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.      

Effect of ethanol on micellization and on decarboxylation of 6-nitrobenzisoxazole-3-carboxylate in aqueous cationic micelles

The effects of ethanol on the critical micellar concentration (cmc) and the rates of decarboxylation of 6-nitrobenzisoxazole-3-carboxylate (6-NBIC) have been investigated in aqueous cationic surfactants of the cetyltrialkylammonium family with bromide [CT(R)ABr], chloride [CT(R)ACl], and nitrate [CT(R)ANO3] counterions, and methyl (CTAX), n-propyl (CTPAX), and n-butyl (CTBAX) as the head group alkyl moieties. Effects upon cmc and reactivity are similar, featuring a break at the ethanol mole fraction, x(EtOH), of ca. 0.055; these effects have been related to changes in solvent structure, with formation of a clathrate at x(EtOH) = 0.055. Rate data in CTBABr were further investigated and fitting of raw kinetic data to the pseudophase model is possible up to x(EtOH) = 0.1, showing an unexpected decrease of rate constant values in the micellar pseudophase, kM', as ethanol content increases: a significant variation of micellar ionization degree could account for this kinetic effect.     

Multi-technique microscopy investigation on bacterial biofilm matrices: a study on Klebsiella pneumoniae clinical strains

Analytical and Bioanalytical Chemistry - Biofilms are communities of bacteria living embedded in a highly hydrated matrix composed of polysaccharides, proteins, and extracellular DNA. This life...     

Plasma deposition of thin films from a fluorine-containing cyclosiloxane

Thin films have been deposited from radio-frequency glow discharges fed with vapors of a silicon- and fluorine-containing organic compound, namely 2,4,6-tris[(3,3,3-trifluoropropyl) (methyl)] cyclotrisiloxane, in mixture with argon. 2,4,6-tris[(3,3,3-trifluoropropyl)(methyl)]cyclotrisiloxane A triode reactor has been utilized to deposit films by independently changing substrate temperature and bias-induced ion-bombardment. Laser interferometry, electron spectroscopy for chemical analysis and Fourier-transform infrared spectroscopy have been used to monitor film growth rate and composition. Results unambiguously show an activating effect of the ion-bombardment, which confirm the validity of the ion-assisted deposition model utilized for the plasma deposition of both teflon- and silicone-like films. In our experiments, low substrate temperature and bias conditions results in films with a “monomer-like” stoichiometry, while drastic conditions give origin to materials with a completely different composition and a markedly increased hardness. © 1994 John Wiley & Sons, Inc.     

Evaluation of rheological properties and swelling behaviour of sonicated scleroglucan samples

Scleroglucan is a natural polysaccharide that has been proposed for various applications. However there is no investigation on its property variations when the molecular weight of this polymer is reduced. Scleroglucan was sonicated at two different polymer concentrations for different periods of time and the effect of sonication was investigated with respect to molecular weight variations and rheological properties. Molar mass, estimated by viscometric measurements, was drastically reduced already after a sonication for a few min. Sonicated samples were used for the preparation of gels in the presence of borate ions. The effect of borax on the new samples was investigated by recording the mechanical spectra and the flow curves. A comparison with the system prepared with the dialysed polymer was also carried out. The anisotropic elongation, observed with tablets of scleroglucan and borax, was remarkably reduced when the sonicated samples were used for the preparation of the gels.     

An unprecedented switching of the second-order nonlinear optical response in aggregate bis(salicylaldiminato)zinc(II) Schiff-base complexes

A luminescent bis(salicylaldiminato)zinc(II) Schiff-base complex, 1, is characterized by a concentration dependent second-order nonlinear optical response, related to the degree of aggregation of the complex in a dichloromethane solution. The formation of the monomeric adduct, by addition of a Lewis base, such as pyridine, to concentrated solutions of 1, leads to a switch-on of the quadratic hyperpolarizability. This represents an unprecedented mode of NLO switching in molecular materials.