全文获取类型
收费全文 | 2030篇 |
免费 | 200篇 |
国内免费 | 1篇 |
出版年
2023年 | 15篇 |
2022年 | 12篇 |
2021年 | 61篇 |
2020年 | 47篇 |
2019年 | 46篇 |
2018年 | 34篇 |
2017年 | 42篇 |
2016年 | 74篇 |
2015年 | 131篇 |
2014年 | 120篇 |
2013年 | 135篇 |
2012年 | 210篇 |
2011年 | 159篇 |
2010年 | 107篇 |
2009年 | 85篇 |
2008年 | 111篇 |
2007年 | 131篇 |
2006年 | 96篇 |
2005年 | 98篇 |
2004年 | 73篇 |
2003年 | 59篇 |
2002年 | 40篇 |
2001年 | 22篇 |
2000年 | 34篇 |
1999年 | 22篇 |
1998年 | 21篇 |
1997年 | 19篇 |
1996年 | 9篇 |
1994年 | 7篇 |
1993年 | 6篇 |
1992年 | 6篇 |
1991年 | 6篇 |
1990年 | 10篇 |
1989年 | 11篇 |
1988年 | 11篇 |
1987年 | 9篇 |
1986年 | 7篇 |
1985年 | 10篇 |
1984年 | 10篇 |
1983年 | 6篇 |
1981年 | 7篇 |
1979年 | 7篇 |
1977年 | 5篇 |
1976年 | 5篇 |
1975年 | 9篇 |
1974年 | 5篇 |
1973年 | 6篇 |
1971年 | 6篇 |
1969年 | 6篇 |
1967年 | 5篇 |
排序方式: 共有2231条查询结果,搜索用时 15 毫秒
41.
Nadia B. Hassounah Ray Nagle Kathylynn Saboda Denise J. Roe Bruce L. Dalkin Kimberly M. McDermott 《PloS one》2013,8(7)
Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Little is known about the role of primary cilia in preinvasive and invasive prostate cancer. However, reduced cilia expression has been observed in human cancers including pancreatic cancer, renal cell carcinoma, breast cancer, cholangiocarcinoma, and melanoma. The aim of this study was to characterize primary cilia expression in preinvasive and invasive human prostate cancer, and to investigate the correlation between primary cilia and the Wnt signaling pathway. Human prostate tissues representative of stages of prostate cancer formation (normal prostate, prostatic intraepithelial neoplasia (PIN), and invasive prostate cancer (including perineural invasion)) were stained for ciliary proteins. The frequency of primary cilia was determined. A decrease in the percentage of ciliated cells in PIN, invasive cancer and perineural invasion lesions was observed when compared to normal. Cilia lengths were also measured to indirectly test functionality. Cilia were shorter in PIN, cancer, and perineural invasion lesions, suggesting dysfunction. Primary cilia have been shown to suppress the Wnt pathway. Increased Wnt signaling has been implicated in prostate cancer. Therefore, we investigated a correlation between loss of primary cilia and increased Wnt signaling in normal prostate and in preinvasive and invasive prostate cancer. To investigate Wnt signaling in our cohort, serial tissue sections were stained for β-catenin as a measure of Wnt signaling. Nuclear β-catenin was analyzed and Wnt signaling was found to be higher in un-ciliated cells in the normal prostate, PIN, a subset of invasive cancers, and perineural invasion. Our results suggest that cilia normally function to suppress the Wnt signaling pathway in epithelial cells and that cilia loss may play a role in increased Wnt signaling in some prostate cancers. These results suggest that cilia are dysfunctional in human prostate cancer, and increase Wnt signaling occurs in a subset of cancers. 相似文献
42.
43.
Jayde A. Gawthorne L. Evan Reddick Snezhana N. Akpunarlieva Katherine S. H. Beckham John M. Christie Neal M. Alto Mads Gabrielsen Andrew J. Roe 《PloS one》2012,7(12)
In this work, we describe the utility of Light, Oxygen, or Voltage-sensing (LOV) flavoprotein domains from plant phototropins as a reporter for protein expression and function. Specifically, we used iLOV, an enhanced and more photostable variant of LOV. A pET-based plasmid for protein expression was constructed, encoding a C terminal iLOV-octahistidine (His8)-tag and a HRV 3C protease cleavage recognition site. Ten different proteins, with various sub-cellular locations, were cloned into the plasmid, creating iLOV-His8 tag fusions. To test protein expression and how iLOV could be used as a reporter, the proteins were expressed in three different cell lines, in four different culture media, at two different temperatures. To establish whether the presence of the iLOV tag could have an impact on the functionality, one of the proteins, EspG, was over-expressed and purified. EspG is an “effector” protein normally produced by enterohemorrhagic E. coli strains and “injected” into host cells via the T3SS. We tested functionality of EspG-iLOV fusion by performing functional studies of EspG in mammalian host cells. When EspG-iLOV was microinjected into the host cell, the Golgi apparatus was completely disrupted as had previously been observed for EspG. 相似文献
44.
Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4+ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes. 相似文献
45.
46.
Penelope A. Ajani Hong Chang Lim Arjun Verma Malwenn Lassudrie Katie McBean Martina A. Doblin Shauna A. Murray 《Phycological Research》2020,68(3):254-259
Certain species of the marine diatom genus Pseudo‐nitzschia are responsible for the production of the domoic acid (DA), a neurotoxin that can bioaccumulate in the food chain and cause amnesic shellfish poisoning (ASP) in animals and humans. This study extends our knowledge by reporting on the first observation of the potentially toxic species Pseudo‐nitzschia simulans from this region. One clonal strain of P. simulans was isolated from the East Australian Current and characterized using light and transmission electron microscopy, and phylogenetic analyses based on regions of the internal transcribed spacer (ITS) and the D1–D3 region of the large subunit (LSU) of the nuclear‐encoded ribosomal deoxyribonucleic acid (rDNA), as well as examined for DA production as measured by liquid chromatography–mass spectrometry. Although this strain was non‐toxic under the defined growth conditions, the results unambiguously confirmed that this isolate is the potentially toxic species P. simulans – the first report of this species from the Southern Hemisphere. 相似文献
47.
48.
Albert L. Harting Michelle M. Barbieri Jason D. Baker Tracy A. Mercer Thea C. Johanos Stacie J. Robinson Charles L. Littnan Katie M. Colegrove Dave S. Rotstein 《Marine Mammal Science》2021,37(1):235-250
Identifying, assessing, and ranking the impact of individual threats is fundamental to the conservation and recovery of rare and endangered species. In this analysis, we quantify not only the frequency of specific causes-of-death (CODs) among Main Hawaiian Island (MHI) monk seals, but also assess the impact of individual CODs on the intrinsic growth rate, λ, of the MHI population. We used gross necropsy results, histopathology, and other evidence to assign probabilities of 11 COD types to each mortality and then used Monte Carlo sampling to evaluate the influence of each COD on λ. By right censoring realizations involving specific CODs, we were able to estimate λ (and its associated uncertainty) when CODs were selectively removed from influencing survival. Applying the analysis to all known and inferred deaths believed to have occurred 2004–2019, the CODs with the largest influence on λ were anthropogenic trauma, anthropogenic drowning, and protozoal disease. In aggregate, anthropogenic CODs had a larger effect on the growth rate than either natural or disease CODs. Possible bias associated with differential carcass detection, recovery, and COD classification are discussed. 相似文献
49.
50.
Katie J. Wolfe Hong Yu Ren Philipp Trepte Douglas M. Cyr 《Molecular biology of the cell》2013,24(23):3588-3602
Conformational diseases are associated with the conversion of normal proteins into aggregation-prone toxic conformers with structures similar to that of β-amyloid. Spatial distribution of amyloid-like proteins into intracellular quality control centers can be beneficial, but cellular mechanisms for protective aggregation remain unclear. We used a high-copy suppressor screen in yeast to identify roles for the Hsp70 system in spatial organization of toxic polyglutamine-expanded Huntingtin (Huntingtin with 103Q glutamine stretch [Htt103Q]) into benign assemblies. Under toxic conditions, Htt103Q accumulates in unassembled states and speckled cytosolic foci. Subtle modulation of Sti1 activity reciprocally affects Htt toxicity and the packaging of Htt103Q into foci. Loss of Sti1 exacerbates Htt toxicity and hinders foci formation, whereas elevation of Sti1 suppresses Htt toxicity while organizing small Htt103Q foci into larger assemblies. Sti1 also suppresses cytotoxicity of the glutamine-rich yeast prion [RNQ+] while reorganizing speckled Rnq1–monomeric red fluorescent protein into distinct foci. Sti1-inducible foci are perinuclear and contain proteins that are bound by the amyloid indicator dye thioflavin-T. Sti1 is an Hsp70 cochaperone that regulates the spatial organization of amyloid-like proteins in the cytosol and thereby buffers proteotoxicity caused by amyloid-like proteins. 相似文献