Mathematical modelling of activation-induced heterogeneity in TNF, IL6, NOS2, and IL1β expression reveals cell state transitions underpinning macrophage responses to LPS

Background: Despite extensive work on macrophage heterogeneity, the mechanisms driving activation induced heterogeneity (AIH) in macrophages remain poorly understood. Here, we aimed to develop mathematical models to explore theoretical cellular states underpinning the empirically observed responses of macrophages following lipopolysaccharide (LPS) challenge. Methods: We obtained empirical data following primary and secondary responses to LPS in two in vitro cellular models (bone marrow-derived macrophages or BMDMs, and RAW 264.7 cells) and single-cell protein measurements for four key inflammatory mediators: TNF, IL-6, pro-IL-1β, and NOS2, and used mathematical modelling to understand heterogeneity. Results: For these four factors, we showed that macrophage community AIH is dependent on LPS dose and that altered AIH kinetics in macrophages responding to a second LPS challenge underpin hypo-responsiveness to LPS. These empirical data can be explained by a mathematical three-state model including negative, positive, and non-responsive states (NRS), but they are also compatible with a four-state model that includes distinct reversibly NRS and non-responsive permanently states (NRPS). Our mathematical model, termed NoRM (Non-Responsive Macrophage) model identifies similarities and differences between BMDM and RAW 264.7 cell responses. In both cell types, transition rates between states in the NoRM model are distinct for each of the tested proteins and, crucially, macrophage hypo-responsiveness is underpinned by changes in transition rates to and from NRS. Conclusions: Overall, we provide a mathematical model for studying macrophage ecology and community dynamics that can be used to elucidate the role of phenotypically negative macrophage populations in AIH and, primary and secondary responses to LPS

Quality assessment of cellular therapies: the emerging role of molecular assays

Cellular therapies are becoming increasingly important in treating cancer, hematologic malignancies, autoimmune disorders, and damaged tissue. These therapies are becoming more effective and are being used more frequently, but they are also becoming more complex. As a result, quality testing is becoming an increasingly important part of cellular therapy. Cellular therapies should be tested at several points during their production. The starting material, intermediate products and the final product are usually analyzed. Products are evaluated at critical steps in the manufacturing process and at the end of production prior to the release of the product for clinical use. In addition, the donor of the starting biologic material is usually evaluated. The testing of cellular therapies for stability, consistency, comparability and potency is especially challenging. We and others have found that global gene and microRNA expression analysis is useful for comparability testing and will likely be useful for potency, stability and consistency testing. Several examples of the use of gene expression analysis for assessing cellular therapies are presented

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Radiation and Plasma Effects Working Team: Overview and Progress Report

To track space weather models’ progress and performance over time, the Community Coordinated Modeling Center (CCMC), together with NASA’s Living with a Star program, has initiated an extensive model validation and assessment efforts involving a community of space environment experts, model and application developers, data providers, forecasters and end-users of space weather products and services (https://ccmc.gsfc.nasa.gov/assessment/). The Radiation and Plasma Effects Working Team deals with five different subtopics: Surface Charging from 10s eV to 40 keV electrons, Internal Charging due to energetic electrons from hundreds keV to several MeVs. Single Event Effects from solar energetic particles (SEPs) and galactic cosmic rays (GCRs) (several MeV to TeVs), Total Dose due to accumulation of doses from electrons and protons in a broad energy range, and Radiation Effects from SEPs and GCRs at aviation altitudes

DEFINING METRICS AND TRACKING PROGRESS FOR NEAR-EARTH PLASMA AND RADIATION ENVIRONMENT MODELING: HIGHLIGHTS FROM THE INTERNATIONAL FORUM ON SPACE WEATHER CAPABILITIES ASSESSMENT

