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 302 毫秒
141.
Sander Kelderman Bianca Heemskerk Harm van Tinteren Rob R. H. van den Brom Geke A. P. Hospers Alfonsus J. M. van den Eertwegh Ellen W. Kapiteijn Jan Willem B. de Groot Patricia Soetekouw Rob L. Jansen Edward Fiets Andrew J. S. Furness Alexandra Renn Marcin Krzystanek Zoltan Szallasi Paul Lorigan Martin E. Gore Ton N. M. Schumacher John B. A. G. Haanen James M. G. Larkin Christian U. Blank 《Cancer immunology, immunotherapy : CII》2014,63(5):449-458
Introduction
Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a ‘real world’ population of patients treated with ipilimumab to identify markers for treatment benefit.Methods
Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes.Results
A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK.Conclusion
In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy. 相似文献142.
Merrin H. Whatley E. Emiel van Loon J. Arie Vonk Harm G. van der Geest Wim Admiraal 《Aquatic Ecology》2014,48(3):267-283
Availability of macrophyte habitat is recognized as an important driver of aquatic insect communities in peatland drainage ditches; however, eutrophication can lead to the decline of submerged vegetation. While emergent vegetation is able to persist in eutrophicated ditches, vegetation removal, carried out during ditch maintenance, can reduce the availability of this habitat. In this study, we applied the landscape filtering approach to determine whether the absence of emergent vegetation is a habitat filter which structures aquatic insect communities in peatland drainage ditches under different trophic conditions. To this end, a field study was carried out in one mesotrophic (Naardermeer) and one eutrophic (Wormer and Jisperveld) peatland in the province of North Holland, The Netherlands. We assigned life history strategies to insect species and applied linear mixed models and redundancy analyses to taxonomic and functional aquatic insect community data. Our results indicate that while differences between peatlands primarily determine the species pool within each wetland, emergent vegetation acted as a secondary filter by structuring functional community composition within ditches. The eutrophic peatland was dominated by insects adapted to abiotic extremes, while species with good dispersal abilities were strongly related to emergent vegetation cover. This study demonstrates the applicability of life history strategies to provide insight into the filtering of species due to availability of emergent macrophyte habitat. To ensure greater diversity of insect communities in ditch habitats, it is recommended that some vegetation be spared during maintenance to leave patches from which insect recolonization can occur. 相似文献
143.
Michael J. Bailey Steven L. Coon David A. Carter Ann Humphries Jong-so Kim Qiong Shi Pascaline Gaildrat Fabrice Morin Surajit Ganguly John B. Hogenesch Joan L. Weller Martin F. Rath Morten M?ller Ruben Baler David Sugden Zoila G. Rangel Peter J. Munson David C. Klein 《The Journal of biological chemistry》2009,284(12):7606-7622
144.
145.
Guidelines for the nomenclature of the human heat shock proteins 总被引:3,自引:2,他引:1
Kampinga HH Hageman J Vos MJ Kubota H Tanguay RM Bruford EA Cheetham ME Chen B Hightower LE 《Cell stress & chaperones》2009,14(1):105-111
The expanding number of members in the various human heat shock protein (HSP) families and the inconsistencies in their nomenclature have often led to confusion. Here, we propose new guidelines for the nomenclature of the human HSP families, HSPH (HSP110), HSPC (HSP90), HSPA (HSP70), DNAJ (HSP40), and HSPB (small HSP) as well as for the human chaperonin families HSPD/E (HSP60/HSP10) and CCT (TRiC). The nomenclature is based largely on the more consistent nomenclature assigned by the HUGO Gene Nomenclature Committee and used in the National Center of Biotechnology Information Entrez Gene database for the heat shock genes. In addition to this nomenclature, we provide a list of the human Entrez Gene IDs and the corresponding Entrez Gene IDs for the mouse orthologs. 相似文献
146.
147.
Rujano MA Bosveld F Salomons FA Dijk F van Waarde MA van der Want JJ de Vos RA Brunt ER Sibon OC Kampinga HH 《PLoS biology》2006,4(12):e417
Disease-associated misfolded proteins or proteins damaged due to cellular stress are generally disposed via the cellular protein quality-control system. However, under saturating conditions, misfolded proteins will aggregate. In higher eukaryotes, these aggregates can be transported to accumulate in aggresomes at the microtubule organizing center. The fate of cells that contain aggresomes is currently unknown. Here we report that cells that have formed aggresomes can undergo normal mitosis. As a result, the aggregated proteins are asymmetrically distributed to one of the daughter cells, leaving the other daughter free of accumulated protein damage. Using both epithelial crypts of the small intestine of patients with a protein folding disease and Drosophila melanogaster neural precursor cells as models, we found that the inheritance of protein aggregates during mitosis occurs with a fixed polarity indicative of a mechanism to preserve the long-lived progeny. 相似文献
148.
