全文获取类型
收费全文 | 2844篇 |
免费 | 256篇 |
专业分类
3100篇 |
出版年
2024年 | 3篇 |
2023年 | 30篇 |
2022年 | 63篇 |
2021年 | 88篇 |
2020年 | 65篇 |
2019年 | 63篇 |
2018年 | 85篇 |
2017年 | 61篇 |
2016年 | 116篇 |
2015年 | 194篇 |
2014年 | 195篇 |
2013年 | 260篇 |
2012年 | 305篇 |
2011年 | 243篇 |
2010年 | 178篇 |
2009年 | 159篇 |
2008年 | 154篇 |
2007年 | 160篇 |
2006年 | 134篇 |
2005年 | 101篇 |
2004年 | 85篇 |
2003年 | 80篇 |
2002年 | 48篇 |
2001年 | 15篇 |
2000年 | 17篇 |
1999年 | 16篇 |
1998年 | 6篇 |
1997年 | 10篇 |
1996年 | 7篇 |
1995年 | 3篇 |
1993年 | 6篇 |
1992年 | 20篇 |
1991年 | 6篇 |
1990年 | 11篇 |
1989年 | 6篇 |
1988年 | 9篇 |
1987年 | 8篇 |
1986年 | 8篇 |
1985年 | 5篇 |
1984年 | 6篇 |
1983年 | 8篇 |
1982年 | 7篇 |
1981年 | 5篇 |
1980年 | 7篇 |
1979年 | 3篇 |
1978年 | 7篇 |
1976年 | 4篇 |
1975年 | 9篇 |
1971年 | 3篇 |
1937年 | 3篇 |
排序方式: 共有3100条查询结果,搜索用时 15 毫秒
991.
992.
Hanitriniaina Rabeony Isabelle Petit-Paris Julien Garnier Christine Barrault Nathalie Pedretti Karline Guilloteau Jean-Fran?ois Jegou Gérard Guillet Vincent Huguier Jean-Claude Lecron Fran?ois-Xavier Bernard Franck Morel 《PloS one》2014,9(7)
Keratinocyte differentiation program leading to an organized epidermis plays a key role in maintaining the first line of defense of the skin. Epidermal integrity is regulated by a tight communication between keratinocytes and leucocytes, particularly under cytokine control. Imbalance of the cytokine network leads to inflammatory diseases such as psoriasis. Our attempt to model skin inflammation showed that the combination of IL-17A, IL-22, IL-1α, OSM and TNFα (Mix M5) synergistically increases chemokine and antimicrobial-peptide expression, recapitulating some features of psoriasis. Other characteristics of psoriasis are acanthosis and down-regulation of keratinocyte differentiation markers. Our aim was to characterize the specific roles of these cytokines on keratinocyte differentiation, and to compare with psoriatic lesion features. All cytokines decrease keratinocyte differentiation markers, but IL-22 and OSM were the most powerful, and the M5 strongly synergized the effects. In addition, IL-22 and OSM induced epidermal hyperplasia in vitro and M5 induced epidermal thickening and decreased differentiation marker expression in a mouse model, as observed in human psoriatic skin lesions. This study highlights the precise role of cytokines in the skin inflammatory response. IL-22 and OSM more specifically drive epidermal hyperplasia and differentiation loss while IL-1α, IL-17A and TNFα were more involved in the activation of innate immunity. 相似文献
993.
Aurélie Cazet Sylvain Julien Marie-Ange Krzewinski-Recchi Anne Harduin-Lepers Sophie Groux-Degroote Philippe Delannoy 《Carbohydrate research》2010,345(10):1377-1383
Changes in cell surface glycosylation are common modifications that occur during oncogenesis, leading to the over-expression of tumour-associated carbohydrate antigens (TACA). Most of these antigens are sialylated and the increase of sialylation is a well-known feature of transformed cells. In breast cancer, expression of TACA such as sialyl-Lewisx or sialyl-Tn is usually associated with a poor prognosis and a decreased overall survival of patients. However, the specific role of these sialylated antigens in breast tumour development and aggressiveness is not clearly understood. These glycosylation changes result from the modification of the expression of genes encoding specific glycosyltransferases involved in glycan biosynthesis and the level of expression of sialyltransferase genes has been proposed to be a prognostic marker for the follow-up of breast cancer patients. Several human cellular models have been developed in order to explain the mechanisms by which carbohydrate antigens can reinforce breast cancer progression and aggressiveness. TACA expression is associated with changes in cell adhesion, migration, proliferation and tumour growth. In addition, recent data on glycolipid biosynthesis indicate an important role of GD3 synthase expression in breast cancer progression. The aim of this review is to summarize our current knowledge of sialylation changes that occur in breast cancer and to describe the cellular models developed to analyze the consequences of these changes on disease progression and aggressiveness. 相似文献
994.
