全文获取类型
收费全文 | 259篇 |
免费 | 16篇 |
出版年
2022年 | 5篇 |
2021年 | 10篇 |
2020年 | 3篇 |
2019年 | 4篇 |
2018年 | 6篇 |
2017年 | 2篇 |
2016年 | 5篇 |
2015年 | 15篇 |
2014年 | 13篇 |
2013年 | 20篇 |
2012年 | 20篇 |
2011年 | 25篇 |
2010年 | 21篇 |
2009年 | 15篇 |
2008年 | 22篇 |
2007年 | 9篇 |
2006年 | 11篇 |
2005年 | 10篇 |
2004年 | 12篇 |
2003年 | 16篇 |
2002年 | 12篇 |
2001年 | 3篇 |
2000年 | 1篇 |
1999年 | 2篇 |
1998年 | 2篇 |
1997年 | 5篇 |
1995年 | 2篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1969年 | 1篇 |
1968年 | 1篇 |
排序方式: 共有275条查询结果,搜索用时 15 毫秒
61.
Troy L Campbell Andrew S Mitchell Elliott M McMillan Darin Bloemberg Dmytro Pavlov Isabelle Messa John G Mielke Joe Quadrilatero 《Experimental biology and medicine (Maywood, N.J.)》2015,240(5):657-668
Apoptosis and autophagy are critical in normal skeletal muscle homeostasis; however, dysregulation can lead to muscle atrophy and dysfunction. Lipotoxicity and/or lipid accumulation may promote apoptosis, as well as directly or indirectly influence autophagic signaling. Therefore, the purpose of this study was to examine the effect of a 16-week high-fat diet on morphological, apoptotic, and autophagic indices in oxidative and glycolytic skeletal muscle of female rats. High-fat feeding resulted in increased fat pad mass, altered glucose tolerance, and lower muscle pAKT levels, as well as lipid accumulation and reactive oxygen species generation in soleus muscle; however, muscle weights, fiber type-specific cross-sectional area, and fiber type distribution were not affected. Moreover, DNA fragmentation and LC3 lipidation as well as several apoptotic (ARC, Bax, Bid, tBid, Hsp70, pBcl-2) and autophagic (ATG7, ATG4B, Beclin 1, BNIP3, p70 s6k, cathepsin activity) indices were not altered in soleus or plantaris following high-fat diet. Interestingly, soleus muscle displayed small increases in caspase-3, caspase-8, and caspase-9 activity, as well as higher ATG12-5 and p62 protein, while both soleus and plantaris muscle showed dramatically reduced Bcl-2 and X-linked inhibitor of apoptosis protein (XIAP) levels. In conclusion, this work demonstrates that 16 weeks of high-fat feeding does not affect tissue morphology or induce a global autophagic or apoptotic phenotype in skeletal muscle of female rats. However, high-fat feeding selectively influenced a number of apoptotic and autophagic indices which could have implications during periods of enhanced muscle stress. 相似文献
62.
63.
Dolezal D Jones CE Lai X Brister JR Mueser TC Nossal NG Hinton DM 《The Journal of biological chemistry》2012,287(22):18596-18607
Efficient DNA replication involves coordinated interactions among DNA polymerase, multiple factors, and the DNA. From bacteriophage T4 to eukaryotes, these factors include a helicase to unwind the DNA ahead of the replication fork, a single-stranded binding protein (SSB) to bind to the ssDNA on the lagging strand, and a helicase loader that associates with the fork, helicase, and SSB. The previously reported structure of the helicase loader in the T4 system, gene product (gp)59, has revealed an N-terminal domain, which shares structural homology with the high mobility group (HMG) proteins from eukaryotic organisms. Modeling of this structure with fork DNA has suggested that the HMG-like domain could bind to the duplex DNA ahead of the fork, whereas the C-terminal portion of gp59 would provide the docking sites for helicase (T4 gp41), SSB (T4 gp32), and the ssDNA fork arms. To test this model, we have used random and targeted mutagenesis to generate mutations throughout gp59. We have assayed the ability of the mutant proteins to bind to fork, primed fork, and ssDNAs, to interact with SSB, to stimulate helicase activity, and to function in leading and lagging strand DNA synthesis. Our results provide strong biochemical support for the role of the N-terminal gp59 HMG motif in fork binding and the interaction of the C-terminal portion of gp59 with helicase and SSB. Our results also suggest that processive replication may involve the switching of gp59 between its interactions with helicase and SSB. 相似文献
64.
65.
Haince JF Ouellet ME McDonald D Hendzel MJ Poirier GG 《Biochimica et biophysica acta》2006,1763(2):226-237
Poly(ADP-ribosyl)ation is a very early cellular response to DNA damage. Poly(ADP-ribose) (PAR) accumulation is transient since PAR is rapidly hydrolyzed by poly(ADP-ribose) glycohydrolase (PARG). PARG may play a prominent role in DNA damage response and repair by removing PAR from modified proteins including PARP-1. Using living cells, we provide evidence that in response to DNA damage induced by gamma-irradiation the cytoplasmic 103 kDa PARG isoform translocates into the nucleus. We further observed that the nuclear GFP-hPARG110 enzyme relocalizes to the cytoplasm in response to DNA damage. Using different GFP-PARG fusion proteins specific for the nuclear and cytoplasmic forms, we demonstrate their dynamic distribution between cytoplasm and nucleoplasm and a high mobility of major PARG isoforms by fluorescence recovery after photobleaching (FRAP). The dynamic relocation of all PARG isoforms presented in this report reveals a novel biological mechanism by which PARG could be involved in DNA damage response. 相似文献
66.
