全文获取类型
收费全文 | 36483篇 |
免费 | 3240篇 |
国内免费 | 2460篇 |
出版年
2024年 | 69篇 |
2023年 | 383篇 |
2022年 | 751篇 |
2021年 | 1358篇 |
2020年 | 1000篇 |
2019年 | 1216篇 |
2018年 | 1209篇 |
2017年 | 849篇 |
2016年 | 1288篇 |
2015年 | 2160篇 |
2014年 | 2420篇 |
2013年 | 2695篇 |
2012年 | 3290篇 |
2011年 | 3057篇 |
2010年 | 1820篇 |
2009年 | 1612篇 |
2008年 | 1991篇 |
2007年 | 1796篇 |
2006年 | 1644篇 |
2005年 | 1378篇 |
2004年 | 1285篇 |
2003年 | 1110篇 |
2002年 | 978篇 |
2001年 | 743篇 |
2000年 | 668篇 |
1999年 | 615篇 |
1998年 | 357篇 |
1997年 | 342篇 |
1996年 | 326篇 |
1995年 | 262篇 |
1994年 | 292篇 |
1993年 | 201篇 |
1992年 | 345篇 |
1991年 | 298篇 |
1990年 | 257篇 |
1989年 | 237篇 |
1988年 | 205篇 |
1987年 | 163篇 |
1986年 | 152篇 |
1985年 | 154篇 |
1984年 | 151篇 |
1983年 | 105篇 |
1982年 | 96篇 |
1981年 | 63篇 |
1979年 | 81篇 |
1978年 | 72篇 |
1977年 | 65篇 |
1976年 | 70篇 |
1975年 | 65篇 |
1974年 | 78篇 |
排序方式: 共有10000条查询结果,搜索用时 62 毫秒
991.
Lin Chen Haiou Liu Jing Liu Yu Zhu Le Xu Hongyong He Heng Zhang Shanshan Wang Qian Wu Weisi Liu Yidong Liu Deng Pan Shifang Ren Jiejie Xu Jianxin Gu 《PloS one》2013,8(3)
Klotho was originally characterized as an aging suppressor gene that predisposed Klotho-deficient mice to premature aging-like syndrome. Although Klotho was recently reported to exhibit tumor suppressive properties during various malignant transformations, the functional role and molecular mechanism of Klotho in hepatocarcinogenesis remains poorly understood. In our present study, immunohistochemical Klotho staining levels in a clinical follow-up of 52 hepatoma patients were significantly associated with liver cirrhosis, tumor multiplicity and venous invasion. The overall survival rate of hepatoma patients with high Klotho expression was significantly lower than those patients with low Klotho expression. Moreover, Klotho overexpression increased cellular migration, anchorage-independent growth, and anoikis resistance in hepatoma cells. Klotho overexpression elevated p21-activated kinase 1 (PAK1) expression and shRNA-mediated PAK1 knockdown and kinase activity inhibition with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor IPA3 treatment reversed anoikis resistance in Klotho-overexpressed hepatoma cells. More importantly, the pivotal significance of upregulated VEGFR2 protein levels mediated by Klotho expression was confirmed by VEGFR2 inhibitor Axitinib and blocking antibody treatment in hepatoma cells. Axitinib treatment sensitized anoikis was reversed by constitutive active mutant PAK1 T423E coexpression in Klotho-overexpressed hepatoma cells. Conversely, knockdown of Klotho reduced VEGFR2/PAK1 dependent anoikis resistance, which could be reversed by PAK1 T423E. These results revealed a novel oncogenic function of Klotho in promoting anoikis resistance via activating VEGFR2/PAK1 signaling, thus facilitating tumor migration and invasion during hepatoma progression, which could provide a putative molecular mechanism for tumor metastasis. 相似文献
992.
