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.     

Molecular Dissection of Escherichia coli CpdB: Roles of the N Domain in Catalysis and Phosphate Inhibition,and of the C Domain in Substrate Specificity and Adenosine Inhibition

CpdB is a 3′-nucleotidase/2′3′-cyclic nucleotide phosphodiesterase, active also with reasonable efficiency on cyclic dinucleotides like c-di-AMP (3′,5′-cyclic diadenosine monophosphate) and c-di-GMP (3′,5′-cyclic diadenosine monophosphate). These are regulators of bacterial physiology, but are also pathogen-associated molecular patterns recognized by STING to induce IFN-β response in infected hosts. The cpdB gene of Gram-negative and its homologs of gram-positive bacteria are virulence factors. Their protein products are extracytoplasmic enzymes (either periplasmic or cell–wall anchored) and can hydrolyze extracellular cyclic dinucleotides, thus reducing the innate immune responses of infected hosts. This makes CpdB(-like) enzymes potential targets for novel therapeutic strategies in infectious diseases, bringing about the necessity to gain insight into the molecular bases of their catalytic behavior. We have dissected the two-domain structure of Escherichia coli CpdB to study the role of its N-terminal and C-terminal domains (CpdB_Ndom and CpdB_Cdom). The specificity, kinetics and inhibitor sensitivity of point mutants of CpdB, and truncated proteins CpdB_Ndom and CpdB_Cdom were investigated. CpdB_Ndom contains the catalytic site, is inhibited by phosphate but not by adenosine, while CpdB_Cdom is inactive but contains a substrate-binding site that determines substrate specificity and adenosine inhibition of CpdB. Among CpdB substrates, 3′-AMP, cyclic dinucleotides and linear dinucleotides are strongly dependent on the CpdB_Cdom binding site for activity, as the isolated CpdB_Ndom showed much-diminished activity on them. In contrast, 2′,3′-cyclic mononucleotides and bis-4-nitrophenylphosphate were actively hydrolyzed by CpdB_Ndom, indicating that they are rather independent of the CpdB_Cdom binding site.     

Survey of MRI Usefulness for the Clinical Assessment of Bone Microstructure

Bone microarchitecture has been shown to provide useful information regarding the evaluation of skeleton quality with an added value to areal bone mineral density, which can be used for the diagnosis of several bone diseases. Bone mineral density estimated from dual-energy X-ray absorptiometry (DXA) has shown to be a limited tool to identify patients’ risk stratification and therapy delivery. Magnetic resonance imaging (MRI) has been proposed as another technique to assess bone quality and fracture risk by evaluating the bone structure and microarchitecture. To date, MRI is the only completely non-invasive and non-ionizing imaging modality that can assess both cortical and trabecular bone in vivo. In this review article, we reported a survey regarding the clinically relevant information MRI could provide for the assessment of the inner trabecular morphology of different bone segments. The last section will be devoted to the upcoming MRI applications (MR spectroscopy and chemical shift encoding MRI, solid state MRI and quantitative susceptibility mapping), which could provide additional biomarkers for the assessment of bone microarchitecture.     

Fermentation of salmon fillets with a variety of lactic acid bacteria

The influence of five strains of lactic acid bacteria (four Lactobacillus and one Carnobacterium) on the quality of fermented salmon fillets was studied. Best starter growth (increase of more than 1 log in 3 days) and acidification of muscle (e.g. pH reduction of approximately 0.7 units in 5 days) were achieved with the two commercial strains L. sake LAD and L. alimentarius BJ33. pH reduction was consistently lower (e.g. reduction of 0.2 units in 5 days) with C. piscicola 85. Protein breakdown as observed on SDS-PAGE gels was similar for all strains. In contrast, the starter strain did influence texture and colour changes. Fast acidifying strains L. sake LAD and L. alimentarius BJ33 brought about a firmer overall texture and a lighter colour, while softening of flesh occurred in samples processed with C. piscicola 85. Sensory evaluations indicated that samples processed with fast acidifying strains were preferred. L. sake LAD and L. alimentarius BJ33 are regarded as suitable starters for fermentation of salmon fillets.     

Electrophoretic polymorphisms and their taxonomic implications in Callitrichini (Primates, Platyrrhini)

Five hundred forty-three blood samples from 15 populations of the four genera of callitrichin primates were studied electrophoretically. Polymorphism and genetic distances were estimated for 20 loci, 13 of which were polymorphic. The lion tamarin (Leontopithecus) studied here exhibited the least variability for these loci, while the monospecific Cebuella showed the most. The genetic distances observed between Callithrix and Cebuella genera support previous evidence indicating a close taxonomic relationship between them. Genetic distance values obtained in this study also support the synonimyzation of the kuhli form with Callithrix jacchus penicillata.     

Heuristiques et effets cognitifs dans l'évaluation du risque.

