Progressive changes in microglia and macrophages in spinal cord and peripheral nerve in the transgenic rat model of amyotrophic lateral sclerosis

<p>Abstract</p> <p>Background</p> <p>The role of neuroinflammation in motor neuron death of amyotrophic lateral sclerosis (ALS) is unclear. The human mutant superoxide dismutase-1 (hmSOD1)-expressing murine transgenic model of ALS has provided some insight into changes in microglia activity during disease progression. The purpose of this study was to gain further knowledge by characterizing the immunological changes during disease progression in the spinal cord and peripheral nerve using the more recently developed hmSOD1 rat transgenic model of ALS.</p> <p>Methods</p> <p>Using immunohistochemistry, the extent and intensity of tissue CD11b expression in spinal cord, lumbar nerve roots, and sciatic nerve were evaluated in hmSOD1 rats that were pre-clinical, at clinical onset, and near disease end-stage. Changes in CD11b expression were compared to the detection of MHC class II and CD68 microglial activation markers in the ventral horn of the spinal cord, as well as to the changes in astrocytic GFAP expression.</p> <p>Results</p> <p>Our study reveals an accumulation of microglia/macrophages both in the spinal cord and peripheral nerve prior to clinical onset based on CD11b tissue expression. The microglia formed focal aggregates in the ventral horn and became more widespread as the disease progressed. Hypertrophic astrocytes were not prominent in the ventral horn until after clinical onset, and the enhancement of GFAP did not have a strong correlation to increased CD11b expression. Detection of MHC class II and CD68 expression was found in the ventral horn only after clinical onset. The macrophages in the ventral nerve root and sciatic nerve of hmSOD1 rats were observed encircling axons.</p> <p>Conclusions</p> <p>These findings describe for the first time in the hmSOD1 rat transgenic model of ALS that enhancement of microglia/macrophage activity occurs pre-clinically both in the peripheral nerve and in the spinal cord. CD11b expression is shown to be a superior indicator for early immunological changes compared to other microglia activation markers and astrogliosis. Furthermore, we suggest that the early activity of microglia/macrophages is involved in the early phase of motor neuron degeneration and propose that studies involving immunomodulation in hmSOD1transgenic models need to consider effects on macrophages in peripheral nerves as well as to microglia in the spinal cord.</p

Strain-dependent variation in the early transcriptional response to CNS injury using a cortical explant system

<p>Abstract</p> <p>Background</p> <p>While it is clear that inbred strains of mice have variations in immunological responsiveness, the influence of genetic background following tissue damage in the central nervous system is not fully understood. A cortical explant system was employed as a model for injury to determine whether the immediate transcriptional response to tissue resection revealed differences among three mouse strains.</p> <p>Methods</p> <p>Immunological mRNAs were measured in cerebral cortex from SJL/J, C57BL/6J, and BALB/cJ mice using real time RT-PCR. Freshly isolated cortical tissue and cortical sections incubated in explant medium were examined. Levels of mRNA, normalized to β-actin, were compared using one way analysis of variance with pooled samples from each mouse strain.</p> <p>Results</p> <p>In freshly isolated cerebral cortex, transcript levels of many pro-inflammatory mediators were not significantly different among the strains or too low for comparison. Constitutive, baseline amounts of CD74 and antisecretory factor (ASF) mRNAs, however, were higher in SJL/J and C57BL/6J, respectively. When sections of cortical tissue were incubated in explant medium, increased message for a number of pro-inflammatory cytokines and chemokines occurred within five hours. Message for chemokines, IL-1α, and COX-2 transcripts were higher in C57BL/6J cortical explants relative to SJL/J and BALB/cJ. IL-1β, IL-12/23 p40, and TNF-α were lower in BALB/cJ explants relative to SJL/J and C57BL/6J. Similar to observations in freshly isolated cortex, CD74 mRNA remained higher in SJL/J explants. The ASF mRNA in SJL/J explants, however, was now lower than levels in both C57BL/6J and BALB/cJ explants.</p> <p>Conclusions</p> <p>The short-term cortical explant model employed in this study provides a basic approach to evaluate an early transcriptional response to neurological damage, and can identify expression differences in genes that are influenced by genetic background.</p

