Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists.

We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties.

Greater performance impairment of black runners than white runners when running in hypoxia.

This study aimed to compare the response of performance-matched black and white runners during maximal and sub-maximal running in normoxic and hypoxic conditions. 14 well-trained runners (8 black, 6 white) performed 2 incremental maximal exercise tests and 2 fatigue resistance tests at 21% O2 (normoxia) or 14% O2 (hypoxia). Respiratory parameters, heart rate (HR), lactate concentration ([La(-)]) as well as arterial saturation (SpO2) were measured.

Suppression of the GLUT4 adaptive response to exercise in fructose-fed rats.

Exercise-induced increase in skeletal muscle GLUT4 expression is associated with hyperacetylation of histone H3 within a 350-bp DNA region surrounding the myocyte enhancer factor 2 (MEF2) element on the Glut4 promoter and increased binding of MEF2A. Previous studies have hypothesized that the increase in MEF2A binding is a result of improved accessibility of this DNA segment. Here, we investigated the impact of fructose consumption on exercise-induced GLUT4 adaptive response and directly measured the accessibility of the above segment to nucleases.

On the cause of the tailing phenomenon during virus disinfection by chlorine dioxide.

This study investigates the mechanisms underlying the deviation from Chick-Watson kinetics, namely a tailing curve, during the disinfection of viruses by chlorine dioxide (ClO2). Tailing has been previously reported, but is typically attributed to the decay in disinfectant concentration. Herein, it is shown that tailing occurs even at constant ClO2 concentrations.

Deamidation of asparagine to aspartate destabilizes Cu, Zn superoxide dismutase, accelerates fibrillization, and mirrors ALS-linked mutations.

The reactivity of asparagine residues in Cu, Zn superoxide dismutase (SOD1) to deamidate to aspartate remains uncharacterized; its occurrence in SOD1 has not been investigated, and the biophysical effects of deamidation on SOD1 are unknown. Deamidation is, nonetheless, chemically equivalent to Asn-to-Asp missense mutations in SOD1 that cause amyotrophic lateral sclerosis (ALS). This study utilized computational methods to identify three asparagine residues in wild-type (WT) SOD1 (i.

Micropollutant dynamics in Vidy Bay--a coupled hydrodynamic-photolysis model to assess the spatial extent of ecotoxicological risk.

The direct discharge of effluent wastewater into Vidy Bay (Lake Geneva) results in the formation of an effluent plume with locally high concentrations of wastewater-derived micropollutants. The micropollutant hotspots above the wastewater outfall present a potential ecotoxicological risk, yet the spatial extent of the plume and the associated ecotoxicological risk zone remain unclear. This work combines the two main processes affecting the spreading of the plume, namely dilution of micropollutants due to mixing and degradation by photolysis, into a coupled hydrodynamic-photolysis model, with which we estimated the spatial extent of the risk zone in Vidy Bay.

Virus removal and inactivation by iron (hydr)oxide-mediated Fenton-like processes under sunlight and in the dark.

Advanced oxidation processes (AOPs) have emerged as a promising alternative to conventional disinfection methods to control microbial water quality, yet little is known about the fate of viruses in AOPs. In this study, we investigated the fate of MS2 coliphage in AOPs that rely on heterogeneous Fenton-like processes catalyzed by iron (hydr)oxide particles. Both physical removal of viruses from solution via adsorption onto particles as well as true inactivation were considered.

Subtle differences in virus composition affect disinfection kinetics and mechanisms.

Viral disinfection kinetics have been studied in depth, but the molecular-level inactivation mechanisms are not understood. Consequently, it is difficult to predict the disinfection behavior of nonculturable viruses, even when related, culturable viruses are available. The objective of this work was to determine how small differences in the composition of the viral genome and proteins impact disinfection.

[The brain as master of the heart].

We admitted a 42 year old woman with clinical signs of shock, coma, and ecg changes consistent with a ST elevation myocardial infarction to percutaneous coronary intervention. Normal coronary arteries were found. Due to the comatose state a cranial computed tomography scan was performed, where a subarachnoid hemorrhage was detected.

Mechanisms of human adenovirus inactivation by sunlight and UVC light as examined by quantitative PCR and quantitative proteomics.

Human adenoviruses (HAdV) are important pathogens in both industrialized and developing nations. HAdV has been shown to be relatively resistant to monochromatic UVC light. Polychromatic UVC light, in contrast, is a more effective means of disinfection, presumably due to the involvement of viral proteins in the inactivation mechanism.

Direct photolysis of human metabolites of the antibiotic sulfamethoxazole: evidence for abiotic back-transformation.

The presence of potentially persistent and bioactive human metabolites in surface waters gives rise to concern; yet little is known to date about the environmental fate of these compounds. This work investigates the direct photolysis of human metabolites of the antibiotic sulfamethoxazole (SMX). In particular, we determined photolysis kinetics and products, as well as their concentrations in lake water.

Lion (Panthera leo) and caracal (Caracal caracal) type IIx single muscle fibre force and power exceed that of trained humans.

This study investigated for the first time maximum force production, shortening velocity (Vmax) and power output in permeabilised single muscle fibres at 12°C from lion, Panthera leo (Linnaeus 1758), and caracal, Caracal caracal (Schreber 1776), and compared the values with those from human cyclists. Additionally, the use and validation of previously frozen tissue for contractile experiments is reported. Only type IIx muscle fibres were identified in the caracal sample, whereas type IIx and only two type I fibres were found in the lion sample.

