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991.
Zhenqian Hu Yan Xiong Xiaofan Han Chenyang Geng Beibei Jiang Yingqing Huo Jincai Luo 《PloS one》2013,8(8)
In the vasculature, physiological levels of nitric oxide (NO) protect against various stressors, including mechanical stretch. While endothelial NO production in response to various stimuli has been studied extensively, the precise mechanism underlying stretch-induced NO production in venous endothelial cells remains incompletely understood. Using a model of continuous cellular stretch, we found that stretch promoted phosphorylation of endothelial NO synthase (eNOS) at Ser1177, Ser633 and Ser615 and NO production in human umbilical vein endothelial cells. Although stretch activated the kinases AMPKα, PKA, Akt, and ERK1/2, stretch-induced eNOS activation was only inhibited by kinase-specific inhibitors of PKA and PI3K/Akt, but not of AMPKα and Erk1/2. Similar results were obtained with knockdown by shRNAs targeting the PKA and Akt genes. Furthermore, inhibition of PKA preferentially attenuated eNOS activation in the early phase, while inhibition of the PI3K/Akt pathway reduced eNOS activation in the late phase, suggesting that the PKA and PI3K/Akt pathways play distinct roles in a time-dependent manner. Finally, we investigated the role of these pathways in stretch-induced endothelial exocytosis and leukocyte adhesion. Interestingly, we found that inhibition of the PI3K/Akt pathway increased stretch-induced Weibel-Palade body exocytosis and leukocyte adhesion, while inhibition of the PKA pathway had the opposite effects, suggesting that the exocytosis-promoting effect of PKA overwhelms the inhibitory effect of PKA-mediated NO production. Taken together, the results suggest that PKA and Akt are important regulators of eNOS activation in venous endothelial cells under mechanical stretch, while playing different roles in the regulation of stretch-induced endothelial exocytosis and leukocyte adhesion. 相似文献
992.
Bingbing Wei You Zhou Zhuoqun Xu Jun Ruan Huan Cheng Ming Zhu Qiang Hu Ke Jin Zhiqiang Yan Deqi Zhou Feng Xuan Hongyi Zhou Zhirong Wang Xing Huang Qiang Wang 《PloS one》2013,8(8)
Background
Glutathione S-transferase P1 (GSTP1) is thought to be involved in the detoxification of reactive carcinogen metabolites. Numerous epidemiological studies have evaluated the association of GSTP1 Ile105Val polymorphism with the risk of prostate cancer. However, the results remain inconclusive. To derive a more precise estimation, a meta-analysis was performed.Methodology/Principal Findings
A comprehensive search was conducted to identify the eligible studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the relationship. The overall association was not significant (Val/Val vs. Ile/Ile OR = 1.06, 95% CI = 0.90–1.25, P = 0.50; Val/Val vs. Val/Ile+Ile/Ile: OR = 1.07, 95% CI = 0.91–1.25, P = 0.44). In subgroup analyses by ethnicity and prostate cancer grade, the similar results were observed. However, in stratified analysis by clinical stage, we found a significant association with low-stage prostate cancer (Val/Val vs. Ile/Ile: OR = 2.70, 95% CI = 1.73–4.22, P<0.001; Val/Val vs. Val/Ile+Ile/Ile: OR = 2.14, 95% CI = 1.38–3.33, P = 0.001). Moreover, there was no statistically significant evidence of multiplicative interactions neither between the GSTP1 Ile105Val polymorphism and GSTM1, nor between smoking status and GSTP1 on prostate cancer risk.Conclusions
This meta-analysis showed that GSTP1 Ile105Val polymorphism might not be significantly associated with overall prostate cancer risk. Further stratified analyses showed a significant association with low-stage prostate cancer. 相似文献993.
