Overview and Evaluation of a Computational Bone Physiology Modeling Toolchain and Its Application to Testing of Exercise Countermeasures

Prolonged microgravity exposure disrupts natural bone remodeling processes and can lead to a significant loss of bone strength, increasing injury risk during missions and placing astronauts at a greater risk of bone fracture later in life. Resistance-based exercise during missions is used to combat bone loss, but current exercise countermeasures do not completely mitigate the effects of microgravity. To address this concern, we present work to develop a personalizable, site-specific computational modeling toolchain of bone remodeling dynamics to understand and estimate changes in volumetric bone mineral density (BMD) in response to microgravity-induced bone unloading and in-flight exercise. The toolchain is evaluated against data collected from subjects in a 70-day bedrest study and is found to provide insight into the amount of exercise stimulus needed to minimize bone loss, quantitatively predicting post-study volumetric BMD of control subjects who did not perform exercise, and qualitatively predicting the effects of exercise. Results suggest that, with additional data, the toolchain could be improved to aid in developing customized in-flight exercise regimens and predict exercise effectiveness

High power breakdown testing of a photonic band-gap accelerator structure with elliptical rods

An improved single-cell photonic band-gap (PBG) structure with an inner row of elliptical rods (PBG-E) was tested with high power at a 60 Hz repetition rate at X-band (11.424 GHz), achieving a gradient of 128  MV/m at a breakdown probability of 3.6×10-3 per pulse per meter at a pulse length of 150 ns. The tested standing-wave structure was a single high-gradient cell with an inner row of elliptical rods and an outer row of round rods; the elliptical rods reduce the peak surface magnetic field by 20% and reduce the temperature rise of the rods during the pulse by several tens of degrees, while maintaining good damping and suppression of high order modes. When compared with a single-cell standing-wave undamped disk-loaded waveguide structure with the same iris geometry under test at the same conditions, the PBG-E structure yielded the same breakdown rate within measurement error. The PBG-E structure showed a greatly reduced breakdown rate compared with earlier tests of a PBG structure with round rods, presumably due to the reduced magnetic fields at the elliptical rods vs the fields at the round rods, as well as use of an improved testing methodology. A post-testing autopsy of the PBG-E structure showed some damage on the surfaces exposed to the highest surface magnetic and electric fields. Despite these changes in surface appearance, no significant change in the breakdown rate was observed in testing. These results demonstrate that PBG structures, when designed with reduced surface magnetic fields and operated to avoid extremely high pulsed heating, can operate at breakdown probabilities comparable to undamped disk-loaded waveguide structures and are thus viable for high-gradient accelerator applications.United States. Dept. of Energy. High Energy Physics Division (Contract DEFG02-91ER40648

Cytokine/chemokine profiles in squamous cell carcinoma correlate with precancerous and cancerous disease stage.

Actinic Keratosis (AK), Intraepidermal Carcinoma (IEC), and Squamous Cell Carcinoma (SCC) are generally considered to be advancing stages of the same disease spectrum. However, while AK often regress spontaneously, and IEC often regress in response to immune-activating treatments, SCC typically do not regress. Therefore, it is vital to define whether fundamental immunological changes occur during progression to SCC. Here we show that proinflammatory cytokine expression, chemokine expression, and immune cell infiltration density change during progression to SCC. Our findings suggest a switch from predominantly proinflammatory cytokine production to chemokine production is a key feature of progression from precancer to cancer. Together, these observations propose a model that can underpin current research and open new avenues of exploration into the clinical significance of these profiles with respect to immunotherapeutic or other treatment outcomes

Influence of Total Western Diet on Docosahexaenoic Acid Suppression of Silica-Triggered Lupus Flaring in NZBWF1 Mice

