全文获取类型
收费全文 | 324篇 |
免费 | 43篇 |
专业分类
367篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 6篇 |
2020年 | 1篇 |
2019年 | 3篇 |
2018年 | 2篇 |
2017年 | 10篇 |
2016年 | 10篇 |
2015年 | 21篇 |
2014年 | 10篇 |
2013年 | 21篇 |
2012年 | 33篇 |
2011年 | 27篇 |
2010年 | 24篇 |
2009年 | 14篇 |
2008年 | 23篇 |
2007年 | 26篇 |
2006年 | 34篇 |
2005年 | 23篇 |
2004年 | 18篇 |
2003年 | 15篇 |
2002年 | 7篇 |
2001年 | 3篇 |
2000年 | 1篇 |
1999年 | 3篇 |
1998年 | 4篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1990年 | 1篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1979年 | 1篇 |
1977年 | 1篇 |
1973年 | 1篇 |
1968年 | 1篇 |
1966年 | 2篇 |
排序方式: 共有367条查询结果,搜索用时 15 毫秒
21.
Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice 总被引:1,自引:0,他引:1 下载免费PDF全文
Martins IC Kuperstein I Wilkinson H Maes E Vanbrabant M Jonckheere W Van Gelder P Hartmann D D'Hooge R De Strooper B Schymkowitz J Rousseau F 《The EMBO journal》2008,27(1):224-233
Although soluble oligomeric and protofibrillar assemblies of Abeta-amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Abeta-fibrils in the amyloid plaques remains controversial. A widely held view in the field suggests that the fibrillization reaction proceeds 'forward' in a near-irreversible manner from the monomeric Abeta peptide through toxic protofibrillar intermediates, which subsequently mature into biologically inert amyloid fibrils that are found in plaques. Here, we show that natural lipids destabilize and rapidly resolubilize mature Abeta amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Abeta but rather toward soluble amyloid protofibrils. We characterized these 'backward' Abeta protofibrils generated from mature Abeta fibers and compared them with previously identified 'forward' Abeta protofibrils obtained from the aggregation of fresh Abeta monomers. We find that backward protofibrils are biochemically and biophysically very similar to forward protofibrils: they consist of a wide range of molecular masses, are toxic to primary neurons and cause memory impairment and tau phosphorylation in mouse. In addition, they diffuse rapidly through the brain into areas relevant to AD. Our findings imply that amyloid plaques are potentially major sources of soluble toxic Abeta-aggregates that could readily be activated by exposure to biological lipids. 相似文献
22.
Anneleen Mortier Tamara Loos Mieke Gouwy Isabelle Ronsse Jo Van Damme Paul Proost 《The Journal of biological chemistry》2010,285(39):29750-29759
Posttranslational modifications, e.g. proteolysis, glycosylation, and citrullination regulate chemokine function, affecting leukocyte migration during inflammatory responses. Here, modification of CXCL5/epithelial cell-derived neutrophil-activating protein-78 (ENA-78) by proteases or peptidylarginine deiminases (PAD) was evaluated. Slow CXCL5(1–78) processing by the myeloid cell marker aminopeptidase N/CD13 into CXCL5(2–78) hardly affected its in vitro activity, but slowed down the activation of CXCL5 by the neutrophil protease cathepsin G. PAD, an enzyme with a potentially important function in autoimmune diseases, site-specifically deiminated Arg9 in CXCL5 to citrulline, generating [Cit9]CXCL5(1–78). Compared with CXCL5(1–78), [Cit9]CXCL5(1–78) less efficiently induced intracellular calcium signaling, phosphorylation of extracellular signal-regulated kinase, internalization of CXCR2, and in vitro neutrophil chemotaxis. In contrast, conversion of CXCL5 into the previously reported natural isoform CXCL5(8–78) provided at least 3-fold enhanced biological activity in these tests. Citrullination, but not NH2-terminal truncation, reduced the capacity of CXCL5 to up-regulate the expression of the integrin α-chain CD11b on neutrophils. Truncation nor citrullination significantly affected the ability of CXCL5 to up-regulate CD11a expression or shedding of CD62L. In line with the in vitro results, CXCL5(8–78) and CXCL5(9–78) induced a more pronounced neutrophil influx in vivo compared with CXCL5(1–78). Administration of 300 pmol of either CXCL5(1–78) or [Cit9]CXCL5(1–78) failed to attract neutrophils to the peritoneal cavity. Citrullination of the more potent CXCL5(9–78) lowers its chemotactic potency in vivo and confirms the tempering effect of citrullination in vitro. The highly divergent effects of modifications of CXCL5 on neutrophil influx underline the potential importance of tissue-specific interactions between chemokines and PAD or proteases. 相似文献
23.
