33 research outputs found

    A Population Genetic Approach to Mapping Neurological Disorder Genes Using Deep Resequencing

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    Deep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders. Here, we present the results from a large-sample resequencing (n = 285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and Schizophrenia. Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts. In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone. Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls. This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies. Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders

    Micrometre-long covalent organic fibres by photoinitiated chain-growth radical polymerization on an alkali-halide surface

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    On-surface polymerization is a promising technique to prepare organic functional nanomaterials that are challenging to synthesize in solution, but it is typically used on metal substrates, which play a catalytic role. Previous examples on insulating surfaces have involved intermediate self-assembled structures, which face high barriers to diffusion, or annealing to higher temperatures, which generally causes rapid dewetting and desorption of the monomers. Here we report the photoinitiated radical polymerization, initiated from a two-dimensional gas phase, of a dimaleimide monomer on an insulating KCl surface. Polymer fibres up to 1 μm long are formed through chain-like rather than step-like growth. Interactions between potassium cations and the dimaleimide’s oxygen atoms facilitate the propagation of the polymer fibres along a preferred axis of the substrate over long distances. Density functional theory calculations, non-contact atomic force microscopy imaging and manipulations at room temperature were used to explore the initiation and propagation processes, as well as the structure and stability of the resulting one-dimensional polymer fibres

    Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

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    In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

    The neurodevelopmental model of schizophrenia: update 2005

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