全文获取类型
收费全文 | 15715篇 |
免费 | 1599篇 |
国内免费 | 2381篇 |
专业分类
19695篇 |
出版年
2024年 | 74篇 |
2023年 | 285篇 |
2022年 | 556篇 |
2021年 | 829篇 |
2020年 | 625篇 |
2019年 | 786篇 |
2018年 | 686篇 |
2017年 | 511篇 |
2016年 | 652篇 |
2015年 | 1090篇 |
2014年 | 1233篇 |
2013年 | 1294篇 |
2012年 | 1579篇 |
2011年 | 1403篇 |
2010年 | 999篇 |
2009年 | 915篇 |
2008年 | 1020篇 |
2007年 | 889篇 |
2006年 | 793篇 |
2005年 | 651篇 |
2004年 | 564篇 |
2003年 | 531篇 |
2002年 | 442篇 |
2001年 | 217篇 |
2000年 | 189篇 |
1999年 | 170篇 |
1998年 | 148篇 |
1997年 | 88篇 |
1996年 | 82篇 |
1995年 | 59篇 |
1994年 | 78篇 |
1993年 | 39篇 |
1992年 | 42篇 |
1991年 | 26篇 |
1990年 | 20篇 |
1989年 | 16篇 |
1988年 | 8篇 |
1987年 | 24篇 |
1986年 | 10篇 |
1985年 | 11篇 |
1984年 | 8篇 |
1983年 | 10篇 |
1982年 | 7篇 |
1981年 | 7篇 |
1979年 | 5篇 |
1976年 | 3篇 |
1973年 | 3篇 |
1972年 | 4篇 |
1966年 | 2篇 |
1965年 | 2篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
992.
Xiaozhou He Yilin Yang Feng Zhi Meredith L. Moore Xuezhi Kang Dongman Chao Rong Wang Gianfranco Balboni Severo Salvadori Dong H. Kim Ying Xia 《PloS one》2013,8(4)
Hypoxic/ischemic injury to kidney is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs are differentially involved in hypoxic/ischemic events and δ-opioid receptor (DOR) activation is known to protect against hypoxic/ischemic injury, we speculated on the involvement of DOR activation in altering the microRNA (miRNA) expression in kidney under hypoxic condition. We selected 31 miRNAs based on microarray data for quantitative PCR analysis. Among them, 14 miRNAs were significantly altered after prolonged hypoxia, DOR activation or a combination of both. We found that 1) DOR activation alters miRNA expression profiles in normoxic conditions; 2) hypoxia differentially alters miRNA expression depending on the duration of hypoxia; and 3) DOR activation can modify hypoxia-induced changes in miRNA expression. For example, 10-day hypoxia reduced the level of miR-212 by over 70%, while DOR activation could mimic such reduction even in normoxic kidney. In contrast, the same stress increased miR-29a by >100%, which was reversed following DOR activation. These first data suggest that hypoxia comprehensively modifies the miRNA profile within the kidney, which can be mimicked or modified by DOR activation. Ascertaining the targeted pathways that regulate the diverse cellular and molecular functions of miRNA may provide new insights into potential therapies for hypoxic/ischemic injury of the kidney. 相似文献
993.
The changing profile of infection over time for Human Parechoviruses (HPeVs) is not well known and no detailed study has been reported to date in China. This investigation on HPeV infection in hospitalized children in Lanzhou, China revealed variations in epidemiological characteristics after a three-year interval. To assess the changes that had occurred, epidemiological and clinical characteristics of HPeVs were characterized and compared with previously reported data by our group. A comparable positivity rate (25.3%, 73/289) was revealed after the three-year interval with the majority of the infected children (95.9%, 70/73) being younger than two years of age. While a temporal change in the seasonal distribution was noted in the current study, HPeVs were more frequently detected during July to November compared to September to December in the previous study. Changes in HPeV genotypes patterns, a temporal change in the prevalence of HPeV1, a younger susceptible age to HPeV3 compared with HPeV1 and a tendency of older children to be infected with HPeV4 are in contrast to our previous report. HPeV2, a rarely reported genotype, was identified for the first time in China. In addition, an exclusive trinucleotide (GAT) insertion in the HPeV4 nucleotide sequence was identified. However, the profiles of co-infection with other enteric related viruses were similar to our previous findings. In summary, these data suggest temporal variation in the seasonal distribution of HPeV and changing patterns of HPeV genotypes over time in the study region. 相似文献
994.