Neuromyelitis Optica Pathogenesis and Aquaporin 4

Neuromyelitis optica (NMO) is a severe, debilitating human disease that predominantly features immunopathology in the optic nerves and the spinal cord. An IgG1 autoantibody (NMO-IgG) that binds aquaporin 4 (AQP4) has been identified in the sera of a significant number of NMO patients, as well as in patients with two related neurologic conditions, bilateral optic neuritis (ON), and longitudinal extensive transverse myelitis (LETM), that are generally considered to lie within the NMO spectrum of diseases. NMO-IgG is not the only autoantibody found in NMO patient sera, but the correlation of pathology in central nervous system (CNS) with tissues that normally express high levels of AQP4 suggests NMO-IgG might be pathogenic. If this is the case, it is important to identify and understand the mechanism(s) whereby an immune response is induced against AQP4. This review focuses on open questions about the events that need to be understood to determine if AQP4 and NMO-IgG are involved in the pathogenesis of NMO. These questions include: 1) How might AQP4-specific T and B cells be primed by either CNS AQP4 or peripheral pools of AQP4? 2) Do the different AQP4-expressing tissues and perhaps the membrane structural organization of AQP4 influence NMO-IgG binding efficacy and thus pathogenesis? 3) Does prior infection, genetic predisposition, or underlying immune dysregulation contribute to a confluence of events which lead to NMO in select individuals? A small animal model of NMO is essential to demonstrate whether AQP4 is indeed the incipient autoantigen capable of inducing NMO-IgG formation and NMO. If the NMO model is consistent with the human disease, it can be used to examine how changes in AQP4 expression and blood-brain barrier (BBB) integrity, both of which can be regulated by CNS inflammation, contribute to inductive events for anti-AQP4-specific immune response. In this review, we identify reagents and experimental questions that need to be developed and addressed to enhance our understanding of the pathogenesis of NMO. Finally, dysregulation of tolerance associated with autoimmune disease appears to have a role in NMO. Animal models would allow manipulation of hormone levels, B cell growth factors, and other elements known to increase the penetrance of autoimmune disease. Thus an AQP4 animal model would provide a means to manipulate events which are now associated with NMO and thus demonstrate what set of events or multiplicity of events can push the anti-AQP4 response to be pathogenic

Neuromyelitis optica pathogenesis and aquaporin 4

Neuromyelitis optica (NMO) is a severe, debilitating human disease that predominantly features immunopathology in the optic nerves and the spinal cord. An IgG1 autoantibody (NMO-IgG) that binds aquaporin 4 (AQP4) has been identified in the sera of a significant number of NMO patients, as well as in patients with two related neurologic conditions, bilateral optic neuritis (ON), and longitudinal extensive transverse myelitis (LETM), that are generally considered to lie within the NMO spectrum of diseases. NMO-IgG is not the only autoantibody found in NMO patient sera, but the correlation of pathology in central nervous system (CNS) with tissues that normally express high levels of AQP4 suggests NMO-IgG might be pathogenic. If this is the case, it is important to identify and understand the mechanism(s) whereby an immune response is induced against AQP4. This review focuses on open questions about the "events" that need to be understood to determine if AQP4 and NMO-IgG are involved in the pathogenesis of NMO. These questions include: 1) How might AQP4-specific T and B cells be primed by either CNS AQP4 or peripheral pools of AQP4? 2) Do the different AQP4-expressing tissues and perhaps the membrane structural organization of AQP4 influence NMO-IgG binding efficacy and thus pathogenesis? 3) Does prior infection, genetic predisposition, or underlying immune dysregulation contribute to a confluence of events which lead to NMO in select individuals? A small animal model of NMO is essential to demonstrate whether AQP4 is indeed the incipient autoantigen capable of inducing NMO-IgG formation and NMO. If the NMO model is consistent with the human disease, it can be used to examine how changes in AQP4 expression and blood-brain barrier (BBB) integrity, both of which can be regulated by CNS inflammation, contribute to inductive events for anti-AQP4-specific immune response. In this review, we identify reagents and experimental questions that need to be developed and addressed to enhance our understanding of the pathogenesis of NMO. Finally, dysregulation of tolerance associated with autoimmune disease appears to have a role in NMO. Animal models would allow manipulation of hormone levels, B cell growth factors, and other elements known to increase the penetrance of autoimmune disease. Thus an AQP4 animal model would provide a means to manipulate events which are now associated with NMO and thus demonstrate what set of events or multiplicity of events can push the anti-AQP4 response to be pathogenic

