Recommendation for a Medical System Concept of Operations for Gateway Missions

NASAs exploration missions to cis-lunar space will establish a permanent gateway to future transport missions to Mars. These missions mandate a significant paradigm change for mission planning, spacecraft design, human systems integration, and in-flight medical care due to constraints on mass, volume, power, resupply, and medical evacuation capability. These constraints require medical system development to be tightly integrated with mission and habitat design to provide a sufficient medical infrastructure and enable mission success. This concept of operations provides a vision of medical care needs that will be used to guide the development of a medical system for the cis-lunar Gateway Habitat. This medical system will serve as the precursor to what is implemented in future exploration missions to Mars. This concept of operations documents an overview of the stakeholder needs and system goals of a medical system and provides examples of the types of activities for which the system will be used during the mission. This concept of operations informs the ExMC systems engineering effort to define the Gateway Habitat Medical System by documenting the medical activities and capabilities relevant to Gateway missions, as identified by the ExMC clinician community. In addition, this concept of operations will inform the subsequent systems engineering process of developing technical requirements, system architectures, interfaces, and verification and validation approaches for the medical system. This document supports the closure of ExMC Gap Med01: We do not have a concept of operations for medical care during exploration missions, corresponding to the ExMC-managed human system risk: Risk of Adverse Health Outcomes & Decrements in Performance due to Inflight Medical Conditions

Medical System Concept of Operations for Mars Exploration Mission-11: Exploration Medical Capability (ExMC) Element - Human Research Program

NASAs exploration missions to Mars will have durations of 2-3 years and will take humans farther away from Earth than ever before. This will result in a paradigm shift for mission planning, spacecraft design, human systems integration, and in-flight medical care. Constraints on real-time communication, resupply, and medical evacuation are major architectural drivers. These constraints require medical system development to be tightly integrated with mission and vehicle design to provide crew autonomy and enable mission success. This concept of operations provides a common vision of medical care for developing a medical system for Mars exploration missions. It documents an overview of the stakeholder needs and goals of a medical system and provides examples of the types of activities the system will be used for during the mission. Development of the concept of operations considers mission variables such as distance from Earth, duration of mission, time to definitive medical care, communication protocols between crewmembers and ground support, personnel capabilities and skill sets, medical hardware and software, and medical data management. The information provided in this document informs the ExMC Systems Engineering effort to define the functions to be provided by the medical system. In addition, this concept of operations will inform the subsequent systems engineering process of developing technical requirements, system architectures, interfaces, and verification and validation approaches for the medical system. This document supports the closure of ExMC Gap Med01: We do not have a concept of operations for medical care during exploration missions, corresponding to the ExMC-managed human system risk: Risk of Adverse Health Outcomes & Decrements in Performance due to Inflight Medical Conditions. This document is applicable to the ExMC Element Systems Engineering process and may be used for collaboration within the Human Research Program

IMPACT Concept of Operations

NASAs future exploration missions mandate a significant paradigm change for mission planning, spacecraft design, human systems integration, and in-flight medical care due to constraints on mass, volume, power, resupply missions, and medical evacuation capabilities. These constraints require further development of the human health and performance system, which includes the medical, task performance, wellness, data, human and other systems necessary to keep the crew healthy and functioning optimally. The human health and performance system will be tightly integrated with mission and habitat design to provide a sufficient human health and performance infrastructure to enable mission success. A suite of systems engineering tools will aid in the decision making process for the development of such a human health and performance system. This Concept of Operations provides a vision for a tool suite to conduct evaluations of human health and performance system options, inform research prioritization, and provide trade study support, based on evidence, risks, and systems engineering principles. The integrated tool suite under development is IMPACT

Multifunctional cytokine production reveals functional superiority of memory CD4 T cells

T cell protective immunity is associated with multifunctional memory cells that produce several different cytokines. Currently, our understanding of when and how these cells are generated is limited. We have used an influenza virus mouse infection model to investigate whether the cytokine profile of memory T cells is reflective of primary responding cells or skewed towards a distinct profile. We found that, in comparison to primary cells, memory T cells tended to make multiple cytokines simultaneously. Analysis of the timings of release of cytokine by influenza virus‐specific T cells, demonstrated that primary responding CD4 T cells from lymphoid organs were unable to produce a sustained cytokine response. In contrast CD8 T cells, memory CD4 T cells, and primary responding CD4 T cells from the lung produced a sustained cytokine response throughout the restimulation period. Moreover, memory CD4 T cells were more resistant than primary responding CD4 T cells to inhibitors that suppress T cell receptor signalling. Together, these data suggest that memory CD4 T cells display superior cytokine responses compared to primary responding cells. These data are key to our ability to identify the cues that drive the generation of protective memory CD4 T cells following infection

Diclofenac identified as a kynurenine 3-monooxygenase binder and inhibitor by molecular similarity techniques

In this study, we apply a battery of molecular similarity techniques to known inhibitors of kynurenine 3-monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar <i>K</i>_D and IC₅₀, respectively, and low millimolar cellular IC₅₀. Hit to drug hopping, as exemplified here for one of the most successful anti-inflammatory medicines ever invented, holds great promise for expansion into new disease areas and highlights the not-yet-fully-exploited potential of drug repurposing

Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice

Impaired glucocorticoid (GC) signaling is a significant factor in aging, stress, and neurodegenerative diseases such as Alzheimer’s disease. Therefore, the study of GC-mediated stress responses to chronic moderately stressful situations, which occur in daily life, is of huge interest for the design of pharmacological strategies toward the prevention of neurodegeneration. To address this issue, SAMP8 mice were exposed to the chronic mild stress (CMS) paradigm for 4 weeks and treated with RL-118, an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor. The inhibition of this enzyme is linked with a reduction in GC levels and cognitive improvement, while CMS exposure has been associated with reduced cognitive performance. The aim of this project was to assess whether RL-118 treatment could reverse the deleterious effects of CMS on cognition and behavioral abilities and to evaluate the molecular mechanisms that compromise healthy aging in SAMP8 mice. First, we confirmed the target engagement between RL-118 and 11β-HSD1. Additionally, we showed that DNA methylation, hydroxymethylation, and histone phosphorylation were decreased by CMS induction, and increased by RL-118 treatment. In addition, CMS exposure caused the accumulation of reactive oxygen species (ROS)-induced damage and increased pro-oxidant enzymes—as well as pro-inflammatory mediators—through the NF-κB pathway and astrogliosis markers, such as GFAP. Of note, these modifications were reversed by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signaling, autophagy was increased in the SAMP8 RL-118-treated mice. We also showed an increase in amyloidogenic processes and a decrease in synaptic plasticity and neuronal remodeling markers in mice under CMS, which were consequently modified by RL-118 treatment. In conclusion, 11β-HSD1 inhibition through RL-118 ameliorated the detrimental effects induced by CMS, including epigenetic and cognitive disturbances, indicating that GC-excess attenuation shows potential as a therapeutic strategy for age-related cognitive decline and AD

Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice

Impaired glucocorticoid (GC) signaling is a significant factor in aging, stress, and neurodegenerative diseases such as Alzheimer's disease. Therefore, the study of GC-mediated stress responses to chronic moderately stressful situations, which occur in daily life, is of huge interest for the design of pharmacological strategies toward the prevention of neurodegeneration. To address this issue, SAMP8 mice were exposed to the chronic mild stress (CMS) paradigm for 4 weeks and treated with RL-118, an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor. The inhibition of this enzyme is linked with a reduction in GC levels and cognitive improvement, while CMS exposure has been associated with reduced cognitive performance. The aim of this project was to assess whether RL-118 treatment could reverse the deleterious effects of CMS on cognition and behavioral abilities and to evaluate the molecular mechanisms that compromise healthy aging in SAMP8 mice. First, we confirmed the target engagement between RL-118 and 11β-HSD1. Additionally, we showed that DNA methylation, hydroxymethylation, and histone phosphorylation were decreased by CMS induction, and increased by RL-118 treatment. In addition, CMS exposure caused the accumulation of reactive oxygen species (ROS)-induced damage and increased pro-oxidant enzymes as well as pro-inflammatory mediators through the NF-κB pathway and astrogliosis markers, such as GFAP. Of note, these modifications were reversed by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signaling, autophagy was increased in the SAMP8 RL-118-treated mice. We also showed an increase in amyloidogenic processes and a decrease in synaptic plasticity and neuronal remodeling markers in mice under CMS, which were consequently modified by RL-118 treatment. In conclusion, 11β-HSD1 inhibition through RL-118 ameliorated the detrimental effects induced by CMS, including epigenetic and cognitive disturbances, indicating that GC-excess attenuation shows potential as a therapeutic strategy for age-related cognitive decline and AD

Enabling Space Exploration Medical System Development Using a Tool Ecosystem

The NASA Human Research Program's (HRP) Exploration Medical Capability (ExMC) Element is utilizing a Model Based Systems Engineering (MBSE) approach to enhance the development of systems engineering products that will be used to advance medical system designs for exploration missions beyond Low Earth Orbit. In support of future missions, the team is capturing content such as system behaviors, functional decompositions, architecture, system requirements and interfaces, and recommendations for clinical capabilities and resources in Systems Modeling Language (SysML) models. As these products mature, SysML models provide a way for ExMC to capture relationships among the various products, which includes supporting more integrated and multi-faceted views of future medical systems. In addition to using SysML models, HRP and ExMC are developing supplementary tools to support two key functions: 1) prioritizing current and future research activities for exploration missions in an objective manner; and 2) enabling risk-informed and evidence-based trade space analysis for future space vehicles, missions, and systems. This paper will discuss the long-term HRP and ExMC vision for the larger ecosystem of tools, which include dynamic Probabilistic Risk Assessment (PRA) capabilities, additional SysML models, a database of system component options, and data visualizations. It also includes a review of an initial Pilot Project focused on enabling medical system trade studies utilizing data that is coordinated across tools for consistent outputs (e.g., mission risk metrics that are associated with medical system mass values and medical conditions addressed). This first Pilot Project demonstrated successful operating procedures and integration across tools. Finally, the paper will also cover a second Pilot Project that utilizes tool enhancements such as medical system optimization capabilities, post-processing, and visualization of generated data for subject matter expert review, and increased integration amongst the tools themselves