Biology subjects

Smith, R.

Publications and source records attributed to Smith, R..

114 records · Page 7Linked to original sources

bioRxiv2019

Pathological tau spreads through communicating brain regions in human Alzheimer's disease

Tau is one of the two pathological hallmarks of Alzheimers disease, and bears a much closer relationship to local neurodegeneration and cognitive impairment than the other hallmark, {beta}-amyloid. Cell and rodent models have shown evidence that tau spreads from cell to cell through anatomical neuronal connections, and that this process is facilitated by the presence of {beta}-amyloid. We test this hypothesis in humans by using an epidemic spreading model (ESM) to simulate the spread of tau over human neuronal connections, and we compare the simulated pattern of progression to the observed pattern measured in the brains of 312 individuals on the Alzheimers disease spectrum, using PET. Fitting our model, we found that the majority of variance in the overall pattern of tau progression could be explained by diffusion of an agent through the human connectome, measured using either functional connectivity or diffusion tractography. These models far exceeded chance, and outperformed models testing the extracellular spread of tau over Euclidian space. Surprisingly, the ESM predicted the spatial patterns of tau irrespective of whether subjects demonstrated evidence for brain {beta}-amyloid. In addition, in {beta}-amyloid-positive subjects only, regions with greater amyloid burden showed greater tau than predicted by connectivity patterns, suggesting a role of amyloid in accelerating the spread of tau in certain isocortical regions. Altogether, our results provide strong evidence that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain {beta}-amyloid.

neuroscience↗

bioRxiv2018

A SOSEKI-based coordinate system interprets global polarity cues in Arabidopsis

Multicellular development requires coordinated cell polarization relative to body axes, and translation to oriented cell division. In plants, it is unknown how cell polarities are connected to organismal axes and translated to division. Here, we identify Arabidopsis SOSEKI (SOK) proteins that integrate apical-basal and radial organismal axes to localize to polar cell edges. Localization does not depend on tissue context, requires cell wall integrity and is defined by a transferrable, protein-specific motif. SOK proteins structurally resemble the DIX oligomerization domain in the animal Dishevelled polarity regulator. The DIX-like domain self-interacts and is required for edge localization and for influencing division orientation. Our work identifies a plant compass, interpreted by SOK proteins. Furthermore, despite fundamental differences, polarity in plants and animals converge upon the same protein domain.

plant biology↗

bioRxiv2018

Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic forms of autism in postmortem human brain tissue.

Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behavior. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular etiology of ASD, we quantified genome-wide patterns of DNA methylation in 233 post-mortem tissues samples isolated from three brain regions (prefrontal cortex, temporal cortex and cerebellum) dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the cerebellum. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically-defined subtype of ASD, were characterized by striking differences in DNA methylation across a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

genomics↗

bioRxiv2017

Identification of key pathways and metabolic fingerprints of longevity in C. elegans

Impaired insulin/IGF-1 signaling (IIS) pathway and caloric restriction (CR) are two well-established interventions to prolong lifespan in worm C. elegans. However, a cross comparison of these longevity pathways using a multi-omics integration approach is lacking. In this study, we aimed to identify key pathways and metabolite fingerprints of longevity that are shared between IIS and CR worm models using a multi-omics integration approach. We generated transcriptomics and metabolomics data from two long-lived mutant worm strains, i.e. daf-2 (impaired IIS pathway) and eat-2 (CR model) and compared them with the N2 strain. Transcriptional profiling identified shared longevity signatures between the two strains, such as an upregulation of lipid storage and defense responses and downregulation of macromolecule synthesis and developmental processes. The shared longevity signatures revealed by metabolomics profiling included an increase in the levels of glycerol-3P, ademine, xanthine, and AMP, and a decrease in the levels of the amino acid pool, the C18:0 and C17:1 fatty acids. After we integrated transcriptomics and metabolomics data based on the annotations in KEGG, our results highlighted a downregulation of pyrimidine metabolism and upregulation of purine metabolism as a commonality between the two longevity mechanisms. Overall, our findings point towards the existence of shared metabolic pathways that are likely important for lifespan extension and provide novel insights into potential regulators and metabolic fingerprints for longevity.

biochemistry↗

bioRxiv2017

A molecular network of the aging brain implicates INPPL1 and PLXNB1 in Alzheimer’s disease

The fact that only symptomatic therapies of small effect are available for Alzheimers disease (AD) today highlights the need for new therapeutic targets with which to prevent a major contributor to aging-related cognitive decline. Here, we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first identify the role of modules of coexpressed genes, and then confirm them in independent AD datasets. Then, we prioritize influential genes in AD-related modules and test our predictions in human model systems. We functionally validate two putative regulator genes in human astrocytes: INPPL1 and PLXNB1, whose activity in AD may be related to semaphorin signalling and type II diabetes, which have both been implicated in AD. This arc of network identification followed by statistical and experimental validation provides specific new targets for therapeutic development and illustrates a network approach to a complex disease.\n\nOne sentence summaryMolecular network analysis of RNA sequencing data from the aging human cortex identifies new Alzheimers and cognitive decline genes.

systems biology↗

bioRxiv2017

European Admixture In Chinchorro DNA

It is widely held that, except for migrations from Beringia or Siberia, there was no contact between the Old World and the New World prior to the colonization of North America by the Norse in the late 10th century AD. Analyses of 23 ancient American DNA samples reveal, however, the presence of European admixture in a sample taken from a Chinchorro mummy of northern Chile dated to 3972-3806 BC. This discovery implies a more complex history of the peopling of the Americas than previously accepted.

genetics↗