Water-membrane partition and the mutant selection window of antimicrobial peptides: insights from liposome studies.

The mutant selection window (MSW) is a range of antimicrobial concentrations, where some bacteria are killed, while others survive. Within this interval resistance may develop. Antimicrobial peptides (AMPs) are a promising class of antimicrobials that generally act by perturbing the integrity of bacterial membranes.

Interplay between classical and quantum dissipation in light-matter dynamics.

A quantum-electrodynamics approach is presented to describe the dynamics of electrons that exchange energy with both photon and phonon baths. Our ansatz is a dissipative quantum Liouville equation, cast in the Redfield form, with two driving terms associated with radiative and vibrational relaxation mechanisms, respectively. Remarkably, within the radiative contribution, there is a term that exactly replicates the expression derived from a semiclassical treatment where the power dissipated by the electronic density is treated as the emission from a classical dipole [Bustamante et al.

Fluorescent Labeling Can Significantly Perturb Measured Binding Affinity and Selectivity of Peptide-Protein Interactions.

Peptide-based drugs are powerful inhibitors of therapeutically relevant protein-protein interactions. Their affinity and selectivity for target proteins are commonly assessed using fluorescence-based assays such as anisotropy/polarization or quantitative microarrays. This study reveals that labeling can perturb peptide/protein binding by more than 1 order of magnitude.

Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.

The vacuolar H-ATPase (V-ATPase) is a functionally conserved multimeric complex localized at the membranes of many organelles where its proton-pumping action is required for proper lumen acidification. The V-ATPase complex is composed of several subunits, some of which have been linked to human disease. We and others previously reported pathogenic dominantly acting variants in ATP6V1B2, the gene encoding the V1B2 subunit, as underlying a clinically variable phenotypic spectrum including dominant deafness-onychodystrophy (DDOD) syndrome, Zimmermann-Laband syndrome (ZLS), and deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures (DOORS) syndrome.

Strategic Single-Residue Substitution in the Antimicrobial Peptide Esc(1-21) Confers Activity against , Including Drug-Resistant and Biofilm Phenotype.

, a bacterium resistant to multiple drugs, is a significant cause of illness and death worldwide. Antimicrobial peptides (AMPs) provide an excellent potential strategy to cope with this threat. Recently, we characterized a derivative of the frog-skin AMP esculentin-1a, Esc(1-21) () that is endowed with potent activity against Gram-negative bacteria but poor efficacy against Gram-positive strains.

Modeling the electroluminescence of atomic wires from quantum dynamics simulations.

Static and time-dependent quantum-mechanical approaches have been employed in the literature to characterize the physics of light-emitting molecules and nanostructures. However, the electromagnetic emission induced by an input current has remained beyond the realm of molecular simulations. This is the challenge addressed here with the help of an equation of motion for the density matrix coupled to a photon bath based on a Redfield formulation.

Kinetic and Thermodynamic Interplay of Polymer-Mediated Liquid-Liquid Phase Separation for Poorly Water-Soluble Drugs.

Understanding the interplay between kinetics and thermodynamics of polymer-mediated liquid-liquid phase separation is crucial for designing and implementing an amorphous solid dispersion formulation strategy for poorly water-soluble drugs. This work investigates the phase behaviors of a poorly water-soluble model drug, celecoxib (CXB), in a supersaturated aqueous solution with and without polymeric additives (PVP, PVPVA, HPMCAS, and HPMCP). Drug-polymer-water ternary phase diagrams were also constructed to estimate the thermodynamic behaviors of the mixtures at room temperature.

Effective Band Structure and Crack Formation Analysis in Pseudomorphic Epitaxial Growth of (InGa)O Alloys: A First-Principles Study.

GaO is a promising material for power electronic applications. Alloying with InO is used for band gap adjustment and reduction of the lattice mismatch. In this study, we calculate the effective band structure of 160-atom (InGa)O supercells generated using special quasi-random structures where indium atoms preferentially substitute octahedral gallium sites in β-GaO.

Computational Evaluation of Peptide-Protein Binding Affinities: Application of Potential of Mean Force Calculations to SH2 Domains.

Many biological functions are mediated by protein-protein interactions (PPIs), often involving specific structural modules, such as SH2 domains. Inhibition of PPIs is a pharmaceutical strategy of growing importance. However, a major challenge in the design of PPI inhibitors is the large interface involved in these interactions, which, in many cases, makes inhibition by small organic molecules ineffective.

Fluorescence Anisotropy and Polarization in the Characterization of Biomolecular Association Processes and Their Application to Study SH2 Domain Binding Affinity.

Fluorescence anisotropy (or polarization) is a powerful technique to study biomolecular association processes, by following the rotational motions of one of the two partners in the interaction, labeled with a fluorophore. It can be used to determine dissociation constants in solution, down to nM values, and unlabeled ligands can be characterized, too, by using competition experiments. In this chapter, we introduce the basic principles of the technique, compare it with other experimental approaches, and discuss the experimental details with specific examples regarding SH2 domain/phosphopeptide association processes.

Rapid Assessment of Susceptibility of Bacteria and Erythrocytes to Antimicrobial Peptides by Single-Cell Impedance Cytometry.

