Advanced Spacesuit Portable Life Support System Oxygen Regulator Development and Testing

The advanced spacesuit portable life support system (PLSS) oxygen regulators represent an evolutionary approach to regulator development. Several technology development prototypes have been produced that borrow much of the mechanical regulator design from the well proven Shuttle/ISS Extravehicular Mobility Unit (EMU) Secondary Oxygen Regulator, but incorporate a motor-settable pressure set-point feature that facilitates significantly greater operational flexibility. For example, this technology would enable EVA to begin at a higher suit pressure, which would reduce pre-breathe time, and then slowly step down to a lower pressure to increase suit mobility for the duration of the EVA. Comprehensive testing of the prototypes was performed on the component level as well as part of the PLSS 1.0 system level testing. Results from these tests characterize individual prototype performance and demonstrate successful operation during multiple nominal and contingency EVA mode

Structural and functional basis for p38-MK2 activated Rsk signalling in Toll-Like receptor-stimulated dendritic cells

Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration. Until recently, Rsk activation was thought to be exclusively initiated by Erk1/2, but in dendritic cells (DC) Rsk is also activated by p38 mitogen-activated protein (MAP) kinase via its downstream substrates, MK2/3. How and why this noncanonical configuration of the MAP kinase pathway is adopted by these key immune cells are not known. We demonstrate that the Erk1/2-activated C-terminal kinase domain of Rsk is dispensable for p38-MK2/3 activation and show that compared with fibroblasts, a greater fraction of p38 and MK2/3 is located in the cytosol of DC prior to stimulation, suggesting a partial explanation for the operation of the noncanonical pathway of Rsk activation in these cells. p38/MK2/3-activated Rsk phosphorylated downstream targets and is physiologically important because in plasmacytoid DC (pDC) stimulated with Toll-like receptor 7 (TLR7) agonists, Erk1/2 activation is very weak relative to p38. As a result, Rsk activation is entirely p38 dependent. We show that this unusual configuration of MAP kinase signaling contributes substantially to production of type I interferons, a hallmark of pDC activation

TLR ligand-induced podosome disassembly in dendritic cells is ADAM17 dependent

Toll-like receptor (TLR) signaling induces a rapid reorganization of the actin cytoskeleton in cultured mouse dendritic cells (DC), leading to enhanced antigen endocytosis and a concomitant loss of filamentous actin–rich podosomes. We show that as podosomes are lost, TLR signaling induces prominent focal contacts and a transient reduction in DC migratory capacity in vitro. We further show that podosomes in mouse DC are foci of pronounced gelatinase activity, dependent on the enzyme membrane type I matrix metalloprotease (MT1-MMP), and that DC transiently lose the ability to degrade the extracellular matrix after TLR signaling. Surprisingly, MMP inhibitors block TLR signaling–induced podosome disassembly, although stimulated endocytosis is unaffected, which demonstrates that the two phenomena are not obligatorily coupled. Podosome disassembly caused by TLR signaling occurs normally in DC lacking MT1-MMP, and instead requires the tumor necrosis factor α–converting enzyme ADAM17 (a disintegrin and metalloprotease 17), which demonstrates a novel role for this “sheddase” in regulating an actin-based structure

Are existing biodiversity conservation strategies appropriate in a changing climate?

Many countries have conservation plans for threatened species, but such plans have generally been developed without taking into account the potential impacts of climate change. Here, we apply a decision framework, specifically developed to identify and prioritise climate change adaptation actions and demonstrate its use for 30 species threatened in the UK. Our aim is to assess whether government conservation recommendations remain appropriate under a changing climate. The species, associated with three different habitats (lowland heath, broadleaved woodland and calcareous grassland), were selected from a range of taxonomic groups (primarily moths and vascular plants, but also including bees, bryophytes, carabid beetles and spiders). We compare the actions identified for these threatened species by the decision framework with those included in existing conservation plans, as developed by the UK Government's statutory adviser on nature conservation. We find that many existing conservation recommendations are also identified by the decision framework. However, there are large differences in the spatial prioritisation of actions when explicitly considering projected climate change impacts. This includes recommendations for actions to be carried out in areas where species do not currently occur, in order to allow them to track movement of suitable conditions for their survival. Uncertainties in climate change projections are not a reason to ignore them. Our results suggest that existing conservation plans, which do not take into account potential changes in suitable climatic conditions for species, may fail to maximise species persistence. Comparisons across species also suggest a more habitat-focused approach could be adopted to enable climate change adaptation for multiple species

Space Suit Portable Life Support System Test Bed (PLSS 1.0) Development and Testing

A multi-year effort has been carried out at NASA-JSC to develop an advanced extra-vehicular activity Portable Life Support System (PLSS) design intended to further the current state of the art by increasing operational flexibility, reducing consumables, and increasing robustness. Previous efforts have focused on modeling and analyzing the advanced PLSS architecture, as well as developing key enabling technologies. Like the current International Space Station Extra-vehicular Mobility Unit PLSS, the advanced PLSS comprises three subsystems required to sustain the crew during extra-vehicular activity including the Thermal, Ventilation, and Oxygen Subsystems. This multi-year effort has culminated in the construction and operation of PLSS 1.0, a test bed that simulates full functionality of the advanced PLSS design. PLSS 1.0 integrates commercial off the shelf hardware with prototype technology development components, including the primary and secondary oxygen regulators, Ventilation Subsystem fan, Rapid Cycle Amine swingbed carbon dioxide and water vapor removal device, and Spacesuit Water Membrane Evaporator heat rejection device. The overall PLSS 1.0 test objective was to demonstrate the capability of the Advanced PLSS to provide key life support functions including suit pressure regulation, carbon dioxide and water vapor removal, thermal control and contingency purge operations. Supplying oxygen was not one of the specific life support functions because the PLSS 1.0 test was not oxygen rated. Nitrogen was used for the working gas. Additional test objectives were to confirm PLSS technology development components performance within an integrated test bed, identify unexpected system level interactions, and map the PLSS 1.0 performance with respect to key variables such as crewmember metabolic rate and suit pressure. Successful PLSS 1.0 testing completed 168 test points over 44 days of testing and produced a large database of test results that characterize system level and component performance. With the exception of several minor anomalies, the PLSS 1.0 test rig performed as expected; furthermore, many system responses trended in accordance with pre-test predictions