Tjon JM Kooy-Winkelaar YM Tack GJ Mommaas AM Schreurs MW Schilham MW Mulder CJ van Bergen J Koning F 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(11):6304-6312
In refractory celiac disease (RCD), intestinal epithelial damage persists despite a gluten-free diet. Characteristic for RCD type II (RCD II) is the presence of aberrant surface TCR-CD3(-) intraepithelial lymphocytes (IELs) that can progressively replace normal IELs and eventually give rise to overt lymphoma. Therefore, RCD II is considered a malignant condition that forms an intermediate stage between celiac disease (CD) and overt lymphoma. We demonstrate in this study that surface TCR-CD3(-) IEL lines isolated from three RCD II patients preferentially lyse epithelial cell lines. FACS analysis revealed that DNAM-1 was strongly expressed on the three RCD cell lines, whereas other activating NK cell receptors were not expressed on all three RCD cell lines. Consistent with this finding, cytotoxicity of the RCD cell lines was mediated mainly by DNAM-1 with only a minor role for other activating NK cell receptors. Furthermore, enterocytes isolated from duodenal biopsies expressed DNAM-1 ligands and were lysed by the RCD cell lines ex vivo. Although DNAM-1 on CD8(+) T cells and NK cells is known to mediate lysis of tumor cells, this study provides, to our knowledge, the first evidence that (pre)malignant cells themselves can acquire the ability to lyse epithelial cells via DNAM-1. This study confirms previous work on epithelial lysis by RCD cell lines and identifies a novel mechanism that potentially contributes to the gluten-independent tissue damage in RCD II and RCD-associated lymphoma. 相似文献
24.
The raffinose family oligosaccharides (RFOs), including raffinose (Gal-α(1 → 6)-Glc-α(1 → 2)β-Fru), stachyose (Gal-α(1 → 6)-Gal-α(1 → 6)-Glc-α(1 → 2)β-Fru) and higher degree of polymerization RFOs are the most widespread galactosyl-oligosaccharides (GOS) in the plant kingdom. Stellaria media is a typical representative of the Caryophyllaceae, a plant family lacking stachyose and the typical galactosyl extensions of stachyose. During cold treatment raffinose, lychnose (Gal-α(1 → 6)-Glc-α(1 → 2)β-Fru-α(1 → 1)-Gal) and stellariose (Gal-α(1 → 6)-[Gal-α(1 → 4)]-Glc-α(1 → 2)β-Fru-α(1 → 1)-Gal) were found to accumulate in S. media stems. Next to these prominent oligosaccharides, two extra GOS were discovered.Biochemical analyses (enzymatic incubations and mild acid hydrolysis) and mass spectrometry identified the first, most abundant oligosaccharide as Glc-α(1 → 2)β-Fru-α(1 → 1)-Gal, a breakdown product of lychnose. The structure of this trisaccharide was confirmed by full NMR characterization. The second, less abundant compound (termed mediose) was identified as Gal-α(1 → 6)-[Gal-α(1 → 4)]Glc-α(1 → 2)β-Fru after biochemical analyses. By partial enzyme purification the presence of discrete lychnose synthase (raffinose:raffinose 1Fru galactosyltransferase) and stellariose synthase (raffinose:lychnose 4Glc galactosyltransferase) activities were shown.A model is presented explaining the structural diversity of GOS in S. media. In the absence of stachyose, raffinose is further elongated by lychnose synthase and stellariose synthase to produce lychnose, mediose and stellariose. Most likely, these compounds are also subject to partial trimming by endogenous α-galactosidases. 相似文献
25.
Kristen Fernandes Mieke van der Heyde Megan Coghlan Grant Wardell‐Johnson Michael Bunce Richard Harris Paul Nevill 《Restoration Ecology》2019,27(5):1177-1186
Invertebrate biomonitoring can reveal crucial information about the status of restoration projects; however, it is routinely underused because of the high level of taxonomic expertise and resources required. Invertebrate DNA metabarcoding has been used to characterize invertebrate biodiversity but its application in restoration remains untested. We use DNA metabarcoding, a new approach for restoration assessment, to explore the invertebrate composition from pitfall traps at two mine site restoration chronosequences in southwestern Australia. Invertebrates were profiled using two cytochrome oxidase subunit 1 assays to investigate invertebrate biodiversity. The data revealed differences between invertebrate communities at the two mines and between the different age plots of the chronosequences. Several characteristic taxa were identified for each age within the chronosequence, including springtails within the youngest sites (Order: Collembola) and millipedes within the oldest and reference sites (Order: Julida). This study facilitates development of a molecular “toolkit” for the monitoring of ecological restoration projects. We suggest that a metabarcoding approach shows promise in complementing current monitoring practices that rely on alpha taxonomy. 相似文献
26.
