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- Pilorge, M, et al.
(författare)
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Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.
- 2016
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 21:7, s. 936-945
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.Molecular Psychiatry advance online publication, 15 September 2015; doi:10.1038/mp.2015.139.
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- Sadrizadeh, Sasan, et al.
(författare)
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Indoor air quality and health in schools : A critical review for developing the roadmap for the future school environment
- 2022
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Ingår i: Journal of Building Engineering. - : Elsevier Ltd. - 2352-7102. ; 57
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Tidskriftsartikel (refereegranskat)abstract
- Several research studies have ranked indoor pollution among the top environmental risks to public health in recent years. Good indoor air quality is an essential component of a healthy indoor environment and significantly affects human health and well-being. Poor air quality in such environments may cause respiratory disease for millions of pupils around the globe and, in the current pandemic-dominated era, require ever more urgent actions to tackle the burden of its impacts. The poor indoor quality in such environments could result from poor management, operation, maintenance, and cleaning. Pupils are a different segment of the population from adults in many ways, and they are more exposed to the poor indoor environment: They breathe in more air per unit weight and are more sensitive to heat/cold and moisture. Thus, their vulnerability is higher than adults, and poor conditions may affect proper development. However, a healthy learning environment can reduce the absence rate, improves test scores, and enhances pupil/teacher learning/teaching productivity. In this article, we analyzed recent literature on indoor air quality and health in schools, with the primary focus on ventilation, thermal comfort, productivity, and exposure risk. This study conducts a comprehensive review to summarizes the existing knowledge to highlight the latest research and solutions and proposes a roadmap for the future school environment. In conclusion, we summarize the critical limitations of the existing studies, reveal insights for future research directions, and propose a roadmap for further improvements in school air quality. More parameters and specific data should be obtained from in-site measurements to get a more in-depth understanding at contaminant characteristics. Meanwhile, site-specific strategies for different school locations, such as proximity to transportation routes and industrial areas, should be developed to suit the characteristics of schools in different regions. The socio-economic consequences of health and performance effects on children in classrooms should be considered. There is a great need for more comprehensive studies with larger sample sizes to study on environmental health exposure, student performance, and indoor satisfaction. More complex mitigation measures should be evaluated by considering energy efficiency, IAQ and health effects.
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- Dear, Alexander J., et al.
(författare)
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The catalytic nature of protein aggregation
- 2020
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 152:4
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Tidskriftsartikel (refereegranskat)abstract
- The formation of amyloid fibrils from soluble peptide is a hallmark of many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Characterization of the microscopic reaction processes that underlie these phenomena have yielded insights into the progression of such diseases and may inform rational approaches for the design of drugs to halt them. Experimental evidence suggests that most of these reaction processes are intrinsically catalytic in nature and may display enzymelike saturation effects under conditions typical of biological systems, yet a unified modeling framework accounting for these saturation effects is still lacking. In this paper, we therefore present a universal kinetic model for biofilament formation in which every fundamental process in the reaction network can be catalytic. The single closed-form expression derived is capable of describing with high accuracy a wide range of mechanisms of biofilament formation and providing the first integrated rate law of a system in which multiple reaction processes are saturated. Moreover, its unprecedented mathematical simplicity permits us to very clearly interpret the effects of increasing saturation on the overall kinetics. The effectiveness of the model is illustrated by fitting it to the data of in vitro Aβ40 aggregation. Remarkably, we find that primary nucleation becomes saturated, demonstrating that it must be heterogeneous, occurring at interfaces and not in solution.
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