ATM Dependent Silencing Links Nucleolar Chromatin Reorganization to DNA Damage Recognition

SummaryResolution of DNA double-strand breaks (DSBs) is essential for the suppression of genome instability. DSB repair in transcriptionally active genomic regions represents a unique challenge that is associated with ataxia telangiectasia mutated (ATM) kinase-mediated transcriptional silencing. Despite emerging insights into the underlying mechanisms, how DSB silencing connects to DNA repair remains undefined. We observe that silencing within the rDNA depends on persistent DSBs. Non-homologous end-joining was the predominant mode of DSB repair allowing transcription to resume. ATM-dependent rDNA silencing in the presence of persistent DSBs led to the large-scale reorganization of nucleolar architecture, with movement of damaged chromatin to nucleolar cap regions. These findings identify ATM-dependent temporal and spatial control of DNA repair and provide insights into how communication between DSB signaling and ongoing transcription promotes genome integrity

A survey to evaluate the association of COVID-19 restrictions on perceived mood and coping in Australian community level athletes

Australian community level athletes faced unprecedented changes to their training andcompetition options as the global COVID-19 pandemic took a stronghold. This disruptionwas predicted to have a negative impact on emotional well-being as communitiesbraced through periods of social isolation and physical distancing requirements. Thisstudy provides an Australian perspective on the emotional well-being of communitylevel athletes and the extent to which they coped during the COVID-19 pandemic.Emotional well-being and coping were measured using the Brief Emotional ExperienceScale and the 28-item Brief Cope Scale. Both instruments were administered alongwith other questions pertaining to participant demographics and training status via anonline survey between April and June 2020. The survey was disseminated to communityathletes through word-of-mouth and social media platforms. No significant differencesin emotional well-being were observed between athlete groups as a result of COVID-19and its associated restrictions. Coping scores also appeared to be preserved in Australiancommunity athletes, which contrasts the impact expected asa result of the COVID-19pandemic. While tentative, the observed preservation in coping may have bufferedpotential declines in emotional well-being, which has beendocumented in professionaland semi-professional athletes and the general population. These unexpected findingsand tentative suppositions warrant further investigationand highlight the importance ofconducting a country- or region-specific approach to examining the impact of COVID-19on community athletes, as responses to COVID-19 are undoubtedly not consistentthroughout the world

Social Entrepreneurship—Building Sustainability Through Business Models and Measurement of Social Impact

Social entrepreneurshipSocial entrepreneurship is gaining unprecedented momentum in the recent years and it is overwhelming to learn how social entrepreneurs are able to create both social and economic value overcoming all odds and sustain and grow their ventures. Social enterprise can be a for-profit or a not-for- profit venture in their constitution. This research study presents a comparative case analysis of four social ventures two of them are not-for-profit organisations and depend mainly on philanthropic partners for funding. The other two are for-profit social venturesNot-for-profit Social venture and create products and services which are commercially viable. Three of the founders are Ashoka fellows and one is a national award winning social entrepreneur, all based in India. Irrespective of the nature of enterprise, developing a viable business modelBusiness model is crucial for the sustainabilitySustainability of the venture. Analysis of these organisations’ business models reveals different patterns. The findings suggest that successful social entrepreneurial organisations proactively create their own ways to partner with multiple stakeholders who share their social visionVision ; deploy resources effectively as an integral part of the business model; and integrate the target group into the social value network

Slow relaxation of magnetization in a bis-mer-tridentate octahedral Co(II) complex

Reaction of a rigid tridentate ligand o-[(1H-imidazol-2-yl)methylideneamino]phenol (2-H(2)imap) with Co(ClO4) in the presence of NaN3, or Co(NO3)(2) without a base yields [Co-II(2-Himap)(2)] 1 and [Co-III(2-Himap) (2)]NO3 center dot MeOH2, respectively. Both complexes exhibit a mer-octahedral geometry with the cobalt centre being distorted along an octahedral-trigonal prismatic pathway. The packing in 1 and 2 is dominated by H-bonding forming 2D sheets and 1D chains, respectively. Detailed dc and ac magnetic studies indicate that 1 is a field-induced single-ion magnet (SIM) with D = 36.7 cm(-1) and E = 2.0 cm(-1). Extensive ab initio calculations support these conclusions and suggest that relaxation of the magnetization occurs principally through direct quantum tunnelling in the ground state, with the Raman process dominant in an applied field. This contrasts with the recently reported series of mer-[Co(L)(2)] (L = monoanionic NNO donor ligand; Inorg. Chem., 2017, 56, 6056-6066) complexes where D is negative, as these compounds have a more ambiguous geometry, and highlights the importance of supramolecular interactions in subtly altering the coordination sphere thereby impacting the magnetic behaviour