Lupus is a debilitating multi-organ autoimmune disease clinically typified by periods of flare and remission. Exposing lupus-prone female NZBWF1 mice to crystalline silica (cSiO2), a known human autoimmune trigger, mimics flaring by inducing interferon-related gene (IRG) expression, inflammation, ectopic lymphoid structure (ELS) development, and autoantibody production in the lung that collectively accelerate glomerulonephritis. cSiO2-triggered flaring in this model can be prevented by supplementing mouse diet with the ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA). A limitation of previous studies was the use of purified diet that, although optimized for rodent health, does not reflect the high American intake of saturated fatty acid (SFA), ω-6 PUFAs, and total fat. To address this, we employed here a modified Total Western Diet (mTWD) emulating the 50th percentile U.S. macronutrient distribution to discern how DHA supplementation and/or SFA and ω-6 reduction influences cSiO2-triggered lupus flaring in female NZBWF1 mice. Six-week-old mice were fed isocaloric experimental diets for 2 wks, intranasally instilled with cSiO2 or saline vehicle weekly for 4 wks, and tissues assessed for lupus endpoints 11 wks following cSiO2 instillation. In mice fed basal mTWD, cSiO2 induced robust IRG expression, proinflammatory cytokine and chemokine elevation, leukocyte infiltration, ELS neogenesis, and autoantibody production in the lung, as well as early kidney nephritis onset compared to vehicle-treated mice fed mTWD. Consumption of mTWD containing DHA at the caloric equivalent to a human dose of 5 g/day dramatically suppressed induction of all lupus-associated endpoints. While decreasing SFA and ω-6 in mTWD modestly inhibited some disease markers, DHA addition to this diet was required for maximal protection against lupus development. Taken together, DHA supplementation at a translationally relevant dose was highly effective in preventing cSiO2-triggered lupus flaring in NZBWF1 mice, even against the background of a typical Western diet

Near-horizon symmetries of extremal black holes

Recent work has demonstrated an attractor mechanism for extremal rotating black holes subject to the assumption of a near-horizon SO(2,1) symmetry. We prove the existence of this symmetry for any extremal black hole with the same number of rotational symmetries as known four and five dimensional solutions (including black rings). The result is valid for a general two-derivative theory of gravity coupled to abelian vectors and uncharged scalars, allowing for a non-trivial scalar potential. We prove that it remains valid in the presence of higher-derivative corrections. We show that SO(2,1)-symmetric near-horizon solutions can be analytically continued to give SU(2)-symmetric black hole solutions. For example, the near-horizon limit of an extremal 5D Myers-Perry black hole is related by analytic continuation to a non-extremal cohomogeneity-1 Myers-Perry solution.Comment: 21 pages, latex. v2: minor improvements v3: Corrected error in argument excluding de Sitter and Poincare-symmetric cases. Results unaffecte

Constructing near-horizon geometries in supergravities with hidden symmetry

We consider the classification of near-horizon geometries in a general two-derivative theory of gravity coupled to abelian gauge fields and uncharged scalars in four and five dimensions, with one and two commuting rotational symmetries respectively. Assuming that the theory of gravity reduces to a 3d non-linear sigma model (as is typically the case for ungauged supergravities), we show that the functional form of any such near-horizon geometry may be determined. As an example we apply this to five dimensional minimal supergravity. We also construct an example of a five parameter near-horizon geometry solution to this theory with S^1 X S^2 horizon topology. We discuss its relation to the near-horizon geometries of the yet to be constructed extremal black rings with both electric and dipole charges.Comment: Latex, 30 pages. v2: discussion in section 5 modified and improved, other minor changes, references adde

Development of Bone Remodeling Model for Spaceflight Bone Physiology Analysis

Current spaceflight exercise countermeasures do not eliminate bone loss. Astronauts lose bone mass at a rate of 1-2% a month (Lang et al. 2004, Buckey 2006, LeBlanc et al. 2007). This may lead to early onset osteoporosis and place the astronauts at greater risk of fracture later in their lives. NASA seeks to improve understanding of the mechanisms of bone remodeling and demineralization in 1g in order to appropriately quantify long term risks to astronauts and improve countermeasures. NASA's Digital Astronaut Project (DAP) is working with NASA's bone discipline to develop a validated computational model to augment research efforts aimed at achieving this goal

