What makes pan-drug resistant? Integrative insights from genomic, transcriptomic, and phenomic analysis of clinical strains resistant to all four major classes of antifungal drugs.

The global epidemic of drug-resistant continues unabated. The initial report on pan-drug resistant (PDR) strains in a hospitalized patient in New York was unprecedented. PDR showed both known and unique mutations in the prominent gene targets of azoles, amphotericin B, echinocandins, and flucytosine.

What makes pan-drug resistant? Integrative insights from genomic, transcriptomic, and phenomic analysis of clinical strains resistant to all four major classes of antifungal drugs.

The global epidemic of drug-resistant continues unabated. We do not know what caused the unprecedented appearance of pan-drug resistant (PDR) strains in a hospitalized patient in New York; the initial report highlighted both known and unique mutations in the prominent gene targets of azoles, amphotericin B, echinocandins, and flucytosine antifungal drugs. However, the factors that allow to acquire multi-drug resistance and pan-drug resistance are not known.

Drug resistance through ribosome splitting and rRNA disordering in mycobacteria.

HflX is known to rescue stalled ribosomes and is implicated in antibiotic resistance in several bacteria. Here we present several high-resolution cryo-EM structures of mycobacterial HflX in complex with the ribosome and its 50S subunit, with and without antibiotics. These structures reveal a distinct mechanism for HflX-mediated ribosome splitting and antibiotic resistance in mycobacteria.

Clinical Course, Antifungal Susceptibility, and Genomic Sequencing of Trichophyton indotineae.

Importance: Trichophyton indotineae is an emerging dermatophyte causing outbreaks of extensive tinea infections often unresponsive to terbinafine. This species has been detected worldwide and in multiple US states, yet detailed US data on infections with T indotineae are sparse and could improve treatment practices and medical understanding of transmission.

Objective: To correlate clinical features of T indotineae infections with in vitro antifungal susceptibility testing results, squalene epoxidase gene sequence variations, and isolate relatedness using whole-genome sequencing.

The structure of a hibernating ribosome in a Lyme disease pathogen.

The spirochete bacterial pathogen Borrelia (Borreliella) burgdorferi (Bbu) affects more than 10% of the world population and causes Lyme disease in about half a million people in the US annually. Therapy for Lyme disease includes antibiotics that target the Bbu ribosome. Here we present the structure of the Bbu 70S ribosome obtained by single particle cryo-electron microscopy at 2.

Starvation sensing by mycobacterial RelA/SpoT homologue through constitutive surveillance of translation.

The stringent response, which leads to persistence of nutrient-starved mycobacteria, is induced by activation of the RelA/SpoT homolog (Rsh) upon entry of a deacylated-tRNA in a translating ribosome. However, the mechanism by which Rsh identifies such ribosomes in vivo remains unclear. Here, we show that conditions inducing ribosome hibernation result in loss of intracellular Rsh in a Clp protease-dependent manner.

The structure of a hibernating ribosome in a Lyme disease pathogen.

The spirochete bacterial pathogen ( ( ) affects more than 10% of the world population and causes Lyme disease in about half a million people in the US annually. Therapy for Lyme disease includes antibiotics that target the ribosome. We determined the structure of the 70S ribosome by single particle cryo-electron microscopy (cryo-EM) at a resolution of 2.

Development and Validation of TaqMan Chemistry Probe-Based Rapid Assay for the Detection of Echinocandin-Resistance in Candida auris.

Candida auris is a multidrug-resistant yeast pathogen causing outbreaks in health care facilities worldwide, and the emergence of echinocandin-resistant C. auris is a concern. Currently used Clinical and Laboratory Standards Institute (CLSI) and commercial antifungal susceptibility tests (AFST) are phenotype-based, slow, and not scalable, limiting their effectiveness in the surveillance of echinocandin-resistant C.

An opinion on the debatable function of brain resident immune protein, T-cell receptor beta subunit in the central nervous system.

