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61.
Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M 《Nature》2006,444(7122):1083-1087
Haploinsufficiency of Dll4, a vascular-specific Notch ligand, has shown that it is essential for embryonic vascular development and arteriogenesis. Mechanistically, it is unclear how the Dll4-mediated Notch pathway contributes to complex vascular processes that demand meticulous coordination of multiple signalling pathways. Here we show that Dll4-mediated Notch signalling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing Dll4 with a Dll4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 inhibited tumour growth in several tumour models. Remarkably, antibodies against Dll4 and antibodies against vascular endothelial growth factor (VEGF) had paradoxically distinct effects on tumour vasculature. Our data also indicate that Dll4-mediated Notch signalling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signalling globally, neutralizing Dll4 had no discernable impact on intestinal goblet cell differentiation, supporting the idea that Dll4-mediated Notch signalling is largely restricted to the vascular compartment. Therefore, targeting Dll4 might represent a broadly efficacious and well-tolerated approach for the treatment of solid tumours. 相似文献
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Ambati BK Nozaki M Singh N Takeda A Jani PD Suthar T Albuquerque RJ Richter E Sakurai E Newcomb MT Kleinman ME Caldwell RB Lin Q Ogura Y Orecchia A Samuelson DA Agnew DW St Leger J Green WR Mahasreshti PJ Curiel DT Kwan D Marsh H Ikeda S Leiper LJ Collinson JM Bogdanovich S Khurana TS Shibuya M Baldwin ME Ferrara N Gerber HP De Falco S Witta J Baffi JZ Raisler BJ Ambati J 《Nature》2006,443(7114):993-997
Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice and Pax6+/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea. 相似文献
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For this study, we synthesized Aurivillius Bi5Ti3FeO15 ceramic using the generic solid-state reaction route and then performed room-temperature X-ray diffraction to confirm that the compound had a single phase with no impurities. The surface morphology of the prepared sample was observed to contain microstructural grains approximately 0.2–2 μm in size. The dielectric properties of the sample were determ-ined as a function of frequency in a range of approximately 100 Hz to 1 MHz at various temperatures (303 K ≤ T ≤ 773 K). Nyquist plots of the impedance data were found to exhibit a semi-circular arc in the high-temperature region, which is explained by the equivalent electrical circuit (R1C1)(R2QC2), where R1 and R2 represent the resistances associated with the grains and grain boundaries, respectively, C1 and C2 are the re-spective capacitances, and Q is the constant phase element (CPE), which accounts for non-Debye type of behavior. Our results indicate that both the resistance and capacitance of the grain boundaries are more prominent than those of the grains. The alternating current (ac) conductiv-ity data were analyzed based on the Jonscher universal power law, which indicated that the conduction process is dominated by the hopping mechanism. The calculated activation energies of the relaxation and conduction processes were very similar (0.32 to 0.53 eV), from which we conclude that the same type of charge carriers are involved in both processes. 相似文献
64.
Cobalt (Co)-modified brownmillerite KBiFe2O5 (KBFO; [KBiFe2(1?x)Co2xO5 (x = 0, 0.05)]) polycrystalline is synthesized following the solid-state reaction route. Rietveld refinement of X-ray diffraction data confirmed the phase purity of KBFO and KBiFe1.9Co0.1O5 (KBFCO). The optical bandgap energy (Eg) of KBFO decreased from 1.59 to 1.51 eV because of Co substitution. The decrease in bandgap can be attributed to the tilting of the Fe–O tetrahedral structure of KBFCO. The observed room-temperature Raman peaks of KBFCO shifted by 3 cm?1 toward a lower wavenumber than that of KBFO. The shift in Raman active modes can be attributed to the change in the bond angles and bond lengths of the Fe–O tetrahedral structure and modification in response to oxygen deficiency in KBFO because of Co doping. Compared with that of KBFO, the frequency-dependent dielectric constant and dielectric loss of KBFCO decrease at room temperature, which is a con-sequence of the reduction in oxygen migration and modification in response to vibrational modes present in the sample. 相似文献
65.
Penny Singh 《Systemic Practice and Action Research》2013,26(3):299-314
Environmental issues are rapidly gaining momentum globally as humans try to find sustainable solutions to the effects of climate change, carbon emissions, and the actions of human-kind (see Olver, Blacklist those who ‘greenwash’. Companies must walk the talk regarding climate. The Times, 2011a; The weather warriors’ war. Real change will come when a few good men and women say ‘enough is enough’. The Times, 2011b). To enhance learning and awareness of environmental issues among Environmental Education students and the community at large, this study situated assessments within communities of practice around the university. Using action engagement within action research students had to work with insiders from the community to identify, formulate action or intervention plans and find solutions to problem situations in the community. Using action engagement within action research in this study definitely enhanced student’s knowledge of their community’s problems. Their personal involvement and the cyclical approach adopted, enhanced students’ emotional understanding and gave them an insider perspective into the situations and problems that required intervention; and trust was built between the students and members of the community as they worked together to accomplish a common goal. 相似文献
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As part of studies on the pathogenesis of exophthalmos of Graves' disease, the biochemical composition of human retrobulbar tissue was investigated. The connective tissue was composed of 72.7% lipid, 23.8% water and 3.5% dried defatted tissue. Total tissue glycosaminoglycan (GAG) amounted to 0.18% of dried defatted tissue. Approximately 27% of the total hexosamine and 19% of the total tissue galactosamine were recovered in the GAG fraction. Cellulose microcolumn fractionation of GAG showed that the hyaluronic acid and dermatan sulfate were the two major GAG species. 相似文献
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