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101.
Cynthia M. Simbulan-Rosenthal Yogameenakshi Haribabu Sahar Vakili Li-Wei Kuo Havens Clark Ryan Dougherty Ryyan Alobaidi Bonnie Carney Peter Sykora Dean S. Rosenthal 《International journal of molecular sciences》2022,23(4)
Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MIC) implicated in tumorigenesis, invasion, and drug resistance, and is characterized by the elevated expression of stem cell markers, including CD133. The siRNA knockdown of CD133 enhances apoptosis induced by the MEK inhibitor trametinib in melanoma cells. This study investigates the underlying mechanisms of CD133’s anti-apoptotic activity in patient-derived BAKP and POT cells, harboring difficult-to-treat NRASQ61K and NRASQ61R drivers, after CRISPR-Cas9 CD133 knockout or Dox-inducible expression of CD133. MACS-sorted CD133(+) BAKP cells were conditionally reprogrammed to derive BAKR cells with sustained CD133 expression and MIC features. Compared to BAKP, CD133(+) BAKR exhibit increased cell survival and reduced apoptosis in response to trametinib or the chemotherapeutic dacarbazine (DTIC). CRISPR-Cas9-mediated CD133 knockout in BAKR cells (BAKR-KO) re-sensitized cells to trametinib. CD133 knockout in BAKP and POT cells increased trametinib-induced apoptosis by reducing anti-apoptotic BCL-xL, p-AKT, and p-BAD and increasing pro-apoptotic BAX. Conversely, Dox-induced CD133 expression diminished apoptosis in both trametinib-treated cell lines, coincident with elevated p-AKT, p-BAD, BCL-2, and BCL-xL and decreased activation of BAX and caspases-3 and -9. AKT1/2 siRNA knockdown or inhibition of BCL-2 family members with navitoclax (ABT-263) in BAKP-KO cells further enhanced caspase-mediated apoptotic PARP cleavage. CD133 may therefore activate a survival pathway where (1) increased AKT phosphorylation and activation induces (2) BAD phosphorylation and inactivation, (3) decreases BAX activation, and (4) reduces caspases-3 and -9 activity and caspase-mediated PARP cleavage, leading to apoptosis suppression and drug resistance in melanoma. Targeting nodes of the CD133, AKT, or BCL-2 survival pathways with trametinib highlights the potential for combination therapies for NRAS-mutant melanoma stem cells for the development of more effective treatments for patients with high-risk melanoma. 相似文献
102.
Matthew K. Boag Angus Roberts Vladimir N. Uversky Linlin Ma Des R. Richardson Dean L. Pountney 《International journal of molecular sciences》2022,23(4)
A major hallmark of Parkinson’s disease (PD) is the fatal destruction of dopaminergic neurons within the substantia nigra pars compacta. This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution of α-synuclein aggregation, iron accumulation, and mitochondrial dysfunction plague nigral neurons, yet the events underlying iron accumulation are poorly understood. Elevated intracellular iron concentrations up-regulate ferritin expression, an iron storage protein that provides cytoprotection against redox stress. The lysosomal degradation pathway, autophagy, can release iron from ferritin stores to facilitate its trafficking in a process termed ferritinophagy. Aggregated α-synuclein inhibits SNARE protein complexes and destabilizes microtubules to halt vesicular trafficking systems, including that of autophagy effectively. The scope of this review is to describe the physiological and pathological relationship between iron regulation and α-synuclein, providing a detailed understanding of iron metabolism within nigral neurons. The underlying mechanisms of autophagy and ferritinophagy are explored in the context of PD, identifying potential therapeutic targets for future investigation. 相似文献
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105.
Richard A. Veazey Amy S. Gandy Derek C. Sinclair Julian S. Dean 《Journal of the American Ceramic Society》2020,103(4):2702-2714
Micro-contact impedance spectroscopy (MCIS) is potentially a powerful tool for the exploration of resistive surface layers on top of a conductive bulk or substrate material. MCIS employs micro-contacts in contrast to conventional IS where macroscopic electrodes are used. To extract the conductivity of each region accurately using MCIS requires the data to be corrected for geometry. Using finite element modeling on a system where the resistivity of the surface layer is at least a factor of ten greater than the bulk/substrate, we show how current flows through the two layers using two typical micro-contact configurations. This allows us to establish if and what is the most accurate and reliable method for extracting conductivity values for both regions. For a top circular micro-contact and a full bottom counter electrode, the surface layer conductivity (σs) can be accurately extracted using a spreading resistance equation if the thickness is ~10 times the micro-contact radius; however, bulk conductivity (σb) values can not be accurately determined. If the contact radius is 10 times the thickness of the resistive surface, a geometrical factor using the micro-contact area provides accurate σs values. In this case, a spreading resistance equation also provides a good approximation for σb. For two top circular micro-contacts on thin resistive surface layers, the MCIS response from the surface layer is independent of the contact separation; however, the bulk response is dependent on the contact separation and at small separations contact interference occurs. As a consequence, there is not a single ideal experimental setup that works; to obtain accurate σs and σb values the micro-contact radius, surface layer thickness and the contact separation must all be considered together. Here we provide scenarios where accurate σs and σb values can be obtained that highlight the importance of experimental design and where appropriate equations can be employed for thin and thick resistive surface layers. 相似文献
106.
