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 Regulation of Canalicular ABC Transporters

The ATP-binding cassette (ABC) transporters expressed at the canalicular membrane of hepatocytes mediate the secretion of several compounds into the bile canaliculi and therefore play a key role in bile secretion. Among these transporters, ABCB11 secretes bile acids, ABCB4 translocates phosphatidylcholine and ABCG5/G8 is responsible for cholesterol secretion, while ABCB1 and ABCC2 transport a variety of drugs and other compounds. The dysfunction of these transporters leads to severe, rare, evolutionary biliary diseases. The development of new therapies for patients with these diseases requires a deep understanding of the biology of these transporters. In this review, we report the current knowledge regarding the regulation of canalicular ABC transporters’ folding, trafficking, membrane stability and function, and we highlight the role of molecular partners in these regulating mechanisms.     

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.     

Isolation and characterization of anti-FcgammaRIII (CD16) llama single-domain antibodies that activate natural killer cells

FcgammaRIII (CD16) plays an important role in the anti-tumor effects of therapeutic antibodies. Bi-specific antibodies (bsAbs) targeting FcgammaRIII represent a powerful alternative to the recruitment of the receptor via the Fc fragment, but are not efficiently produced. Single-domain antibodies (sdAbs) endowed with many valuable structural features might help to bypass this problem. In the present work, we have isolated anti-FcgammaRIII sdAbs (C21 and C28) from a phage library generated from a llama immunized with FcgammaRIIIB extra-cellular domains. These sdAbs bind FcgammaRIIIA+ NK cells and FcgammaRIIIB+ polymorphonuclear cells, but not FcgammaRI+ or FcgammaRII+ cells, as detected by indirect immunofluorescence. Competition experiments showed that C21 and C28 sdAbs bind different FcgammaRIII epitopes, with C21 recognizing a linear and C28 a conformational epitope of the receptor. Surface plasmon resonance experiments showed that C21 and C28 sdAbs bind FcgammaRIII with a K(D) in the 10 and 80 nM range, respectively. Importantly, the engagement by both molecules of FcgammaRIIIA expressed by transfected Jurkat T cells or by NK cells derived from peripheral blood induced a strong IL-2 and IFN-gamma production, respectively. These anti-FcgammaRIII sdAbs represent versatile tools for generating bsAbs under various formats, able to recruit FcgammaRIII killer cells to target and destroy tumor cells.     

Marine diatom Navicula jeffreyi from biochemical composition and physico-chemical surface properties to understanding the first step of benthic biofilm formation

To understand the first step of marine benthic microbial mat formation and biofouling phenomena, caused by diatoms in the marine environment, the surface properties of the epipelic diatom Navicula jeffreyi were studied and the composition of its bound Extracellular Polymeric Substances (EPS) was determined. These parameters are determining factors for the initial adhesion step of diatoms to other constituents that start marine fouling. Surface energy of a diatom cell layer was determined using the sessile drop technique and highlights that diatoms show a moderate hydrophobic character (contact angle with water >68°), no Lewis acid character (γ⁺?<1?mJ/m²), and a low Lewis basic character (γ^??=?16.1?mJ/m²). An extraction procedure using a cationic resin subtracted only the bound EPS. Biochemical assays showed that there were 2.5 times more proteins than sugars. The propensity of Navicula jeffreyi diatom to adhere to five different solid surfaces, showing a gradient in their hydrophobic and hydrophilic character, was measured. The attachment densities were high on hydrophobic surfaces such as polytetrafluoroethylene and very low on substrata with surface free energy over 40–50?mJ/m². Using a thermodynamic approach, the free energy of adhesion of the diatom to the five substrata was determined, and led to a very strong correlation with attachment densities for polytetrafluoroethylene, polyamide, polyethylene, and stainless steel.     

