全文获取类型
收费全文 | 5539篇 |
免费 | 432篇 |
国内免费 | 290篇 |
出版年
2023年 | 52篇 |
2022年 | 126篇 |
2021年 | 266篇 |
2020年 | 183篇 |
2019年 | 214篇 |
2018年 | 194篇 |
2017年 | 141篇 |
2016年 | 216篇 |
2015年 | 348篇 |
2014年 | 391篇 |
2013年 | 429篇 |
2012年 | 514篇 |
2011年 | 456篇 |
2010年 | 282篇 |
2009年 | 255篇 |
2008年 | 279篇 |
2007年 | 245篇 |
2006年 | 194篇 |
2005年 | 177篇 |
2004年 | 167篇 |
2003年 | 122篇 |
2002年 | 110篇 |
2001年 | 108篇 |
2000年 | 93篇 |
1999年 | 101篇 |
1998年 | 44篇 |
1997年 | 52篇 |
1996年 | 42篇 |
1995年 | 38篇 |
1994年 | 31篇 |
1993年 | 34篇 |
1992年 | 41篇 |
1991年 | 37篇 |
1990年 | 47篇 |
1989年 | 36篇 |
1988年 | 23篇 |
1987年 | 24篇 |
1986年 | 13篇 |
1985年 | 14篇 |
1984年 | 10篇 |
1983年 | 10篇 |
1982年 | 9篇 |
1981年 | 8篇 |
1979年 | 14篇 |
1978年 | 8篇 |
1975年 | 5篇 |
1973年 | 9篇 |
1972年 | 6篇 |
1971年 | 9篇 |
1968年 | 5篇 |
排序方式: 共有6261条查询结果,搜索用时 15 毫秒
781.
Christopher Liao Yonatan Klausner David Starobinski Eran Simhon Azer Bestavros 《Cluster computing》2018,21(3):1595-1606
Many research institutions are deploying computing clusters based on a shared/buy-in paradigm. Such clusters combine shared computers, which are free to be used by all users, and buy-in computers, which are computers purchased by users for semi-exclusive use. The purpose of this paper is to characterize the typical behavior and performance of a shared/buy-in computing cluster, using data traces from the Shared Computing Cluster (SCC) at Boston University that runs under this paradigm as a case study. Among our main findings, we show that the semi-exclusive policy, which allows any SCC user to use idle buy-in resources for a limited time, increases the utilization of buy-in resources by 17.4%, thus significantly improving the performance of the system as a whole. We find that jobs allowed to run on idle buy-in resources arrive more frequently and run for a shorter time than other jobs. Finally, we identify the run time limit (i.e., the maximum time during which a job is allowed to use resources) and the type of parallel environment as two factors that have a significant impact on the different performance experienced by shared and buy-in jobs. 相似文献
782.
Guangming Yan Jie Chen Guiying Yang Guangyou Duan Zhiyong Du Zubin Yu Jing Peng Wei Liao Hong Li 《BMC anesthesiology》2018,18(1):192
Objective
To compare the analgesic effects of patient-controlled intravenous analgesia (PCA) with hydromorphone and sufentanil after thoracic surgery on postoperative pulmonary complications (PPCs).Methods
A total of 142 patients who were scheduled for thoracic surgery were randomly allocated to receive PCA with hydromorphone (group A: experimental group): hydromorphone 0.2?mg/kg?+?dezocine 0.5?mg/kg?+?ramosetron 0.6?mg diluted with normal saline to 200?mL; or with sufentanil (group B: control group): sufentanil 3.0μg/kg?+?dezocine 0.5?mg/kg?+?ramosetron 0.6?mg diluted with normal saline to 200?mL. The parameters of intravenous analgesia pump were set as background dose 4?ml/h, PCA dose 1?mL, locking time 15?min. Pain NRS (numerical rating scale), Ramsay sedation score, nausea or vomiting score were evaluated at 0?h, 6?h, 12?h, 24?h, 48?h after operation. The cases of PPCs (atelectasis, pulmonary infection, respiratory failure), CRP (C-reaction protein) and inflammatory cells (white cell count and percentage of neutrophils) and blood gas analysis at 12?h after operation, length of ICU and postoperative stay were recorded for each patient.Results
Data of 136 patients were analyzed. Compared with group B (4[IQR:2,2]), the pain NRS in group A (2[IQR:4,4]) was significantly lower at 6?h after operation (P?=?0.000). The CRP in group A (69.79?±?32.13?mg/L) were lower than group B (76.76?±?43.42?mg/L) after operation, but the difference was not significant (P?=?0.427). No difference of nausea or vomiting was found between group A (7.3%) and group B (5.8%) postoperatively (P?=?0.999). The PPCs were happened in 11 patients in group A (16.2%) and 22 patients in group B (32.4%) and the difference between two groups was significant (P?=?0.027). Seven patients in group A (10.3%) and eighteen patients in group B (26.5%) had clinical evidence of pneumonia and the difference between two groups was significant (P?=?0.014). The length of ICU and postoperative stay in group A were 2.73?h and 1.82?days less than group B respectively but the differences were not significant (P?=?0.234, P?=?0.186 respectively).Conclusion
Compared with sufentanil, hydromorphone may provide better postoperative analgesic effect with less pulmonary complications for patients undergoing thoracic surgery, and it may accelerate patients’ rehabilitation.Trial registration
Randomized Controlled Trials ChiCTR1800014282c. Registered 3 January 2018.783.
