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951.
Wei Xie Hade Wulin Guo Shao Liqin Wei Ruifang Qi Baohui Ma Naihong Chen Ruili Shi 《Basic & clinical pharmacology & toxicology》2020,127(3):196-204
Cerebral ischaemia is a common cerebrovascular disease and often induces neuronal apoptosis, leading to brain damage. Polygalasaponin F (PGSF) is one of the components in Polygala japonica Houtt, and it is a triterpenoid saponin monomer. This research focused on anti‐apoptotic effect of PGSF during oxygen‐glucose deprivation and reoxygenation (OGD/R) injury in rat adrenal pheochromocytoma cells (PC12) and primary rat cortical neurons. OGD/R treatment reduced viability of PC12 cells and primary neurons. This reduced viability was prevented by PGSF, as shown by MTT assay. OGD/R insult decreased expression of Bcl‐2/Bax both in PC12 cells and primary neurons but elevated levels of caspase‐3 in primary neurons. However, PGSF may up‐regulate expression of Bcl‐2/Bax and down‐regulate caspase‐3 in these particular cells. Furthermore, Bcl‐2/Bax and the ratio between phosphorylated Akt and total Akt were decreased in PC12 cells treated with OGD/R, and both were increased by PGSF. Moreover, increase in the ratios of Bcl‐2/Bax and phosphorylated Akt/total Akt in PC12 cells was suppressed by phosphatidylinositol 3‐kinase (PI3K) inhibitor. Data suggest PGSF might prevent OGD/R‐induced injury via activation of PI3K/Akt signalling. The ability of PGSF to block the effects of OGD/R appears to involve regulation of Bcl‐2, Bax and caspase‐3, which are related to apoptosis. 相似文献
952.
Ramsay E. Beveridge Heidi Ackerly Wallweber Avi Ashkenazi Maureen Beresini Kevin R. Clark Paul Gibbons Elise Ghiro Susan Kaufman Alexandre Larive Melissa Leblanc Jean-Philippe Leclerc Alexandre Lemire Cuong Ly Joachim Rudolph Jacob B. Schwarz Sanjay Srivastava Weiru Wang Liang Zhao Marie-Gabrielle Braun 《ACS medicinal chemistry letters》2020,11(12):2389
Amino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity. 相似文献
953.
Xiaohan Zhou Kun Shi Ying Hao Chengli Yang Ruoyu Zha Cheng Yi Zhiyong Qian 《Asian Journal of Pharmaceutical Sciences》2020,15(1):26-41
Oral tyrosine kinase inhibitors(TKIs) against epidermal growth factor receptor(EGFR) family have been introduced into the clinic to treat human malignancies for decades. Despite superior properties of EGFR-TKIs as small molecule targeted drugs, their applications are still restricted due to their low solubility, capricious oral bioavailability, large requirement of daily dose, high binding tendency to plasma albumin and initial/acquired drug resistance. Nanotechnology is a promising tool to improve efficacy of these drugs. Through non-oral routes. Various nanotechnology-based delivery approaches have been developed for providing efficient delivery of EGFR-TKIs with a better pharmacokinetic profile and tissue-targeting ability. This review aims to indicate the advantage of nanocarriers for EGFR-TKIs delivery. 相似文献
954.
目的探讨循环miR-1-3p在多柔比星诱导食蟹猴心肌损伤模型中的表达水平和诊断价值。方法选取3~5岁普通级雄性食蟹猴17只,随机分为对照组(7只)和实验组(10只),静脉注射盐酸多柔比星注射液(2.5 mg/kg)4周,收集外周血浆标本和心脏组织标本,应用液相芯片技术测定肌酸激酶同工酶(CK-MB)、肌钙蛋白I(cTnI)和NT-proBNP表达水平,且应用实时定量PCR技术测定miR-1-3p表达的水平,并进行相关性分析。结果成功建立药物致食蟹猴心肌损伤模型;两组CK-MB、cTnI和NT-proBNP水平比较差异有统计学意义(P<0.05);实验组miR-1-3p的表达水平在给药4周后较给药前和对照组相比明显升高(P<0.05);miR-1-3p的表达水平与CK-MB、cTnI和NT-proBNP改变呈现了相同的升高趋势,且二者之间具有明显相关性。结论miR-1-3p可作为药物引起心肌损伤的生物学诊断标志物之一。 相似文献
955.
