Influence of permanent night work on the circadian rhythm of blood pressure

Abstract. Night workers exercise their labours activities and rest in contrary schedules to the chronobiological standards. This inversion leads the body to several adaptations, including changes in the circadian rhythm of blood pressure (BP). Objectives: To evaluate the BP in individuals who perform work at night, in order to objectively detail the BP circadian rhythm adaptations infixed night workers. Methods: A cross-sectional study enrolling 23 fixed night workers, both genders, was performed, with 24h BP measured with ambulatory blood pressure monitoring (ABPM) during a normal working day. Risk factors, anthropometric and lifestyle information were collected using a standard questionnaire. Results: Ambulatory BP demonstrated a pattern of adaptation to the sleep/activity cycle in all participants. BP dropped during the sleeping period (mean drop: -11.35±6.85) and was higher during the awakening period, reaching the highest results and greater BP variability during the working period. The chronobiological adaptation of the 24h BP was not dependent on sociodemographic or clinical characteristics. In addition, age, male gender, obesity, and those working less time were associated with higher BP mean values. Conclu-sions: The circadian rhythm of BP follows the working circadian profile of the individual.info:eu-repo/semantics/publishedVersio

Aggregate Unemployment Decreases Individual Returns to Education

On the basis of a theoretical model, we argue that higher aggregate unemployment affects individual returns to education. We therefore include aggregate unemployment and an interaction term between unemployment and the individual education level in a standard Mincer equation. Our results show that an increase in regional unemployment by 1% decreases the returns to education by 0.005 percentage points. This implies that higher skilled employees are better sheltered from labour market changes with respect to their jobs but encounter larger wage changes than less skilled employees. Differences in regional unemployment can in addition almost fully explain the observed large differences in regional returns to education. We use representative individual data and regional panel variation in unemployment between different German regions and for different employee groups. We demonstrate that our results are robust with respect to aggregation bias, time lags and potential endogeneity of the unemployment variable

Selective methylation of histone H3 variant H3.1 regulates heterochromatin replication

Histone variants have been proposed to act as determinants for posttranslational modifications with widespread regulatory functions. We identify a histone-modifying enzyme that selectively methylates the replication-dependent histone H3 variant H3.1. The crystal structure of the SET domain of the histone H3 lysine-27 (H3K27) methyltransferase ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) in complex with a H3.1 peptide shows that ATXR5 contains a bipartite catalytic domain that specifically "reads" alanine-31 of H3.1. Variation at position 31 between H3.1 and replication-independent H3.3 is conserved in plants and animals, and threonine-31 in H3.3 is responsible for inhibiting the activity of ATXR5 and its paralog, ATXR6. Our results suggest a simple model for the mitotic inheritance of the heterochromatic mark H3K27me1 and the protection of H3.3-enriched genes against heterochromatization during DNA replication

Efficacy in asthma of once-daily treatment with fluticasone furoate: a randomized, placebo-controlled trial

<p>Abstract</p> <p>Background</p> <p>Fluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). This double-blind, placebo-controlled randomized study evaluated the efficacy and safety of FF 200 mcg or 400 mcg once daily, either in the morning or in the evening, and FF 200 mcg twice daily (morning and evening), for 8 weeks in patients with persistent asthma.</p> <p>Methods</p> <p>Asthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV₁) 50-80% of predicted normal value and FEV₁reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV₁at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV₁.</p> <p>Results</p> <p>A total of 545 patients received one of five FF treatment groups and 101 patients received placebo (intent-to-treat population). Each of the five FF treatment groups produced a statistically significant improvement in pre-dose FEV₁compared with placebo (p < 0.05). FF 400 mcg once daily in the evening and FF 200 mcg twice daily produced similar placebo-adjusted improvements in evening pre-dose FEV₁at week 8 (240 ml vs. 235 ml). FF 400 mcg once daily in the morning, although effective, resulted in a smaller improvement in morning pre-dose FEV₁than FF 200 mcg twice daily at week 8 (315 ml vs. 202 ml). The incidence of oral candidiasis was low (0-4%) and UC excretion was comparable with placebo for all FF groups.</p> <p>Conclusions</p> <p>FF at total daily doses of 200 mcg or 400 mcg was significantly more effective than placebo. FF 400 mcg once daily in the evening had similar efficacy to FF 200 mcg twice daily and all FF regimens had a safety tolerability profile generally similar to placebo. This indicates that inhaled FF is an effective and well tolerated once-daily treatment for mild-to-moderate asthma.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00398645">NCT00398645</a></p

FACT Prevents the Accumulation of Free Histones Evicted from Transcribed Chromatin and a Subsequent Cell Cycle Delay in G1

