\u27Other habits\u27 and \u27other places\u27 : Ninagawa\u27s Twelfth Night

『NINAGAWA十二夜』は、演出家蜷川幸雄にとって、最初の冒険であり、シェイクスピア劇の最初の歌舞伎化でもあった。歌舞伎劇場の壮大な可能性を活かして、蜷川は観客を舞台に引き込み、演劇の世界へ誘う。この作品では2人の役者に複数の役を演じさせることによって、この喜劇の二重性(doubleness)を物理的に表現しようと試みている。本稿では、この試みが原作の構成上の制約によって制限される度合、また蜷川が原作から離れることによって『十二夜』にかなりの新しい解釈をもたらしている点を考察する

Metaphorical systems from the newspaper page to the EFL classroom

文学作品以外で用いられる比喩表現は、外国語教師にとっても学習者にとっても理解が難しい場合がある。本稿は、英語と日本語で書かれた2つの新聞記事を分析したものであるが、そこでは隠喩が多く用いられ、隠喩の中には文脈に依存しているものと、教育的に広く応用できるもがあることがわかった。さらに、句動詞を含むものや、時と場所を表す前置詞を含む隠喩表現は、EFLの教師・学生にとって特に重要であることも明らかになった。本稿では、英語と日本語の新聞記事における隠喩表現の関連性を踏まえ、教材としての隠喩表現の有効性を考察し、教室において比喩表現を使用する能力を身に付けるための方法を提案する

FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops

© The Author(s) 2019. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Telomerase negative immortal cancer cells elongate telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. While sustained telomeric replicative stress is required to maintain ALT, it might also lead to cell death when excessive. Here, we show that the ATPase/translocase activity of FANCM keeps telomeric replicative stress in check specifically in ALT cells. When FANCM is depleted in ALT cells, telomeres become dysfunctional, and cells stop proliferating and die. FANCM depletion also increases ALT-associated marks and de novo synthesis of telomeric DNA. Depletion of the BLM helicase reduces the telomeric replication stress and cell proliferation defects induced by FANCM inactivation. Finally, FANCM unwinds telomeric R-loops in vitro and suppresses their accumulation in cells. Overexpression of RNaseH1 completely abolishes the replication stress remaining in cells codepleted for FANCM and BLM. Thus, FANCM allows controlled ALT activity and ALT cell proliferation by limiting the toxicity of uncontrolled BLM and telomeric R-loops.Research in the Azzalin laboratory was supported by the Swiss National Science Foundation (31003A_160338), the European Molecular Biology Organization (IG3576) and the Fundação para a Ciência e a Tecnologia (IF/01269/2015; PTDC/MED-ONC/28282/2017; PTDC/BIA-MOL/29352/2017). R.P. was supported by a Swiss National Science Foundation Doc.Mobility fellowship (P1EZP3-168771). Research in the Deans laboratory was supported by the Cancer Council of Victoria, Australian National Health and Medical Research Council (APP1139099), Buxton trust and the Victorian Government’s OIS Program. A.J.D is a Victorian Cancer Agency fellow. Publication costs were supported by UID/BIM/50005/2019, project funded by the Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado.info:eu-repo/semantics/publishedVersio

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) U-Pb carbonate geochronology: strategies, progress, and limitations

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) U–Pb geochronology of carbonate minerals, calcite in particular, is rapidly gaining popularity as an absolute dating method. The high spatial resolution of LA-ICP-MS U–Pb carbonate geochronology has benefits over traditional isotope dilution methods, particularly for diagenetic and hydrothermal calcite, because uranium and lead are heterogeneously distributed on the sub-millimetre scale. At the same time, this can provide limitations to the method, as locating zones of radiogenic lead can be time-consuming and “hit or miss”. Here, we present strategies for dating carbonates with in situ techniques, through imaging and petrographic techniques to data interpretation; our examples are drawn from the dating of fracture-filling calcite, but our discussion is relevant to all carbonate applications. We review several limitations to the method, including open-system behaviour, variable initial-lead compositions, and U–daughter disequilibrium. We also discuss two approaches to data collection: traditional spot analyses guided by petrographic and elemental imaging and image-based dating that utilises LA-ICP-MS elemental and isotopic map data

Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine induced cell death

Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8, is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of wild-type and global ZnT8-/- mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, wild-type islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNFα, IFNγ, IL1β) treatment induced islet cell death, but to a lesser extent in islets from ZnT8-/- mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in wild-type islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8-/- mice as compared to wild-type islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8-/- mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man

Myocardial fibrosis in asymptomatic and symptomatic chronic severe primary mitral regurgitation and relationship to tissue characterisation and left ventricular function on cardiovascular magnetic resonance

