全文获取类型
收费全文 | 2039篇 |
免费 | 183篇 |
出版年
2022年 | 15篇 |
2021年 | 59篇 |
2020年 | 37篇 |
2019年 | 36篇 |
2018年 | 33篇 |
2017年 | 32篇 |
2016年 | 43篇 |
2015年 | 98篇 |
2014年 | 95篇 |
2013年 | 99篇 |
2012年 | 115篇 |
2011年 | 142篇 |
2010年 | 78篇 |
2009年 | 69篇 |
2008年 | 89篇 |
2007年 | 125篇 |
2006年 | 86篇 |
2005年 | 81篇 |
2004年 | 72篇 |
2003年 | 79篇 |
2002年 | 67篇 |
2001年 | 30篇 |
2000年 | 23篇 |
1999年 | 16篇 |
1998年 | 21篇 |
1997年 | 16篇 |
1996年 | 12篇 |
1995年 | 15篇 |
1992年 | 13篇 |
1991年 | 13篇 |
1990年 | 17篇 |
1989年 | 17篇 |
1988年 | 11篇 |
1986年 | 15篇 |
1984年 | 14篇 |
1983年 | 15篇 |
1982年 | 18篇 |
1981年 | 12篇 |
1979年 | 11篇 |
1978年 | 15篇 |
1977年 | 11篇 |
1976年 | 18篇 |
1974年 | 15篇 |
1968年 | 11篇 |
1967年 | 10篇 |
1964年 | 14篇 |
1963年 | 10篇 |
1962年 | 11篇 |
1940年 | 9篇 |
1938年 | 9篇 |
排序方式: 共有2222条查询结果,搜索用时 15 毫秒
71.
Julie In Valeriy Lukyanenko Jennifer Foulke-Abel Ann L. Hubbard Michael Delannoy Anne-Marie Hansen James B. Kaper Nadia Boisen James P. Nataro Chengru Zhu Edgar C. Boedeker Jorge A. Girón Olga Kovbasnjuk 《PloS one》2013,8(7)
Life-threatening intestinal and systemic effects of the Shiga toxins produced by enterohemorrhagic Escherichia coli (EHEC) require toxin uptake and transcytosis across intestinal epithelial cells. We have recently demonstrated that EHEC infection of intestinal epithelial cells stimulates toxin macropinocytosis, an actin-dependent endocytic pathway. Host actin rearrangement necessary for EHEC attachment to enterocytes is mediated by the type 3 secretion system which functions as a molecular syringe to translocate bacterial effector proteins directly into host cells. Actin-dependent EHEC attachment also requires the outer membrane protein intimin, a major EHEC adhesin. Here, we investigate the role of type 3 secretion in actin turnover occurring during toxin macropinocytosis. Toxin macropinocytosis is independent of EHEC type 3 secretion and intimin attachment. EHEC soluble factors are sufficient to stimulate macropinocytosis and deliver toxin into enterocytes in vitro and in vivo; intact bacteria are not required. Intimin-negative enteroaggregative Escherichia coli (EAEC) O104:H4 robustly stimulate Shiga toxin macropinocytosis into intestinal epithelial cells. The apical macropinosomes formed in intestinal epithelial cells move through the cells and release their cargo at these cells’ basolateral sides. Further analysis of EHEC secreted proteins shows that a serine protease EspP alone is able to stimulate host actin remodeling and toxin macropinocytosis. The observation that soluble factors, possibly serine proteases including EspP, from each of two genetically distinct toxin-producing strains, can stimulate Shiga toxin macropinocytosis and transcellular transcytosis alters current ideas concerning mechanisms whereby Shiga toxin interacts with human enterocytes. Mechanisms important for this macropinocytic pathway could suggest new potential therapeutic targets for Shiga toxin-induced disease. 相似文献
72.
Elizabeth B. Oliveira-Sales Edgar Maquigussa Patricia Semedo Luciana G. Pereira Vanessa M. Ferreira Niels O. Camara Cassia T. Bergamaschi Ruy R. Campos Mirian A. Boim 《PloS one》2013,8(11)
Renovascular hypertension induced by 2 Kidney-1 Clip (2K-1C) is a renin-angiotensin-system (RAS)-dependent model, leading to renal vascular rarefaction and renal failure. RAS inhibitors are not able to reduce arterial pressure (AP) and/or preserve the renal function, and thus, alternative therapies are needed. Three weeks after left renal artery occlusion, fluorescently tagged mesenchymal stem cells (MSC) (2×105 cells/animal) were injected weekly into the tail vein in 2K-1C hypertensive rats. Flow cytometry showed labeled MSC in the cortex and medulla of the clipped kidney. MSC prevented a further increase in the AP, significantly reduced proteinuria and decreased sympathetic hyperactivity in 2K-1C rats. Renal function parameters were unchanged, except for an increase in urinary volume observed in 2K-1C rats, which was not corrected by MSC. The treatment improved the morphology and decreased the fibrotic areas in the clipped kidney and also significantly reduced renal vascular rarefaction typical of 2K-1C model. Expression levels of IL-1β, TNF-α angiotensinogen, ACE, and Ang II receptor AT1 were elevated, whereas AT2 levels were decreased in the medulla of the clipped kidney. MSC normalized these expression levels. In conclusion, MSC therapy in the 2K-1C model (i) prevented the progressive increase of AP, (ii) improved renal morphology and microvascular rarefaction, (iii) reduced fibrosis, proteinuria and inflammatory cytokines, (iv) suppressed the intrarenal RAS, iv) decreased sympathetic hyperactivity in anesthetized animals and v) MSC were detected at the CNS suggesting that the cells crossed the blood-brain barrier. This therapy may be a promising strategy to treat renovascular hypertension and its renal consequences in the near future. 相似文献
73.