Yan Zhen Yanfen Ye Xiaoli Yu Chunping Mai Ying Zhou Yan Chen Huiling Yang Xiaoming Lyu Ye Song Qiangyun Wu Qiaofen Fu Mengyang Zhao Shengni Hua Hao Wang Zhen Liu Yajie Zhang Weiyi Fang 《PloS one》2013,8(6)
Background
The role of CTGF varies in different types of cancer. The purpose of this study is to investigate the involvement of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC).Experimental design
CTGF expression levels were examined in NPC tissues and cells, nasopharynx (NP) tissues, and NP69 cells. The effects and molecular mechanisms of CTGF expression on cell proliferation, migration, invasion, and cell cycle were also explored.Results
NPC cells exhibited decreased mRNA expression of CTGF compared to immortalized human nasopharyngeal epithelial cell line NP69. Similarly, CTGF was observed to be downregulated in NPC compared to normal tissues at mRNA and protein levels. Furthermore, reduced CTGF was negatively associated with the progression of NPC. Knocking down CTGF expression enhanced the colony formation, cell migration, invasion, and G1/S cell cycle transition. Mechanistic analysis revealed that CTGF suppression activated FAK/PI3K/AKT and its downstream signals regulating the cell cycle, epithelial-mesenchymal transition (EMT) and MMPs. Finally, DNA methylation microarray revealed a lack of hypermethylation at the CTGF promoter, suggesting other mechanisms are associated with suppression of CTGF in NPC.Conclusion
Our study demonstrates that reduced expression of CTGF promoted cell proliferation, migration, invasion and cell cycle progression through FAK/PI3K/AKT, EMT and MMP pathways in NPC. 相似文献995.
996.
Aggregatibacter actinomycetemcomitans, a specific pathogen of localized aggressive periodontitis, produces a cytolethal distending toxin (CDT) that arrests eukaryotic cells irreversibly in G0/G1 or G2/M phase of the cell cycle. Although structural studies show that the aromatic patch region of CdtA plays an important role in its biological activity, the functional sites of CdtA have not been firmly established. In this study, site-specific mutagenesis strategy was employed for cdtA point mutations construction so as to examine the contributions of individual amino acids to receptor binding and the biological activity of holotoxin. The binding ability was reduced in CdtAY181ABC holotoxin and the biological function of CDT was not weaken in CdtAY105ABC, CdtAY125ABC, CdtAF109ABC and CdtAS106NBC holotoxin suggesting that these sites were not critical to CDT. But the binding activity and cell cycle arrest ability of holotoxin complexes were inhibited in CdtAW115GBC. And this site did not affect the holotoxin assembly by size exclusion chromatography. Therefore, W115 might be a critical site of CdtA binding ability. These findings suggest that the functional sites of CdtA are not only in the aromatic patch region. W115, the new functional site is critical for receptor binding and cell cycle arrest, which provides potential targets for pharmacological disruption of CDT activity. 相似文献
997.
Lianzheng Yu Chao Jiang Jun Na Ning Li Wenli Diao Yuan Gu Li Zhao Yan Zou Ying Chen Li Liu Huijuan Mu Yunyong Liu Liya Yu Xiaoli Yang Guowei Pan 《PloS one》2013,8(4)
Background
This study aimed to assess whether Chinese men who have sex with men (MSM) had a significantly elevated prevalence of psychiatric disorders compared to urban males in China.Methods
807 MSM were recruited using a respondent-driven sampling (RDS) method in urban area of northeast China. Psychiatric disorders were assessed employing the Composite International Diagnostic Interview (CIDI. Version 1.0) according to the criteria of the DSM-III-R.Results
Chinese MSM had a significantly elevated standardized prevalence ratios (SPR) for lifetime prevalence of any disorder (SPR = 2.8; 95%CI: 2.5–3.2), mood disorder (SPR = 3.0; 95%CI: 2.3–3.7), anxiety disorder (SPR = 5.5; 95% CI: 4.6–6.5), alcohol use disorder (SPR = 2.4, 95%CI: 2.0–2.8), and combination of disorders (SPR = 4.2; 95%CI: 3.4–5.1).Conclusions
Chinese MSM had significantly elevated prevalence and comorbidity of psychiatric disorders. RDS is a suitable sampling method for psychiatric epidemiological survey in MSM population. 相似文献998.
