Targeted Synthesis of Complex Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors

Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small-molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild-type tumors; however, it also revealed dose-limiting hematological toxicities and drug-induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less-frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro-oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96_MDM2. The designed molecules required the targeted synthesis of structurally complex spiro[indole-3,2′-pyrrolo[2,3-c]pyrrole]-2,4′-diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI-0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on-target adverse effects.     

Analysis of intraparticle diffusion on adsorption of crystal violet on bentonite

Abstract

In the present work, kinetics of crystal violet (CV) adsorption on bentonite was studied by pore volume and surface diffusion model (PVSDM), surface diffusion model (SDM), and pore volume diffusion model (PVDM). The adsorption decay curves were obtained in batch system using different adsorbent dosages. The PVDM model did not interpreted the kinetic adsorption since the calculated value of D_p equal to 5.64?×?10^?7 cm² s^?1 predicted a slower adsorption than that obtained by the experimental data. The PVSDM results indicates that the intraparticle diffusion is predominantly due to surface diffusion (93%) and the pore volume diffusion can be negligible. Once the surface diffusion was the limiting step, the estimation with one (D_s) and two (D_sq and α) parameters were tested in the SDM model. The statistical analysis revealed that the one-parameter SDM model was most appropriate to predict the CV adsorption on bentonite. The optimal values of Ds ranged from 6.19?×?10^?10 to 6.49?×?10^?10 cm² s^?1, and decrease with the adsorbent dosage.     

Adaptive neuro-fuzzy inference system (ANIFS) and artificial neural network (ANN) applied for indium (III) adsorption on carbonaceous materials

Abstract

In this paper, we present an initial study relating the adsorption of indium (III) onto carbonaceous materials, namely the activated carbon (AC), multiwalled carbon nanotubes functionalized with OH (MWCNT–OH), and the multiwalled carbon nanotubes functionalized with COOH (MWCNT–COOH). The main objective of this study is the development of the adaptive neuro-fuzzy inference system (ANFIS) and an artificial neural network (ANN) for predicting the adsorption capacity in different operating conditions for different materials. Both models take into account the adsorbent type, adsorbent dosage (0.05, 0.25, 0.5, 1.0, 1.5, and 2.0?g L^?1), and the contact time (5, 20, 60, and 120?min) for predicting the adsorption capacity, which varied from 12.896 to 981.000?mg g^?1, a total record of 72 was used. Both modeling methodologies applied can represent the experimental data, taking into account the statistical values obtained. The ANFIS achieved the best performance when the hybrid method was selected, this leads into R of 0.9998, RMSE of 48,373 with 250 epochs. On the other hand, the ANN can represent the best performance when using the Levenberg–Marquardt algorithm, reaching an R of 0.9831, MSE of 0.0180 and 9 epochs. Considering the modeling and experimental aspects indicates that the increase of the adsorbent dosage diminished the adsorbent capacity. The increase of the contact time causes the effect to increase the adsorption capacity until its equilibrium. Lastly, it is possible to conclude that the MWCNT–COOH is the most suitable adsorbent to be used between the selected materials.     

Metal content determination in four fish species from the Adriatic Sea

Concentrations of As, Cd, Cu, Hg and Pb were measured by atomic absorption spectrometry (AAS) in muscle tissues of four fish species: anchovy (Engraulis encrasicholus), mackerel (Scomber japonicus), red mullet (Mullus surmuletus) and picarel (Spicara smaris) from the Croatian waters of the Adriatic Sea during 2008 and 2009. Metal levels measured in anchovy were in the following ranges (mg kg⁻¹): As 0.01–54.8, Cd 0.001–0.02, Cu 0.001–6.29, Hg 0.001–0.52 and Pb 0.001–0.34 mg kg⁻¹. Metal ranges in red mullet were (mg kg⁻¹): As 0.01–70.9, Cd 0.002–0.85, Cu 0.001–57.3, Hg 0.001–2.07 and Pb 0.001–0.27 mg kg⁻¹. Metal level ranges measured in mackerel were (mg kg⁻¹): As 0.01–36.4, Cd 0.001–0.1, Cu 0.001–15.9, Hg 0.001–0.78 and Pb 0.002–0.24 mg kg⁻¹. In picarel, metal level ranges were (mg kg⁻¹): As 0.01–54.6, Cd 0.001–0.1, Cu 0.08–32.9, Hg 0.001–0.207 and Pb 0.001–0.46 mg kg⁻¹. Significant differences in metal concentrations were found among fish species. The results presented on metal contents in the examined species give an indication of the environmental conditions. Concentrations of Cd, Cu, Hg and Pb obtained were far below the established values by the European Community regulations. However, arsenic levels found in red mullet were higher than the recommended legal limits for human consumption and as such may present a human health issue.     

Are ethical consumption and charitable giving substitutes or not? Insights into consumers’ coffee choice

While charitable giving stagnates, Fair Trade and organic labelling as well as Cause-related Marketing campaigns are on the rise in Germany. The question as to whether the efficiency of the different systems is of relevance for consumers has received little attention in the literature so far. A latent class model for discrete choice analysis reveals five consumer segments with well distinguished preferences and willingness to pay measures for the modes of ethical consumption as well as for different donation amounts. For 27% of the 484 respondents ethical consumption occurs at the expense of other forms of ethical behaviour such as charitable giving.     

A Microfluidic 3D Endothelium-on-a-Chip Model to Study Transendothelial Migration of T Cells in Health and Disease

The recruitment of T cells is a crucial component in the inflammatory cascade of the body. The process involves the transport of T cells through the vascular system and their stable arrest to vessel walls at the site of inflammation, followed by extravasation and subsequent infiltration into tissue. Here, we describe an assay to study 3D T cell dynamics under flow in real time using a high-throughput, artificial membrane-free microfluidic platform that allows unimpeded extravasation of T cells. We show that primary human T cells adhere to endothelial vessel walls upon perfusion of microvessels and can be stimulated to undergo transendothelial migration (TEM) by TNFα-mediated vascular inflammation and the presence of CXCL12 gradients or ECM-embedded melanoma cells. Notably, migratory behavior was found to differ depending on T cell activation states. The assay is unique in its comprehensiveness for modelling T cell trafficking, arrest, extravasation and migration, all in one system, combined with its throughput, quality of imaging and ease of use. We envision routine use of this assay to study immunological processes and expect it to spur research in the fields of immunological disorders, immuno-oncology and the development of novel immunotherapeutics.     

Mitochondrial HSP70 Chaperone System—The Influence of Post-Translational Modifications and Involvement in Human Diseases

Since their discovery, heat shock proteins (HSPs) have been identified in all domains of life, which demonstrates their importance and conserved functional role in maintaining protein homeostasis. Mitochondria possess several members of the major HSP sub-families that perform essential tasks for keeping the organelle in a fully functional and healthy state. In humans, the mitochondrial HSP70 chaperone system comprises a central molecular chaperone, mtHSP70 or mortalin (HSPA9), which is actively involved in stabilizing and importing nuclear gene products and in refolding mitochondrial precursor proteins, and three co-chaperones (HSP70-escort protein 1—HEP1, tumorous imaginal disc protein 1—TID-1, and Gro-P like protein E—GRPE), which regulate and accelerate its protein folding functions. In this review, we summarize the roles of mitochondrial molecular chaperones with particular focus on the human mtHsp70 and its co-chaperones, whose deregulated expression, mutations, and post-translational modifications are often considered to be the main cause of neurological disorders, genetic diseases, and malignant growth.