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"Brown, Andrew C."
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Atomic partial wave meter by attosecond coincidence metrology
Attosecond chronoscopy is central to the understanding of ultrafast electron dynamics in matter from gas to the condensed phase with attosecond temporal resolution. It has, however, not yet been possible to determine the timing of individual partial waves, and steering their contribution has been a substantial challenge. Here, we develop a polarization-skewed attosecond chronoscopy serving as a partial wave meter to reveal the role of each partial wave from the angle-resolved photoionization phase shifts in rare gas atoms. We steer the relative ratio between different partial waves and realize a magnetic-sublevel-resolved atomic phase shift measurement. Our experimental observations are well supported by time-dependent R-matrix numerical simulations and analytical soft-photon approximation analysis. The symmetry-resolved, partial-wave analysis identifies the transition rate and phase shift property in the attosecond photoelectron emission dynamics. Our findings provide critical insights into the ubiquitous attosecond optical timer and the underlying attosecond photoionization dynamics.
Understanding the photoelectron emission time after the interaction of photon with atoms and molecules is of fundamental interest. Here the authors examine the role of partial waves to the photoionization phase shift of atoms using an attosecond clock and electron-ion coincidence spectroscopy.
Journal Article
Epigenomic analysis reveals a dynamic and context-specific macrophage enhancer landscape associated with innate immune activation and tolerance
Background
Chromatin states and enhancers associate gene expression, cell identity and disease. Here, we systematically delineate the acute innate immune response to endotoxin in terms of human macrophage enhancer activity and contrast with endotoxin tolerance, profiling the coding and non-coding transcriptome, chromatin accessibility and epigenetic modifications.
Results
We describe the spectrum of enhancers under acute and tolerance conditions and the regulatory networks between these enhancers and biological processes including gene expression, splicing regulation, transcription factor binding and enhancer RNA signatures. We demonstrate that the vast majority of differentially regulated enhancers on acute stimulation are subject to tolerance and that expression quantitative trait loci, disease-risk variants and eRNAs are enriched in these regulatory regions and related to context-specific gene expression. We find enrichment for context-specific eQTL involving endotoxin response and specific infections and delineate specific differential regions informative for GWAS variants in inflammatory bowel disease and multiple sclerosis, together with a context-specific enhancer involving a bacterial infection eQTL for
KLF4
. We show enrichment in differential enhancers for tolerance involving transcription factors NFκB-p65, STATs and IRFs and prioritize putative causal genes directly linking genetic variants and disease risk enhancers. We further delineate similarities and differences in epigenetic landscape between stem cell-derived macrophages and primary cells and characterize the context-specific enhancer activities for key innate immune response genes
KLF4
,
SLAMF1
and
IL2RA
.
Conclusions
Our study demonstrates the importance of context-specific macrophage enhancers in gene regulation and utility for interpreting disease associations, providing a roadmap to link genetic variants with molecular and cellular functions.
Journal Article
Mapping the epigenomic landscape of human monocytes following innate immune activation reveals context-specific mechanisms driving endotoxin tolerance
Background
Monocytes are key mediators of innate immunity to infection, undergoing profound and dynamic changes in epigenetic state and immune function which are broadly protective but may be dysregulated in disease. Here, we aimed to advance understanding of epigenetic regulation following innate immune activation, acutely and in endotoxin tolerant states.
Methods
We exposed human primary monocytes from healthy donors (
n
= 6) to interferon-γ or differing combinations of endotoxin (lipopolysaccharide), including acute response (2 h) and two models of endotoxin tolerance: repeated stimulations (6 + 6 h) and prolonged exposure to endotoxin (24 h). Another subset of monocytes was left untreated (naïve). We identified context-specific regulatory elements based on epigenetic signatures for chromatin accessibility (ATAC-seq) and regulatory non-coding RNAs from total RNA sequencing.
Results
We present an atlas of differential gene expression for endotoxin and interferon response, identifying widespread context specific changes. Across assayed states, only 24–29% of genes showing differential exon usage are also differential at the gene level. Overall, 19.9% (6,884 of 34,616) of repeatedly observed ATAC peaks were differential in at least one condition, the majority upregulated on stimulation and located in distal regions (64.1% vs 45.9% of non-differential peaks) within which sequences were less conserved than non-differential peaks. We identified enhancer-derived RNA signatures specific to different monocyte states that correlated with chromatin accessibility changes. The endotoxin tolerance models showed distinct chromatin accessibility and transcriptomic signatures, with integrated analysis identifying genes and pathways involved in the inflammatory response, detoxification, metabolism and wound healing. We leveraged eQTL mapping for the same monocyte activation states to link potential enhancers with specific genes, identifying 1,946 unique differential ATAC peaks with 1,340 expression associated genes. We further use this to inform understanding of reported GWAS, for example involving
FCHO1
and coronary artery disease.
Conclusion
This study reports context-specific regulatory elements based on transcriptomic profiling and epigenetic signatures for enhancer-derived RNAs and chromatin accessibility in immune tolerant monocyte states, and demonstrates the informativeness of linking such elements and eQTL to inform future mechanistic studies aimed at defining therapeutic targets of immunosuppression and diseases.
Journal Article
Heterodyne analysis of high-order partial waves in attosecond photoionization of helium
Partial wave analysis is key to interpretation of the photoionization of atoms and molecules on the attosecond timescale. Here we propose a heterodyne analysis approach, based on the delay-resolved anisotropy parameters to reveal the role played by high-order partial waves during photoionization. This extends the Reconstruction of Attosecond Beating By Interference of Two-photon Transitions technique into the few-photon regime. We demonstrate that even for moderate ( ~ 1TW/cm
2
) intensities, near-infrared-assisted photoionization of helium through Rydberg states results in a tiny contribution from the
g
0
wave, which has a significant impact on the photoelectron angular distributions via interference with the
s
- and
d
0
-waves. This modulation also causes a substantial deviation in the angular distribution of the recovered spectral phase shift. Our analysis provides an efficient method to resolve isolated partial wave contributions beyond the perturbative regime, and paves the way towards understanding resonance-enhancement of partial waves.
