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.     

Application of organosilane coatings for improved anti-adhesive properties enabling facilitated demolding in polymer processing

Easy and residue-free demolding is an everlasting topic in the plastics processing industry. Typically, facile ejection of the produced parts from the mold is provided by separation agents (silicon sprays, surface coatings). In this work, a perfluoroalkyl-based organosilane coating is applied to exchangeable substrates of an injection mold. Besides the simple application, the coating can also be restored easily in a procedure based on flame treatment. Coating and recoating are proven by contact angle measurements with water, while the anti-adhesive effect and the related relief during demolding are evaluated using a special measuring device in an instrumented two-plate injection mold. The results reveal that the organosilane layer reduces the demolding forces and the resulting static friction coefficient by 50%. Furthermore, multiple recoating significantly improves the durability of the anti-adhesive coating. Based on these findings, the easily applicable and renewable organosilane coating represents a suitable alternative to conventional release coatings.     

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.     

Multifaceted Analysis of IL-23A- and/or EBI3-Including Cytokines Produced by Psoriatic Keratinocytes

Interleukin (IL) 23 (p19/p40) plays a critical role in the pathogenesis of psoriasis and is upregulated in psoriasis skin lesions. In clinical practice, anti-IL-23Ap19 antibodies are highly effective against psoriasis. IL-39 (p19/ Epstein-Barr virus-induced (EBI) 3), a newly discovered cytokine in 2015, shares the p19 subunit with IL-23. Anti-IL-23Ap19 antibodies may bind to IL-39; also, the cytokine may contribute to the pathogenesis of psoriasis. To investigate IL23Ap19- and/or EBI3-including cytokines in psoriatic keratinocytes, we analyzed IL-23Ap19 and EBI3 expressions in psoriasis skin lesions, using immunohistochemistry and normal human epidermal keratinocytes (NHEKs) stimulated with inflammatory cytokines, using quantitative real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and liquid chromatography-electrospray tandem mass spectrometry (LC-Ms/Ms). Immunohistochemical analysis showed that IL-23Ap19 and EBI3 expressions were upregulated in the psoriasis skin lesions. In vitro, these expressions were synergistically induced by the triple combination of tumor necrosis factor (TNF)-α, IL-17A, and interferon (IFN)-γ, and suppressed by dexamethasone, vitamin D3, and acitretin. In ELISA and LC-Ms/Ms analyses, keratinocyte-derived IL-23Ap19 and EBI3, but not heterodimeric forms, were detected with humanized anti-IL-23Ap19 monoclonal antibodies, tildrakizumab, and anti-EBI3 antibodies, respectively. Psoriatic keratinocytes may express IL-23Ap19 and EBI3 proteins in a monomer or homopolymer, such as homodimer or homotrimer.     

High‐Temperature Neutron Diffraction,Raman Spectroscopy,and First‐Principles Calculations of Ti3SnC2 and Ti2SnC

Herein, we report—for the first time—on the additive‐free bulk synthesis of Ti₃SnC₂. A detailed experimental study of the structure of the latter together with a secondary phase, Ti₂SnC, is presented through the use of X‐ray diffraction (XRD), and high‐resolution transmission microscopy (HRTEM). A previous sample of Ti₃SnC₂, made using Fe as an additive and Ti₂SnC as a secondary phase, was studied by high‐temperature neutron diffraction (HTND) and XRD. The room‐temperature crystallographic parameters of the two MAX phases in the two samples are quite similar. Based on Rietveld analysis of the HTND data, the average linear thermal expansion coefficients of Ti₃SnC₂ in the a and c directions were found to be 8.5 (2)·10^?6 K^?1 and 8.9 (1)·10^?6 K^?1, respectively. The respective values for the Ti₂SnC phase are 10.1 (3)·10^?6 K^?1 and 10.8 (6)·10^?6 K^?1. Unlike other MAX phases, the atomic displacement parameters of the Sn atoms in Ti₃SnC₂ are comparable to those of the Ti and C atoms. When the predictions of the atomic displacement parameters obtained from density functional theory are compared to the experimental results, good quantitative agreement is found for the Sn atoms. In the case of the Ti and C atoms, the agreement is more qualitative. We also used first principles to calculate the elastic properties of both Ti₂SnC and Ti₃SnC₂ and their Raman active modes. The latter are compared to experiment and the agreement was found to be good.     

Synthesis of Cellulose-Based Macromolecular Coupling Agent and its Utilization in Poly (butylene succinate)/Wood Flour Composites

A long fatty side chain was introduced into the macromolecule of hydroxyethyl cellulose (HEC) via esterification reaction. The hydrophobicity of hydroxyethyl cellulose lauric acid ester (HECLAE) was enhanced in comparison with HEC. The obtained HECLAE was used as macromolecular coupling agent in poly (butylene succinate)/wood flour composites and exhibited a positive influence on improving the mechanical performance of composites. Besides, HECLAE plays a role as a hydrophobic agent in composites. A significant increase in storage modulus (E’) was observed upon the incorporation of treated wood flour. SEM images showed that the dispersion of treated wood flour in PBS matrix was improved.     

The Impact of Zeta Potential and Physicochemical Properties of TiO2‐Based Nanocomposites on Their Biological Activity

The aim of this research was to observe the relationship between zeta potential, morphology, surface area, porosity, chemical composition, and ecotoxicity of nanocomposite powders such as Au/TiO₂, Ag₂O/TiO₂, PdO/TiO₂, Ag/TiO₂/SiO₂, Ag/N(C)TiO₂, and SiO₂/TiO₂ from which Ag₂O/TiO₂, Ag/N(C)/TiO_2, and Ag/TiO₂/SiO₂ were exhibiting good antimicrobial properties. It was observed, that nanomaterials characterized by similar morphology and zeta potential revealed the similar toxic behavior. The samples of higher agglomeration and higher zeta potential, especially Ag/TiO₂/SiO₂ xerogel and TiO₂/SiO₂ aerogel were generally less ecotoxic to water organisms and plants. They were also not genotoxic in concentrations up to 500 and 250 mg/L, respectively.     

Ribosomal Synthesis of Natural‐Product‐Like Bicyclic Peptides in Escherichia coli

Methods to access natural‐product‐like macrocyclic peptides can disclose new opportunities for the exploration of this important structural class for chemical biology and drug discovery applications. Here, the scope and mechanism of a novel strategy for directing the biosynthesis of thioether‐bridged bicyclic peptides in bacterial cells was investigated. This method entails split intein‐catalyzed head‐to‐tail cyclization of a ribosomally produced precursor peptide, combined with inter‐side‐chain crosslinking through a genetically encoded cysteine‐reactive amino acid. This strategy could be successfully applied to achieve formation of structurally diverse bicyclic peptides with high efficiency and selectivity in Escherichia coli. Insights into the sequence of reactions underlying the peptide bicyclization process were gained from time‐course experiments. Finally, the potential utility of this methodology toward the discovery of macrocyclic peptides with enhanced functional properties was demonstrated through the isolation of a bicyclic peptide with sub‐micromolar affinity for streptavidin.     

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.