Discovery of a small molecule probe that post-translationally stabilizes the survival motor neuron protein for the treatment of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA

Checklist and distribution of the liverworts of the Andasibe (Périnet) region (Madagascar)

This updated checklist of Marchantiophyta (liverworts) of Andasibé (Périnet) region, Madagascar was compiled from the literature, from herbarium specimens and recent collections. A total of 222 species including 9 infraspecific taxa, from 62 genera are recorded. Five species: Cheilolejeunea ngongensis Malombe et Pócs, Cheilolejeunea unciloba (Lindenb.) Malombe, Heteroscyphus grandistipus (Steph.) Schiffn., Lejeunea angulifolia Mitt. and Kymatocalyx africanus Vána et Wigginton are newly reported for Madagascar. Detailed informations on species occurrences are provided as a basis for subsequent research on species distributions and conservation

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

N-Acetylcysteine ameliorates skeletal muscle pathophysiology in mdx mice

Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by a mutation in the gene encoding dystrophin, a protein linking the cytoskeleton to the extracellular matrix. In this study we investigated whether the antioxidant N-acetylcysteine (NAC) provided protection against dystrophic muscle damage in the mdx mouse, an animal model of DMD. In isolated mdx muscles, NAC prevented the increased membrane permeability and reduced the force deficit associated with stretch-induced muscle damage. Three-week-old mdx mice were treated with NAC in the drinking water for 6 weeks. Dihydroethidium staining showed that NAC treatment reduced the concentration of reactive oxygen species (ROS) in mdx muscles. This was accompanied by a significant decrease in centrally nucleated fibres in muscles from NAC-treated mdx mice. Immunoblotting showed that NAC treatment decreased the nuclear protein expression of NF-κB, a transcription factor involved in pro-inflammatory cytokine expression. Finally, we show that NAC treatment reduced caveolin-3 protein levels and increased the sarcolemmal expression of β-dystroglycan and the dystrophin homologue, utrophin. Taken together, our findings suggest that ROS play an important role in the dystrophic pathogenesis, both in terms of activating damage pathways and in regulating the expression of some dystrophin-associated membrane proteins. These results offer the prospect that antioxidants such as NAC could have therapeutic potential for DMD patients

A multi-taxon analysis of European Red Lists reveals major threats to biodiversity.

Biodiversity loss is a major global challenge and minimizing extinction rates is the goal of several multilateral environmental agreements. Policy decisions require comprehensive, spatially explicit information on species’ distributions and threats. We present an analysis of the conservation status of 14,669 European terrestrial, freshwater and marine species (ca. 10% of the continental fauna and flora), including all vertebrates and selected groups of invertebrates and plants. Our results reveal that 19% of European species are threatened with extinction, with higher extinction risks for plants (27%) and invertebrates (24%) compared to vertebrates (18%). These numbers exceed recent IPBES (Intergovernmental Platform on Biodiversity and Ecosystem Services) assumptions of extinction risk. Changes in agricultural practices and associated habitat loss, overharvesting, pollution and development are major threats to biodiversity. Maintaining and restoring sustainable land and water use practices is crucial to minimize future biodiversity declines