The FACT complex participates in chromatin assembly and disassembly during transcription elongation. The yeast mutants affected in the SPT16 gene, which encodes one of the FACT subunits, alter the expression of G1 cyclins and exhibit defects in the G1/S transition. Here we show that the dysfunction of chromatin reassembly factors, like FACT or Spt6, down-regulates the expression of the gene encoding the cyclin that modulates the G1 length (CLN3) in START by specifically triggering the repression of its promoter. The G1 delay undergone by spt16 mutants is not mediated by the DNA–damage checkpoint, although the mutation of RAD53, which is otherwise involved in histone degradation, enhances the cell-cycle defects of spt16-197. We reveal how FACT dysfunction triggers an accumulation of free histones evicted from transcribed chromatin. This accumulation is enhanced in a rad53 background and leads to a delay in G1. Consistently, we show that the overexpression of histones in wild-type cells down-regulates CLN3 in START and causes a delay in G1. Our work shows that chromatin reassembly factors are essential players in controlling the free histones potentially released from transcribed chromatin and describes a new cell cycle phenomenon that allows cells to respond to excess histones before starting DNA replication

Crystal Structure of TDRD3 and Methyl-Arginine Binding Characterization of TDRD3, SMN and SPF30

SMN (Survival motor neuron protein) was characterized as a dimethyl-arginine binding protein over ten years ago. TDRD3 (Tudor domain-containing protein 3) and SPF30 (Splicing factor 30 kDa) were found to bind to various methyl-arginine proteins including Sm proteins as well later on. Recently, TDRD3 was shown to be a transcriptional coactivator, and its transcriptional activity is dependent on its ability to bind arginine-methylated histone marks. In this study, we systematically characterized the binding specificity and affinity of the Tudor domains of these three proteins quantitatively. Our results show that TDRD3 preferentially recognizes asymmetrical dimethylated arginine mark, and SMN is a very promiscuous effector molecule, which recognizes different arginine containing sequence motifs and preferentially binds symmetrical dimethylated arginine. SPF30 is the weakest methyl-arginine binder, which only binds the GAR motif sequences in our library. In addition, we also reported high-resolution crystal structures of the Tudor domain of TDRD3 in complex with two small molecules, which occupy the aromatic cage of TDRD3

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity

Mutant Versions of the S. cerevisiae Transcription Elongation Factor Spt16 Define Regions of Spt16 That Functionally Interact with Histone H3

In eukaryotic cells, the highly conserved FACT (FAcilitates Chromatin Transcription) complex plays important roles in several chromatin-based processes including transcription initiation and elongation. During transcription elongation, the FACT complex interacts directly with nucleosomes to facilitate histone removal upon RNA polymerase II (Pol II) passage and assists in the reconstitution of nucleosomes following Pol II passage. Although the contribution of the FACT complex to the process of transcription elongation has been well established, the mechanisms that govern interactions between FACT and chromatin still remain to be fully elucidated. Using the budding yeast Saccharomyces cerevisiae as a model system, we provide evidence that the middle domain of the FACT subunit Spt16 – the Spt16-M domain – is involved in functional interactions with histone H3. Our results show that the Spt16-M domain plays a role in the prevention of cryptic intragenic transcription during transcription elongation and also suggest that the Spt16-M domain has a function in regulating dissociation of Spt16 from chromatin at the end of the transcription process. We also provide evidence for a role for the extreme carboxy terminus of Spt16 in functional interactions with histone H3. Taken together, our studies point to previously undescribed roles for the Spt16 M-domain and extreme carboxy terminus in regulating interactions between Spt16 and chromatin during the process of transcription elongation

Targeted reprogramming of H3K27me3 resets epigenetic memory in plant paternal chromatin

Epigenetic marks are reprogrammed in the gametes to reset genomic potential in the next generation. In mammals, paternal chromatin is extensively reprogrammed through the global erasure of DNA methylation and the exchange of histones with protamines(1,2). Precisely how the paternal epigenome is reprogrammed in flowering plants has remained unclear since DNA is not demethylated and histones are retained in sperm(3,4). Here, we describe a multi-layered mechanism by which H3K27me3 is globally lost from histone-based sperm chromatin in Arabidopsis. This mechanism involves the silencing of H3K27me3 writers, activity of H3K27me3 erasers and deposition of a sperm-specific histone, H3.10 (ref. (5)), which we show is immune to lysine 27 methylation. The loss of H3K27me3 facilitates the transcription of genes essential for spermatogenesis and pre-configures sperm with a chromatin state that forecasts gene expression in the next generation. Thus, plants have evolved a specific mechanism to simultaneously differentiate male gametes and reprogram the paternal epigenome

A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047

<p>Abstract</p> <p>Background</p> <p>Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.</p> <p>Methods</p> <p>A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI₅₀(dose required for 50% relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.</p> <p>Results</p> <p>The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI₅₀values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.</p> <p>Conclusions</p> <p>A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition.</p> <p>See the related commentary by Benes and Settleman: <url>http://www.biomedcentral.com/1741-7015/7/78</url></p