Ambient particulate air pollution induces oxidative stress and alterations of mitochondria and gene expression in brown and white adipose tissues

<p>Abstract</p> <p>Background</p> <p>Prior studies have demonstrated a link between air pollution and metabolic diseases such as type II diabetes. Changes in adipose tissue and its mitochondrial content/function are closely associated with the development of insulin resistance and attendant metabolic complications. We investigated changes in adipose tissue structure and function in brown and white adipose depots in response to chronic ambient air pollutant exposure in a rodent model.</p> <p>Methods</p> <p>Male ApoE knockout (ApoE^-/-) mice inhaled concentrated fine ambient PM (PM < 2.5 μm in aerodynamic diameter; PM_2.5) or filtered air (FA) for 6 hours/day, 5 days/week, for 2 months. We examined superoxide production by dihydroethidium staining; inflammatory responses by immunohistochemistry; and changes in white and brown adipocyte-specific gene profiles by real-time PCR and mitochondria by transmission electron microscopy in response to PM_2.5exposure in different adipose depots of ApoE^-/-mice to understand responses to chronic inhalational stimuli.</p> <p>Results</p> <p>Exposure to PM_2.5induced an increase in the production of reactive oxygen species (ROS) in brown adipose depots. Additionally, exposure to PM_2.5decreased expression of uncoupling protein 1 in brown adipose tissue as measured by immunohistochemistry and Western blot. Mitochondrial number was significantly reduced in white (WAT) and brown adipose tissues (BAT), while mitochondrial size was also reduced in BAT. In BAT, PM_2.5exposure down-regulated brown adipocyte-specific genes, while white adipocyte-specific genes were differentially up-regulated.</p> <p>Conclusions</p> <p>PM_2.5exposure triggers oxidative stress in BAT, and results in key alterations in mitochondrial gene expression and mitochondrial alterations that are pronounced in BAT. We postulate that exposure to PM_2.5may induce imbalance between white and brown adipose tissue functionality and thereby predispose to metabolic dysfunction.</p

Uniqueness of near-horizon geometries of rotating extremal AdS(4) black holes

We consider stationary extremal black hole solutions of the Einstein-Maxwell equations with a negative cosmological constant in four dimensions. We determine all non-static axisymmetric near-horizon geometries (with non-toroidal horizon topology) and all static near-horizon geometries for black holes of this kind. This allows us to deduce that the most general near-horizon geometry of an asymptotically globally AdS(4) rotating extremal black hole, is the near-horizon limit of extremal Kerr-Newman-AdS(4). We also identify the subset of near-horizon geometries which are supersymmetric. Finally, we show which physical quantities of extremal black holes may be computed from the near-horizon limit alone, and point out a simple formula for the entropy of the known supersymmetric AdS(4) black hole. Analogous results are presented in the case of vanishing cosmological constant.Comment: 18 pages, Latex. v2: footnote added on pg. 12. v3: assumption of non-toroidal horizon topology made explicit, minor clarification

Early Universe Dynamics in Semi-Classical Loop Quantum Cosmology

Within the framework of loop quantum cosmology, there exists a semi-classical regime where spacetime may be approximated in terms of a continuous manifold, but where the standard Friedmann equations of classical Einstein gravity receive non-perturbative quantum corrections. An approximate, analytical approach to studying cosmic dynamics in this regime is developed for both spatially flat and positively-curved isotropic universes sourced by a self-interacting scalar field. In the former case, a direct correspondence between the classical and semi-classical field equations can be established together with a scale factor duality that directly relates different expanding and contracting universes. Some examples of non-singular, bouncing cosmologies are presented together with a scaling, power-law solution.Comment: 14 pages, In Press, JCA