Cooperative stabilisation of 14-3-3σ protein–protein interactions via covalent protein modification

14-3-3 proteins are an important family of hub proteins that play important roles in many cellular processes via a large network of interactions with partner proteins. Many of these protein–protein interactions (PPI) are implicated in human diseases such as cancer and neurodegeneration. The stabilisation of selected 14-3-3 PPIs using drug-like ‘molecular glues’ is a novel therapeutic strategy with high potential. However, the examples reported to date have a number of drawbacks in terms of selectivity and potency. Here, we report that WR-1065, the active species of the approved drug amifostine, covalently modifies 14-3-3σ at an isoform-unique cysteine residue, Cys38. This modification leads to isoform-specific stabilisation of two 14-3-3σ PPIs in a manner that is cooperative with a well characterised molecular glue, fusicoccin A. Our findings reveal a novel stabilisation mechanism for 14-3-3σ, an isoform with particular involvement in cancer pathways. This mechanism can be exploited to harness the enhanced potency conveyed by covalent drug molecules and dual ligand cooperativity. This is demonstrated in two cancer cell lines whereby the cooperative behaviour of fusicoccin A and WR-1065 leads to enhanced efficacy for inducing cell death and attenuating cell growth.

The aminothiol WR-1065 covalently modifies 14-3-3σ to stabilse its interactions with p53 and ERα. It enhances the effect of fusicoccin A via a cooperative mechanism that leads to 14-3-3 partner-protein specific activty against cancer cells.      

On-column polymer-imbedded graphite inlet electrode for capillary electrophoresis coupled on-line with flow injection analysis in a poly(dimethylsiloxane) interface

A method for coupling an electrophoretic driven separation to a liquid flow, using conventional fused-silica capillaries and a soft polymeric interface is presented. A novel design of the electrode providing high voltage to the electrophoretic separation was also developed. The electrode consisted of a conductive polyimide/graphite imbedded coating immobilized onto the capillary electrophoresis (CE) column inlet. This integrated electrode gave the same separation performance as a commonly used platinum electrode. The on-column electrode also showed good electrochemical stability in chronoamperometric experiments. In addition, with this electrode design, the electrode position relative to the inlet end of the CE column will always be constant and well defined. The on-line flow injection analysis (FIA)-CE system was used with electrospray ionization (ESI)-time of flight (TOF)-mass spectrometry detection. The preparation of the PDMS (poly(dimethylsiloxane)) interface for FIA-CE is described in detail and used for initial tests of the on-column polymer-imbedded graphite inlet electrode. In this interface, a pressure-driven liquid flow, a make up CE electrolyte and a CE column inlet meet in a two-level cross (95 microm ID) in the PDMS structure, enabling independent flow characterization.     

Dynamic properties of soy globulin adsorbed films at the air-water interface

In this paper we present surface dilatational properties of soy globulins (beta-conglycinin, glycinin, and reduced glycinin with 10 mM of dithiothreitol (DTT)) adsorbed onto the air-water interface, as a function of adsorption time. The experiments were performed at constant temperature (20 degrees C), pH (8.0), and ionic strength (0.05 M). The surface rheological parameters were measured as a function of protein concentration (ranging from 1 to 1x10(-3)% wt/wt). We found that the surface dilatational modulus, E, increases, and the phase angle, phi, decreases with time, theta, which may be associated with protein adsorption. These phenomena have been related to protein adsorption, unfolding, and/or protein-protein interactions (at long-term adsorption) as a function of protein concentration in solution. From a rheological point of view, the surface viscoelastic characteristics of soy globulin films adsorbed at the air-water interface are practically elastic. The main conclusion is that the dilatational properties of the adsorbed films depend on the molecular structure of the protein.     

Direct synthesis of isothiocyanates from isonitriles by molybdenum-catalyzed sulfur transfer with elemental sulfur

The direct molybdenum-catalyzed sulfuration of a variety of isonitriles with elemental sulfur or propene sulfide as sulfur donors affords the corresponding isothiocyanates in good yields and under mild reaction conditions. A catalytic cycle is suggested, in which the molybdenum oxo disulfur complex operates as the active sulfur-transferring species. A novel adduct between the isonitrile and the molybdenum complex has been characterized by X-ray analysis and its association constant determined by UV-vis spectroscopy, but this adduct appears not to be involved in the sulfur-transfer process.     