Advanced Space Suit PLSS 2.0 Cooling Loop Evaluation and PLSS 2.5 Recommendations

From 2012 to 2015 The NASA/JSC AdvSS (Advanced Space Suit) PLSS (Primary Life Support Subsystem) team, with support from UTC Aerospace Systems, performed the build-up, packaging and testing of PLSS 2.0. A key aspect of that testing was the evaluation of the long-term health of the water cooling circuit and the interfacing components. Intermittent and end-of-test water, residue and hardware analyses provided valuable information on the status of the water cooling circuit, and the approaches that would be necessary to enhance water cooling circuit health in the future. The evaluated data has been consolidated, interpreted and woven into an action plan for the maintenance of water cooling circuit health for the planned FY (fiscal year) 2016 through FY 2018 PLSS 2.5 testing. This paper provides an overview of the PLSS 2.0 water cooling circuit findings and the associated steps to be taken in that regard for the PLSS 2.5 testing

Assessing and monitoring intratumor heterogeneity in glioblastoma: how far has multimodal imaging come?

Glioblastoma demonstrates imaging features of intratumor heterogeneity that result from underlying heterogeneous biological properties. This stems from variations in cellular behavior that result from genetic mutations that either drive, or are driven by, heterogeneous microenvironment conditions. Among all imaging methods available, only T1-weighted contrast-enhancing and T2-weighted fluid-attenuated inversion recovery are used in standard clinical glioblastoma assessment and monitoring. Advanced imaging modalities are still considered emerging techniques as appropriate end points and robust methodologies are missing from clinical trials. Discovering how these images specifically relate to the underlying tumor biology may aid in improving quality of clinical trials and understanding the factors involved in regional responses to treatment, including variable drug uptake and effect of radiotherapy. Upon validation and standardization of emerging MR techniques, providing information based on the underlying tumor biology, these images may allow for clinical decision-making that is tailored to an individual's response to treatment.Stephen Price is funded by a Clinician Scientist Award from the National Institute for Health Research.This is the author accepted manuscript. The final version is available from Future Medicine via http://dx.doi.org/10.2217/cns.15.2

The PDK1-Rsk signaling pathway controls Langerhans cell proliferation and patterning

Langerhans cells (LC), the dendritic cells of the epidermis, are distributed in a distinctive regularly spaced array. In the mouse, the LC array is established in the first few days of life from proliferating local precursors, but the regulating signaling pathways are not fully understood. We found that mice lacking the kinase phosphoinositide-dependent kinase 1 selectively lack LC. Deletion of the phosphoinositide-dependent kinase 1 target kinases, ribosomal S6 kinase 1 (Rsk1) and Rsk2, produced a striking perturbation in the LC network: LC density was reduced 2-fold, but LC size was increased by the same magnitude. Reduced LC numbers in Rsk1/2?/? mice was not due to accelerated emigration from the skin but rather to reduced proliferation at least in adults. Rsk1/2 were required for normal LC patterning in neonates, but not when LC were ablated in adults and replaced by bone marrow–derived cells. Increased LC size was an intrinsic response to reduced LC numbers, reversible on LC emigration, and could be observed in wild type epidermis where LC size also correlated inversely with LC density. Our results identify a key signaling pathway needed to establish a normal LC network and suggest that LC might maintain epidermal surveillance by increasing their “footprint” when their numbers are limite

Advanced Space Suit PLSS 2.0 Cooling Loop Evaluation and PLSS 2.5 Recommendations

From 2012 to 2015 The NASA/JSC AdvSS (Advanced Space Suit) PLSS (Portable Life Support Subsystem) team, with support from UTC Aerospace Systems, performed the build-up, packaging and testing of PLSS 2.0. One aspect of that testing was the evaluation of the long-term health of the water cooling circuit and the interfacing components. Periodic and end-of-test water, residue and hardware analyses provided valuable information on the status of the water cooling circuit, and the approaches that would be necessary to enhance water cooling circuit health in the future. The evaluated data has been consolidated, interpreted and woven into an action plan for the maintenance of water cooling circuit health for the planned FY (fiscal year) 2016 through FY 2018 PLSS 2.5 testing. This paper provides an overview of the PLSS 2.0 water cooling circuit findings and the associated steps to be taken in that regard for the PLSS 2.5

Lysosomes and lysosome-related organelles in immune responses

The catabolic, degradative capacity of the endo-lysosome system is put to good use in mammalian immune responses as is their recently established status as signaling platforms. From the ‘creative destruction’ of antigenic and ‘self’ material for antigen presentation to T cells to the re-purposing of lysosomes as toxic exocytosable lysosome-related organelles (granules) in leukocytes such as CD8 T cells and eosinophils, endo-lysosomes are key players in host defense. Signaled responses to some pathogen products initiate in endo-lysosomes and these organelles are emerging as important in distinct ways in the unique immunobiology of dendritic cells. Potential self-inflicted toxicity from lysosomal and granule proteases is countered by expression of serpin and cystatin family members.</p