全文获取类型
收费全文 | 150篇 |
免费 | 3篇 |
专业分类
系统科学 | 3篇 |
丛书文集 | 1篇 |
教育与普及 | 1篇 |
理论与方法论 | 7篇 |
现状及发展 | 25篇 |
研究方法 | 29篇 |
综合类 | 87篇 |
出版年
2021年 | 2篇 |
2020年 | 1篇 |
2019年 | 1篇 |
2017年 | 1篇 |
2016年 | 2篇 |
2014年 | 2篇 |
2013年 | 2篇 |
2012年 | 15篇 |
2011年 | 25篇 |
2010年 | 8篇 |
2009年 | 3篇 |
2008年 | 14篇 |
2007年 | 12篇 |
2006年 | 15篇 |
2005年 | 9篇 |
2004年 | 8篇 |
2003年 | 11篇 |
2002年 | 10篇 |
1999年 | 4篇 |
1998年 | 2篇 |
1997年 | 1篇 |
1992年 | 2篇 |
1990年 | 1篇 |
1961年 | 1篇 |
1959年 | 1篇 |
排序方式: 共有153条查询结果,搜索用时 15 毫秒
11.
Notch1 functions as a tumor suppressor in mouse skin 总被引:24,自引:0,他引:24
Nicolas M Wolfer A Raj K Kummer JA Mill P van Noort M Hui CC Clevers H Dotto GP Radtke F 《Nature genetics》2003,33(3):416-421
Notch proteins are important in binary cell-fate decisions and inhibiting differentiation in many developmental systems, and aberrant Notch signaling is associated with tumorigenesis. The role of Notch signaling in mammalian skin is less well characterized and is mainly based on in vitro studies, which suggest that Notch signaling induces differentiation in mammalian skin. Conventional gene targeting is not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1-/- embryos die during gestation. Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed beta-catenin signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch1 receptor. This leads to a reduction in the signaling-competent pool of beta-catenin, indicating that Notch1 can inhibit beta-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin. 相似文献
12.
13.
Clay minerals in surface sediments of the Pearl River drainage basin and their contribution to the South China Sea 总被引:5,自引:0,他引:5
LIU ZhiFei Christophe COLIN HUANG Wei CHEN Zhong Alain TRENTESAUX CHEN JianFang 《科学通报(英文版)》2007,52(8):1101-1111
Clay minerals have played a significant role in the study of the East Asian monsoon evolution in the South China Sea by being able to track oceanic current variations and to reveal contemporaneous paleoclimaUc changes prevailing in continental source areas. As one of the most important rivers inputting terrigenous matters to the northern South China Sea, the Pearl River was not previously paid attention to from the viewpoint of clay mineralogy. This paper presents a detailed study on clay minerals in surface sediments collected from the Pearl River drainage basin (including all three main channels, various branches, and the Lingdingyang in the estuary) by using the X-ray diffraction (XRD) method. The results indicate that the clay mineral assemblage consists dominantly of kaolinite (35%-65%), lesser abundance of chlorite (20%-35%) and illite (12%-42%), and very scare smectite occurrences (generally 〈5%). Their respective distribution does not present any obvious difference throughout the Pearl River drainage basin. However, downstream the Pearl River to the northern South China Sea, the clay mineral assemblage varies significantly: kaolinite decreases gradually, smecUte and illite increase gradually. Additionally, illite chemistry index steps down and illite crystallinity steps up. These variations indicate the contribution of major kaolinite, lesser illite and chlorite, and very scarce smecUte to the northern South China Sea from the Pearl River drainage basin. The maximum contribution of clay minerals from the Pearl River is 72% to the northern margin and only 15% to the northern slope of the South China Sea. In both glacials and interglacials, kaolinite indicates that the ability of mechanical erosion occurred in the Pearl River drainage basin. 相似文献
14.
