全文获取类型
收费全文 | 194篇 |
免费 | 24篇 |
专业分类
218篇 |
出版年
2022年 | 1篇 |
2021年 | 2篇 |
2020年 | 1篇 |
2019年 | 3篇 |
2018年 | 2篇 |
2017年 | 2篇 |
2016年 | 1篇 |
2015年 | 4篇 |
2014年 | 9篇 |
2013年 | 4篇 |
2012年 | 12篇 |
2011年 | 12篇 |
2010年 | 11篇 |
2009年 | 5篇 |
2008年 | 5篇 |
2007年 | 11篇 |
2006年 | 6篇 |
2005年 | 17篇 |
2004年 | 17篇 |
2003年 | 3篇 |
2002年 | 11篇 |
2001年 | 8篇 |
2000年 | 3篇 |
1999年 | 5篇 |
1998年 | 4篇 |
1997年 | 4篇 |
1996年 | 3篇 |
1995年 | 1篇 |
1994年 | 5篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1991年 | 5篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 2篇 |
1987年 | 4篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 2篇 |
1970年 | 1篇 |
1954年 | 2篇 |
1947年 | 1篇 |
排序方式: 共有218条查询结果,搜索用时 8 毫秒
171.
In most mammals under natural conditions weaning is gradual. Weaning occurs after the mammary gland naturally produces much less milk than it did at peak and established lactation. Involution occurs following the cessation of milk evacuation from the mammary glands. The abrupt termination of the evacuation of milk from the mammary gland at peak and established lactation induces abrupt involution. Evidence on mice has shown that during abrupt involution, mammary gland utilizes some of the same tissue remodeling programs that are activated during wound healing. These results led to the proposition of the “involution hypothesis”. According to the involution hypothesis, involution is associated with increased risk for developing breast cancer. However, the involution hypothesis is challenged by the metabolic and immunological events that characterize the involution process that follows gradual weaning. It has been shown that gradual weaning is associated with pre-adaption to the forthcoming break between dam and offspring and is followed by an orderly reprogramming of the mammary gland tissue. As discussed herein, such response may actually protect the mammary glands against the development of breast cancer and thus, may explain the protective effect of extended breastfeeding. On the other hand, the termination of breastfeeding during the first 6 months of lactation is likely associated with an abrupt involution and thus with an increased risk for developing breast cancer. Review of the literature on the epidemiology of breast cancer principally supports those conclusions. 相似文献
172.
Gene trap as a tool for genome annotation and analysis of X chromosome inactivation in human embryonic stem cells 总被引:6,自引:0,他引:6 下载免费PDF全文
Human embryonic stem (ES) cells were suggested to be an important tool in transplantation medicine. However, they also play a major role in human genetics. Using the gene trap strategy, we have created a bank of clones with insertion mutations in human ES cells. These insertions occurred within known, predicted and unknown genes, and thus assist us in annotating the genes in the human genome. The insertions into the genome occurred in multiple chromosomes with a preference to larger chromosomes. Utilizing a clone where the integration occurred in the X chromosome, we have studied X-chromosome inactivation in human cells. We thus show that in undifferentiated female human ES cells both X chromosomes remain active and upon differentiation one chromosome undergoes inactivation. In the differentiated embryonic cells the inactivation is random, while in the extra-embryonic cells it is non-random. In addition, using a selection methodology, we demonstrate that in a minority of the cells partial inactivation and XIST expression occur even in the undifferentiated cells. We suggest that X chromosome inactivation during human embryogenesis, which coincides with differentiation, may be separated from the differentiation process. The genetic manipulation of human ES cells now opens new ways of analyzing chromosome status and gene expression in humans. 相似文献
173.
The two TORCs and Akt 总被引:3,自引:0,他引:3
The regulatory circuits that control the activities of the two distinct target of rapamycin (TOR) complexes, TORC1 and TORC2, and of Akt have been a focus of intense research in recent years. It has become increasingly evident that these regulatory circuits control some of the most fundamental aspects of metabolism, cell growth, proliferation, survival, and differentiation at both the cellular and organismal levels. As such, they also play a pivotal role in the genesis of diseases including cancer, diabetes, aging, and degenerative diseases. This review highlights recent developments aimed at deciphering the interplay between Akt and mTORCs as well as their role in embryonic development and in cancer. 相似文献
174.
175.
Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos 总被引:1,自引:0,他引:1
Eiges R Urbach A Malcov M Frumkin T Schwartz T Amit A Yaron Y Eden A Yanuka O Benvenisty N Ben-Yosef D 《Cell Stem Cell》2007,1(5):568-577
We report on the establishment of a human embryonic stem cell (HESC) line from a preimplantation fragile X-affected embryo and demonstrate its value as an appropriate model to study developmentally regulated events that are involved in the pathogenesis of this disorder. Fragile X syndrome results from FMR1 gene inactivation due to a CGG expansion at the 5'UTR region of the gene. Early events in FMR1 silencing have not been fully characterized due to the lack of appropriate animal or cellular models. Here we show that, despite the presence of a full mutation, affected undifferentiated HESCs express FMR1 and are DNA unmethylated. However, epigenetic silencing by DNA methylation and histone modification occurs upon differentiation. Our unique cell system allows the dissection of the sequence by which these epigenetic changes are acquired and illustrates the importance of HESCs in unraveling developmentally regulated mechanisms associated with human genetic disorders. 相似文献
176.
