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Despite being in the midst of a global pandemic of infections caused by the pathogen Chlamydia trachomatis, a vaccine capable of inducing protective immunity remains elusive. Given the C. trachomatis mucosal port of entry, a formulation compatible with mucosal administration and capable of eliciting potent genital tract immunity is highly desirable. While subunit vaccines are considered safer and better tolerated, these are typically poorly immunogenic and require co-formulation with immune-potentiating adjuvants. However, of the adjuvants licensed for use in humans, very few drive robust cellular responses, a pre-requisite for protection against C. trachomatis infection. Recently, the cationic adjuvant formulations (CAF) have been shown to induce robust humoral and cellular immunity in pre-clinical models of chlamydia, malaria and tuberculosis (TB). Here, we demonstrate that CAF01 induces potent immune responses when combined with the major outer membrane protein (MOMP) of C. trachomatis following parenteral immunisation and also as part of a heterologous prime/boost regime. We show that a subcutaneous prime with CAF01-adjuvanted recombinant MOMP licenses antigen-specific immunity at distant mucosal sites which can be activated following oral antigen re-encounter in the absence of concomitant adjuvant stimulation. Finally, we shed light on the mechanism(s) through which CAF01 elicits robust antigen-specific immunity to co-formulated MOMP via type I interferon (IFN) signalling.

Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2 −/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell. IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.

We document the development of the first version of the U.K. Earth System Model UKESM1. The model represents a major advance on its predecessor HadGEM2‐ES, with enhancements to all component models and new feedback mechanisms. These include a new core physical model with a well‐resolved stratosphere; terrestrial biogeochemistry with coupled carbon and nitrogen cycles and enhanced land management; tropospheric‐stratospheric chemistry allowing the holistic simulation of radiative forcing from ozone, methane, and nitrous oxide; two‐moment, five‐species, modal aerosol; and ocean biogeochemistry with two‐way coupling to the carbon cycle and atmospheric aerosols. The complexity of coupling between the ocean, land, and atmosphere physical climate and biogeochemical cycles in UKESM1 is unprecedented for an Earth system model. We describe in detail the process by which the coupled model was developed and tuned to achieve acceptable performance in key physical and Earth system quantities and discuss the challenges involved in mitigating biases in a model with complex connections between its components. Overall, the model performs well, with a stable pre‐industrial state and good agreement with observations in the latter period of its historical simulations. However, global mean surface temperature exhibits stronger‐than‐observed cooling from 1950 to 1970, followed by rapid warming from 1980 to 2014. Metrics from idealized simulations show a high climate sensitivity relative to previous generations of models: Equilibrium climate sensitivity is 5.4 K, transient climate response ranges from 2.68 to 2.85 K, and transient climate response to cumulative emissions is 2.49 to 2.66 K TtC−1. Plain Language Summary We describe the development and behavior of UKESM1, a novel climate model that includes improved representations of processes in the atmosphere, ocean, and on land. These processes are inter‐related: For example, dust is produced on the land and blown up into the atmosphere where it affects the amount of sunlight falling on Earth. Dust can also be dissolved in the ocean, where it affects marine life. This in turn changes both the amount of carbon dioxide absorbed by the ocean and the material emitted from the surface into the atmosphere, which has an affect on the formation of clouds. UKESM1 includes many processes and interactions such as these, giving it a high level of complexity. Ensuring realistic process behavior is a major challenge in the development of our model, and we have carefully tested this. UKESM1 performs well, correctly exhibiting stable results from a continuous pre‐industrial simulation (used to provide a reference for future experiments) and showing good agreement with observations toward the end of its historical simulations. Results for some properties—including the degree to which average surface temperature changes with increased amounts of carbon dioxide in the atmosphere—are examined in detail. Key Points UKESM1 represents a major advance over its predecessor HadGEM2‐ES, both in the complexity of its components and its internal coupling The complex coupling presents challenges to the model development; we document the tuning process employed to obtain acceptable performance UKESM1 performs well, having a stable pre‐industrial state and showing good agreement with observations in a wide variety of contexts