Juan Chen Duan-Ye Xiong Wen-Hua Wang Wen-Jun Hu Martin Simon Qiang Xiao Juan Chen Ting-Wu Liu Xiang Liu Hai-Lei Zheng 《PloS one》2013,8(8)
It is well known that nitric oxide (NO) enhances salt tolerance of glycophytes. However, the effect of NO on modulating ionic balance in halophytes is not very clear. This study focuses on the role of NO in mediating K+/Na+ balance in a mangrove species, Kandelia obovata Sheue, Liu and Yong. We first analyzed the effects of sodium nitroprusside (SNP), an NO donor, on ion content and ion flux in the roots of K. obovata under high salinity. The results showed that 100 μM SNP significantly increased K+ content and Na+ efflux, but decreased Na+ content and K+ efflux. These effects of NO were reversed by specific NO synthesis inhibitor and scavenger, which confirmed the role of NO in retaining K+ and reducing Na+ in K. obovata roots. Using western-blot analysis, we found that NO increased the protein expression of plasma membrane (PM) H+-ATPase and vacuolar Na+/H+ antiporter, which were crucial proteins for ionic balance. To further clarify the molecular mechanism of NO-modulated K+/Na+ balance, partial cDNA fragments of inward-rectifying K+ channel, PM Na+/H+ antiporter, PM H+-ATPase, vacuolar Na+/H+ antiporter and vacuolar H+-ATPase subunit c were isolated. Results of quantitative real-time PCR showed that NO increased the relative expression levels of these genes, while this increase was blocked by NO synthesis inhibitors and scavenger. Above results indicate that NO greatly contribute to K+/Na+ balance in high salinity-treated K. obovata roots, by activating AKT1-type K+ channel and Na+/H+ antiporter, which are the critical components in K+/Na+ transport system. 相似文献
994.
Ai-Hsiang Chou Chia-Chyi Liu Jui-Yuan Chang Renee Jiang Yi-Chin Hsieh Amanda Tsao Chien-Long Wu Ju-Lan Huang Chang-Phone Fung Szu-Min Hsieh Ya-Fang Wang Jen-Ren Wang Mei-Hua Hu Jen-Ron Chiang Ih-Jen Su Pele Choi-Sing Chong 《PloS one》2013,8(11)
Background
Enterovirus 71 (EV71) has caused several epidemics of hand, foot and mouth diseases (HFMD) in Asia. No effective EV71 vaccine is available. A randomized and open-label phase I clinical study registered with ClinicalTrials.gov #NCT01268787, aims to evaluate the safety, reactogenicity and immunogenicity of a formalin-inactivated EV71 vaccine candidate (EV71vac) at 5- and 10-µg doses. In this study we report the cross-neutralizing antibody responses from each volunteer against different subgenotypes of EV71 and CVA16.Methods
Sixty eligible healthy adults were recruited and vaccinated. Blood samples were obtained on day 0, 21 and 42 and tested against B1, B4, B5, C2, C4A, C4B and CVA16 for cross-neutralizing antibody responses.Results
The immunogenicity of both 5- and 10- µg doses were found to be very similar. Approximately 45% of the participants had <8 pre-vaccination neutralization titers (Nt) against the B4 vaccine strain. After the first EV71vac immunization, 95% of vaccinees have >4-fold increase in Nt, but there was no further increase in Nt after the second dose. EV71vac induced very strong cross-neutralizing antibody responses in >85% of volunteers without pre-existing Nt against subgenotype B1, B5 and C4A. EV71vac elicited weak cross-neutralizing antibody responses (∼20% of participants) against a C4B and Coxsackie virus A16. Over 90% of vaccinated volunteers did not develop cross-neutralizing antibody responses (Nt<8) against a C2 strain. EV71vac can boost and significantly enhance the neutralizing antibody responses in volunteers who already had pre-vaccination antibodies against EV71 and/or CVA16.Conclusion
EV71vac is efficient in eliciting cross-neutralizing antibody responses against EV71 subgenotypes B1, B4, B5, and C4A, and provides the rationale for its evaluation in phase II clinical trials.Trial Registration
ClinicalTrials.gov __NCT01268787 相似文献995.
Li-Yu Hu Cheng-Che Shen Yu-Wen Hu Mu-Hong Chen Chia-Fen Tsai Huey-Ling Chiang Chiu-Mei Yeh Wei-Shu Wang Pan-Ming Chen Tsung-Ming Hu Tzeng-Ji Chen Tung-Ping Su Chia-Jen Liu 《PloS one》2013,8(8)
Background
Thyroid disorders have long been associated with psychiatric illness, often with symptoms suggestive of mood disorders. The most common clinical features associated with hyperthyroidism are anxiety and depression. The risk of bipolar disorders, especially bipolar mania, among patients with thyroid disorders has not been well characterized.Objective
We explored the relationship of hyperthyroidism and the subsequent development of bipolar disorders, and examined the risk factors for bipolar disorders in patients with hyperthyroidism.Methods
We identified patients who were diagnosed with hyperthyroidism between 2000 and 2010 in the Taiwan National Health Insurance Research Database. A comparison cohort without hyperthyroidism was matched based on age, sex, and comorbidities. The occurrence of bipolar disorders was evaluated in both cohorts based on diagnosis and the use of mood stabilizer drugs.Results
The hyperthyroidism cohort consisted of 21, 574 patients, and the comparison cohort consisted of 21, 574 matched control patients without hyperthyroidism. The incidence of bipolar disorders (incidence rate ratio [IRR], 2.31, 95% CI 1.80–2.99, P<.001) was higher for the hyperthyroidism patients than the control patients. Multivariate, matched regression models showed that women (HR 2.02, 95% CI 1.34–3.05, P = .001), patients with alcohol use disorders (HR 3.03, 95% CI 1.58–5.79, P = .001), and those with asthma (HR 1.70, 95% CI 1.18–2.43, P = .004) were independent risk factors for the development of bipolar disorders in hyperthyroidism patients.Conclusions
Although a possibility that the diagnosis of bipolar disorders in this study actually includes "bipolar disorders due to hyperthyroidism" cannot be excluded, this study suggests that hyperthyroidism may increase the risk of developing bipolar disorders. 相似文献996.
