Genome-wide characterization of cytosine-specific 5-hydroxymethylation in normal breast tissue.

Despite recent evidence that 5-hydroxymethylcytosine (5hmC) possesses roles in gene regulation distinct from 5-methylcytosine (5mC), relatively little is known regarding the functions of 5hmC in mammalian tissues. To address this issue, we utilized an approach combining both paired bisulfite (BS) and oxidative bisulfite (oxBS) DNA treatment, to resolve genome-wide patterns of 5hmC and 5mC in normal breast tissue from disease-free women. Although less abundant than 5mC, 5hmC was differentially distributed, and consistently enriched among breast-specific enhancers and transcriptionally active chromatin. In contrast, regulatory regions associated with transcriptional inactivity, such as heterochromatin and repressed Polycomb regions, were relatively depleted of 5hmC. Gene regions containing abundant 5hmC were significantly associated with lactate oxidation, immune cell function, and prolactin signaling pathways. Furthermore, genes containing abundant 5hmC were enriched among those actively transcribed in normal breast tissue. Finally, in independent data sets, normal breast tissue 5hmC was significantly enriched among CpG loci demonstrated to have altered methylation in pre-invasive breast cancer and invasive breast tumors. Primarily, our findings identify genomic loci containing abundant 5hmC in breast tissues and provide a genome-wide map of nucleotide-level 5hmC in normal breast tissue. Additionally, these data suggest 5hmC may participate in gene regulatory programs that are dysregulated during breast-related carcinogenesis

Enrichment of CpG island shore region hypermethylation in epigenetic breast field cancerization

While changes in DNA methylation are known to occur early in breast carcinogenesis and the landscape of breast tumour DNA methylation is profoundly altered compared with normal tissue, there have been limited efforts to identify DNA methylation field cancerization effects in histologically normal breast tissue adjacent to tumour. Matched tumour, histologically normal tissue of the ipsilateral breast (ipsilateral-normal), and histologically normal tissue of the contralateral breast (contralateral-normal) were obtained from nine women undergoing bilateral mastectomy. Laser capture microdissection was used to select epithelial cells from normal tissue, and neoplastic cells from tumour for genome-scale measures of DNA methylation with the Illumina HumanMethylationEPIC array. We identified substantially more CpG loci that were differentially methylated between contralateral-normal and tumour (63,271 CpG loci q \u3c 0.01), than between ipsilateral-normal and tumour (38,346 CpG loci q \u3c 0.01). We identified differential methylation in ipsilateral-normal relative to contralateral-normal tissue (9,562 CpG loci p \u3c 0.01). In this comparison, hypomethylated loci were significantly enriched for breast cancer-relevant transcription factor binding sites including those for ESR1, FoxA1, and GATA3 and hypermethylated loci were significantly enriched for CpG island shore regions. In addition, progression of shore hypermethylation was observed in tumours compared to matched ipsilateral normal tissue, and these alterations tracked to several well-established tumour suppressor genes. Our results indicate an epigenetic field effect in surrounding histologically normal tissue. This work offers an opportunity to focus investigations of early DNA methylation alterations in breast carcinogenesis and potentially develop epigenetic biomarkers of disease risk

Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS):study protocol for a randomised controlled trial

BACKGROUND: We have recently completed an evaluation of the safety and feasibility of intravenous delivery of autologous bone marrow in patients with progressive multiple sclerosis (MS). The possibility of repair was suggested by improvement in the neurophysiological secondary outcome measure seen in all participants. The current study will examine the efficacy of intravenous delivery of autologous marrow in progressive MS. Laboratory studies performed in parallel with the clinical trial will further investigate the biology of bone marrow-derived stem cell infusion in MS, including mechanisms underlying repair. METHODS/DESIGN: A prospective, randomised, double-blind, placebo-controlled, stepped wedge design will be employed at a single centre (Bristol, UK). Eighty patients with progressive MS will be recruited; 60 will have secondary progressive disease (SPMS) but a subset (n = 20) will have primary progressive disease (PPMS). Participants will be randomised to either early or late (1 year) intravenous infusion of autologous, unfractionated bone marrow. The placebo intervention is infusion of autologous blood. The primary outcome measure is global evoked potential derived from multimodal evoked potentials. Secondary outcome measures include adverse event reporting, clinical (EDSS and MSFC) and self-assessment (MSIS-29) rating scales, optical coherence tomography (OCT) as well as brain and spine MRI. Participants will be followed up for a further year following the final intervention. Outcomes will be analysed on an intention-to-treat basis. DISCUSSION: Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS) is the first randomised, placebo-controlled trial of non-myeloablative autologous bone marrow-derived stem cell therapy in MS. It will determine whether bone marrow cell therapy can, as was suggested by the phase I safety study, improve conduction in multiple central nervous system pathways affected in progressive MS. Furthermore, laboratory studies performed in parallel with the clinical trial will inform our understanding of the cellular pharmacodynamics of bone marrow infusion in MS patients and the mechanisms underlying cell therapy. TRIAL REGISTRATION: ISRCTN27232902 Registration date 11/09/2012. NCT01815632 Registration date 19/03/201

