Coordinated repression of BIM and PUMA by Epstein-Barr virus latent genes maintains the survival of Burkitt lymphoma cells.

While the association of Epstein-Barr virus (EBV) with Burkitt lymphoma (BL) has long been recognised, the precise role of the virus in BL pathogenesis is not fully resolved. EBV can be lost spontaneously from some BL cell lines, and these EBV-loss lymphoma cells reportedly have a survival disadvantage. Here we have generated an extensive panel of EBV-loss clones from multiple BL backgrounds and examined their phenotype comparing them to their isogenic EBV-positive counterparts. We report that, while loss of EBV from BL cells is rare, it is consistently associated with an enhanced predisposition to undergo apoptosis and reduced tumorigenicity in vivo. Importantly, reinfection of EBV-loss clones with EBV, but surprisingly not transduction with individual BL-associated latent viral genes, restored protection from apoptosis. Expression profiling and functional analysis of apoptosis-related proteins and transcripts in BL cells revealed that EBV inhibits the upregulation of the proapoptotic BH3-only proteins, BIM and PUMA. We conclude that latent EBV genes cooperatively enhance the survival of BL cells by suppression of the intrinsic apoptosis pathway signalling via inhibition of the potent apoptosis initiators, BIM and PUMA.Cell Death and Differentiation advance online publication, 29 September 2017; doi:10.1038/cdd.2017.150

Evolving health information technology and the timely availability of visit diagnoses from ambulatory visits: A natural experiment in an integrated delivery system

<p>Abstract</p> <p>Background</p> <p>Health information technology (HIT) may improve health care quality and outcomes, in part by making information available in a timelier manner. However, there are few studies documenting the changes in timely availability of data with the use of a sophisticated electronic medical record (EMR), nor a description of how the timely availability of data might differ with different types of EMRs. We hypothesized that timely availability of data would improve with use of increasingly sophisticated forms of HIT.</p> <p>Methods</p> <p>We used an historical observation design (2004–2006) using electronic data from office visits in an integrated delivery system with three types of HIT: Basic, Intermediate, and Advanced. We calculated the monthly percentage of visits using the various types of HIT for entry of visit diagnoses into the delivery system's electronic database, and the time between the visit and the availability of the visit diagnoses in the database.</p> <p>Results</p> <p>In January 2004, when only Basic HIT was available, 10% of office visits had diagnoses entered on the same day as the visit and 90% within a week; 85% of office visits used paper forms for recording visit diagnoses, 16% used Basic at that time. By December 2006, 95% of all office visits had diagnoses available on the same day as the visit, when 98% of office visits used some form of HIT for entry of visit diagnoses (Advanced HIT for 67% of visits).</p> <p>Conclusion</p> <p>Use of HIT systems is associated with dramatic increases in the timely availability of diagnostic information, though the effects may vary by sophistication of HIT system. Timely clinical data are critical for real-time population surveillance, and valuable for routine clinical care.</p

The DeepMIP contribution to PMIP4: methodologies for selection, compilation and analysis of latest Paleocene and early Eocene climate proxy data, incorporating version 0.1 of the DeepMIP database

This is the final version of the article. Available from European Geosciences Union via the DOI in this record.Data availability. The data referenced in this manuscript are provided as Supplement Data Files 1 to 8. In the final version, these files will form DeepMIP database version 0.1 and will be accessible online via a citable DOI reference.The early Eocene (56 to 48 million years ago) is inferred to have been the most recent time that Earth's atmospheric CO2 concentrations exceeded 1000 ppm. Global mean temperatures were also substantially warmer than those of the present day. As such, the study of early Eocene climate provides insight into how a super-warm Earth system behaves and offers an opportunity to evaluate climate models under conditions of high greenhouse gas forcing. The Deep Time Model Intercomparison Project (DeepMIP) is a systematic model–model and model–data intercomparison of three early Paleogene time slices: latest Paleocene, Paleocene–Eocene thermal maximum (PETM) and early Eocene climatic optimum (EECO). A previous article outlined the model experimental design for climate model simulations. In this article, we outline the methodologies to be used for the compilation and analysis of climate proxy data, primarily proxies for temperature and CO2. This paper establishes the protocols for a concerted and coordinated effort to compile the climate proxy records across a wide geographic range. The resulting climate “atlas” will be used to constrain and evaluate climate models for the three selected time intervals and provide insights into the mechanisms that control these warm climate states. We provide version 0.1 of this database, in anticipation that this will be expanded in subsequent publications.Natural Environment Research Council (NERC)GNS Science Global Change through Time ProgrammeNational Science Foundation (NSF)KU Leuve

Estimating fine-root production by tree species and understorey functional groups in two contrasting peatland forests

Background and aims Estimation of root-mediated carbon fluxes in forested peatlands is needed for understanding ecosystem functioning and supporting greenhouse gas inventories. Here, we aim to determine the optimal methodology for utilizing ingrowth cores in estimating annual fine-root production (FRP) and its vertical distribution in trees, shrubs and herbs. Methods We used 3-year data obtained with modified ingrowth core method and tested two calculation methods: 'ingrowth-dividing' and `ingrowth-subtracting'. Results The ingrowth-dividing method combined with a 2-year incubation of ingrowth cores can be used for the 'best estimate' of FRP. The FRP in the nutrient-rich fen forest (561 g m(-2)) was more than twice that in the nutrient-poor bog forest (244 g m(-2)). Most FRP occurred in the top 20-cm layer (76-82 %). Tree FRP accounted for 71 % of total FRP in the bog and 94 % in the fen forests, respectively, following the aboveground vegetation patterns; however, in fen forest the proportions of spruce and birch in FRP were higher than their proportions in stand basal area. Conclusions Our methodology may be used to study peatland FRP patterns more widely and will reduce the volume of labour-intensive work, but will benefit from verification with other methods, as is the case in all in situ FRP studies.Peer reviewe

Team Learning: the Missing Construct from a Cross-Cultural Examination of Higher Education?