In recent years scientific research has established that the nervous and immune systems have shared molecular signaling components. Proteins native to immune cells, which are also found in the brain, have neuronal functions in the nervous system where they affect synaptic plasticity, axonal regeneration, neurogenesis, and neurotransmission. Certain native immune molecules like major histocompatibility complex I (MHC-I), paired immunoglobulin receptor B (PirB), toll-like receptor (TLR), cluster of differentiation-3 zeta (CD3ζ), CD4 co-receptor, and T-cell receptor beta (TCR-β) expression in neurons have been extensively documented.

Restorative Action of Vitamin D3 on Motor Dysfunction Through Enhancement of Neurotrophins and Antioxidant Expression in the Striatum.

A number of studies has explored a positive correlation between low levels of serum Vitamin D (VD; cholecalciferol) and development of neurodegenerative diseases including Huntington's disease (HD). In the present study, the prophylactic effect of VD on motor dysfunction was studied in an experimental model of HD. An HD-like syndrome was induced in male C57BL/6 mice through an intraperitoneal injection (i.

Structural Articulation of Biochemical Reactions Using Restrained Geometries and Topology Switching.

A strategy named "restrained geometries and topology switching" (RGATS) is presented to obtain detailed trajectories for complex biochemical reactions using molecular mechanics (MM) methods. It enables prediction of realistic dynamical pathways for chemical reactions, especially for accurately characterizing the structural adjustments of highly complex environments to any proximal biochemical reaction. It can be used to generate reactive conformations, model stepwise or concerted reactions in complex environments, and probe the influence of changes in the environment.

Cytosine unstacking and strand slippage at an insertion-deletion mutation sequence in an overhang-containing DNA duplex.

Base unstacking in template strands, when accompanied by strand slippage, can result in deletion mutations during strand extension by nucleic acid polymerases. In a GCCC mutation hot-spot sequence, which was previously identified to have a 50% probability of causing such mutations during DNA replication by a Y-family polymerase, a single-base deletion mutation could result from such unstacking of any one of its three template cytosines. In this study, the intrinsic energetic differences in unstacking among these three cytosines in a solvated DNA duplex overhang model were examined using umbrella sampling molecular dynamics simulations.

A large-scale evaluation of computational protein function prediction.

Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high.

A comparative study of quantum transport properties of silver and copper nanowires using first principles calculations.

The electronic structure and transport properties of silver (Ag) and copper (Cu) nanowires of diameters up to 1.7 nm are investigated using first principles density functional theory and the Landauer formalism in conjunction with a supercell approach. A direct comparison of the ballistic conductances, quantum capacitances, and kinetic inductances indicates that Ag and Cu nanowires show very similar performances.

Solvation, solute rotation and vibration relaxation, and electron-transfer reactions in room-temperature ionic liquids.

A brief account of recent simulation and theoretical model studies of various solution-phase processes in room-temperature ionic liquids is given. These include structure and dynamics of equilibrium and nonequilibrium solvation, solute rotation and vibrational energy relaxation, and free energetics and dynamics of unimolecular electron-transfer reactions. Special attention is paid to both the aspects shared by and the contrasts with polar solvents under normal conditions.

Free energy, entropy and volume of activation for electron transfer reactions in a polar solvent.

A continuum theory with account of cavity size fluctuations is employed to study free energy, volume and entropy of activation for nonadiabatic electron transfer (ET) reactions in polar solvents. By using a two-sphere cavity description, model calculations are performed for charge separation and recombination processes in acetonitrile under ambient conditions. It is found that the cavity size at the transition state varies with the free energy of reaction as well as with the thermodynamic conditions.

Temperature- and pressure-dependence of the outer-sphere reorganization free energy for electron transfer reactions: a continuum approach.

The outer-sphere reorganization free energy for electron-transfer reactions in polar solvents and its variations with temperature and pressure are studied in the dielectric continuum framework by extending the recent fluctuating cavity description [J. Chem. Phys.

On the temperature and pressure dependences of cavities in the dielectric continuum picture.

Cavity size at equilibrium and its variations with thermodynamic conditions are studied in the dielectric continuum framework of solvents. By employing Gibbs' theory of dividing surfaces, the fluctuating cavity description of Kim [H.J.