Suppressed Far-UV stellar activity and low planetary mass-loss in the WASP-18 system

WASP-18 hosts a massive, very close-in Jupiter-like planet. Despite its young age (R′HK activity parameter lies slightly below the basal level; there is no significant time-variability in the log R′HK value; there is no detection of the star in the X-rays. We present results of far-UV observations of WASP-18 obtained with COS on board of HST aimed at explaining this anomaly. From the star’s spectral energy distribution, we infer the extinction (E(B − V) ≈ 0.01mag) and then the ISM column density for a number of ions, concluding that ISM absorption is not the origin of the anomaly. We measure the flux of the four stellar emission features detected in the COS spectrum (C II, C III, C IV, Si IV). Comparing the C II/C IV flux ratio measured for WASP-18 with that derived from spectra of nearby stars with known age, we see that the far-UV spectrum of WASP-18 resembles that of old (>5Gyr), inactive stars, in stark contrast with its young age. We conclude that WASP-18 has an intrinsically low activity level, possibly caused by star-planet tidal interaction, as suggested by previous studies. Re-scaling the solar irradiance reference spectrum to match the flux of the Si IV line, yields an XUV integrated flux at the planet orbit of 10.2 erg s−1 cm−2. We employ the rescaled XUV solar fluxes to model of the planetary upper atmosphere, deriving an extremely low thermal mass-loss rate of 10−20MJ Gyr−1. For such high-mass planets, thermal escape is not energy limited, but driven by Jeans escape

The Similarity of Broad Iron Lines in X-ray Binaries and Active Galactic Nuclei

We have compared the 2001 XMM-Newton spectra of the stellar mass black hole binary XTE J1650-500 and the active galaxy MGC-6-30-15, focusing on the broad, excess emission features at ~4--7 keV displayed by both sources. Such features are frequently observed in both low mass X-ray binaries and active galactic nuclei. For the former case it is generally accepted that the excess arises due to iron emission, but there is some controversy over whether their width is partially enhanced by instrumental processes, and hence also over the intrinsic broadening mechanism. Meanwhile, in the latter case, the origin of this feature is still subject to debate; physically motivated reflection and absorption interpretations are both able to reproduce the observed spectra. In this work we make use of the contemporaneous BeppoSAX data to demonstrate that the breadth of the excess observed in XTE J1650-500 is astrophysical rather than instrumental, and proceed to highlight the similarity of the excesses present in this source and MGC-6-30-15. Both optically thick accretion discs and optically thin coronae, which in combination naturally give rise to relativistically-broadened iron lines when the disc extends close to the black hole, are commonly observed in both class of object. The simplest solution is that the broad emission features present arise from a common process, which we argue must be reflection from the inner regions of an accretion disc around a rapidly rotating black hole; for XTE J1650-500 we find spin constraints of 0.84 < a* < 0.98 at the 90 per cent confidence level. Other interpretations proposed for AGN add potentially unnecessary complexities to the theoretical framework of accretion in strong gravity.Comment: Accepted for publication in MNRAS; 22 pages, 17 figure

Natural experiments and long-term monitoring are critical to understand and predict marine host-microbe ecology and evolution

