Hydrogen-Borrowing-Based Methods for the Construction of Quaternary Stereocentres.

Compounds containing quaternary stereocentres are a valuable motif in biologically active compounds. Herein we present our strategy to utilise the hydrogen borrowing manifold to access α-quaternary ketones via a tandem acceptorless dehydrogenation-cyclisation cascade. This new application of the methodology results in the formation of five- and six-membered carbocycles with a high degree of diastereoselectivity.

Expedited SARS-CoV-2 Main Protease Inhibitor Discovery through Modular 'Direct-to-Biology' Screening.

Reactive fragment (RF) screening has emerged as an efficient method for ligand discovery across the proteome, irrespective of a target's perceived tractability. To date, however, the efficiency of subsequent optimisation campaigns has largely been low-throughput, constrained by the need for synthesis and purification of target compounds. We report an efficient platform for 'direct-to-biology' (D2B) screening of cysteine-targeting chloroacetamide RFs, wherein synthesis is performed in 384-well plates allowing direct assessment in downstream biological assays without purification.

Retrospective cohort study investigating the relationship between diarrhea during the preweaning period and subsequent survival, health, and production in dairy cows.

The primary objective of this study was to evaluate the association between preweaning diarrhea and measures of survival, health, and production. The measures of interest included survival (mortality before first calving and time to removal from the herd), health (retained fetal membranes, metritis, mastitis, and SCC), and production (305-d mature-equivalent milk yield and time to first calving). A secondary objective was to investigate if these associations varied according to the age of the calf when the case of diarrhea occurred.

Evaluation of point-of-care tests for identification of pathogens to inform clinical mastitis treatment decisions in pasture- and confinement-managed dairy cows in Australia.

To support antimicrobial stewardship in livestock production, there is a growing array of point-of-care diagnostics to guide antimicrobial treatment. The primary objective of this observational study was to evaluate the diagnostic performance of 5 point-of-care tests currently available in Australia for guiding lactational treatment of nonsevere clinical mastitis. A secondary objective was to describe the pathogen profiles of mastitis-causing organisms in cows managed in barns ("intensive") and on pasture ("nonintensive").

Etiology and epidemiology of digital dermatitis in Australian dairy herds.

Bovine digital dermatitis (BDD) is an important cause of lameness in dairy cows worldwide. However, very little is known about this disease in Australian herds, which are predominantly managed on pasture. The primary objectives of this cross-sectional study were to describe the presence and prevalence of BDD in Australian dairy herds and to characterize the microbiota of healthy skin and M4 lesions of BDD-affected, pasture-managed cows.

Synthesis of Cyclopropanes via Hydrogen-Borrowing Catalysis.

Cyclopropanes are highly useful motifs that are often incorporated into drug candidates to improve potency, metabolic stability, or pharmacokinetic properties. An expedient method for the α-cyclopropanation of ketones using hydrogen borrowing (HB) catalysis is described. The transformation occurs via HB alkylation of a hindered ketone with subsequent intramolecular displacement of a pendant leaving group affording the cyclopropanated product.

Negatively controlled trial investigating the effects of dry cow therapy on clinical mastitis and culling in multiparous cows.

Blanket dry cow therapy (DCT) is a major contributor to overall antibiotic usage on dairy farms in the United States. With low prevalence of intramammary infections at dry-off in US herds today, alternative DCT approaches have been the focus of much research. We hypothesized that complete cessation of DCT [i.

Selective dry-cow therapy can be implemented successfully in cows of all milk production levels.

Antibiotic stewardship on dairy farms can be heightened through the implementation of selective dry-cow therapy (SDCT). However, some producers are concerned that this practice may be related to poor udder health outcomes in cows with high milk production at the time of dry-off. The objective of this study was to evaluate if the effect of culture-guided SDCT (Cult-SDCT) and algorithm-guided SDCT (Alg-SDCT) on dry-period intramammary infection (IMI) dynamics and postcalving udder health and performance [when compared with blanket dry-cow therapy (BDCT)] varied according to milk production level before dry-off.

Can apps be used to formulate fluid therapy plans in veterinary medicine?

Background: Formulating sophisticated fluid therapy plans can be complicated and time consuming. Consequently, veterinarians in the field who lack experience, time, or confidence may formulate suboptimal fluid therapy plans.

Objectives: Compare conventional and app-guided fluid therapy plans for simulated cases of neonatal calf diarrhea.

Invited review: Selective use of antimicrobials in dairy cattle at drying-off.

