Early Sepsis Metabolic Changes in Kidney and Liver Precede Clinical Evidence of Organ Dysfunction.

Organ-specific metabolic pathways, including those related to mitochondrial metabolism, could provide insight to mechanisms underlying sepsis-induced organ dysfunction. However, it remains unclear if metabolic changes result from or precede clinical organ dysfunction. To determine if blood levels of the mitochondrial metabolites acetylcarnitine and L-carnitine correlate with organ-specific signals of sepsis-induced dysfunction, we performed a series of translational analyses of two cohorts of human sepsis and experiments using a murine model of polymicrobial sepsis.

Critical review of chronic toxicity testing approaches with the saltwater mysid (Americamysis bahia) used in pesticide registration.

The United States Environmental Protection Agency (USEPA) has a conditional requirement for a chronic toxicity test with mysids (Americamysis bahia) for registration of pesticide products. Achieving performance acceptability criteria in control treatments for this study can be challenging because the current draft test guideline, which was published in 1996 under USEPA Office of Prevention, Pesticides, and Toxic Substances (OPPTS) 850.1350, Mysid Chronic Toxicity Test, provides limited information on study design and conduct.

Sex and race disparities in emergency department patients with chest pain and a detectable or mildly elevated troponin.

Background: Identifying and eliminating health disparities is a public health priority. The goal of this analysis is to determine whether cardiac testing or outcome disparities exist by race or sex in patients with detectable to mildly elevated serum troponin.

Methods: We conducted a secondary analysis of the CMR-IMPACT trial that randomized patients with symptoms suggestive of acute coronary syndrome and a detectable or mildly elevated troponin measure from 4 US hospitals to an early invasive angiography or cardiac MRI strategy.

Corrigendum: A sulfuryl group transfer strategy to selectively prepare sulfated steroids and isotopically labelled derivatives.

[This corrects the article DOI: 10.3389/fmolb.2021.

The Role of Medium Polarity in the Efficiency of Albumin Binding with Hydrophobic Ligands: Experimental Studies and a Molecular Dynamics Investigation.

This study evaluates how the polarity of the medium affects the binding efficiency of hydrophobic ligands with human serum albumin (HSA). The polarity of the aqueous medium was changed by adding 1,4-dioxane in concentrations of 0%, 10%, and 20% /, resulting in solvent mixtures with decreasing dielectric constants (ε = 80, 72, and 63). The addition of 1,4-dioxane did not affect the integrity of the protein, as confirmed by Far-UV-CD, Rayleigh scattering, and time-resolved fluorescence experiments.

VPS26 Moonlights as a β-Arrestin-like Adapter for a 7-Transmembrane RGS Protein in .

Extracellular signals perceived by 7-transmembrane (7TM)-spanning receptors initiate desensitization that involves the removal of these receptors from the plasma membrane. Agonist binding often evokes phosphorylation in the flexible C-terminal region and/or intracellular loop 3 of many 7TM G-protein-coupled receptors in animal cells, which consequently recruits a cytoplasmic intermediate adaptor, β-arrestin, resulting in clathrin-mediated endocytosis (CME) and downstream signaling such as transcriptional changes. Some 7TM receptors undergo CME without recruiting β-arrestin, but it is not clear how.

Ethnic Diversity and Distinctive Features of Familial Versus Multifactorial Chylomicronemia Syndrome: Insights From the UK FCS National Registry.

Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS).

Methods: The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project.

High Reliability in a Safety Net Hospital Leading to Operational Excellence.

Objective: The objective of this work was to establish sustainable systems for quality improvement in an Academic Medical Center and Safety Net Hospital.

Method: High reliability principles of leadership engagement, a culture of safety, and sustainable performance improvement were used. Target areas for improvement were clinical outcomes for patients, public reputation scores, and lower cost of care.

Electrochemical Synthesis of the -oxide Metabolites of Phenothiazine-Containing Antipsychotic Medications.

The tractable preparation of Phase I drug metabolites is a critical step to understand the first-pass behaviour of novel chemical entities (NCEs) in drug discovery. In this study, we have developed a structure-electroactivity relationship (SeAR)-informed electrochemical reaction of the parent 2-chlorophenothiazine and the antipsychotic medication, chlorpromazine. With the ability to dial-in under current controlled conditions, the formation of -oxide and novel ,-dioxide metabolites has been achieved for the first time on a multi-milligram scale using a direct batch electrode platform.

Chemical approaches to the sulfation of small molecules: current progress and future directions.

Sulfation is one of the most important modifications that occur to a wide range of bioactive small molecules including polysaccharides, proteins, flavonoids, and steroids. In turn, these sulfated molecules have significant biological and pharmacological roles in diverse processes including cell signalling, modulation of immune and inflammation response, anti-coagulation, anti-atherosclerosis, and anti-adhesive properties. This Essay summarises the most encountered chemical sulfation methods of small molecules.

A synchronized, large-scale field experiment using Arabidopsis thaliana reveals the significance of the UV-B photoreceptor UVR8 under natural conditions.

This study determines the functional role of the plant ultraviolet-B radiation (UV-B) photoreceptor, UV RESISTANCE LOCUS 8 (UVR8) under natural conditions using a large-scale 'synchronized-genetic-perturbation-field-experiment'. Laboratory experiments have demonstrated a role for UVR8 in UV-B responses but do not reflect the complexity of outdoor conditions where 'genotype × environment' interactions can mask laboratory-observed responses. Arabidopsis thaliana knockout mutant, uvr8-7, and the corresponding Wassilewskija wild type, were sown outdoors on the same date at 21 locations across Europe, ranging from 39°N to 67°N latitude.