Early inflammatory mediator gene expression in two models of traumatic brain injury: ex vivo cortical slice in mice and in vivo cortical impact in piglets

Background: The immunological response during the first 24 hours after traumatic brain injury (TBI) may be a critical therapeutic interval for limiting the secondary neuronal damage that is influenced by enhanced inflammatory mediator expression. Methods: To gain further insight of the early injury response, we examined the expression of several inflammatory genes by real-time qPCR as a function of time or distance from injury in two distinct mammalian models: an ex vivo mouse cortical slice injury system and an in vivo piglet model of brain injury. Results: Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), chemokine ligands 2 (CCL2), 3 (CCL3), 4 (CCL4), and prostaglandin-endoperoxide synthase 2 (PTGS2) mRNAs increased within 5 h after injury in mouse cortical slices. Chemokine and PTGS2 mRNAs remained elevated in slices at 24 h, whereas IL-1β and TNF-α expressions decreased from earlier peak levels. At 24 h after cortical injury in 1-month-old piglets, the expression of CCL2 mRNA was significantly increased in the lesion core and in the penumbra region. The expression of PTGS2, IL-1β, and TNF-α was variable among the piglets. Conclusions: These in vitro and large animal models of cortical injury expand our understanding of the early timing and spread of the immunological response and can serve as preclinical systems to facilitate the discovery of therapeutic agents for TBI aimed at regulating inflammatory mediator expression

International Space Station (ISS) Anomalies Trending Study

The NASA Engineering and Safety Center (NESC) set out to utilize data mining and trending techniques to review the anomaly history of the International Space Station (ISS) and provide tools for discipline experts not involved with the ISS Program to search anomaly data to aid in identification of areas that may warrant further investigation. Additionally, the assessment team aimed to develop an approach and skillset for integrating data sets, with the intent of providing an enriched data set for discipline experts to investigate that is easier to navigate, particularly in light of ISS aging and the plan to extend its life into the late 2020s. This document contains the Appendices to the Volume I report

International Space Station (ISS) Anomalies Trending Study

The NASA Engineering and Safety Center (NESC) set out to utilize data mining and trending techniques to review the anomaly history of the International Space Station (ISS) and provide tools for discipline experts not involved with the ISS Program to search anomaly data to aid in identification of areas that may warrant further investigation. Additionally, the assessment team aimed to develop an approach and skillset for integrating data sets, with the intent of providing an enriched data set for discipline experts to investigate that is easier to navigate, particularly in light of ISS aging and the plan to extend its life into the late 2020s. This report contains the outcome of the NESC Assessment

Constraining the Nature of the 18 min Periodic Radio Transient GLEAM-X J162759.5-523504.3 via Multiwavelength Observations and Magneto-thermal Simulations