Antimicrobial peptides (AMPs) represent a promising class of compounds to fight antibiotic-resistant infections. In most cases, they kill bacteria by making their membrane permeable and therefore exhibit low propensity to induce bacterial resistance. In addition, they are often selective, killing bacteria at concentrations lower than those at which they are toxic to the host.

Effects of antimicrobial peptides on membrane dynamics: A comparison of fluorescence and NMR experiments.

Antimicrobial peptides (AMPs) represent a promising class of compounds to fight resistant infections. They are commonly thought to kill bacteria by perturbing the permeability of their cell membranes. However, bacterial killing requires a high coverage of the cell surface by bound peptides, at least in the case of cationic and amphipathic AMPs.

Isoamphipathic antibacterial molecules regulating activity and toxicity through positional isomerism.

Peptidomimetic antimicrobials exhibit a selective interaction with bacterial cells over mammalian cells once they have achieved an optimum amphiphilic balance (hydrophobicity/hydrophilicity) in the molecular architecture. To date, hydrophobicity and cationic charge have been considered the crucial parameters to attain such amphiphilic balance. However, optimization of these properties is not enough to circumvent unwanted toxicity towards mammalian cells.

Fluorescence in quantum dynamics: Accurate spectra require post-mean-field approaches.

Real time modeling of fluorescence with vibronic resolution entails the representation of the light-matter interaction coupled to a quantum-mechanical description of the phonons and is therefore a challenging problem. In this work, taking advantage of the difference in timescales characterizing internal conversion and radiative relaxation-which allows us to decouple these two phenomena by sequentially modeling one after the other-we simulate the electron dynamics of fluorescence through a master equation derived from the Redfield formalism. Moreover, we explore the use of a recent semiclassical dissipative equation of motion [C.

Structural and Functional Characterization of the Newly Designed Antimicrobial Peptide Crabrolin21.

(1) Background: antimicrobial resistance is becoming a dramatic problem for public health, and the design of new antimicrobial agents is an active research area. (2) Methods: based on our previous work, we designed an improved version of the crabrolin peptide and characterized its functional and structural properties with a wide range of techniques. (3) Results: the newly designed peptide, crabrolin21, is much more active than the previous ones and shows specific selectivity towards bacterial cells.

KuQuinone as a Highly Stable and Reusable Organic Photocatalyst in Selective Oxidation of Thioethers to Sulfoxides.

A chemoselective photocatalytic system to perform thioether oxidation to sulfoxide is presented. The light-induced oxidation process is here promoted by a metal-free quinoid catalyst, namely 1-hexylKuQuinone (KuQ). Reactions performed in a fluorinated solvent (i.

Characterization and Performance Enhancement of Cement-Based Thermoelectric Materials.

Thermoelectric materials enable the direct conversion of thermal to electrical energy. One application of this is ambient heat energy harvesting where relatively stable temperature gradients existing between the inside and outside of a building could be utilized to produce electricity. Buildings can thus change from energy consumers to energy generators.

Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state.

The Src-homology 2 domain containing phosphatase 2 (SHP2) plays a critical role in crucial signaling pathways and is involved in oncogenesis and in developmental disorders. Its structure includes two SH2 domains (N-SH2 and C-SH2), and a protein tyrosine phosphatase (PTP) domain. Under basal conditions, SHP2 is auto-inhibited, with the N-SH2 domain blocking the PTP active site.

Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions.

We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2-20 times higher than for the wild-type protein.

Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

Among many methods to mitigate the solubility limitations of drug compounds, amorphous solid dispersion (ASD) is considered to be one of the most promising strategies to enhance the dissolution and bioavailability of poorly water-soluble drugs. The enhancement of ASD in the oral absorption of drugs has been mainly attributed to the high apparent drug solubility during the dissolution. In the last decade, with the implementations of new knowledge and advanced analytical techniques, a drug-rich transient metastable phase was frequently highlighted within the supersaturation stage of the ASD dissolution.

Inoculum effect of antimicrobial peptides.

The activity of many antibiotics depends on the initial density of cells used in bacterial growth inhibition assays. This phenomenon, termed the inoculum effect, can have important consequences for the therapeutic efficacy of the drugs, because bacterial loads vary by several orders of magnitude in clinically relevant infections. Antimicrobial peptides are a promising class of molecules in the fight against drug-resistant bacteria because they act mainly by perturbing the cell membranes rather than by inhibiting intracellular targets.

Effect of Phlorotannins from Brown Seaweeds on the In Vitro Digestibility of Pig Feed.

Phlorotannins have been reported to have positive effects on pig health, including improved gut health and digestibility. In this study, we investigate the effect of phenolics found in two brown seaweeds, and , on in vitro dry matter digestibility of seaweeds and commercial pig feed. Phlorotannin extracts and whole seaweeds were supplemented into pig feed to test their effect on digestibility.

A Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl/H-Exchanger, Causes Early-Onset Neurodegeneration.

Dysfunction of the endolysosomal system is often associated with neurodegenerative disease because postmitotic neurons are particularly reliant on the elimination of intracellular aggregates. Adequate function of endosomes and lysosomes requires finely tuned luminal ion homeostasis and transmembrane ion fluxes. Endolysosomal CLC Cl/H exchangers function as electric shunts for proton pumping and in luminal Cl accumulation.

Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum.

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.