全文获取类型
收费全文 | 551篇 |
免费 | 54篇 |
国内免费 | 2篇 |
出版年
2023年 | 2篇 |
2021年 | 13篇 |
2020年 | 1篇 |
2019年 | 5篇 |
2018年 | 9篇 |
2017年 | 5篇 |
2016年 | 12篇 |
2015年 | 33篇 |
2014年 | 27篇 |
2013年 | 33篇 |
2012年 | 49篇 |
2011年 | 38篇 |
2010年 | 25篇 |
2009年 | 15篇 |
2008年 | 25篇 |
2007年 | 27篇 |
2006年 | 24篇 |
2005年 | 25篇 |
2004年 | 34篇 |
2003年 | 21篇 |
2002年 | 27篇 |
2001年 | 11篇 |
2000年 | 15篇 |
1999年 | 15篇 |
1998年 | 5篇 |
1997年 | 3篇 |
1996年 | 6篇 |
1995年 | 1篇 |
1994年 | 5篇 |
1993年 | 7篇 |
1992年 | 13篇 |
1991年 | 4篇 |
1990年 | 13篇 |
1989年 | 7篇 |
1988年 | 3篇 |
1987年 | 7篇 |
1986年 | 5篇 |
1985年 | 6篇 |
1984年 | 6篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 5篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1976年 | 2篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有607条查询结果,搜索用时 62 毫秒
181.
182.
Benjamin Liou Wendy D. Haffey Kenneth D. Greis Gregory A. Grabowski 《The Journal of biological chemistry》2014,289(43):30063-30074
The acid β-glucosidase (glucocerbrosidase (GCase)) binding sequence to LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome, has been identified. Heterologous expression of deletion constructs, the available GCase crystal structures, and binding and co-localization of identified peptides or mutant GCases were used to identify and characterize a highly conserved 11-amino acid sequence, DSPIIVDITKD, within human GCase. The binding to LIMP-2 is not dependent upon a single amino acid, but the interactions of GCase with LIMP-2 are heavily influenced by Asp399 and the di-isoleucines, Ile402 and Ile403. A single alanine substitution at any of these decreases GCase binding to LIMP-2 and alters its pH-dependent binding as well as diminishing the trafficking of GCase to the lysosome and significantly increasing GCase secretion. Enterovirus 71 also binds to LIMP-2 (also known as SCARB2) on the external surface of the plasma membrane. However, the LIMP-2/SCARB2 binding sequences for enterovirus 71 and GCase are not similar, indicating that LIMP-2/SCARB2 may have multiple or overlapping binding sites with differing specificities. These findings have therapeutic implications for the production of GCase and the distribution of this enzyme that is delivered to various organs. 相似文献
183.
184.
Two isoforms of human membrane-bound alpha Ig resulting from alternative mRNA splicing in the membrane segment 总被引:2,自引:0,他引:2
L M Yu C Peng S M Starnes R S Liou T W Chang 《Journal of immunology (Baltimore, Md. : 1950)》1990,145(11):3932-3936
Antibodies specific for membrane-bound Ig (mIg) but not for their secreted forms would be useful not only for studying the function of mIg but also for modulating B cell activities in vivo. We have proposed that the extracellular portions of the membrane anchor peptides of mIg can be used as antigenic sites for isotype-specific targeting of B cells. Clones containing the genes of human Ig alpha 1 or alpha 2 subclasses were isolated from a genomic DNA library. The gene segments encoding the membrane peptides and their flanking regions were amplified by polymerase chain reaction, subcloned into plasmid pUC19, and the DNA sequences were determined. Human alpha 1 and alpha 2 genes, like murine alpha gene, each has only one membrane exon. The sequences of the human alpha 1 and alpha 2 genes are almost identical in the membrane peptide-coding region. The mRNA from a human mIgA-expressing B cell line, DAKIKI, was isolated, its cDNA prepared, and the segments spanning the membrane peptide-coding region and a part of the constant domain 3 amplified by polymerase chain reaction. DNA sequences revealed that there are two isoforms of alpha 1-chain, resulting from the alternative splicing of the third constant domain of H chain to two acceptor sites in the membrane exon. One isoform has a segment of 32 and the other 26 amino acid residues in the extracellular portion of the membrane peptide. These segments may serve as isotype-specific antigenic epitopes for antibody targeting of mIgA-bearing B cells. 相似文献
185.
