全文获取类型
收费全文 | 1417篇 |
免费 | 100篇 |
专业分类
1517篇 |
出版年
2023年 | 13篇 |
2022年 | 13篇 |
2021年 | 30篇 |
2020年 | 23篇 |
2019年 | 31篇 |
2018年 | 27篇 |
2017年 | 35篇 |
2016年 | 39篇 |
2015年 | 65篇 |
2014年 | 78篇 |
2013年 | 76篇 |
2012年 | 95篇 |
2011年 | 102篇 |
2010年 | 86篇 |
2009年 | 71篇 |
2008年 | 85篇 |
2007年 | 73篇 |
2006年 | 70篇 |
2005年 | 65篇 |
2004年 | 74篇 |
2003年 | 53篇 |
2002年 | 45篇 |
2001年 | 23篇 |
2000年 | 22篇 |
1999年 | 18篇 |
1998年 | 20篇 |
1997年 | 9篇 |
1996年 | 13篇 |
1995年 | 5篇 |
1994年 | 10篇 |
1992年 | 6篇 |
1991年 | 11篇 |
1990年 | 7篇 |
1989年 | 14篇 |
1988年 | 10篇 |
1987年 | 8篇 |
1986年 | 8篇 |
1985年 | 8篇 |
1984年 | 8篇 |
1982年 | 3篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1979年 | 5篇 |
1978年 | 3篇 |
1977年 | 6篇 |
1976年 | 7篇 |
1975年 | 6篇 |
1974年 | 7篇 |
1971年 | 3篇 |
1970年 | 4篇 |
排序方式: 共有1517条查询结果,搜索用时 0 毫秒
101.
Areti Gkourtsa Janny van den Burg Karin Strijbis Teja Avula Sietske Bijvoets Dave Timm Frans Hochstenbach Ben Distel 《Eukaryotic cell》2015,14(2):182-193
Membrane reshaping resides at the core of many important cellular processes, and among its mediators are the BAR (Bin, Amphiphysin, Rvs) domain-containing proteins. We have explored the diversity and function of the Rvs BAR proteins in Candida albicans and identified a novel family member, Rvs167-3 (orf19.1861). We show that Rvs167-3 specifically interacts with Rvs162 to form a stable BAR heterodimer able to bind liposomes in vitro. A second, distinct heterodimer is formed by the canonical BAR proteins Rvs161 and Rvs167. Purified Rvs161/Rvs167 complex also binds liposomes, indicating that C. albicans expresses two functional BAR heterodimers. We used live-cell imaging to localize green fluorescent protein (GFP)-tagged Rvs167-3 and Rvs167 and show that both proteins concentrate in small cortical spots. However, while Rvs167 strictly colocalizes with the endocytic marker protein Abp1, we do not observe any colocalization of Rvs167-3 with sites of endocytosis marked by Abp1. Furthermore, the rvs167-3Δ/Δ mutant is not defective in endocytosis and strains lacking Rvs167-3 or its partner Rvs162 do not display increased sensitivity to high salt concentrations or decreased cell wall integrity, phenotypes which have been observed for rvs167Δ/Δ and rvs161Δ/Δ strains and which are linked to endocytosis defects. Taken together, our results indicate different roles for the two BAR heterodimers in C. albicans: the canonical Rvs161/Rvs167 heterodimer functions in endocytosis, whereas the novel Rvs162/Rvs167-3 heterodimer seems not to be involved in this process. Nevertheless, despite their different roles, our phenotypic analysis revealed a genetic interaction between the two BAR heterodimers, suggesting that they may have related but distinct membrane-associated functions. 相似文献
102.
Melissa L. Potestio Jamie M. Boyd Sean M. Bagshaw Daren Heyland Peter Oxland Christopher J. Doig Dave Zygun Henry T. Stelfox 《PloS one》2015,10(11)
Objective
To engage the public to understand how to improve the care of critically ill patients.Design
A qualitative content analysis of an open community forum (Café Scientifique).Setting
Public venue in Calgary, Alberta, Canada.Participants
Members of the general public including patients, families of patients, health care providers, and members of the community at large.Methods
A panel of researchers, decision-makers, and a family member led a Café Scientifique, an informal dialogue between the populace and experts, over three-hours to engage the public to understand how to improve the care of critically ill patients. Conventional qualitative content analysis was used to analyze the data. The inductive analysis occurred in three phases: coding, categorizing, and developing themes.Results
Thirty-eight members of the public (former ICU patients, family members of patients, providers, community members) attended. Participants focused the discussion and provided concrete suggestions for improvement around communication (family as surrogate voice, timing of conversations, decision tools) and provider well-being and engagement, as opposed to medical interventions in critical care.Conclusions
Café participants believe patient and family centered care is important to ensure high-quality care in the ICU. A Café Scientifique is a valuable forum to engage the public to contribute to priority setting areas for research in critical care, as well as a platform to share lived experience. Research stakeholders including health care organizations, governments, and funding organizations should provide more opportunities for the public to engage in meaningful conversations about how to best improve healthcare. 相似文献103.
104.
