全文获取类型
收费全文 | 155篇 |
免费 | 17篇 |
出版年
2023年 | 1篇 |
2021年 | 5篇 |
2020年 | 4篇 |
2019年 | 5篇 |
2018年 | 9篇 |
2017年 | 5篇 |
2016年 | 5篇 |
2015年 | 13篇 |
2014年 | 8篇 |
2013年 | 12篇 |
2012年 | 10篇 |
2011年 | 7篇 |
2010年 | 10篇 |
2009年 | 12篇 |
2008年 | 5篇 |
2007年 | 5篇 |
2006年 | 8篇 |
2005年 | 2篇 |
2004年 | 5篇 |
2003年 | 4篇 |
2002年 | 3篇 |
2001年 | 4篇 |
2000年 | 1篇 |
1999年 | 3篇 |
1998年 | 3篇 |
1997年 | 1篇 |
1996年 | 1篇 |
1994年 | 1篇 |
1993年 | 2篇 |
1991年 | 2篇 |
1990年 | 4篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1984年 | 3篇 |
1983年 | 1篇 |
1977年 | 2篇 |
1969年 | 1篇 |
排序方式: 共有172条查询结果,搜索用时 15 毫秒
51.
Angèle Nalbandian Katrina J. Llewellyn Christopher Nguyen Puya G. Yazdi Virginia E. Kimonis 《PloS one》2015,10(4)
Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion body myopathy (hIBM) associated with Paget disease of bone (PDB), frontotemporal dementia (FTD), more recently termed multisystem proteinopathy (MSP). Affected individuals exhibit scapular winging and die from progressive muscle weakness, and cardiac and respiratory failure, typically in their 40s to 50s. Histologically, patients show the presence of rimmed vacuoles and TAR DNA-binding protein 43 (TDP-43)-positive large ubiquitinated inclusion bodies in the muscles. We have generated a VCPR155H/+ mouse model which recapitulates the disease phenotype and impaired autophagy typically observed in patients with VCP disease. Autophagy-modifying agents, such as rapamycin and chloroquine, at pharmacological doses have previously shown to alter the autophagic flux. Herein, we report results of administration of rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, and chloroquine, a lysosomal inhibitor which reverses autophagy by accumulating in lysosomes, responsible for blocking autophagy in 20-month old VCPR155H/+ mice. Rapamycin-treated mice demonstrated significant improvement in muscle performance, quadriceps histological analysis, and rescue of ubiquitin, and TDP-43 pathology and defective autophagy as indicated by decreased protein expression levels of LC3-I/II, p62/SQSTM1, optineurin and inhibiting the mTORC1 substrates. Conversely, chloroquine-treated VCPR155H/+ mice revealed progressive muscle weakness, cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-I/II, p62/SQSTM1, and optineurin expression levels. Our in vitro patient myoblasts studies treated with rapamycin demonstrated an overall improvement in the autophagy markers. Targeting the mTOR pathway ameliorates an increasing list of disorders, and these findings suggest that VCP disease and related neurodegenerative multisystem proteinopathies can now be included as disorders that can potentially be ameliorated by rapalogs. 相似文献
52.
53.
Samira Yazdi Johan Nikesj Williams Miranda Valentina Corradi D. Peter Tieleman Sergei Yu. Noskov H. Peter Larsson Sara I. Liin 《The Journal of general physiology》2021,153(6)
Polyunsaturated fatty acids (PUFAs), but not saturated fatty acids, modulate ion channels such as the cardiac KCNQ1 channel, although the mechanism is not completely understood. Using both simulations and experiments, we find that PUFAs interact directly with the KCNQ1 channel via two different binding sites: one at the voltage sensor and one at the pore. These two amphiphilic binding pockets stabilize the negatively charged PUFA head group by electrostatic interactions with R218, R221, and K316, while the hydrophobic PUFA tail is selectively stabilized by cassettes of hydrophobic residues. The rigid saturated tail of stearic acid prevents close contacts with KCNQ1. By contrast, the mobile tail of PUFA linoleic acid can be accommodated in the crevice of the hydrophobic cassette, a defining feature of PUFA selectivity in KCNQ1. In addition, we identify Y268 as a critical PUFA anchor point underlying fatty acid selectivity. Combined, this study provides molecular models of direct interactions between PUFAs and KCNQ1 and identifies selectivity mechanisms. Long term, this understanding may open new avenues for drug development based on PUFA mechanisms. 相似文献
54.
