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

Marsh migration and beyond: A scalable framework to assess tidal wetland resilience and support strategic management.

Tidal wetlands are critical but highly threatened ecosystems that provide vital services. Efficient stewardship of tidal wetlands requires robust comparative assessments of different marshes to understand their resilience to stressors, particularly in the face of relative sea level rise. Existing assessment frameworks aim to address tidal marsh resilience, but many are either too localized or too general, and few directly translate resilience evaluations to recommendations for management strategies. In response to the deficiencies in existing frameworks, we identified a set of metrics that influence overall marsh resilience that can be assessed at any spatial scale. We then developed a new comprehensive assessment framework to rank relative marsh resilience using these metrics, which are nested within three categories. We represent resilience as the sum of results across the three metric categories: current condition, adaptive capacity, and vulnerability. Users of this framework can add scores from each category to generate a total resilience score to compare across marshes or take the score from each category and refer to recommended management actions we developed based on expert elicitation for each combination of category results. We then applied the framework across the contiguous United States using publicly available data, and summarized results at multiple spatial scales, from regions to coastal states to National Estuarine Research Reserves to finer scale marsh units, to demonstrate the framework's value across these scales. Our national analysis allowed for comparison of tidal marsh resilience across geographies, which is valuable for determining where to prioritize management actions for desired future marsh conditions. In combination, the assessment framework and recommended management actions function as a broadly applicable decision-support tool that will enable resource managers to evaluate tidal marshes and select appropriate strategies for conservation, restoration, and other stewardship goals

Regional Perfusion During Venoarterial Extracorporeal Membrane Oxygenation: A Case Report and Educational Modules on the Concept of Dual Circulations

A challenging aspect of managing patients on venoarterial extracorporeal membrane oxygenation (V-A ECMO) is a thorough understanding of the relationship between oxygenated blood from the ECMO circuit and blood being pumped from the patient’s native heart. We present an adult V-A ECMO case report, which illustrates a unique encounter with the concept of “dual circulations.” Despite blood gases from the ECMO arterial line showing respiratory acidosis, this patient with cardiogenic shock demonstrated regional respiratory alkalosis when blood was sampled from the right radial arterial line. In response, a sample was obtained from the left radial arterial line, which mimicked the ECMO arterial blood but was dramatically different from the blood sampled from the right radial arterial line. A retrospective analysis of patient data revealed that the mismatch of blood gas values in this patient corresponded to an increased pulse pressure. Having three arterial blood sampling sites and data on the patient’s pulse pressure provided a dynamic view of blood mixing and guided proper management, which contributed to a successful patient outcome that otherwise may not have occurred. As a result of this unique encounter, we created and distributed graphics representing the concept of “dual circulations” to facilitate the education of ECMO specialists at our institution

Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition

In cellular immunity, T cells recognize peptide antigens bound and presented by major histocompatibility complex (MHC) proteins. The motions of peptides bound to MHC proteins play a significant role in determining immunogenicity. However, existing approaches for investigating peptide/MHC motional dynamics are challenging or of low throughput, hindering the development of algorithms for predicting immunogenicity from large databases, such as those of tumor or genetically unstable viral genomes. We addressed this by performing extensive molecular dynamics simulations on a large structural database of peptides bound to the most commonly expressed human class-I MHC protein, HLA-A*0201. The simulations reproduced experimental indicators of motion and were used to generate simple models for predicting site-specific, rapid motions of bound peptides through differences in their sequence and chemical composition alone. The models can easily be applied on their own or incorporated into immunogenicity prediction algorithms. Beyond their predictive power, the models provide insight into how amino acid substitutions can influence peptide and protein motions and how dynamic information is communicated across peptides. They also indicate a link between peptide rigidity and hydrophobicity, two features known to be important in influencing cellular immune responses

Highly Soluble β-Glucan Fiber Modulates Mechanisms of Blood Glucose Regulation and Intestinal Permeability

