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Although the hormone-stimulated synthesis of 3-phosphorylated inositol lipids is known to form an intracellular signalling system, there is no consensus on the crucial receptor-regulated event in this pathway and it is still not clear which of the intermediates represent potential output signals. We show here that the key step in the synthesis of 3-phosphorylated inositol lipids in 3T3 cells stimulated by platelet-derived growth factor is the activation of a phosphatidylinositol(4,5)-bisphosphate (3)-hydroxy (PtdIns(4,5)P2 3-OH) kinase. A similar conclusion has been applied to explain the actions of formyl-Met-Leu-Phe on neutrophils, and it may be that receptors that couple through intrinsic tyrosine kinases or through G proteins stimulate the same step in 3-phosphorylated inositol lipid metabolism. The close parallel between these two mechanisms for the activation of PtdIns(4,5)P2 3-OH kinase and those described for the activation of another key signalling enzyme, phospholipase C (ref. 7), focuses attention on the product of the PtdIns(4,5)P2 3-OH kinase, PtdIns(3,4,5)P3, as a possible new second messenger. 相似文献
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Pepys MB Hirschfield GM Tennent GA Gallimore JR Kahan MC Bellotti V Hawkins PN Myers RM Smith MD Polara A Cobb AJ Ley SV Aquilina JA Robinson CV Sharif I Gray GA Sabin CA Jenvey MC Kolstoe SE Thompson D Wood SP 《Nature》2006,440(7088):1217-1221
Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury. 相似文献
8.
Identification of human brain tumour initiating cells 总被引:3,自引:0,他引:3
Singh SK Hawkins C Clarke ID Squire JA Bayani J Hide T Henkelman RM Cusimano MD Dirks PB 《Nature》2004,432(7015):396-401
The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 10(5) CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies. 相似文献
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Gretarsdottir S Thorleifsson G Reynisdottir ST Manolescu A Jonsdottir S Jonsdottir T Gudmundsdottir T Bjarnadottir SM Einarsson OB Gudjonsdottir HM Hawkins M Gudmundsson G Gudmundsdottir H Andrason H Gudmundsdottir AS Sigurdardottir M Chou TT Nahmias J Goss S Sveinbjörnsdottir S Valdimarsson EM Jakobsson F Agnarsson U Gudnason V Thorgeirsson G Fingerle J Gurney M Gudbjartsson D Frigge ML Kong A Stefansson K Gulcher JR 《Nature genetics》2003,35(2):131-138
We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke. 相似文献
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Thomas Hawkins 《Archive for History of Exact Sciences》2008,62(6):655-717
The theory of nonnegative matrices is an example of a theory motivated in its origins and development by purely mathematical
concerns that later proved to have a remarkably broad spectrum of applications to such diverse fields as probability theory,
numerical analysis, economics, dynamical programming, and demography. At the heart of the theory is what is usually known
as the Perron–Frobenius Theorem. It was inspired by a theorem of Oskar Perron on positive matrices, usually called Perron’s
Theorem. This paper is primarily concerned with the origins of Perron’s Theorem in his masterful work on ordinary and generalized
continued fractions (1907) and its role in inspiring the remarkable work of Frobenius on nonnegative matrices (1912) that
produced, inter alia, the Perron–Frobenius Theorem. The paper is not at all intended exclusively for readers with expertise
in the theory of nonnegative matrices. Anyone with a basic grounding in linear algebra should be able to read this article
and come away with a good understanding of the Perron–Frobenius Theorem as well as its historical origins. The final section
of the paper considers the first major application of the Perron–Frobenius Theorem, namely, to the theory of Markov chains.
When he introduced the eponymous chains in 1908, Markov adumbrated several key notions and results of the Perron–Frobenius
theory albeit within the much simpler context of stochastic matrices; but it was by means of Frobenius’ 1912 paper that the
linear algebraic foundations of Markov’s theory for nonpositive stochastic matrices were first established by R. Von Mises
and V.I. Romanovsky. 相似文献