Atrophin proteins: an overview of a new class of nuclear receptor corepressors

The normal development and physiological functions of multicellular organisms are regulated by complex gene transcriptional networks that include myriad transcription factors, their associating coregulators, and multiple chromatin-modifying factors. Aberrant gene transcriptional regulation resulting from mutations among these elements often leads to developmental defects and diseases. This review article concentrates on the Atrophin family proteins, including vertebrate Atrophin-1 (ATN1), vertebrate arginine-glutamic acid dipeptide repeats protein (RERE), and Drosophila Atrophin (Atro), which we recently identified as nuclear receptor corepressors. Disruption of Atrophin-mediated pathways causes multiple developmental defects in mouse, zebrafish, and Drosophila, while an aberrant form of ATN1 and altered expression levels of RERE are associated with neurodegenerative disease and cancer in humans, respectively. We here provide an overview of current knowledge about these Atrophin proteins. We hope that this information on Atrophin proteins may help stimulate fresh ideas about how this newly identified class of nuclear receptor corepressors aids specific nuclear receptors and other transcriptional factors in regulating gene transcription, manifesting physiological effects, and causing diseases

The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation

Epstein-Barr virus (EBV) is a human herpesvirus that persists as a largely subclinical infection in the vast majority of adults worldwide. Recent evidence indicates that an important component of the persistence strategy involves active interference with the MHC class I antigen processing pathway during the lytic replication cycle. We have now identified a novel role for the lytic cycle gene, BILF1, which encodes a glycoprotein with the properties of a constitutive signaling G-protein-coupled receptor (GPCR). BILF1 reduced the levels of MHC class I at the cell surface and inhibited CD8+ T cell recognition of endogenous target antigens. The underlying mechanism involves physical association of BILF1 with MHC class I molecules, an increased turnover from the cell surface, and enhanced degradation via lysosomal proteases. The BILF1 protein of the closely related CeHV15 c1-herpesvirus of the Rhesus Old World primate (80% amino acid sequence identity) downregulated surface MHC class I similarly to EBV BILF1. Amongst the human herpesviruses, the GPCR encoded by the ORF74 of the KSHV c2-herpesvirus is most closely related to EBV BILF1 (15% amino acid sequence identity) but did not affect levels of surface MHC class I. An engineered mutant of BILF1 that was unable to activate G protein signaling pathways retained the ability to downregulate MHC class I, indicating that the immune-modulating and GPCR-signaling properties are two distinct functions of BILF1. These findings extend our understanding of the normal biology of an important human pathogen. The discovery of a third EBV lytic cycle gene that cooperates to interfere with MHC class I antigen processing underscores the importance of the need for EBV to be able to evade CD8+ T cell responses during the lytic replication cycle, at a time when such a large number of potential viral targets are expressed

Use of complementary and alternative medicine at Norwegian and Danish hospitals

<p>Abstract</p> <p>Background</p> <p>Several studies have found that a high proportion of the population in western countries use complementary and alternative medicine (CAM). However, little is known about whether CAM is offered in hospitals. The aim of this study was to describe to what extent CAM is offered in Norwegian and Danish hospitals and investigate possible changes in Norway since 2001.</p> <p>Methods</p> <p>A one-page questionnaire was sent to all included hospitals in both countries. The questionnaire was sent to the person responsible for the clinical activity, typically the medical director. 99 hospitals in the authority (85%) in Norway and 126 in Denmark (97%) responded. Given contact persons were interviewed.</p> <p>Results</p> <p>CAM is presently offered in about 50% of Norwegian hospitals and one-third of Danish hospitals. In Norway CAM was offered in 50 hospitals, 40 of which involved acupuncture. 19 hospitals gave other alternative therapies like biofeedback, hypnosis, cupping, ear-acupuncture, herbal medicine, art therapy, homeopathy, reflexology, thought field therapy, gestalt therapy, aromatherapy, tai chi, acupressure, yoga, pilates and other. 9 hospitals offered more than one therapy form. In Denmark 38 hospitals offered acupuncture and one Eye Movement Desensitization and Reprocessing Light Therapy. The most commonly reported reason for offering CAM was scientific evidence in Denmark. In Norway it was the interest of a hospital employee, except for acupuncture where the introduction is more often initiated by the leadership and is more based on scientific evidence of effect. All persons (except one) responsible for the alternative treatment had a medical or allied health professional background and their education/training in CAM treatment varied substantially.</p> <p>Conclusions</p> <p>The extent of CAM being offered has increased substantially in Norway during the first decade of the 21^stcentury. This might indicate a shift in attitude regarding CAM within the conventional health care system.</p

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge

Availability of data and materials: The datasets used and analysed during the current study are available from the corresponding author on reasonable request.Supplementary information is available online at: https://link.springer.com/article/10.1186/s12974-023-02945-0#Sec20 .Copyright © The Author(s) 2023. Background: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer’s disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer’s disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. Methods: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. Results: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. Conclusions: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer’s disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer’s disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer’s disease should aim to enhance protective microglial actions.This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This project received funding and access to the [18F]florbetapir and [18F]AV1451 PET tracers from Avid and Lilly UK. Avid and Lilly UK were not involved in data analysis and interpretation. This project has received funding from the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. This research was supported by the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This research was supported by researchers at the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A partnership between UCL and University College London Hospitals NHS Foundation Trust. This work was funded in part through the MRC Proximity to Discovery: Industry Engagement Fund (External Collaboration, Innovation and Entrepreneurism: Translational Medicine in Exeter 2 (EXCITEME2) ref. MC_PC_17189) awarded to Dr Creese and MRC grant MR/N015746/1

