Design,Synthesis and Evaluation of a Series of 1,5-Diaryl-1,2,3-triazole-4-carbohydrazones as Inhibitors of the YAP-TAZ/TEAD Complex

Starting from our previously reported hit, a series of 1,5-diaryl-1,2,3-triazole-4-carbohydrazones were synthesized and evaluated as inhibitors of the YAP/TAZ-TEAD complex. Their binding to hTEAD2 was confirmed by nanodifferential scanning fluorimetry, and some of the compounds were also found to moderately disrupt the YAP-TEAD interaction, as assessed by a fluorescence polarization assay. A TEAD luciferase gene reporter assay performed in HEK293T cells and RTqPCR measurements in MDA-MB231 cells showed that these compounds inhibit YAP/TAZ-TEAD activity to cells in the micromolar range. In spite of the cytotoxic effects displayed by some of the compounds of this series, they are still good starting points and can be suitably modified into an effective and viable YAP-TEAD disruptor in the future.     

Propagation in road tunnels: a statistical analysis of the field distribution and impact of the traffic

This paper presents a narrowband statistical analysis of the field distribution inside a road tunnel. Both fixed and mobile antennas are situated inside the tunnel and the transmitting frequency is 2.1 GHz. A theoretical propagation model based on the image theory is first used and the results are then compared to those obtained from experiments carried out either in an empty tunnel or in presence of traffic.     

Peptides in rainbow trout (Oncorhynchus mykiss) muscle subjected to ice storage and cooking

Although proteolysis during post mortem storage is an important factor affecting fish texture, little is known about degradation end-products. This study was performed to investigate the occurrence of low molecular weight peptides (<5 kDa) in post mortem rainbow trout muscle, during ice storage, and to evaluate their stability during cooking. It combined quantitative (amino acid analysis) and qualitative approaches (mass spectrometry). The results showed that muscle of trout was poor in peptides. These were mainly anserine and glutathione. Their concentration was almost unaffected by the seven days of ice storage and vacuum cooking for 5 min at 70 °C. MS analysis revealed a limited but highly reproducible appearance of small peptides in trout muscle during the ice storage and after cooking. The compounds detected by MS analysis remain to be characterised.     

The fair use doctrine: History, application, and implications for (new media) writing teachers

Writing teachers have always had to contend with plagiarism. However, the technology of the Internet and the thorny issues of copyright law complicate how we teach legal and ethical use of others’ materials in the networked classroom. Our pedagogy and curriculum choices and our students’ writing practices are shaped by a legal infrastructure that includes the fair use doctrine. Our understanding and knowledge of the fair use doctrine should become second nature to us. Critical awareness of fair use, the four-factor test, and how to conduct appropriate analyses when using others’ materials must become part of the everyday digital writing/new media classroom curriculum. To this end, the author summarizes the salient points of law and practice of fair use and demonstrates, in small ways, how the fair use doctrine can inform the teaching of writing in digital contexts. As teachers, researchers, and experts of writing, the discourse of fair use must be considered in addition to the discourse of plagiarism.     

Surface Functionalization with Phosphazenes: Part 6. Modification of Polyethylene-Co-Polyvinylalcohol Copolymer Surface Plates with Fluorinated Alcohols and Azobenzene Derivatives Using Chlorinated Phosphazenes as Coupling Agents

In this paper we describe a two-step surface modification process of poly(ethylene-co-vinyl alcohol) by exploiting hexachlorocyclophosphazene and poly(dichlorophosphazene) as coupling agents. Part of the P–Cl groups of the chlorophosphazenes is first reacted with the surface hydroxylic groups of the substrate to form covalent P–O–C bonds, the remaining being utilized for successive substitution reactions with different nucleophiles (i.e. 2,2,2-trifluoroethanol, heptadecafluorononanol and 4-hydroxyazobenzene). Modified surface properties, such as hydrophobicity improvement with fluorinated alcohols and photochromic features with the azobenzene derivative, were verified by contact angle measurements and UV–Vis spectroscopy, respectively, while changes in surface composition were demonstrated through XPS spectroscopy.     