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine.

In this article, we introduce a proof-of-concept strategy, Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM), to expedite the discovery of drug metabolites. The use of a bioactive natural product, piperine, that has a well-curated metabolite profile but an unpredictable computational metabolism (Biotransformer v3.0) was selected.

A Comparison of In Vitro Metabolic Clearance of Various Regulatory Fish Species Using Hepatic S9 Fractions.

Bioaccumulation predictions can be substantially improved by combining in vitro metabolic rate measurements derived from rainbow trout hepatocytes and/or hepatic S9 fractions with quantitative structure-activity relationship (QSAR) modeling approaches. Compared with in vivo testing guidelines Organisation for Economic Co-operation and Development (OECD) 305 and Office of Chemical Safety and Pollution Prevention (OCSPP; an office of the US Environmental Protection Agency) 850.1730, the recently adopted OECD test guidelines 319A and 319B are in vitro approaches that have the potential to provide a time- and cost-efficient, humane solution, reducing animal use while addressing uncertainties in bioaccumulation across species.

How the Xenopus eleutheroembryonic thyroid assay compares to the amphibian metamorphosis assay for detecting thyroid active chemicals.

The Xenopus Eleutheroembryonic Thyroid Assay (XETA) was recently published as an OECD Test Guideline for detecting chemicals acting on the thyroid axis. However, the OECD validation did not cover all mechanisms that can potentially be detected by the XETA. This study was therefore initiated to investigate and consolidate the applicability domain of the XETA regarding the following mechanisms: thyroid hormone receptor (THR) agonism, sodium-iodide symporter (NIS) inhibition, thyroperoxidase (TPO) inhibition, deiodinase (DIO) inhibition, glucocorticoid receptor (GR) agonism, and uridine 5'-diphospho-glucuronosyltransferase (UDPGT) induction.

A General Method to Access Underexplored Ylideneamino Sulfates as Interrupted Beckmann-Type Rearrangement Intermediates.

The Beckmann rearrangement of ketoximes to their corresponding amides, using a Brønsted acid-mediated fragmentation and migration sequence, has found wide-spread industrial application. We postulated that the development of a methodology to access ylideneamino sulfates using tributylsulfoammonium betaine (TBSAB) would afford isolable Beckmann-type intermediates and competent partners for subsequent rearrangement cascades. The ylideneamino sulfates generated, isolated as their tributylammonium salts, are sufficiently activated to undergo Beckmann rearrangement without additional reagent activation.

Rearrangement of Arylsulfamates and Sulfates to -Sulfonyl Anilines and Phenols.

The (sp)-aryl sulfonate functional group is found in bioactive molecules, but their synthesis can involve extreme temperatures (>190 °C or flash vacuum pyrolysis) and strongly acidic reaction conditions. Inspired by the 1917 Tyrer industrial process for a sulfa dye that involved an aniline (sp)-SO intermediate to a (sp)-SO rearranged product, we investigated tributylsulfoammonium betaine (TBSAB) as a milder -sulfamation to -sulfonate relay reagent. Initial investigations of a stepwise route involving TBSAB on selected anilines at room temperature enabled the isolation of (sp)-sulfamate.

Concentration units used to report blood- and breath-alcohol concentration for legal purposes differ between countries which is important to consider when blood/breath ratios of alcohol are compared and contrasted.

This technical note reviews the plethora of concentration units used to report blood-alcohol concentration (BAC) and breath-alcohol concentrations (BrAC) for legal purposes in different countries. The choice of units sometimes causes confusion when scientific papers originating from a certain country might be introduced into evidence via expert testimony, such as when alcohol-related crimes are prosecuted. The concentration units are also important to consider when blood/breath ratios (BBRs) of alcohol are calculated and compared between countries.

Validation of the familial chylomicronaemia syndrome (FCS) score in an ethnically diverse cohort from UK FCS registry: Implications for diagnosis and differentiation from multifactorial chylomicronaemia syndrome (MCS).

Background And Aims: Prognosis and management differ between familial chylomicronaemia syndrome (FCS), a rare autosomal recessive disorder, and multifactorial chylomicronaemia syndrome (MCS) or severe mixed hyperlipidaemia. A clinical scoring tool to differentiate these conditions has been devised but not been validated in other populations. The objective of this study was to validate this score in the UK population and identify any additional factors that might improve it.

Novel Glycomimetics Protect against Glycated Low-Density Lipoprotein-Induced Vascular Calcification In Vitro via Attenuation of the RAGE/ERK/CREB Pathway.

Heparan sulphate (HS) can act as a co-receptor on the cell surface and alterations in this process underpin many pathological conditions. We have previously described the usefulness of mimics of HS (glycomimetics) in protection against β-glycerophosphate-induced vascular calcification and in the restoration of the functional capacity of diabetic endothelial colony-forming cells in vitro. This study aims to investigate whether our novel glycomimetic compounds can attenuate glycated low-density lipoprotein (g-LDL)-induced calcification by inhibiting RAGE signalling within the context of critical limb ischemia (CLI).

Dubowski's stages of alcohol influence and clinical signs and symptoms of drunkenness in relation to a person's blood-alcohol concentration-Historical background.

This article traces the origin of various charts and tables delineating the stages of alcohol influence in relation to the clinical signs and symptoms of drunkenness and a person's blood-alcohol concentration (BAC). In forensic science and legal medicine, the most widely used such table was created by Professor Kurt M. Dubowski (University of Oklahoma).