Unlocking nature's antioxidants: a novel method for synthesising plasmalogens.

Plasmalogens are glycerophospholipids distinguished by their -()-vinyl ether at the -1 position. These lipids are implicated in several disease states requiring analytical, diagnostic and therapeutic interventions, which demand synthetic availability for a variety of structural types. By deploying the new -protecting group 1,4-dimethoxynaphthyl-2-methyl ('DIMON') and a new stereospecific method for accessing -vinyl ethers, a reproducible, versatile synthetic route to plasmalogens [plasmenyl phosphocholines] has been developed.

The action of coenzyme B12-dependent diol dehydratase on 3,3,3-trifluoro-1,2-propanediol results in elimination of all the fluorides with formation of acetaldehyde.

3,3,3-Trifluoro-1,2-propanediol undergoes complete defluorination in two distinct steps: first, the conversion into 3,3,3-trifluoropropionaldehyde catalyzed by adenosylcobalamin (coenzyme B12)-dependent diol dehydratase; second, non-enzymatic elimination of all three fluorides from this aldehyde to afford malonic semialdehyde (3-oxopropanoic acid), which is decarboxylated to acetaldehyde. Diol dehydratase accepts 3,3,3-trifluoro-1,2-propanediol as a relatively poor substrate, albeit without significant mechanism-based inactivation of the enzyme during catalysis. Optical and electron paramagnetic resonance (EPR) spectra revealed the steady-state formation of cob(II)alamin and a substrate-derived intermediate organic radical (3,3,3-trifluoro-1,2-dihydroxyprop-1-yl).

Factor VIII moiety of recombinant Factor VIII Fc fusion protein impacts Fc effector function and CD16 NK cell activation.

Recombinant Factor VIII-Fc fusion protein (rFVIIIFc) is an enhanced half-life therapeutic protein product used for the management of hemophilia A. Recent studies have demonstrated that rFVIIIFc interacts with Fc gamma receptors (FcγR) resulting in the activation or inhibition of various FcγR-expressing immune cells. We previously demonstrated that rFVIIIFc, unlike recombinant Factor IX-Fc (rFIXFc), activates natural killer (NK) cells via Fc-mediated interactions with FcγRIIIA (CD16).

Dosing Strategy of Immunoglobulin (IgG) Replacement Therapies in Obese and Overweight Patients with Primary Immunodeficiency Diseases (PIDDs): A Meta-Analysis of Clinical Trials.

The current dosing strategy of immune globulin products for the treatment of primary immunodeficiency diseases (PIDDs) in the USA is based on total body weight (BW). The aim of our study was to assess the relationship between dose and trough level, and to determine whether an alternative dosing strategy should be considered for patients who are overweight or obese. We analyzed data in a total of 533 patients from 11 studies.

Emerging approaches to induce immune tolerance to therapeutic proteins.

Immunogenicity affects the safety and efficacy of therapeutic proteins. This review is focused on approaches for inducing immunological tolerance to circumvent the immunogenicity of therapeutic proteins in the clinic. The few immune tolerance strategies that are used in the clinic tend to be inefficient and expensive and typically involve global immunosuppression, putting patients at risk of infections.

1,4-Dimethoxynaphthalene-2-methyl ('DIMON'), an oxidatively labile protecting group for synthesis of polyunsaturated lipids.

A new benzyl-type protecting group (1,4-dimethoxynaphthalene-2-methyl, 'DIMON') for hydroxyl functions can be selectively removed under oxidative conditions without damaging polyunsaturated fatty acyl groups. Its application is shown by the first synthesis of an ether (plasmanyl) phospholipid containing the docosa-(4,7,10,13,16,19)-hexaenoyl group.

Probing gallic acid-starch interactions through Rapid ViscoAnalyzer in vitro digestion.

Phenolic compounds are known inhibitors of starch digestion through binding with α-amylase. However, a growing body of research shows that phenolic-starch interactions at the molecular level may interfere with this inhibition potential. In this study, we evaluated the effect of Gallic Acid (GA) as a model phenolic compound on starch digestion kinetics carried out in vitro in a Rapid ViscoAnalyzer (RVA).

Harnessing the Peterson Reaction for the Stereospecific Synthesis of Z-Vinyl Ethers.

Vinyl ethers are valuable synthetic intermediates which are also found as natural products, including aflatoxins, rifamycins and plasmalogens. The latter are ubiquitous phospholipids in human cells and contain a vinyl ether moiety with specifically Z configuration. Although numerous methods are available for synthesis of vinyl ethers, there is a lack of methods for obtaining Z isomers of molecules of the type RCH=CHOR' that are applicable to plasmalogens.

Building partnerships with local schools.

Background: Medical schools have a responsibility to support their students in developing an understanding of the complex concepts of a 'VUCA' (volatile, uncertain, complex and ambiguous) world. To achieve this, service learning approaches have been increasingly successfully employed for students to learn through participating in activities addressing local community priorities. Sharing outcomes and lessons from such programmes is essential for advancing service learning.

