Annotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding and gene-regulatory annotations are highly incomplete
. Here we present EpiMap, a ...compendium comprising 10,000 epigenomic maps across 800 samples, which we used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators and downstream target genes. We used this resource to annotate 30,000 genetic loci that were associated with 540 traits
, predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers and candidate tissue-specific target genes for each. We partitioned multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease comorbidity patterns, and revealed both single-factor monotropic and multifactor pleiotropic loci. Top-scoring loci frequently had multiple predicted driver variants, converging through multiple enhancers with a common target gene, multiple genes in common tissues, or multiple genes and multiple tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for the investigation of complex traits.
Full text
Available for:
GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Why do some dictatorships establish institutions that may constrain their leaders? We argue that institutions promote the survival of dictatorships by facilitating authoritarian power-sharing. ...Specifically, institutions such as parties, legislatures, and advisory councils alleviate commitment and monitoring problems between the dictator and his allies caused by the secrecy in authoritarian governance. However, because authoritarian power-sharing succeeds only when it is backed by a credible threat of a rebellion by the dictator’s allies, institutions will be ineffective or break down when an imbalance of power within the ruling coalition undermines this threat’s credibility. Our arguments clarify the complex interaction between collective action, commitment, and monitoring problems in authoritarian governance. We use both historical and large-N data to assess new empirical predictions about the relationship between political institutions, leader survival, and the concentration of power in dictatorships.
Full text
Available for:
BFBNIB, DOBA, INZLJ, IZUM, KILJ, NMLJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, ZRSKP
This article updates and describes a widely used data set on democracy. Covering 1800–2007 and 219 countries, it represents the most comprehensive dichotomous measure of democracy currently ...available. We argue that our measure’s distinguishing features—a concrete, dichotomous coding and a long time span—are of critical value to empirical work on democracy. Inspired by Robert Dahl, we define a country as democratic if it satisfies conditions for both contestation and participation. Specifically, democracies feature political leaders chosen through free and fair elections and satisfy a threshold value of suffrage. After comparing our coding to that of other popular measures, we illustrate how democracy’s predictive factors have evolved since 1800. In particular, we show that economic modernization variables have steadily declined in their correlation with democracy over time.
Full text
Available for:
NUK, OILJ, PRFLJ, SAZU, UKNU, UL, UM, UPUK
An incisive history of the changing relationship between democracy and capitalism
The twentieth century witnessed the triumph of democratic capitalism in the industrialized West, with widespread ...popular support for both free markets and representative elections. Today, that political consensus appears to be breaking down, disrupted by polarization and income inequality, widespread dissatisfaction with democratic institutions, and insurgent populism. Tracing the history of democratic capitalism over the past two centuries, Carles Boix explains how we got here-and where we could be headed.
Boix looks at three defining stages of capitalism, each originating in a distinct time and place with its unique political challenges, structure of production and employment, and relationship with democracy. He begins in nineteenth-century Manchester, where factory owners employed unskilled laborers at low wages, generating rampant inequality and a restrictive electoral franchise. He then moves to Detroit in the early 1900s, where the invention of the modern assembly line shifted labor demand to skilled blue-collar workers. Boix shows how growing wages, declining inequality, and an expanding middle class enabled democratic capitalism to flourish. Today, however, the information revolution that began in Silicon Valley in the 1970s is benefitting the highly educated at the expense of the traditional working class, jobs are going offshore, and inequality has risen sharply, making many wonder whether democracy and capitalism are still compatible.
Essential reading for these uncertain times,Democratic Capitalism at the Crossroadsproposes sensible policy solutions that can help harness the unruly forces of capitalism to preserve democracy and meet the challenges that lie ahead.
Abstract
The GENCODE project annotates human and mouse genes and transcripts supported by experimental data with high accuracy, providing a foundational resource that supports genome biology and ...clinical genomics. GENCODE annotation processes make use of primary data and bioinformatic tools and analysis generated both within the consortium and externally to support the creation of transcript structures and the determination of their function. Here, we present improvements to our annotation infrastructure, bioinformatics tools, and analysis, and the advances they support in the annotation of the human and mouse genomes including: the completion of first pass manual annotation for the mouse reference genome; targeted improvements to the annotation of genes associated with SARS-CoV-2 infection; collaborative projects to achieve convergence across reference annotation databases for the annotation of human and mouse protein-coding genes; and the first GENCODE manually supervised automated annotation of lncRNAs. Our annotation is accessible via Ensembl, the UCSC Genome Browser and https://www.gencodegenes.org.
