74 resultados para K-Ras
Resumo:
The mineral harmotome (Ba,Na,K)1-2(Si,Al)8O16⋅6H2O is a crystalline sodium calcium silicate which has the potential to be used in plaster boards and other industrial applications. It is a natural zeolite with catalytic potential. Raman bands at 1020 and 1102 cm−1 are assigned to the SiO stretching vibrations of three dimensional siloxane units. Raman bands at 428, 470 and 491 cm−1 are assigned to OSiO bending modes. The broad Raman bands at around 699, 728, 768 cm−1 are attributed to water librational modes. Intense Raman bands in the 3100 to 3800 cm−1 spectral range are assigned to OH stretching vibrations of water in harmotome. Infrared spectra are in harmony with the Raman spectra. A sharp infrared band at 3731 cm−1 is assigned to the OH stretching vibration of SiOH units. Raman spectroscopy with complimentary infrared spectroscopy enables the characterization of the silicate mineral harmotome.
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Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.
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Biphasic vasodilatory responses to adenosine and 5'-N-ethylcarboxamidoadenosine (NECA) were observed in the coronary vasculature of K(+)-arrested perfused rat hearts. Dose-response data for both agonists were best represented by two-site models. For adenosine, two sites with negative log ED50 (pED50) values of 8.1 +/- 0.1 (mean +/- S.E.M) and 5.2 +/- 0.1 were obtained, mediating 31 +/- 2% and 69 +/- 2% of the total response. In the presence of 8-phenyltheophylline, the vasodilatory response to adenosine remained best fitted to a two-site model with pED50 values of 7.0 +/- 0.2 and 5.4 +/- 0.2. The relative contribution of each site to the total response remained unchanged. For NECA, pED50 values of 9.6 +/- 0.1 and 6.8 +/- 0.2 were obtained, representing 48 +/- 3% and 52 +/- 3% of the sites, respectively. In contrast, ATP produced a monophasic response with a pED50 value of 8.8 +/- 0.1. These results provide evidence of adenosine receptor and response heterogeneity in the in situ coronary vasculature.
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Purpose To evaluate the influence of cone location and corneal cylinder on RGP corrected visual acuities and residual astigmatism in patients with keratoconus. Methods In this prospective study, 156 eyes from 134 patients were enrolled. Complete ophthalmologic examination including manifest refraction, Best spectacle visual acuity (BSCVA), slit-lamp biomicroscopy was performed and corneal topography analysis was done. According to the cone location on the topographic map, the patients were divided into central and paracentral cone groups. Trial RGP lenses were selected based on the flat Sim K readings and a ‘three-point touch’ fitting approach was used. Over contact lens refraction was performed, residual astigmatism (RA) was measured and best-corrected RGP visual acuities (RGPVA) were recorded. Results The mean age (±SD) was 22.1 ± 5.3 years. 76 eyes (48.6%) had central and 80 eyes (51.4%) had paracentral cone. Prior to RGP lenses fitting mean (±SD) subjective refraction spherical equivalent (SRSE), subjective refraction astigmatism (SRAST) and BSCVA (logMAR) were −5.04 ± 2.27 D, −3.51 ± 1.68 D and 0.34 ± 0.14, respectively. There were statistically significant differences between central and paracentral cone groups in mean values of SRSE, SRAST, flat meridian (Sim K1), steep meridian (Sim K2), mean K and corneal cylinder (p-values < 0.05). Comparison of BSCVA to RGPVA shows that vision has improved 0.3 logMAR by RGP lenses (p < 0.0001). Mean (±SD) RA was −0.72 ± 0.39 D. There were no statistically significant differences between RGPVAs and RAs of central and paracentral cone groups (p = 0.22) and (p = 0.42), respectively. Pearson's correlation analysis shows that there is a statistically significant relationship between corneal cylinder and BSCVA and RGPVA, However, the relationship between corneal cylinder and residual astigmatism was not significant. Conclusions Cone location has no effect on the RGP corrected visual acuities and residual astigmatism in patients with keratoconus. Corneal cylinder and Sim K values influence RGP-corrected visual acuities but do not influence residual astigmatism.
