Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance

Given the increase in resistance to antibacterial agents, there is an urgent need for the development of new agents with novel modes of action. As an interim solution, it is also prudent to reinvestigate old or abandoned antibacterial compounds to assess their efficacy in the context of widespread resistance to conventional agents. In the 1970s, much work was performed on the development of peptide mimetics, exemplified by the phosphonopeptide, alafosfalin. We investigated the activity of alafosfalin, di-alanyl fosfalin and β-chloro-L-alanyl-β-chloro-L-alanine against 297 bacterial isolates, including carbapenemase-producing Enterobacterales (CPE) (n = 128), methicillin-resistant Staphylococcus aureus (MRSA) (n = 37) and glycopeptide-resistant enterococci (GRE) (n = 43). The interaction of alafosfalin with meropenem was also examined against 20 isolates of CPE. The MIC50 and MIC90 of alafosfalin for CPE were 1 mg/L and 4 mg/L, respectively and alafosfalin acted synergistically when combined with meropenem against 16 of 20 isolates of CPE. Di-alanyl fosfalin showed potent activity against glycopeptide-resistant isolates of Enterococcus faecalis (MIC90; 0.5 mg/L) and Enterococcus faecium (MIC90; 2 mg/L). Alafosfalin was only moderately active against MRSA (MIC90; 8 mg/L), whereas β-chloro-L-alanyl-β-chloro-L-alanine was slightly more active (MIC90; 4 mg/L). This study shows that phosphonopeptides, including alafosfalin, may have a therapeutic role to play in an era of increasing antibacterial resistance

An Overview of the 13:8 Mean Motion Resonance between Venus and Earth

It is known since the seminal study of Laskar (1989) that the inner planetary system is chaotic with respect to its orbits and even escapes are not impossible, although in time scales of billions of years. The aim of this investigation is to locate the orbits of Venus and Earth in phase space, respectively to see how close their orbits are to chaotic motion which would lead to unstable orbits for the inner planets on much shorter time scales. Therefore we did numerical experiments in different dynamical models with different initial conditions -- on one hand the couple Venus-Earth was set close to different mean motion resonances (MMR), and on the other hand Venus' orbital eccentricity (or inclination) was set to values as large as e = 0.36 (i = 40deg). The couple Venus-Earth is almost exactly in the 13:8 mean motion resonance. The stronger acting 8:5 MMR inside, and the 5:3 MMR outside the 13:8 resonance are within a small shift in the Earth's semimajor axis (only 1.5 percent). Especially Mercury is strongly affected by relatively small changes in eccentricity and/or inclination of Venus in these resonances. Even escapes for the innermost planet are possible which may happen quite rapidly.Comment: 14 pages, 11 figures, submitted to CMD

La2010: A new orbital solution for the long term motion of the Earth

We present here a new solution for the astronomical computation of the orbital motion of the Earth spanning from 0 to -250 Myr. The main improvement with respect to the previous numerical solution La2004 (Laskar et al. 2004) is an improved adjustment of the parameters and initial conditions through a fit over 1 Myr to a special version of the high accurate numerical ephemeris INPOP08 (Fienga et al. 2009). The precession equations have also been entirely revised and are no longer averaged over the orbital motion of the Earth and Moon. This new orbital solution is now valid over more than 50 Myr in the past or in the future with proper phases of the eccentricity variations. Due to chaotic behavior, the precision of the solution decreases rapidly beyond this time span, and we discuss the behavior of various solutions beyond 50 Myr. For paleoclimate calibrations, we provide several different solutions that are all compatible with the most precise planetary ephemeris. We have thus reached the time where geological data are now required to discriminate among planetary orbital solutions beyond 50 Myr.Comment: 17 pages, 14 figure

An Exactly Conservative Integrator for the n-Body Problem

The two-dimensional n-body problem of classical mechanics is a non-integrable Hamiltonian system for n > 2. Traditional numerical integration algorithms, which are polynomials in the time step, typically lead to systematic drifts in the computed value of the total energy and angular momentum. Even symplectic integration schemes exactly conserve only an approximate Hamiltonian. We present an algorithm that conserves the true Hamiltonian and the total angular momentum to machine precision. It is derived by applying conventional discretizations in a new space obtained by transformation of the dependent variables. We develop the method first for the restricted circular three-body problem, then for the general two-dimensional three-body problem, and finally for the planar n-body problem. Jacobi coordinates are used to reduce the two-dimensional n-body problem to an (n-1)-body problem that incorporates the constant linear momentum and center of mass constraints. For a four-body choreography, we find that a larger time step can be used with our conservative algorithm than with symplectic and conventional integrators.Comment: 17 pages, 3 figures; to appear in J. Phys. A.: Math. Ge

The Relativistic Factor in the Orbital Dynamics of Point Masses

There is a growing population of relativistically relevant minor bodies in the Solar System and a growing population of massive extrasolar planets with orbits very close to the central star where relativistic effects should have some signature. Our purpose is to review how general relativity affects the orbital dynamics of the planetary systems and to define a suitable relativistic correction for Solar System orbital studies when only point masses are considered. Using relativistic formulae for the N body problem suited for a planetary system given in the literature we present a series of numerical orbital integrations designed to test the relevance of the effects due to the general theory of relativity in the case of our Solar System. Comparison between different algorithms for accounting for the relativistic corrections are performed. Relativistic effects generated by the Sun or by the central star are the most relevant ones and produce evident modifications in the secular dynamics of the inner Solar System. The Kozai mechanism, for example, is modified due to the relativistic effects on the argument of the perihelion. Relativistic effects generated by planets instead are of very low relevance but detectable in numerical simulations

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

The opportunities and challenges posed by the new generation of deep learning-based protein structure predictors

The function of proteins can often be inferred from their three-dimensional structures. Experimental structural biologists spent decades studying these structures, but the accelerated pace of protein sequencing continuously increases the gaps between sequences and structures. The early 2020s saw the advent of a new generation of deep learning-based protein structure prediction tools that offer the potential to predict structures based on any number of protein sequences. In this review, we give an overview of the impact of this new generation of structure prediction tools, with examples of the impacted field in the life sciences. We discuss the novel opportunities and new scientific and technical challenges these tools present to the broader scientific community. Finally, we highlight some potential directions for the future of computational protein structure prediction