全文获取类型
收费全文 | 167885篇 |
免费 | 6782篇 |
国内免费 | 5598篇 |
专业分类
180265篇 |
出版年
2024年 | 138篇 |
2023年 | 901篇 |
2022年 | 2076篇 |
2021年 | 3603篇 |
2020年 | 2326篇 |
2019年 | 2839篇 |
2018年 | 13996篇 |
2017年 | 12111篇 |
2016年 | 9932篇 |
2015年 | 5138篇 |
2014年 | 5554篇 |
2013年 | 6231篇 |
2012年 | 10869篇 |
2011年 | 18596篇 |
2010年 | 15310篇 |
2009年 | 11244篇 |
2008年 | 13572篇 |
2007年 | 14672篇 |
2006年 | 3413篇 |
2005年 | 3158篇 |
2004年 | 3190篇 |
2003年 | 2952篇 |
2002年 | 2485篇 |
2001年 | 1810篇 |
2000年 | 1722篇 |
1999年 | 1470篇 |
1998年 | 855篇 |
1997年 | 818篇 |
1996年 | 817篇 |
1995年 | 736篇 |
1994年 | 693篇 |
1993年 | 559篇 |
1992年 | 838篇 |
1991年 | 694篇 |
1990年 | 608篇 |
1989年 | 538篇 |
1988年 | 438篇 |
1987年 | 375篇 |
1986年 | 336篇 |
1985年 | 299篇 |
1984年 | 228篇 |
1983年 | 216篇 |
1982年 | 114篇 |
1981年 | 118篇 |
1979年 | 147篇 |
1977年 | 95篇 |
1975年 | 115篇 |
1974年 | 116篇 |
1972年 | 307篇 |
1971年 | 317篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
931.
In some clinical development programs, there are potential biomarkers with promising but uncertain predictive effect, while the probability of success in the overall population cannot be readily dismissed. It is risky to focus only on the overall population, or just the biomarker subpopulation. In 2009, Chen and Beckman proposed a Bayesian decision framework to optimize the type I error rate (alpha) allocation in a Phase III clinical study with possible predictive subset effect. The utilization of internal data in this framework is of particular interest because it provides an opportunity to mitigate the potential risk of misspecified study assumptions using an auto-adaptive strategy. In this paper, we examine this auto-adaptive strategy in detail through extensive numerical case studies and provide guidance on the appropriate use of partial current trial (internal) data in this data-driven optimization framework. We show that internal data can be used to inform the alpha allocation to hypothesis testing in the overall population and the subgroup. The resulting adaptive testing strategy is robust with respect to the uncertainty in the predictive subgroup effect and biomarker prevalence. 相似文献
932.
Thompson JA Srivastava MK Bosch JJ Clements VK Ksander BR Ostrand-Rosenberg S 《Cancer immunology, immunotherapy : CII》2008,57(3):389-398
Activation of tumor-reactive T lymphocytes is a promising approach for the prevention and treatment of patients with metastatic
cancers. Strategies that activate CD8+ T cells are particularly promising because of the cytotoxicity and specificity of CD8+ T cells for tumor cells. Optimal CD8+ T cell activity requires the co-activation of CD4+ T cells, which are critical for immune memory and protection against latent metastatic disease. Therefore, we are developing
“MHC II” vaccines that activate tumor-reactive CD4+ T cells. MHC II vaccines are MHC class I+ tumor cells that are transduced with costimulatory molecules and MHC II alleles syngeneic to the prospective recipient. Because
the vaccine cells do not express the MHC II-associated invariant chain (Ii), we hypothesized that they will present endogenously synthesized tumor peptides that are not presented by professional Ii+ antigen presenting cells (APC) and will therefore overcome tolerance to activate CD4+ T cells. We now report that MHC II vaccines prepared from human MCF10 mammary carcinoma cells are more efficient than Ii+ APC for priming and boosting Type 1 CD4+ T cells. MHC II vaccines consistently induce greater expansion of CD4+ T cells which secrete more IFNγ and they activate an overlapping, but distinct repertoire of CD4+ T cells as measured by T cell receptor Vβ usage, compared to Ii+ APC. Therefore, the absence of Ii facilitates a robust CD4+ T cell response that includes the presentation of peptides that are presented by traditional APC, as well as peptides that
are uniquely presented by the Ii− vaccine cells. 相似文献
933.
934.
935.