Reconstruction of attosecond beating by interference of two-photon transitions (RABBITT) is a technique used to study photoionization of atoms occurring on attosecond timescales. Here the authors implement a heterodyne approach to detect higher-order partial-waves due to multi-photon transitions, opening a path towards analysis of the strong field regime.
Journal Article
Evidence for enhancer activity in intron 1 of TNFRSF1A using CRISPR/Cas9 in human induced pluripotent stem cell-derived macrophages
TNFα is a common drug target in the treatment of autoimmune diseases, with pro-inflammatory functions that are primarily mediated through its receptor, TNFRSF1A.
TNFRSF1A
has been genetically associated with many immune-mediated diseases including ankylosing spondylitis, multiple sclerosis, and inflammatory bowel disease. Many of the genetic variants within or near
TNFRSF1A
that have been associated with disease through genome-wide association studies (GWAS) lie in non-coding regions of the genome. Understanding the functional consequences of these genetic variants is limited by incomplete understanding of
TNFRSF1A
gene regulation, including for specific cellular contexts relevant to inflammation and immunity such as macrophages. This work used CRISPR/Cas9 in human induced pluripotent stem cells followed by differentiation into macrophages to investigate putative regulatory elements in the
TNFRSF1A
gene locus. Through gene editing, with functional genomic readouts including the assay for transposase-accessible chromatin using sequencing (ATAC-Seq), chromatin immunoprecipitation with sequencing (ChIP-Seq), and RNA-Seq to assess the consequences of these edits, we present evidence for an enhancer of
TNFRSF1A
contained within an intron of the gene. Understanding gene regulation and the genomic context in which GWAS variants lie could bring us closer to deconvoluting the genetic basis of common disease aetiology and uncover effective drug targets.
Journal Article
Using de novo assembly to identify structural variation of eight complex immune system gene regions
Driven by the necessity to survive environmental pathogens, the human immune system has evolved exceptional diversity and plasticity, to which several factors contribute including inheritable structural polymorphism of the underlying genes. Characterizing this variation is challenging due to the complexity of these loci, which contain extensive regions of paralogy, segmental duplication and high copy-number repeats, but recent progress in long-read sequencing and optical mapping techniques suggests this problem may now be tractable. Here we assess this by using long-read sequencing platforms from PacBio and Oxford Nanopore, supplemented with short-read sequencing and Bionano optical mapping, to sequence DNA extracted from CD14 + monocytes and peripheral blood mononuclear cells from a single European individual identified as HV31. We use this data to build a de novo assembly of eight genomic regions encoding four key components of the immune system, namely the human leukocyte antigen, immunoglobulins, T cell receptors, and killer-cell immunoglobulin-like receptors. Validation of our assembly using k-mer based and alignment approaches suggests that it has high accuracy, with estimated base-level error rates below 1 in 10 kb, although we identify a small number of remaining structural errors. We use the assembly to identify heterozygous and homozygous structural variation in comparison to GRCh38. Despite analyzing only a single individual, we find multiple large structural variants affecting core genes at all three immunoglobulin regions and at two of the three T cell receptor regions. Several of these variants are not accurately callable using current algorithms, implying that further methodological improvements are needed. Our results demonstrate that assessing haplotype variation in these regions is possible given sufficiently accurate long-read and associated data. Continued reductions in the cost of these technologies will enable application of these methods to larger samples and provide a broader catalogue of germline structural variation at these loci, an important step toward making these regions accessible to large-scale genetic association studies.
Journal Article
Interaction of MEQ protein and C-terminal-binding protein is critical for induction of lymphomas by Marek's disease virus
Marek's disease virus (MDV) is an oncogenic herpesvirus that induces fatal T cell lymphomas in chickens. With more than 20 billion doses of vaccine used annually, vaccination constitutes the cornerstone of Marek's disease control. Despite the success of vaccination, evolution of virulence among MDV strains continues to threaten the effectiveness of the current Marek's disease vaccines. MDV-encoded protein MEQ (MDV EcoRI Q) probably acts as a transcription factor and is considered to be the major MDV oncoprotein. MEQ sequence shows a Pro-Leu-Asp-Leu-Ser (PLDLS) motif known to bind C-terminal-binding protein (CtBP), a highly conserved cellular transcriptional corepressor with roles in the regulation of development, proliferation, and apoptosis. Here we show that MEQ can physically and functionally interact with CtBP through this motif and that this interaction is critical for oncogenesis because mutations in the CtBP-interaction domain completely abolished oncogenicity. This direct role for MEQ-CtBP interaction in MDV oncogenicity highlights the convergent evolution of molecular mechanisms of neoplastic transformation by herpesviruses because Epstein-Barr virus oncoproteins EBNA 3A and 3C also interact with CtBP. We also demonstrate that the nononcogenic MDV generated by mutagenesis of the CtBP-interaction domain of MEQ has the potential to be an improved vaccine against virulent MDV infection. Engineering MDV with precisely defined attenuating mutations, therefore, represents an effective strategy for generating new vaccines against this major poultry disease.
Journal Article
International Adoption Law: A Comparative Analysis
Comparative study of United States federal law and international and foreign domestic law relating to foreign adoption - operation of the Hague Convention on Intercountry Adoption - effect on the laws of international adoption - comparison between the laws of Russia as a non-party to the Convention with the laws of China as a party to the Convention - despite its weaknesses, the Convention is a vital tool for the protection of children adopted internationally.
Journal Article