We investigated the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), prosurvival kinase Akt, oxidative stress, and autophagy in the cytotoxicity of parkinsonian ...neurotoxin 1-methyl-4-phenyl piridinium (MPP+) towards SH-SY5Y human neuroblastoma cells. MPP+-mediated oxidative stress, mitochondrial depolarization, and apoptotic cell death were associated with rapid (within 2 h) activation of AMPK, its target Raptor, and prosurvival kinase Akt. Antioxidants N-acetylcysteine and butylated hydroxyanisole suppressed MPP+-induced cytotoxicity, AMPK, and Akt activation. A genetic or pharmacological inhibition of AMPK increased MPP+-triggered production of reactive oxygen species and cell death, and diminished Akt phosphorylation, while AMPK activation protected SH-SY5Y cells from MPP+. On the other hand, genetic or pharmacological inactivation of Akt stimulated MPP+-triggered oxidative stress and neurotoxicity, but did not affect AMPK activation. At later time-points (16–24 h), MPP+ inhibited the main autophagy repressor mammalian target of rapamycin, which coincided with the increase in the levels of autophagy marker microtubule-associated protein 1 light-chain 3B. MPP+ also increased the concentration of a selective autophagic target sequestosome-1/p62 and reduced the levels of lysosomal-associated membrane protein 1 and cytoplasmic acidification, suggesting that MPP+-induced autophagy was coupled with a decrease in autophagic flux. Nevertheless, further pharmacological inhibition of autophagy sensitized SH-SY5Y cells to MPP+-induced death. Antioxidants and AMPK knockdown reduced, whereas genetic inactivation of Akt potentiated neurotoxin-triggered autophagy. These results suggest that MPP+-induced oxidative stress stimulates AMPK, which protects SH-SY5Y cells through early activation of antioxidative Akt and late induction of cytoprotective autophagy.
We investigate effects of catalyst activity, catalyst particle shape (sphere, slab, and hollow cylinder), size (i.e., diffusion length), catalyst distribution (uniform vs eggshell type distribution ...for a spherical particle), and process conditions (temperature, pressure, syngas composition, and conversion level) on catalyst effectiveness factor and methane selectivity inside the catalyst pellet. In numerical simulations we utilize kinetic parameters for CO consumption rate and CH4 formation rate determined from experiments with a highly active Co/Re/γ-Al2O3 catalyst. It is found that the use of small spherical particles (0.2–0.5 mm) or eggshell distribution for larger spherical particles with catalyst layer thickness less than approximately 0.13 mm is needed to avoid negative impact of diffusional limitations on CH4 selectivity under typical Fischer–Tropsch synthesis operating conditions. For monolith reactors with wash-coated catalyst, diffusional limitations can be avoided by using a catalyst layer thickness less than 0.11 mm at base case conditions (473 K, 25 bar, and H2/CO molar ratio of 2).
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We investigated the role of the intracellular energy-sensing AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in the in vitro antiglioma effect of the ...cyclooxygenase (COX) inhibitor indomethacin. Indomethacin was more potent than COX inhibitors diclofenac, naproxen, and ketoprofen in reducing the viability of U251 human glioma cells. Antiglioma effect of the drug was associated with p21 increase and G2M cell cycle arrest, as well as with oxidative stress, mitochondrial depolarization, caspase activation, and the induction of apoptosis. Indomethacin increased the phosphorylation of AMPK and its targets Raptor and acetyl-CoA carboxylase (ACC), and reduced the phosphorylation of mTOR and mTOR complex 1 (mTORC1) substrates p70S6 kinase and PRAS40 (Ser183). AMPK knockdown by RNA interference, as well as the treatment with the mTORC1 activator leucine, prevented indomethacin-mediated mTORC1 inhibition and cytotoxic action, while AMPK activators metformin and AICAR mimicked the effects of the drug. AMPK activation by indomethacin correlated with intracellular ATP depletion and increase in AMP/ATP ratio, and was apparently independent of COX inhibition or the increase in intracellular calcium. Finally, the toxicity of indomethacin towards primary human glioma cells was associated with the activation of AMPK/Raptor/ACC and subsequent suppression of mTORC1/S6K. By demonstrating the involvement of AMPK/mTORC1 pathway in the antiglioma action of indomethacin, our results support its further exploration in glioma therapy.
In the past decade a certain number of studies have suggested that shape grammars and their capability for producing alternative solutions represent an adequate tool for overcoming complexities ...regarding urban design. In this paper we present a critical analysis of various approaches to shape grammar application in urban design. The aim of this research is to provide an insight into the current state-of-the-art developments and give a critical evaluation on the basis of the criteria of interactivity and flexibility in the approach. We identify two main concepts of grammar application in urban design and outline their characteristics. We conclude that a generic or context-independent approach to shape grammars can provide high levels of flexibility and interaction with the user. This, coupled with their ability to encode different layers of information, facilitates their use for design exploration and problem solving in an urban context.
