Exercise Prior to Pregnancy Enhances the Suppressive Function of Tregs in Offspring in a Mouse Model of Asthma

Regulatory T cells (Tregs) are a specialized subset of T cells responsible for peripheral tolerance and the mediation of inappropriate immune responses, such as those seen in asthma and allergy. Our lab is interested in the role that exercise plays in Treg responses. Using a mouse model of asthma, we have shown that exercise increases both the number and suppressive function of Tregs. It has been shown that exposing nursing dams to allergens confers protection against airway hyperresponsiveness and inflammation (trademarks of asthma) in pups exposed to the same allergen. In the present study, we wanted to determine if the exercise-induced increase in number and suppressive function of Tregs would be similarly passed from dams to their pups. Male pups from dams that were exercised prior to pregnancy (E) and pups from sedentary dams (S) were OVA-sensitized and challenged beginning at 4wks of age. Mice were sacrificed and tissues were taken for cell analysis. When co-cultured with CD4+CD25- responder cells, Tregs from E pups enhanced suppression of responder cells between 8.4-10% when compared to Tregs from S pups. While the number of Tregs from the mediastinal lymph node was not significantly different between E and S pups, there was a significant decrease in the number of CD4+ and CD8+ T cells in E pups from S pups (51.24% + 10.2 vs. 33.51% + 3.3 and 21.42% + 7.3 vs. 12.94% + 1.2, respectively), indicating a reduction in cellular infiltration and a muted immune response to allergen. Although not significant, there was a doubling of the number of Tregs in the thymus and bone marrow of E pups compared to S pups. This study indicates that exercise prior to pregnancy may confer some Treg-mediated protection against asthma

Risk of Crew Adverse Health Event Due to Altered Immune Response

Determining the effect of space travel on the human immune system has proven to be extremely challenging. Limited opportunities for in-flight studies, varying mission durations, technical and logistical obstacles, small subject numbers, and a broad range of potential assays have contributed to this problem. Additionally, the inherent complexity of the immune system, with its vast array of cell populations, sub-populations, diverse regulatory molecules, and broad interactions with other physiological systems, makes determining precise variables to measure very difficult. There is also the challenge of determining the clinical significance of any observed immune alterations. Will such a change lead to disease, or is it a transient subclinical observation related to short-term stress? The effect of this problem may be observed by scanning publications associated with immunity and spaceflight, which began to appear during the 1970s. Although individually they are each valid studies, the comprehensive literature to date suffers from widely varying sampling methods and assay techniques, low subject counts, and sometimes a disparate focus on narrow aspects of immunity. The most clinically relevant data are derived from in-flight human studies, which have demonstrated altered cell-mediated immunity and reactivation of latent herpes viruses. Much more data are available from post-flight testing of humans, with clear evidence of altered cytokine production patterns, altered leukocyte distribution, continued latent viral reactivation, and evidence of dramatically altered virus-specific immunity. It is unknown if post-flight assessments relate to the in-flight condition or are a response to landing stress and readaptation. In-flight culture of cells has clearly demonstrated that immune cells are gravity-sensitive and display altered functional characteristics. It is unknown if these data are related to in vivo immune cell function or are an artifact of microgravity culture. Ground analog testing of humans and animals, as well as microgravity-analog cell culture, has demonstrated utility. However, in all cases, it is not known with certainty if these data would reflect similar testing during space travel. Given their ready availability, ground analogs may be extremely useful for assay development and the evaluation of potential countermeasures. In general, the evidence base suffers from widely disparate studies on small numbers of subjects that do not directly correlate well with each other or spaceflight itself. Also lacking are investigations of the effect of gender on adaption to spaceflight. This results in significant knowledge 'gaps' that must be filled by future studies to completely determine any clinical risk related to immunity for human exploration-class space missions. These gaps include a significant lack of in-flight data, particularly during long-duration space missions. The International Space Station represents an excellent science platform with which to address this knowledge gap. Other knowledge gaps include lack of a single validated ground analog for the phenomenon and a lack of flight-compatible laboratory equipment capable of monitoring astronauts (for either clinical or research purposes). However, enough significant data exist, as described in this manuscript, to warrant addressing this phenomenon during the utilization phase of the ISS. A recent Space Shuttle investigation has confirmed the 31 in-flight nature of immune dysregulation, demonstrating that it is not merely a post-flight phenomenon. Several current studies are ongoing onboard the ISS that should thoroughly characterize the phenomenon. NASA recognizes that if spaceflight-associated immune dysregulation persists during exploration flights in conjunction with other dangers, such as high-energy radiation, the result may be a significant clinical risk. This emphasizes the need for a continued integrated comprehensive approach to determining the effect of prolonged spaceflight, separated from transient launch and landing stresses, on human immunity. After such studies, the phenomenon will be understood, and, hopefully, a monitoring strategy will have been developed that could be used to monitor the effectiveness of countermeasur