Team learning should be an important construct in organizational management research because team learning can enhance organizational learning and overall performance. However, there is limited understanding of how team learning works in different cultural contexts. Using an international comparative research approach, we developed a framework of antecedents and outcomes in the higher education context and tested it with samples from the UK and Vietnam. The results show that a common framework is applicable in the two different contexts, subject to slight modifications. However, this study does not find that team learning (measured via the proxy of “attitude towards team learning”) exhibits any statistically significant relationship as a predictor of the proposed outcomes. Other findings from this study on educational contexts are important not only to scholars in this field, but also for practicing managers, particularly those who study and operate in the extensive global market

High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation for Metastatic Rhabdomyosarcoma—A Systematic Review

INTRODUCTION: Patients with metastatic rhabdomyosarcoma (RMS) have a poor prognosis. The aim of this systematic review is to investigate whether high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with metastatic RMS has additional benefit or harm compared to standard chemotherapy. METHODS: Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to February 2010. PubMed was searched in June 2010 for a last update. In addition to randomized and non-randomized controlled trials, case series and case reports were included to complement results from scant data. The primary outcome was overall survival. A meta-analysis was performed using the hazard ratio as primary effect measure, which was estimated from Cox proportional hazard models or from summary statistics of Kaplan Meier product-limit estimations. RESULTS: A total of 40 studies with 287 transplant patients with metastatic RMS (age range 0 to 32 years) were included in the assessment. We identified 3 non-randomized controlled trials. The 3-year overall survival ranged from 22% to 53% in the transplant groups vs. 18% to 55% in the control groups. Meta-analysis on overall survival in controlled trials showed no difference between treatments. Result of meta-analysis of pooled individual survival data of case series and case reports, and results from uncontrolled studies with aggregate data were in the range of those from controlled data. The risk of bias was high in all studies due to methodological flaws. CONCLUSIONS: HDCT followed by autologous HSCT in patients with RMS remains an experimental treatment. At present, it does not appear justifiable to use this treatment except in appropriately designed controlled trials

Early T Cell Recognition of B Cells following Epstein-Barr Virus Infection: Identifying Potential Targets for Prophylactic Vaccination

Epstein-Barr virus, a B-lymphotropic herpesvirus, is the cause of infectious mononucleosis, has strong aetiologic links with several malignancies and has been implicated in certain autoimmune diseases. Efforts to develop a prophylactic vaccine to prevent or reduce EBV-associated disease have, to date, focused on the induction of neutralising antibody responses. However, such vaccines might be further improved by inducing T cell responses capable of recognising and killing recently-infected B cells. In that context, EBNA2, EBNA-LP and BHRF1 are the first viral antigens expressed during the initial stage of B cell growth transformation, yet have been poorly characterised as CD8+ T cell targets. Here we describe CD8+ T cell responses against each of these three "first wave" proteins, identifying target epitopes and HLA restricting alleles. While EBNA-LP and BHRF1 each contained one strong CD8 epitope, epitopes within EBNA2 induced immunodominant responses through several less common HLA class I alleles (e.g. B*3801 and B*5501), as well as subdominant responses through common class I alleles (e.g. B7 and C*0304). Importantly, such EBNA2-specific CD8+ T cells recognised B cells within the first day post-infection, prior to CD8+ T cells against well-characterised latent target antigens such as EBNA3B or LMP2, and effectively inhibited outgrowth of EBV-transformed B cell lines. We infer that "first wave" antigens of the growth-transforming infection, especially EBNA2, constitute potential CD8+ T cell immunogens for inclusion in prophylactic EBV vaccine design

Seasonality in Human Zoonotic Enteric Diseases: A Systematic Review

BACKGROUND: Although seasonality is a defining characteristic of many infectious diseases, few studies have described and compared seasonal patterns across diseases globally, impeding our understanding of putative mechanisms. Here, we review seasonal patterns across five enteric zoonotic diseases: campylobacteriosis, salmonellosis, vero-cytotoxigenic Escherichia coli (VTEC), cryptosporidiosis and giardiasis in the context of two primary drivers of seasonality: (i) environmental effects on pathogen occurrence and pathogen-host associations and (ii) population characteristics/behaviour. METHODOLOGY/PRINCIPAL FINDINGS: We systematically reviewed published literature from 1960-2010, resulting in the review of 86 studies across the five diseases. The Gini coefficient compared temporal variations in incidence across diseases and the monthly seasonality index characterised timing of seasonal peaks. Consistent seasonal patterns across transnational boundaries, albeit with regional variations was observed. The bacterial diseases all had a distinct summer peak, with identical Gini values for campylobacteriosis and salmonellosis (0.22) and a higher index for VTEC (Gini  0.36). Cryptosporidiosis displayed a bi-modal peak with spring and summer highs and the most marked temporal variation (Gini = 0.39). Giardiasis showed a relatively small summer increase and was the least variable (Gini = 0.18). CONCLUSIONS/SIGNIFICANCE: Seasonal variation in enteric zoonotic diseases is ubiquitous, with regional variations highlighting complex environment-pathogen-host interactions. Results suggest that proximal environmental influences and host population dynamics, together with distal, longer-term climatic variability could have important direct and indirect consequences for future enteric disease risk. Additional understanding of the concerted influence of these factors on disease patterns may improve assessment and prediction of enteric disease burden in temperate, developed countries