We observed the periodic radio transient GLEAM-X J162759.5-523504.3 (GLEAM-X J1627) using the Chandra X-ray Observatory for about 30 ks on 2022 January 22–23, simultaneously with radio observations from the Murchison Widefield Array, MeerKAT, and the Australia Telescope Compact Array. Its radio emission and 18 min periodicity led the source to be tentatively interpreted as an extreme magnetar or a peculiar highly magnetic white dwarf. The source was not detected in the 0.3–8 keV energy range with a 3σ upper limit on the count rate of 3 × 10−4 counts s−1. No radio emission was detected during our X-ray observations either. Furthermore, we studied the field around GLEAM-X J1627 using archival European Southern Observatory and DECam Plane Survey data, as well as recent Southern African Large Telescope observations. Many sources are present close to the position of GLEAM-X J1627, but only two within the 2'' radio position uncertainty. Depending on the assumed spectral distribution, the upper limits converted to an X-ray luminosity of LX < 6.5 × 1029 erg s−1 for a blackbody with temperature kT = 0.3 keV, or LX < 9 × 1029 erg s−1 for a power law with photon index Γ = 2 (assuming a 1.3 kpc distance). Furthermore, we performed magneto-thermal simulations for neutron stars considering crust- and core-dominated field configurations. Based on our multiband limits, we conclude that (i) in the magnetar scenario, the X-ray upper limits suggest that GLEAM-X J1627 should be older than ∼1 Myr, unless it has a core-dominated magnetic field or has experienced fast cooling; (ii) in the white dwarf scenario, we can rule out most binary systems, a hot sub-dwarf, and a hot magnetic isolated white dwarf (T ≳ 10.000 K), while a cold isolated white dwarf is still compatible with our limits.N.R., F.C.Z., C.D., M.R., V.G., C.P., A.B., and E.P. are supported by the ERC Consolidator Grant "MAGNESIA" under grant agreement No. 817661, and National Spanish grant No. PGC2018-095512-BI00. F.C.Z., A.B., and V.G. are also supported by Juan de la Cierva Fellowships. C.D., M.R., and C.A.'s work has been carried out within the framework of the doctoral program in Physics of the Universitat Autónoma de Barcelona. N.H.W. is supported by an Australian Research Council Future Fellowship (project number FT190100231) funded by the Australian Government. D.d.M. acknowledges financial support from the Italian Space Agency (ASI) and National Institute for Astrophysics (INAF) under agreements ASI-INAF I/037/12/0 and ASI-INAF n.2017-14-H.0 and from INAF "Sostegno alla ricerca scientifica main streams dell'INAF," Presidential Decree 43/2018 and from INAF "SKA/CTA projects," Presidential Decree 70/2016. D.B. acknowledges support from the South African National Research Foundation. D.V. is supported by the ERC Starting Grant "IMAGINE" under grant agreement No. 948582. This work was also partially supported by the program Unidad de Excelencia Maria de Maetzu de Maeztu CEX2020-001058-M and by the PHAROS COST Action (grant No. CA16214)

A reverse pathway? Actual and perceived skill proficiency and physical activity

Purpose: Motor skills are considered a prerequisite to physical activity, yet the relationship may be reciprocal and perceived sports competence might mediate associations.Methods: In 2006/2007, 215 adolescents completed motor skill proficiency (Get Skilled Get Active), perceived sport competence (Physical Self-Perception Profile) and physical activity assessments (Adolescent Physical Activity Recall Questionnaire) as part of the Physical Activity and Skills Study. Using AMOS (Version 7.0), reciprocal relationships were examined between motor skill (object control and locomotor) and moderate to vigorous physical activity (MVPA). Both models were then run in different versions to understand the role of perceived sports competence as a potential mediator. Results: Mean age was 16.4 yr (SD = 0.6), 51.6% (111/215) were females. A reciprocal relationship between object control and MVPA and a one-way relationship from MVPA to locomotor skill was found. When perceived sports competence was examined as a mediator, the best-fitting model versions explained 16% (R&sup2; = 0.16)MVPA variation, and 30% object control (R&sup2; = 0.30), and 12% locomotor skill variation (R&sup2; = 0.12) (reverse relationship). Perceived sports competence partially mediates the relationship between object control proficiency and physical activity for both directions and fully mediates the relationship between physical activity and locomotor skill; but only when locomotor skill is the outcome.Conclusions: If the relationship between object control skill and physical activity is viewed as a &lsquo;&lsquo;positive feedback loop,&rsquo;&rsquo; skill development and increasing physical activity should simultaneously be targeted in physical activity interventions. Increasing perceived sport competence should also be an intervention focus.<br /