Ambipolar Diffusion in the Magnetorotational Instability

The effects of ambipolar diffusion on the linear stability of weakly ionised accretion discs are examined. Earlier work on this topic has focused on axial magnetic fields and perturbation wavenumbers. We consider here more general field and wavenumber geometries, and find that qualitatively new results are obtained. Provided a radial wavenumber and azimuthal field are present along with their axial counterparts, ambipolar diffusion will always be destabilising, with unstable local modes appearing at well-defined wavenumber bands. The wavenumber corresponding to the maximum growth rate need not, in general, lie along the vertical axis. Growth rates become small relative to the local angular velocity when the ion-neutral collision time exceeds the orbital time. In common with Hall electromotive forces, ambipolar diffusion destabilises both positive and negative angular velocity gradients. In at least some cases, therefore, uniformly rotating molecular cloud cores may reflect the marginally stable state of the ambipolar magnetorotational instability.Comment: Submitted to MN, 6 pages, 3 figs, MN style file v2.

A single exercise bout enhances the manufacture of viral-specific T-cells from healthy donors: implications for allogeneic adoptive transfer immunotherapy

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The adoptive transfer of donor-derived viral-specific cytotoxic T-cells (VSTs) is an effective treatment for controlling CMV and EBV infections after HSCT; however, new practical methods are required to augment the ex vivo manufacture of multi-VSTs from healthy donors. This study investigated the effects of a single exercise bout on the ex vivo manufacture of multi-VSTs. PBMCs isolated from healthy CMV/EBV seropositive participants before (PRE) and immediately after (POST) 30-minutes of cycling exercise were stimulated with CMV (pp65 and IE1) and EBV (LMP2A and BMLF1) peptides and expanded over 8 days. The number (fold difference from PRE) of T-cells specific for CMV pp65 (2.6), EBV LMP2A (2.5), and EBV BMLF1 (4.4) was greater among the VSTs expanded POST. VSTs expanded PRE and POST had similar phenotype characteristics and were equally capable of MHC-restricted killing of autologous target cells. We conclude that a single exercise bout enhances the manufacture of multi-VSTs from healthy donors without altering their phenotype or function and may serve as a simple and economical adjuvant to boost the production of multi-VSTs for allogeneic adoptive transfer immunotherapy