Fuzzy Rough Sets: The Forgotten Step

Traditional rough set theory uses equivalence relations to compute lower and upper approximations of sets. The corresponding equivalence classes either coincide or are disjoint. This behaviour is lost when moving on to a fuzzy T-equivalence relation. However, none of the existing studies on fuzzy rough set theory tries to exploit the fact that an element can belong to some degree to several "soft similarity classes" at the same time. In this paper we show that taking this truly fuzzy characteristic into account may lead to new and interesting definitions of lower and upper approximations. We explore two of them in detail and we investigate under which conditions they differ from the commonly used definitions. Finally we show the possible practical relevance of the newly introduced approximations for query refinement     

The pure parsimony haplotyping problem: overview and computational advances

Haplotyping estimation from aligned single-nucleotide polymorphism fragments has attracted more and more attention in recent years due to its importance in analysis of many fine-scale genetic data. Its application fields range from mapping of complex disease genes to inferring population histories, passing through designing drugs, functional genomics, and pharmacogenetics. The literature proposes a number of estimation criteria to select a set of haplotypes among possible alternatives. Usually, such criteria can be expressed under the form of objective functions, and the sets of haplotypes that optimize them are referred to as optimal. One of the most important estimation criteria is the pure parsimony, which states that the optimal set of haplotypes for a given set of genotypes is that having minimal cardinality. Finding the minimal number of haplotypes necessary to explain a given set of genotypes involves solving an optimization problem, called the pure parsimony haplotyping (PPH) estimation problem, which is notoriously     -hard. This article provides an overview of PPH, and discusses the different approaches to solution that occur in the literature.     

Using textile topography to analyze X‐ray CT data of composite microstructure

The 3‐dimensional yarn architecture in a 2‐dimensional woven fabric reinforced composite is nonuniform. Many structural features appear that are not obvious from consideration only of the yarn architecture in the single layer textile fabric. A complete set of 3‐dimensional image data was acquired for a representative volume of the composite using X‐ray micro‐computed tomography. Extensive image analysis was, however, necessary to reveal the yarn architecture due to relatively low signal‐to‐noise ratio and contrast levels relative to optical microscopy of polished cross sections.     

Therapeutic Intervention with Anti-Complement Component 5 Antibody Does Not Reduce NASH but Does Attenuate Atherosclerosis and MIF Concentrations in Ldlr-/-.Leiden Mice

Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains unclear. Methods: After 20 weeks of high-fat diet (HFD) feeding, obese Ldlr-/-.Leiden mice were treated twice a week with an established anti-C5 antibody (BB5.1) or vehicle control. A separate group of mice was kept on a chow diet as a healthy reference. After 12 weeks of treatment, NASH was analyzed histopathologically, and genome-wide hepatic gene expression was analyzed by next-generation sequencing and pathway analysis. Atherosclerotic lesion area and severity were quantified histopathologically in the aortic roots. Results: Anti-C5 treatment considerably reduced complement system activity in plasma and MAC deposition in the liver but did not affect NASH. Anti-C5 did, however, reduce the development of atherosclerosis, limiting the total lesion size and severity independently of an effect on plasma cholesterol but with reductions in oxidized LDL (oxLDL) and macrophage migration inhibitory factor (MIF). Conclusion: We show, for the first time, that treatment with an anti-C5 antibody in advanced stages of NASH is not sufficient to reduce the disease, while therapeutic intervention against established atherosclerosis is beneficial to limit further progression.     

Proteome changes during pork meat ageing following use of two different pre-slaughter handling procedures

The influence of postmortem storage time and pre-slaughter conditions (transport the day before slaughter or immediately before slaughter) on proteome changes of pork meat was investigated over a 72 h ageing period. Intensities of 37 spots varied significantly (p<0.05) with ageing time. Changes indicated proteolysis of troponin T, actin, -crystallin, myokinase, creatine kinase and mitochondrial ATPase, but also of proteins constitutive of the Z-lines, namely cypher proteins and myozenin. Other modifications were the intensity increase of a full-length protein of the sarcoplasmic reticulum, which may be linked to its increased extractibility after membrane disruption, and a gradual shift in pHi towards alkaline values of some forms of myosin light chains (MLC) 2 and 3. The pre-slaughter conditions affected significantly (p<0.05) 8 spots. Mitochondrial ATPase was over-expressed in the group transported immediately before slaughter, also characterised by a faster pH fall, and the shift in pHi of MLC 2 was more pronounced. The pre-slaughter conditions had no significant effect on the above proteolytic events.