Sabrina I?igo Astrid Nagels Durand Andrés Ritter Sabine Le Gall Martin Termathe Roland Klassen Takayuki Tohge Barbara De Coninck Jelle Van Leene Rebecca De Clercq Bruno P.A. Cammue Alisdair R. Fernie Kris Gevaert Geert De Jaeger Sebastian A. Leidel Raffael Schaffrath Mieke Van Lijsebettens Laurens Pauwels Alain Goossens 《Plant physiology》2016,172(2):858-873
27.
28.
Czerednik A Busscher M Bielen BA Wolters-Arts M de Maagd RA Angenent GC 《Journal of experimental botany》2012,63(7):2605-2617
Growth of tomato fruits is determined by cell division and cell expansion, which are tightly controlled by factors that drive the core cell cycle. The cyclin-dependent kinases (CDKs) and their interacting partners, the cyclins, play a key role in the progression of the cell cycle. In this study the role of CDKA1, CDKB1, and CDKB2 in fruit development was characterized by fruit-specific overexpression and down-regulation. CDKA1 is expressed in the pericarp throughout development, but is strongly up-regulated in the outer pericarp cell layers at the end of the growth period, when CDKB gene expression has ceased. Overexpression of the CDKB genes at later stages of development and the down-regulation of CDKA1 result in a very similar fruit phenotype, showing a reduction in the number of cell layers in the pericarp and alterations in the desiccation of the fruits. Expression studies revealed that CDKA1 is down-regulated by the expression of CDKB1/2 in CDKB1 and CDKB2 overexpression mutants, suggesting opposite roles for these types of CDK proteins in tomato pericarp development. 相似文献
29.
Gijsbers K Gouwy M Struyf S Wuyts A Proost P Opdenakker G Penninckx F Ectors N Geboes K Van Damme J 《Experimental cell research》2005,303(2):331-342
The precise role of chemokines in neovascularization during inflammation or tumor growth is not yet fully understood. We show here that the chemokines granulocyte chemotactic protein-2 (GCP-2/CXCL6), interleukin-8 (IL-8/CXCL8), and monocyte chemotactic protein-1 (MCP-1/CCL2) are co-induced in microvascular endothelial cells after stimulation with pro-inflammatory stimuli. In contrast with its weak proliferative effect on endothelial cells, GCP-2 synergized with MCP-1 in neutrophil chemotaxis. This synergy may represent a mechanism for tumor development and metastasis by providing efficient leukocyte infiltration in the absence of exogenous immune modulators. To mimic endothelial cell-derived GCP-2 in vivo, GCP-2 was intravenously injected and shown to provoke a dose-dependent systemic response, composed of an immediate granulopenia, followed by a profound granulocytosis. By immunohistochemistry, GCP-2 was further shown to be expressed by endothelial cells from human patients with gastrointestinal (GI) malignancies. GCP-2 staining correlated with leukocyte infiltration into the tumor and with the expression of the matrix metalloproteinase-9 (MMP-9/gelatinase B). Together with previous findings, these data suggest that the production of GCP-2 by endothelial cells within the tumor can contribute to tumor development through neovascularization due to endothelial cell chemotaxis and to tumor cell invasion and metastasis by attracting and activating neutrophils loaded with proteases that promote matrix degradation. 相似文献
30.
Identification of a Novel, Putative Rho-specific
GDP/GTP Exchange Factor and a RhoA-binding Protein:
Control of Neuronal Morphology 总被引:12,自引:2,他引:12 下载免费PDF全文
Martijn F.B.G. Gebbink Onno Kranenburg Mieke Poland Francis P.G. van Horck Brahim Houssa Wouter H. Moolenaar 《The Journal of cell biology》1997,137(7):1603-1613
The small GTP-binding protein Rho has been implicated in the control of neuronal morphology. In N1E-115 neuronal cells, the Rho-inactivating C3 toxin stimulates neurite outgrowth and prevents actomyosin-based neurite retraction and cell rounding induced by lysophosphatidic acid (LPA), sphingosine-1-phosphate, or thrombin acting on their cognate G protein–coupled receptors. We have identified a novel putative GDP/GTP exchange factor, RhoGEF (190 kD), that interacts with both wild-type and activated RhoA, but not with Rac or Cdc42. RhoGEF, like activated RhoA, mimics receptor stimulation in inducing cell rounding and in preventing neurite outgrowth. Furthermore, we have identified a 116-kD protein, p116Rip, that interacts with both the GDP- and GTP-bound forms of RhoA in N1E-115 cells. Overexpression of p116Rip stimulates cell flattening and neurite outgrowth in a similar way to dominant-negative RhoA and C3 toxin. Cells overexpressing p116Rip fail to change their shape in response to LPA, as is observed after Rho inactivation. Our results indicate that (a) RhoGEF may link G protein–coupled receptors to RhoA activation and ensuing neurite retraction and cell rounding; and (b) p116Rip inhibits RhoA-stimulated contractility and promotes neurite outgrowth. 相似文献