Neurocomputing strategies in structural design — on analysing weights of feedforward neural networks

The sequel of two papers explores the applicability of selected neurocomputing strategies in the optimization of structural systems. The present paper describes the use of interconnection weights of a multilayer, feedforward neural network to extract information pertinent to a design space modelled by such a network. It is shown that aweights analysis provides a technique to assess the effect of all input quantities on a given output. Such dependencies are expressed in the form of atransition matrix, and their evaluation is reduced to the inspection of elements of a matrix row. Explicit formulae are derived for networks with one and two hidden layers and can easily be generalized to networks with an arbitrary number of hidden layers. In addition to its use as a tool to partition design spaces, the weights analysis may be employed to assist in determining the size of hidden layers and an adequate number of training patterns (input-output pairs). Several numerical examples from the field of structural analysis are provided, and the paper underscores the utility of the present technique in decomposition driven optimal design; such optimization is treated in full in the companion paper.     

Chemistry towards Biology—Instruct: Snapshot

The knowledge of interactions between different molecules is undoubtedly the driving force of all contemporary biomedical and biological sciences. Chemical biology/biological chemistry has become an important multidisciplinary bridge connecting the perspectives of chemistry and biology to the study of small molecules/peptidomimetics and their interactions in biological systems. Advances in structural biology research, in particular linking atomic structure to molecular properties and cellular context, are essential for the sophisticated design of new medicines that exhibit a high degree of druggability and very importantly, druglikeness. The authors of this contribution are outstanding scientists in the field who provided a brief overview of their work, which is arranged from in silico investigation through the characterization of interactions of compounds with biomolecules to bioactive materials.     

Mixture Effects of Tryptophan Intestinal Microbial Metabolites on Aryl Hydrocarbon Receptor Activity

Aryl hydrocarbon receptor (AHR) plays pivotal roles in intestinal physiology and pathophysiology. Intestinal AHR is activated by numerous dietary, endogenous, and microbial ligands. Whereas the effects of individual compounds on AHR are mostly known, the effects of real physiological mixtures occurring in the intestine have not been studied. Using reporter gene assays and RT-PCR, we evaluated the combinatorial effects (3520 combinations) of 11 microbial catabolites of tryptophan (MICTs) on AHR. We robustly (n = 30) determined the potencies and relative efficacies of single MICTs. Synergistic effects of MICT binary mixtures were observed between low- or medium-efficacy agonists, in particular for combinations of indole-3-propionate and indole-3-lactate. Combinations comprising highly efficacious agonists such as indole-3-pyruvate displayed rather antagonist effects, caused by saturation of the assay response. These synergistic effects were confirmed by RT-PCR as CYP1A1 mRNA expression. We also tested mimic multicomponent and binary mixtures of MICTs, prepared based on the metabolomic analyses of human feces and colonoscopy aspirates, respectively. In this case, AHR responsiveness did not correlate with type of diet or health status, and the indole concentrations in the mixtures were determinative of gross AHR activity. Future systematic research on the synergistic activation of AHR by microbial metabolites and other ligands is needed.     

Fraxetin Interacts Additively with Cisplatin and Mitoxantrone,Antagonistically with Docetaxel in Various Human Melanoma Cell Lines—An Isobolographic Analysis

Malignant melanoma is a skin cancer characterized by rapid development, poor prognosis and high mortality. Due to the frequent drug resistance and/or early metastases in melanoma, new therapeutic methods are urgently needed. The study aimed at assessing the cytotoxic and antiproliferative effects of scoparone and fraxetin in vitro, when used alone and in combination with three cytostatics: cisplatin, mitoxantrone, and docetaxel in four human melanoma cell lines. Our experiments showed that scoparone in the concentration range tested up to 200 µM had no significant effect on the viability of human malignant melanoma (therefore, it was not possible to evaluate it in combination with other cytostatics), while fraxetin inhibited cell proliferation with IC₅₀ doses in the range of 32.42–73.16 µM, depending on the cell line. Isobolographic analysis allowed for the assessment of the interactions between the studied compounds. Importantly, fraxetin was not cytotoxic to normal keratinocytes (HaCaT) and melanocytes (HEMa-LP), although it slightly inhibited their viability at high concentrations. The combination of fraxetin with cisplatin and mitoxantrone showed the additive interaction, which seems to be a promising direction in melanoma therapy. Unfortunately, the combination of fraxetin with docetaxel may not be beneficial due to the antagonistic antiproliferative effect of both drugs used in the mixture.     