Background: Myocardial fbrosis occurs in end-stage heart failure secondary to mitral regurgitation (MR), but it is not known whether this is present before onset of symptoms or myocardial dysfunction. This study aimed to characterise myocardial fbrosis in chronic severe primary MR on histology, compare this to tissue characterisation on cardiovascular magnetic resonance (CMR) imaging, and investigate associations with symptoms, left ventricular (LV) function, and exercise capacity. Methods: Patients with class I or IIa indications for surgery underwent CMR and cardiopulmonary exercise testing. LV biopsies were taken at surgery and the extent of fbrosis was quantifed on histology using collagen volume fraction (CVFmean) compared to autopsy controls without cardiac pathology. Results: 120 consecutive patients (64±13 years; 71% male) were recruited; 105 patients underwent MV repair while 15 chose conservative management. LV biopsies were obtained in 86 patients (234 biopsy samples in total). MR patients had more fbrosis compared to 8 autopsy controls (median: 14.6% [interquartile range 7.4–20.3] vs. 3.3% [2.6–6.1], P<0.001); this diference persisted in the asymptomatic patients (CVFmean 13.6% [6.3–18.8], P<0.001), but severity of fbrosis was not signifcantly higher in NYHA II-III symptomatic MR (CVFmean 15.7% [9.9–23.1] (P=0.083). Fibrosis was patchy across biopsy sites (intraclass correlation 0.23, 95% CI 0.08–0.39, P=0.001). No signifcant relationships were identifed between CVFmean and CMR tissue characterisation [native T1, extracellular volume (ECV) or late gadolinium enhancement] or measures of LV function [LV ejection fraction (LVEF), global longitudinal strain (GLS)]. Although the range of ECV was small (27.3±3.2%), ECV correlated with multiple measures of LV function (LVEF: Rho=−0.22, P=0.029, GLS: Rho=0.29, P=0.003), as well as NTproBNP (Rho=0.54, P<0.001) and exercise capacity (%PredVO2max: R=−0.22, P=0.030). Conclusions: Patients with chronic primary MR have increased fbrosis before the onset of symptoms. Due to the patchy nature of fbrosis, CMR derived ECV may be a better marker of global myocardial status. Clinical trial registration Mitral FINDER study; Clinical Trials NCT02355418, Registered 4 February 2015, https://clinicaltr ials.gov/ct2/show/NCT0235541

Historical simulations with HadGEM3-GC3.1 for CMIP6

We describe and evaluate historical simulations which use the third Hadley Centre Global Environment Model in the Global Coupled configuration 3.1 (HadGEM3-GC3.1) model and which form part of the UK's contribution to the sixth Coupled Model Intercomparison Project, CMIP6. These simulations, run at two resolutions, respond to historically evolving forcings such as greenhouse gases, aerosols, solar irradiance, volcanic aerosols, land use, and ozone concentrations. We assess the response of the simulations to these historical forcings and compare against the observational record. This includes the evolution of global mean surface temperature, ocean heat content, sea ice extent, ice sheet mass balance, permafrost extent, snow cover, North Atlantic sea surface temperature and circulation, and decadal precipitation. We find that the simulated time evolution of global mean surface temperature broadly follows the observed record but with important quantitative differences which we find are most likely attributable to strong effective radiative forcing from anthropogenic aerosols and a weak pattern of sea surface temperature response in the low to middle latitudes to volcanic eruptions. We also find evidence that anthropogenic aerosol forcings play a role in driving the Atlantic Multidecadal Variability and the Atlantic Meridional Overturning Circulation, which are key features of the North Atlantic ocean. Overall, the model historical simulations show many features in common with the observed record over the period 1850–2014 and so provide a basis for future in-depth study of recent climate change

Innovative remote plasma source for atomic layer deposition for GaN devices

High-quality dielectric films could enable GaN normally off high-electron-mobility transistors (HEMTs). Plasma atomic layer deposition (ALD) is known to allow for controlled high-quality thin-film deposition, and in order to not exceed energy and flux levels leading to device damage, the plasma used should preferably be remote for many applications. This article outlines ion energy flux distribution functions and flux levels for a new remote plasma ALD system, Oxford Instruments Atomfab™, which includes an innovative, RF-driven, remote plasma source. The source design is optimized for ALD for GaN HEMTs for substrates up to 200 mm in diameter and allows for Al2O3 ALD cycles of less than 1 s. Modest ion energies of &lt;50 eV and very low ion flux levels of &lt;1013 cm−2 s−1 were found at low-damage conditions. The ion flux can be increased to the high 1014 cm−2 s−1 range if desired for other applications. Using low-damage conditions, fast ALD saturation behavior and good uniformity were demonstrated for Al2O3. For films of 20 nm thickness, a breakdown voltage value of 8.9 MV/cm was obtained and the Al2O3 films were demonstrated to be suitable for GaN HEMT devices where the combination with plasma pretreatment and postdeposition anneals resulted in the best device parameters

A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available