全文获取类型
收费全文 | 723篇 |
免费 | 58篇 |
专业分类
781篇 |
出版年
2022年 | 5篇 |
2021年 | 9篇 |
2020年 | 4篇 |
2019年 | 9篇 |
2018年 | 9篇 |
2017年 | 8篇 |
2016年 | 23篇 |
2015年 | 42篇 |
2014年 | 27篇 |
2013年 | 34篇 |
2012年 | 42篇 |
2011年 | 58篇 |
2010年 | 32篇 |
2009年 | 31篇 |
2008年 | 33篇 |
2007年 | 41篇 |
2006年 | 32篇 |
2005年 | 33篇 |
2004年 | 29篇 |
2003年 | 26篇 |
2002年 | 31篇 |
2001年 | 9篇 |
1999年 | 5篇 |
1998年 | 11篇 |
1997年 | 12篇 |
1996年 | 12篇 |
1995年 | 6篇 |
1994年 | 8篇 |
1993年 | 4篇 |
1992年 | 9篇 |
1991年 | 5篇 |
1990年 | 8篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 5篇 |
1985年 | 9篇 |
1982年 | 8篇 |
1981年 | 4篇 |
1980年 | 5篇 |
1979年 | 4篇 |
1978年 | 5篇 |
1977年 | 6篇 |
1973年 | 4篇 |
1972年 | 5篇 |
1970年 | 4篇 |
1966年 | 4篇 |
1965年 | 4篇 |
1964年 | 7篇 |
1963年 | 5篇 |
1951年 | 3篇 |
排序方式: 共有781条查询结果,搜索用时 0 毫秒
61.
62.
A single-chain class II MHC-IgG3 fusion protein inhibits autoimmune arthritis by induction of antigen-specific hyporesponsiveness 总被引:1,自引:0,他引:1
Zuo L Cullen CM DeLay ML Thornton S Myers LK Rosloniec EF Boivin GP Hirsch R 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(5):2554-2559
T cells play a central role in many autoimmune diseases. A method to specifically target the function of autoreactive T cell clones would avoid the global immunosuppression associated with current therapies. To develop a molecule capable of inhibiting autoreactive T cell responses in vivo, single-chain peptide-I-A-IgG3 fusion proteins were constructed and expressed in both mammalian and insect cells. The fusion proteins were designed with an IgG3 Fc moiety to make them divalent, allowing TCR cross-linking, while lacking FcR binding and costimulation. The fusion proteins stimulated T cell hybridomas in vitro in a peptide-specific, MHC-restricted manner but failed to do so in soluble form. In vivo administration of an I-A(q) fusion protein, containing an immunodominant collagen II peptide, significantly delayed the onset and reduced the severity of collagen-induced arthritis in DBA/1 mice by induction of Ag-specific hyporesponsiveness. Such fusion proteins may be useful to study novel therapeutic approaches for T cell-mediated autoimmune diseases. 相似文献
63.
64.
Anjana Bhardwaj Nivetha Ganesan Kazunoshin Tachibana Kimal Rajapakshe Constance T. Albarracin Preethi H. Gunaratne Cristian Coarfa Isabelle Bedrosian 《PloS one》2015,10(5)
IntroductionAnnexin A1 (ANXA1) is an anti-inflammatory protein reported to play a role in cell proliferation and apoptosis, and to be deregulated in breast cancer. The exact role of annexin A1 in the biology of breast cancer remains unclear. We hypothesized that the annexin A1 plays an oncogenic role in basal subtype of breast cancer by modulating key growth pathway(s).MethodsBy mining the Cancer Genome Atlas (TCGA)-Breast Cancer dataset and manipulating annexin A1 levels in breast cancer cell lines, we studied the role of annexin A1 in breast cancer and underlying signaling pathways.ResultsOur in-silico analysis of TCGA-breast cancer dataset demonstrated that annexin A1 mRNA expression is higher in basal subtype compared to luminal and HER2 subtypes. Within the basal subtype, patients show significantly poorer overall survival associated with higher expression of annexin A1. In both TCGA patient samples and cell lines, annexin A1 levels were significantly higher in basal-like breast cancer than luminal and Her2/neu-positive breast cancer. Stable annexin A1 knockdown in TNBC cell lines suppressed the mTOR-S6 pathway likely through activation of AMPK but had no impact on the MAPK, c-Met, and EGFR pathways. In a cell migration assay, annexin A1-depleted TNBC cells showed delayed migration as compared to wild-type cells, which could be responsible for poor patient prognosis in basal like breast cancers that are known to express higher annexin A1.ConclusionsOur data suggest that annexin A1 is prognostic only in patients with basal like breast cancer. This appears to be in part due to the role of annexin A1 in activating mTOR-pS6 pathway. 相似文献
65.
