inhibition of phosphorylation of ERK, but not that of Akt or p38 MAPK, blocked the baicalein‐induced increase in K1/K10 expression, suggesting that ERK activation is involved in this increase. Removal of extracellular Ca2+ or blockade of Ca2+ influx by pharmacological inhibition or silencing of the TRPV4 receptor did not affect growth arrest, ROS generation or apoptosis, but inhibited baicalein‐induced ERK phosphorylation and K1/K10 expression. Thus, baicalein treatment increases differentiation, and decreases proliferation, of keratinocytes. The mechanism of differentiation of keratinocytes is distinct from that of proliferation, the former being Ca2+ dependent and the latter Ca2+ independent. 相似文献
9.
目的:观察中药木鳖子不同提取部位体内体外的抗肿瘤作用,并考察其中抗肿瘤效果显著的木鳖子乙酸乙酯提取部位的抗肿瘤作用机制。方法:采用索氏提取技术将中药木鳖子按照溶剂极性顺序依次提取,得到不同成分,采用细胞增殖实验结合动物抗肿瘤模型方法进行药效评价,运用现代分子生物学技术阐明其中最优部位可能的抗肿瘤作用机制。结果:中药木鳖子乙酸乙酯提取部位在体外和体内实验中均可表现出明显的抑制肿瘤生长能力(P0.05),且对实验动物无明显的毒副作用,本研究首次发现木鳖子乙酸乙酯提取部位可影响表皮生长因子(EGFR)激酶活性(P0.05),并可明显抑制EGFR蛋白磷酸化表达(P0.05),可明显抑制丝裂原活化蛋白激酶家族(mitogen activated protein kinase,MAPKs)通路上重要节点蛋白细胞外信号调节激酶(extracellular regulated protein kinases,ERK1/2),氨基末端激酶(C-Jun N-terminal kinase,JNK)和丝裂原激活蛋白激酶p38的磷酸化水平(P0.05),且具有浓度依赖关系。结论:中药木鳖子乙酸乙酯提取部位可通过抑制EGFR蛋白及相关通路蛋白活性,在体内外实验中显著抑制肿瘤的生长。 相似文献
10.
目的:研究氧化苦参碱(OMT)对醛固酮(ALD)诱导心肌细胞损伤的改善作用及其作用机制。方法:采用胰酶消化法和差速贴壁法分离和纯化新生大鼠心肌细胞进行培养,采用1×10~(-5)mol·L~(-1)ALD建立心肌细胞损伤模型。实验分为空白组,模型组(1×10~(-5)mol·L~(-1)ALD),ALD+OMT高浓度(3.78×10-4mol·L~(-1))组,ALD+OMT低浓度(1.89×10-4mol·L~(-1))组,ALD+JNK抑制剂(JNK I,5×10~(-6)mol·L~(-1))组,ALD+阿司匹林(Asp,1×10~(-5)mol·L~(-1))组,即OMT,JNK抑制剂和阿司匹林组先以相应药物预处理2 h后加入终浓度为1×10~(-5)mol·L~(-1)的ALD共同孵育24 h。二甲基噻唑蓝(MTT)法检测细胞存活率,Giemsa染色观察心肌细胞形态学变化情况。蛋白免疫印迹法(Western blot)及实时荧光定量PCR(Real-time PCR)分析OMT对ALD诱导JNK蛋白表达水平,JNK磷酸化(p-JNK)水平及mRNA表达的影响。结果:与空白组比较,ALD可显著降低心肌细胞存活率(P0.01)并改变细胞形态,OMT可显著改善醛固酮诱导的心肌细胞存活率降低(P0.01)并使细胞恢复至正常形态;Western blot结果显示ALD可诱导JNK蛋白磷酸化水平升高(P0.01),而OMT可显著抑制ALD诱导的p-JNK表达增加(P0.01);Real-time PCR结果显示,与空白组比较,ALD可诱导JNK mRNA表达增加(P0.01),使用OMT进行预保护后,各组基因表达均没有显著改变。结论:OMT对ALD诱导的心肌细胞损伤具有保护作用,其作用机制与抑制JNK蛋白磷酸化密切相关。 相似文献