Helicity-dependent generalized parton distributions for nonzero skewness

We investigate the helicity dependent generalized parton distributions (GPDs) in momentum as well as transverse position (impact) spaces for up and down quarks in a proton when the momentum transfer in both the transverse and longitudinal directions are nonzero. The GPDs are evaluated using the light-front wavefunctions of a quark-diquark model for nucleon where the wavefunctions are constructed by the soft-wall AdS/QCD correspondence. We also express the GPDs in the boost-invariant longitudinal position space.Comment: 13 pages, 10 figures; to appear in Eur. Phys. J. C. arXiv admin note: text overlap with arXiv:1509.0059

Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization.

Vascular endothelial growth factor A (VEGF-A) is a master regulator of angiogenesis, vascular development and function. In this study we investigated the transcriptional regulation of VEGF-A-responsive genes in primary human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs) using genome-wide global run-on sequencing (GRO-Seq). We demonstrate that half of VEGF-A-regulated gene promoters are characterized by a transcriptionally competent paused RNA polymerase II (Pol II). We show that transition into productive elongation is a major mechanism of gene activation of virtually all VEGF-regulated genes, whereas only ∼40% of the genes are induced at the level of initiation. In addition, we report a comprehensive chromatin interaction map generated in HUVECs using tethered conformation capture (TCC) and characterize chromatin interactions in relation to transcriptional activity. We demonstrate that sites of active transcription are more likely to engage in chromatin looping and cell type-specific transcriptional activity reflects the boundaries of chromatin interactions. Furthermore, we identify large chromatin compartments with a tendency to be coordinately transcribed upon VEGF-A stimulation. We provide evidence that these compartments are enriched for clusters of regulatory regions such as super-enhancers and for disease-associated single nucleotide polymorphisms (SNPs). Collectively, these findings provide new insights into mechanisms behind VEGF-A-regulated transcriptional programs in endothelial cells

Work-Related Exposures and Sickness Absence Trajectories: A Nationally Representative Follow-up Study among Finnish Working-Aged People

The contribution of physically demanding work to the developmental trajectories of sickness absence (SA) has seldom been examined. We analyzed the associations of 12 physical work exposures, individually and in combination, with SA trajectories among the occupationally active in the Finnish nationally representative Health 2000 survey. We included 3814 participants aged 30–59 years at baseline, when exposure history to work-related factors was reported. The survey and interview responses were linked with the annual number of medically confirmed SA spells through 2002–2008 from national registries. Trajectory analyses identified three SA subgroups: 1 = low (54.6%), 2 = slowly increasing (33.7%), and 3 = high (11.7%). After adjustments, sitting or use of keyboard >1 year was inversely associated with the high SA trajectory (odds ratio, OR, 0.57; 95% 95% confidence interval, CI, 0.43–0.77). The odds of belonging to the trajectory of high SA increased with an increasing number of risk factors, and was highest for those with ≥4 physical workload factors (OR 2.71; 95% CI 1.99–3.69). In conclusion, these findings highlight the need to find ways to better maintain the work ability of those in physically loading work, particularly when there occurs exposure to several workload factors

Polycomb Repressive Complex 2 Enacts Wnt Signaling in Intestinal Homeostasis and Contributes to the Instigation of Stemness in Diseases Entailing Epithelial Hyperplasia or Neoplasia

Abstract Canonical Wnt/β-catenin signaling regulates the homeostasis of intestinal epithelium by controlling the balance between intestinal stem cell self-renewal and differentiation but epigenetic mechanisms enacting the process are not known. We hypothesized that epigenetic regulator, Polycomb Repressive Complex-2 (PRC2), is involved in Wnt-mediated epithelial homeostasis on the crypt-villus axis and aberrancies therein are implicated both in celiac disease and in intestinal malignancies. We found that PRC2 establishes repressive crypt and villus specific trimethylation of histone H3 lysine 27 (H3K27me3) signature on genes responsible for, for example, nutrient transport and cell killing in crypts and, for example, proliferation and differentiation in mature villi, suggesting that PRC2 facilitates the Wnt-governed intestinal homeostasis. When celiac patients are on gluten-containing diet PRC2 is out-of-bounds active and consequently its target genes were found affected in intestinal epithelium. Significant set of effective intestinal PRC2 targets are also differentially expressed in colorectal adenoma and carcinomas. Our results suggest that PRC2 gives rise and maintains polar crypt and villus specific H3K27me3 signatures. As H3K27me3 is a mark enriched in developmentally important genes, identified intestinal PRC2 targets are possibly imperative drivers for enterocyte differentiation and intestinal stem cell maintenance downstream to Wnt-signaling. Our work also elucidates the mechanism sustaining the crypt hyperplasia in celiac disease and suggest that PRC2-dependent fostering of epithelial stemness is a common attribute in intestinal diseases in which epithelial hyperplasia or neoplasia prevails. Finally, this work demonstrates that in intestine PRC2 represses genes having both pro-stemness and pro-differentiation functions, fact need to be considered when designing epigenetic therapies including PRC2 as a drug target.</jats:p