Yan Hu Brian L. Ellis Ying Y. Yiu Melanie M. Miller Joseph F. Urban Linda Z. Shi Raffi V. Aroian 《PloS one》2013,8(7)
Soil-transmitted helminths are parasitic nematodes that inhabit the human intestine. These parasites, which include two hookworm species,
Ancylostoma
duodenale
and Necator americanus, the whipworm
Trichuris
trichiura
, and the large roundworm
Ascaris
lumbricoides
, infect upwards of two billion people and are a major cause of disease burden in children and pregnant women. The challenge with treating these diseases is that poverty, safety, and inefficient public health policy have marginalized drug development and distribution to control infection in humans. Anthelmintics (anti-worm drugs) have historically been developed and tested for treatment of non-human parasitic nematodes that infect livestock and companion animals. Here we systematically compare the in vitro efficacy of all major anthelmintic classes currently used in human therapy (benzimidazoles, nicotinic acetylcholine receptor agonists, macrocyclic lactones, nitazoxanide) against species closely related to human parasitic nematodes-Ancylostoma ceylanicum,
Trichuris
muris
, and
Ascaris
suum
--- as well as a rodent parasitic nematode used in veterinary drug discovery,
Heligmosomoides
bakeri
, and the free-living nematode Caenorhabditis elegans. Extensive in vitro data is complemented with single-dose in vivo data in three rodent models of parasitic diseases. We find that the effects of the drugs in vitro and in vivo can vary greatly among these nematode species, e.g., the efficacy of albendazole is strong on A. ceylanicum but weak on
H
. bakeri
. Nonetheless, certain commonalities of the in vitro effects of the drugs can be seen, e.g., nitazoxanide consistently shows an all-or-nothing response. Our in vitro data suggest that further optimization of the clinical efficacy of some of these anthelmintics could be achieved by altering the treatment routine and/or dosing. Most importantly, our in vitro and in vivo data indicate that the hookworm A. ceylanicum is a particularly sensitive and useful model for anthelmintic studies and should be incorporated early on in drug screens for broad-spectrum human soil-transmitted helminth therapies. 相似文献
999.
Objective
To develop a simple predictive model for significant fibrosis and cirrhosis in chronic hepatitis B (CHB) using the routine hematological parameters of a complete blood count.Methods
A total of 458 eligible CHB patients who had undergone a liver biopsy were randomly divided into two cohorts: an estimation group (n = 310) and a validation group (n = 148). Liver histology was assessed according to the Metavir scoring scheme. All common demographics, hematological parameters, HBeAg status, HBV DNA, and liver biochemistry were analyzed.Results
Based on routinely available clinical parameters (age, sex, HBeAg status, HBV DNA, common hematological parameters of a complete blood cell count), a model for predicting significant fibrosis (Metavir score ≥2) in the estimation group was derived using platelets and red cell distribution width (RDW), and another model for predicting cirrhosis (Metavir score = 4) was derived using platelets, RDW and hemoglobin. A novel index, the RDW to platelet ratio (RPR), was developed to amplify the opposing effects of liver fibrosis on the RDW and platelets. The AUCs of the RPR for predicting significant fibrosis and cirrhosis were 0.825 and 0.884, respectively, which is superior to the AAR, FIB-4 and APRI in the estimation group. Compared with the two derived models, the RPR has a comparable predictive power for significant fibrosis and cirrhosis. Using optimized cutoffs (0.10 and 0.16), the RPR accurately predicted 63.1% of cases with significant fibrosis and 73.7% of cases with cirrhosis and accurately excluded 85.5% of the cases with mild fibrosis and 93.0% of the cases with no cirrhosis.Conclusion
The RPR, a routinely available, inexpensive and easily calculated index, can predict significant fibrosis and cirrhosis in CHB patients with relatively high accuracy. The application of this index may reduce the need for liver biopsy in CHB patients. 相似文献1000.
Tiejun Zhang Xiuhong Tian Fuchang Ma Ying Yang Feng Yu Yanping Zhao Meiyang Gao Yingying Ding Qingwu Jiang Na He 《PloS one》2013,8(4)