Targeting DNA Methylation in Leukemia,Myelodysplastic Syndrome,and Lymphoma: A Potential Diagnostic,Prognostic, and Therapeutic Tool

DNA methylation represents a crucial mechanism of epigenetic regulation in hematologic malignancies. The methylation process is controlled by specific DNA methyl transferases and other regulators, which are often affected by genetic alterations. Global hypomethylation and hypermethylation of tumor suppressor genes are associated with hematologic cancer development and progression. Several epi-drugs have been successfully implicated in the treatment of hematologic malignancies, including the hypomethylating agents (HMAs) decitabine and azacytidine. However, combinations with other treatment modalities and the discovery of new molecules are still the subject of research to increase sensitivity to anti-cancer therapies and improve patient outcomes. In this review, we summarized the main functions of DNA methylation regulators and genetic events leading to changes in methylation landscapes. We provide current knowledge about target genes with aberrant methylation levels in leukemias, myelodysplastic syndromes, and malignant lymphomas. Moreover, we provide an overview of the clinical trials, focused mainly on the combined therapy of HMAs with other treatments and its impact on adverse events, treatment efficacy, and survival rates among hematologic cancer patients. In the era of precision medicine, a transition from genes to their regulation opens up the possibility of an epigenetic-based approach as a diagnostic, prognostic, and therapeutic tool.     

Computer-Aided Search for 5-Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1-Based Multidrug Resistance

ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5-arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug-resistant (MDR) ABCB1-overexpressing T-lymphoma cancer cells using cytotoxicity assays. The ABCB1-modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp-Glo™ Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP-TLC). Pharmacophore-based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents (p-fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T-lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1-modulating action; in particular, two 5-benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar.     

Palm Oil-Rich Diet Affects Murine Liver Proteome and S-Palmitoylome

Palmitic acid (C16:0) is the most abundant saturated fatty acid in animals serving as a substrate in synthesis and β-oxidation of other lipids, and in the modification of proteins called palmitoylation. The influence of dietary palmitic acid on protein S-palmitoylation remains largely unknown. In this study we performed high-throughput proteomic analyses of a membrane-enriched fraction of murine liver to examine the influence of a palm oil-rich diet (HPD) on S-palmitoylation of proteins. HPD feeding for 4 weeks led to an accumulation of C16:0 and C18:1 fatty acids in livers which disappeared after 12-week feeding, in contrast to an accumulation of C16:0 in peritoneal macrophages. Parallel proteomic studies revealed that HPD feeding induced a sequence of changes of the level and/or S-palmitoylation of diverse liver proteins involved in fatty acid, cholesterol and amino acid metabolism, hemostasis, and neutrophil degranulation. The HPD diet did not lead to liver damage, however, it caused progressing obesity, hypercholesterolemia and hyperglycemia. We conclude that the relatively mild negative impact of such diet on liver functioning can be attributed to a lower bioavailability of palm oil-derived C16:0 vs. that of C18:1 and the efficiency of mechanisms preventing liver injury, possibly including dynamic protein S-palmitoylation.     

Catalytic graphene formation in coal tar pitch- derived carbon structure in the presence of SiO2 nanoparticles

A simple and effective way to manufacture graphene from a coal tar pitch (CTP) is demonstrated. Silica (SiO₂) nanoparticles were used to modify the CTP as carbon precursor. A silica nanofiller introduced into the CTP matrix underwent carboreduction during heat treatment to 2000 °C, resulting in the formation of silicon carbide. Surfaces of SiC grains were sites for graphene formation. The influence of SiO₂ on the structure and microstructure of CTP- based carbon matrix, after annealing up to 2800 °C, was studied. Carbon samples were analyzed using X- ray Diffraction (XRD), Transmission Electron Microscopy (TEM) and Raman Spectroscopy. Crystallite sizes (L_a, L_c) and interplanar distance (d₀₀₂) were determined. The presence of SiO₂ in CTP carbon precursor favored the crystallites’ growth in the ‘a′ crystallographic graphite direction, and inhibited their growth on the ‘c′ axis. The crystallites composing of graphene layers, were characterized by an elongated dimension in the ‘a′ axis direction. Above 2000 °C silicon carbide decomposed, followed by the sublimation of silicon from the carbon matrix.