Enhanced Mechanistic Understanding Through the Detection of Radical Intermediates in Organic Reactions.

Two applications of a radical trap based on a homolytic substitution reaction (SH2') are presented for the trapping of short-lived radical intermediates in organic reactions. The first example is a photochemical cyanomethylation catalyzed by a Ru complex. Two intermediate radicals in the radical chain propagation have been trapped and detected using mass spectrometry (MS), along with the starting materials, products and catalyst degradation fragments.

Virtual pulmonary rehabilitation approaches in patients with post COVID syndrome: a pilot study.

Background: The characteristics of optimal virtual pulmonary rehabilitation (PR) for individuals with post-COVID syndrome (PCS) have not been identified. This study aimed to assess the feasibility, safety, and satisfaction associated with a virtual PR program with the exercise component delivered through group or self-directed sessions.

Methods: Adults with PCS-respiratory symptoms were randomly assigned to the video conference (PR) or self-directed (PR) group and completed an exercise program (aerobic, strengthening, and breathing exercises) three times/week for eight weeks.

A comparison between erythrocytapheresis and venesection for the treatment of JAK2-mutated polycythaemia.

Background: JAK2-mutated polycythaemia vera (PV) is associated with reduced survival because of thrombotic events and haematological disease transformation. Therapeutic venesection has traditionally been used to lower haematocrit, but the technique of erythrocytapheresis has emerged over the last decade.

Aim: To compare erythrocytapheresis with venesection as treatment for PV by assessing medical efficacy and financial viability.

Combination of computational new approach methodologies for enhancing evidence of biological pathway conservation across species.

The ability to predict which chemicals are of concern for environmental safety is dependent, in part, on the ability to extrapolate chemical effects across many species. This work investigated the complementary use of two computational new approach methodologies to support cross-species predictions of chemical susceptibility: the US Environmental Protection Agency Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool and Unilever's recently developed Genes to Pathways - Species Conservation Analysis (G2P-SCAN) tool. These stand-alone tools rely on existing biological knowledge to help understand chemical susceptibility and biological pathway conservation across species.

Method validation and environmental monitoring of triethanolamine ester quaternary ammonium compounds.

In this study water and sediment samples, collected from the River Nene (Northamptonshire) at several sites in the vicinity of the Great Billing sewage treatment plant (STP), were analysed for triethanolamine quaternary compounds (TEAQ, ester quats). A method was developed using liquid chromatography tandem mass spectrometry (LC/MS/MS) with a electrospray ionisation source (ESI). Ten components were determined using a characterised commercial sample of Tallow TEAQ as a standard.

Effects of sub-lethal doses of fentanyl on vital physiologic functions and withdrawal-like behaviors in adult goats.

Synthetic opioids like fentanyl have improved the standard of care for many patients in the clinical setting, but their abuse leads to tens of thousands of overdose deaths annually. The current opioid epidemic underscores a critical need for insights into the physiological effects of fentanyl on vital functions. High doses of opioids in small mammals cause opioid-induced respiratory depression (OIRD) leading to hypoventilation, hypoxemia, and hypercapnia.

Kinetics and Mechanism of Azole n-π*-Catalyzed Amine Acylation.

Azole anions are highly competent in the activation of weak acyl donors, but, unlike neutral (aprotic) Lewis bases, are not yet widely applied as acylation catalysts. Using a combination of and stopped-flow H/F NMR spectroscopy, kinetics, isotopic labeling, H DOSY, and electronic structure calculations, we have investigated azole-catalyzed aminolysis of -fluorophenyl acetate. The global kinetics have been elucidated under four sets of conditions, and the key elementary steps underpinning catalysis deconvoluted using a range of intermediates and transition state probes.

Partitioning into phosphatidylcholine-cholesterol membranes: liposome measurements, coarse-grained simulations, and implications for bioaccumulation.

Membrane-water partitioning is an important physical property for the assessment of bioaccumulation and environmental impact. Here, we advance simulation methodology for predicting the partitioning of small molecules into lipid membranes and compare the computational predictions to experimental measurements in liposomes. As a step towards high-throughput screening, we present an automated mapping and parametrization procedure to produce coarse-grained models compatible with the Martini 3 force field.