Yu Sun Hongxia Zhang Ruimin Hu Jianyong Sun Xing Mao Zhonghua Zhao Qi Chen Zhigang Zhang 《PloS one》2014,9(4)
Growing evidence suggests that there are many common cell biological features shared by neurons and podocytes; however, the mechanism of podocyte foot process formation remains unclear. Comparing the mechanisms of process formation between two cell types should provide useful guidance from the progress of neuron research. Studies have shown that some mature proteins of podocytes, such as podocin, nephrin, and synaptopodin, were also expressed in neurons. In this study, using cell biological experiments and immunohistochemical techniques, we showed that some neuronal iconic molecules, such as Neuron-specific enolase, nestin and Neuron-specific nuclear protein, were also expressed in podocytes. We further inhibited the expression of Neuron-specific enolase, nestin, synaptopodin and Ubiquitin carboxy terminal hydrolase-1 by Small interfering RNA in cultured mouse podocytes and observed the significant morphological changes in treated podocytes. When podocytes were treated with Adriamycin, the protein expression of Neuron-specific enolase, nestin, synaptopodin and Ubiquitin carboxy terminal hydrolase-1 decreased over time. Meanwhile, the morphological changes in the podocytes were consistent with results of the Small interfering RNA treatment of these proteins. The data demonstrated that neuronal iconic proteins play important roles in maintaining and regulating the formation and function of podocyte processes. 相似文献
936.
Basavegowdanadoddi Marinaik Chandranaik Sonnahallipura Munivenkatappa Byregowda Mudalagiri Dasappagupta Venkatesha Kantharajapura Ramanna Ramesha Poojappa Nandini Poorvi Reddy Thushara Bindu KV Beechagondahalli Papanna Shivashankar Byadarahalli Puttaswamy Shankar Methuku Sobha Rani 《European Journal of Wildlife Research》2018,64(1):4
We report the molecular epidemiology of highly pathogenic avian influenza (HPAI) virus involved in an outbreak causing death in free-ranging wild birds at Mysore, Karnataka state of India. The virus was typed as HPAI A(H5N8) by conventional and TaqMan probe based real-time PCR assays. Six isolates of HPAI virus were recovered in 9-day-old embryonated chicken eggs. Haemagglutinin gene-based phylogeny of virus isolates showed >?99.9% nucleotide sequence identity with HPAI A(H5N8) isolates from migratory birds and domestic poultry from China and Korea indicating either these wild birds have routed their migration through Korea and/or eastern China or these dead birds must have directly or indirectly contacted with wild birds migrating from Eastern China and/or Korean regions. The study emphasises the role of migratory wild birds in spread of HPAI across the globe. 相似文献
937.
Kunnimalaiyaan M Traeger K Chen H 《American journal of physiology. Gastrointestinal and liver physiology》2005,289(4):G636-G642
Gastrointestinal (GI) carcinoid cells secrete multiple neuroendocrine (NE) markers and hormones including 5-hydroxytryptamine and chromogranin A. We were interested in determining whether activation of the Notch1 signal transduction pathway in carcinoid cells could modulate production of NE markers and hormones. Human pancreatic carcinoid cells (BON cells) were stably transduced with an estrogen-inducible Notch1 construct, creating BON-NIER cells. In the present study, we found that Notch1 is not detectable in human GI carcinoid tumor cells. The induction of Notch1 in human BON carcinoid cells led to high levels of functional Notch1, as measured by CBF-1 binding studies, resulting in activation of the Notch1 pathway. Similar to its developmental role in the GI tract, Notch1 pathway activation led to an increase in hairy enhancer of split 1 (HES-1) protein and a concomitant silencing of human Notch1/HES-1/achaete-scute homolog 1. Furthermore, Notch1 activation led to a significant reduction in NE markers. Most interestingly, activation of the Notch1 pathway caused a significant reduction in 5-hydroxytryptamine, an important bioactive hormone in carcinoid syndrome. In addition, persistent activation of the Notch1 pathway in BON cells led to a notable reduction in cellular proliferation. These results demonstrate that the Notch1 pathway, which plays a critical role in the differentiation of enteroendocrine cells, is highly conserved in the gut. Therefore, manipulation of the Notch1 signaling pathway may be useful for expanding the targets for therapeutic and palliative treatment of patients with carcinoid tumors. 相似文献
938.