Modulation of cyclic nucleotide phosphodiesterase by dietary fats in rat heart

Feeding oils of different fatty acid composition modifies the fatty acid composition of cardiac membrane phospholipids, thereby inducing changes in cardiac contractility and altering response of adenylate cyclase to catecholamines. In the present study, the effect of such dietary manipulations on cyclic nucleotide phosphodiesterase, which is involved in the control of cyclic nucleotide intracellular levels and in the control of cardiac contractility, was investigated. Rats were fed either a saturated fatty acid-enriched diet (8 weight percent [%] coconut oil +2% sunflower oil), an n−6 fatty acid-enriched diet (10% sunflower oil) or an n−3 fatty acid-enriched diet (8% fish oil +2% sunflower oil). The fatty acid composition of cardiac phospholipids, as well as the nonesterified fatty acid content of heart were markedly altered by the diets. The 18∶2n−6 and 20∶4n−6 content of cardiac phospholipids was markedly (−49%) depressed by fish oil as compared with sunflower oil feeding, but the nonesterified fatty acid level of heart membrane was lowest in coconut oil-fed rats. In addition, fish oil feeding more drastically depressed the n−6/n−3 fatty acid ratio in the nonesterified fatty acid pool than in cardiac phospholipids. Cyclic AMP phosphodiesterase activity was the lowest in both the particulate and soluble fractions of heart from rats fed sunflower oil, whereas cyclic GMP phosphodiesterase activity was not altered by the diets. Cyclic AMP phosphodiesterase activity was decreased by 18 and 12% in heart membranes of the sunflower oil group as compared to that of the coconut oil and fish oil groups, respectively. In heart cytosol, the activity decreased by 30% when compared with the activity of the coconut oil group. Additionalin vitro experiments showed that polyunsaturated fatty acids were more potent inhibitors of cyclic AMP phosphodiesterase than saturated fatty acids. These results suggest that polyunsaturated fatty acid-enriched diets might decrease heart cyclic AMP phosphodiesterase activity by increasing non-esterified polyunsaturated fatty acids, especially those of the n−6 series, but more complex and indirect mechanisms are very likely to be involved.     

Male Aggregation Pheromone of Date Palm Fruit Stalk Borer Oryctes elegans

Laboratory and field investigations were carried out to characterize the chemical communication system of the date palm fruit stalk borer, Oryctes elegans, and to develop pheromone-based trapping in Eastern Iran. Adults of both sexes feeding on date palm pieces attracted conspecifics, whereas date palm alone was minimally attractive. Males were twice as attractive as females. More beetles were captured at the palm crown than at ground level. Odors from adults feeding on sugarcane were sampled and analyzed by gas chromatography and mass spectrometry. Whereas females did not emit sex specific volatiles, males emitted a blend of 4-methyloctanoic acid (1: major component) and ethyl 4-methyloctanoate (2), occasionally mixed with minor components: 4-methyloctanyl acetate (3), methyl 4-methyloctanoate (4), 4-methyloctanol (5), and nonanyl acetate (6). Electroantennography and field trapping experiments demonstrated that compound 1 is an essential component of the male aggregation pheromone of O. elegans. It was barely attractive by itself but synergistic with fresh date palm odor. It attracted many more beetles than any of compounds 2-6. The addition of one or several of compounds 2-6 to 1 did not improve trap captures. During the course of 2 years, we captured 4000 beetles, with a weekly average of 6.3 beetles/trap, and were able to monitor the seasonal flight of O. elegans. Our results provide the basis for developing mass trapping for control of this pest.     

A pilot scale study of reverse osmosis for the purification of condensate arising from distillery stillage concentration plant

Reverse osmosis (RO) is an interesting process to eliminate small organic solutes (carboxylic acids and alcohols) from distillery condensates before recycling them into the fermentation step. This work investigates the influence of transmembrane pressure, pH and volume reduction factor (VRF) on the efficiency of reverse osmosis treatment of condensate from distillery stillage concentration at pilot scale using three pre-selected membranes (CPA2 and ESPA2 from Hydranautics, BW30 from DOW). Performances were assessed according to permeate flux, solutes rejection and abatement of fermentation inhibition. Transmembrane pressure increase leads to an increase of these three parameters with a plateau for rejections and abatement at 20 bar; however, in order to comply with membranes manufacturer's recommendations and to limit or delay polarization and fouling, it was decided to keep the permeate flux below a value of 30 L h⁻¹ m⁻². This corresponded to a maximum pressure of 10 bar for CPA2 and ESPA2 membranes and 25 bar for BW30 membrane. pH increase leads to a diminution of permeate flux and an increase of carboxylic acids rejection whatever the membrane; nevertheless, no abatement of fermentation inhibition is observed. Increasing VRF provokes a decrease of the permeate flux. Although local rejections are stable, the mean rejection assessed with the raw condensate (feed) and the mean permeate decreases. However, the fermentation inhibition remains under 10% up to a VRF of 8. BW30 membrane exhibits the highest rejections and inhibition abatement. On the basis of the pilot scale results with the BW30 membrane, a preliminary estimation of the membrane area is proposed for an industrial plant with 100 m³ h⁻¹ of condensate flow rate and the optimized parameters (pressure 25 bar, no pH modification, VRF 4 and 8).