全文获取类型
收费全文 | 587篇 |
免费 | 52篇 |
国内免费 | 1篇 |
出版年
2024年 | 1篇 |
2023年 | 4篇 |
2022年 | 2篇 |
2021年 | 26篇 |
2020年 | 7篇 |
2019年 | 21篇 |
2018年 | 17篇 |
2017年 | 15篇 |
2016年 | 20篇 |
2015年 | 50篇 |
2014年 | 48篇 |
2013年 | 53篇 |
2012年 | 57篇 |
2011年 | 33篇 |
2010年 | 29篇 |
2009年 | 31篇 |
2008年 | 31篇 |
2007年 | 30篇 |
2006年 | 33篇 |
2005年 | 27篇 |
2004年 | 21篇 |
2003年 | 17篇 |
2002年 | 12篇 |
2001年 | 5篇 |
2000年 | 3篇 |
1999年 | 2篇 |
1998年 | 4篇 |
1997年 | 4篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 5篇 |
1992年 | 1篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1983年 | 1篇 |
1979年 | 1篇 |
1960年 | 1篇 |
1957年 | 1篇 |
1956年 | 1篇 |
1955年 | 1篇 |
1947年 | 2篇 |
1946年 | 1篇 |
1937年 | 2篇 |
1934年 | 4篇 |
1933年 | 1篇 |
1931年 | 1篇 |
1929年 | 2篇 |
1928年 | 2篇 |
1926年 | 1篇 |
1925年 | 1篇 |
排序方式: 共有640条查询结果,搜索用时 421 毫秒
131.
Clémence Feneyrolles Léa Guiet Mathilde Singer Nathalie Van Hijfte Bénédicte Daydé-Cazals Bénédicte Fauvel Gwénaël Chevé Abdelaziz Yasri 《Bioorganic & medicinal chemistry letters》2017,27(4):862-866
AXL is a receptor tyrosine kinase that plays a key role in tumor growth and proliferation. The scientific community has validated AXL as therapeutic target in the treatment of cancers for several years now, and several AXL inhibitors have been developed but none of them are approved. In this context, we started to design new kinase inhibitors targeting AXL from the 7-azaindole scaffold well known to interact with the ATP binding site of the kinase. Focused screening and chemical diversification around 7-azaindole scaffold were developed, based on modeling studies and medicinal chemistry rational, leading to the discovery of a new family of hits with potent inhibitory activity against AXL. 相似文献
132.
133.
Summary The nuclei in the skin, and in the neutrophils, have been studied in men and women, in relation to a diagnosis of the sex chromosomes in non-dividing nuclei.It has been shown in the skin, that the appearance of chromocenters, which are presumably formed by the X and Y, can vary according to metabolic conditions, but that a determination of the percent of nuclei with different numbers of chromocenters and nucleoli in the young and old spinous cells, gives a characteristic distribution of nuclear types in each of the two sexes.Since such a determination includes cells with individual X and Y chromocenters, it should be possible to detect by this method not only cases that are XX or XY, but also cases with abnormal sex chromosome constitutions. 相似文献
134.
135.
Fauconnier M Palomo J Bourigault ML Meme S Szeremeta F Beloeil JC Danneels A Charron S Rihet P Ryffel B Quesniaux VF 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(4):1905-1914
A Th1 response is required for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The role of pro-Th1 IL-12 in malaria is complex and controversial. In this study, we addressed the role of IL-12Rβ2 in ECM development. C57BL/6 mice deficient for IL-12Rβ2, IL-12p40, or IL-12p35 were analyzed for ECM development after blood-stage PbA infection in terms of ischemia and blood flow by noninvasive magnetic resonance imaging and angiography, T cell recruitment, and gene expression. Without IL-12Rβ2, no neurologic sign of ECM developed upon PbA infection. Although wild-type mice developed distinct brain microvascular pathology, ECM-resistant, IL-12Rβ2-deficient mice showed unaltered cerebral microcirculation and the absence of ischemia after PbA infection. In contrast, mice deficient for IL-12p40 or IL-12p35 were sensitive to ECM development. The resistance of IL-12Rβ2-deficient mice to ECM correlated with reduced recruitment of activated T cells and impaired overexpression of lymphotoxin-α, TNF-α, and IFN-γ in the brain after PbA infection. Therefore, IL-12Rβ2 signaling is essential for ECM development but independent from IL-12p40 and IL-12p35. We document a novel link between IL-12Rβ2 and lymphotoxin-α, TNF-α, and IFN-γ expression, key cytokines for ECM pathogenesis. 相似文献
136.