The Apache Point Observatory Galactic Evolution Experiment (APOGEE) Spectrographs

We describe the design and performance of the near-infrared (1.51--1.70 micron), fiber-fed, multi-object (300 fibers), high resolution (R = lambda/delta lambda ~ 22,500) spectrograph built for the Apache Point Observatory Galactic Evolution Experiment (APOGEE). APOGEE is a survey of ~ 10^5 red giant stars that systematically sampled all Milky Way populations (bulge, disk, and halo) to study the Galaxy's chemical and kinematical history. It was part of the Sloan Digital Sky Survey III (SDSS-III) from 2011 -- 2014 using the 2.5 m Sloan Foundation Telescope at Apache Point Observatory, New Mexico. The APOGEE-2 survey is now using the spectrograph as part of SDSS-IV, as well as a second spectrograph, a close copy of the first, operating at the 2.5 m du Pont Telescope at Las Campanas Observatory in Chile. Although several fiber-fed, multi-object, high resolution spectrographs have been built for visual wavelength spectroscopy, the APOGEE spectrograph is one of the first such instruments built for observations in the near-infrared. The instrument's successful development was enabled by several key innovations, including a "gang connector" to allow simultaneous connections of 300 fibers; hermetically sealed feedthroughs to allow fibers to pass through the cryostat wall continuously; the first cryogenically deployed mosaic volume phase holographic grating; and a large refractive camera that includes mono-crystalline silicon and fused silica elements with diameters as large as ~ 400 mm. This paper contains a comprehensive description of all aspects of the instrument including the fiber system, optics and opto-mechanics, detector arrays, mechanics and cryogenics, instrument control, calibration system, optical performance and stability, lessons learned, and design changes for the second instrument.Comment: 81 pages, 67 figures, PASP, accepte

The Multi-Object, Fiber-Fed Spectrographs for SDSS and the Baryon Oscillation Spectroscopic Survey

We present the design and performance of the multi-object fiber spectrographs for the Sloan Digital Sky Survey (SDSS) and their upgrade for the Baryon Oscillation Spectroscopic Survey (BOSS). Originally commissioned in Fall 1999 on the 2.5-m aperture Sloan Telescope at Apache Point Observatory, the spectrographs produced more than 1.5 million spectra for the SDSS and SDSS-II surveys, enabling a wide variety of Galactic and extra-galactic science including the first observation of baryon acoustic oscillations in 2005. The spectrographs were upgraded in 2009 and are currently in use for BOSS, the flagship survey of the third-generation SDSS-III project. BOSS will measure redshifts of 1.35 million massive galaxies to redshift 0.7 and Lyman-alpha absorption of 160,000 high redshift quasars over 10,000 square degrees of sky, making percent level measurements of the absolute cosmic distance scale of the Universe and placing tight constraints on the equation of state of dark energy. The twin multi-object fiber spectrographs utilize a simple optical layout with reflective collimators, gratings, all-refractive cameras, and state-of-the-art CCD detectors to produce hundreds of spectra simultaneously in two channels over a bandpass covering the near ultraviolet to the near infrared, with a resolving power R = \lambda/FWHM ~ 2000. Building on proven heritage, the spectrographs were upgraded for BOSS with volume-phase holographic gratings and modern CCD detectors, improving the peak throughput by nearly a factor of two, extending the bandpass to cover 360 < \lambda < 1000 nm, and increasing the number of fibers from 640 to 1000 per exposure. In this paper we describe the original SDSS spectrograph design and the upgrades implemented for BOSS, and document the predicted and measured performances.Comment: 43 pages, 42 figures, revised according to referee report and accepted by AJ. Provides background for the instrument responsible for SDSS and BOSS spectra. 4th in a series of survey technical papers released in Summer 2012, including arXiv:1207.7137 (DR9), arXiv:1207.7326 (Spectral Classification), and arXiv:1208.0022 (BOSS Overview

