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"Myers, Richard M"
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The Canadian regime : an introduction to parliamentary government in Canada
\"Now in its sixth edition, The Canadian Regime continues to provide the most accessible introduction to the institutions, processes, and principles of the Canadian political system. The book's focus on the inner logic of parliamentary government explains the rationale for Canada's relatively complex political system, which the authors encourage readers to think of as an organic entity, where change in one area inevitably ripples through the rest of the system.\"-- From publisher's website.
Book
Carrollian partition functions and the flat limit of AdS
A
bstract
The formulation of the S-matrix as a path integral with specified asymptotic boundary conditions naturally leads to the realization of a Carrollian partition function defined on the boundary of Minkowski space. This partition function, specified at past and future null infinity in the case of massless particles, generates Carrollian correlation functions that encode the S-matrix. We explore this connection, including the realization of symmetries, soft theorems arising from large gauge transformations, and the correspondence with standard momentum space amplitudes. This framework is also well-suited for embedding the Minkowski space S-matrix into the AdS/CFT duality in the large radius limit. In particular, we identify the AdS and Carrollian partition functions through a simple map between their respective asymptotic data, establishing a direct correspondence between the actions of symmetries on both sides. Our approach thus provides a coherent framework that ties together various topics extensively studied in recent and past literature.
Journal Article
Carrollian partition function for bulk Yang-Mills theory
A
bstract
The path integral over massless quantum fields in Minkowski space with scattering boundary conditions defines a Carrollian partition function on the null boundary. We develop this framework for non-Abelian gauge theory, both from a general perspective and through explicit examples that highlight subtle aspects of soft modes and asymptotic symmetries. These include falloff conditions, Goldstone modes and their antipodal matching, and factors of two associated with conditionally convergent integrals arising in the derivation of soft theorems. We employ path integral (rather than canonical) methods throughout.
Journal Article
S-matrix path integral approach to symmetries and soft theorems
A
bstract
We explore a formulation of the S-matrix in terms of the path integral with specified asymptotic data, as originally proposed by Arefeva, Faddeev, and Slavnov. In the tree approximation the S-matrix is equal to the exponential of the classical action evaluated on-shell. This formulation is well-suited to questions involving asymptotic symmetries, as it avoids reference to non-gauge/diffeomorphism invariant bulk correlators or sources at intermediate stages. We show that the soft photon theorem, originally derived by Weinberg and more recently connected to asymptotic symmetries by Strominger and collaborators, follows rather simply from invariance of the action under large gauge transformations applied to the asymptotic data. We also show that this formalism allows for efficient computation of the S-matrix in curved spacetime, including particle production due to a time dependent metric.
Journal Article
Assembly of the threespine stickleback Y chromosome reveals convergent signatures of sex chromosome evolution
Background
Heteromorphic sex chromosomes have evolved repeatedly across diverse species. Suppression of recombination between X and Y chromosomes leads to degeneration of the Y chromosome. The progression of degeneration is not well understood, as complete sequence assemblies of heteromorphic Y chromosomes have only been generated across a handful of taxa with highly degenerate sex chromosomes. Here, we describe the assembly of the threespine stickleback (
Gasterosteus aculeatus
) Y chromosome, which is less than 26 million years old and at an intermediate stage of degeneration. Our previous work identified that the non-recombining region between the X and the Y spans approximately 17.5 Mb on the X chromosome.
Results
We combine long-read sequencing with a Hi-C-based proximity guided assembly to generate a 15.87 Mb assembly of the Y chromosome. Our assembly is concordant with cytogenetic maps and Sanger sequences of over 90 Y chromosome BAC clones. We find three evolutionary strata on the Y chromosome, consistent with the three inversions identified by our previous cytogenetic analyses. The threespine stickleback Y shows convergence with more degenerate sex chromosomes in the retention of haploinsufficient genes and the accumulation of genes with testis-biased expression, many of which are recent duplicates. However, we find no evidence for large amplicons identified in other sex chromosome systems. We also report an excellent candidate for the master sex-determination gene: a translocated copy of Amh (
Amhy
).
Conclusions
Together, our work shows that the evolutionary forces shaping sex chromosomes can cause relatively rapid changes in the overall genetic architecture of Y chromosomes.
Journal Article
Systematics of boundary actions in gauge theory and gravity
A
bstract
We undertake a general study of the boundary (or edge) modes that arise in gauge and gravitational theories defined on a space with boundary, either asymptotic or at finite distance, focusing on efficient techniques for computing the corresponding boundary action. Such actions capture all the dynamics of the system that are implied by its asymptotic symmetry group, such as correlation functions of the corresponding conserved currents. Working in the covariant phase space formalism, we develop a collection of approaches for isolating the boundary modes and their dynamics, and illustrate with various examples, notably AdS
3
gravity (with and without a gravitational Chern-Simons terms) subject to assorted boundary conditions.