以离子液体为新型萃取剂萃取稀贵金属具有萃取效率高、选择性强、清洁环保等优点,近年来不断被应用于湿法冶金领域,并取得一定研究成果。本文研究了咪唑类离子液体从高值废线路板浸出液中萃取Au(III)的行为。考察了萃取体系、萃取相比、萃取pH值、萃取时间对Au(III)的影响。结果表明,DBC+[BMIM][NTF2]萃取体系可实现室温下绿色、高效萃取Au(III),对Au(III)选择性强,不与Ni(II)、Cu(II)等其他金属离子共萃。在pH值为0.5、O/A为1:2、萃取时间2min时,可与Au(III)形成稳定络合物,萃取率达到100%。采用1mol草酸对DBC+[BMIM][NTF2]含Au(III)萃取体系进行反萃,O/A为1:10,反萃时间10min时,可实现Au(III)从有机相中全部分离。该研究可为含Au(III)萃取溶液Au(III)与其余金属离子的分离提纯提供数据基础和理论指导。 相似文献
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108.
中国地应力场分布规律统计分析 总被引:13,自引:0,他引:13
查阅迄今为止中国现有的实测地应力资料,参照霍克–布朗的地应力分析、统计和拟合方法,形成实测平均水平地应力与垂直地应力的比值随深度变化的散点图,回归实测平均水平地应力与垂直地应力的比值随深度的变化曲线并与霍克–布朗曲线进行比较,发现深度超过1 200 m以后,中国实测平均水平地应力与垂直地应力的比值统计值大于霍克–布朗曲线中值,且最大应力包线与霍克–布朗包线基本吻合,而最小应力包线的应力水平小于霍克–布朗包线的应力水平。进一步分析回归中国岩浆岩、沉积岩和变质岩等3种岩性的地应力统计结果,得到类似的回归曲线。统计结果对了解中国地应力场的宏观分布情况具有重要参考价值,对进行深埋地下结构分析计算和辅助设计具有重要的实用价值。 相似文献
109.
Namchu Kim Dean A. McHenry Sei-Joo Jang Thomas R. Shrout 《Journal of the American Ceramic Society》1990,73(4):923-928
The physical, dielectric, and optical properties of hot isostatically pressed lead magnesium niobate polycrystalline ceramics modified with 1/2 mol% La2 O3 , Pb1–3/2 x La x □ x /2 -(Mg1/3 Nb2/3 )O3 , have been investigated. Methods used to characterize the ceramics included determination of the dielectric permittivity, optical transmittance, and refractive index dispersion. The materials exhibited relaxor ferroelectric type behavior with a peak dielectric constant K > 14000 and average T c ∼−35°C. Various sintering, hot isostatic pressing, and annealing conditions were examined to produce highly dense and optically transparent materials. Through the use of hot isostatic pressing, densities more than 99.5% theoretical and transmittance greater than 50% at 633-nm wavelength were obtained. Hot isostatic pressing technique appears to be a good alternative to hot uniaxial pressing without the associated problem of PbO volatility, reactivity with the pressure vessel, and geometrical constraints. 相似文献
110.
Yuanji Dong Michael D. Hays N. Dean Smith John S. Kinsey 《Journal of aerosol science》2004,35(12):1497-1512
In this paper, the inversion processing of cascade impactor data to construe continuous size distributions within fine particulate matter (PM2.5) is examined for residential oil furnace and fireplace appliance emissions. Impactor data from tests with these emissions sources are selected for the challenges they pose to comprehending the size distributions of aerosol mass and chemical species. In specific, the oil furnace aerosol offers an opportunity to apply data inversion to study a bimodal lognormal distribution in which much of the aerosol mass is impactor-penetrating nanoparticles . The fireplace emissions on the other hand cover the issue of a chemical size distribution, which is subject to particle loss and characterized by a single lognormal, accumulation mode peak. Computational steps relevant to the application of the data inversion are illustrated in detail. Evaluation of correlation coefficients (0.992) indicates that the inversion model predictions fit the impactor data well. Simulations of systematic measurement error (±10%) at each impactor stage are shown to have a negligible impact on the inversion results for test data. It is concluded that data inversion can be effective when (i) source emissions contain a portion of particles that falls outside the measurement range of cascade impactors, (ii) a mass size distribution of an individual species is determined without the knowledge of the total mass concentration for that species, or when (iii) losses in the particle charger system are significant. 相似文献