Work rate adjustments needed to maintain heart rate and RPE during high-intensity interval training in the heat.

Introduction: Higher work rates may be sustainable when maintaining target rating of perceived exertion (RPE) compared to maintaining target heart rate (THR) during high-intensity interval training (HIIT) exercise in hot conditions, but may also result in greater thermal strain and cardiovascular drift, as well as greater decrements in maximal oxygen uptake ( O).

Purpose: To test the hypotheses that maintaining target RPE compared to THR during HIIT in the heat results in 1) smaller work rate adjustments, 2) greater thermal and cardiovascular strain, and 3) larger decreases in O.

Methods: Eight adults (4 women) completed a graded exercise test on a cycle ergometer in 22°C and then 4 cycling trials in 35°C, consisting of an 8-min warm-up at 70% maximal heart rate (HR) or 12 RPE followed by 1 (15 and 15) or 5 (43 and 43) rounds of HIIT (1 round = 4 min work at 90% HR or 17 RPE and 3 min recovery at 70% HR or 12 RPE) totaling 15 min or 43 min of exercise, respectively.

Distinct journeys and unique stories: how individuals from multiple professions cultivate careers in healthcare leadership.

Introduction: Strong hospital leadership is critical to navigating the challenges of the Canadian healthcare system. Currently, physicians and nurses tend to be selected to fulfil hospital executive roles. To date, we found only limited research exploring who else or should be in these roles, or how more diverse groups of professionals navigate the journey into these roles.

Protocols for Metallo- and Serine-β-Lactamase Free Energy Predictions: Insights from Cross-Class Inhibitors.

While relative binding free energy (RBFE) calculations using alchemical methods are routinely carried out for many pharmaceutically relevant protein targets, challenges remain. For example, open-source tools do not support the easy setup and simulation of metalloproteins, particularly when ligands directly coordinate to the metal site. Here, we evaluate the performance of RBFE methods for KPC-2, a serine-β-lactamase (SBL), and two nonbonded metal parameter setups for VIM-2, a metallo-β-lactamase (MBL) with two active site zinc ions.

Dynamical responses predict a distal site that modulates activity in an antibiotic resistance enzyme.

β-Lactamases, which hydrolyse β-lactam antibiotics, are key determinants of antibiotic resistance. Predicting the sites and effects of distal mutations in enzymes is challenging. For β-lactamases, the ability to make such predictions would contribute to understanding activity against, and development of, antibiotics and inhibitors to combat resistance.

Metabolic Heat Production Modulates the Cardiovascular Drift-V̇O 2max Relationship Independent of Aerobic Fitness in Women.

Introduction/purpose: The purpose of this study was to test the hypothesis that cardiovascular (CV) drift and associated decrements in maximal oxygen uptake (V̇O 2max ) are greater in high-fit compared with low-fit women during exercise at the same %V̇O 2max , but comparable at the same rate of metabolic heat production.

Methods: Six high-fit (HI) and six low-fit (LO) women cycled in 35°C for 15 or 45 min at the same relative intensity (60% V̇O 2max ; 15REL and 45REL) or fixed rate of heat production (500 W; 15FX and 45FX), immediately followed by a graded exercise test to measure V̇O 2max . The separate 15- and 45-min trials permitted measurements of V̇O 2max over the same time interval as CV drift.

Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against and Hit Validation by Biological Assays.

is the single most important global infectious disease killer and a World Health Organization critical priority pathogen for development of new antimicrobials. DNA gyrase is a validated target for anti-TB agents, but those in current use target DNA breakage-reunion, rather than the ATPase activity of the GyrB subunit. Here, virtual screening, subsequently validated by whole-cell and enzyme inhibition assays, was applied to identify candidate compounds that inhibit GyrB ATPase activity from the Specs compound library.

Epistasis arises from shifting the rate-limiting step during enzyme evolution of a β-lactamase.

Epistasis, the non-additive effect of mutations, can provide combinatorial improvements to enzyme activity that substantially exceed the gains from individual mutations. Yet the molecular mechanisms of epistasis remain elusive, undermining our ability to predict pathogen evolution and engineer biocatalysts. Here we reveal how directed evolution of a β-lactamase yielded highly epistatic activity enhancements.

Multilevel quantum mechanical calculations show the role of promoter molecules in the dehydration of methanol to dimethyl ether in H-ZSM-5.

Methyl carboxylate esters promote the formation of dimethyl ether (DME) from the dehydration of methanol in H-ZSM-5 zeolite. We employ a multilevel quantum method to explore the possible associative and dissociative mechanisms in the presence, and absence, of six methyl ester promoters. This hybrid method combines density functional theory, with dispersion corrections (DFT-D3), for the full periodic system, with second-order Møller-Plesset perturbation theory (MP2) for small clusters representing the reaction site, and coupled cluster with single, double, and perturbative triple substitution (CCSD(T)) for the reacting molecules.

Signal Propagation in the ATPase Domain of DNA Gyrase from Dynamical-Nonequilibrium Molecular Dynamics Simulations.

