Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based DHODH inhibitors through a scaffold hop from a pyrrole-based series.

CDS2 expression regulates de novo phosphatidic acid synthesis.

CDS enzymes (CDS1 and 2 in mammals) convert phosphatidic acid (PA) to CDP-DG, an essential intermediate in the de novo synthesis of PI. Genetic deletion of CDS2 in primary mouse macrophages resulted in only modest changes in the steady-state levels of major phospholipid species, including PI, but substantial increases in several species of PA, CDP-DG, DG and TG. Stable isotope labelling experiments employing both 13C6- and 13C6D7-glucose revealed loss of CDS2 resulted in a minimal reduction in the rate of de novo PI synthesis but a substantial increase in the rate of de novo PA synthesis from G3P, derived from DHAP via glycolysis.

Evidence of longitudinal differences in spring migration strategies of an Arctic-nesting goose.

During spring, migratory birds are required to optimally balance energetic costs of migration across heterogeneous landscapes and weather conditions to survive and reproduce successfully. Therefore, an individual's migratory performance may influence reproductive outcomes. Given large-scale changes in land use, climate, and potential carry-over effects, understanding how individuals migrate in relation to breeding outcomes is critical to predicting how future scenarios may affect populations.

Human-Induced Range Expansions Result in a Recent Hybrid Zone between Sister Species of Ducks.

Landscapes are consistently under pressure from human-induced ecological change, often resulting in shifting species distributions. For some species, changing the geographical breadth of their niche space results in matching range shifts to regions other than those in which they are formally found. In this study, we employ a population genomics approach to assess potential conservation issues arising from purported range expansions into the south Texas Brush Country of two sister species of ducks: mottled () and Mexican () ducks.

Relationship between trauma, psychological distress and help-seeking among corrective service workers.

Background: Corrective service workers (CSWs) are at high risk of post-traumatic stress disorder (PTSD) and other mental health problems. Prevalence rates and help-seeking behaviours are under-researched within this population.

Aims: To assess rates of PTSD and distress, and identify predictors of intention to seek help, among workers at an Australian corrective service agency.

Flood-irrigated agriculture mediates climate-induced wetland scarcity for summering sandhill cranes in western North America.

Information about species distributions is lacking in many regions of the world, forcing resource managers to answer complex ecological questions with incomplete data. Information gaps are compounded by climate change, driving ecological bottlenecks that can act as new demographic constraints on fauna. Here, we construct greater sandhill crane () summering range in western North America using movement data from 120 GPS-tagged individuals to determine how landscape composition shaped their distributions.

Analysis of SARS-CoV-2 Variant-Specific Serum Antibody Post-Vaccination Utilizing Immortalized Human Hepatocyte-Like Cells (HLC) to Assess Development of Immunity.

Background: Our previous studies demonstrated that SARS-CoV-2 spike protein could bind to primary hepatocytes and immortalized Hepatocyte-like cells (HLC) via the asialoglycoprotein receptor-1 (ASGR-1). The binding of biotinylated spike protein could be inhibited by Spike-neutralizing monoclonal antibodies, anti-ASGR-1 antibodies and unlabeled spike protein. The cells were unable to bind Spike S1 and Spike S1 was incapable of blocking labeled Spike protein, suggesting that the Receptor Binding Domain (RBD) was not involved in the binding event.

Selective Prevention of Depression in Workers Using a Smartphone App: Randomized Controlled Trial.

Background: There is increasing evidence that depression can be prevented; however, universal approaches have had limited success. Appropriate targeting of interventions to at-risk populations has been shown to have potential, but how to selectively determine at-risk individuals remains unclear. Workplace stress is a risk factor for depression and a target for intervention, but few interventions exist to prevent depression among workers at risk due to heightened stress.

Mental health and unemployment: A systematic review and meta-analysis of interventions to improve depression and anxiety outcomes.

Background: Unemployment is associated with substantially greater depression and anxiety, constituting a considerable public health concern. The current review provides the most comprehensive synthesis to date, and first meta-analysis, of controlled intervention trials aimed at improving depression and anxiety outcomes during unemployment.

Methods: Searches were conducted within PsycInfo, Cochrane Central, PubMed and Embase from their inception to September 2022.

The development of a smartphone app to enhance post-traumatic stress disorder treatment in high-risk workers.

Objective: Post-traumatic stress disorder (PTSD) is highly prevalent in certain populations. However, evidence indicates that many individuals do not respond to treatment. Digital supports hold promise for increasing service provision and engagement but there is a lack of evidence on blended care options and still less research guiding the development of such tools.

Pilot Trial of Workable: A Therapist-Supported Digital Program for Injured Workers.