Work-Related Exposures and Sickness Absence Trajectories: A Nationally Representative Follow-up Study among Finnish Working-Aged People

The contribution of physically demanding work to the developmental trajectories of sickness absence (SA) has seldom been examined. We analyzed the associations of 12 physical work exposures, individually and in combination, with SA trajectories among the occupationally active in the Finnish nationally representative Health 2000 survey. We included 3814 participants aged 30–59 years at baseline, when exposure history to work-related factors was reported. The survey and interview responses were linked with the annual number of medically confirmed SA spells through 2002–2008 from national registries. Trajectory analyses identified three SA subgroups: 1 = low (54.6%), 2 = slowly increasing (33.7%), and 3 = high (11.7%). After adjustments, sitting or use of keyboard >1 year was inversely associated with the high SA trajectory (odds ratio, OR, 0.57; 95% 95% confidence interval, CI, 0.43–0.77). The odds of belonging to the trajectory of high SA increased with an increasing number of risk factors, and was highest for those with ≥4 physical workload factors (OR 2.71; 95% CI 1.99–3.69). In conclusion, these findings highlight the need to find ways to better maintain the work ability of those in physically loading work, particularly when there occurs exposure to several workload factors

Polycomb Repressive Complex 2 Regulates Genes Necessary for Intestinal Microfold Cell (M Cell) Development

BACKGROUND & AIMS: Microfold cells (M cells) are immunosurveillance epithelial cells located in the Peyer's patches (PPs) in the intestine and are responsible for monitoring and transcytosis of antigens, microorganisms, and pathogens. Mature M cells use the receptor glycoprotein 2 (GP2) to aid in transcytosis. Recent studies have shown transcription factors, Spi-B and SRY-Box Transcription Factor 8 (Sox8). are necessary for M-cell differentiation, but not sufficient. An exhaustive set of factors sufficient for differentiation and development of a mature GP2+ M cell remains elusive. Our aim was to understand the role of polycomb repressive complex 2 (PRC2) as an epigenetic regulator of M-cell development. Estrogen-related-receptor gamma (Esrrg), identified as a PRC2-regulated gene, was studied in depth, in addition to its relationship with Spi-B and Sox8. METHODS: Comparative chromatin immunoprecipitation and global run-on sequencing analysis of mouse intestinal organoids were performed in stem condition, enterocyte conditions, and receptor activator of nuclear factor kappa B ligand-induced M-cell condition. Esrrg, which was identified as one of the PRC2-regulated transcription factors, was studied in wild-type mice and knocked out in intestinal organoids using guide RNA's. Sox8 null mice were used to study Esrrg and its relation to Sox8. RESULTS: chromatin immunoprecipitation and global run-on sequencing analysis showed 12 novel PRC2 regulated transcription factors, PRC2-regulated Esrrg is a novel M-cell-specific transcription factor acting on a receptor activator of nuclear factor kappa B ligand-receptor activator of nuclear factor kappa B-induced nuclear factor-kappa B pathway, upstream of Sox8, and necessary but not sufficient for a mature M-cell marker of Gp2 expression. CONCLUSIONS: PRC2 regulates a significant set of genes in M cells including Esrrg, which is critical for M-cell development and differentiation. Loss of Esrrg led to an immature M-cell phenotype lacking in Sox8 and Gp2 expression. Transcript profiling: the data have been deposited in the NCBI Gene Expression Omnibus database (GSE157629).Peer reviewe