Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes.

Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles. Epigenomically similar regions exist in RA cells and are associated with active enhancers and promoters and specific transcription factor binding motifs. Differentially marked genes are enriched for immunological and unexpected pathways, with "Huntington's Disease Signaling" identified as particularly prominent. We validate the relevance of this pathway to RA by showing that Huntingtin-interacting protein-1 regulates FLS invasion into matrix. This work establishes a high-resolution epigenomic landscape of RA and demonstrates the potential for integrative analyses to identify unanticipated therapeutic targets

The WARPS Survey: VI. Galaxy Cluster and Source Identifications from Phase I

We present in catalog form the optical identifications for objects from the first phase of the Wide Angle ROSAT Pointed Survey (WARPS). WARPS is a serendipitous survey of relatively deep, pointed ROSAT observations for clusters of galaxies. The X-ray source detection algorithm used by WARPS is Voronoi Tessellation and Percolation (VTP), a technique which is equally sensitive to point sources and extended sources of low surface brightness. WARPS-I is based on the central regions of 86 ROSAT PSPC fields, covering an area of 16.2 square degrees. We describe here the X-ray source screening and optical identification process for WARPS-I, which yielded 34 clusters at 0.06<z<0.75. Twenty-two of these clusters form a complete, statistically well defined sample drawn from 75 of these 86 fields, covering an area of 14.1 square degrees, with a flux limit of F (0.5-2.0 keV) = 6.5 \times 10^{-14} erg cm^{-2} s^{-1}}. This sample can be used to study the properties and evolution of the gas, galaxy and dark matter content of clusters, and to constrain cosmological parameters. We compare in detail the identification process and findings of WARPS to those from other recently published X-ray surveys for clusters, including RDCS, SHARC-Bright, SHARC-south and the CfA 160 deg$^2$ survey.Comment: v3 reflects minor updates to tables 2 and

The impact of COVID-19 pandemic on vascular registries and clinical trials.

Quality improvement programs and clinical trial research experienced disruption due to the coronavirus disease 2019 (COVID-19) pandemic. Vascular registries showed an immediate impact with significant declines in second-quarter vascular procedure volumes witnessed across Europe and the United States. To better understand the magnitude and impact of the pandemic, organizations and study groups sent grass roots surveys to vascular specialists for needs assessment. Several vascular registries responded quickly by insertion of COVID-19 variables into their data collection forms. More than 80% of clinical trials have been reported delayed or not started due to factors that included loss of enrollment from patient concerns or mandated institutional shutdowns, weighing the risk of trial participation on patient safety. Preliminary data of patients undergoing vascular surgery with active COVID-19 infection show inferior outcomes (morbidity) and increased mortality. Disease-specific vascular surgery study collaboratives about COVID-19 were created for the desire to study the disease in a more focused manner than possible through registry outcomes. This review describes the pandemic effect on multiple VASCUNET registries including Germany (GermanVasc), Sweden (SwedVasc), United Kingdom (UK National Vascular Registry), Australia and New Zealand (bi-national Australasian Vascular Audit), as well as the United States (Society for Vascular Surgery Vascular Quality Initiative). We will highlight the continued collaboration of VASCUNET with the Vascular Quality Initiative in the International Consortium of Vascular Registries as part of the Medical Device Epidemiology Network coordinated registry network. Vascular registries must remain flexible and responsive to new and future real-world problems affecting vascular patients

An Initial Survey of White Dwarfs in the Sloan Digital Sky Survey

An initial assessment is made of white dwarf and hot subdwarf stars observed in the Sloan Digital Sky Survey. In a small area of sky (190 square degrees), observed much like the full survey will be, 269 white dwarfs and 56 hot subdwarfs are identified spectroscopically where only 44 white dwarfs and 5 hot subdwarfs were known previously. Most are ordinary DA (hydrogen atmosphere) and DB (helium) types. In addition, in the full survey to date, a number of WDs have been found with uncommon spectral types. Among these are blue DQ stars displaying lines of atomic carbon; red DQ stars showing molecular bands of C_2 with a wide variety of strengths; DZ stars where Ca and occasionally Mg, Na, and/or Fe lines are detected; and magnetic WDs with a wide range of magnetic field strengths in DA, DB, DQ, and (probably) DZ spectral types. Photometry alone allows identification of stars hotter than 12000 K, and the density of these stars for 15<g<20 is found to be ~2.2 deg^{-2} at Galactic latitudes 29-62 deg. Spectra are obtained for roughly half of these hot stars. The spectra show that, for 15<g<17, 40% of hot stars are WDs and the fraction of WDs rises to ~90% at g=20. The remainder are hot sdB and sdO stars.Comment: Accepted for AJ; 43 pages, including 12 figures and 5 table

