RESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Although most cases are sporadic and occur later in life, 10-15% of cases are genetic. Loss-of-function mutations in the ring-between-ring E3 ubiquitin ligase parkin, encoded by the PRKN gene, cause autosomal recessive forms of early onset PD. Together with the kinase PINK1, parkin forms a mitochondrial quality control pathway that tags damaged mitochondria for clearance. Under basal conditions, parkin is inhibited and compounds that increase its activity have been proposed as a therapy for PD. Recently, several naturally occurring hyperactive parkin variants were identified, which increased mitophagy in cultured cells. Here, we validate the hyperactivities of these variants in vitro and compare the levels of activity of the variants to those of the wild-type and the well-characterized hyperactive variant, W403A. We also study the effects of mutating the parkin ACT (activating element) on parkin activity in vitro. This work advances our understanding of the pathogenicity of parkin variants and is an important first step in the design of molecules to increase parkin activity.
Asunto(s)
Ubiquitina-Proteína Ligasas , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Mutación , Mitofagia/genética , Mitocondrias/metabolismo , Mitocondrias/genética , Células HEK293RESUMEN
Here, we report the whole genome sequence of Stutzerimonas stutzeri strain NGHE31, isolated from Dekhar Haor, following the 2017 flash flood that resulted in mass die-offs of local wildlife. The predicted genome size is 4,434,670 bp, with 63.97% GC content, 4,035 coding sequences, 3 rRNAs, and 50 tRNAs.
RESUMEN
We conducted a cluster-randomized trial to measure the effect of community-level mask distribution and promotion on symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in rural Bangladesh from November 2020 to April 2021 (N = 600 villages, N = 342,183 adults). We cross-randomized mask type (cloth versus surgical) and promotion strategies at the village and household level. Proper mask-wearing increased from 13.3% in the control group to 42.3% in the intervention arm (adjusted percentage point difference = 0.29; 95% confidence interval = [0.26, 0.31]). The intervention reduced symptomatic seroprevalence (adjusted prevalence ratio = 0.91 [0.82, 1.00]), especially among adults ≥60 years old in villages where surgical masks were distributed (adjusted prevalence ratio = 0.65 [0.45, 0.85]). Mask distribution with promotion was a scalable and effective method to reduce symptomatic SARS-CoV-2 infections.