Journal Article
Genome-Wide Mapping of in Vivo Protein-DNA Interactions
In vivo protein-DNA interactions connect each transcription factor with its direct targets to form a gene network scaffold. To map these protein-DNA interactions comprehensively across entire mammalian genomes, we developed a large-scale chromatin immunoprecipitation assay (ChIPSeq) based on direct ultrahigh-throughput DNA sequencing. This sequence census method was then used to map in vivo binding of the neuron-restrictive silencer factor (NRSF; also known as REST, for repressor element-1 silencing transcription factor) to 1946 locations in the human genome. The data display sharp resolution of binding position [±50 base pairs (bp)], which facilitated our finding motifs and allowed us to identify noncanonical NRSF-binding motifs. These ChIPSeq data also have high sensitivity and specificity [ROC (receiver operator characteristic) area >= 0.96] and statistical confidence (P <10⁻⁴), properties that were important for inferring new candidate interactions. These include key transcription factors in the gene network that regulates pancreatic islet cell development.
Journal Article
Occupancy maps of 208 chromatin-associated proteins in one human cell type
Transcription factors are DNA-binding proteins that have key roles in gene regulation
1
,
2
. Genome-wide occupancy maps of transcriptional regulators are important for understanding gene regulation and its effects on diverse biological processes
3
–
6
. However, only a minority of the more than 1,600 transcription factors encoded in the human genome has been assayed. Here we present, as part of the ENCODE (Encyclopedia of DNA Elements) project, data and analyses from chromatin immunoprecipitation followed by high-throughput sequencing (ChIP–seq) experiments using the human HepG2 cell line for 208 chromatin-associated proteins (CAPs). These comprise 171 transcription factors and 37 transcriptional cofactors and chromatin regulator proteins, and represent nearly one-quarter of CAPs expressed in HepG2 cells. The binding profiles of these CAPs form major groups associated predominantly with promoters or enhancers, or with both. We confirm and expand the current catalogue of DNA sequence motifs for transcription factors, and describe motifs that correspond to other transcription factors that are co-enriched with the primary ChIP target. For example, FOX family motifs are enriched in ChIP–seq peaks of 37 other CAPs. We show that motif content and occupancy patterns can distinguish between promoters and enhancers. This catalogue reveals high-occupancy target regions at which many CAPs associate, although each contains motifs for only a minority of the numerous associated transcription factors. These analyses provide a more complete overview of the gene regulatory networks that define this cell type, and demonstrate the usefulness of the large-scale production efforts of the ENCODE Consortium.
ChIP–seq and CETCh–seq data are used to analyse binding maps for 208 transcription factors and other chromatin-associated proteins in a single human cell type, providing a comprehensive catalogue of the transcription factor landscape and gene regulatory networks in these cells.
Journal Article
Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation
The methylation of cytosines in CpG dinucleotides is essential for cellular differentiation and the progression of many cancers, and it plays an important role in gametic imprinting. To assess variation and inheritance of genome-wide patterns of DNA methylation simultaneously in humans, we applied reduced representation bisulfite sequencing (RRBS) to somatic DNA from six members of a three-generation family. We observed that 8.1% of heterozygous SNPs are associated with differential methylation in cis, which provides a robust signature for Mendelian transmission and relatedness. The vast majority of differential methylation between homologous chromosomes (>92%) occurs on a particular haplotype as opposed to being associated with the gender of the parent of origin, indicating that genotype affects DNA methylation of far more loci than does gametic imprinting. We found that 75% of genotype-dependent differential methylation events in the family are also seen in unrelated individuals and that overall genotype can explain 80% of the variation in DNA methylation. These events are under-represented in CpG islands, enriched in intergenic regions, and located in regions of low evolutionary conservation. Even though they are generally not in functionally constrained regions, 22% (twice as many as expected by chance) of genes harboring genotype-dependent DNA methylation exhibited allele-specific gene expression as measured by RNA-seq of a lymphoblastoid cell line, indicating that some of these events are associated with gene expression differences. Overall, our results demonstrate that the influence of genotype on patterns of DNA methylation is widespread in the genome and greatly exceeds the influence of imprinting on genome-wide methylation patterns.
Journal Article
Inference of cell type content from human brain transcriptomic datasets illuminates the effects of age, manner of death, dissection, and psychiatric diagnosis
Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this method, we found that the principal components of variation in the datasets strongly correlated with the predicted neuronal/glial content of the samples. This variability was not simply due to dissection-the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data.
Journal Article