Workplace sickness absence is a major public health and economic problem, and common mental disorders (CMDs) such as anxiety and depression are associated with particularly high rates of long-term sickness absence. Effective return-to-work (RTW) interventions are required. This pilot study investigates the feasibility, acceptability, and potential effectiveness of a new therapist-assisted Web-based RTW intervention ( for injured workers on sick leave for a psychological or physical injury.

Joint use of location and acceleration data reveals influences on transitions among habitats in wintering birds.

Quantifying relationships between animal behavior and habitat use is essential to understanding animal decision-making. High-resolution location and acceleration data allows unprecedented insights into animal movement and behavior. These data types allow researchers to study the complex linkages between behavioral plasticity and habitat distribution.

A Qualitative Exploration of Challenges and Opportunities for Dog Welfare in Ireland Post COVID-19, as Perceived by Dog Welfare Organisations.

This novel qualitative study identifies challenges and opportunities to improve dog welfare in Ireland, as perceived by dog welfare organisations (DWOs), a previously underutilised stakeholder. This study sought the views of this predominantly voluntary sector of the next steps for policy and action in dog welfare, in light of the effects of the "puppy pandemic", increased costs and COVID-19 restrictions. An integrated online focus group and interview design involving DWOs was analysed using inductive thematic analysis.

Caught in the act: Monitoring OO bond cleavage in Acylperoxoferric cytochrome P450cam to form compound I in real time.

While monitoring the reaction of ferric cytochrome P450cam (Cyp101) with substituted peroxybenzoic acids using rapid-scanning, stopped-flow (RSSF) spectroscopy, an intermediate appears en route to formation of the high-valent moiety known as Compound I [Fe(IV)=O/porphyrin radical cation] that is thought to be the key catalytic species for O-atom transfer to substrate. We have previously suggested (Spolitak, T., Dawson, J.

Understanding the dog population in the Republic of Ireland: insight from existing data sources?

Background: Reliable information about national pet dog populations is an important contributor to informed decision-making, both by governments and national dog welfare organisations. In some countries, there is an improved understanding of aspects of the national pet dog population, but as yet limited published information is available in Ireland. The current study reviews the utility of existing data to inform our understanding of recent changes to the pet dog population in Ireland, including both biological and organisational processes.

Acyl chain selection couples the consumption and synthesis of phosphoinositides.

Phosphoinositides (PIPn) in mammalian tissues are enriched in the stearoyl/arachidonoyl acyl chain species ("C38:4"), but its functional significance is unclear. We have used metabolic tracers (isotopologues of inositol, glucose and water) to study PIPn synthesis in cell lines in which this enrichment is preserved to differing relative extents. We show that PIs synthesised from glucose are initially enriched in shorter/more saturated acyl chains, but then rapidly remodelled towards the C38:4 species.

Differentiation of immortalized human multi-lineage progenitor to alveolar type 2-like cells: angiotensin-converting enzyme 2 expression and binding of severe acute respiratory syndrome coronavirus 2 spike and spike 1 proteins.

Along with the nasal epithelium, the lung epithelium is a portal of entry for sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and many other respiratory viruses. In the case of SARS-CoV-2, the virus surface spike proteins bind to the angiotensin-converting enzyme 2 (ACE-2) receptor to facilitate entry into the respiratory epithelium. Alveolar type 2 (AT2) cells are committed respiratory progenitor cells responsible for the integrity and regeneration of the respiratory epithelium and production of respiratory surfactant proteins.

Binding of the SARS-CoV-2 Spike Protein to the Asialoglycoprotein Receptor on Human Primary Hepatocytes and Immortalized Hepatocyte-Like Cells by Confocal Analysis.

Background: The SARS-CoV-2 virus may have direct or indirect effects on other human organs beyond the respiratory system and including the liver, via binding of the spike protein. This study investigated the potential direct interactions with the liver by comparing the binding of SARS-CoV-2 spike proteins to human AT2-like cells, primary human hepatocytes and immortalized hepatocyte-like hybrid cells. Receptors with binding specificity for SARS-CoV-2 spike protein on AT2 cells and hepatocytes were identified.

CRISPR/Cas9-Based Lateral Flow and Fluorescence Diagnostics.

Clustered regularly interspaced short palindromic repeat (CRISPR/Cas) proteins can be designed to bind specified DNA and RNA sequences and hold great promise for the accurate detection of nucleic acids for diagnostics. We integrated commercially available reagents into a CRISPR/Cas9-based lateral flow assay that can detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequences with single-base specificity. This approach requires minimal equipment and represents a simplified platform for field-based deployment.