Yuan Mao Mei Ping Lu Hong Lin Da Wei Zhang Ying Liu Qing Dong Li Zhi Gang Lv Jia Ren Xu Ren Jie Chen Jin Zhu 《PloS one》2013,8(4)
Background
Epstein-Barr virus (EBV) infection has been associated with lymphoma development. EBV latent membrane protein 1 (LMP1) is essential for EBV-mediated transformation and progression of different human cells, including lymphocytes. This meta-analysis investigated LMP1 expression with prognosis of patients with lymphoma.Methods
The electronic databases of PubMed, Embase, and Chinese Biomedicine Databases were searched. There were 15 published studies available for a random effects model analysis. Quality assessment was performed using the Newcastle-Ottawa Quality Assessment Scale for cohort studies. A funnel plot was used to investigate publication bias, and sources of heterogeneity were identified by meta-regression analysis. The combined hazard ratios (HR) and their corresponding 95% confidence intervals of LMP1 expression were calculated by comparison to the overall survival.Results
Overall, there was no statistical significance found between LMP1 expression and survival of lymphoma patients (HR 1.25 [95% CI, 0.92–1.68]). In subgroup analyses, LMP1 expression was associated with survival in patients with non-Hodgkin lymphoma (NHL) (HR = 1.84, 95% CI: 1.02–3.34), but not with survival of patients with Hodgkin disease (HD) (HR = 1.03, 95% CI: 0.74–1.44). In addition, significant heterogeneity was present and the meta-regression revealed that the outcome of analysis was mainly influenced by the cutoff value.Conclusions
This meta-analysis demonstrated that LMP1 expression appears to be an unfavorable prognostic factor for overall survival of NHL patients. The data suggested that EBV infection and LMP1 expression may be an important factor for NHL development or progression. 相似文献993.
A plethora of algorithmic assemblers have been proposed for the de novo assembly of genomes, however, no individual assembler guarantees the optimal assembly for diverse species. Optimizing various parameters in an assembler is often performed in order to generate the most optimal assembly. However, few efforts have been pursued to take advantage of multiple assemblies to yield an assembly of high accuracy. In this study, we employ various state-of-the-art assemblers to generate different sets of contigs for bacterial genomes. A tool, named CISA, has been developed to integrate the assemblies into a hybrid set of contigs, resulting in assemblies of superior contiguity and accuracy, compared with the assemblies generated by the state-of-the-art assemblers and the hybrid assemblies merged by existing tools. This tool is implemented in Python and requires MUMmer and BLAST+ to be installed on the local machine. The source code of CISA and examples of its use are available at http://sb.nhri.org.tw/CISA/. 相似文献
994.
Jing Lu Shengchang Xin Huan Meng Matt Veldman David Schoenfeld Chao Che Ruibin Yan Hanbing Zhong Song Li Shuo Lin 《PloS one》2013,8(4)
Polo-like kinase 1 (PLK1), one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every∼30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of∼60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics. 相似文献
995.
Beatriz Grinsztejn Paula M. Luz Antonio G. Pacheco Desiree V. G. Santos Luciane Velasque Ronaldo I. Moreira Maria Regina C. Guimar?es Estev?o P. Nunes Alberto S. Lemos Sayonara R. Ribeiro Dayse P. Campos Marco A. A. Vitoria Valdilea G. Veloso 《PloS one》2013,8(4)
Introduction
We describe temporal trends in the mortality rates and factors associated with AIDS and non-AIDS related mortality at the Evandro Chagas Clinical Research Institute (IPEC), Oswaldo Cruz Foundation (FIOCRUZ).Methods
Adult patients enrolling from 1986 through 2009 with a minimum follow up of 60 days were included. Vital status was exhaustively checked using patients’ medical charts, through active contact with individuals and family members and by linkage with the Rio de Janeiro Mortality database using a previously validated algorithm. The CoDe protocol was used to establish the cause of death. Extended Cox proportional hazards models were used for multivariate modeling.Results
A total of 3530 individuals met the inclusion criteria, out of which 868 (24.6%) deceased; median follow up per patient was 3.9 years (interquartile range 1.7–9.2 years). The dramatic decrease in the overall mortality rates was driven by AIDS-related causes that decreased from 9.19 deaths/100PYs n 1986–1991 to 1.35/100PYs in 2007–2009. Non-AIDS related mortality rates remained stable overtime, at around 1 death/100PYs. Immunodeficiency significantly increased the hazard of both AIDS-related and non-AIDS-related causes of death, while HAART use was strongly associated with a lower hazard of death from either cause.Conclusions
Our results confirm the remarkable decrease in AIDS-related mortality as the HIV epidemic evolved and alerts to the conditions not traditionally related to HIV/AIDS which are now becoming more frequent, needing careful monitoring. 相似文献996.
