全文获取类型
收费全文 | 315篇 |
免费 | 29篇 |
出版年
2022年 | 3篇 |
2021年 | 4篇 |
2020年 | 3篇 |
2019年 | 2篇 |
2018年 | 2篇 |
2017年 | 4篇 |
2016年 | 6篇 |
2015年 | 20篇 |
2014年 | 34篇 |
2013年 | 15篇 |
2012年 | 22篇 |
2011年 | 26篇 |
2010年 | 10篇 |
2009年 | 14篇 |
2008年 | 17篇 |
2007年 | 20篇 |
2006年 | 5篇 |
2005年 | 16篇 |
2004年 | 12篇 |
2003年 | 10篇 |
2002年 | 14篇 |
2001年 | 4篇 |
2000年 | 5篇 |
1999年 | 2篇 |
1998年 | 5篇 |
1996年 | 3篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 3篇 |
1991年 | 2篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1976年 | 5篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1970年 | 4篇 |
1969年 | 3篇 |
1968年 | 5篇 |
1967年 | 1篇 |
1964年 | 1篇 |
1963年 | 3篇 |
1960年 | 2篇 |
1959年 | 1篇 |
1951年 | 1篇 |
1931年 | 2篇 |
排序方式: 共有344条查询结果,搜索用时 17 毫秒
281.
Maarten Niemantsverdriet Peter Nagle Roland K. Chiu Johannes A. Langendijk Harm H. Kampinga Robert P. Coppes 《PloS one》2012,7(12)
The p53 homolog p73 is frequently overexpressed in cancers. Especially the transactivation domain truncated isoform ΔNp73 has oncogenic properties and its upregulation is associated with poor patient survival. It has been shown that ΔNp73 has an inhibitory effect on the transactivation capacity of p53 and other p73 isoforms. Here, we confirm this finding but surprisingly find that ΔNp73 may also stimulate the expression of TGF-β signaling targets. Promoter-reporter analysis indicated that the presence of Smad Binding Elements (SBE) in the promoter is sufficient for stimulation of gene expression by ΔNp73. TGF-β signaling was less efficient in ΔNp73 downregulated cells, whereas tetracycline induced ΔNp73 increased expression of endogenous TGF-β regulated genes PAI-1 and Col1a1. Pull-down assays with SBE DNA suggest that ΔNp73 enhances smad3/4 binding to SBEs, thereby stimulating TGF-β signaling. Chromatin immunoprecipitation assays confirmed a direct interaction between ΔNp73 and SBE. Given the role of TGF-β signaling in carcinogenesis, tumor invasion and metastasis via targets like PAI-1 and Col1a1, our data suggest a model on how this effect of ΔNp73 could be a contributing factor in cancer progression. 相似文献
282.
Heldens L van Genesen ST Hanssen LL Hageman J Kampinga HH Lubsen NH 《Cell stress & chaperones》2012,17(5):603-613
Post-heat shock refolding of luciferase requires chaperones. Expression of a dominant negative HSF1 mutant (dnHSF1), which among other effects depletes cells of HSF1-regulated chaperones, blocked post-heat shock refolding of luciferase targeted to the cytoplasm, nucleus, or peroxisomes, while refolding of endoplasmic reticulum (ER)-targeted luciferase was inhibited by about 50 %. Luciferase refolding in the cytoplasm could be partially restored by expression of HSPA1A and fully by both HSPA1A and DNAJB1. For full refolding of ER luciferase, HSPA1A expression sufficed. Neither nuclear nor peroxisomal refolding was rescued by HSPA1A. A stimulatory effect of DNAJB1 on post-heat shock peroxisomal luciferase refolding was seen in control cells, while refolding in the cytoplasm or nucleus in control cells was inhibited by DNAJB1 expression in the absence of added HSPA1A. HSPB1 also improved refolding of peroxisomal luciferase in control cells, but not in dnHSF1 expressing cells. HSP90, HSPA5, HSPA6, and phosphomevalonate kinase (of which the synthesis is also downregulated by dnHSF1) had no effect on peroxisomal refolding in either control or chaperone-depleted cells. The chaperone requirement for post-heat shock refolding of peroxisomal luciferase in control cells is thus unusual in that it can be augmented by DNAJB1 or HSPB1 but not by HSPA1A; in dnHSF1 expressing cells, expression of none of the (co)-chaperones tested was effective, and an as yet to be identified, HSF1-regulated function is required. 相似文献
283.
