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61.
Cancer is a complex, multiscale process, in which genetic mutations occurring at a subcellular level manifest themselves as functional and morphological changes at the cellular and tissue scale. The importance of interactions between tumour cells and their microenvironment is currently of great interest in experimental as well as computational modelling. Both the immediate microenvironment (e.g. cell-cell signalling or cell-matrix interactions) and the extended microenvironment (e.g. nutrient supply or a host tissue structure) are thought to play crucial roles in both tumour progression and suppression. In this paper we focus on tumour invasion, as defined by the emergence of a fingering morphology, which has previously been shown to be dependent upon harsh microenvironmental conditions. Using three different modelling approaches at two different spatial scales we examine the impact of nutrient availability as a driving force for invasion. Specifically we investigate how cell metabolism (the intrinsic rate of nutrient consumption and cell resistance to starvation) influences the growing tumour. We also discuss how dynamical changes in genetic makeup and morphological characteristics, of the tumour population, are driven by extreme changes in nutrient supply during tumour development. The simulation results indicate that aggressive phenotypes produce tumour fingering in poor nutrient, but not rich, microenvironments. The implication of these results is that an invasive outcome appears to be co-dependent upon the evolutionary dynamics of the tumour population driven by the microenvironment. 相似文献
62.
Thomas Pitterna Jérôme Cassayre Ottmar Franz Hüter Pierre M.J. Jung Peter Maienfisch Fiona Murphy Kessabi Laura Quaranta Hans Tobler 《Bioorganic & medicinal chemistry》2009,17(12):4085-4095
An overview is given on recent work towards new avermectin derivatives of extremely high insecticidal and acaricidal activity. These compounds were prepared from commercially available abamectin (avermectin B1) 1. For the synthesis, many novel entries have been opened up, making use of modern synthetic methods and applying them, for the first time, to the chemistry of avermectins. Several types of avermectin derivatives can be regarded as key innovations in the field. These are, in particular, 4″-deoxy-4″-(S)-amino avermectins 3, 4′-O-alkoxyalkyl avermectin monosaccharides 5, 4″-deoxy-4″-C-substituted 4″-amino avermectins 6 and 2″-substituted avermectins 7. 4″-Deoxy-4″-(S)-amino avermectins 3 were obtained by the consecutive application of the Staudinger and Aza-Wittig reaction. 4′-O-Alkoxyalkyl avermectin monosaccharides 5 were prepared by alkoxyalkylation of 5-O-protected avermectin monosaccharide. For the synthesis of 4″-deoxy-4″-C-substituted 4″-amino avermectins 6, several methods were used to construct the fully substituted 4″-carbon centre, such as a modified Strecker synthesis, the addition of organometallics to a 4″-sulfinimine and a modified Ugi approach. In order to prepare 2″-substituted avermectins 7, 5-O-protected avermectin monosaccharide was coupled with carbohydrate building blocks. An alternative synthesis involved the hitherto unknown enol ether chemistry of 4″-oxo-avermectin and the conjugate addition of a cuprate to an avermectin 2″,3″-en-4″-one. In addition, a number of other highly potent derivatives were synthesised. Examples are 4″-O-amino avermectins 8, as well as products arising from intramolecular rhodium catalysed amidations and carbene insertions. A radical cyclisation led to an intriguing rearrangement of the avermectin skeleton. Many of the new avermectins surpassed the activity of abamectin 1 against insects and mites. 相似文献
63.
64.
β-catenin is an essential component of two cellular systems: cadherin-based adherens junctions (AJ) and the Wnt signaling pathway. A functional or physical connection between these β-catenin pools has been suggested in previous studies, but not conclusively demonstrated to date. To further examine this intersection, we treated A431 cell colonies with lysophosphatidic acid (LPA), which forces rapid and synchronized dissociation of AJ. A combination of immunostaining, time-lapse microscopy using photoactivatable-GFP-tagged β-catenin, and image analyses indicate that the cadherin-bound pool of β-catenin, internalized together with E-cadherin, accumulates at the perinuclear endocytic recycling compartment (ERC) upon AJ dissociation, and can be translocated into the cell nucleus upon Wnt pathway activation. These results suggest that the ERC may be a site of residence for β-catenin destined to enter the nucleus, and that dissociation of AJ may influence β-catenin levels in the ERC, effectively affecting β-catenin substrate levels available downstream for the Wnt pathway. This intersection provides a mechanism for integrating cell-cell adhesion with Wnt signaling and could be critical in developmental and cancer processes that rely on β-catenin-dependent gene expression. 相似文献
65.
Ricardo Guerra Peixe Marcela Santana Bastos Boechat Alba Lucinia Peixoto Rangel Rh?nia Fran?a Gomes Rosa Maria Luiza Petzl-Erler Lilian MG Bahia-Oliveira 《Memórias do Instituto Oswaldo Cruz》2014,109(1):99-107
The association of single nucleotide polymorphisms (SNPs) in the interferon (IFN)-γ
gene ( IFNG ) with different types of retinal scar lesions
presumably caused by toxoplasmosis were investigated in a cross-sectional
population-based genetic study. Ten SNPs were investigated and after Bonferroni
correction, only the associations between SNPs rs2069718 and
rs3181035 with retinal/retinochoroidal scar lesions type A (most
severe scar lesions) and C (least severe scar lesions), respectively, remained
significant. The associations of two different IFNG SNPs with two
different types of retinal lesions attributable to toxoplasmosis support the
hypothesis that different inflammatory mechanisms underlie the development of these
lesions. The in vitro analysis of IFN-γ secretion by peripheral blood mononuclear
cells stimulated with Toxoplasma gondii antigens was also
investigated. The association between SNP rs2069718 and type A scar
lesions revealed that differential IFN-γ levels are correlated with distinct
genotypes. However, no correlation was observed with IFN-γ secretion levels and the
SNP rs3181035 , which was significantly associated with type C scar
lesions. Our findings strongly suggest that immunogenetic studies of individuals with
congenital or postnatally acquired infection are needed to better understand the role
of IFN-γ and its polymorphisms in the pathogenesis of ocular toxoplasmosis. 相似文献
66.
Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution 总被引:16,自引:0,他引:16 下载免费PDF全文
Schenk S Hintermann E Bilban M Koshikawa N Hojilla C Khokha R Quaranta V 《The Journal of cell biology》2003,161(1):197-209
Extracellular matrix (ECM) fragments or cryptic sites unmasked by proteinases have been postulated to affect tissue remodeling and cancer progression. Therefore, the elucidation of their identities and functions is of great interest. Here, we show that matrix metalloproteinases (MMPs) generate a domain (DIII) from the ECM macromolecule laminin-5. Binding of a recombinant DIII fragment to epidermal growth factor receptor stimulates downstream signaling (mitogen-activated protein kinase), MMP-2 gene expression, and cell migration. Appearance of this cryptic ECM ligand in remodeling mammary gland coincides with MMP-mediated involution in wild-type mice, but not in tissue inhibitor of metalloproteinase 3 (TIMP-3)-deficient mice, supporting physiological regulation of DIII liberation. These findings indicate that ECM cues may operate via direct stimulation of receptor tyrosine kinases in tissue remodeling, and possibly cancer invasion. 相似文献
67.
Malorni W Quaranta MG Straface E Falzano L Fabbri A Viora M Fiorentini C 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(8):4195-4202
The cell cytoskeleton is widely acknowledged as a master for NK cell function. Specifically, actin filaments guide the NK cell binding to target cells, engendering the formation of the so-called immunological synapse, while microtubules direct the killer behavior. All these cytoskeleton-dependent activities are competently governed by the Rho GTPases, a family of regulatory molecules encompassing the three different subfamilies, Rho, Rac, and Cdc42. By using a Rac GTPase-activating bacterial protein toxin from Escherichia coli named cytotoxic necrotizing factor 1 (CNF1), we obtained results supporting the activation of Rac GTPase as a booster for effector cell-binding efficiency, recruitment ability, and, consequently, cytotoxicity. In particular, the augmented killer capacity of CNF1-treated NK cells was associated with the increased expression of certain cell adhesion or activation-associated molecules and the reshaping of the actin and microtubule networks. Importantly, CNF1 counteracted the activity exerted by toxins disrupting the cytoskeletal architecture. Hence, the activation of Rho GTPases, particularly Rac, induced by CNF1, appears to orchestrate a dynamic cross talk between microtubules and actin filaments, leading to a fruitful NK cell activity and polarization state. Our findings suggest that protein toxins might be viewed as modulators of NK cell cytotoxic activity and could possibly be regarded as useful pharmacological tools for certain Rho-linked immune diseases in the near future. 相似文献
68.
Nucleotide sequence comparisons were used to investigate the evolution of P
transposable elements and the possibility that horizontal transfer has
played a role in their occurrence in natural populations of Drosophila and
other Diptera. The phylogeny of P elements was examined using published
sequences from eight dipteran taxa and a new, partial sequence from
Scaptomyza elmoi. The results from a number of different analyses are
highly consistent and reveal a P-element phylogeny that contradicts the
phylogeny of the species. At least three instances of horizontal transfer
are necessary to explain this incongruence, but other explanations cannot
be ruled out at this time.
相似文献
69.
Differences in growth and water relations among Phaseolus vulgaris cultivars in response to induced drought stress 总被引:3,自引:0,他引:3
Costa França MG Pham Thi AT Pimentel C Pereyra Rossiello RO Zuily-Fodil Y Laffray D 《Environmental and Experimental Botany》2000,43(3):227-237
Relatively little ecophysiological research has been conducted to determine the responses to drought of Phaseolus vulgaris. Four bean cultivars (cvs.) from Brazil, A320, Carioca, Ouro Negro and Xodó were submitted to an imposed water deficit in order to evaluate the importance of some adaptive mechanisms of drought resistance through the analysis of growth parameters, water status, gas exchange and indicators of tolerance mechanisms at the cellular level. During the drought treatment, relative growth rates were more reduced for A320 and Xodó than Carioca and Ouro Negro. A320 closed its stomata very rapidly and complete stomatal closure was obtained at Psi(w)=-0.6 MPa, in contrast to the other cvs. where stomata were fully closed only at Psi(w)=-0.9 MPa. Net assimilation rates were closely related to stomatal conductances. Mechanisms at the cellular level appeared to be mostly important for higher tolerance. Carioca and Ouro Negro, when compared to A320 and Xodó, were characterized by having better drought tolerance mechanisms and higher tissue water retention capacity leading to a better growth under water deficits. The leaf dehydration rates of those cvs. were slow whereas those of the drought sensitive cvs. were rapid. The results were confirmed by the electrolyte leakage test and leaf osmotic potential measurements, which indicated higher membrane resistance and osmotic adjustment in the two tolerant cvs. Carioca and Ouro Negro. It appears from this study that despite being cultivated in the same geographical region, the four cvs. of P. vulgaris displayed somewhat different drought adaptive capacities for prolonged drought during the vegetative phase. 相似文献
70.