Genes-to-Pathways Species Conservation Analysis: Enabling the Exploration of Conservation of Biological Pathways and Processes Across Species.

The last two decades have witnessed a strong momentum toward integration of cell-based and computational approaches in safety assessments. This is fueling a global regulatory paradigm shift toward reduction and replacement of the use of animals in toxicity tests while promoting the use of new approach methodologies. The understanding of conservation of molecular targets and pathways provides an opportunity to extrapolate effects across species and ultimately to determine the taxonomic applicability domain of assays and biological effects.

Using membrane-water partition coefficients in a critical membrane burden approach to aid the identification of neutral and ionizable chemicals that induce acute toxicity below narcosis levels.

The risk assessment of thousands of chemicals used in our society benefits from adequate grouping of chemicals based on the mode and mechanism of toxic action (MoA). We measure the phospholipid membrane-water distribution ratio () using a chromatographic assay (IAM-HPLC) for 121 neutral and ionized organic chemicals and screen other methods to derive . We use IAM-HPLC based as a chemical property to distinguish between baseline narcosis and specific MoA, for reported acute toxicity endpoints on two separate sets of chemicals.

Construction of an In Silico Structural Profiling Tool Facilitating Mechanistically Grounded Classification of Aquatic Toxicants.

The performance of chemical safety assessment within the domain of environmental toxicology is often impeded by a shortfall of appropriate experimental data describing potential hazards across the many compounds in regular industrial use. In silico schemes for assigning aquatic-relevant modes or mechanisms of toxic action to substances, based solely on consideration of chemical structure, have seen widespread employment─including those of Verhaar, Russom, and later Bauer (MechoA). Recently, development of a further system was reported by Sapounidou, which, in common with MechoA, seeks to ground its classifications in understanding and appreciation of molecular initiating events.

Toxicity by descent: A comparative approach for chemical hazard assessment.

Toxicology is traditionally divided between human and eco-toxicology. In the shared pursuit of environmental health, this separation does not account for discoveries made in the comparative studies of animal genomes. Here, we provide evidence on the feasibility of understanding the health impact of chemicals on all animals, including ecological keystone species and humans, based on a significant number of conserved genes and their functional associations to health-related outcomes across much of animal diversity.

A scheme to evaluate structural alerts to predict toxicity - Assessing confidence by characterising uncertainties.

Structure-activity relationships (SARs) in toxicology have enabled the formation of structural rules which, when coded as structural alerts, are essential tools in in silico toxicology. Whilst other in silico methods have approaches for their evaluation, there is no formal process to assess the confidence that may be associated with a structural alert. This investigation proposes twelve criteria to assess the uncertainty associated with structural alerts, allowing for an assessment of confidence.

Data-driven learning of narcosis mode of action identifies a CNS transcriptional signature shared between whole organism Caenorhabditis elegans and a fish gill cell line.

With the large numbers of man-made chemicals produced and released in the environment, there is a need to provide assessments on their potential effects on environmental safety and human health. Current regulatory frameworks rely on a mix of both hazard and risk-based approaches to make safety decisions, but the large number of chemicals in commerce combined with an increased need to conduct assessments in the absence of animal testing makes this increasingly challenging. This challenge is catalysing the use of more mechanistic knowledge in safety assessment from both in silico and in vitro approaches in the hope that this will increase confidence in being able to identify modes of action (MoA) for the chemicals in question.

Skin Blood Flow Responses to Acetylcholine, Local Heating, and to 60% VO2max exercise with and without Nitric Oxide inhibition, in Boys vs. Girls.

Purpose: To determine sex-related differences in the skin blood flow (SkBF) response to exercise, local heating, and acetylcholine (ACh) in children, and to assess nitric oxide contribution to the SkBF response.

Methods: Forearm SkBF during local heating (44°C), ACh iontophoresis, and exercise (30-min cycling and 60% of maximum oxygen consumption) was assessed, using laser Doppler fluxmetry, in 12 boys and 12 girls (7-13 y old), with and without nitric oxide synthase inhibition, using Nω-nitro-L-arginine methyl ester iontophoresis.