Sammy De Grave Kevin G. Smith Nils A. Adeler Dave J. Allen Fernando Alvarez Arthur Anker Yixiong Cai Savrina F. Carrizo Werner Klotz Fernando L. Mantelatto Timothy J. Page Jhy-Yun Shy José Luis Villalobos Daisy Wowor 《PloS one》2015,10(3)
We present the first global assessment of extinction risk for a major group of freshwater invertebrates, caridean shrimps. The risk of extinction for all 763 species was assessed using the IUCN Red List criteria that include geographic ranges, habitats, ecology and past and present threats. The Indo-Malayan region holds over half of global species diversity, with a peak in Indo-China and southern China. Shrimps primarily inhabit flowing water; however, a significant subterranean component is present, which is more threatened than the surface fauna. Two species are extinct with a further 10 possibly extinct, and almost one third of species are either threatened or Near Threatened (NT). Threats to freshwater shrimps include agricultural and urban pollution impact over two-thirds of threatened and NT species. Invasive species and climate change have the greatest overall impact of all threats (based on combined timing, scope and severity of threats). 相似文献
105.
Richard B. Lanman Stefanie A. Mortimer Oliver A. Zill Dragan Sebisanovic Rene Lopez Sibel Blau Eric A. Collisson Stephen G. Divers Dave S. B. Hoon E. Scott Kopetz Jeeyun Lee Petros G. Nikolinakos Arthur M. Baca Bahram G. Kermani Helmy Eltoukhy AmirAli Talasaz 《PloS one》2015,10(10)
Next-generation sequencing of cell-free circulating solid tumor DNA addresses two challenges in contemporary cancer care. First this method of massively parallel and deep sequencing enables assessment of a comprehensive panel of genomic targets from a single sample, and second, it obviates the need for repeat invasive tissue biopsies. Digital SequencingTM is a novel method for high-quality sequencing of circulating tumor DNA simultaneously across a comprehensive panel of over 50 cancer-related genes with a simple blood test. Here we report the analytic and clinical validation of the gene panel. Analytic sensitivity down to 0.1% mutant allele fraction is demonstrated via serial dilution studies of known samples. Near-perfect analytic specificity (> 99.9999%) enables complete coverage of many genes without the false positives typically seen with traditional sequencing assays at mutant allele frequencies or fractions below 5%. We compared digital sequencing of plasma-derived cell-free DNA to tissue-based sequencing on 165 consecutive matched samples from five outside centers in patients with stage III-IV solid tumor cancers. Clinical sensitivity of plasma-derived NGS was 85.0%, comparable to 80.7% sensitivity for tissue. The assay success rate on 1,000 consecutive samples in clinical practice was 99.8%. Digital sequencing of plasma-derived DNA is indicated in advanced cancer patients to prevent repeated invasive biopsies when the initial biopsy is inadequate, unobtainable for genomic testing, or uninformative, or when the patient’s cancer has progressed despite treatment. Its clinical utility is derived from reduction in the costs, complications and delays associated with invasive tissue biopsies for genomic testing. 相似文献
106.
107.
108.
109.
Ahmed S Abdel-Moneim Ahmad E Abdel-Ghany Salama AS Shany 《Journal of biomedical science》2010,17(1):25
Background
The highly pathogenic H5N1 is a major avian pathogen that crosses species barriers and seriously affects humans as well as some mammals. It mutates in an intensified manner and is considered a potential candidate for the possible next pandemic with all the catastrophic consequences. 相似文献110.
Prakash Peddi Charles W. Loftin Jennifer S. Dickey Jessica M. Hair Kara J. Burns Khaled Aziz Dave C. Francisco Mihalis I. Panayiotidis Olga A. Sedelnikova William M. Bonner Thomas A. Winters Alexandros G. Georgakilas 《Free radical biology & medicine》2010,48(10):1435-1443
DNA-dependent protein kinase (DNA-PK) is a key non-homologous-end-joining (NHEJ) nuclear serine/threonine protein kinase involved in various DNA metabolic and damage signaling pathways contributing to the maintenance of genomic stability and prevention of cancer. To examine the role of DNA-PK in processing of non-DSB clustered DNA damage, we have used three models of DNA-PK deficiency, i.e., chemical inactivation of its kinase activity by the novel inhibitors IC86621 and NU7026, knockdown and complete absence of the protein in human breast cancer (MCF-7) and glioblastoma cell lines (MO59-J/K). A compromised DNA-PK repair pathway led to the accumulation of clustered DNA lesions induced by γ-rays. Tumor cells lacking protein expression or with inhibited kinase activity showed a marked decrease in their ability to process oxidatively induced non-DSB clustered DNA lesions measured using a modified version of pulsed-field gel electrophoresis or single-cell gel electrophoresis (comet assay). In all cases, DNA-PK inactivation led to a higher level of lesion persistence even after 24–72 h of repair. We suggest a model in which DNA-PK deficiency affects the processing of these clusters first by compromising base excision repair and second by the presence of catalytically inactive DNA-PK inhibiting the efficient processing of these lesions owing to the failure of DNA-PK to disassociate from the DNA ends. The information rendered will be important for understanding not only cancer etiology in the presence of an NHEJ deficiency but also cancer treatments based on the induction of oxidative stress and inhibition of cluster repair. 相似文献