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The unique combination of landscapes and processes that are present and operate on Fraser Island (K'gari) create a dynamic setting that is capable of recording past environmental events, climate variations and former landscapes. Likewise, its geographic position makes Fraser Island sensitive to those events and processes. Based on optically stimulated luminescence dating, the records archived within the world's largest sand island span a period that has the potential to exceed 750 ka and contain specific records that are of extremely high resolution over the past 40,000 years. This is due to the geographic position of Fraser Island, which lies in the coastal subtropical region of Queensland Australia. Fraser Island is exposed to the open ocean currents of the Coral Sea on the east coast and the waters of Hervey Bay on its western margin and is positioned to receive moisture from the Indo-Australian monsoon, southeast trade winds and experiences occasional tropical and ex-tropical cyclones. We review literature that presents the current level of understanding of sea level change, ecological variation and environmental change on Fraser Island. The previous works illustrate the importance of Fraser Island and may link processes, environments and climates on Fraser Island with global records.
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More than 140 countries offer what has become the international norm for preteritiary education, namely a kindergarten through grade 12 (K-12) system. Why kindergarten? Because, research attests to the long-term learning and social benefits of school readiness programs. Why 12 grades? Because experience in many countries shows that a K-12 system of schooling is the minimum necessary to acquire the knowledge and expertise for university education, employment training, or decent work.
Resumo:
A 59-year-old man was mistakenly prescribed Slow-Na instead of Slow-K due to incorrect selection from a drop-down list in the prescribing software. This error was identified by a pharmacist during a home medicine review (HMR) before the patient began taking the supplement. The reported error emphasizes the need for vigilance due to the emergence of novel look-alike, sound-alike (LASA) drug pairings. This case highlights the important role of pharmacists in medication safety.
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In a very recent study [1] the Renormalisation Group (RNG) turbulence model was used to obtain flow predictions in a strongly swirling quarl burner, and was found to perform well in predicting certain features that are not well captured using less sophisticated models of turbulence. The implication is that the RNG approach should provide an economical and reliable tool for the prediction of swirling flows in combustor and furnace geometries commonly encountered in technological applications. To test this hypothesis the present work considers flow in a model furnace for which experimental data is available [2]. The essential features of the flow which differentiate it from the previous study [1] are that the annular air jet entry is relatively narrow and the base wall of the cylindrical furnace is at 90 degrees to the inlet pipe. For swirl numbers of order 1 the resulting flow is highly complex with significant inner and outer recirculation regions. The RNG and standard k-epsilon models are used to model the flow for both swirling and non-swirling entry jets and the results compared with experimental data [2]. Near wall viscous effects are accounted for in both models via the standard wall function formulation [3]. For the RNG model, additional computations with grid placement extending well inside the near wall viscous-affected sublayer are performed in order to assess the low Reynolds number capabilities of the model.
Resumo:
In this work we numerically model isothermal turbulent swirling flow in a cylindrical burner. Three versions of the RNG k-epsilon model are assessed against performance of the standard k-epsilon model. Sensitivity of numerical predictions to grid refinement, differing convective differencing schemes and choice of (unknown) inlet dissipation rate, were closely scrutinised to ensure accuracy. Particular attention is paid to modelling the inlet conditions to within the range of uncertainty of the experimental data, as model predictions proved to be significantly sensitive to relatively small changes in upstream flow conditions. We also examine the characteristics of the swirl--induced recirculation zone predicted by the models over an extended range of inlet conditions. Our main findings are: - (i) the standard k-epsilon model performed best compared with experiment; - (ii) no one inlet specification can simultaneously optimize the performance of the models considered; - (iii) the RNG models predict both single-cell and double-cell IRZ characteristics, the latter both with and without additional internal stagnation points. The first finding indicates that the examined RNG modifications to the standard k-e model do not result in an improved eddy viscosity based model for the prediction of swirl flows. The second finding suggests that tuning established models for optimal performance in swirl flows a priori is not straightforward. The third finding indicates that the RNG based models exhibit a greater variety of structural behaviour, despite being of the same level of complexity as the standard k-e model. The plausibility of the predicted IRZ features are discussed in terms of known vortex breakdown phenomena.
