Obesity, insulin resistance, type 2 diabetes mellitus and cardiovascular disease form a metabolic disease continuum that has seen a dramatic increase in prevalence in developed and developing ...countries over the past two decades. Dyslipidaemia resulting from hypercaloric diets is a major contributor to the pathogenesis of metabolic disease, and lipid-lowering therapies are the main therapeutic option for this group of disorders. However, the fact that dysfunctional lipid metabolism extends far beyond cholesterol and triglycerides is becoming increasingly clear. Lipidomic studies and mouse models are helping to explain the complex interactions between diet, lipid metabolism and metabolic disease. These studies are not only improving our understanding of this complex biology, but are also identifying potential therapeutic avenues to combat this growing epidemic. This Review examines what is currently known about phospholipid and sphingolipid metabolism in the setting of obesity and how metabolic pathways are being modulated for therapeutic effect.
One Health is the collaborative effort of multiple health science professions to attain optimal health for people, domestic animals, wildlife, plants, and our environment. The drivers of ...antimicrobial resistance include antimicrobial use and abuse in human, animal, and environmental sectors and the spread of resistant bacteria and resistance determinants within and between these sectors and around the globe. Most of the classes of antimicrobials used to treat bacterial infections in humans are also used in animals. Given the important and interdependent human, animal, and environmental dimensions of antimicrobial resistance, it is logical to take a One Health approach when addressing this problem. This includes taking steps to preserve the continued effectiveness of existing antimicrobials by eliminating their inappropriate use and by limiting the spread of infection. Major concerns in the animal health and agriculture sectors are mass medication of animals with antimicrobials that are critically important for humans, such as third-generation cephalosporins and fluoroquinolones, and the long-term, in-feed use of medically important antimicrobials, such as colistin, tetracyclines, and macrolides, for growth promotion. In the human sector it is essential to prevent infections, reduce over-prescribing of antimicrobials, improve sanitation, and improve hygiene and infection control. Pollution from inadequate treatment of industrial, residential, and farm waste is expanding the resistome in the environment. Numerous countries and several international agencies have included a One Health approach within their action plans to address antimicrobial resistance. Necessary actions include improvements in antimicrobial use regulation and policy, surveillance, stewardship, infection control, sanitation, animal husbandry, and alternatives to antimicrobials. WHO recently has launched new guidelines on the use of medically important antimicrobials in food-producing animals, recommending that farmers and the food industry stop using antimicrobials routinely to promote growth and prevent disease in healthy animals. These guidelines aim to help preserve the effectiveness of antimicrobials that are important for human medicine by reducing their use in animals.
A copper-mediated radiofluorination of aryl- and vinylboronic acids with K18F is described. This method exhibits high functional group tolerance and is effective for the radiofluorination of a range ...of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and vinylboronic acids. This method has been applied to the synthesis of 18FFPEB, a PET radiotracer for quantifying metabotropic glutamate 5 receptors.
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IJS, KILJ, NUK, PNG, UL, UM
A practical, rapid, and highly regioselective Cu-catalyzed radiofluorination of (mesityl)(aryl)iodonium salts is described. This protocol utilizes 18FKF to access 18F-labeled electron-rich, ...-neutral, and -deficient aryl fluorides under a single set of mild conditions. This methodology is applied to the synthesis of protected versions of two important radiotracers: 4-18Ffluorophenylalanine and 6-18FfluoroDOPA.
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IJS, KILJ, NUK, PNG, UL, UM
The last 2-3 years have seen numerous relationships develop between organometallic chemists, fluorine chemists and PET Centers around the world. These collaborations have led to the development of ...many new strategies for the late-stage introduction of fluorine-18 into complex bioactive molecules. In this perspective we highlight recent developments and key milestones since 2011.
In this perspective we highlight recent developments and key milestones in "late-stage fluorination" since 2011.