目的探讨干扰素α2b给药途径治疗小儿病毒性肺炎的疗效及其对T淋巴细胞亚群与血清KL-6、ICAM-1、TNF-α的影响。方法选取我院2017年3月至2019年3月收治的92例病毒性肺炎患儿,随机分为雾化组与肌注组,每组46例。比较两组治疗1周后的总有效率,记录两组治疗前及治疗1 d、2 d、3 d、4 d、5 d、6 d、7 d后的临床症状总评分,比较两组治疗前与治疗7 d后的血清CD^+_3、CD^+_4、CD^+_8、CD^+_4/CD^+_8、KL-6、ICAM-1、TNF-α水平与不良反应。结果两组的整体疗效与总有效率比较差异无统计学意义(P>0.05)。两组治疗后的临床症状总评分均呈下降趋势,组内前后差异有统计学意义(P<0.05)。雾化组治疗4 d、5 d、6 d、7 d的临床症状总评分低于肌注组(P<0.05)。治疗7 d后,两组CD^+_3、CD^+_4和CD^+_4/CD^+_8升高,CD^+_8降低(P<0.05);雾化组治疗7 d后CD^+_3、CD^+_4和CD^+_4/CD^+_8高于肌注组,CD^+_8低于肌注组(P<0.05)。治疗7 d后,两组各项血清学指标均明显降低(P<0.05),雾化组治疗后的血清ICAM-1、TNF-α低于肌注组(P<0.05),两组KL-6比较差异无统计学意义(P>0.05)。结论干扰素α2b雾化吸入给药可取得与肌注给药相当的疗效,同时可加速患儿症状缓解,调节免疫,血清ICAM-1、TNF-α下降幅度大,安全性良好。 相似文献
956.
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959.
《Ultrastructural pathology》2013,37(4):160-164
ABSTRACTThe human pro-monocytic leukemia U937 cell line was previously reported to become ρ°cells after a long-term ethidium bromide exposure. In the authors' extensive PCR studies with different pairs of primers for the mtDNA molecule they showed that these U937-ρ° cells, after being cultured in their laboratory for a time, did replete their mtDNA. That the cells grew well in the normal medium (RPMI 1640 plus 10% fetal calf serum and 2 mM L-glutamine) as the parental cells also suggests that these cells contain functional mitochondria and mtDNA molecules. Further experiments showed that the cells cultured in the medium with pyruvate and uridine rather rapidly and strongly adhered on the culture flask walls while the cells cultured in the medium without pyruvate and uridine either floated or only very loosely covered the culture flask walls. Ultrastructural examination showed that the floating cells, which were often found in the culture without pyruvate and uridine, were rather similar to monocytes in nature, like the original U937 cells, while the attached larger cells appearing earlier in the culture with pyruvate and uridine demonstrated macrophage differentiation, indicating a differentiation effect of pyruvate and uridine on the cells. 相似文献
960.
Pietro Crivello Nina Lauterbach Laura Zito Federico Sizzano Cristina Toffalori Jessica Marcon Laura Curci Arend Mulder Lotte Wieten Elisabetta Zino Christien E.M. Voorter Marcel G.J. Tilanus Katharina Fleischhauer 《Human immunology》2013
The functional relevance of polymorphisms outside the peptide binding groove of HLA molecules is poorly understood. Here we have addressed this issue by studying HLA-DP3, a common antigen relevant for functional matching algorithms of unrelated hematopoietic stem cell transplantation (HSCT) encoded by two transmembrane (TM) region variants, DPB1*03:01 and DPB1*104:01. The two HLA-DP3 variants were found at a overall allelic frequency of 10.4% in 201 volunteer stem cell donors, at a ratio of 4.2:1. No significant differences were observed in cell surface expression levels of the two variants on B lymphoblastoid cell lines (BLCL), primary B cells or monocytes. Three different alloreactive T cell lines or clones showed similar levels of activation marker CD107a and/or CD137 upregulation in response to HLA-DP3 encoded by DPB1*03:01 and DPB1*104:01, either endogenously on BLCL or after lentiveral-vector mediated transfer into the same cellular background. These data provide, for the first time, direct evidence for a limited functional role of a TM region polymorphism on expression and allorecognition of HLA-DP3 and are compatible with the notion that the two variants can be considered as a single functional entity for unrelated stem cell donor selection. 相似文献