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"Bradley, Joseph"
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Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders
Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer’s disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer’s disease, Parkinson’s disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases.
Yang et al. generated a genomic atlas of protein levels in brain, cerebrospinal fluid and plasma and used human genetics approaches to identify proteins implicated in neurological diseases as well as druggable targets.
Journal Article
Structural design for the stage
\"The follow-up to the 2000 Golden Pen Award-winning Structural Design for the Stage, this second edition provides the theater technician with a foundation in structural design, allowing an intuitive understanding of \"why sets stand up.\" It introduces the basics of statics and the study of the strength of materials as they apply to typical scenery, emphasizing conservative approaches to real world examples. This is an invaluable reference for any serious theatre technician throughout their career, from the initial study of the fundamental concepts, to the day-to-day use of the techniques and reference materials.Now in hardcover, with nearly 200 new pages of content, it has been completely revised and updated to reflect the latest recommended practices of the lumber and steel industries, while also including aluminum design for the first time. \"-- Provided by publisher.
Book
A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain
Background
Alzheimer’s disease (AD) is the most common form of dementia. This neurodegenerative disorder is associated with neuronal death and gliosis heavily impacting the cerebral cortex. AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex genetic architectures. Using bulk RNA-seq from the parietal lobes and deconvolution methods, we previously reported that brains exhibiting different AD genetic architecture exhibit different cellular proportions. Here, we sought to directly investigate AD brain changes in cell proportion and gene expression using single-cell resolution.
Methods
We generated unsorted single-nuclei RNA sequencing data from brain tissue. We leveraged the tissue donated from a carrier of a Mendelian genetic mutation,
PSEN1 p.A79V
, and two family members who suffer from sporadic AD, but do not carry any autosomal mutations. We evaluated alternative alignment approaches to maximize the titer of reads, genes, and cells with high quality. In addition, we employed distinct clustering strategies to determine the best approach to identify cell clusters that reveal neuronal and glial cell types and avoid artifacts such as sample and batch effects. We propose an approach to cluster cells that reduces biases and enable further analyses.
Results
We identified distinct types of neurons, both excitatory and inhibitory, and glial cells, including astrocytes, oligodendrocytes, and microglia, among others. In particular, we identified a reduced proportion of excitatory neurons in the Mendelian mutation carrier, but a similar distribution of inhibitory neurons. Furthermore, we investigated whether single-nuclei RNA-seq from the human brains recapitulate the expression profile of disease-associated microglia (DAM) discovered in mouse models. We also determined that when analyzing human single-nuclei data, it is critical to control for biases introduced by donor-specific expression profiles.
Conclusion
We propose a collection of best practices to generate a highly detailed molecular cell atlas of highly informative frozen tissue stored in brain banks. Importantly, we have developed a new web application to make this unique single-nuclei molecular atlas publicly available.
Journal Article
The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion
Apart from amyloid β deposition and tau neurofibrillary tangles, Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and astrocytosis in the cerebral cortex. The goal of this study is to investigate genetic factors associated with the neuronal proportion in health and disease. To identify cell-autonomous genetic variants associated with neuronal proportion in cortical tissues, we inferred cellular population structure from bulk RNA-Seq derived from 1536 individuals. We identified the variant rs1990621 located in the
TMEM106B
gene region as significantly associated with neuronal proportion (
p
value = 6.40 × 10
−07
) and replicated this finding in an independent dataset (
p
value = 7.41 × 10
−04
) surpassing the genome-wide threshold in the meta-analysis (
p
value = 9.42 × 10
−09
). This variant is in high LD with the
TMEM106B
non-synonymous variant p.T185S (rs3173615;
r
2
= 0.98) which was previously identified as a protective variant for frontotemporal lobar degeneration (FTLD). We stratified the samples by disease status, and discovered that this variant modulates neuronal proportion not only in AD cases, but also several neurodegenerative diseases and in elderly cognitively healthy controls. Furthermore, we did not find a significant association in younger controls or schizophrenia patients, suggesting that this variant might increase neuronal survival or confer resilience to the neurodegenerative process. The single variant and gene-based analyses also identified an overall genetic association between neuronal proportion, AD and FTLD risk. These results suggest that common pathways are implicated in these neurodegenerative diseases, that implicate neuronal survival. In summary, we identified a protective variant in the
TMEM106B
gene that may have a neuronal protection effect against general aging, independent of disease status, which could help elucidate the relationship between aging and neuronal survival in the presence or absence of neurodegenerative disorders. Our findings suggest that
TMEM106B
could be a potential target for neuronal protection therapies to ameliorate cognitive and functional deficits.