The Impact of Long Duration Spaceflight on Plasma Antimicrobial Proteins

Introduction: Robust immunity is essential for further human exploration of the solar system beyond Earth’s orbit. Spaceflight has been associated with immune perturbations and latent viral reactivation. However, logistical constraints have restricted many of these studies to simple pre- and post-flight measures, which are greatly confounded by the stressors associated with launch, landing and re-adaptation to the 1G environment. More in-flight immune data are required particularly during long-duration (3-6 months) spaceflight missions. This study examined the effects of spaceflight on plasma antimicrobial proteins (AMPs) and reactivation of latent herpesviruses. Methods: Plasma, saliva and urine samples were obtained from 20 crewmembers who spent ~6-months on the International Space Station (ISS). Samples were collected 180 and 45-days before launch, in-flight (at ‘early, ‘mid’ and ‘late’ stages of the mission), immediately upon return to Earth (R+0) and 30 days following return (R+30). Plasma LL-37, HNP 1-3 and lysozyme concentrations were determined by ELISA. Saliva Epstein-Barr virus (EBV), varicella zoster virus (VZV) and urine cytomegalovirus (CMV) DNA levels were quantified by Real-Time PCR. Maximum likelihood linear mixed models (LMM) were used to determine main effects of time (pre-flight, in-flight, R+0 and R+30), and EBV, VZV and CMV viral shedding status (shedding or non-shedding) on the concentration of each AMPs. Results: Lower plasma levels of LL-37 were found at R+0, compared to pre-flight, in-flight and R+30 (-80.6%, -80.2% and -73.49% respectively; p \u3c 0.01). Plasma HNP 1-3 levels were elevated above pre-flight level during flight, at R+0 and R+30 (+24%, +40% and +17% respectively; p \u3c 0.01). Only those crewmembers found to shed CMV had a significant reduction in plasma LL-37 at R+0 (p \u3c 0.05). Similarly, crewmembers found to shed VZV at R+0 had lower HNP 1-3 concentrations than crewmembers who did not shed VZV (-68.9%; p \u3c 0.01). Finally, only those crewmembers who shed EBV had increased plasma levels of HNP 1-3 at R+0 (p \u3c 0.01). Plasma lysozyme levels were unaffected by spaceflight or latent viral shedding. Conclusion: Long-duration spaceflight alters plasma LL-37 and HNP 1-3 levels and are linked to the reactivation of latent herpesviruses. The in-flight changes observed for HNP 1-3 indicate that certain immune perturbations may be independent of launch/landing stress. Future studies are required to determine if spaceflight induced immune dysregulation increases the risk of an adverse health event before exploration-class planetary missions (i.e. to Mars) can be considered

Evaluation of techniques for performing cellular isolation and preservation during microgravity conditions

Genomic and epigenomic studies require the precise transfer of microliter volumes among different types of tubes in order to purify DNA, RNA, or protein from biological samples and subsequently perform analyses of DNA methylation, RNA expression, and chromatin modifications on a genome-wide scale. Epigenomic and transcriptional analyses of human blood cells, for example, require separation of purified cell types to avoid confounding contributions of altered cellular proportions, and long-term preservation of these cells requires their isolation and transfer into appropriate freezing media. There are currently no protocols for these cellular isolation procedures on the International Space Station (ISS). Currently human blood samples are either frozen as mixed cell populations (within the CPT collection tubes) with poor yield of viable cells required for cell-type isolations, or returned under ambient conditions, which requires timing with Soyuz missions. Here we evaluate the feasibility of translating terrestrial cell purification techniques to the ISS. Our evaluations were performed in microgravity conditions during parabolic atmospheric flight. The pipetting of open liquids in microgravity was evaluated using analog-blood fluids and several types of pipette hardware. The best-performing pipettors were used to evaluate the pipetting steps required for peripheral blood mononuclear cell (PBMC) isolation following terrestrial density-gradient centrifugation. Evaluation of actual blood products was performed for both the overlay of diluted blood, and the transfer of isolated PBMCs. We also validated magnetic purification of cells. We found that positive-displacement pipettors avoided air bubbles, and the tips allowed the strong surface tension of water, glycerol, and blood to maintain a patent meniscus and withstand robust pipetting in microgravity. These procedures will greatly increase the breadth of research that can be performed on board the ISS, and allow improvised experimentation by astronauts on extraterrestrial missions

Resistive jet simulations extending radially self-similar magnetohydrodynamic models