Administering intramammary antimicrobials to all mammary quarters of dairy cows at drying-off [i.e., blanket dry cow therapy (BDCT)] has been a mainstay of mastitis prevention and control.

The microbiome of common bedding materials before and after use on commercial dairy farms.

Background: Bovine mastitis is one of the most economically important diseases affecting dairy cows. The choice of bedding material has been identified as an important risk factor contributing to the development of mastitis. However, few reports examine both the culturable and nonculturable microbial composition of commonly used bedding materials, i.

Energetics of lipid transport by the ABC transporter MsbA is lipid dependent.

The ABC multidrug exporter MsbA mediates the translocation of lipopolysaccharides and phospholipids across the plasma membrane in Gram-negative bacteria. Although MsbA is structurally well characterised, the energetic requirements of lipid transport remain unknown. Here, we report that, similar to the transport of small-molecule antibiotics and cytotoxic agents, the flopping of physiologically relevant long-acyl-chain 1,2-dioleoyl (C18)-phosphatidylethanolamine in proteoliposomes requires the simultaneous input of ATP binding and hydrolysis and the chemical proton gradient as sources of metabolic energy.

The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions.

Bacterial infections caused by 'superbugs' are increasing globally, and conventional antibiotics are becoming less effective against these bacteria, such that we risk entering a post-antibiotic era. In recent years, antimicrobial peptides (AMPs) have gained significant attention for their clinical potential as a new class of antibiotics to combat antimicrobial resistance. In this review, we discuss several facets of AMPs including their diversity, physicochemical properties, mechanisms of action, and effects of environmental factors on these features.

Micronutrients and respiratory infections: the biological rationale and current state of clinical evaluation.

A range of nutrients has been studied or proposed for use in preventing respiratory tract infections and reducing their severity. This article gives a narrative review of the existing literature, biological rationales and current state of clinical evaluation for micronutrient therapies. The importance of vitamin A, the B vitamins, vitamin C, vitamin D, eicosapentaenoic acid, vitamin E, selenium, zinc and a range of combination therapies are discussed, looking at their effects on reducing rates of infection, reducing severity of infection and improved recovery from infection.

Reducing False Positives through the Application of Fluorescence Lifetime Technology: A Comparative Study Using TYK2 Kinase as a Model System.

The predominant assay detection methodologies used for enzyme inhibitor identification during early-stage drug discovery are fluorescence-based. Each fluorophore has a characteristic fluorescence decay, known as the fluorescence lifetime, that occurs throughout a nanosecond-to-millisecond timescale. The measurement of fluorescence lifetime as a reporter for biological activity is less common than fluorescence intensity, even though the latter has numerous issues that can lead to false-positive readouts.

Longitudinal study of herd udder hygiene and its association with clinical mastitis in pasture-based dairy cows.

The objectives of this exploratory study were to (1) describe the association between herd-level udder hygiene and clinical mastitis and (2) investigate how sample size and milking stage affect the accuracy and precision of herd udder hygiene assessments made at milking time. A prospective longitudinal study was conducted in a dairy herd in Northern Australia as part of a previously published clinical trial of premilking teat disinfection. Video footage from 35 afternoon milkings was used to conduct 12,544 udder hygiene scores from 504 cows during an 89-d period and measure udder hygiene of the herd (proportion of cows with udder hygiene ≥3 out of 4).

Evaluation of three immunological assays to mitigate the risk of transboundary spread of Coxiella burnetii by alpacas.

Coxiella burnetii causes coxiellosis in animals and Q fever in humans, a potentially debilitating zoonotic disease commonly transmitted through domestic ruminants. To prevent transboundary spread of C. burnetii, animals may be tested prior to export.

The role of chemical synthesis in developing RiPP antibiotics.

The growing antimicrobial resistance crisis necessitates the discovery and development of novel classes of antibiotics if a 'postantibiotic era' is to be avoided. Ribosomally synthesised and post-translationally modified peptides, or RiPPs, are becoming increasingly recognised as a potential source of antimicrobial drugs. This is due to a combination of their potent antimicrobial activity and their high stability relative to unmodified linear peptides.

The Emerging Role of Vitamin C in the Prevention and Treatment of COVID-19.

Investigation into the role of vitamin C in the prevention and treatment of pneumonia and sepsis has been underway for many decades. This research has laid a strong foundation for translation of these findings into patients with severe coronavirus disease (COVID-19). Research has indicated that patients with pneumonia and sepsis have low vitamin C status and elevated oxidative stress.