To understand disease mechanisms, a large-scale analysis of human-yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human-yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS)-associated genes, such as optineurin () and angiogenin (), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport. When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy. The toxicity modifiers identified in this study may deepen our understanding of the pathogenic mechanisms of ALS and other devastating diseases.
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http://dx.doi.org/10.1101/gr.211649.116 | DOI Listing |
Rheumatol Int
December 2024
Clinic of Rheumatology, UMHAT "Kaspela", Medical University of Plovaffiliation, 64 Sofia str, Plovaffiliation, 4000, Bulgaria.
Background: Rheumatoid arthritis is a progressive disease that requires continuous treatment. Despite the excellent results, treatment with biologics and target-specific disease-modifying anti-rheumatic drugs often has to be interrupted due to insufficient therapeutic effectiveness, toxicity, or side effects.
Purpose: The purpose of this study is to identify the reasons and factors influencing treatment discontinuation with biologic and target-specific drugs among the Bulgarian patients with rheumatoid arthritis.
Adv Mater
December 2024
Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore.
The unprecedented success of mRNA vaccines against COVID-19 has inspired scientists to develop mRNA vaccines for cancer immunotherapy. However, using nucleoside modified mRNA as vaccine, though evading innate immune toxicity, diminishes its therapeutic efficacy for cancers. Here, we report a polyvalent stimulator of interferon genes (STING) activating polymer (termed as PD) to bolster the immunogenicity of mRNA vaccine.
View Article and Find Full Text PDFFront Vet Sci
December 2024
Department of Radiobiology, Military Faculty of Medicine, University of Defence, Hradec Kralove, Czechia.
The past 30 years have brought undeniable progress in medicine, biology, physics, and research. Knowledge of the nature of the human body, diseases, and disorders has been constantly improving, and the same is true regarding their treatment and diagnosis. One of the greatest advances in recent years has been the introduction of nanoparticles (NPs) into medicine.
View Article and Find Full Text PDFNucleic Acids Res
December 2024
Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (Leibniz-HKI), Beutenbergstraße 11A, 07745 Jena, Germany.
Increasing antifungal drug resistance is a major concern associated with human fungal pathogens like Aspergillus fumigatus. Genetic mutation and epimutation mechanisms clearly drive resistance, yet the epitranscriptome remains relatively untested. Here, deletion of the A.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
Introduction: Genetic variation in the lysosomal and transmembrane protein 106B (TMEM106B) modifies risk for several neurodegenerative disorders, especially frontotemporal lobar degeneration (FTLD). The C-terminal (CT) domain of TMEM106B occurs as fibrillar protein deposits in the brains of dementia patients.
Methods: To determine the TMEM CT aggregation propensity and neurodegenerative potential, we generated transgenic Caenorhabditis elegans expressing the human TMEM CT fragment aggregating in FTLD cases.
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