Wang Z Potter CS Sundberg JP Hogenesch H 《Journal of cellular and molecular medicine》2012,16(10):2271-2279
Mice with spontaneous mutations in the Sharpin gene develop chronic proliferative dermatitis that is characterized by eosinophilic inflammation of the skin and other organs with increased expression of type 2 cytokines and dysregulated development of lymphoid tissues. The mutant mice share phenotypic features with human hypereosinophilic syndromes. The biological function of SHARPIN and how its absence leads to such a complex inflammatory phenotype in mice are poorly understood. However, recent studies identified SHARPIN as a novel modulator of immune and inflammatory responses. The emerging mechanistic model suggests that SHARPIN functions as an important adaptor component of the linear ubiquitin chain assembly complex that modulates activation of NF-κB signalling pathway, thereby regulating cell survival and apoptosis, cytokine production and development of lymphoid tissues. In this review, we will summarize the current understanding of the ubiquitin-dependent regulatory mechanisms involved in NF-κB signalling, and incorporate the recently obtained molecular insights of SHARPIN into this pathway. Recent studies identified SHARPIN as an inhibitor of β1-integrin activation and signalling, and this may be another mechanism by which SHARPIN regulates inflammation. Furthermore, the disrupted lymphoid organogenesis in SHARPIN-deficient mice suggests that SHARPIN-mediated NF-κB regulation is important for de novo development of lymphoid tissues. 相似文献
284.
285.
286.
Hans Wouters Liset Van Dijk Harm C. J. Geers Nina A. Winters Erica C. G. Van Geffen Anne M. Stiggelbout Marcel L. Bouvy 《PloS one》2016,11(1)
Background
Non-adherence to statins is substantial and is associated with numerous perceptions and experiences. However, time limits in clinical practice constrain in depth explorations of these perceptions and experiences.Objectives
To propose and examine a strategy aimed at an efficient assessment of a wide array of perceptions and experiences regarding the efficacy, side effects, and practical problems of statins. Furthermore, to assess associations between this wide array of experiences and perceptions and non-adherence and to examine whether patients'' ''perceived self-efficacy'' moderated these associations.Methods
Patients were recruited through community pharmacies. A wide array of specific patient perceptions and experiences was efficiently assessed using the electronic Tailored Medicine Inventory that allows people to skip irrelevant questions. Adherence was measured through self-report and pharmacy refill data.Results
Of the two-hundred twenty-nine patients who participated (mean age 63.9, standard deviation 10.2), 40%-70% doubted the necessity of or lacked knowledge about the efficacy of statins, 20%-35% of the patients were worried about joint and muscle side effects or had experienced these, and 23% had encountered practical problems regarding information about statins, intake of tablets, the package, or the blister. Experiencing more practical problems was associated with increased unintentional non-adherence (Odds ratio 1.54, 95%CI:1.13–2.10, P < 0.01), whereas worrying about side effects was associated with increased intentional non-adherence (Odds ratio 1.90, 95%CI:1.17–3.08, P < 0.01). Higher ''perceived self-efficacy'' did not moderate these associations.Conclusions
Insight into patients'' specific barriers with regard to appropriate statin use may reveal personal reasons for being non-adherent. The Tailored Medicine Inventory is a promising tool to devise individualized intervention strategies aimed at improving adherence by the clinician-patient alliance. 相似文献287.
288.
The purpose of the present study was to examine the changes in apparent mechanical properties of trabecular bone in the mandibular condyle during fetal development and to investigate the contributions of altering architecture, and degree and distribution of mineralization to this change. Three-dimensional, high-resolution micro-computed tomography (microCT) reconstructions were utilized to assess the altering architecture and mineralization during development. From the reconstructions, inhomogeneous finite element models were constructed, in which the tissue moduli were scaled to the local degree of mineralization of bone (DMB). In addition, homogeneous models were devised to study the separate influence of architectural and DMB changes on apparent mechanical properties. It was found that the bone structure became stiffer with age. Both the mechanical and structural anisotropies pointed to a rod-like structure that was predominantly oriented from anteroinferior to posterosuperior. Resistance against shear, also increasing with age, was highest in the sagittal plane. The reorganization of trabecular elements, which occurred without a change in bone volume fraction, contributed to the increase in apparent stiffness. The increase in DMB, however, contributed more dominantly. Incorporating the observed inhomogeneous distribution of mineralization decreased the apparent stiffness, but increased the mechanical anisotropy. This denotes that there might be a directional dependency of the DMB of trabecular elements, i.e. differently orientated trabecular elements might have different DMBs. In conclusion, the changes in DMB and its distribution are important to consider when studying mechanical properties during development and should be considered in other situations where differences in DMB are expected. 相似文献
289.
Jesus A. Silvas Desarey Morales Vasquez Jun-Gyu Park Kevin Chiem Anna Allu-Guardia Andreu Garcia-Vilanova Roy Neal Platt Lisa Miorin Thomas Kehrer Anastasija Cupic Ana S. Gonzalez-Reiche Harm van Bakel Adolfo García-Sastre Tim Anderson Jordi B. Torrelles Chengjin Ye Luis Martinez-Sobrido 《Journal of virology》2021,95(17)
290.