Inhibition of Antiapoptotic BCL-XL, BCL-2, and MCL-1 Proteins by Small Molecule Mimetics

Informatics and computational design methods were used to create new molecules that could potentially bind antiapoptotic proteins, thus promoting death of cancer cells. Apoptosis is a cellular process that leads to the death of damaged cells. Its malfunction can cause cancer and poor response to conventional chemotherapy. After being activated by cellular stress signals, proapoptotic proteins bind antiapoptotic proteins, thus allowing apoptosis to go forward. An excess of antiapoptotic proteins can prevent apoptosis. Designed molecules that mimic the roles of proapoptotic proteins can promote the death of cancer cells. The goal of our study was to create new putative mimetics that could simultaneously bind several antiapoptotic proteins. Five new small molecules were designed that formed stable complexes with BCL-2, BCL-XL, and MCL-1 antiapoptotic proteins. These results are novel because, to our knowledge, there are not many, if any, small molecules known to bind all three proteins. Drug-likeness studies performed on the designed molecules, as well as previous experimental and preclinical studies on similar agents, strongly suggest that the designed molecules may indeed be promising drug candidates. All five molecules showed “drug-like” properties and had overall drug-likeness scores between 81% and 96%. A single drug based on these mimetics should cost less and cause fewer side effects than a combination of drugs each aimed at a single protein. Computer-based molecular design promises to accelerate drug research by predicting potential effectiveness of designed molecules prior to laborious experiments and costly preclinical trials

The Wonder of Colors and the Principle of Ariadne

The Principle of Ariadne, formulated in 1988 ago by Walter Carnielli and Carlos Di Prisco and later published in 1993, is an infinitary principle that is independent of the Axiom of Choice in ZF, although it can be consistently added to the remaining ZF axioms. The present paper surveys, and motivates, the foundational importance of the Principle of Ariadne and proposes the Ariadne Game, showing that the Principle of Ariadne, corresponds precisely to a winning strategy for the Ariadne Game. Some relations to other alternative. set-theoretical principles are also briefly discussed

Group I metabotropic glutamate receptors activate burst firing in rat midbrain dopaminergic neurons

We have investigated the changes in the spontaneous firing pattern induced by DHPG ((S)-3,5-dihydroxyphenylglycine) and NMDA (N-methyl-d-aspartic acid) on rat dopaminergic neurons in substantia nigra pars compacta (SNc) using sharp microelectrode recordings in in vitro conditions. Twenty-five out of 33 cells modified the regular single-pacemaker activity in burst firing when exposed to the Group I metabotropic glutamate receptor (mGluR) agonist DHPG (30 muM) and d-tubocurarine (500 muM) (d-TC), whereas they all fired in bursts during NMDA (20 muM) plus d-TC application. The blockade of SK-channels by d-TC and apamin was essential for the production of both types of bursts. Although the two drugs induced a similar number of action potentials per burst, the DHPG-induced bursts had a lower frequency, a longer duration and a longer plateau period without spikes. In addition, the DHPG-induced bursting had a longer wash-out, could be reduced or blocked by the mGluR I selective, non-competitive antagonist CPCCOEt (7-cyclopropan[b]chromen-1a-carboxylic acid ethyl ester) (100 muM) while it was not affected by the mGluR 5 selective antagonist MPEP (2-methyl-6-(phenylethynyl)-pyridine (10 muM). These results suggest that both the activation of glutamate metabotropic type I and NMDA ionotropic receptors induce burst firing in the dopaminergic cells of the ventral midbrain when the activity of the SK-channels is reduced. (C) 2002 Elsevier Science Ltd. All rights reserved

Experimental tests on shallow foundations of onshore wind turbine towers

The current effort towards the progressive switch from carbon-based to renewable energy production is leading to a relevant spreading of both on- and off-shore wind turbine towers. Regarding reinforced concrete shallow foundations of onshore wind turbine steel towers, possible reductions of reinforcement may increase their sustainability, speed of erection, and competitiveness. The article presents the results of an experimental program carried out at Politecnico di Milano concerning both cyclic and monotonic loading, simulating extreme wind conditions on 1:15 scaled models of wind turbine steel towers connected by stud bolt adapters to reinforced concrete shallow foundations embedded in a sandy soil. Three couples of foundation specimens were tested with different reinforcement layouts: (a) similar to current praxis, (b) without shear reinforcement, and (c) without shear reinforcement and with 50% of ordinary steel rebars replaced by steel fibers. Additional vertical loads were added to the small-scale models in order to ensure similarity in terms of stresses. The test results allowed to (i) characterize the mechanical behavior of the foundation element considering soil-structure interaction under both service and ultimate load conditions, (ii) assess the foundation failure mode, (iii) highlight the role of each typology of reinforcing bars forming the cage, and (iv) provide hints for the optimization of these latter

Expansion-Free Cavity Evolution: Some exact Analytical Models

We consider spherically symmetric distributions of anisotropic fluids with a central vacuum cavity, evolving under the condition of vanishing expansion scalar. Some analytical solutions are found satisfying Darmois junction conditions on both delimiting boundary surfaces, while some others require the presence of thin shells on either (or both) boundary surfaces. The solutions here obtained model the evolution of the vacuum cavity and the surrounding fluid distribution, emerging after a central explosion. This study complements a previously published work where modeling of the evolution of such kind of systems was achieved through a different kinematical condition.Comment: 9 pages, Revtex. Typos corrected. Published in Int. J. Mod. Phys.

Friction-Stir Welding of AA 2198 Butt Joints: Mechanical Characterization of the Process and of the Welds Through DOE Analysis

In this study, rolled plates of AA 2198 T3 aluminium alloy are friction-stir welded in butt configuration varying two fundamental process parameters: rotational and welding speeds. Two sets of empirical models based on regression analysis are developed. The first one predicts the stationary values of the in-plane and downwards forging welding forces in dependence of the process parameters under investigation. The second one predicts the mechanical strength, in particular yield and tensile strength, of the friction-stir welded joints as function of the same parameters. For the development of the empirical models, two 32 full factorial designs are used: one having the stationary values of the welding forces and the other having the yield and tensile strength as observed responses, respectively. Statistical tools such as analysis of variance, F tests, Mallows’ CP, coefficient of determination etc. are used to build and to validate the developed models. By using the desirability function approach, the optimum process parameters to simultaneously obtain maximum possible yield and tensile strength are found within the investigated range. The developed models can be effectively used to predict the stationary forces and the mechanical proprieties of the joints at 95% confidence level