Biology subjects

Hamel, P.

Publications and source records attributed to Hamel, P..

3 recordsLinked to original sources

bioRxiv2023

Vitamin B5 Metabolism is Essential for Vacuolar and Mitochondrial Integrity and Xenobiotic Detoxification in Fungi

Fungal infections, a leading cause of mortality among eukaryotic pathogens, pose a growing global health threat due to the rise of drug-resistant strains. New therapeutic strategies are urgently needed to combat this challenge. The PCA pathway for biosynthesis of Co-enzyme A (CoA) and Acetyl-CoA (AcCoA) from vitamin B5 (pantothenic acid) has been validated as an excellent target for the development of new antimicrobials against fungi and protozoa. The pathway regulates key cellular processes including metabolism of fatty acids, amino acids, sterols, and heme. In this study, we provide genetic evidence that disruption of the PCA pathway results in a significant alteration in the susceptibility of fungi to a wide range of xenobiotics, including clinically approved antifungal drugs through alteration of vacuolar integrity and drug detoxification. The drug potentiation-mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies.

microbiology↗

bioRxiv2022

Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 Disrupt N-Glycosylation and Reduce Protein Stability

PTCHD1 has been implicated in Autism Spectrum Disorders (ASD) and/or intellectual disability, where copy number variant losses or loss-of-function coding mutations segregate with disease in an X-linked recessive fashion. Missense variants of PTCHD1 have also been reported in patients. However, the significance of these mutations remains undetermined since the activities, subcellular localization and regulation of the PTCHD1 protein are currently unknown. This paucity of data concerning PTCHD1 prevents the effective evaluation of sequence variants identified during diagnostic screening. Here, we characterize PTCHD1 protein binding partners, extending previously reported interactions with postsynaptic scaffolding protein, SAP102. Six rare missense variants of PTCHD1 were also identified from patients with neurodevelopmental disorders. After modelling these variants on a hypothetical three-dimensional structure of PTCHD1, based on the solved structure of NPC1, PTCHD1 variants harboring these mutations were assessed for protein stability, post-translational processing and protein trafficking. We show here that wild-type PTCHD1 post-translational modification includes complex N-glycosylation and that specific mutant proteins disrupt normal N-link glycosylation processing. However, regardless of their processing, these mutants still localized to PSD95-containing dendritic processes and remained competent for complexing SAP102.

molecular biology↗

bioRxiv2020

Evaluating urban greening scenarios for urban heat mitigation: a spatially-explicit approach

Urban green infrastructure, especially trees, are widely regarded as one of the most effective ways to reducing urban temperatures in extreme heat events, and alleviate its adverse impacts on human health and well-being. Nevertheless, urban planners and decision-makers are still lacking methods and tools to spatially evaluate the cooling effects of urban green spaces and exploit them to assess greening strategies at the urban agglomeration scale. This article introduces a novel spatially-explicit approach to simulate urban greening scenarios by increasing the tree canopy cover in the existing urban fabric, and evaluating their heat mitigation potential. The latter is achieved by applying the InVEST urban cooling model to the synthetic land use/land cover maps generated for the greening scenarios. A case study in the urban agglomeration of Lausanne, Switzerland, illustrates the development of tree canopy scenarios following distinct spatial distribution strategies. The spatial pattern of the tree canopy strongly influences the human exposure to the highest temperatures, and small increases in the abundance of tree canopy cover with the appropriate spatial configuration can have major impacts on human health and well-being. The proposed approach supports urban planning and the design of nature-based solutions to enhance climate resilience.

ecology↗