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AMP-activated protein kinase (AMPK) has a broad role in the regulation of glucose and lipid metabolism making it a promising target in the treatment of type 2 diabetes mellitus. We therefore sought to characterise for the first time the effects of chronic AMPK activation on skeletal muscle carbohydrate metabolism in carriers of the rare gain-of-function mutation of the gene encoding AMPKγ3 subunit, PRKAG3 R225W. Aspects of fuel metabolism were studied in vitro in myocytes isolated from vastus lateralis of PRKAG3 R225W carriers and matched control participants. In vivo, muscular strength and fatigue were evaluated by isokinetic dynamometer and surface electromyography, respectively. Glucose uptake in exercising quadriceps was determined using [18F]fluorodeoxyglucose and positron emission tomography . Myotubes from PRKAG3 R225W carriers had threefold higher mitochondrial content ( p < 0.01) and oxidative capacity, higher leak-dependent respiration (1.6-fold, p < 0.05), higher basal glucose uptake (twofold, p < 0.01) and higher glycogen synthesis rates (twofold, p < 0.05) than control myotubes. They also had higher levels of intracellular glycogen ( p < 0.01) and a trend for lower intramuscular triacylglycerol stores. R225W carriers showed remarkable resistance to muscular fatigue and a trend for increased glucose uptake in exercising muscle in vivo. Through the enhancement of skeletal muscle glucose uptake and increased mitochondrial content, the R225W mutation may significantly enhance exercise performance. These findings are also consistent with the hypothesis that the γ3 subunit of AMPK is a promising tissue-specific target for the treatment of type 2 diabetes mellitus, a condition in which glucose uptake and mitochondrial function are impaired. [ABSTRACT FROM AUTHOR]

Between 1972 (Stockholm) and 1996 (Rimouski), global awareness in relation to coastal management moved from a sectoral to a comprehensiveand integrated approach, from the protection of the marine environment and coastal resources to the concept of sustainable development. This paper summarizes the progress made at the international level in relation to coastal management issues, with particular emphasis to the post-UNCED Rio Declaration. A synthesis of the main highlights and outcomes of the Coastal Zone Canada '96 International Conference (CZC'96) held at Rimouski, Canada, is then presented. Two declarations ofprinciple (The Rimouski Declaration and Call for International Action) were adopted by the participants at CZC'96. They call for Canada and other international governments to better define national objectives, programs, and mechanisms permitting coastal communities to play afull and active role in the intelligent and practical management of coastal and maritime resources, and to meet their international coastal and ocean obligations thereby contributing to the sustainability of the oceans. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is a leading cause of intramammary infections (IMI). We recently demonstrated that Staph. aureus strains express the gene guaA during bovine IMI. This gene codes for a guanosine monophosphate synthetase and its expression is regulated by a guanine riboswitch. The guanine analog 2,5,6-triaminopyrimidine-4-one (PC1) is a ligand of the guanine riboswitch. Interactions between PC1 and its target result in inhibition of guanosine monophosphate synthesis and subsequent death of the bacterium. The present study describes the investigational use of PC1 for therapy of Staph. aureus IMI in lactating cows. The in vitro minimal inhibitory concentration of PC1 ranged from 0.5 to 4 µg/mL for a variety of Staph. aureus and Staphylococcus epidermidis strains and required a reducing agent for stability and full potency. A safety assessment study was performed, whereby the healthy quarters of 4 cows were infused with increasing doses of PC1 (0, 150, 250, and 500 mg). Over the 44 h following infusions, no obvious adverse effect was observed. Ten Holstein multiparous cows in mid lactation were then experimentally infused into 3 of the quarters with approximately 50 cfu of Staph. aureus strain SHY97-3906 and infection was allowed to progress for 2 wk before starting PC1 treatment. Bacterial counts reached then about 10³ to 104 cfu/mL of milk. Infected quarters were treated with 1 of 3 doses of PC1 (0, 250, or 500 mg) after each morning and evening milking for 7 d (i.e., 14 intramammary infusions of PC1). During the treatment period, milk from PC1-treated quarters showed a significant reduction in bacterial concentrations. However, this reduction of Staph. aureus count in milk was not maintained during the 4 wk following the end of the treatment and only 15% of the PC1-treated quarters underwent bacteriological cure. The somatic cell count and the quarter milk production were not affected by treatments. Although bacterial clearance was not achieved following treatment with PC1, these results demonstrate that the Staph. aureus guanine riboswitch represents a relevant and promising drug target for a novel class of antibiotics for the animal food industry. [ABSTRACT FROM AUTHOR]

Biomolecular condensates are key features of intracellular compartmentalization. As the most prominent nuclear condensate in eukaryotes, the nucleolus is a layered multiphase liquid-like structure and the site of ribosome biogenesis. In the nucleolus, ribosomal RNAs (rRNAs) are transcribed and processed, undergoing multiple maturation steps that ultimately result in formation of the ribosomal small subunit (SSU) and large subunit (LSU). However, how rRNA processing is coupled to the layered nucleolar organization is poorly understood due to a lack of tools to precisely monitor and perturb nucleolar rRNA processing dynamics. Here, we developed two complementary approaches to spatiotemporally map rRNA processing and engineer de novo nucleoli. Using sequencing in parallel with imaging, we found that rRNA processing steps are spatially segregated, with sequential maturation of rRNA required for its outward movement through nucleolar phases. Furthermore, by generating synthetic de novo nucleoli through an engineered rDNA plasmid system in cells, we show that defects in SSU processing can alter the ordering of nucleolar phases, resulting in inside-out nucleoli and preventing rRNA outflux, while LSU precursors are necessary to build the outermost layer of the nucleolus. These findings demonstrate how rRNA is both a scaffold and substrate for the nucleolus, with rRNA acting as a programmable blueprint for the multiphase architecture that facilitates assembly of an essential molecular machine., Competing Interests: Competing interests C.P.B. is a scientific founder, Scientific Advisory Board member, shareholder, and consultant for Nereid Therapeutics.

Purpose: To evaluate the prognostic accuracy of intraprocedural and 4-8-week (current standard) post-microwave ablation zone (AZ) and margin assessments for prediction of local tumor progression (LTP) using 3-dimensional (3D) software., Materials and Methods: Data regarding 100 colorectal liver metastases (CLMs) in 75 patients were collected from 2 prospective fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT)-guided microwave ablation (MWA) trials. The target CLMs and theoretical 5- and 10-mm margins were segmented and registered intraprocedurally and at 4-8 weeks after MWA contrast-enhanced CT (or magnetic resonance [MR] imaging) using the same methodology and 3D software. Tumor and 5- and 10-mm minimal margin (MM) volumes not covered by the AZ were defined as volumes of insufficient coverage (VICs). The intraprocedural and 4-8-week post-MWA VICs were compared as predictors of LTP using receiver operating characteristic curve analysis., Results: The median follow-up time was 19.6 months (interquartile range, 7.97-36.5 months). VICs for 5- and 10-mm MMs were predictive of LTP at both time assessments. The highest accuracy for the prediction of LTP was documented with the intra-ablation 5-mm VIC (area under the curve [AUC], 0.78; 95% confidence interval, 0.66-0.89). LTP for a VIC of 6-10-mm margin category was 11.4% compared with 4.3% for >10-mm margin category (P < .001)., Conclusions: A 3D 5-mm MM is a critical endpoint of thermal ablation, whereas optimal local tumor control is noted with a 10-mm MM. Higher AUCs for prediction of LTP were achieved for intraprocedural evaluation than for the 4-8-week postablation 3D evaluation of the AZ., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)