DNA gyrases catalyze negative supercoiling of DNA, are essential for bacterial DNA replication, transcription, and recombination, and are important antibacterial targets in multiple pathogens, including , which in 2021 caused >1.5 million deaths worldwide. DNA gyrase is a tetrameric (AB) protein formed from two subunit types: gyrase A (GyrA) carries the breakage-reunion active site, whereas gyrase B (GyrB) catalyzes ATP hydrolysis required for energy transduction and DNA translocation.

Electric Fields Are a Key Determinant of Carbapenemase Activity in Class A β-Lactamases.

Resistance to antibiotics is a public health crisis. Although carbapenems are less susceptible to resistance than other β-lactam antibiotics, β-lactamases mediating resistance against these drugs are spreading. Here, we dissect the contributions of electric fields to carbapenemase activity in class A β-lactamases.

glycan biosynthesis modulates host immune cell recognition and response.

Introduction: The pathogenic bacterium has evolved glycan-mediated mechanisms to evade host immune defenses. This study tests the hypothesis that genetic disruption of glycan biosynthesis alters immune recognition and response by human gastric epithelial cells and monocyte-derived dendritic cells.

Methods: To test this hypothesis, human cell lines were challenged with wildtype alongside an array of glycosylation mutants.

Fluctuation Relations to Calculate Protein Redox Potentials from Molecular Dynamics Simulations.

The tunable design of protein redox potentials promises to open a range of applications in biotechnology and catalysis. Here, we introduce a method to calculate redox potential changes by combining fluctuation relations with molecular dynamics simulations. It involves the simulation of reduced and oxidized states, followed by the instantaneous conversion between them.

Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary Approaches Based on Unbiased Molecular Dynamics Simulations.

Protein functions are dynamically regulated by allostery, which enables conformational communication even between faraway residues, and expresses itself in many forms, akin to different "languages": allosteric control pathways predominating in an unperturbed protein are often unintuitively reshaped whenever biochemical perturbations arise (, mutations). To accurately model allostery, unbiased molecular dynamics (MD) simulations require integration with a reliable method able to, , detect incipient allosteric changes or likely perturbation pathways; this is because allostery can operate at longer time scales than those accessible by plain MD. Such methods are typically applied singularly, but we here argue their joint application─as a "multilingual" approach─could work significantly better.

generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2.

Background: Due to COVID-19, pandemic preparedness emerges as a key imperative, necessitating new approaches to accelerate development of reagents against infectious pathogens.

Methods: Here, we developed an integrated approach combining synthetic, computational and structural methods with antibody selection and immunization to design, produce and validate nature-inspired nanoparticle-based reagents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Results: Our approach resulted in two innovations: (i) a thermostable nasal vaccine called ADDoCoV, displaying multiple copies of a SARS-CoV-2 receptor binding motif derived epitope and (ii) a multivalent nanoparticle superbinder, called Gigabody, against SARS-CoV-2 including immune-evasive variants of concern (VOCs).

Free energy along drug-protein binding pathways interactively sampled in virtual reality.

We describe a two-step approach for combining interactive molecular dynamics in virtual reality (iMD-VR) with free energy (FE) calculation to explore the dynamics of biological processes at the molecular level. We refer to this combined approach as iMD-VR-FE. Stage one involves using a state-of-the-art 'human-in-the-loop' iMD-VR framework to generate a diverse range of protein-ligand unbinding pathways, benefitting from the sophistication of human spatial and chemical intuition.

Interactive molecular dynamics in virtual reality for modelling materials and catalysts.

Interactive molecular dynamics simulation in virtual reality (iMD-VR) is emerging as a promising technique in molecular science. Here, we demonstrate its use in a range of fifteen applications in materials science and heterogeneous catalysis. In this work, the iMD-VR package Narupa is used with the MD package, DL_POLY [1].

Acute work rate adjustments during high-intensity interval training in a hot and temperate environment.

Heart rate drifts upward over time during interval exercise and during exercise in hot conditions. As such, work rate must be lowered to maintain target heart rate. The purpose was to characterize acute work rate adjustments during high-intensity interval training based on target heart rate.

Four additional natural 7-deazaguanine derivatives in phages and how to make them.

Bacteriophages and bacteria are engaged in a constant arms race, continually evolving new molecular tools to survive one another. To protect their genomic DNA from restriction enzymes, the most common bacterial defence systems, double-stranded DNA phages have evolved complex modifications that affect all four bases. This study focuses on modifications at position 7 of guanines.

Enhancement by pyrazolones of colistin efficacy against mcr-1-expressing E. coli: an in silico and in vitro investigation.

Owing to the emergence of antibiotic resistance, the polymyxin colistin has been recently revived to treat acute, multidrug-resistant Gram-negative bacterial infections. Positively charged colistin binds to negatively charged lipids and damages the outer membrane of Gram-negative bacteria. However, the MCR-1 protein, encoded by the mobile colistin resistance (mcr) gene, is involved in bacterial colistin resistance by catalysing phosphoethanolamine (PEA) transfer onto lipid A, neutralising its negative charge, and thereby reducing its interaction with colistin.