Masanori Yasuo Shiro Mizuno Jeremy Allegood Donatas Kraskauskas Harm J. Bogaard Sarah Spiegel Norbert F. Voelkel 《PloS one》2013,8(1)
Sphingolipids play a role in the development of emphysema and ceramide levels are increased in experimental models of emphysema; however, the mechanisms of ceramide-related pulmonary emphysema are not fully understood. Here we examine mechanisms of ceramide-induced pulmonary emphysema. Male Sprague-Dawley rats were treated with fenretinide (20 mg/kg BW), a synthetic derivative of retinoic acid that causes the formation of ceramide, and we postulated that the effects of fenretinide could be offset by administering sphingosine 1-phosphate (S1P) (100 µg/kg BW). Lung tissues were analyzed and mean alveolar airspace area, total length of the alveolar perimeter and the number of caspase-3 positive cells were measured. Hypoxia-inducible factor alpha (HIF-1α), vascular endothelial growth factor (VEGF) and other related proteins were analyzed by Western blot analysis. Immunohistochemical analysis of HIF-1α was also performed. Ceramide, dihydroceramide, S1P, and dihydro-S1P were measured by mass spectrometer. Chronic intraperitoneal injection of fenretinide increased the alveolar airspace surface area and increased the number of caspase-3 positive cells in rat lungs. Fenretinide also suppressed HIF-1α and VEGF protein expression in rat lungs. Concomitant injection of S1P prevented the decrease in the expression of HIF-1α, VEGF, histone deacetylase 2 (HDAC2), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein expression in the lungs. S1P injection also increased phosphorylated sphingosine kinase 1. Dihydroceramide was significantly increased by fenretinide injection and S1P treatment prevented the increase in dihydroceramide levels in rat lungs. These data support the concept that increased de novo ceramide production causes alveolar septal cell apoptosis and causes emphysema via suppressing HIF-1α. Concomitant treatment with S1P normalizes the ceramide-S1P balance in the rat lungs and increases HIF-1α protein expression via activation of sphingosine kinase 1; as a consequence, S1P salvages fenretinide induced emphysema in rat lungs. 相似文献
149.
Darryl Tio Edward Leter Bart Boerrigter Anco Boonstra Anton Vonk-Noordegraaf Harm Jan Bogaard 《PloS one》2013,8(10)
Introduction
When hemoptysis complicates pulmonary arterial hypertension (PAH), it is assumed to result from bronchial artery hypertrophy. In heritable PAH, the most common mutation is in the BMPR2 gene, which regulates growth, differentiation and apoptosis of mesenchymal cells. The aim of this study is to determine the relationship in PAH between the occurrence of hemoptysis, and disease progression, bronchial artery hypertrophy, pulmonary artery dilation and BMPR2 mutations.Methods
129 IPAH patients underwent baseline pulmonary imaging (CT angio or MRI) and repeated right-sided heart catheterization. Gene mutations were assessed in a subset of patients.Results
Hemoptysis was associated with a greater presence of hypertrophic bronchial arteries and more rapid hemodynamic deterioration. The presence of a BMPR2 mutation did not predispose to the development of hemoptysis, but was associated with a greater number of hypertrophic bronchial arteries and a worse baseline hemodynamic profile.Conclusion
Hemoptysis in PAH is associated with bronchial artery hypertrophy and faster disease progression. Although the presence of a BMPR2 mutation did not correlate with a greater incidence of hemoptysis in our patient cohort, its association with worse hemodynamics and a trend of greater bronchial arterial hypertrophy may increase the risk of hemoptysis. 相似文献150.
The DNAJB6 and DNAJB8 Protein Chaperones Prevent Intracellular Aggregation of Polyglutamine Peptides
Judith Gillis Sabine Schipper-Krom Katrin Juenemann Anna Gruber Silvia Coolen Rian van den Nieuwendijk Henk van Veen Hermen Overkleeft Joachim Goedhart Harm H. Kampinga Eric A. Reits 《The Journal of biological chemistry》2013,288(24):17225-17237
Fragments of proteins containing an expanded polyglutamine (polyQ) tract are thought to initiate aggregation and toxicity in at least nine neurodegenerative diseases, including Huntington''s disease. Because proteasomes appear unable to digest the polyQ tract, which can initiate intracellular protein aggregation, preventing polyQ peptide aggregation by chaperones should greatly improve polyQ clearance and prevent aggregate formation. Here we expressed polyQ peptides in cells and show that their intracellular aggregation is prevented by DNAJB6 and DNAJB8, members of the DNAJ (Hsp40) chaperone family. In contrast, HSPA/Hsp70 and DNAJB1, also members of the DNAJ chaperone family, did not prevent peptide-initiated aggregation. Intriguingly, DNAJB6 and DNAJB8 also affected the soluble levels of polyQ peptides, indicating that DNAJB6 and DNAJB8 inhibit polyQ peptide aggregation directly. Together with recent data showing that purified DNAJB6 can suppress fibrillation of polyQ peptides far more efficiently than polyQ expanded protein fragments in vitro, we conclude that the mechanism of DNAJB6 and DNAJB8 is suppression of polyQ protein aggregation by directly binding the polyQ tract. 相似文献