Jake K Nikota Fernando M Botelho Carla MT Bauer Manel Jordana Anthony J Coyle Alison A Humbles Martin R Stampfli 《Respiratory research》2011,12(1):39
Background
While the presence of the chitinase-like molecule YKL40 has been reported in COPD and asthma, its relevance to inflammatory processes elicited by cigarette smoke and common environmental allergens, such as house dust mite (HDM), is not well understood. The objective of the current study was to assess expression and function of BRP-39, the murine equivalent of YKL40 in a murine model of cigarette smoke-induced inflammation and contrast expression and function to a model of HDM-induced allergic airway inflammation.Methods
CD1, C57BL/6, and BALB/c mice were room air- or cigarette smoke-exposed for 4 days in a whole-body exposure system. In separate experiments, BALB/c mice were challenged with HDM extract once a day for 10 days. BRP-39 was assessed by ELISA and immunohistochemistry. IL-13, IL-1R1, IL-18, and BRP-39 knock out (KO) mice were utilized to assess the mechanism and relevance of BRP-39 in cigarette smoke- and HDM-induced airway inflammation.Results
Cigarette smoke exposure elicited a robust induction of BRP-39 but not the catalytically active chitinase, AMCase, in lung epithelial cells and alveolar macrophages of all mouse strains tested. Both BRP-39 and AMCase were increased in lung tissue after HDM exposure. Examining smoke-exposed IL-1R1, IL-18, and IL-13 deficient mice, BRP-39 induction was found to be IL-1 and not IL-18 or IL-13 dependent, while induction of BRP-39 by HDM was independent of IL-1 and IL-13. Despite the importance of BRP-39 in cellular inflammation in HDM-induced airway inflammation, BRP-39 was found to be redundant for cigarette smoke-induced airway inflammation and the adjuvant properties of cigarette smoke.Conclusions
These data highlight the contrast between the importance of BRP-39 in HDM- and cigarette smoke-induced inflammation. While functionally important in HDM-induced inflammation, BRP-39 is a biomarker of cigarette smoke induced inflammation which is the byproduct of an IL-1 inflammatory pathway. 相似文献55.
56.
BACKGROUND: Cystic neoplasms of the pancreas comprise a pathologically heterogeneous group of lesions that usually present with similar, nonspecific clinical features. Based on the diagnosis, treatment varies from watchful observation of the lesion to total surgical resection of the pancreas. Therefore the importance of a precise and accurate diagnosis on fine needle aspiration (FNA) biopsy cannot be overemphasized from the patient management standpoint. There is debate regarding the accuracy of FNA diagnosis of cystic lesions of the pancreas. We report 4 cases and review the literature to explore and highlight the cytologic findings and diagnostic pitfalls that may help the cytopathologist accurately distinguish mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), serous cystadenoma (SCA) and ductal adenocarcinoma (DAC). CASES: We present 4 cases of patients with abdominal masses who underwent either computed tomography (CT)-guided or endoscopic ultrasound (EUS)-guided FNA biopsy as preoperative workup. Based on the cytologic diagnosis, the patients underwent surgery. CONCLUSION: Our cases illustrate the cytologic criteria that help the cytopathologist distinguish among MCN, IPMN, SCA and DAC. Correlation with clinical and radiologic findings is strongly advocated for accurate diagnosis. We describe the diagnostic pitfalls frequently encountered in these cases and how to avoid them. 相似文献
57.
58.
Caruggi Noemi Lucisano Mara Feyissa Aberham Hailu Rahimi Yazdi Saeed Mohammadifar Mohammad Amin 《Food biophysics》2019,14(3):249-259
Food Biophysics - This study aimed to describe the effects of ohmic heat treatment (OHT) of milk on the formation and properties of acid milk gels. The influence of voltage gradient (25, 40,... 相似文献
59.
Ewa Przybytkowski Elizabeth Lenkiewicz Michael T Barrett Kathleen Klein Sheida Nabavi Celia MT Greenwood Mark Basik 《BMC genomics》2014,15(1)