Di Filippo M Créhalet H Samson-Bouma ME Bonnet V Aggerbeck LP Rabès JP Gottrand F Luc G Bozon D Sassolas A 《Journal of lipid research》2012,53(3):548-555
Abetalipoproteinemia (ABL) is an inherited disease characterized by the defective assembly and secretion of apolipoprotein B-containing lipoproteins caused by mutations in the microsomal triglyceride transfer protein large subunit (MTP) gene (MTTP). We report here a female patient with an unusual clinical and biochemical ABL phenotype. She presented with severe liver injury, low levels of LDL-cholesterol, and subnormal levels of vitamin E, but only mild fat malabsorption and no retinitis pigmentosa or acanthocytosis. Our objective was to search for MTTP mutations and to determine the relationship between the genotype and this particular phenotype. The subject exhibited compound heterozygosity for two novel MTTP mutations: one missense mutation (p.Leu435His) and an intronic deletion (c.619-5_619-2del). COS-1 cells expressing the missense mutant protein exhibited negligible levels of MTP activity. In contrast, the minigene splicing reporter assay showed an incomplete splicing defect of the intronic deletion, with 26% of the normal splicing being maintained in the transfected HeLa cells. The small amount of MTP activity resulting from the residual normal splicing in the patient explains the atypical phenotype observed. Our investigation provides an example of a functional analysis of unclassified variations, which is an absolute necessity for the molecular diagnosis of atypical ABL cases. 相似文献
137.
Schindler M Fabre C de Weille J Carreau S Mersel M Bakalara N 《Molecular endocrinology (Baltimore, Md.)》2012,26(7):1102-1116
As one of the nine hereditary neurodegenerative polyQ disorders, spinal and bulbar muscular atrophy (SBMA) results from a polyQ tract expansion in androgen receptor (AR). Although protein aggregates are the pathological hallmark of many neurodegenerative diseases, their direct role in the neurodegeneration is more and more questioned. To determine the early molecular mechanisms causing motor neuron degeneration in SBMA, we established an in vitro system based on the tetracycline-inducible expression of normal (AR20Q), the mutated, 51 glutamine-extended (AR51Q), or polyQ-deleted (AR0Q) AR in NSC34, a motor neuron-like cell line lacking endogenous AR. Although no intracellular aggregates were formed, the expression of the AR51Q leads to a loss of function characterized by reduced neurite outgrowth and to a toxic gain of function resulting in decreased cell viability. In this study, we show that both AR20Q and AR51Q are recruited to lipid rafts in response to testosterone stimulation. However, whereas testosterone induces the activation of the c-jun N-terminal kinase/c-jun pathway via membrane-associated AR20Q, it does not so in NSC34 expressing AR51Q. Phosphorylation of c-jun N-terminal kinase plays a crucial role in AR20Q-dependent survival and differentiation of NSC34. Moreover, c-jun protein levels decrease more slowly in AR20Q- than in AR51Q-expressing NSC34 cells. This is due to a rapid and transient inhibition of glycogen synthase kinase 3α occurring in a phosphatidylinositol 3-kinase-independent manner. Our results demonstrate that the deregulation of nongenomic AR signaling may be involved in SBMA establishment, opening new therapeutic perspectives. 相似文献
138.
Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf 总被引:1,自引:0,他引:1
Amer A Franchi L Kanneganti TD Body-Malapel M Ozören N Brady G Meshinchi S Jagirdar R Gewirtz A Akira S Núñez G 《The Journal of biological chemistry》2006,281(46):35217-35223
Legionella pneumophila is an intracellular bacterium that causes an acute form of pneumonia called Legionnaires' disease. After infection of human macrophages, the Legionella-containing phagosome (LCP) avoids fusion with the lysosome allowing intracellular replication of the bacterium. In macrophages derived from most mouse strains, the LCP is delivered to the lysosome resulting in Legionella degradation and restricted bacterial growth. Mouse macrophages lacking the NLR protein Ipaf or its downstream effector caspase-1 are permissive to intracellular Legionella replication. However, the mechanism by which Ipaf restricts Legionella replication is not well understood. Here we demonstrate that the presence of flagellin and a competent type IV secretion system are critical for Legionella to activate caspase-1 in macrophages. Activation of caspase-1 in response to Legionella infection also required host Ipaf, but not TLR5. In the absence of Ipaf or caspase-1 activation, the LCP acquired endoplasmic reticulum-derived vesicles, avoided fusion with the lysosome, and allowed Legionella replication. Accordingly a Legionella mutant lacking flagellin did not activate caspase-1, avoided degradation, and replicated in wild-type macrophages. The regulation of phagosome maturation by Ipaf occurred within 2 h after infection and was independent of macrophage cell death. In vivo studies confirmed that flagellin and Ipaf play an important role in the control of Legionella clearance. These results reveal that Ipaf restricts Legionella replication through the regulation of phagosome maturation, providing a novel function for NLR proteins in host defense against an intracellular bacterium. 相似文献
139.
Mathilde Schapira Laurent Seuront Valérie Gentilhomme 《Journal of experimental marine biology and ecology》2006,335(1):27-38
The response of Phaeocystis globosa to small-scale turbulence was studied in 5 l microcosms. Turbulence was generated by oscillating grids. The effect of small-scale turbulence was examined under 3 turbulence levels representative of the P. globosa natural environment, and in non-turbulent control cultures. Single cell numbers, nitrogen concentrations and colony formation (number and diameter) were followed over 13 days in each experimental culture. Small-scale turbulence decreased single cell growth and also influenced colony formation. More colonies were formed when turbulence increased to a given threshold, but above this turbulence level, fewer and smaller colonies were observed in P. globosa cultures. The ecological significance of these results, particularly, the potential influence of small-scale turbulence on competition mechanisms between P. globosa and diatoms are finally discussed and suggested as a key factor to understand phytoplankton successions in the Eastern English Channel. 相似文献
140.
France’s heat health watch warning system 总被引:2,自引:0,他引:2
Pascal M Laaidi K Ledrans M Baffert E Caserio-Schönemann C Le Tertre A Manach J Medina S Rudant J Empereur-Bissonnet P 《International journal of biometeorology》2006,50(3):144-153
In 2003, a Heat Health Watch Warning System was developed in France to anticipate heat waves that may result in a large excess
of mortality. The system was developed on the basis of a retrospective analysis of mortality and meteorological data in fourteen
pilot cities. Several meteorological indicators were tested in relation to levels of excess mortality. Computations of sensibility
and specificity were used to choose the meteorological indicators and the cut-offs. An indicator that mixes minimum and maximum
temperatures was chosen. The cut-offs were set in order to anticipate events resulting in an excess mortality above 100% in
the smallest cities and above 50% in Paris, Lyon, Marseille and Lille. The system was extended nationwide using the 98th percentile
of the distribution of minimum and maximum temperatures. A national action plan was set up, using this watch warning system.
It was activated on 1st June 2004 on a national scale. The system implies a close cooperation between the French Weather Bureau
(Météo France), the National Institute of Health Surveillance (InVS) and the Ministry of Health. The system is supported by
a panel of preventive actions, to prevent the sanitary impact of heat waves. 相似文献