A Titanium(IV)‐Based Metal–Organic Framework Featuring Defect‐Rich Ti‐O Sheets as an Oxidative Desulfurization Catalyst

While titanium‐based metal–organic frameworks (MOFs) have been widely studied for their (photo)catalytic potential, only a few Ti^IV MOFs have been reported owing to the high reactivity of the employed titanium precursors. The synthesis of COK‐47 is now presented, the first Ti carboxylate MOF based on sheets of Ti^IVO₆ octahedra, which can be synthesized with a range of different linkers. COK‐47 can be synthesized as an inherently defective nanoparticulate material, rendering it a highly efficient catalyst for the oxidation of thiophenes. Its structure was determined by continuous rotation electron diffraction and studied in depth by X‐ray total scattering, EXAFS, and solid‐state NMR. Furthermore, its photoactivity was investigated by electron paramagnetic resonance and demonstrated by catalytic photodegradation of rhodamine 6G.     

A telescoped Knochel-Hauser/Kumada-Corriu coupling strategy to functionalized aromatic heterocycles

The direct application of Knochel-Hauser derivative arylmagnesium halides in Kumada-Corriu couplings is described. By utilizing the in situ-generated Grignard reagents, the transmetalation with stoichiometric zinc salts to known Negishi coupling conditions is avoided, thereby streamlining the transformation. Several aromatic hetereocycles participate in the deprotonation and couple with a variety of phenyl iodides and bromides in isolated yields up to 81%. The parent system is demonstrated on 6?g scale with 79% yield, and monitored via ReactIR to show the stability of the Grignard and progression of the deprotonation/CC coupling reaction.     

2 alpha-(3-hydroxypropyl)- and 2 alpha-(3-hydroxypropoxy)-1 alpha,25-dihydroxyvitamin D3 accessible to vitamin D receptor mutant related to hereditary vitamin D-resistant rickets

Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder caused by mutations in the vitamin D receptor, which lead to resistance to 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)]. We found that the A ring-modified analogues, 2alpha-(3-hydroxypropyl)- and 2alpha-(3-hydroxypropoxy)-1alpha,25(OH)(2)D(3), (O1C3 and O2C3) can bind better than the natural hormone to the mutant VDR (R274A), which similar to the HVDRR mutant, R274L, had lost the hydrogen bond to the 1alpha-hydroxyl group of 1alpha,25(OH)(2)D(3).     

Application of microemulsions for the removal of synthetic resins from paintings on canvas

Abstract

Traditional cleaning methods with organic solvents often are not suitable for removal of aged resin so researchers have to find new formulations. In this work, a case study is reported in which new microemulsions were applied on the surface of a painting covered by some aged resin layers used during a previous restoration. Based on the quality of the intervention and the analysis of a sample of the varnish carried out with both MALDI-TOF and ATR-IR spectrometers, it was conjectured that this undesired material could be an acrylic polymer. So it was chosen to use xylene, ethyl acetate and propylene carbonate (XYL and EAPC) microemulsions (O/W oil in water). The first is able to solubilise only acrylic polymers, the second may solve both acrylic and vinyl resins. The first has had the greatest effect allowing complete varnish removal and original artwork restoration.     

Self‐Healing Polyester Urethane Supramolecular Elastomers Reinforced with Cellulose Nanocrystals for Biomedical Applications

Stretchable self‐healing urethane‐based biomaterials have always been crucial for biomedical applications; however, the strength is the main constraint of utilization of these healable materials. Here, a series of novel, healable, elastomeric, supramolecular polyester urethane nanocomposites of poly(1,8‐octanediol citrate) and hexamethylene diisocyanate reinforced with cellulose nanocrystals (CNCs) are introduced. Nanocomposites with various amounts of CNCs from 10 to 50 wt% are prepared using solvent casting technique followed by the evaluation of their microstructural features, mechanical properties, healability, and biocompatibility. The synthesized nanocomposites indicate significantly higher tensile modulus (approximately 36–500‐fold) in comparison to the supramolecular polymer alone. Upon exposure to heat, the materials can reheal, but nevertheless when the amount of CNC is greater than 10 wt%, the self‐healing ability of nanocomposites is deteriorated. These materials are capable of rebonding ruptured parts and fully restoring their mechanical properties. In vitro cytotoxicity test of the nanocomposites using human dermal fibroblasts confirms their good cytocompatibility. The optimized structure, self‐healing attributes, and noncytotoxicity make these nanocomposites highly promising for tissue engineering and other biomedical applications.     

CoII Cryptates Convert CO2 into CO and CH4 under Visible Light

Three Co^II octaazacryptates, with different substituents on the aromatic rings (Br, NO₂, CCH), were synthesised and characterised. These and the already published non-substituted cryptate catalysed CO₂ photoreduction to CO and CH₄ under blue visible light at room temperature. Although CO was observed after short irradiation times and a large range of catalyst concentrations, CH₄ was only observed after longer irradiation periods, such as 30 h, but with a small catalyst concentration (25 nm ). Experiments with ¹³C labelled CO₂ showed that CO is formed and reacts further when the reaction time is long. The CCH catalyst is deactivated faster than the others and the more efficient catalyst for CH₄ production is the one with Br. This reactivity trend was explained by an energy decomposition analysis based on DFT calculations.