Thiopeptin, a sulfur-containing antibiotic, was found to inhibit protein synthesis in a bacterial ribosomal system. The pretreatment of ribosomal subunits with the antibiotic revealed that thiopeptin may act on the 50 S ribosomal subunit. The elongation of peptide chain on the ribosome is more profoundly blocked by the antibiotic than the initiation of protein synthesis. It was demonstrated that thiopeptin inhibits elongation factor (EF)-Tu-dependent GTP hydrolysis and binding of aminoacyl-tRNA to the ribosome. The peptidyl transferase-catalyzed puromycin reaction is not significantly affected by the antibiotic. Thiopeptin inhibits EF-G-associated GTPase reaction, and translocation of peptidyl-tRNA and mRNA from the acceptor site to the donor site. Protein synthesis in ribosomal systems, obtained from rat liver and rabbit reticulocytes are insensitive to the antibiotic. 相似文献
186.
Ying Sun Jane Florer Christopher N. Mayhew Zhanfeng Jia Zhiying Zhao Kui Xu Huimin Ran Benjamin Liou Wujuan Zhang Kenneth D. R. Setchell Jianguo Gu Gregory A. Grabowski 《PloS one》2015,10(3)
Gaucher disease (GD) is caused by insufficient activity of acid β-glucosidase (GCase) resulting from mutations in GBA1. To understand the pathogenesis of the neuronopathic GD, induced pluripotent stem cells (iPSCs) were generated from fibroblasts isolated from three GD type 2 (GD2) and 2 unaffected (normal and GD carrier) individuals. The iPSCs were converted to neural precursor cells (NPCs) which were further differentiated into neurons. Parental GD2 fibroblasts as well as iPSCs, NPCs, and neurons had similar degrees of GCase deficiency. Lipid analyses showed increases of glucosylsphingosine and glucosylceramide in the GD2 cells. In addition, GD2 neurons showed increased α-synuclein protein compared to control neurons. Whole cell patch-clamping of the GD2 and control iPSCs-derived neurons demonstrated excitation characteristics of neurons, but intriguingly, those from GD2 exhibited consistently less negative resting membrane potentials with various degree of reduction in action potential amplitudes, sodium and potassium currents. Culture of control neurons in the presence of the GCase inhibitor (conduritol B epoxide) recapitulated these findings, providing a functional link between decreased GCase activity in GD and abnormal neuronal electrophysiological properties. To our knowledge, this study is first to report abnormal electrophysiological properties in GD2 iPSC-derived neurons that may underlie the neuropathic phenotype in Gaucher disease. 相似文献
187.
Wei-Te Wu Su-Shan Tsai Tung-Sheng Shih Ming-Hsiu Lin Tzu-Chieh Chou Hua Ting Trong-Neng Wu Saou-Hsing Liou 《PloS one》2015,10(6)
Purpose
The purpose of this study was to investigate the association between apnea-hypopnea index (AHI) and metabolic markers and whether the elevated risk of Metabolic Syndrome (MetS) is related to Obstructive Sleep Apnea (OSA).Methods
This cross-sectional study recruited 246 male bus drivers from one transportation company in Taiwan. Each participant was evaluated by a polysomnography (PSG) test and by blood lipids examination. Severity of OSA was categorized according to the apnea-hypopnea index (AHI).Results
The results showed that a 73.3% prevalence of MetS in OSA (AHI > 15) and a 80.0% prevalence of MetS in severe OSA (AHI > 30) were found. After adjusting for confounding variables, an increased level of Body-Mass Index (BMI) and two non-MetS cardiovascular risk factors, total cholesterol/HDL-C ratio and TG/HDL-C ratio was significantly associated with AHI in subjects with severe OSA. MetS was about three times to be present in subjects with severe OSA, even adjusted for BMI.Conclusions
The findings showed a high prevalence of MetS in OSA among professional drivers, especially in the severe group category. BMI was the major contributing factor to OSA. However, the present study did not find a sensitive clinical marker of a detrimental metabolic profile in OSA patients. 相似文献188.
Ai-Wen Hwang Chia-Feng Yen Tsan-Hon Liou Rune J. Simeonsson Wen-Chou Chi Donald J. Lollar Hua-Fang Liao Lin-Ju Kang Ting-Fang Wu Sue-Wen Teng Wen-Ta Chiu 《PloS one》2015,10(5)
Background
Independence and frequency are two distinct dimensions of participation in daily life. The gap between independence and frequency may reflect the role of the environment on participation, but this distinction has not been fully explored.Methods
A total of 18,119 parents or primary caregivers of children with disabilities aged 6.0-17.9 years were interviewed in a cross-sectional nationwide survey with the Functioning Scale of the Disability Evaluation System - Child version (FUNDES-Child). A section consisting of 20 items measured the children’s daily participation in 4 environmental settings: home, neighborhood/community, school, and home/community. Higher independence and frequency restriction scores indicated greater limitation of participation in daily activities. Scores for independence, frequency and independence-frequency gaps were examined across ages along with trend analysis. ANOVA was used to compare the gaps across settings and diagnoses for children with mild levels of severity of impairment.Findings
A negative independence-frequency gap (restriction of frequency was greater than that of independence) was found for children with mild to severe levels of impairment. A positive gap (restriction of independence was greater than that of frequency) was found for children with profound levels of severity. The gaps became wider with age in most settings of children with mild impairment and different diagnoses. Widest negative gaps were found for the neighborhood/community settings than for the other three settings for children with mild to severe impairment.Conclusions
Children’s participation and independence-frequency gaps depend not only on the severity of their impairments or diagnoses, but also on their age, the setting and the support provided by their environment. In Taiwan, more frequency restrictions than ability restrictions were found for children with mild to moderate severity, especially in the neighborhood/community setting, and increased with age. Further identification of environmental opportunities that positively impact frequency of participation is needed. 相似文献189.