Sandrine Turcotte Thérèse Laferrière Christine Hamel Alain Breuleux 《Systemic Practice and Action Research》2010,23(4):285-299
Small remote rural schools in Quebec face an ongoing challenge to provide similar quality educational services than bigger
schools. Since 2002, the Remote Network Schools (RNS) initiative afforded schools the opportunity to reinvent their practice
by using online tools to experience collaborative learning activities with other remote schools. Teachers and students experienced
quality learning and demonstrated agency by implementing the RNS in their context. Measures include: diversity of learning
activities, quality of online classroom interactions, changes in teacher beliefs, and shifts in teacher and student roles.
Our results show that it is a viable operating method for such schools and that other schools could contemplate implementing
such innovative practices. 相似文献
15.
16.
17.
Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity 总被引:10,自引:0,他引:10
Descargues P Deraison C Bonnart C Kreft M Kishibe M Ishida-Yamamoto A Elias P Barrandon Y Zambruno G Sonnenberg A Hovnanian A 《Nature genetics》2005,37(1):56-65
Mutations in SPINK5, encoding the serine protease inhibitor LEKTI, cause Netherton syndrome, a severe autosomal recessive genodermatosis. Spink5(-/-) mice faithfully replicate key features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation and a skin barrier defect. LEKTI deficiency causes abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein 1 due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme-like hyperactivity. This leads to defective stratum corneum adhesion and resultant loss of skin barrier function. Profilaggrin processing is increased and implicates LEKTI in the cornification process. This work identifies LEKTI as a key regulator of epidermal protease activity and degradation of desmoglein 1 as the primary pathogenic event in Netherton syndrome. 相似文献
18.
DNA breaks are extremely harmful lesions that need to be repaired efficiently throughout the genome. However, the packaging of DNA into nucleosomes is a significant barrier to DNA repair, and the mechanisms of repair in the context of chromatin are poorly understood. Here we show that lysine 56 (K56) acetylation is an abundant modification of newly synthesized histone H3 molecules that are incorporated into chromosomes during S phase. Defects in the acetylation of K56 in histone H3 result in sensitivity to genotoxic agents that cause DNA strand breaks during replication. In the absence of DNA damage, the acetylation of histone H3 K56 largely disappears in G2. In contrast, cells with DNA breaks maintain high levels of acetylation, and the persistence of the modification is dependent on DNA damage checkpoint proteins. We suggest that the acetylation of histone H3 K56 creates a favourable chromatin environment for DNA repair and that a key component of the DNA damage response is to preserve this acetylation. 相似文献
19.
Vertebrate eggs awaiting fertilization are arrested at metaphase of meiosis II by a biochemical activity termed cytostatic factor (CSF). This activity inhibits the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that triggers anaphase onset and mitotic/meiotic exit by targeting securin and M-phase cyclins for destruction. On fertilization a transient rise in free intracellular calcium causes release from CSF arrest and thus APC/C activation. Although it has previously been shown that calcium induces the release of APC/C from CSF inhibition through calmodulin-dependent protein kinase II (CaMKII), the relevant substrates of this kinase have not been identified. Recently, we characterized XErp1 (Emi2), an inhibitor of the APC/C and key component of CSF activity in Xenopus egg extract. Here we show that calcium-activated CaMKII triggers exit from meiosis II by sensitizing the APC/C inhibitor XErp1 for polo-like kinase 1 (Plx1)-dependent degradation. Phosphorylation of XErp1 by CaMKII leads to the recruitment of Plx1 that in turn triggers the destruction of XErp1 by phosphorylating a site known to serve as a phosphorylation-dependent degradation signal. These results provide a molecular explanation for how the fertilization-induced calcium increase triggers exit from meiosis II. 相似文献
20.
Illing PT Vivian JP Dudek NL Kostenko L Chen Z Bharadwaj M Miles JJ Kjer-Nielsen L Gras S Williamson NA Burrows SR Purcell AW Rossjohn J McCluskey J 《Nature》2012,486(7404):554-558
Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T?cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs?6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs. 相似文献