全文获取类型
收费全文 | 813篇 |
免费 | 120篇 |
国内免费 | 1篇 |
专业分类
934篇 |
出版年
2022年 | 9篇 |
2021年 | 23篇 |
2019年 | 19篇 |
2018年 | 12篇 |
2017年 | 25篇 |
2016年 | 23篇 |
2015年 | 42篇 |
2014年 | 28篇 |
2013年 | 44篇 |
2012年 | 53篇 |
2011年 | 44篇 |
2010年 | 49篇 |
2009年 | 26篇 |
2008年 | 48篇 |
2007年 | 39篇 |
2006年 | 40篇 |
2005年 | 33篇 |
2004年 | 36篇 |
2003年 | 37篇 |
2002年 | 21篇 |
2001年 | 17篇 |
2000年 | 17篇 |
1999年 | 22篇 |
1998年 | 4篇 |
1997年 | 8篇 |
1996年 | 7篇 |
1995年 | 6篇 |
1994年 | 8篇 |
1993年 | 5篇 |
1992年 | 11篇 |
1991年 | 8篇 |
1990年 | 14篇 |
1989年 | 9篇 |
1988年 | 12篇 |
1987年 | 7篇 |
1986年 | 6篇 |
1985年 | 6篇 |
1984年 | 7篇 |
1983年 | 10篇 |
1982年 | 7篇 |
1981年 | 6篇 |
1980年 | 7篇 |
1979年 | 6篇 |
1978年 | 7篇 |
1977年 | 6篇 |
1976年 | 7篇 |
1974年 | 5篇 |
1972年 | 8篇 |
1971年 | 8篇 |
1969年 | 4篇 |
排序方式: 共有934条查询结果,搜索用时 0 毫秒
41.
42.
A proteomics approach to identifying key protein targets involved in VEGF inhibitor mediated attenuation of bleomycin‐induced pulmonary fibrosis 下载免费PDF全文
Yogesh M. Kulkarni Sucharita Dutta Anand Krishnan V. Iyer Rajkumar Venkatadri Vivek Kaushik Vani Ramesh Clayton A. Wright Oliver John Semmes Juan S. Yakisich Neelam Azad 《Proteomics》2016,16(1):33-46
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a life expectancy of less than 5 years post diagnosis for most patients. Poor molecular characterization of IPF has led to insufficient understanding of the pathogenesis of the disease, resulting in lack of effective therapies. In this study, we have integrated a label‐free LC‐MS based approach with systems biology to identify signaling pathways and regulatory nodes within protein interaction networks that govern phenotypic changes that may lead to IPF. Ingenuity Pathway Analysis of proteins modulated in response to bleomycin treatment identified PI3K/Akt and Wnt signaling as the most significant profibrotic pathways. Similar analysis of proteins modulated in response to vascular endothelial growth factor (VEGF) inhibitor (CBO‐P11) treatment identified natural killer cell signaling and PTEN signaling as the most significant antifibrotic pathways. Mechanistic/mammalian target of rapamycin (mTOR) and extracellular signal‐regulated kinase (ERK) were identified to be key mediators of pro‐ and antifibrotic response, where bleomycin (BLM) treatment resulted in increased expression and VEGF inhibitor treatment attenuated expression of mTOR and ERK. Using a BLM mouse model of pulmonary fibrosis and VEGF inhibitor CBO‐P11 as a therapeutic measure, we identified a comprehensive set of signaling pathways and proteins that contribute to the pathogenesis of pulmonary fibrosis that can be targeted for therapy against this fatal disease. 相似文献
43.
Julia A. Sabet Lara K. Park Lakshmanan K. Iyer Albert K. Tai Gar Yee Koh Anna C. Pfalzer Laurence D. Parnell Joel B. Mason Zhenhua Liu Alexander J. Byun Jimmy W. Crott 《PloS one》2016,11(3)
Background
The importance of maternal nutrition to offspring health and risk of disease is well established. Emerging evidence suggests paternal diet may affect offspring health as well.Objective
In the current study we sought to determine whether modulating pre-conception paternal B vitamin intake alters intestinal tumor formation in offspring. Additionally, we sought to identify potential mechanisms for the observed weight differential among offspring by profiling hepatic gene expression and lipid content.Methods
Male Apc1638N mice (prone to intestinal tumor formation) were fed diets containing replete (control, CTRL), mildly deficient (DEF), or supplemental (SUPP) quantities of vitamins B2, B6, B12, and folate for 8 weeks before mating with control-fed wild type females. Wild type offspring were euthanized at weaning and hepatic gene expression profiled. Apc1638N offspring were fed a replete diet and euthanized at 28 weeks of age to assess tumor burden.Results
No differences in intestinal tumor incidence or burden were found between male Apc1638N offspring of different paternal diet groups. Although in female Apc1638N offspring there were no differences in tumor incidence or multiplicity, a stepwise increase in tumor volume with increasing paternal B vitamin intake was observed. Interestingly, female offspring of SUPP and DEF fathers had a significantly lower body weight than those of CTRL fed fathers. Moreover, hepatic trigylcerides and cholesterol were elevated 3-fold in adult female offspring of SUPP fathers. Weanling offspring of the same fathers displayed altered expression of several key lipid-metabolism genes. Hundreds of differentially methylated regions were identified in the paternal sperm in response to DEF and SUPP diets. Aside from a few genes including Igf2, there was a striking lack of overlap between these genes differentially methylated in sperm and differentially expressed in offspring.Conclusions
In this animal model, modulation of paternal B vitamin intake prior to mating alters offspring weight gain, lipid metabolism and tumor growth in a sex-specific fashion. These results highlight the need to better define how paternal nutrition affects the health of offspring. 相似文献44.