Fassett JT Hu X Xu X Lu Z Zhang P Chen Y Bache RJ 《American journal of physiology. Heart and circulatory physiology》2011,300(5):H1722-H1732
There is evidence that extracellular adenosine can attenuate cardiac hypertrophy, but the mechanism by which this occurs is not clear. Here we investigated the role of adenosine receptors and adenosine metabolism in attenuation of cardiomyocyte hypertrophy. Phenylephrine (PE) caused hypertrophy of neonatal rat cardiomyocytes with increases of cell surface area, protein synthesis, and atrial natriuretic peptide (ANP) expression. These responses were attenuated by 5 μM 2-chloroadenosine (CADO; adenosine deaminase resistant adenosine analog) or 10 μM adenosine. While antagonism of adenosine receptors partially blocked the reduction of ANP expression produced by CADO, it did not restore cell size or protein synthesis. In support of a role for intracellular adenosine metabolism in regulating hypertrophy, the adenosine kinase (AK) inhibitors iodotubercidin and ABT-702 completely reversed the attenuation of cell size, protein synthesis, and expression of ANP by CADO or ADO. Examination of PE-induced phosphosignaling pathways revealed that CADO treatment did not reduce AKT(Ser??3) phosphorylation but did attenuate sustained phosphorylation of Raf(Ser33?) (24-48 h), mTOR(Ser2???) (24-48 h), p70S6k(Thr3??) (2.5-48 h), and ERK(Thr2?2/Tyr2??) (48 h). Inhibition of AK restored activation of these enzymes in the presence of CADO. Using dominant negative and constitutively active Raf adenoviruses, we found that Raf activation is necessary and sufficient for PE-induced mTORC1 signaling and cardiomyocyte hypertrophy. CADO treatment still blocked p70S6k(Thr3??) phosphorylation and hypertrophy downstream of constitutively active Raf, however, despite a high level phosphorylation of ERK(Thr202/Tyr204) and AKT(Ser??3). Reduction of Raf-induced p70S6k(Thr3??) phosphorylation and hypertrophy by CADO was reversed by inhibiting AK. Together, these results identify AK as an important mediator of adenosine attenuation of cardiomyocyte hypertrophy, which acts, at least in part, through inhibition of Raf signaling to mTOR/p70S6k. 相似文献
939.
ABSTRACT: OBJECTIVE: To study the clinico-pathological characteristics of Langerhans cell sarcoma (LCS) which involving epidermis. METHODS: A case of primary multifocal LCS was analyzed in histopathology and immunophenotype. RESULTS: A 41-year-old man with multifocal cutaneous LCS involving the inguina and waist was reported. Clinical and pathology data were available. Neoplastic cells with markedly malignant cytological features were observed. Tumor cells exhibited irregular shape with abundant and eosinophilic red staining cytoplasm; large, irregular-shaped, showing lobulated or dented nucleus and some cells with a longitudinal nuclear groove and prominent nucleoli. The tumor cells expressed CD1a, Langerin (CD207), S-100 protein, CD68 and vimentin, and did not express pan-T or B cell markers and epithelial markers. The patient died less than 1 year after diagnosis due to local recurrence and metastasis to the lung, despite the administration of local radiation and chemotherapy. CONCLUSIONS: LCS is a tumor with markedly malignant cytological features that originates from Langerhans cells. Primary multifocal neoplasms involving epidermis is even rare. Accurate diagnosis is based on the histopathological and immunohistochemical of the tumor cells.Virtual slideThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1182345104754765. 相似文献
940.
Łukasz Kajtoch Elżbieta Cieślak Zoltán Varga Wojciech Paul Miłosz A. Mazur Gábor Sramkó Daniel Kubisz 《Biodiversity and Conservation》2016,25(12):2309-2339
The phylogeography of species associated with European steppes and extrazonal xeric grasslands is poorly understood. This paper summarizes the results of recent studies on the phylogeography and conservation genetics of animals (20 taxa of beetles, butterflies, reptiles and rodents) and flowering plants (18 taxa) of such, "steppic" habitats in Eastern Central Europe. Most species show a similar phylogeographic pattern: relatively high genetic similarity within regional groups of populations and moderate-to-high genetic distinctiveness of populations from currently isolated regions located in the studied area. This distinctiveness of populations suggests a survival here during glacial maxima, including areas north of the Bohemian Massif-Carpathians arc. Steppic species generally do not follow the paradigmatic patterns known for temperate biota (south-north “contraction–expansion”), but to some extent are similar to those of arctic-alpine taxa. There are three main groups of taxa within Eastern Central Europe that differ in their contemporary distribution pattern, which may reflect historical origin and expansion routes. Present diversity patterns of the studied steppic species suggest that they share a unique genetic signature and distinct assemblages exist in each of the now isolated areas rich in steppic habitats. At least some of these areas probably act as present “interglacial refugia” for steppic species. This study strongly supports the need to protect steppic species throughout their entire ranges in the region, as the continuous destruction of steppic habitats in some areas may lead not only to the disappearance of local populations, but also to the extinction of unique evolutionary units. 相似文献