Yutian Lei Yifan Xiong Lin Zhang Hao Yan Zhenyuan Li Liou Cao Jiaying Huang Aiping Gu Zhaohui Ni Jiaqi Qian Wei Fang 《PloS one》2015,10(5)
ObjectiveTo investigate the long-term outcomes of peritoneal dialysis (PD) patients with diabetes as primary renal disease and patients with diabetes as a comorbid condition.MethodsAll diabetic patients who commenced PD between January 1, 1995 and June 30, 2012 at Ren Ji Hospital, China were included. Patients were divided into diabetic nephropathy group (DN group) and non-diabetic nephropathy group (NDN group) according to their diagnosis of primary renal disease at the initiation of PD. They were followed until death, cessation of PD, transferred to other centers or to the end of study (June 30, 2013). Outcomes were analyzed by Kaplan-Meier method and Cox regression models.ResultsA total of 163 diabetic patients were enrolled in the study, including 121 (74.2%) in DN group and 42 (25.8%) in NDN group. The 1-, 2-, 3- and 5-year patient survival rates were 89%, 78%, 66% and 51% for DN group, and 85%, 63%, 53% and 25% for NDN group, respectively. Kaplan-Meier analysis showed that patients in NDN group had a worse patient survival compared with DN group (log rank 4.830, P=0.028). Patients in NDN group had a marginally shorter peritonitis-free period (log rank 3.297, P=0.069), however, there was no significant difference in technique survival (log rank 0.040, P=0.841). Multivariate Cox regression analysis showed that older age (HR 1.047, 95% CI 1.022-1.073, p<0.001), cardiovascular disease comorbidity (HR 2.200, 95% CI 0.1.269-3.814, P=0.005) and diabetes as a comorbidity condition (HR 1.806, 95% CI 1.003-3.158, P=0.038) were the independent predictors of increased mortality.ConclusionsPD patients with diabetes as a comorbidity had an inferior patient survival compared to those with diabetic nephropathy, and closer monitoring and extra attention in the former subgroup of patients are therefore warranted. 相似文献
190.
DJ-1 is an oncoprotein that promotes survival of cancer cells through anti-apoptosis. However, DJ-1 also plays a role in regulating IL-1β expression, and whether inflammatory microenvironment built by dysregulated DJ-1 affects cancer progression is still unclear. This study thus aimed to compare the metastatic abilities of melanoma cells in wild-type (WT) and DJ-1 knockout (KO) mice, and to check whether inflammatory microenvironment built in DJ-1 KO mice plays a role in migration of cancer cells to lungs. First, B16F10 melanoma cells (at 6×104) were injected into the femoral vein of mice, and formation of lung nodules, levels of lung IL-1β and serum cytokines, and accumulation of myeloid-derived suppressor cells (MDSCs) were compared between WT and DJ-1 KO mice. Second, the cancer-bearing mice were treated with an interleukin-1 beta (IL-1β) neutralizing antibody to see whether IL-1β is involved in the cancer migration. Finally, cultured RAW 264.7 macrophage and B16F10 melanoma cells were respectively treated with DJ-1 shRNA and recombinant IL-1β to explore underlying molecular mechanisms. Our results showed that IL-1β enhanced survival and colony formation of cultured melanoma cells, and that IL-1β levels were elevated both in DJ-1 KO mice and in cultured macrophage cells with DJ-1 knockdown. The elevated IL-1β correlated with higher accumulation of immunosuppressive MDSCs and formation of melanoma module in the lung of DJ-1 KO mice, and both can be decreased by treating mice with IL-1β neutralizing antibodies. Taken together, these results indicate that immunosuppressive tissue microenvironment built in DJ-1 KO mice can enhance lung migration of cancer, and IL-1β plays an important role in promoting the cancer migration. 相似文献