Mark Pennington Aleksandra Gentry-Maharaj Chloe Karpinskyj Alec Miners Julie Taylor Ranjit Manchanda Rema Iyer Michelle Griffin Andy Ryan Ian Jacobs Usha Menon Rosa Legood 《PloS one》2016,11(11)
BackgroundThere is limited evidence on the costs of Endometrial Cancer (EC) by stage of disease. We estimated the long-term secondary care costs of EC according to stage at diagnosis in an English population-based cohort.MethodsWomen participating in UKCTOCS and diagnosed with EC following enrolment (2001–2005) and prior to 31st Dec 2009 were identified to have EC through multiple sources. Survival was calculated through data linkage to death registry. Costs estimates were derived from hospital records accessed from Hospital Episode Statistics (HES) with additional patient level covariates derived from case notes and patient questionnaires. Missing and censored data was imputed using Multiple Imputation. Regression analysis of cost and survival was undertaken.Results491 of 641 women with EC were included. Five year total costs were strongly dependent on stage, ranging from £9,475 (diagnosis at stage IA/IB) to £26,080 (diagnosis at stage III). Stage, grade and BMI were the strongest predictors of costs. The majority of costs for stage I/II EC were incurred in the first six months after diagnosis while for stage III / IV considerable costs accrued after the first six months.ConclusionsIn addition to survival advantages, there are significant cost savings if patients with EC are detected earlier. 相似文献
45.
46.
Prabakaran Nagarajan Paula A. Agudelo Garcia Chitra C. Iyer Liudmila V. Popova William D. Arnold Mark R. Parthun 《Aging cell》2019,18(5)
Histone acetyltransferase 1 (Hat1) is responsible for the acetylation of newly synthesized histone H4 on lysines 5 and 12 during the process of chromatin assembly. To understand the broader biological role of Hat1, we have generated a conditional mouse knockout model of this enzyme. We previously reported that Hat1 is required for viability and important for mammalian development and genome stability. In this study, we show that haploinsufficiency of Hat1 results in a significant decrease in lifespan. Defects observed in Hat1+/? mice are consistent with an early‐onset aging phenotype. These include lordokyphosis (hunchback), muscle atrophy, minor growth retardation, reduced subcutaneous fat, cancer, and paralysis. In addition, the expression of Hat1 is linked to the normal aging process as Hat1 mRNA and protein becomes undetectable in many tissues in old mice. At the cellular level, fibroblasts from Hat1 haploinsufficient embryos undergo early senescence and accumulate high levels of p21. Hat1+/? mouse embryonic fibroblasts (MEFs) display modest increases in endogenous DNA damage but have significantly higher levels of reactive oxygen species (ROS). Consistently, further studies show that Hat1?/? MEFs exhibit mitochondrial defects suggesting a critical role for Hat1 in mitochondrial function. Taken together, these data show that loss of Hat1 induces multiple hallmarks of early‐onset aging. 相似文献
47.
Amyotrophic lateral sclerosis (ALS), a progressive motor-neurone disease, affects individuals usually aged between 50 and 70 years. C21orf2, recently identified as the new ALS susceptibility gene, harbours rare missense mutations that cause this fatal disease. We used bioinformatics and molecular modelling approaches to study specific ALS-associated mutations in C21orf2. Both native and mutant structures of the protein obtained from homology modelling were analysed in detail to gain insights into the potential impact of these mutations on the protein structure and its function. Our analyses reveal that more than 75% of the mutations are likely to be deleterious. These effects seem to carry through to mouse C21orf2 as well, indicating that mouse would make a viable animal model to study this ALS gene in detail. 相似文献
48.
49.
50.
Iyer VR 《Trends in biotechnology》2004,22(10):498-500
Genomic approaches are valuable for understanding the complex layer of gene regulation that involves the control of RNA processing, localization and stability. Recent work provides a prime example of the power of unbiased microarray-based methods to discover unexpected functions for proteins in the RNA world. The challenges ahead relate to extending such approaches to larger genomes and to integrating this type of information with that generated by standard expression profiling. 相似文献