Studied the influence of various cognitive modalities on risk assessment. Human Ss: 78 normal male and female French adults (university students). Ss were presented with information related to a potential environmental danger and asked to evaluate the degree of risk. The information involved 3 categories of data presented under 3 experimental conditions: representativeness, availability, and anchoring of the relevant information. A control condition offering no information on which to base the risk assessment was also included. Subjective evaluations of the degree of risk served as the dependent variable. (English abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The relationship between fatty acid peroxidation and α-tocopherol consumption in isolated normal and transformed hepatocytes

The response of normal and transformed rat hepatocytes to oxidative stress was investigated. Isolated normal rat hepatocytes and differentiated hepatoma cells (the Fao cell line was derived from the Reuber H 35 rat hepatoma) in suspension were incubated with the ADP/Fe³⁺ chelate for 30 min at 37°C. Membrane lipid oxidation was assessed by measuring (i) free malondialdehyde (MDA) production by a high-performance liquid chromatography (HPLC) procedure, (ii) membrane fatty acid disappearance as judged by capillary gas chromatography, and (iii) α-tocopherol oxidation as determined by HPLC and electrochemical detection. The addition of iron led to increased MDA production in normal as well as in transformed cells, and to simultaneous consumption of polyunsaturated fatty acids (PUFA) and α-tocopherol. In addition, in Fao cells more α-tocopherol was consumed during lipid peroxidation while less PUFA was oxidized. Lipid peroxidation was lower in tumoral hepatocytes than in normal cells. This could be due to a difference in membrane lipid composition because of a lower PUFA content and a higher α-tocopherol level in Fao cells. During oxidation, Fao cells produced 1.5 to 2 times less MDA than normal cells, while in the tumoral cells the amount of oxidized PUFA having 3 or more double bonds was 7 to 8 times lower. Therefore, measuring MDA alone as an index of lipid peroxidation did not allow for proper comparison of the membrane lipid oxidizability of transformed cellsvs. the membrane lipid oxidizability of normal cells.     

Trifluoperazine increases fatty acid turnover in phospholipids in cultured human fibroblasts

A 24-hr pretreatment of cultured human fibroblasts with trifluoperazine induced a marked increase in incorporation of saturated (stearic, palmitic) and unsaturated (oleic, arachidonic) fatty acids into phospholipids (1.5- to 2-fold for 5.10⁻⁵ M trifluoperazine). Concomitantly, incorporation into cholesteryl esters was strongly inhibited (20% of control for 5.10⁻⁵ M trifluoperazine). The drug did not change the phospholipid composition of treated cells. The effect of trifluoperazine on oleic acid incorporation into phospholipids was time-dependent and reached a maximum after a six-hr preincubation with the drug. Trifluoperazine also induced an increase in the rate of chase of oleic acid from the different phospholipid classes. In vitro preincubation of cell-free extracts with trifluoperazine resulted in activation of phospholipid acyltransferases, whereas cholesterol acyltransferase activity was decreased. The rapid effect of trifluoperazine together with its effect on a cell-free system suggests a direct action of this amphiphilic drug on the acyltransferase activities, probably by modification of the structural organization of cellular membranes.     

Effect of extrusion-cooking on the hypoglycaemic properties of citrus fibre: An in-vitro study

Orange and lemon peels were extruded under controlled conditions of varying severity, and their physico-chemical characteristics and effect on the enzymatic hydrolysis of starch and glucose diffusion were studied. Extrusion-cooking treatment increased the soluble fraction of dietary fibre as well as solubilised pectic substances and arabino-galactomannan chains. The apparent viscosities of aqueous extracts of extruded fibre were increased slightly for orange and more markedly for lemon fibre. With both fibre sources, viscosities values were higher in Tris-maleate buffer (0.1 M) than in NaCl (154 mM). However, these modifications had no effect on starch hydrolysis and glucose diffusion in vitro.     

Influence of Solvent Additive 1,8‐Octanedithiol on P3HT:PCBM Solar Cells

Processing solvent additives in polymer:fullerene bulk heterojunction systems are known as a promising method to enhance photovoltaic performance. It is generally agreed that solvent additives enable polymers to have a high degree of molecular order which increases the device performance. However, the understanding of the efficiency enhancement is not complete. There is a lack of insight regarding the quantitative determination of the molecular miscibility between polymer and fullerene as well as the inner morphology changes induced by the additives. In this work, understanding of the influence of the solvent additive 1,8‐octanedithiol (ODT) is provided on the classic system poly(3‐hexylthiophene‐2,5‐diyl):[6,6]‐phenyl‐C61 butyric acid methyl ester (P3HT:PCBM) films. The impact on polymer crystallinity, surface structure, inner morphology, and quantitative molecular miscibility of P3HT and PCBM is studied as a function of ODT volume concentration. The crystallinity is probed with absorption spectroscopy and grazing incidence wide‐angle X‐ray scattering. The morphology and miscibility are characterized via atomic force microscopy and time‐of‐flight grazing incidence small angle neutron scattering. Besides an increased crystallinity and prominent phase separation, ODT increases the solubility of PCBM in P3HT and reduces the size of amorphous P3HT domains. Moreover, solvent processing with a high ODT concentration alters the vertical material composition of the active layer.