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IJS, KILJ, NUK, UL, UM, UPUK
This phase 3 trial evaluated the safety and efficacy of inclisiran, a small interfering RNA that inhibits hepatic PCSK9 synthesis, in 482 adults with heterozygous familial hypercholesterolemia, who ...received subcutaneous injections of inclisiran or placebo on days 1, 90, 270, and 450. Changes in cholesterol were assessed up to day 540.
The iridium‐catalysed borylation of aromatic C−H bonds has become the preferred method for the synthesis of aromatic organoboron compounds. The reaction is highly efficient, tolerant of a broad range ...of substituents and can be applied to both carbocyclic and heterocyclic substrates. The regioselectivity of C−H activation is dominated by steric considerations and there have been considerable efforts to develop more selective processes for less constrained substrates. However, most of these have focused on benzenoid‐type substrates and in contrast, heteroarenes remain much desired but more challenging substrates with the position and/or nature of the heteroatom(s) significantly affecting reactivity and regioselectivity. This review will survey the borylation of heteroarenes, focusing on the influence of steric and electronic effects on regiochemical outcome and, by linking to current mechanistic understandings, will provide insights to what is currently possible and where further developments are required.
Which C−H bond? The iridium‐catalysed C−H borylation reaction is a powerful method for the preparation of aromatic organoboronate esters. Sterically regulated regioselectivity dominates carbocyclic aromatic C−H borylation. In contrast, heterocyclic aromatics display a much greater influence from electronic effects. In this review, examples of heterocyclic C−H borylation are surveyed, and the origins of heterocyclic C−H borylation regioselectivities discussed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Harnessing the power of microbial consortia is integral to a diverse range of sectors, from healthcare to biotechnology to environmental remediation. To fully realize this potential, it is critical ...to understand the mechanisms behind the interactions that structure microbial consortia and determine their functions. Constraint-based reconstruction and analysis (COBRA) approaches, employing genome-scale metabolic models (GEMs), have emerged as the state-of-the-art tool to simulate the behavior of microbial communities from their constituent genomes. In the last decade, many tools have been developed that use COBRA approaches to simulate multi-species consortia, under either steady-state, dynamic, or spatiotemporally varying scenarios. Yet, these tools have not been systematically evaluated regarding their software quality, most suitable application, and predictive power. Hence, it is uncertain which tools users should apply to their system and what are the most urgent directions that developers should take in the future to improve existing capacities. This study conducted a systematic evaluation of COBRA-based tools for microbial communities using datasets from two-member communities as test cases. First, we performed a qualitative assessment in which we evaluated 24 published tools based on a list of FAIR (Findability, Accessibility, Interoperability, and Reusability) features essential for software quality. Next, we quantitatively tested the predictions in a subset of 14 of these tools against experimental data from three different case studies: a) syngas fermentation by C. autoethanogenum and C. kluyveri for the static tools, b) glucose/xylose fermentation with engineered E. coli and S. cerevisiae for the dynamic tools, and c) a Petri dish of E. coli and S. enterica for tools incorporating spatiotemporal variation. Our results show varying performance levels of the best qualitatively assessed tools when examining the different categories of tools. The differences in the mathematical formulation of the approaches and their relation to the results were also discussed. Ultimately, we provide recommendations for refining future GEM microbial modeling tools.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A copper-mediated nucleophilic radiofluorination of aryl- and vinylstannanes with 18FKF is described. This method is fast, uses commercially available reagents, and is compatible with both ...electron-rich and electron-deficient arene substrates. This method has been applied to the manual synthesis of a variety of clinically relevant radiotracers including protected 18FF-phenylalanine and 18FF-DOPA. In addition, an automated synthesis of 18FMPPF is demonstrated that delivers a clinically validated dose of 200 ± 20 mCi with a high specific activity of 2400 ± 900 Ci/mmol.
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IJS, KILJ, NUK, PNG, UL, UM
![Synthesis of [18F]Arenes vi...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1523-7060_1523-7052/small "Synthesis of [18F]Arenes via the Copper-Mediated [18F]Fluorination of Boronic Acids")
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