Mechanisms for stalled replication fork stabilization: new targets for synthetic lethality strategies in cancer treatments
下载免费PDF全文
![点击此处可从《EMBO reports》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Timely and faithful duplication of the entire genome depends on completion of replication. Replication forks frequently encounter obstacles that may cause genotoxic fork stalling. Nevertheless, failure to complete replication rarely occurs under normal conditions, which is attributed to an intricate network of proteins that serves to stabilize, repair and restart stalled forks. Indeed, many of the components in this network are encoded by tumour suppressor genes, and their loss of function by mutation or deletion generates genomic instability, a hallmark of cancer. Paradoxically, the same fork‐protective network also confers resistance of cancer cells to chemotherapeutic drugs that induce high‐level replication stress. Here, we review the mechanisms and major pathways rescuing stalled replication forks, with a focus on fork stabilization preventing fork collapse. A coherent understanding of how cells protect their replication forks will not only provide insight into how cells maintain genome stability, but also unravel potential therapeutic targets for cancers refractory to conventional chemotherapies. 相似文献
784.
Linc00483 as ceRNA regulates proliferation and apoptosis through activating MAPKs in gastric cancer
下载免费PDF全文
![点击此处可从《Journal of cellular and molecular medicine》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Defeng Li Meifeng Yang Aijun Liao Bing Zeng Diqun Liu Yuhong Yao Guangsheng Hu Xuanmin Chen Zhiqiang Feng Yanlei Du Youlian Zhou Jie He Yuqiang Nie 《Journal of cellular and molecular medicine》2018,22(8):3875-3886
Long non‐coding RNAs (lncRNAs) are important regulators of many cellular processes, and their aberrant expression and/or function is associated with many different diseases, including cancer. However, the identification of functional lncRNAs in gastric cancer is still a challenge. In this study, we describe a novel functional lncRNA, linc00483, that is upregulated and associated with tumorigenesis, tumour size, metastasis and poor prognosis in gastric cancer. In our study, linc00483 promoted gastric cancer cell proliferation, invasiveness and metastasis in vitro and in vivo. Mechanistically, upregulated expression of linc00483 in gastric cancer acts as a sponge to absorb endogenous tumour suppressor miR‐30a‐3p. Furthermore, it restores SPAG9 expression, which is negatively regulated by miR‐30a‐3p, and actives MAPK signaling pathway in gastric cancer cells. Thus, linc00483 is an oncogenic lncRNA in gastric cancer and targeting linc00483 or its pathway can potentially be useful in development of targeted therapies for patients with gastric cancer. Our results show that linc00483 is an important regulator in carcinogenesis and may be a useful biomarker to predict prognosis of gastric cancer patients. We believe our findings are novel and will be of interest to scientists working in many areas related to biomarkers in cancer. 相似文献
785.
FGF1 improves functional recovery through inducing PRDX1 to regulate autophagy and anti‐ROS after spinal cord injury
下载免费PDF全文
![点击此处可从《Journal of cellular and molecular medicine》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Jiawei Li Qingqing Wang Hanxiao Cai Zili He Haoli Wang Jian Chen Zengming Zheng Jiayu Yin Zhiyong Liao Huazi Xu Jian Xiao Fanghua Gong 《Journal of cellular and molecular medicine》2018,22(5):2727-2738
Fibroblast growth factor 1 (FGF1) is thought to exert protective and regenerative effects on neurons following spinal cord injury (SCI), although the mechanism of these effects is not well understood. The use of FGF1 as a therapeutic agent is limited by its lack of physicochemical stability and its limited capacity to cross the blood‐spinal cord barrier. Here, we demonstrated that overexpression of FGF1 in spinal cord following SCI significantly reduced tissue loss, protected neurons in the ventricornu, ameliorated pathological morphology of the lesion, dramatically improved tissue recovery via neuroprotection, and promoted axonal regeneration and remyelination both in vivo and in vivo. In addition, the autophagy and the expression levels of PRDX1 (an antioxidant protein) were induced by AAV‐FGF1 in PC12 cells after H2O2 treatment. Furthermore, the autophagy levels were not changed in PRDX1‐suppressing cells that were treated by AAV‐FGF1. Taken together, these results suggest that FGF1 improves functional recovery mainly through inducing PRDX1 expression to increase autophagy and anti‐ROS activity after SCI. 相似文献
786.