74.
75.
76.
Franziska G. Rauscher Catharine M. Chisholm David F. Edgar John L. Barbur 《Cell and tissue research》2013,353(2):297-310
The effects of glaucoma on binocular visual sensitivity for the detection of various stimulus attributes are investigated at the fovea and in four paracentral retinal regions. The study employed a number of visual stimuli designed to isolate the processing of various stimulus attributes. We measured absolute contrast detection thresholds and functional contrast sensitivity by using Landolt ring stimuli. This psychophysical Landolt C-based contrast test of detection and gap discrimination allowed us to test parafoveally at 6 ° from fixation and foveally by employing interleaved testing locations. First-order motion perception was examined by using moving stimuli embedded in static luminance contrast noise. Red/green (RG) and yellow/blue (YB) colour thresholds were measured with the Colour Assessment and Diagnosis (CAD) test, which utilises random dynamic luminance contrast noise (± 45 %) to ensure that only colour and not luminance signals are available for target detection. Subjects were normal controls (n?=?65) and glaucoma patients with binocular visual field defects (n?=?15) classified based on their Humphrey Field Analyzer mean deviation (MD) scores. The impairment of visual function varied depending on the stimulus attribute and location tested. Progression of loss was noted for all tests as the degree of glaucoma increased. For subjects with mild glaucoma (MD ?0.01 dB to ?6.00 dB) significantly more data points fell outside the normal age-representative range for RG colour thresholds than for any other visual test, followed by motion thresholds. This was particularly the case for the parafoveal data compared with the foveal data. Thus, a multifaceted measure of binocular visual performance, incorporating RG colour and motion test at multiple locations, might provide a better index for comparison with quality of life measures in glaucoma. 相似文献
77.
78.
Paige Beck Susan Mahaffey Francisco J. Urbano Edgar Garcia‐Rill 《Journal of neurochemistry》2013,126(6):705-714
The pedunculopontine nucleus (PPN), the cholinergic arm of the reticular activating system, regulates waking and rapid eye movement sleep. Here, we demonstrate immunohistochemical labeling of the leptin receptor signaling isoform in PPN neurons, and investigated the effects of G‐protein modulation and the leptin triple antagonist (TA) on the action of leptin in the PPN. Whole‐cell patch clamp recordings were performed in rat brainstem slices from 9 to 17 day old pups. Previous results showed that leptin caused a partial blockade of sodium (INa) and h‐current (IH) in PPN neurons. TA (100 nM) reduced the blockade of INa (~ 50% reduction) and IH (~ 93% reduction) caused by leptin. Intracellular guanosine 5′‐[β‐thio]diphosphate trilithium salt (a G‐protein inhibitor) significantly reduced the effect of leptin on INa(~ 60% reduction) but not on IH (~ 25% reduction). Intracellular GTPγS (a G‐protein activator) reduced the effect of leptin on both INa (~ 80% reduction) and IH (~ 90% reduction). These results suggest that the effects of leptin on the intrinsic properties of PPN neurons are leptin receptor‐ and G‐protein dependent. We also found that leptin enhanced NMDA receptor‐mediated responses in single neurons and in the PPN population as a whole, an effect blocked by TA. These experiments further strengthen the association between leptin dysregulation and sleep disturbances.
79.
Pradinunt Eiamsa-ard Akkharawit Kanjana-Opas Edgar B. Cahoon Pichit Chodok Sireewan Kaewsuwan 《Applied microbiology and biotechnology》2013,97(8):3485-3497
The lower plant Physcomitrella patens synthesizes several long-chain polyunsaturated fatty acids (LC-PUFAs) by a series of desaturation and elongation reactions. In the present study, the full-length cDNAs for two novel fatty acid elongases designated PpELO1 and PpELO2 were isolated from P. patens using a PCR-based cloning strategy. These cDNAs encoding proteins of 335 and 280 amino acids with predicted molecular masses of 38.7 and 32.9 kDa, respectively, are predicted to contain seven transmembrane domains with a possible localization in the subcellular endoplasmic reticulum. Sequence comparisons and phylogenetic analysis revealed that they are closely related to other LC-PUFA elongases of the lower eukaryotes such as the Δ5- and Δ6-elongases of Marchantia polymorpha as well as the Δ6-elongase of P. patens. Heterologous expression of the PpELO1 in Saccharomyces cerevisiae led to the elongation of Δ9-, Δ6-C18, and Δ5-C20 LC-PUFAs, whereas only Δ9- and Δ6-C18 LC-PUFA substrates were used by PpELO2. Chimeric proteins were constructed to identify the amino acid regions most likely to be involved in the determination of the fatty acid substrate specificity. The expression of eight chimeric proteins in yeast revealed that substitution of the C-terminal 50 amino acids from PpELO1 into PpELO2 resulted in a high specificity for C20 fatty acid substrates. As a result, we suggest that the C-terminal region of PpELO1 is sufficient for C20 substrate elongation. Overall, these results provide important insights into the structural basis for substrate specificity of PUFA-generating ELO enzymes. 相似文献
80.