Journal Article
India : top sights, authentic experiences
Lonely Planet's Best of India is your passport to the most relevant, up-to-date advice on what to see and skip, and what hidden discoveries await you. Marvel at the intricate floral designs on the Taj Mahal, float along Kerala's backwaters as the sun sinks behind whispering palms, and dive into the teeming bazaars, mighty fortresses and fine dining of Jaipur - all with your trusted travel companion. Discover the best of India and begin your journey now!
Book
Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease
Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, phagosome, and mTOR signaling pathways altered in AD early and late stages. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Furthermore, we leveraged single-nuclei RNA-seq data to identify distinct cell-types that most likely mediate molecular profiles. Lastly, we identified that the multimodal clusters uncovered cerebrospinal fluid biomarkers poised to monitor AD progression and possibly cognition. Our cross-omics analyses provide novel critical molecular insights into AD.
Journal Article
Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer’s Disease
The genetic component of early-onset Alzheimer disease (EOAD), accounting for ~10% of all Alzheimer’s disease (AD) cases, is largely unexplained. Recent studies suggest that EOAD may be enriched for variants acting in the lipid pathway. The current study examines the shared genetic heritability between EOAD and the lipid pathway using genome-wide multi-trait genetic covariance analyses. Summary statistics were obtained from the GWAS meta-analyses of EOAD by the Alzheimer’s Disease Genetics Consortium ( n =19,668) and five blood lipid traits by the Global Lipids Genetics Consortium ( n =1,320,016). The significant results were compared between the EOAD and lipids GWAS and genetic covariance analyses were performed via SUPERGNOVA. Genes in linkage disequilibrium (LD) with top EOAD hits in identified regions of covariance with lipid traits were scored and ranked for causality by combining evidence from gene-based analysis, AD-risk scores incorporating transcriptomic and proteomic evidence, eQTL data, eQTL colocalization analyses, DNA methylation data, and single-cell RNA sequencing analyses. Direct comparison of GWAS results showed 5 loci overlapping between EOAD and at least one lipid trait harboring APOE , TREM2 , MS4A4E , LILRA5 , and LRRC25 . Local genetic covariance analyses identified 3 regions of covariance between EOAD and at least one lipid trait. Gene prioritization nominated 3 likely causative genes at these loci: ANKDD1B , CUZD1 , and MS4A64 .The current study identified genetic covariance between EOAD and lipids, providing further evidence of shared genetic architecture and mechanistic pathways between the two traits.
Journal Article
Branding and a child’s brain: an fMRI study of neural responses to logos
Branding and advertising have a powerful effect on both familiarity and preference for products, yet no neuroimaging studies have examined neural response to logos in children. Food advertising is particularly pervasive and effective in manipulating choices in children. The purpose of this study was to examine how healthy children’s brains respond to common food and other logos. A pilot validation study was first conducted with 32 children to select the most culturally familiar logos, and to match food and non-food logos on valence and intensity. A new sample of 17 healthy weight children were then scanned using functional magnetic resonance imaging. Food logos compared to baseline were associated with increased activation in orbitofrontal cortex and inferior prefrontal cortex. Compared to non-food logos, food logos elicited increased activation in posterior cingulate cortex. Results confirmed that food logos activate some brain regions in children known to be associated with motivation. This marks the first study in children to examine brain responses to culturally familiar logos. Considering the pervasiveness of advertising, research should further investigate how children respond at the neural level to marketing.
Journal Article