New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds

Antimicrobial resistance (AMR) poses a serious threat to our society from both the medical and economic point of view, while the antibiotic discovery pipeline has been dwindling over the last decades. Targeting non-essential bacterial pathways, such as those leading to antibiotic persistence, a bacterial bet-hedging strategy, will lead to new molecular entities displaying low selective pressure, thereby reducing the insurgence of AMR. Here, we describe a way to target (p)ppGpp (guanosine tetra- or penta-phosphate) signaling, a non-essential pathway involved in the formation of persisters, with a structure-based approach. A superfamily of enzymes called RSH (RelA/SpoT Homolog) regulates the intracellular levels of this alarmone. We virtually screened several fragment libraries against the (p)ppGpp synthetase domain of our RSH chosen model Rel_Seq, selected three main chemotypes, and measured their interaction with Rel_Seq by thermal shift assay and STD-NMR. Most of the tested fragments are selective for the synthetase domain, allowing us to select the aminobenzoic acid scaffold as a hit for lead development.     

A comparison of the structure,flexibility and mesogenic properties of 4-methoxy-4′-cyanobiphenyl and the α,α,α-trifluorinated derivative

Abstract

The compound 4-cyano-4′-(α,α,α-trifluoromethoxy)biphenyl (1OCBF₃) has been synthesized. Unlike the fully protonated analogue, 4-cyano-4′-methoxybiphenyl (1OCB), it does not show a liquid crystalline phase on cooling from the melting point (51°C) to room temperature. The transition temperature to a monotropic nematic phase was obtained as approximately 0°C by determining the transition temperatures of mixtures with 1OCB. The structures, conformational properties and orientational ordering of both 1OCB and 1OCBF₃ as solutes in a nematic solvent ZLI 1132 have been investigated via the 17 dipolar couplings obtained by analysing the proton and fluorine NMR spectra of these solutions. It is concluded that the major difference between the two molecules lies in the potential, V(φ₂), governing rotation about the ring–oxygen bonds. In 1OCB the potential has the same form as in anisole, with a minimum when the C–O bond is in the plane of the attached ring (φ₂ = 0°), and a maximum of about 15 kJ mol^?1 when φ₂ is 90°. In 1OCBF₃ the barrier to rotation about the ring–O bond decreases substantially to being near zero.     

Heat Release by Controlled Continuous-Time Markov Jump Processes

We derive the equations governing the protocols minimizing the heat released by a continuous-time Markov jump process on a one-dimensional countable state space during a transition between assigned initial and final probability distributions in a finite time horizon. In particular, we identify the hypotheses on the transition rates under which the optimal control strategy and the probability distribution of the Markov jump problem obey a system of differential equations of Hamilton-Jacobi-Bellman-type. As the state-space mesh tends to zero, these equations converge to those satisfied by the diffusion process minimizing the heat released in the Langevin formulation of the same problem. We also show that in full analogy with the continuum case, heat minimization is equivalent to entropy production minimization. Thus, our results may be interpreted as a refined version of the second law of thermodynamics.     

Temperature dependence of the time-resolved emissions of CsI:Tl

Abstract

Time-resolved emissions of Csl:T1 are investigated. The system is laser-excited in the A-band at 308 nm and the emissions are observed in the range 370–650 nm, from 30 K to 300 K. Their analysis by means of a deconvolution permits the valuation of decay-times down to 1 ns. At every temperature many bands are observed and some of them show slow and fast components. The decay-times of the fast components are in the range 1–10 ns while the slow ones are even longer than 1 μs. In many cases intermediate decay-times of the order of 100 ns exist. The competition among the bands interests the application of this system as active material for tunable solid-state laser.     

Ionic electroactive polymer metal composites: Fabricating,modeling, and applications of postsilicon smart devices

Smart systems adapt to the surrounding environments in a number of ways. They are capable to scavenge energy from available sources, sense and elaborate external stimuli and adequately react. Electro Active Polymers are playing a main role in the realization of smart systems for applications if fields such as bio inspired and autonomous robotics, medicine, and aerospace. This paper focus on the possibility to use Ionic Polymer Metal Composites as a class of materials relevant to the realization of post silicon smart systems. The three main aspects of this new technology, i.e., fabrication methods, modeling, and applications are described with emphasis to most recent results. Attention is given to main challenges and shortcomings to be solved for technology, modelling, and control of IPMC based devices that need to be solved before this new technology can be fully exploited in real world applications. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2013     

KAM for Reversible Derivative Wave Equations

We prove the existence of Cantor families of small amplitude, analytic, linearly stable quasi-periodic solutions of reversible derivative wave equations.     

Free energy and states of fractional-order hereditariness

Complex materials, often encountered in recent engineering and material sciences applications, show no complete separations between solid and fluid phases. This aspect is reflected in the continuous relaxation time spectra recorded in cyclic load tests. As a consequence the material free energy cannot be defined in a unique manner yielding a significative lack of knowledge of the maximum recoverable work that can extracted from the material. The non-uniqueness of the free energy function is removed in the paper for power-laws relaxation/creep function by using a recently proposed mechanical analogue to fractional-order hereditariness.