An incisive history of the changing relationship between democracy and capitalism The twentieth century witnessed the triumph of democratic capitalism in the industrialized West, with widespread ...popular support for both free markets and representative elections. Today, that political consensus appears to be breaking down, disrupted by polarization and income inequality, widespread dissatisfaction with democratic institutions, and insurgent populism. Tracing the history of democratic capitalism over the past two centuries, Carles Boix explains how we got here—and where we could be headed.Boix looks at three defining stages of capitalism, each originating in a distinct time and place with its unique political challenges, structure of production and employment, and relationship with democracy. He begins in nineteenth-century Manchester, where factory owners employed unskilled laborers at low wages, generating rampant inequality and a restrictive electoral franchise. He then moves to Detroit in the early 1900s, where the invention of the modern assembly line shifted labor demand to skilled blue- collar workers. Boix shows how growing wages, declining inequality, and an expanding middle class enabled democratic capitalism to flourish. Today, however, the information revolution that began in Silicon Valley in the 1970s is benefitting the highly educated at the expense of the traditional working class, jobs are going offshore, and inequality has risen sharply, making many wonder whether democracy and capitalism are still compatible.Essential reading for these uncertain times, Democratic Capitalism at the Crossroads proposes sensible policy solutions that can help harness the unruly forces of capitalism to preserve democracy and meet the challenges that lie ahead.
This study examines channel dynamics and bed load transport through a riffle and pool sequence forced by downstream channel width variations within an experimental flume. The experiment consisted of ...four runs across, which we compare and contrast local and spatially averaged bed surface texture and topography, sediment transport rates, and sediment mobility at five locations across a pool‐riffle pair. Sediment transport was measured using mini Helley‐Smith samplers and particle tracers seeded in the monitored riffle and pool. In this study, “local” sediment transport rates were highly variable across the five monitoring locations. The lowest sediment transport rate was recorded at the riffle tail whereas the highest rates were measured at the riffle head and the pool center. The texture of the bed surface and transported load do not explain measured bed load transport trends and depending on how the measurements are aggregated differing interpretations are supported. In general, the bed texture in the pool was finer than the texture in the riffle, however, specific grain‐size percentile classes derived from pooled population analysis suggests little to no difference between pool and riffle texture. The combined results highlight the importance of acknowledging and applying analysis techniques to better understand the inherent variability of bed load transport within channel reaches where morphology differs, such as pools and riffles.
Key Points
We conducted flume experiments to study sediment transport, bed surface texture, and sediment mobility across pool‐riffle unit
Differences in sediment transport occur within the same location, between sampling locations, during the same run, and between runs
“Noise” is an important feature of bed load transport particularly for channel with local variations of width and bed topography
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Recent work has identified dozens of non-coding loci for Alzheimer’s disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile ...epigenomic and transcriptomic landscapes of 850,000 nuclei from prefrontal cortexes of 92 individuals with and without AD to build a map of the brain regulome, including epigenomic profiles, transcriptional regulators, co-accessibility modules, and peak-to-gene links in a cell-type-specific manner. We develop methods for multimodal integration and detecting regulatory modules using peak-to-gene linking. We show AD risk loci are enriched in microglial enhancers and for specific TFs including SPI1, ELF2, and RUNX1. We detect 9,628 cell-type-specific ATAC-QTL loci, which we integrate alongside peak-to-gene links to prioritize AD variant regulatory circuits. We report differential accessibility of regulatory modules in late AD in glia and in early AD in neurons. Strikingly, late-stage AD brains show global epigenome dysregulation indicative of epigenome erosion and cell identity loss.
Display omitted
•Brain regulome from 850,000 RNA and ATAC cells in 92 individuals with and without AD•Methodology to jointly integrate snRNA and snATAC cells and link peaks to genes•AD risk loci prioritization and interpretation with regulatory links and ATAC-QTLs•Late-stage AD shows global epigenomic erosion accompanied by cell identity loss
A large-scale single-cell transcriptomic and epigenomic atlas of Alzheimer’s disease (AD) dissects regulatory programs during AD progression. This study highlights key genetic risk loci and ATAC-QTLs and also reveals epigenomic erosion and cell identity loss during late-stage AD.
Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus microglial transcriptomes and epigenomes across ...443 human subjects and diverse Alzheimer’s disease (AD) pathological phenotypes. We annotate 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. We identify 1,542 AD-differentially-expressed genes, including both microglia-state-specific and disease-stage-specific alterations. By integrating epigenomic, transcriptomic, and motif information, we infer upstream regulators of microglial cell states, gene-regulatory networks, enhancer-gene links, and transcription-factor-driven microglial state transitions. We demonstrate that ectopic expression of our predicted homeostatic-state activators induces homeostatic features in human iPSC-derived microglia-like cells, while inhibiting activators of inflammation can block inflammatory progression. Lastly, we pinpoint the expression of AD-risk genes in microglial states and differential expression of AD-risk genes and their regulators during AD progression. Overall, we provide insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution.
Display omitted
•Single-nucleus transcriptomes and epigenomes of human microglia•Microglia state-specific and disease-stage-specific profile in Alzheimer’s disease•Chromatin accessibility poorly captured microglia transcriptional state diversity•Transcription factor networks regulate microglial states and their transitions
Microglia states showing Alzheimer’s disease (AD)-risk-gene expression and AD-progression-associated expression differences were identified from the microglial transcriptome and epigenomes from the 443 human subjects spanning brain regions and diverse clinical and pathological states. Computational framework and functional studies using iPSC-derived microglia defined the diversity of microglial states across disease, the disease-stage changes of gene expression, and the regulatory network that governs microglial state transitions during the progression of AD.
PDF