Results: Local-heating-induced and ACh-induced SkBF increase were not different between boys and girls (local heating: 1445% [900%] and 1432% [582%] of baseline, P = .

Screening the baseline fish bioconcentration factor of various types of surfactants using phospholipid binding data.

Fish bioconcentration factors (BCFs) are commonly used in chemical hazard and risk assessment. For neutral organic chemicals BCFs are positively correlated with the octanol-water partition ratio (), but is not a reliable parameter for surfactants. Membrane lipid-water distribution ratios () can be accurately measured for all kinds of surfactants, using phospholipid-based sorbents.

A comprehensive study of the epidemiology of haematological malignancies in North Queensland.

Background: There is an absence of clinically relevant epidemiological data in regional Australia pertaining to haematological malignancies.

Aim: To determine the incidence and geographical variation of haematological malignancies in North Queensland using a clinically appropriate disease classification.

Methods: Retrospective, observational study of individual patient data records of all adults diagnosed with a haematological malignancy between 2005 and 2014 and residing within The Townsville Hospital Haematology catchment region.

Severe mental illness is associated with increased mortality and severe course of COVID-19.

Objective: Psychiatric disorders have been associated with unfavourable outcome following respiratory infections. Whether this also applies to coronavirus disease 2019 (COVID-19) has been scarcely investigated.

Methods: Using the Danish administrative databases, we identified all patients with a positive real-time reverse transcription-polymerase chain reaction test for COVID-19 in Denmark up to and including 2 January 2021.

Harmonized and high-quality datasets of aerosol optical depth at a US continental site, 1997-2018.

Aerosol optical depth (AOD) characterizes the aerosol burden in the atmosphere, while its wavelength dependence is a sign of particle size. Long-term records of wavelength-resolved AOD with high quality and suitable continuity are required for climate change assessment. Typically, climate-related studies use AOD products provided by several, and perhaps different, ground-based instruments.

Development of an Enhanced Mechanistically Driven Mode of Action Classification Scheme for Adverse Effects on Environmental Species.

This study developed a novel classification scheme to assign chemicals to a verifiable mechanism of (eco-)toxicological action to allow for grouping, read-across, and model generation. The new classification scheme unifies and extends existing schemes and has, at its heart, direct reference to molecular initiating events (MIEs) promoting adverse outcomes. The scheme is based on three broad domains of toxic action representing nonspecific toxicity (e.

Pedagogy, Partnership, and Collaboration: A Longitudinal, Empirical Study of Serious Educational Gameplay in Secondary Biology Classrooms.

The use of serious educational games has the potential to increase student learning outcomes in science education by providing students with opportunities to explore phenomena in ways that vary from traditional instruction; yet, empirical research to support this assertion is limited. This study aimed to explore deeply what learning gains were associated with the use of three serious educational games (SEGs) created for use in secondary biology classrooms that partner teachers implemented during a 2-week curriculum unit. This longitudinal, mixed method study includes a control year, in which we examined how six highly qualified teachers taught students ( = 407) a 2-week curriculum unit addressing cellular biology the SEGs, followed by 2 years in which the teachers integrated the SEGs into the curriculum unit with students ( =871).

Linking the hemodynamic consequences of adverse childhood experiences to an altered HPA axis and acute stress response.

Adverse childhood experiences (ACEs), such as maltreatment and severe household dysfunction, represent a significant threat to public health as ACEs are associated with increased prevalence of several chronic diseases. Biological embedding, believed to be rooted in dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, is the prevailing theory by which chronic diseases become imprinted in individuals following childhood adversity. A shift towards HPA axis hypoactivity occurs in response to ACEs exposure and is proposed to contribute towards altered cortisol secretion, chronic low-grade inflammation, and dysregulated hemodynamic and autonomic function.

Association between biomarkers and COVID-19 severity and mortality: a nationwide Danish cohort study.

Objective: To evaluate the association between common biomarkers, death and intensive care unit (ICU) admission in patients with COVID-19.

Design: Retrospective cohort study. From electronic national registry data, we used Cox analysis and bootstrapping to evaluate associations between baseline levels of biomarkers and standardised absolute risks of death/ICU admission, adjusted for age and gender.