Objective
This study determined the prevalence and factors associated with peripheral neuropathy (PN) in subjects with diabetes mellitus, impaired glucose regulation (IGR), and normal glucose tolerance (NGT) in a community-based Chinese population.Research Design and Methods
A total of 2035 subjects in Shanghai were classified as having NGT, IGR, or diabetes. All subjects underwent complete foot examination. PN was assessed according to the neuropathy symptom and neuropathy disability scores. Binary logistic regression was performed to analyze the contributions of factors to PN.Results
The prevalence of PN was 8.4%, 2.8%, and 1.5% in diabetes mellitus, IGR, and NGT subjects, respectively (P<0.05 for diabetes vs. NGT, and IGR). The subjects with known diabetes had the highest frequency of PN (13.1%). Among the subjects without diabetes, those with PN were older, had a higher waist circumference and 2-h postprandial plasma glucose levels, and were more likely to be hypertensive. Among the IGR subjects, other than age, the 2-h postprandial plasma glucose level was an independent factor significantly associated with PN. Meanwhile, among the subjects with diabetes, PN was associated with fasting plasma glucose, duration of diabetes, and decreased estimated glomerular filtration rate.Conclusions
The prevalence of PN is slightly higher in individuals with IGR than that in individuals with NGT, but small fibre damage in IGR as the earliest nerve fibre deficit may be underestimated in our study. As an independent risk factor, postprandial plasma glucose level may be an important target for strategies to prevent or improve PN in IGR subjects. 相似文献997.
Hong-Min Luo Ming-Hua Du Zhi-Long Lin Lin Zhang Li Ma Huan Wang Wen Yu Yi Lv Jiang-Yang Lu Yu-Li Pi Sen Hu Zhi-Yong Sheng 《PloS one》2013,8(10)
Objective
Burn-induced gut dysfunction plays an important role in the development of sepsis and multiple organ dysfunction. Emerging evidence suggests that hypoxia-inducible factor-1α (HIF-1α) is critical in paracelluar barrier functions via regulating vascular endothelial growth factor (VEGF) and myosin light chain kinase (MLCK) expression. Previous studies have also demonstrated that histone deacetylase inhibitors (HDACIs) can repress HIF-1α. This study aims to examine whether valproic acid (VPA), a HDACI, protects against burn-induced gut barrier dysfunction via repressing HIF-1α-dependent upregulation of VEGF and MLCK expression.Methods
Rats were subjected to third degree 55% TBSA burns and treated with/ without VPA (300mg/kg). Intestinal barrier dysfunction was evaluated by permeability of intestinal mucosa to fluorescein isothiocyanate (FITC)-dextran and histologic evaluation. Histone acetylation, tight junction protein zonula occludens 1 (ZO-1), VEGF, MLCK and HIF-1α were measured. In addition, CaCO2 cells were transfected with siRNA directed against HIF-1α and were stimulated with CoCl2 (1mM) for 24 hours with/without VPA (2mM) followed by analysis of HIF-1α, MLCK, VEGF and ZO-1.Results
Burn insults resulted in a significant increase in intestinal permeability and mucosal damage, accompanied by a significant reduction in histone acetylation, ZO-1, upregulation of VEGF, MLCK expression, and an increase in HIF-1α accumulation. VPA significantly attenuated the increase in intestinal permeability, mucosa damage, histone deacetylation and changes in ZO-1 expression. VPA also attenuated the increased VEGF, MLCK and HIF-1α protein levels. VPA reduced HIF-1α, MLCK and VEGF production and prevented ZO-1 loss in CoCl2-stimulated Caco-2 cells. Moreover, transfection of siRNA directed against HIF-1α led to inhibition of MLCK and VEGF production, accompanied by upregulation of ZO-1.Conclusions
These results indicate that VPA can protect against burn-induced gut barrier dysfunction. These protective effects may be due to its inhibitory action on HIF-1α, leading to a reduction in intestinal VEGF and MLCK expression and minimizing ZO-1 degradation. 相似文献998.