Yi-Hsuan Lin Yi-Chun Chen Yen-Han Tseng Ming-Hwai Lin Shinn-Jang Hwang Tzeng-Ji Chen Li-Fang Chou 《PloS one》2013,8(4)
Aims
The palliative care has spread rapidly worldwide in the recent two decades. The development of hospice services in rural areas usually lags behind that in urban areas. The aim of our study was to investigate whether the urban-rural disparity widens in a country with a hospital-based hospice system.Methods
From the nationwide claims database within the National Health Insurance in Taiwan, admissions to hospices from 2000 to 2006 were identified. Hospices and patients in each year were analyzed according to geographic location and residence.Results
A total of 26,292 cancer patients had been admitted to hospices. The proportion of rural patients to all patients increased with time from 17.8% in 2000 to 25.7% in 2006. Although the numbers of beds and the utilizations in both urban and rural hospices expanded rapidly, the increasing trend in rural areas was more marked than that in urban areas. However, still two-thirds (898/1,357) of rural patients were admitted to urban hospices in 2006.Conclusions
The gap of hospice utilizations between urban and rural areas in Taiwan did not widen with time. There was room for improvement in sufficient supply of rural hospices or efficient referral of rural patients. 相似文献997.
Zhen-Zhu Su Li-Juan Mao Na Li Xiao-Xiao Feng Zhi-Lin Yuan Li-Wei Wang Fu-Cheng Lin Chu-Long Zhang 《PloS one》2013,8(4)
The mutualism pattern of the dark septate endophyte (DSE) Harpophora oryzae in rice roots and its biocontrol potential in rice blast disease caused by Magnaporthe oryzae were investigated. Fluorescent protein-expressing H. oryzae was used to monitor the colonization pattern. Hyphae invaded from the epidermis to the inner cortex, but not into the root stele. Fungal colonization increased with root tissue maturation, showing no colonization in the meristematic zone, slight colonization in the elongation zone, and heavy colonization in the differentiation zone. H. oryzae adopted a biotrophic lifestyle in roots accompanied by programmed cell death. Real-time PCR facilitated the accurate quantification of fungal growth and the respective plant response. The biocontrol potential of H. oryzae was visualized by inoculation with eGFP-tagged M. oryzae in rice. H. oryzae protected rice from M. oryzae root invasion by the accumulation of H2O2 and elevated antioxidative capacity. H. oryzae also induced systemic resistance against rice blast. This systemic resistance was mediated by the OsWRKY45-dependent salicylic acid (SA) signaling pathway, as indicated by the strongly upregulated expression of OsWRKY45. The colonization pattern of H. oryzae was consistent with the typical characteristics of DSEs. H. oryzae enhanced local resistance by reactive oxygen species (ROS) and high antioxidative level and induced OsWRKY45-dependent SA-mediated systemic resistance against rice blast. 相似文献
998.
Janet Newman Shane Seabrook Regina Surjadi Charlotte C. Williams Del Lucent Matthew Wilding Colin Scott Thomas S. Peat 《PloS one》2013,8(3)
Escherichia coli possesses two acyl ornithine aminotransferases, one catabolic (AstC) and the other anabolic (ArgD), that participate in L-arginine metabolism. Although only 58% identical, the enzymes have been shown to be functionally interchangeable. Here we have purified AstC and have obtained X-ray crystal structures of apo and holo-AstC and of the enzyme complexed with its physiological substrate, succinylornithine. We compare the structures obtained in this study with those of ArgD from Salmonella typhimurium obtained elsewhere, finding several notable differences. Docking studies were used to explore the docking modes of several substrates (ornithine, succinylornithine and acetylornithine) and the co-substrate glutamate/α-ketogluterate. The docking studies support our observations that AstC has a strong preference for acylated ornithine species over ornithine itself, and suggest that the increase in specificity associated with acylation is caused by steric and desolvation effects rather than specific interactions between the substrate and enzyme. 相似文献
999.
1000.