ChromaSig: A Probabilistic Approach to Finding Common Chromatin Signatures in the Human Genome

Computational methods to identify functional genomic elements using genetic information have been very successful in determining gene structure and in identifying a handful of cis-regulatory elements. But the vast majority of regulatory elements have yet to be discovered, and it has become increasingly apparent that their discovery will not come from using genetic information alone. Recently, high-throughput technologies have enabled the creation of information-rich epigenetic maps, most notably for histone modifications. However, tools that search for functional elements using this epigenetic information have been lacking. Here, we describe an unsupervised learning method called ChromaSig to find, in an unbiased fashion, commonly occurring chromatin signatures in both tiling microarray and sequencing data. Applying this algorithm to nine chromatin marks across a 1% sampling of the human genome in HeLa cells, we recover eight clusters of distinct chromatin signatures, five of which correspond to known patterns associated with transcriptional promoters and enhancers. Interestingly, we observe that the distinct chromatin signatures found at enhancers mark distinct functional classes of enhancers in terms of transcription factor and coactivator binding. In addition, we identify three clusters of novel chromatin signatures that contain evolutionarily conserved sequences and potential cis-regulatory elements. Applying ChromaSig to a panel of 21 chromatin marks mapped genomewide by ChIP-Seq reveals 16 classes of genomic elements marked by distinct chromatin signatures. Interestingly, four classes containing enrichment for repressive histone modifications appear to be locally heterochromatic sites and are enriched in quickly evolving regions of the genome. The utility of this approach in uncovering novel, functionally significant genomic elements will aid future efforts of genome annotation via chromatin modifications

Plasminogen Alleles Influence Susceptibility to Invasive Aspergillosis

Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection

Identification and Clonal Characterisation of a Progenitor Cell Sub-Population in Normal Human Articular Cartilage

Background: Articular cartilage displays a poor repair capacity. The aim of cell-based therapies for cartilage defects is to repair damaged joint surfaces with a functional replacement tissue. Currently, chondrocytes removed from a healthy region of the cartilage are used but they are unable to retain their phenotype in expanded culture. The resulting repair tissue is fibrocartilaginous rather than hyaline, potentially compromising long-term repair. Mesenchymal stem cells, particularly bone marrow stromal cells (BMSC), are of interest for cartilage repair due to their inherent replicative potential. However, chondrocyte differentiated BMSCs display an endochondral phenotype, that is, can terminally differentiate and form a calcified matrix, leading to failure in long-term defect repair. Here, we investigate the isolation and characterisation of a human cartilage progenitor population that is resident within permanent adult articular cartilage. Methods and Findings: Human articular cartilage samples were digested and clonal populations isolated using a differential adhesion assay to fibronectin. Clonal cell lines were expanded in growth media to high population doublings and karyotype analysis performed. We present data to show that this cell population demonstrates a restricted differential potential during chondrogenic induction in a 3D pellet culture system. Furthermore, evidence of high telomerase activity and maintenance of telomere length, characteristic of a mesenchymal stem cell population, were observed in this clonal cell population. Lastly, as proof of principle, we carried out a pilot repair study in a goat in vivo model demonstrating the ability of goat cartilage progenitors to form a cartilage-like repair tissue in a chondral defect. Conclusions: In conclusion, we propose that we have identified and characterised a novel cartilage progenitor population resident in human articular cartilage which will greatly benefit future cell-based cartilage repair therapies due to its ability to maintain chondrogenicity upon extensive expansion unlike full-depth chondrocytes that lose this ability at only seven population doublings