Anusha van Samkar Matthijs C. Brouwer Constance Schultsz Arie van der Ende Diederik van de Beek 《PLoS neglected tropical diseases》2015,9(10)
Background
Streptococcus suis is the most common cause of meningitis in pork consuming and pig rearing countries in South-East Asia. We performed a systematic review of studies on S. suis meningitis to define the clinical characteristics, predisposing factors and outcome.Methodology
Studies published between January 1, 1980 and August 1, 2015 were identified from main literature databases and reference lists. Studies were included if they were written in West-European languages and described at least 5 adult patients with S. suis meningitis in whom at least one clinical characteristic was described.Findings
We identified 913 patients with S. suis meningitis included in 24 studies between 1980 and 2015. The mean age was 49 years and 581 of 711 patients were male (82%). Exposure to pigs or pork was present in 395 of 648 patients (61%) while other predisposing factors were less common. 514 of 528 patients presented with fever (97%), 429 of 451 with headache (95%), 462 of 496 with neck stiffness (93%) and 78 of 384 patients (20%) had a skin injury in the presence of pig/pork contact. The case fatality rate was 2.9% and hearing loss was a common sequel occurring in 259 of 489 patients (53%). Treatment included dexamethasone in 157 of 300 (52%) of patients and was associated with reduced hearing loss in S. suis meningitis patients included in a randomized controlled trial.Conclusion
S. suis meningitis has a clear association with pig and pork contact. Mortality is low, but hearing loss occurs frequently. Dexamethasone was shown to reduce hearing loss. 相似文献66.
Malaria and HIV co-infection is a growing health priority. However, most research on malaria or HIV currently focuses on each infection individually. Although understanding the disease dynamics for each of these pathogens independently is vital, it is also important that the interactions between these pathogens are investigated and understood. We have developed a versatile in vitro model of HIV-malaria co-infection to study host immune responses to malaria in the context of HIV infection. Our model allows the study of secreted factors in cellular supernatants, cell surface and intracellular protein markers, as well as RNA expression levels. The experimental design and methods used limit variability and promote data reliability and reproducibility. All pathogens used in this model are natural human pathogens (Plasmodium falciparum and HIV-1), and all infected cells are naturally infected and used fresh. We use human erythrocytes parasitized with P. falciparum and maintained in continuous in vitro culture. We obtain freshly isolated peripheral blood mononuclear cells from chronically HIV-infected volunteers. Every condition used has an appropriate control (P. falciparum parasitized vs. normal erythrocytes), and every HIV-infected donor has an HIV uninfected control, from which cells are harvested on the same day. This model provides a realistic environment to study the interactions between malaria parasites and human immune cells in the context of HIV infection. 相似文献
67.