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This commentary was stimulated by Yeping Li's first editorial (2014) citing one of the journal's goals as adding multidisciplinary perspectives to current studies of single disciplines comprising the focus of other journals. In this commentary I argue for a greater focus on STEM integration, with a more equitable representation of the four disciplines in studies purporting to advance STEM learning. The STEM acronym is often used in reference to just one of the disciplines, commonly science. Although the integration of STEM disciplines is increasingly advocated in the literature, studies that address multiple disciplines appear scant with mixed findings and inadequate directions for STEM advancement. Perspectives on how discipline integration can be achieved are varied, with reference to multidisciplinary, interdisciplinary, and transdisciplinary approaches adding to the debates. Such approaches include core concepts and skills being taught separately in each discipline but housed within a common theme; the introduction of closely linked concepts and skills from two or more disciplines with the aim of deepening understanding and skills; and the adoption of a transdisciplinary approach, where knowledge and skills from two or more disciplines are applied to real-world problems and projects with the aim of shaping the total learning experience. Research that targets STEM integration is an embryonic field with respect to advancing curriculum development and various student outcomes. For example, we still need more studies on how student learning outcomes arise not only from different forms of STEM integration but also from the particular disciplines that are being integrated. As noted in this commentary, it seems that mathematics learning benefits less than the other disciplines in programs claiming to focus on STEM integration. Factors contributing to this finding warrant more scrutiny. Likewise, learning outcomes for engineering within K-12 integrated STEM programs appear under-researched. This commentary advocates a greater focus on these two disciplines within integrated STEM education research. Drawing on recommendations from the literature, suggestions are offered for addressing the challenges of integrating multiple disciplines faced by the STEM community.
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Birds represent the most diverse extant tetrapod clade, with ca. 10,000 extant species, and the timing of the crown avian radiation remains hotly debated. The fossil record supports a primarily Cenozoic radiation of crown birds, whereas molecular divergence dating analyses generally imply that this radiation was well underway during the Cretaceous. Furthermore, substantial differences have been noted between published divergence estimates. These have been variously attributed to clock model, calibration regime, and gene type. One underappreciated phenomenon is that disparity between fossil ages and molecular dates tends to be proportionally greater for shallower nodes in the avian Tree of Life. Here, we explore potential drivers of disparity in avian divergence dates through a set of analyses applying various calibration strategies and coding methods to a mitochondrial genome dataset and an 18-gene nuclear dataset, both sampled across 72 taxa. Our analyses support the occurrence of two deep divergences (i.e., the Palaeognathae/Neognathae split and the Galloanserae/Neoaves split) well within the Cretaceous, followed by a rapid radiation of Neoaves near the K-Pg boundary. However, 95% highest posterior density intervals for most basal divergences in Neoaves cross the boundary, and we emphasize that, barring unreasonably strict prior distributions, distinguishing between a rapid Early Paleocene radiation and a Late Cretaceous radiation may be beyond the resolving power of currently favored divergence dating methods. In contrast to recent observations for placental mammals, constraining all divergences within Neoaves to occur in the Cenozoic does not result in unreasonably high inferred substitution rates. Comparisons of nuclear DNA (nDNA) versus mitochondrial DNA (mtDNA) datasets and NT- versus RY-coded mitochondrial data reveal patterns of disparity that are consistent with substitution model misspecifications that result in tree compression/tree extension artifacts, which may explain some discordance between previous divergence estimates based on different sequence types. Comparisons of fully calibrated and nominally calibrated trees support a correlation between body mass and apparent dating error. Overall, our results are consistent with (but do not require) a Paleogene radiation for most major clades of crown birds.
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The evolutionary success of beetles and numerous other terrestrial insects is generally attributed to co-radiation with flowering plants but most studies have focused on herbivorous or pollinating insects. Non-herbivores represent a significant proportion of beetle diversity yet potential factors that influence their diversification have been largely unexamined. In the present study, we examine the factors driving diversification within the Scarabaeidae, a speciose beetle family with a range of both herbivorous and non-herbivorous ecologies. In particular, it has been long debated whether the key event in the evolution of dung beetles (Scarabaeidae: Scarabaeinae) was an adaptation to feeding on dinosaur or mammalian dung. Here we present molecular evidence to show that the origin of dung beetles occurred in the middle of the Cretaceous, likely in association with dinosaur dung, but more surprisingly the timing is consistent with the rise of the angiosperms. We hypothesize that the switch in dinosaur diet to incorporate more nutritious and less fibrous angiosperm foliage provided a palatable dung source that ultimately created a new niche for diversification. Given the well-accepted mass extinction of non-avian dinosaurs at the Cretaceous-Paleogene boundary, we examine a potential co-extinction of dung beetles due to the loss of an important evolutionary resource, i.e., dinosaur dung. The biogeography of dung beetles is also examined to explore the previously proposed "out of Africa" hypothesis. Given the inferred age of Scarabaeinae as originating in the Lower Cretaceous, the major radiation of dung feeders prior to the Cenomanian, and the early divergence of both African and Gondwanan lineages, we hypothesise that that faunal exchange between Africa and Gondwanaland occurred during the earliest evolution of the Scarabaeinae. Therefore we propose that both Gondwanan vicariance and dispersal of African lineages is responsible for present day distribution of scarabaeine dung beetles and provide examples.