A centriole- and RanGTP-independent spindle assembly pathway in meiosis I of vertebrate oocytes 下载免费PDF全文
Dumont J Petri S Pellegrin F Terret ME Bohnsack MT Rassinier P Georget V Kalab P Gruss OJ Verlhac MH 《The Journal of cell biology》2007,176(3):295-305
Spindle formation is essential for stable inheritance of genetic material. Experiments in various systems indicate that Ran GTPase is crucial for meiotic and mitotic spindle assembly. Such an important role for Ran in chromatin-induced spindle assembly was initially demonstrated in Xenopus laevis egg extracts. However, the requirement of RanGTP in living meiotic cells has not been shown. In this study, we used a fluorescence resonance energy transfer probe to measure RanGTP-regulated release of importin beta. A RanGTP-regulated gradient was established during meiosis I and was centered on chromosomes throughout mouse meiotic maturation. Manipulating levels of RanGTP in mice and X. laevis oocytes did not inhibit assembly of functional meiosis I spindles. However, meiosis II spindle assembly did not tolerate changes in the level of RanGTP in both species. These findings suggest that a mechanism common to vertebrates promotes meiosis I spindle formation in the absence of chromatin-induced microtubule production and centriole-based microtubule organizing centers. 相似文献
995.
Olivier Julien Subhrangsu Chatterjee Angela Thiessen Steffen P. Graether Brian D. Sykes 《Protein science : a publication of the Protein Society》2009,18(10):2172-2182
Prion diseases, or transmissible spongiform encephalopathies, are a group of infectious neurological diseases associated with the structural conversion of an endogenous protein (PrP) in the central nervous system. There are two major forms of this protein: the native and noninfectious cellular form, PrPC; and the misfolded, infectious, and proteinase K‐resistant form, PrPSc. The C‐terminal domain of PrPC is mainly α‐helical in structure, whereas PrPSc in known to aggregate into an assembly of β‐sheets, forming amyloid fibrils. To identify the regions of PrPC potentially involved in the initial steps of the conversion to the infectious conformation, we have used high‐resolution NMR spectroscopy to characterize the stability and structure of bovine recombinant PrPC (residues 121 to 230) during unfolding with the denaturant urea. Analysis of the 800 MHz 1H NMR spectra reveals region‐specific information about the structural changes occurring upon unfolding. Our data suggest that the dissociation of the native β‐sheet of PrPC is a primary step in the urea‐induced unfolding process, while strong hydrophobic interactions between helices α1 and α3, and between α2 and α3, stabilize these regions even at very high concentrations of urea. 相似文献
996.
Bonnet P Bonnet S Boissière J Le Net JL Gautier M Dumas de la Roque E Eder V 《American journal of physiology. Heart and circulatory physiology》2004,287(3):H1023-H1028
The purpose of this study was to evaluate the reversibility of right ventricular (RV) remodelling after pulmonary artery hypertension (PAHT) secondary to 3 wk of hypobaric hypoxia. A group of 10 adult male Wistar rats were studied and were the following: control normoxic (C), after 3 wk of chronic hypoxia (CH), and after 3 wk of exposure to hypoxia followed by 3 wk of normoxia recovery (N-RE). Mean pulmonary artery pressure was 11 +/- 2 mmHg in the C group, 35 +/- 2 mmHg in the CH group, and 14 +/- 3 mmHg in the N-RE group. RV function was assessed by echocardiography. In the CH group, the pulmonary flow measured in Doppler mode depicted a midsystolic notch and a decrease of the pulmonary acceleration time compared with control [17 +/- 1 vs. 34 +/- 1 ms (n = 10), respectively; P < 0.05]. RV thickening measured in M-mode was apparent in the CH group compared with the control group [2.84 +/- 0.40 vs. 1.73 +/- 0.26 mm (n = 10), P < 0.05]. In the N-RE group, the RV wall was significantly thinner compared with the CH group [1.56 +/- 0.08 vs. 1.73 +/- 0.26 mm (n = 10), P < 0.05]. The calculated RV diameter shortness fraction was not different between the CH group and C group (34 +/- 4.2% vs. 36 +/- 2.8%) but decreased in the N-RE group [20 +/- 2.4% (n = 10), P < 0.01]. The E-to-A wave ratio on the tricuspid Doppler inflow was significantly lower in the CH group and N-RE group compared with the C group [0.70 +/- 0.8 and 0.72 +/- 0.1 vs. 0.88 +/- 0.2 (n = 10), respectively; P < 0.05]. In the isolated perfused heart using the Langendorff method, RV compliance was increased in the CH group and decreased in the N-RE group. In the N-RE group, fibrous bands with metaplasia were observed on histological sections of the RV free wall. We conclude that PAHT induces nonreversible RV dysfunction with dysplasia. 相似文献
997.
