排序方式: 共有65条查询结果,搜索用时 453 毫秒
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Sarno S Mazzorana M Traynor R Ruzzene M Cozza G Pagano MA Meggio F Zagotto G Battistutta R Pinna LA 《Cellular and molecular life sciences : CMLS》2012,69(3):449-460
8-hydroxy-4-methyl-9-nitrobenzo(g)chromen-2-one (NBC) has been found to be a fairly potent ATP site-directed inhibitor of
protein kinase CK2 (Ki = 0.22 μM). Here, we show that NBC also inhibits PIM kinases, especially PIM1 and PIM3, the latter
as potently as CK2. Upon removal of the nitro group, to give 8-hydroxy-4-methyl-benzo(g)chromen-2-one (here referred to as
“denitro NBC”, dNBC), the inhibitory power toward CK2 is almost entirely lost (IC50 > 30 μM) whereas that toward PIM1 and PIM3 is maintained; in addition, dNBC is a potent inhibitor of a number of other kinases
that are weakly inhibited or unaffected by NBC, with special reference to DYRK1A whose IC50 values with NBC and dNBC are 15 and 0.60 μM, respectively. Therefore, the observation that NBC, unlike dNBC, is a potent
inducer of apoptosis is consistent with the notion that this effect is mediated by inhibition of endogenous CK2. The structural
features underlying NBC selectivity have been revealed by inspecting its 3D structure in complex with the catalytic subunit
of Z. mays CK2. The crucial role of the nitro group is exerted both through a direct electrostatic interaction with the side chain of Lys68
and, indirectly, by enhancing the acidic dissociation constant of the adjacent hydroxyl group which interacts with a conserved
water molecule in the deepest part of the cavity. By contrast, the very same nitro group is deleterious for the binding to
the active site of DYRK1A, as disclosed by molecular docking. This provides the rationale for preferential inhibition of DYRK1A
by dNBC. 相似文献
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Caffau E Bonifacio P François P Sbordone L Monaco L Spite M Spite F Ludwig HG Cayrel R Zaggia S Hammer F Randich S Molaro P Hill V 《Nature》2011,477(7362):67-69
The early Universe had a chemical composition consisting of hydrogen, helium and traces of lithium; almost all other elements were subsequently created in stars and supernovae. The mass fraction of elements more massive than helium, Z, is known as 'metallicity'. A number of very metal-poor stars has been found, some of which have a low iron abundance but are rich in carbon, nitrogen and oxygen. For theoretical reasons and because of an observed absence of stars with Z?1.5?×?10(-5), it has been suggested that low-mass stars cannot form from the primitive interstellar medium until it has been enriched above a critical value of Z, estimated to lie in the range 1.5?×?10(-8) to 1.5?×?10(-6) (ref. 8), although competing theories claiming the contrary do exist. (We use 'low-mass' here to mean a stellar mass of less than 0.8 solar masses, the stars that survive to the present day.) Here we report the chemical composition of a star in the Galactic halo with a very low Z (≤?6.9?×?10(-7), which is 4.5?×?10(-5) times that of the Sun) and a chemical pattern typical of classical extremely metal-poor stars--that is, without enrichment of carbon, nitrogen and oxygen. This shows that low-mass stars can be formed at very low metallicity, that is, below the critical value of Z. Lithium is not detected, suggesting a low-metallicity extension of the previously observed trend in lithium depletion. Such lithium depletion implies that the stellar material must have experienced temperatures above two million kelvin in its history, given that this is necessary to destroy lithium. 相似文献
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Lorenzo Magnani 《Foundations of Science》2004,9(3):219-247
What I call theoretical abduction (sentential and model-based)certainly illustrates much of what is important in abductive reasoning, especially the objective of selecting and creating a set of hypotheses that are able to dispense good (preferred) explanations of data, but fails to account for many cases of explanation occurring in science or in everyday reasoning when the exploitation of the environment is crucial. The concept of manipulative abduction is devoted to capture the role of action in many interesting situations: action provides otherwise unavailable information that enables the agent to solve problems by starting and performing a suitable abductive process of generation or selection of hypotheses. Many external things, usually inert from the epistemological point of view, can be transformed into what I callepistemic mediators, which are illustrated in the last part of the paper, together with an analysis of the related notions of ``perceptual and inceptual rehearsal' and of ``external representation'. 相似文献
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Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy 总被引:22,自引:0,他引:22
Delettre C Lenaers G Griffoin JM Gigarel N Lorenzo C Belenguer P Pelloquin L Grosgeorge J Turc-Carel C Perret E Astarie-Dequeker C Lasquellec L Arnaud B Ducommun B Kaplan J Hamel CP 《Nature genetics》2000,26(2):207-210
Optic atrophy type 1 (OPA1, MIM 165500) is a dominantly inherited optic neuropathy occurring in 1 in 50,000 individuals that features progressive loss in visual acuity leading, in many cases, to legal blindness. Phenotypic variations and loss of retinal ganglion cells, as found in Leber hereditary optic neuropathy (LHON), have suggested possible mitochondrial impairment. The OPA1 gene has been localized to 3q28-q29 (refs 13-19). We describe here a nuclear gene, OPA1, that maps within the candidate region and encodes a dynamin-related protein localized to mitochondria. We found four different OPA1 mutations, including frameshift and missense mutations, to segregate with the disease, demonstrating a role for mitochondria in retinal ganglion cell pathophysiology. 相似文献
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Cell-cycle checkpoints help to protect the genomes of proliferating cells under genotoxic stress. In multicellular organisms, cell proliferation is often directed toward differentiation during development and throughout adult homeostasis. To prevent the formation of differentiated cells with genetic instability, we hypothesized that genotoxic stress may trigger a differentiation checkpoint. Here we show that exposure to genotoxic agents causes a reversible inhibition of myogenic differentiation. Muscle-specific gene expression is suppressed by DNA-damaging agents if applied prior to differentiation induction but not after the differentiation program is established. The myogenic determination factor, MyoD (encoded by Myod1), is a target of the differentiation checkpoint in myoblasts. The inhibition of MyoD by DNA damage requires a functional c-Abl tyrosine kinase (encoded by Abl1), but occurs in cells deficient for p53 (transformation-related protein 53, encoded by Trp53) or c-Jun (encoded by the oncogene Jun). These results support the idea that genotoxic stress can regulate differentiation, and identify a new biological function for DNA damage-activated signaling network. 相似文献