全文获取类型
收费全文 | 1304篇 |
免费 | 150篇 |
国内免费 | 53篇 |
学科分类
医药卫生 | 1507篇 |
出版年
2024年 | 7篇 |
2023年 | 40篇 |
2022年 | 65篇 |
2021年 | 92篇 |
2020年 | 69篇 |
2019年 | 44篇 |
2018年 | 54篇 |
2017年 | 57篇 |
2016年 | 61篇 |
2015年 | 103篇 |
2014年 | 84篇 |
2013年 | 123篇 |
2012年 | 83篇 |
2011年 | 81篇 |
2010年 | 57篇 |
2009年 | 63篇 |
2008年 | 72篇 |
2007年 | 52篇 |
2006年 | 35篇 |
2005年 | 43篇 |
2004年 | 48篇 |
2003年 | 36篇 |
2002年 | 23篇 |
2001年 | 16篇 |
2000年 | 23篇 |
1999年 | 7篇 |
1998年 | 11篇 |
1997年 | 6篇 |
1996年 | 2篇 |
1995年 | 4篇 |
1994年 | 3篇 |
1993年 | 8篇 |
1992年 | 5篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1989年 | 6篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 5篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1976年 | 1篇 |
排序方式: 共有1507条查询结果,搜索用时 15 毫秒
41.
AIM: Telomere shortening has been reported in several diseases including atherosclerosis and Type 1 diabetes. Asian Indians have an increased predilection for Type 2 diabetes and premature coronary artery disease. The aim of this study was to determine whether telomeric shortening occurs in Asian Indian Type 2 diabetic patients. METHODS: Using Southern-blot analysis we determined mean terminal restriction fragment (TRF) length, a measure of average telomere size, in leucocyte DNA. Type 2 diabetic patients without any diabetes-related complications (n = 40) and age- and sex-matched control non-diabetic subjects (n = 40) were selected from the Chennai Urban Rural Epidemiology Study (CURES). Plasma level of malondialdehyde (MDA), a marker of lipid peroxidation, was measured by TBARS (thiobarbituric acid reactive substances) using a fluorescence method. RESULTS: Mean (+/- SE) TRF lengths of the Type 2 diabetic patients (6.01 +/- 0.2 kb) were significantly shorter than those of the control subjects (9.11 +/- 0.6 kb) (P = 0.0001). Among the biochemical parameters, only levels of TBARS showed a negative correlation with shortened telomeres in the diabetic subjects (r = -0.36; P = 0.02). However, telomere lengths were negatively correlated with insulin resistance (HOMA-IR) (r = -0.4; P = 0.01) and age (r = -0.3; P = 0.058) and positively correlated with HDL levels (r = 0.4; P = 0.01) in the control subjects. Multiple linear regression (MLR) analysis revealed diabetes to be significantly (P < 0.0001) associated with shortening of TRF lengths. CONCLUSIONS: Telomere shortening occurs in Asian Indian Type 2 diabetic patients. 相似文献
42.
43.
Mahito Sadaie Rafik Salama Thomas Carroll Kosuke Tomimatsu Tamir Chandra Andrew R.J. Young Masako Narita Pedro A. Pérez-Mancera Dorothy C. Bennett Heung Chong Hiroshi Kimura Masashi Narita 《Genes & development》2013,27(16):1800-1808
Senescence is a stress-responsive form of stable cell cycle exit. Senescent cells have a distinct gene expression profile, which is often accompanied by the spatial redistribution of heterochromatin into senescence-associated heterochromatic foci (SAHFs). Studying a key component of the nuclear lamina lamin B1 (LMNB1), we report dynamic alterations in its genomic profile and their implications for SAHF formation and gene regulation during senescence. Genome-wide mapping reveals that LMNB1 is depleted during senescence, preferentially from the central regions of lamina-associated domains (LADs), which are enriched for Lys9 trimethylation on histone H3 (H3K9me3). LMNB1 knockdown facilitates the spatial relocalization of perinuclear H3K9me3-positive heterochromatin, thus promoting SAHF formation, which could be inhibited by ectopic LMNB1 expression. Furthermore, despite the global reduction in LMNB1 protein levels, LMNB1 binding increases during senescence in a small subset of gene-rich regions where H3K27me3 also increases and gene expression becomes repressed. These results suggest that LMNB1 may contribute to senescence in at least two ways due to its uneven genome-wide redistribution: first, through the spatial reorganization of chromatin and, second, through gene repression. 相似文献
44.