Community action projects: community-engaged quality improvement for medical students.

Background: Healthcare Quality Improvement (QI) is an essential skill for medical students to acquire, although there is insufficient empirical research which suggests the best educational methods to do this. This study explored the experiences of medical students participating in two versions of a Community Action Project (CAP) which gave medical students the opportunity to learn QI skills in a community setting. The first version (GPCAP) was pre-pandemic where students identified and delivered QI projects on placement in general practice to improve local population health.

Community-engaged primary care medical education.

Background: Community-engaged medical education (CEME) requires medical schools to partner with local communities to help address community priorities, whilst enhancing the learning experiences of students. Current literature on CEME has focused on evaluating its effects on students; however, there remains a gap in exploring whether CEME initiatives can have a sustainable impact for communities.

Approach: The Community Action Project (CAP) at Imperial College London, is an eight-week, community-engaged, quality improvement project for Year 3 medical students.

NAFLD and NASH biomarker qualification in the LITMUS consortium - Lessons learned.

Biomarkers have the potential to accelerate drug development, as early indicators of improved clinical response, to improve patient safety, and for personalised medicine. However, few have been approved through the biomarker qualification pathways of the regulatory agencies. This paper outlines how biomarkers can accelerate drug development, and reviews the lessons learned by the EU IMI2-funded LITMUS consortium, which has had several interactions with regulatory agencies in both the US and EU regarding biomarker qualification in patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

Build-Couple-Transform: A Paradigm for Lead-like Library Synthesis with Scaffold Diversity.

High-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks using single reaction types.

A structural homology approach to identify potential cross-reactive antibody responses following SARS-CoV-2 infection.

The emergence of the novel SARS-CoV-2 virus is the most important public-health issue of our time. Understanding the diverse clinical presentations of the ensuing disease, COVID-19, remains a critical unmet need. Here we present a comprehensive listing of the diverse clinical indications associated with COVID-19.

Shedding light: A qualitative study of women's view on Men's Sheds in Ireland and Australia.

Older men are less likely than women to meet in social groups and have greater difficulty developing social relationships beyond paid work. Yet they are joining Men's Sheds in ever greater numbers, often with the support of women, as wives, partners and daughters. Little is known about women's perspectives of Men's Sheds and what women get from men's participation in Sheds.

Influence of the methyl group in isoprene epoxides on reactivity compared to butadiene epoxides: Biological significance.

Reactions of the epoxides of 1,3-butadiene and isoprene (2-methyl-1,3-butadiene) with oxygen, nitrogen and sulfur nucleophiles have been compared to enable a better molecular understanding of the relative human toxicities of these epoxides. Hydrolysis of rac.-ethenyloxirane in (O)water gave 77% (2-O)but-3-ene-1,2-diol and 23% (1-O)but-3-ene-1,2-diol.

Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity.

Cyclizations and fragmentations in the alkylation of 6-chloro-5-hydroxy-4-aminopyrimidines with aminoalkyl chlorides.

Substituted aminopyrimidines are an important class of compounds, in part because they frequently show biological activity. Facile synthesis of polysubstituted aminopyrimidines is highly desirable for the synthesis of screening libraries. We describe a route to 4,6-diamino-5-alkoxypyrimidines via a SAr-alkylation-SAr sequence from readily available 4,6-dichloro-5-methoxypyrimidine, which allows the synthesis of such compounds with regiochemical control.

Community-engaged medical education: helping to address child health and social inequality.

Medical education has a key role in helping to address child health and social inequality. In this paper we describe the rationale for developing a community-engaged approach to education, whereby medical schools partner with local communities. This symbiotic relationship enables medical students to experience authentic learning through working with communities to address local health and social priorities.

Pharmacokinetics and Efficacy of Human Hyperimmune Intravenous Immunoglobulin Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Adult Syrian Hamsters.

Background: After the failure of antibody therapies in treating hospitalized patients with coronavirus disease 2019 (COVID-19), we investigated the impact of viral replication on the pharmacokinetics and efficacy of a hyperimmune severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin (CoVIG) product in treating SARS-CoV-2 infection using an adult Syrian hamster model.

Methods: The CoVIG was manufactured from plasma donors who had recovered from COVID-19. The dose used (400 mg/kg) was based on the dose given in clinical trials to hospitalized patients with COVID-19.

Epitope diversity of SARS-CoV-2 hyperimmune intravenous human immunoglobulins and neutralization of variants of concern.

Hyperimmune immunoglobulin (hCoV-2IG) generated from SARS-CoV-2 convalescent plasma (CP) are under evaluation in clinical trials. Here we explored the antibody epitope repertoire, and virus neutralizing capacity of six hCoV-2IG batches as well as nine CP against SARS-CoV-2 and emerging variants of concern (VOCs). Epitope-mapping by gene-fragment phage display library spanning the SARS-CoV-2 spike demonstrated broad recognition of multiple antigenic sites spanning the entire spike that was higher for hCoV-2IG than CP, with predominant binding to the fusion peptide.