We investigated the in vitro and in vivo anticancer effect of combining lysosomal membrane permeabilization (LMP)-inducing agent N-dodecylimidazole (NDI) with glycolytic inhibitor 2-deoxy-d-glucose ...(2DG). NDI-triggered LMP and 2DG-mediated glycolysis block synergized in inducing rapid ATP depletion, mitochondrial damage, and reactive oxygen species production, eventually leading to necrotic death of U251 glioma cells but not primary astrocytes. NDI/2DG-induced death of glioma cells was partly prevented by lysosomal cathepsin inhibitor E64 and antioxidant α-tocopherol, suggesting the involvement of LMP and oxidative stress in the observed cytotoxicity. LMP-inducing agent chloroquine also displayed a synergistic anticancer effect with 2DG, whereas glucose deprivation or glycolytic inhibitors iodoacetate and sodium fluoride synergistically cooperated with NDI, thus further indicating that the anticancer effect of NDI/2DG combination was indeed due to LMP and glycolysis block. The two agents synergistically induced ATP depletion, mitochondrial depolarization, oxidative stress, and necrotic death also in B16 mouse melanoma cells. Moreover, the combined oral administration of NDI and 2DG reduced in vivo melanoma growth in C57BL/6 mice by inducing necrotic death of tumor cells, without causing liver, spleen, or kidney toxicity. Based on these results, we propose that NDI-triggered LMP causes initial mitochondrial damage that is further increased by 2DG due to the lack of glycolytic ATP required to maintain mitochondrial health. This leads to a positive feedback cycle of mitochondrial dysfunction, ATP loss, and reactive oxygen species production, culminating in necrotic cell death. Therefore, the combination of LMP-inducing agents and glycolysis inhibitors seems worthy of further exploration as an anticancer strategy.
A multiphase fixed-bed reactor (FBR) model for Fischer–Tropsch Synthesis has been developed. A high level of details is considered for description of the phenomena on the reactor and particle scale. ...Detailed kinetics is used, with parameters estimated from experiments with a cobalt-based catalyst. Model robustness has been validated using literature data. Performance analysis was made for a conventional scale FBR with egg-shell distribution of catalyst and a millimeter-scale FBR with small particles and uniform distribution. In both cases, diffusion limitations are almost eliminated due to use of small diffusion lengths. For similar qualitative results, a milli-scaled design would result in a significantly lower reactor volume, but the capital costs could be high due to large wall area and a vast number of tubes. Heat removal is efficient in both cases, and pressure drop in the milli-scale reactor is low due to the use of a shorter bed and lower velocity.
Our previously developed mathematical model is used for parametric sensitivity and optimization study of conventional and milliscale fixed-bed reactors (FBRs) for Fischer–Tropsch synthesis (FTS). ...Five indicators are chosen to analyze the influence of eight parameters on the FBRs’ performance. The results show the scale of the effects caused by changing single parameter values and highlight the most important ones. Subsequently, the model is used to perform a rigorous multivariable optimization of the FBRs’ performance in the steady state. Three optimization functions are used, depicting different reactor costs. Four design parameters (tube length and diameter, particle diameter, and catalyst layer thickness) and five operating parameters (inlet and wall temperature, inlet pressure, H2/CO ratio, velocity) are optimized simultaneously. The results indicate that optimal results, in terms of reactor design and operating parameters and FBR performance, highly depend on the selected objective function and values of constrained parameters (especially methane selectivity and the partial pressure of water).
Within the compressive sensing (CS) paradigm, sparse signals can be reconstructed based on a reduced set of measurements, whereby reliability of the solution is determined by its uniqueness. With its ...mathematically tractable and feasible calculation, the coherence index is one of very few CS uniqueness metrics with considerable practical importance. We propose an improvement of the coherence-based uniqueness relation for the matching pursuit algorithms. Starting from a simple and intuitive derivation of the standard uniqueness condition, based on the coherence index, we derive a less conservative coherence index-based lower bound for signal sparsity. The results are generalized to the uniqueness condition of the <inline-formula><tex-math notation="LaTeX">l_0</tex-math></inline-formula>-norm minimization for a signal represented in two orthonormal bases.
•Decomposition of multicomponent multivariate signals which partially overlap in the joint time-frequency domain is presented.•The method is based on the eigenvectors of the signal autocorrelation ...matrix.•The multivariate signal components are obtained as linear combinations of the eigenvectors that minimize the concentration measure in the time-frequency domain.•Simulation results validate the proposed method.
With their ability to cater for simultaneously for multifaceted information, multichannel (multivariate) signals have been used to solve problems that are normally not solvable with signals obtained from a single source. One such problem is the decomposition of signals which comprise several components for which the domains of support significantly overlap in both the time, frequency and the joint time-frequency domain. Earlier, we proposed a solution to this problem based on the Wigner distribution of multichannel signals, which requires the attenuation of the cross-terms. In this paper, an advanced solution is proposed, based on eigenvalue analysis of the multichannel signal autocorrelation matrix, followed by the minimization of their time-frequency concentration measure. The analysis offers less restrictive conditions for the signal decomposition, compared to the case of the Wigner distribution. The algorithm for the separation of components is based on concentration measures of the eigenvector time-frequency representation, which represent linear combinations of the overlapping signal components. With an increased number of sensors/channels, the robustness of the decomposition process to additive noise is also demonstrated. The theory is supported by numerical examples, whereby the required channel dissimilarity is also statistically investigated.
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