We describe the scientific and technical implementation of two models for a core set of experiments contributing to the sixth phase of the Coupled Model Intercomparison Project (CMIP6). The models used are the physical atmosphere‐land‐ocean‐sea ice model HadGEM3‐GC3.1 and the Earth system model UKESM1 which adds a carbon‐nitrogen cycle and atmospheric chemistry to HadGEM3‐GC3.1. The model results are constrained by the external boundary conditions (forcing data) and initial conditions. We outline the scientific rationale and assumptions made in specifying these. Notable details of the implementation include an ozone redistribution scheme for prescribed ozone simulations (HadGEM3‐GC3.1) to avoid inconsistencies with the model's thermal tropopause, and land use change in dynamic vegetation simulations (UKESM1) whose influence will be subject to potential biases in the simulation of background natural vegetation. We discuss the implications of these decisions for interpretation of the simulation results. These simulations are expensive in terms of human and CPU resources and will underpin many further experiments; we describe some of the technical steps taken to ensure their scientific robustness and reproducibility. Plain Language Summary Complex models of the Earth system are valuable tools for understanding the processes responsible for our changing climate. The Coupled Model Intercomparison Project (CMIP) is a well‐established activity of the World Climate Research Programme that brings together results from these models to better understand their process representation and to pool their projections for robust understanding of future climate pathways. The latest phase of CMIP (CMIP6) is larger and more ambitious than previous phases. We detail the setup of two U.K. models (HadGEM3‐GC3.1 and UKESM1) for a core set of experiments contributing to CMIP6, including simulations of historical and future periods covering 1850 to 2300. We highlight assumptions made in applying the prescribed CMIP6 input data to these models. We outline the technical steps to ensure the reproducibility of these simulations. Key Points We describe the implementation of U.K. Earth system models for CMIP6 experiments We document the assumptions made in implementing the external forcing in line with experiment protocols Special attention was paid to ensuring that these expensive simulations were reproducible

Background Involving patient and community stakeholders in clinical trials adds value by ensuring research prioritizes patient goals both in conduct of the study and application of the research. The use of stakeholder committees and their impact on the conduct of a multicenter clinical trial have been underreported clinically and academically. The aim of this study is to describe how Study Advisory Committee (SAC) recommendations were implemented throughout the Emergency Medicine Palliative Care Access (EMPallA) trial. EMPallA is a multi-center, pragmatic two-arm randomized controlled trial (RCT) comparing the effectiveness of nurse-led telephonic case management and specialty, outpatient palliative care of older adults with advanced illness. Methods A SAC consisting of 18 individuals, including patients with palliative care experience, members of healthcare organizations, and payers was convened for the EMPallA trial. The SAC engaged in community-based participatory research and assisted in all aspects from study design to dissemination. The SAC met with the research team quarterly and annually from project inception to dissemination. Using meeting notes and recordings we completed a qualitative thematic analysis using an iterative process to develop themes and subthemes to summarize SAC recommendations throughout the project’s duration. Results The SAC convened 16 times between 2017 and 2020. Over the course of the project, the SAC provided 41 unique recommendations. Twenty-six of the 41 (63%) recommendations were adapted into formal Institutional Review Board (IRB) study modifications. Recommendations were coded into four major themes: Scientific, Pragmatic, Resource and Dissemination. A majority of the recommendations were related to either the Scientific (46%) or Pragmatic (29%) themes. Recommendations were not mutually exclusive across three study phases: Preparatory, execution and translational. A vast majority (94%) of the recommendations made were related to the execution phase. Major IRB study modifications were made based on their recommendations including data collection of novel dependent variables and expanding recruitment to Spanish-speaking patients. Conclusions Our study provides an example of successful integration of a SAC in the conduct of a pragmatic, multi-center RCT. Future trials should engage with SACs in all study phases to ensure trials are relevant, inclusive, patient-focused, and attentive to gaps between health care and patient and family needs. Trial Registration : Clinicaltrials.gov Identifier: NCT03325985, 10/30/2017. Plain English summary Clinical research should involve patient and community stakeholder perspectives to make sure the study addresses questions important to the studied population. One way to do this is by creating a group of stakeholders who can advise on the conduct of a study. We assembled a Study Advisory Committee (SAC) for the Emergency Medicine Palliative Care Access (EMPallA) trial. The purpose of this clinical trial is to compare the effectiveness of nurse-led telephonic case management and specialty, outpatient palliative care of older adults with advanced illness. This paper describes how the SACs involvement translated into direct impacts on the EMPallA trial. The trial research team held regular meetings with the SAC throughout the trial process. Their involvement led to many significant changes in the trial, such as  expanding recruitment inclusion criteria (Spanish-speaking patients), and including survey instruments to measure lonelines and caregiver burden. The SAC also devised strategies to overcome patient and caregiver recruitment and retention challenges, including the creation of patient-friendly materials and training for research coordinators. This study provides a successful example of how actively engaging patient and community stakeholders, through committee engagement, can promote patient priorities in all phases of a trial while facilitating patient recruitment and retention.