β-glucans found in cereal grains have been previously demonstrated to improve blood glucose control; however, current understanding points to their high viscosity as the primary mechanism of action. In this work, we present a novel, highly soluble, low-viscosity β-glucan fiber (HS-BG fiber) and a preclinical dataset that demonstrates its impact on two mechanisms related to the prevention of hyperglycemia. Our results show that HS-BG inhibits the activity of two key proteins involved in glucose metabolism, the α-glucosidase enzyme and the SGLT1 transporter, thereby having the potential to slow starch digestion and subsequent glucose uptake. Furthermore, we demonstrate in a multi-donor fecal fermentation model that HS-BG is metabolized by several different members of the gut microbiome, producing high amounts of short-chain fatty acids (SCFAs), known agonists of GPR43 receptors in the gut related to GLP-1 secretion. The production of SCFAs was verified in the translational gut model, SHIME®. Moreover, HS-BG fiber fermentation produces compounds that restored permeability in disrupted epithelial cells, decreased inflammatory chemokines (CXCL10, MCP-1, and IL-8), and increased anti-inflammatory marker (IL-10), which could improve insulin resistance. Together, these data suggest that the novel HS-BG fiber is a promising new functional ingredient that can be used to modulate postprandial glycemic responses while the high solubility and low viscosity enable easy formulation in both beverage and solid food matrices

Soil incubation methods lead to large differences in inferred methane production temperature sensitivity

Quantifying the temperature sensitivity of methane (CH _4 ) production is crucial for predicting how wetland ecosystems will respond to climate warming. Typically, the temperature sensitivity (often quantified as a Q _10 value) is derived from laboratory incubation studies and then used in biogeochemical models. However, studies report wide variation in incubation-inferred Q _10 values, with a large portion of this variation remaining unexplained. Here we applied observations in a thawing permafrost peatland (Stordalen Mire) and a well-tested process-rich model ( ecosys ) to interpret incubation observations and investigate controls on inferred CH _4 production temperature sensitivity. We developed a field-storage-incubation modeling approach to mimic the full incubation sequence, including field sampling at a particular time in the growing season, refrigerated storage, and laboratory incubation, followed by model evaluation. We found that CH _4 production rates during incubation are regulated by substrate availability and active microbial biomass of key microbial functional groups, which are affected by soil storage duration and temperature. Seasonal variation in substrate availability and active microbial biomass of key microbial functional groups led to strong time-of-sampling impacts on CH _4 production. CH _4 production is higher with less perturbation post-sampling, i.e. shorter storage duration and lower storage temperature. We found a wide range of inferred Q _10 values (1.2–3.5), which we attribute to incubation temperatures, incubation duration, storage duration, and sampling time. We also show that Q _10 values of CH _4 production are controlled by interacting biological, biochemical, and physical processes, which cause the inferred Q _10 values to differ substantially from those of the component processes. Terrestrial ecosystem models that use a constant Q _10 value to represent temperature responses may therefore predict biased soil carbon cycling under future climate scenarios

Development of the Adult ECMO Specialist Certification Examination.

The American Society of Extracorporeal Technology Board of Directors, consistent with the American Society of Extracorporeal Technology\u27s safe patient care improvement mission, charged the International Board of Blood Management to write a knowledge and skill certification examination for healthcare personnel employed as adult extracorporeal membrane oxygenation (ECMO) specialists. Nineteen nationally recognized ECMO subject-matter experts were selected to complete the examination development. A job analysis was performed, yielding a job description and examination plan focused on 16 job categories. Multiple-choice test items were created and validated. Qualified ECMO specialists were identified to complete a pilot examination and both pre- and post-examination surveys. The examination item difficulty and candidate performance were ranked and matched using Rasch methodology. Candidates\u27 examination scores were compared with their profession, training, and experience as ECMO specialists. The 120-item pilot examination form ranked 76 ECMO specialist candidates consistent with their licensure, ECMO training, and clinical experience. Forty-three registered nurses, 28 registered respiratory therapists, four certified clinical perfusionists, and one physician assistant completed the pilot examination process. Rasch statistics revealed examination reliability coefficients of .83 for candidates and .88 for test items. Candidates ranked the appropriateness for examination items consistent with the item content, difficulty, and their personal examination score. The pilot examination pass rate was 80%. The completed examination product scheduled for enrollment in March 2020 includes 100 verified test items with an expected pass rate of 84% at a cut score of 67%. The online certification examination based on a verified job analysis provides an extramural assessment that ranks minimally prepared ECMO specialists\u27 knowledge, skills, and abilities (KSA) consistent with safe ECMO patient care and circuit management. It is anticipated that ECMO facilities and ECMO service providers will incorporate the certification examination as part of their process improvement, safety, and quality assurance plans