BackgroundHigher numbers of senescent cells have been implicated in age-related disease pathologies. However, whether different diseases have different senescent phenotypes is unknown. Here we provide a systematic overview of the current available evidence of senescent cells in age-related diseases pathologies in humans and the markers currently used to detect senescence levels in humans.MethodsPubMed, Web of Science and EMBASE were systematically searched from inception to the 29th of September 2019, using keywords related to ‘senescence’, ‘age-related diseases’ and ‘biopsies’.ResultsIn total 12,590 articles were retrieved of which 103 articles were included in this review. The role of senescence in age-related disease has been assessed in 9 different human organ system and 27 different age-related diseases of which heart (27/103) and the respiratory systems (18/103) are the most investigated. Overall, 27 different markers of senescence have been used to determine cellular senescence and the cell cycle regulator p16ink4a is most often used (23/27 age-related pathologies).ConclusionThis review demonstrates that a higher expression of senescence markers are observed within disease pathologies. However, not all markers to detect senescence have been assessed in all tissue types. 相似文献
45.
46.
It has been widely accepted that telomere shortening acts as a cell division counting mechanism that beyond a set critical
length signals cells to enter replicative senescence. In this study, we demonstrate that by simply lowering the oxygen content
of the cell culture environment 10-fold (20–2%) extends the replicative lifespan of fetal bovine fibroblasts at least five-times
(30–150 days). Although, low oxygen fibroblasts display a slightly slower rate (P > 0.05) of telomere attrition than their high oxygen counterparts (171 bp versus 182 bp/PD), late passage fibroblasts (>50 PD)
that have extended their replicative capacity under low oxygen conditions exhibited significantly (P < 0.05) shorter telomere lengths (11,135 ± 467 bp) compared to senescent cells (25–34 PD) cultured under high oxygen conditions
(14,827 ± 1173 bp). There was a significant increase (P < 0.05) in chromosomal abnormalities with continual cell division under both high and low oxygen environments, however, fibroblasts
displayed a significant reduction (P < 0.001) in chromosomal abnormalities at low oxygen tensions compared to those under 20% oxygen. These apparent protective
effects on telomere shortening, delayed senescence and reduced chromosomal aberrations may be attributed to the up-regulation
of telomerase activity observed for fibroblasts cultured under low oxygen. These results are consistent with the idea that
a critically short telomere length may not be the sole trigger of replicative senescence, but may be regulated by the integrity
of telomere structure itself and/or the amount of oxidative DNA damage in the cell. 相似文献
47.
Hagai Yanai Albert Shteinberg Ziv Porat Arie Budovsky Alex Braiman Rolf Zeische Vadim E. Fraifeld 《Aging》2015,7(9):664-672
Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with unknown etiology and no effective treatment. In this study, we show that primary cultures of fibroblasts derived from lung biopsies of IPF patients exhibited (i) accelerated replicative cellular senescence (CS); (ii) high resistance to oxidative-stress-induced cytotoxicity or CS; (iii) a CS-like morphology (even at the proliferative phase); and (iv) rapid accumulation of senescent cells expressing the myofibroblast marker α-SMA. Our findings suggest that CS could serve as a bridge connecting lung aging and its quite frequent outcome -- pulmonary fibrosis, and be an important player in the disease progression. Consequently, targeting senescent cells offers the potential of being a promising therapeutic approach. 相似文献
48.
To date, most studies of Shc family of signaling adaptor proteins have been focused on the near-ubiquitously expressed ShcA, indicating its relevance to age-related diseases and longevity. Although the role of the neuronal ShcC protein is much less investigated, accumulated evidence suggests its importance for neuroprotection against such aging-associated conditions as brain ischemia and oxidative stress. Here, we summarize more than decade of studies on the ShcC expression and function in normal brain, age-related brain pathologies and immune disorders with a focus on the interactions of ShcC with signaling proteins/pathways, and the possible implications of these interactions for changes associated with aging. 相似文献
49.
Klotho是重要的内源性多效蛋白,参与衰老和钙磷代谢等病理生理过程,与心血管疾病密切相关。近期的临床研究发现低水平的Klotho与更多的心血管危险因素关联,并能预测心血管疾病的发病风险和不良预后;基础研究也表明Klotho在维持血管稳态和正常心功能中发挥了至关重要的作用。Klotho可以促进一氧化氮(NO)的生成,抑制炎症因子和黏附分子的表达,介导抗氧化、抗凋亡、抗衰老的生物学效应,延缓动脉粥样硬化及血管钙化,并抑制心肌肥厚和纤维化。Klotho或可作为一个新的干预靶点,为心血管疾病的防治提供新的思路。文章就Klotho与心血管疾病的关系及其潜在的生物学机制做一综述。 相似文献
50.