French JP Quindry JC Falk DJ Staib JL Lee Y Wang KK Powers SK 《American journal of physiology. Heart and circulatory physiology》2006,290(1):H128-H136
The Ca2+-activated protease calpain has been shown to play a deleterious role in the heart during ischemia-reperfusion (I/R). We tested the hypothesis that exercise training would minimize I/R-induced calpain activation and provide cardioprotection against I/R-induced injury. Hearts from adult male rats were isolated in a working heart preparation, and myocardial injury was induced with 25 min of global ischemia followed by 45 min of reperfusion. In sedentary control rats, I/R significantly increased calpain activity and impaired cardiac performance (cardiac work during reperfusion = 24% of baseline). Compared with sedentary animals, exercise training prevented the I/R-induced rise in calpain activity and improved cardiac work (recovery = 80% of baseline). Similar to exercise, pharmacological inhibition of calpain activity resulted in comparable cardioprotection against I/R injury (recovery = 86% of baseline). The exercise-induced protection against I/R-induced calpain activation was not due to altered myocardial protein levels of calpain or calpastatin. However, exercise training was associated with increased myocardial antioxidant enzyme activity (Mn-SOD, catalase) and a reduction in oxidative stress. Importantly, exercise training also prevented the I/R-induced degradation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a. These findings suggest that increases in endogenous antioxidants may diminish the free radical-mediated damage and/or degradation of Ca2+ handling proteins (such as SERCA2a) typically observed after I/R. In conclusion, these results support the concept that calpain activation is an important component of I/R-induced injury and that exercise training provides cardioprotection against I/R injury, at least in part, by attenuating I/R-induced calpain activation. 相似文献
67.
Min Zhong Minna Bui Wang Shen Subramanian Baskaran Darin A. Allen Robert A. Elling W. Michael Flanagan Amy D. Fung Emily J. Hanan Shannon O. Harris Stacey A. Heumann Ute Hoch Sheryl N. Ivy Jeffrey W. Jacobs Stuart Lam Heman Lee Robert S. McDowell Johan D. Oslob Hans E. Purkey Michael J. Romanowski Willard Lew 《Bioorganic & medicinal chemistry letters》2009,19(17):5158-5161
This Letter describes the discovery and key structure–activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314. 相似文献
68.
Darin Andrew Croft Federico Anaya David Auerbach Carmala Garzione Bruce J. MacFadden 《Journal of Mammalian Evolution》2009,16(3):175-198
We provide the first faunal report for the early/middle Miocene fauna of Cerdas, Bolivia (16.5–15.3 Ma; 20° 52′ S, 66° 19′ W), based primarily on new specimens collected in 2007. As many as twelve species of mammals in nine families are represented. Notoungulates include Palyeidodon obtusum (Toxodontidae), Protypotherium cf. attenuatum and Protypotherium sp. nov. (Interatheriidae), ‘Plesiotypotherium’ minus and possibly Microtypotherium choquecotense (Mesotheriidae), and Hegetotherium? sp. nov. (Hegetotheriidae). Xenarthrans include Stenotatus planus and Prozaedyus sp. (Cingulata: Dasypodidae), Peltephilidae gen. et sp. nov. (Cingulata), and Xyophorus cf. bondesioi (Pilosa: Nothrotheriidae). A new species of litoptern is also present (Macraucheniidae) as well as an unidentified rodent (Chinchillidae: Lagostominae). Two of these Cerdas species occur in Friasian sensu stricto/Colloncuran SALMA faunas of Patagonia, and perhaps one in Santacrucian SALMA faunas. Among middle latitude localities, Cerdas resembles Chucal, Chile (late early Miocene, Santacrucian SALMA) in community composition (e.g., abundant mesotheriids, few rodent species), but has no species in common; it shares one species with Quebrada Honda, Bolivia (middle Miocene, Laventan SALMA), and perhaps as many as three more. These observations indicate that Cerdas is not referable to the Santacrucian, and that the upper limit of this SALMA in the middle latitudes falls somewhere between 17.5 Ma (the top of Chucal) and 16.5 Ma (the base of Cerdas). Based on the range of dates proposed for the youngest Santacrucian intervals in Patagonia, a diachronous offset of up to 2.1 Ma may exist at this point in the SALMA sequence between middle and high latitude faunas. 相似文献
69.
70.
Blood AJ Iosifescu DV Makris N Perlis RH Kennedy DN Dougherty DD Kim BW Lee MJ Wu S Lee S Calhoun J Hodge SM Fava M Rosen BR Smoller JW Gasic GP Breiter HC;Phenotype Genotype Project on Addiction Mood Disorders 《PloS one》2010,5(11):e13945