Working conditions and Work-Family Conflict in German hospital physicians: psychosocial and organisational predictors and consequences

<p>Abstract</p> <p>Background</p> <p>Germany currently experiences a situation of major physician attrition. The incompatibility between work and family has been discussed as one of the major reasons for the increasing departure of German physicians for non-clinical occupations or abroad. This study investigates predictors for one particular direction of Work-Family Conflict – namely work interfering with family conflict (WIF) – which are located within the psychosocial work environment or work organisation of hospital physicians. Furthermore, effects of WIF on the individual physicians' physical and mental health were examined. Analyses were performed with an emphasis on gender differences. Comparisons with the general German population were made.</p> <p>Methods</p> <p>Data were collected by questionnaires as part of a study on <it>Psychosocial work hazards and strains of German hospital physicians </it>during April–July 2005. Two hundred and ninety-six hospital physicians (response rate 38.9%) participated in the survey. The Copenhagen Psychosocial Questionnaire (COPSOQ), work interfering with family conflict scale (WIF), and hospital-specific single items on work organisation were used to assess WIF, its predictors, and consequences.</p> <p>Results</p> <p>German hospital physicians reported elevated levels of WIF (mean = 74) compared to the general German population (mean = 45, <it>p </it>< .01). No significant gender difference was found. Predictors for the WIF were lower age, high quantitative demands at work, elevated number of days at work despite own illness, and consequences of short-notice changes in the duty roster. Good sense of community at work was a protective factor. Compared to the general German population, we observed a significant higher level of quantitative work demands among hospital physicians (mean = 73 vs. mean = 57, <it>p </it>< .01). High values of WIF were significantly correlated to higher rates of personal burnout, behavioural and cognitive stress symptoms, and the intention to leave the job. In contrast, low levels of WIF predicted higher job satisfaction, better self-judged general health status, better work ability, and higher satisfaction with life in general. Compared to the German general population, physicians showed significantly higher levels of individual stress and quality of life as well as lower levels for well-being. This has to be judged as an alerting finding regarding the state of physicians' health.</p> <p>Conclusion</p> <p>In our study, work interfering with family conflict (WIF) as part of Work-Family Conflict (WFC) was highly prevalent among German hospital physicians. Factors of work organisation as well as factors of interpersonal relations at work were identified as significant predictors for WIF. Some of these predictors are accessible to alteration by improving work organisation in hospitals.</p

Advancing our understanding of functional genome organisation through studies in the fission yeast

Significant progress has been made in understanding the functional organisation of the cell nucleus. Still many questions remain to be answered about the relationship between the spatial organisation of the nucleus and the regulation of the genome function. There are many conflicting data in the field making it very difficult to merge published results on mammalian cells into one model on subnuclear chromatin organisation. The fission yeast, Schizosaccharomyces pombe, over the last decades has emerged as a valuable model organism in understanding basic biological mechanisms, especially the cell cycle and chromosome biology. In this review we describe and compare the nuclear organisation in mammalian and fission yeast cells. We believe that fission yeast is a good tool to resolve at least some of the contradictions and unanswered questions concerning functional nuclear architecture, since S. pombe has chromosomes structurally similar to that of human. S. pombe also has the advantage over higher eukaryotes in that the genome can easily be manipulated via homologous recombination making it possible to integrate the tools needed for visualisation of chromosomes using live-cell microscopy. Classical genetic experiments can be used to elucidate what factors are involved in a certain mechanism. The knowledge we have gained during the last few years indicates similarities between the genome organisation in fission yeast and mammalian cells. We therefore propose the use of fission yeast for further advancement of our understanding of functional nuclear organisation

O alcoolismo, suas causas e tratemento nas representacoes sociais de profissionais de Saude da Familia = Alcoholism, its causes and treatment in the social representations constructed by Brazilian Family Health professionals

Health sciences define alcoholism as a multifaceted syndrome. Guidelines for treatment include adoption of the harm reduction paradigm and the essential role of Primary Health Care (PHC) towards the wide range of alcohol problems. This research aimed at understanding the social representations of alcoholism constructed by Brazilian PHC professionals, working at Family Health Centers (FHC). We conducted semi-structured interviews with 40 graduated health professionals who worked in 11 different FHC located in a municipality in southeast Brazil. Data were treated with thematic content analysis. We highlight the following results: professionals objectified the alcoholic as a patient who did not search for treatment and/or who threatened the normal functioning of the FHC; professionals considered social and psychological factors as the main causes of alcoholism; they did not mention the concept of harm reduction, nor well-defined treatment protocols. The causal attribution and the representational field inherent to the social representations contributed to anchor alcoholism as a "plague" of poverty. The FHC were perceived simultaneously as important and impotent towards alcoholism. We conclude that the implementation of alcohol-related care strategies must consider the intergroup relations between professionals and patients

Self-Rated Health in the Baltic Countries, 1994–1999

Numerous studies have examined the explanations of mortality fluctuations in the former USSR during the last decade of the twentieth century-a time of considerable political and socio-economic changes-but fewer studies have considered the health of these populations during this period. Using individual data from the Norbalt surveys held in 1994 and 1999 in the three Baltic countries, we examine the determinants of self-rated health in the three countries and for the two periods, by way of Bayesian structural equation modelling and directed acyclic graphs. The model takes into account, as possible determinants, alcohol consumption, physical health, psychological distress, education, locus of control, and social support. A major result is the remarkable stability of the model's parameters whatever the country, year, gender, ethnicity, or age-group. Particular attention is given to the role of alcohol consumption and to the association observed between better self-assessed health and higher drinking. © 2010 Springer Science+Business Media B.V