Yih-Ru Wu Kuo-Hsuan Chang Wen-Teng Chang Ya-Chin Hsiao Hsuan-Chu Hsu Pei-Ru Jiang Yi-Chun Chen Chih-Ying Chao Yi-Chung Chang Bo-Hsun Lee Fen-Ju Hu Wan-Ling Chen Guey-Jen Lee-Chen Chiung-Mei Chen 《PloS one》2013,8(12)
Genetic variants of leucine-rich repeat kinase 2 (LRRK2) were reported to alter the risk for Parkinson’s disease (PD). However, the genetic spectrum of LRRK2 variants has not been clearly disclosed yet in Taiwanese population. Herein, we sequenced LRRK2 coding region in 70 Taiwanese early onset PD patients (age at onset ≤ 50), and found six amino acid-changing single nucleotide polymorphisms (SNPs, N551K, R1398H, R1628P, S1647T, G2385R and M2397T), one reported (R1441H) and 2 novel missense (R767H and S885N) mutations. We examined the frequency of identified LRRK2 variants by genotyping 573 Taiwanese patients with PD and 503 age-matched control subjects. The results showed that PD patients demonstrated a higher frequency of G2385R A allele (4.6%) than control subjects (2.1%; odds ratio = 2.27, 95% confidence interval: 1.38–3.88, P = 0.0017). Fewer PD patients (27.7%) carried the 1647T-2397T haplotype as compared with the control subjects (33.0%; odds ratio = 0.80, 95% confidence interval: 0.65–0.97, P = 0.0215). However, the frequency of 1647T-2385R-2397T haplotype (4.3%) in PD patients was still higher than in control subjects (1.9%, odds ratio: 2.15, 95% confidence interval: 1.27–3.78, P = 0.0058). While no additional subject was found to carry R767H and R1441H, one more patient was observed to carry the S885N variant. Our results indicate a robust risk association regarding G2385R and a new possible protective haplotype (1647T-2397T). Gene-environmental interaction and a larger cohort study are warranted to validate our findings. Additionally, two new missense mutations (R767H and S885N) regarding LRRK2 in PD patients were identified. Functional studies are needed to elucidate the effects of these LRRK2 variants on protein function. 相似文献
999.
Weihua Zhou Caifeng Yue Jinyun Deng Ronghuan Hu Jie Xu Long Feng Qiongyu Lan Wenfeng Zhang Dexiang Ji Jianbing Wu Quentin Liu Anwen Liu 《PloS one》2013,8(11)
Beclin 1, a key regulator of autophagy, has been found to be aberrantly expressed in a variety of human malignancies. Herein, we employed immunohistochemistry (IHC) to detect the protein expression of Beclin 1 in non-small cell lung cancer (NSCLC) and paired normal adjacent lung tissues, and analyzed its clinicopathological/prognostic significance in NSCLC. Receiver operating characteristic (ROC) curve analysis was utilized to determine a cutoff point (>2 VS. ≤2) for Beclin 1 expression in a training set (n = 105). For validation, the ROC-derived cutoff value was subjected to analysis of the association of Beclin 1 with patients’ clinical characteristics and outcome in a testing set (n = 111) and the overall patient cohort (n = 216). Our data showed that Beclin 1 was significantly lower in NSCLC tissues compared with the adjacent normal tissues, negatively associating with tumor recurrence rate (65.8% VS 32.3%; p < 0.001). In the testing set and the overall patient cohort, low expression of Beclin 1 showed significantly inferior overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) compared to high expression of Beclin 1. In the testing set and the overall patient cohort, the median duration of OS for patients with high and low expression of Beclin 1 was 108 VS. 24.5 months (p < 0.001) and 108 VS. 28 months (p < 0.001), respectively. Furthermore, low expression of Beclin 1 was also a poor prognostic factor within each stage of NSCLC patients. Multivariate analysis identified that Beclin 1 was an independent prognostic factor for NSCLC. Our findings in the present study provided evidence that Beclin 1 may thus emerge as an independent prognostic biomarker in this tumor entity in the future. 相似文献
1000.