Sequential decline in fruit resource allocation within inflorescences of Sagittaria trifolia: a test of non‐uniform pollination hypothesis
下载免费PDF全文
![点击此处可从《Plant Species Biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Flowering plants often exhibit declining resource investment to floral organs, fruits and seeds temporally or spatially in an inflorescence. To account for such variances, non‐uniform pollination hypothesis, which highlights various mating environments each flower experiences, provides adaptive significance for allocation patterns but with controversial supports. Sagittaria trifolia (Alismataceae) was used to examine differences in seed number, seed weight and germination rate among sequential fruits within inflorescences. Ovule number was also investigated to evaluate allocation patterns in the floral stage. To test the non‐uniform pollination hypothesis, we used three polymorphic microsatellite loci of S. trifolia to estimate the seed outcrossing rate in proximal and distal fruits. The results showed that the seed number, average seed weight and seed germination rate of S. trifolia gradually decreased from proximal to distal fruits within inflorescences. The percent of decrease in seed number between two contiguous fruits was 14.68 ± 3.22%, which was much stronger than the percent of decrease in ovule number at 6.95 ± 1.60%. Both proximal and distal fruits within inflorescences had high outcrossing rates (81.5 ± 5.0%, proximal; 82.3 ± 6.9%, distal) and they did not differ significantly. Overall, there was an acropetal decline of resource allocation to fruits within inflorescences of S. trifolia. Allocation pattern to ovules was not a limiting factor for seed production. The lack of difference in outcrossing rate between proximal and distal fruits indicated that the allocation strategy was probably not caused by non‐uniform pollination, but more likely position effects. 相似文献
787.
Quntao Yu Hongmao Zhang Yuan Li Chao Liu Shaohui Wang Xiaomei Liao 《Molecular neurobiology》2018,55(5):3812-3821
In conditions of proteasomal impairment, the damaged or misfolded proteins, collectively known as aggresome, can accumulate in the perinuclear space and be subsequently eliminated by autophagy. Abnormal aggregation of microtubule-associated protein tau in the cytoplasm is a common neuropathological feature of tauopathies. The deficiency in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a proteasomal deubiquitinating enzyme, is closely related to tau aggregation; however, the associated mechanisms remain unclear. Here, we showed that UCH-L1 inhibition interrupts proteasomal impairment-induced tau aggresome formation. By reducing the production of lysine (K63)-linked ubiquitin chains, UCH-L1 inhibition decreases HDAC6 deacetylase activity and attenuates the interaction of HDAC6 and tau protein, finally leading to tau aggresome formation impairment. All these results indicated that UCH-L1 plays a key role in the process of tau aggresome formation by regulating HDAC6 deacetylase activity and implied that UCH-L1 may act as a signaling molecule to coordinate the effects of the ubiquitin-proteasome system and the autophagy-lysosome pathway, which mediate protein aggregates degradation in the cytoplasm. 相似文献
788.
Chengming Ding Jun He Jun Zhao Junhua Li Jie Chen Wenyan Liao Yi Zeng Jing Zhong Chaoying Wei Liming Zhang Mei Zhou Zeming Jia Yaoting Zhang Hui Li Yuzheng Zhou Xiaolong Xiao Dong Han Chong Li Zhu Zhu Zanxian Xia Jian Peng 《Cell proliferation》2018,51(5)
Objective
β‐catenin is one of the most critical oncogenes associated with many kinds of human cancers, especially in the human CRC. Innate immunity recognizes tumour derived damage‐associated molecular patterns (DAMPs) and primes the anti‐tumour adaptive responses. While the function of β‐catenin in CRC tumourigenesis is well established, its impact on innate immune evasion is largely unknown. The aim of this study is to characterize the role of β‐catenin in inhibiting RIG‐I‐like receptor (RLR)‐mediated IFN‐β signalling in colorectal cancer.Materials and Methods
Immunohistochemical staining and western blotting were conducted to study the expression of β‐catenin, IRF3 and phospho‐IRF3 (p‐IRF3) in CRC samples and cell lines. Plaque assay determining virus replication was performed to assess the regulation of β‐catenin on IFN‐β signalling. The inhibition of β‐catenin on RLR‐mediated IFN‐β signalling was further studied by real‐time analyses and reporter assays in the context of lentiviral‐mediated β‐catenin stably knocking down. Lastly, co‐immunoprecipitation and nuclear fractionation assay were conducted to monitor the interaction between β‐catenin and IRF3.Results
We found that high expression of β‐catenin positively correlated with the expression of IRF3 in CRC cells. Overexpression of β‐catenin increased the viral replication. Conversely knocking down of β‐catenin inhibited viral replication. Furthermore, our data demonstrated that β‐catenin could inhibit the expression of IFN‐β and interferon‐stimulated gene 56 (ISG56). Mechanistically, we found that β‐catenin interacted with IRF3 and blocked its nuclear translocation.Conclusion
Our study reveals an unprecedented role of β‐catenin in enabling innate immune evasion in CRC.789.
Yixian Liao Yiming Guo Sumei Li Lei Wang Yongmei Tang Tianmiao Li Weihao Chen Guohua Zhong Gaopeng Song 《Bioorganic & medicinal chemistry letters》2018,28(7):1188-1193
This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC50 of 0.88?µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH3O group or CF3O group to the phenyl ring at the para-position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation. 相似文献
790.