Mechanisms controlling DNA resection at sites of damage and affecting genome stability have been the subject of deep investigation, though their complexity is not yet fully understood. Specifically, the regulatory role of post-translational modifications in the localization, stability and function of DNA repair proteins is an important aspect of such complexity. Here, we took advantage of the superior resolution of phosphorylated proteins provided by Phos-Tag technology to study pathways controlling the reversible phosphorylation of yeast Exo1, an exonuclease involved in a number of DNA repair pathways. We report that Rad53, a checkpoint kinase downstream of Mec1, is responsible for Exo1 phosphorylation in response to DNA replication stress and we demonstrate a role for the type-2A protein phosphatase Pph3 in the dephosphorylation of both Rad53 and Exo1 during checkpoint recovery. Fluorescence microscopy studies showed that Rad53-dependent phosphorylation is not required for the recruitment or the release of Exo1 from the nucleus, whereas 14-3-3 proteins are necessary for Exo1 nuclear translocation. By shedding light on the mechanism of Exo1 control, these data underscore the importance of post-translational modifications and protein interactions in the regulation of DNA end resection. 相似文献
177.
178.
Acute heat stress brings down milk secretion in dairy cows by up-regulating the activity of the milk-borne negative feedback regulatory system 总被引:2,自引:0,他引:2
Background
The objective of this study was to determine if acute heat stress (HS) decreases milk secretion by activating the milk-borne negative feedback system, as an emergency physiological response to prevent a life-threatening situation. To induce HS, summer acclimatized dairy cows were exposed to full sun under mid-summer Mediterranean conditions, with and without conventional cooling procedures. 相似文献179.
Changhong Li Pan Chen Andrew Palladino Srinivas Narayan Laurie K. Russell Samir Sayed Guoxiang Xiong Jie Chen David Stokes Yasmeen M. Butt Patricia M. Jones Heather W. Collins Noam A. Cohen Akiva S. Cohen Itzhak Nissim Thomas J. Smith Arnold W. Strauss Franz M. Matschinsky Michael J. Bennett Charles A. Stanley 《The Journal of biological chemistry》2010,285(41):31806-31818
The mechanism of insulin dysregulation in children with hyperinsulinism associated with inactivating mutations of short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) was examined in mice with a knock-out of the hadh gene (hadh−/−). The hadh−/− mice had reduced levels of plasma glucose and elevated plasma insulin levels, similar to children with SCHAD deficiency. hadh−/− mice were hypersensitive to oral amino acid with decrease of glucose level and elevation of insulin. Hypersensitivity to oral amino acid in hadh−/− mice can be explained by abnormal insulin responses to a physiological mixture of amino acids and increased sensitivity to leucine stimulation in isolated perifused islets. Measurement of cytosolic calcium showed normal basal levels and abnormal responses to amino acids in hadh−/− islets. Leucine, glutamine, and alanine are responsible for amino acid hypersensitivity in islets. hadh−/− islets have lower intracellular glutamate and aspartate levels, and this decrease can be prevented by high glucose. hadh−/− islets also have increased [U-14C]glutamine oxidation. In contrast, hadh−/− mice have similar glucose tolerance and insulin sensitivity compared with controls. Perifused hadh−/− islets showed no differences from controls in response to glucose-stimulated insulin secretion, even with addition of either a medium-chain fatty acid (octanoate) or a long-chain fatty acid (palmitate). Pull-down experiments with SCHAD, anti-SCHAD, or anti-GDH antibodies showed protein-protein interactions between SCHAD and GDH. GDH enzyme kinetics of hadh−/− islets showed an increase in GDH affinity for its substrate, α-ketoglutarate. These studies indicate that SCHAD deficiency causes hyperinsulinism by activation of GDH via loss of inhibitory regulation of GDH by SCHAD. 相似文献
180.
Rat fetuses of 17-19-day gestation were injected in utero with 5-azacytidine (two to three daily injections of 40 micrograms/fetus). Neonates were injected with seven daily injections (1 mg/kg). DNA samples were isolated from the fetal and neonatal livers and neonatal spleen and subjected to analysis of their methylation status. Overall methylation was analyzed by the nearest-neighbor analysis (at CpG sites) and the pattern of methylation at CCGG sites by Southern blot analysis using phosphoenolpyruvate carboxykinase (PEPCK) sequences as probes. While DNAs from the liver and spleen undergo hypomethylation to the same extent in response to the 5-azacytidine treatment, the changes in the methylation patterns of the PEPCK gene in the two tissues are strikingly different. The changes observed indicate that a decrease in the methylase activity (inhibition by 5-azacytidine) results in site- and tissue-specific hypomethylation. The tissue-specific changes in the methylation pattern are associated with a tissue-specific expression of the PEPCK gene. Although the gene is hypomethylated by azacytidine in both liver and spleen, it is expressed only in the liver. The expression of already active genes (PEPCK in the kidney and albumin in the liver) is not further enhanced by the drug. 相似文献