Rnf8 deficiency impairs class switch recombination, spermatogenesis, and genomic integrity and predisposes for cancer

Signaling and repair of DNA double-strand breaks (DSBs) are critical for preventing immunodeficiency and cancer. These DNA breaks result from exogenous and endogenous DNA insults but are also programmed to occur during physiological processes such as meiosis and immunoglobulin heavy chain (IgH) class switch recombination (CSR). Recent studies reported that the E3 ligase RNF8 plays important roles in propagating DNA DSB signals and thereby facilitating the recruitment of various DNA damage response proteins, such as 53BP1 and BRCA1, to sites of damage. Using mouse models for Rnf8 mutation, we report that Rnf8 deficiency leads to impaired spermatogenesis and increased sensitivity to ionizing radiation both in vitro and in vivo. We also demonstrate the existence of alternative Rnf8-independent mechanisms that respond to irradiation and accounts for the partial recruitment of 53bp1 to sites of DNA damage in activated Rnf8−/− B cells. Remarkably, IgH CSR is impaired in a gene dose-dependent manner in Rnf8 mutant mice, revealing that these mice are immunodeficient. In addition, Rnf8−/− mice exhibit increased genomic instability and elevated risks for tumorigenesis indicating that Rnf8 is a novel tumor suppressor. These data unravel the in vivo pleiotropic effects of Rnf8

The metabolic enzyme hexokinase 2 localizes to the nucleus in AML and normal haematopoietic stem and progenitor cells to maintain stemness

Thomas, Egan et al. report that hexokinase 2 localizes to the nucleus of leukaemic and normal haematopoietic cells to maintain stemness by interacting with nuclear proteins and modulating chromatin accessibility independently of its kinase activity. Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem cell properties and decreases differentiation, whereas selective nuclear HK2 knockdown promotes differentiation and decreases stem cell function. Nuclear HK2 localization is phosphorylation-dependent, requires active import and export, and regulates differentiation independently of its enzymatic activity. HK2 interacts with nuclear proteins regulating chromatin openness, increasing chromatin accessibilities at leukaemic stem cell-positive signature and DNA-repair sites. Nuclear HK2 overexpression decreases double-strand breaks and confers chemoresistance, which may contribute to the mechanism by which leukaemic stem cells resist DNA-damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes influence stem cell function independently of their metabolic function

A Scoping Review of the Quality and the Design of Evaluations of Mobile Health, Telehealth, Smart Pump and Monitoring Technologies Performed in a Pharmacy-Related Setting.

Background: There is currently a need for high quality evaluations of new mobile health, telehealth, smart pump and monitoring technologies undertaken in a pharmacy-related setting. We aim to evaluate the use of these monitoring technologies performed in this setting. Methods: A systematic searching of English articles that examined the quality and the design of technologies conducted in pharmacy-related facilities was performed using the following databases: MEDLINE and Cumulative index to Nursing and Allied Health Literature (CINAHL) to identify original studies examining the quality and the design of technologies and published in peer-reviewed journals. Extraction of articles and quality assessment of included articles were performed independently by two authors. Quality scores over 75% are classed as being acceptable using a "relatively conservative" quality benchmark. Scores over 55% are included using a "relatively liberal" cut-off point. Results: Screening resulted in the selection of 40 formal evaluations. A substantial number of studies (32, 80.00%) were performed in the United States, quantitative in approach (33, 82.50%) and retrospective cohort (24, 60.00%) in study design. The most common pharmacy-related settings were: 22 primary care (55.00%); 10 hospital pharmacy (25.00%); 7 community pharmacy (17.50%); one primary care and hospital pharmacy (2.50%). The majority of the evaluations (33, 82.50%) reported clinical outcomes, six (15.00%) measured clinical and economic outcomes, and one (2.50%) economic only. Twelve (30.00%) quantitative studies and no qualitative study met objective criteria for "relatively conservative" quality. Using a lower "relatively liberal" benchmark, 27 quantitative (81.82%) and four qualitative (57.41%) studies met the lower quality criterion. Conclusion: Worldwide, few evaluations of mobile health, telehealth, smart pump and monitoring technologies in pharmacy-related setting have been published.Their quality is often below the standard necessary for inclusion in a systematic review mainly due to inadequate study design