Gabriela B. Gomez Nicola Foster Daniella Brals Heleen E. Nelissen Oladimeji A. Bolarinwa Marleen E. Hendriks Alexander C. Boers Diederik van Eck Nicole Rosendaal Peju Adenusi Kayode Agbede Tanimola M. Akande Michael Boele van Hensbroek Ferdinand W. Wit Catherine A. Hankins Constance Schultsz 《PloS one》2015,10(9)
Background
While the Nigerian government has made progress towards the Millennium Development Goals, further investments are needed to achieve the targets of post-2015 Sustainable Development Goals, including Universal Health Coverage. Economic evaluations of innovative interventions can help inform investment decisions in resource-constrained settings. We aim to assess the cost and cost-effectiveness of maternal care provided within the new Kwara State Health Insurance program (KSHI) in rural Nigeria.Methods and Findings
We used a decision analytic model to simulate a cohort of pregnant women. The primary outcome is the incremental cost effectiveness ratio (ICER) of the KSHI scenario compared to the current standard of care. Intervention cost from a healthcare provider perspective included service delivery costs and above-service level costs; these were evaluated in a participating hospital and using financial records from the managing organisations, respectively. Standard of care costs from a provider perspective were derived from the literature using an ingredient approach. We generated 95% credibility intervals around the primary outcome through probabilistic sensitivity analysis (PSA) based on a Monte Carlo simulation. We conducted one-way sensitivity analyses across key model parameters and assessed the sensitivity of our results to the performance of the base case separately through a scenario analysis. Finally, we assessed the sustainability and feasibility of this program’s scale up within the State’s healthcare financing structure through a budget impact analysis. The KSHI scenario results in a health benefit to patients at a higher cost compared to the base case. The mean ICER (US$46.4/disability-adjusted life year averted) is considered very cost-effective compared to a willingness-to-pay threshold of one gross domestic product per capita (Nigeria, US$ 2012, 2,730). Our conclusion was robust to uncertainty in parameters estimates (PSA: median US$49.1, 95% credible interval 21.9–152.3), during one-way sensitivity analyses, and when cost, quality, cost and utilization parameters of the base case scenario were changed. The sustainability of this program’s scale up by the State is dependent on further investments in healthcare.Conclusions
This study provides evidence that the investment made by the KSHI program in rural Nigeria is likely to have been cost-effective; however, further healthcare investments are needed for this program to be successfully expanded within Kwara State. Policy makers should consider supporting financial initiatives to reduce maternal mortality tackling both supply and demand issues in the access to care. 相似文献68.
Higham JP Brent LJ Dubuc C Accamando AK Engelhardt A Gerald MS Heistermann M Stevens M 《Behavioral ecology》2010,21(4):739-746
Animal coloration has provided many classical examples of both natural and sexual selection. Methods to study color signals range from human assessment to models of receiver vision, with objective measurements commonly involving spectrometry or digital photography. However, signal assessment by a receiver is not objective but linked to receiver perception. Here, we use standardized digital photographs of female rhesus macaque (Macaca mulatta) face and hindquarter regions, combined with estimates of the timing of the female fertile phase, to assess how color varies with respect to this timing. We compare objective color measures (camera sensor responses) with models of rhesus vision (retinal receptor stimulation and visual discriminability). Due to differences in spectral separation between camera sensors and rhesus receptors, camera measures overestimated color variation and underestimated luminance variation compared with rhesus macaques. Consequently, objective digital camera measurements can produce statistically significant relationships that are probably undetectable to rhesus macaques, and hence biologically irrelevant, while missing variation in the measure that may be relevant. Discrimination modeling provided results that were most meaningful (as they were directly related to receiver perception) and were easiest to relate to underlying physiology. Further, this gave new insight into the function of such signals, revealing perceptually salient signal luminance changes outside of the fertile phase that could potentially enhance paternity confusion. Our study demonstrates how, even for species with similar visual systems to humans, models of vision may provide more accurate and meaningful information on the form and function of visual signals than objective color measures do. 相似文献
69.
Joseph Karem Stephen A. Woods Francis Drummond Constance Stubbs 《Biocontrol Science and Technology》2010,20(3):257-274
This was the first study to have surveyed the spatial and temporal structure of Apocrita wasps in lowbush blueberry fields, a unique native agricultural landscape in Maine and eastern Canada. The relative abundances of wasps associated with lowbush blueberry (Vaccinium angustifolium Ait.) were investigated in 33 blueberry fields throughout Washington County, Maine, USA. Native wasps were captured during the springs and summers of 1997 and 1998 in Malaise traps erected along a transect in each field. Vegetation sampling was also conducted along these transects to quantify available floral resources. Data indicate the abundance of the total wasp community was positively associated with the abundance of sheep laurel (Kalmia angustifolia L.). Relationships between trap capture of 13 wasp morphospecies and other flowering weeds were also investigated. Most taxa in 1998 were positively associated with one or more of the following flowering plants: bunchberry (Cornus canadensis L.), bush honeysuckle (Diervilla lonicera P. Mill.), dogbane (Apocynum androsaemifolium L.), sheep laurel, and witherod (Viburnum nudum var. cassinoides L.). Similar results were not evident in 1997 because the method used to sample vegetation was not as extensive as that used in 1998. However, sheep laurel was positively associated with the wasp genera Microplitis spp. and Phanerotoma spp. during both years. 相似文献
70.