The international forum on space weather capabilities assessment aims to quantify scientificprogress in the area of space weather. More specifically it aims to deliver a framework for the application of metrics in order to measure performance/progress of space weather modelling and to construct a library of metric and validation techniques which may be used thereby harmonizing comparisons and validations which are made. One of the working groups acting under this umbrella focusses on space plasma and radiation environments and effects. In this domain there are clearly established standards for defining an environment which spacecraft must survive. Each major agency has its own standards which drive requirements. This is less mature in the domain of commercial aviation. The aim of the working group is to connect the space weather modelling community with experts on environment specification in order to define environmental quantities (scientific predictands) which are representative of the environment driving an effect thus addressing user needs. The effects covered by the working group include surface charging, internal charging, total (ionizing and non-ionizing) dose, single event effects and effects on aircraft. In addition to the scientific (or environmental) predictand an associated effect quantity (and associated timescale) is defined for which tools are readily available to transform quantities from the environment to the effect. Finally, a set of statistical metrics are defined to evaluated the accuracy of model outputs. The acceptance of quantities will simplify to task of space weather modelers in validating their model and provide an objective comparison between models to show which are more reliable for a given effect over a given timescale. This talk presents the progress of the working group thus far to define concrete quantities which shall constitute space weather metrics in this domain

NEAR-EARTH RADIATION AND PLASMA ENVIRONMENT COMMUNITY APPROACH TO MODEL VALIDATION REGARDING IMPACTS ON (AERO)SPACE ASSETS

In order to assess the performance of space environment models that are relevant to various impacts on (aero)space assets, the ISWAT Near-Earth Radiation and Plasma Environment community has been actively involved in engaging different communities together with the goal of addressing the issue from a systematic perspective. Information will be provided in first defining the essential space environment quantities (ESEQ) that are most relevant to the impacts (also directly measurable) and the corresponding essential effect quantities that are more easily understandable/useful for end-users. Metrics for measuring the model performance for different impacts/applications, uncertainties of models and observations, and methods of carrying out and archiving such model validation efforts/results for long-term performance assessment and tracking will be the focus of the presentation

Assessment of Radiation and Plasma Environment Modeling Capabilities

In order to make space weather environment models more useful to engineers and the user community throughout different phases of a satellite lifecycle (mission concept/planning/design/build, launch, operation and anomaly resolution) or assessing radiation effects at aviation altitudes, it is important to track their performance over time with well-defined, user-focused metrics and to maintain active, ongoing communication channels in order to understand each other’s needs. To this end, working with experts in both science and engineering areas and the community in general, CCMC has launched the International Forum for Space Weather Modeling Capabilities Assessment (https://ccmc.gsfc.nasa.gov/assessment/). In this presentation, we will report the progress made from our Space Radiation and Plasma Effects Working Team. Two sets of metrics/physical quantities have been chosen with one set that are outputs of space environment models (constituting critical physical parameters/inputs directly relevant to effects quantification) and the other relevant to engineering models of effects. The initial results and follow-on activities will be discussed

Space Radiation and Plasma Effects on Satellites and Aviation: Quantities and Metrics for Tracking Performance of Space Weather Environment Models.

The Community Coordinated Modeling Center has been leading community-wide space science and space weather model validation projects for many years. These efforts have been broadened and extended via the newly launched International Forum for Space Weather Modeling Capabilities Assessment (https://ccmc.gsfc.nasa.gov/assessment/). Its objective is to track space weather models' progress and performance over time, a capability that is critically needed in space weather operations and different user communities in general. The Space Radiation and Plasma Effects Working Team of the aforementioned International Forum works on one of the many focused evaluation topics and deals with five different subtopics (https://ccmc.gsfc.nasa.gov/assessment/topics/radiation-all.php) and varieties of particle populations: Surface Charging from tens of eV to 50-keV electrons and internal charging due to energetic electrons from hundreds keV to several MeVs. Single-event effects from solar energetic particles and galactic cosmic rays (several MeV to TeV), total dose due to accumulation of doses from electrons (>100 keV) and protons (>1 MeV) in a broad energy range, and radiation effects from solar energetic particles and galactic cosmic rays at aviation altitudes. A unique aspect of the Space Radiation and Plasma Effects focus area is that it bridges the space environments, engineering, and user communities. The intent of the paper is to provide an overview of the current status and to suggest a guide for how to best validate space environment models for operational/engineering use, which includes selection of essential space environment and effect quantities and appropriate metrics