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Leray, M., Wilkins, L. G. E., Apprill, A., Bik, H. M., Clever, F., Connolly, S. R., De Leon, M. E., Duffy, J. E., Ezzat, L., Gignoux-Wolfsohn, S., Herre, E. A., Kaye, J. Z., Kline, D. I., Kueneman, J. G., McCormick, M. K., McMillan, W. O., O’Dea, A., Pereira, T. J., Petersen, J. M., Petticord, D. F., Torchin, M. E., Thurber, R. V., Videvall, E., Wcislo, W. T., Yuen, B., Eisen, J. A. . Natural experiments and long-term monitoring are critical to understand and predict marine host-microbe ecology and evolution. Plos Biology, 19(8), (2021): e3001322, https://doi.org/10.1371/journal.pbio.3001322.Marine multicellular organisms host a diverse collection of bacteria, archaea, microbial eukaryotes, and viruses that form their microbiome. Such host-associated microbes can significantly influence the host’s physiological capacities; however, the identity and functional role(s) of key members of the microbiome (“core microbiome”) in most marine hosts coexisting in natural settings remain obscure. Also unclear is how dynamic interactions between hosts and the immense standing pool of microbial genetic variation will affect marine ecosystems’ capacity to adjust to environmental changes. Here, we argue that significantly advancing our understanding of how host-associated microbes shape marine hosts’ plastic and adaptive responses to environmental change requires (i) recognizing that individual host–microbe systems do not exist in an ecological or evolutionary vacuum and (ii) expanding the field toward long-term, multidisciplinary research on entire communities of hosts and microbes. Natural experiments, such as time-calibrated geological events associated with well-characterized environmental gradients, provide unique ecological and evolutionary contexts to address this challenge. We focus here particularly on mutualistic interactions between hosts and microbes, but note that many of the same lessons and approaches would apply to other types of interactions.Financial support for the workshop was provided by grant GBMF5603 (https://doi.org/10.37807/GBMF5603) from the Gordon and Betty Moore Foundation (W.T. Wcislo, J.A. Eisen, co-PIs), and additional funding from the Smithsonian Tropical Research Institute and the Office of the Provost of the Smithsonian Institution (W.T. Wcislo, J.P. Meganigal, and R.C. Fleischer, co-PIs). JP was supported by a WWTF VRG Grant and the ERC Starting Grant 'EvoLucin'. LGEW has received funding from the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014-2020) under the Marie Sklodowska-Curie Grant Agreement No. 101025649. AO was supported by the Sistema Nacional de Investigadores (SENACYT, Panamá). A. Apprill was supported by NSF award OCE-1938147. D.I. Kline, M. Leray, S.R. Connolly, and M.E. Torchin were supported by a Rohr Family Foundation grant for the Rohr Reef Resilience Project, for which this is contribution #2. This is contribution #85 from the Smithsonian’s MarineGEO and Tennenbaum Marine Observatories Network.

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

The association between workplace smoking bans and self-perceived, work-related stress among smoking workers

<p>Abstract</p> <p>Background</p> <p>There is substantial empirical evidence on the benefits of smoking bans; however, the unintended consequences of this anti-smoking measure have received little attention. This paper examines whether workplace smoking bans (WSB's) are associated with higher self-perceived, work-related stress among smoking workers.</p> <p>Methods</p> <p>A longitudinal representative sample of 3,237 individuals from the Canadian National Population Health Survey from 2000 to 2008 is used. Work-related stress is derived from a 12-item job questionnaire. Two categories of WSB's, full and partial, are included in the analysis, with no ban being the reference category. Analysis also controls for individual socio-demographic characteristics, health status, provincial and occupational fixed-effects. We use fixed-effects linear regression to control for individual time-invariant confounders, both measured and unmeasured, which can affect the relationship between WSB's and work-related stress. To examine the heterogeneous effects of WSB's, the analysis is stratified by gender and age. We check the robustness of our results by re-estimating the baseline specification with the addition of different control variables and a separate analysis for non-smokers.</p> <p>Results</p> <p>Multivariate analysis reveals a positive and statistically significant association between full <it>(β = 0.75, CI = 0.19-1.32) </it>or partial <it>(β = 0.69, CI = 0.12-1.26) </it>WSB's, and the level of self-perceived, work-related stress among smoking workers compared to those with no WSB. We also find that this association varies by gender and age. In particular, WSB's are significantly associated with higher work stress only for males and young adults (aged 18-40). No statistically significant association is found between WSB's and the level of self-perceived work-related stress among non-smoking workers.</p> <p>Conclusion</p> <p>The results of this study do not imply that WSB's are the main determinant of self-perceived, work-related stress among smokers but provides suggestive evidence that these may be positively related.</p