998.
999.
Zinc deficiency leads to lipofuscin accumulation in the retinal pigment epithelium of pigmented rats
Background
Age-related macular degeneration (AMD) is associated with lipofuscin accumulation whereas the content of melanosomes decreases. Melanosomes are the main storage of zinc in the pigmented tissues. Since the elderly population, as the most affected group for AMD, is prone to zinc deficit, we investigated the chemical and ultrastructural effects of zinc deficiency in pigmented rat eyes after a six-month zinc penury diet.Methodology/Principal Findings
Adult Long Evans (LE) rats were investigated. The control animals were fed with a normal alimentation whereas the zinc-deficiency rats (ZD-LE) were fed with a zinc deficient diet for six months. Quantitative Energy Dispersive X-ray (EDX) microanalysis yielded the zinc mole fractions of melanosomes in the retinal pigment epithelium (RPE). The lateral resolution of the analysis was 100 nm. The zinc mole fractions of melanosomes were significantly smaller in the RPE of ZD-LE rats as compared to the LE control rats. Light, fluorescence and electron microscopy, as well as immunohistochemistry were performed. The numbers of lipofuscin granules in the RPE and of infiltrated cells (Ø>3 µm) found in the choroid were quantified. The number of lipofuscin granules significantly increased in ZD-LE as compared to control rats. Infiltrated cells bigger than 3 µm were only detected in the choroid of ZD-LE animals. Moreover, the thickness of the Bruch''s membrane of ZD-LE rats varied between 0.4–3 µm and thin, rangy ED1 positive macrophages were found attached at these sites of Bruch''s membrane or even inside it.Conclusions/Significance
In pigmented rats, zinc deficiency yielded an accumulation of lipofuscin in the RPE and of large pigmented macrophages in the choroids as well as the appearance of thin, rangy macrophages at Bruch''s membrane. Moreover, we showed that a zinc diet reduced the zinc mole fraction of melanosomes in the RPE and modulated the thickness of the Bruch''s membrane. 相似文献1000.
Dairou J Pluvinage B Noiran J Petit E Vinh J Haddad I Mary J Dupret JM Rodrigues-Lima F 《Journal of molecular biology》2007,372(4):1009-1021
Muscle glycogen phosphorylase (GP) is a key enzyme in glucose metabolism, and its impairment can lead to muscle dysfunction. Tyrosine nitration of glycogen phosphorylase occurs during aging and has been suggested to be involved in progressive loss of muscle performance. Here, we show that GP (in its T and R form) is irreversibly impaired by exposure to peroxynitrite, a biological nitrogen species known to nitrate reactive tyrosine residues, and to be involved in physiological and pathological processes. Kinetic and biochemical analysis indicated that irreversible inactivation of GP by peroxynitrite is due to the fast (k(inact)=3 x 10(4) M(-1) s(-1)) nitration of a unique tyrosine residue of the enzyme. Endogenous GP was tyrosine nitrated and irreversibly inactivated in skeletal muscle cells upon exposure to peroxynitrite, with concomitant impairment of glycogen mobilization. Ligand protection assays and mass spectrometry analysis using purified GP suggested that the peroxynitrite-dependent inactivation of the enzyme could be due to the nitration of Tyr613, a key amino acid of the allosteric inhibitor site of the enzyme. Our findings suggest that GP functions may be regulated by tyrosine nitration. 相似文献