Virus inactivation mechanisms: impact of disinfectants on virus function and structural integrity.

Oxidative processes are often harnessed as tools for pathogen disinfection. Although the pathways responsible for bacterial inactivation with various biocides are fairly well understood, virus inactivation mechanisms are often contradictory or equivocal. In this study, we provide a quantitative analysis of the total damage incurred by a model virus (bacteriophage MS2) upon inactivation induced by five common virucidal agents (heat, UV, hypochlorous acid, singlet oxygen, and chlorine dioxide).

Inactivation of bacteriophage MS2 with potassium ferrate(VI).

Ferrate [Fe(VI); FeO(4)(2-)] is an emerging oxidizing agent capable of controlling chemical and microbial water contaminants. Here, inactivation of MS2 coliphage by Fe(VI) was examined. The inactivation kinetics observed in individual batch experiments was well described by a Chick-Watson model with first-order dependences on disinfectant and infective phage concentrations.

Inactivation and tailing during UV254 disinfection of viruses: contributions of viral aggregation, light shielding within viral aggregates, and recombination.

UV disinfection of viruses frequently leads to tailing after an initial exponential decay. Aggregation, light shielding, recombination, or resistant virus subpopulations have been proposed as explanations; however, none of these options has been conclusively demonstrated. This study investigates how aggregation affects virus inactivation by UV(254) in general, and the tailing phenomenon in particular.

High oxidative capacity and type IIx fibre content in springbok and fallow deer skeletal muscle suggest fast sprinters with a resistance to fatigue.

Some wild antelopes are fast sprinters and more resistant to fatigue than others. This study therefore investigated two wild antelope species to better understand their reported performance capability. Muscle samples collected post mortem from the vastus lateralis and longissimus lumborum of fallow deer (Dama dama) and springbok (Antidorcas marsupialis) were analysed for myosin heavy chain isoform content, citrate synthase, 3-hydroxyacyl CoA dehydrogenase, phosphofructokinase, lactate dehydrogenase and creatine kinase activities.

Discovery and in vivo evaluation of dual PI3Kβ/δ inhibitors.

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis.

Virus disinfection mechanisms: the role of virus composition, structure, and function.

Drinking waters are treated for enteric virus via a number of disinfection techniques including chemical oxidants, irradiation, and heat, however the inactivation mechanisms during disinfection remain elusive. Owing to the fact that a number of significant waterborne virus strains are not readily culturable in vitro at this time (e.g.

UV radiation induces genome-mediated, site-specific cleavage in viral proteins.

Much research has been dedicated to understanding the molecular basis of UV damage to biomolecules, yet many questions remain regarding the specific pathways involved. Here we describe a genome-mediated mechanism that causes site-specific virus protein cleavage upon UV irradiation. Bacteriophage MS2 was disinfected with 254 nm UV, and protein damage was characterized with ESI- and MALDI-based FT-ICR, Orbitrap, and TOF mass spectroscopy.

Photoinactivation of virus on iron-oxide coated sand: enhancing inactivation in sunlit waters.

Adsorption onto iron oxides can enhance the removal of waterborne viruses in constructed wetlands and soils. If reversible adsorption is not coupled with inactivation, however, infective viruses may be released when changes in solution conditions cause desorption. The goals of this study were to investigate the release of infective bacteriophages MS2 and ΦX174 (two human viral indicators) after adsorption onto an iron oxide coated sand (IOCS), and to promote viral inactivation by exploiting the photoreactive properties of the IOCS.

Black wildebeest skeletal muscle exhibits high oxidative capacity and a high proportion of type IIx fibres.

The aim of the study was to investigate the skeletal muscle characteristics of black wildebeest (Connochaetes gnou) in terms of fibre type and metabolism. Samples were obtained post mortem from the vastus lateralis and longissimus lumborum muscles and analysed for myosin heavy chain (MHC) content. Citrate synthase (CS), 3-hydroxyacyl co A dehydrogenase (3HAD), phosphofructokinase (PFK), lactate dehydrogenase (LDH) and creatine kinase (CK) activities were measured spectrophotometrically to represent the major metabolic pathways in these muscles.

Role of temperature and Suwannee River natural organic matter on inactivation kinetics of rotavirus and bacteriophage MS2 by solar irradiation.

Although the sunlight-mediated inactivation of viruses has been recognized as an important process that controls surface water quality, the mechanisms of virus inactivation by sunlight are not yet clearly understood. We investigated the synergistic role of temperature and Suwannee River natural organic matter (SRNOM), an exogenous sensitizer, for sunlight-mediated inactivation of porcine rotavirus and MS2 bacteriophage. Upon irradiation by a full spectrum of simulated sunlight in the absence of SRNOM and in the temperature range of 14-42 °C, high inactivation rate constants, k(obs), of MS2 (k(obs) ≤ 3.

Impact of virus aggregation on inactivation by peracetic acid and implications for other disinfectants.

Viruses in wastewater and natural environments are often present as aggregates. The disinfectant dose required for their inactivation, however, is typically determined with dispersed viruses. This study investigates how aggregation affects virus inactivation by chemical disinfectants.

Fate of the pathogen indicators phage ΦX174 and Ascaris suum eggs during the production of struvite fertilizer from source-separated urine.

Human urine has the potential to be a sustainable, locally and continuously available source of nutrients for agriculture. Phosphate can be efficiently recovered from human urine in the form of the mineral struvite (MgNH4PO4·6H2O). However, struvite formation may be coupled with the precipitation of other constituents present in urine including pathogens, pharmaceuticals, and heavy metals.