Numerical simulations with self-similar initial and boundary conditions provide a link between theoretical and numerical investigations of jet dynamics. We perform axisymmetric resistive magnetohydrodynamic (MHD) simulations for a generalised solution of the Blandford & Payne type, and compare them with the corresponding analytical and numerical ideal-MHD solutions. We disentangle the effects of the numerical and physical diffusivity. The latter could occur in outflows above an accretion disk, being transferred from the underlying disk into the disk corona by MHD turbulence (anomalous turbulent diffusivity), or as a result of ambipolar diffusion in partially ionized flows. We conclude that while the classical magnetic Reynolds number $R_{\rm m}$ measures the importance of resistive effects in the induction equation, a new introduced number, \rbeta=(\beta/2)R_{\rm m} with $\beta$ the plasma beta, measures the importance of the resistive effects in the energy equation. Thus, in magnetised jets with $\beta<2$, when \rbeta \la 1 resistive effects are non-negligible and affect mostly the energy equation. The presented simulations indeed show that for a range of magnetic diffusivities corresponding to \rbeta \ga 1 the flow remains close to the ideal-MHD self-similar solution.Comment: Accepted for publication in MNRA

Magnetorotational instability in protoplanetary discs

We investigate the linear growth and vertical structure of the magnetorotational instability (MRI) in weakly ionised, stratified accretion discs. The magnetic field is initially vertical and dust grains are assumed to have settled towards the midplane, so charges are carried by electrons and ions only. Solutions are obtained at representative radial locations from the central protostar for different choices of the initial magnetic field strength, sources of ionisation, and disc surface density. The MRI is active over a wide range of magnetic field strengths and fluid conditions in low conductivity discs. For the minimum-mass solar nebula model, incorporating cosmic ray ionisation, perturbations grow at 1 AU for B < 8 G. For a significant subset of these strengths (0.2 - 5 G), the growth rate is of order the ideal MHD rate (0.75 Omega). Similarly, when cosmic rays are assumed to be excluded from the disc by the winds emitted by the magnetically active protostar, unstable modes grow at this radius for B less than about 2 G. This study shows that, despite the low magnetic coupling, the magnetic field is dynamically important for a large range of fluid conditions and field strengths in protostellar discs. Hall diffusion largely determines the structure and growth rate of these perturbations for all studied radii. At radii of order 1 AU, in particular, it is crucial to incorporate the full conductivity tensor in studies of the dynamics of astrophysical discs. (Abridged)Comment: 26 pages, 15 figures, submitted to MNRA

Inside-Out Evacuation of Transitional Protoplanetary Disks by the Magneto-Rotational Instability

How do T Tauri disks accrete? The magneto-rotational instability (MRI) supplies one means, but protoplanetary disk gas is typically too poorly ionized to be magnetically active. Here we show that the MRI can, in fact, explain observed accretion rates for the sub-class of T Tauri disks known as transitional systems. Transitional disks are swept clean of dust inside rim radii of ~10 AU. Stellar coronal X-rays ionize material in the disk rim, activating the MRI there. Gas flows from the rim to the star, at a rate limited by the depth to which X-rays ionize the rim wall. The wider the rim, the larger the surface area that the rim wall exposes to X-rays, and the greater the accretion rate. Interior to the rim, the MRI continues to transport gas; the MRI is sustained even at the disk midplane by super-keV X-rays that Compton scatter down from the disk surface. Accretion is therefore steady inside the rim. Blown out by radiation pressure, dust largely fails to accrete with gas. Contrary to what is usually assumed, ambipolar diffusion, not Ohmic dissipation, limits how much gas is MRI-active. We infer values for the transport parameter alpha on the order of 0.01 for GM Aur, TW Hyd, and DM Tau. Because the MRI can only afflict a finite radial column of gas at the rim, disk properties inside the rim are insensitive to those outside. Thus our picture provides one robust setting for planet-disk interaction: a protoplanet interior to the rim will interact with gas whose density, temperature, and transport properties are definite and decoupled from uncertain initial conditions. Our study also supplies half the answer to how disks dissipate: the inner disk drains from the inside out by the MRI, while the outer disk photoevaporates by stellar ultraviolet radiation.Comment: Accepted to Nature Physics June 7, 2007. The manuscript for publication is embargoed per Nature policy. This arxiv.org version contains more technical details and discussion, and is distributed with permission from the editors. 10 pages, 4 figure