SERCA pump activity is physiologically regulated by presenilin and regulates amyloid β production

In addition to disrupting the regulated intramembraneous proteolysis of key substrates, mutations in the presenilins also alter calcium homeostasis, but the mechanism linking presenilins and calcium regulation is unresolved. At rest, cytosolic Ca2+ is maintained at low levels by pumping Ca2+ into stores in the endoplasmic reticulum (ER) via the sarco ER Ca2+-ATPase (SERCA) pumps. We show that SERCA activity is diminished in fibroblasts lacking both PS1 and PS2 genes, despite elevated SERCA2b steady-state levels, and we show that presenilins and SERCA physically interact. Enhancing presenilin levels in Xenopus laevis oocytes accelerates clearance of cytosolic Ca2+, whereas higher levels of SERCA2b phenocopy PS1 overexpression, accelerating Ca2+ clearance and exaggerating inositol 1,4,5-trisphosphate–mediated Ca2+ liberation. The critical role that SERCA2b plays in the pathogenesis of Alzheimer's disease is underscored by our findings that modulating SERCA activity alters amyloid β production. Our results point to a physiological role for the presenilins in Ca2+ signaling via regulation of the SERCA pump

Investigations of Physical Processes in Microgravity Relevant to Space Electrochemical Power Systems

NASA has performed physical science microgravity flight experiments in the areas of combustion science, fluid physics, material science and fundamental physics research on the International Space Station (ISS) since 2001. The orbital conditions on the ISS provide an environment where gravity driven phenomena, such as buoyant convection, are nearly negligible. Gravity strongly affects fluid behavior by creating forces that drive motion, shape phase boundaries and compress gases. The need for a better understanding of fluid physics has created a vigorous, multidisciplinary research community whose ongoing vitality is marked by the continuous emergence of new fields in both basic and applied science. In particular, the low-gravity environment offers a unique opportunity for the study of fluid physics and transport phenomena that are very relevant to management of fluid - gas separations in fuel cell and electrolysis systems. Experiments conducted in space have yielded rich results. These results provided valuable insights into fundamental fluid and gas phase behavior that apply to space environments and could not be observed in Earth-based labs. As an example, recent capillary flow results have discovered both an unexpected sensitivity to symmetric geometries associated with fluid container shape, and identified key regime maps for design of corner or wedge-shaped passive gas-liquid phase separators. In this presentation we will also briefly review some of physical science related to flight experiments, such as boiling, that have applicability to electrochemical systems, along with ground-based (drop tower, low gravity aircraft) microgravity electrochemical research. These same buoyancy and interfacial phenomena effects will apply to electrochemical power and energy storage systems that perform two-phase separation, such as water-oxygen separation in life support electrolysis, and primary space power generation devices such as passive primary fuel cell

LBT/LUCIFER Observations of the z~2 Lensed Galaxy J0900+2234

We present rest-frame optical images and spectra of the gravitationally lensed, star-forming galaxy J0900+2234 (z=2.03). The observations were performed with the newly commissioned LUCIFER1 near-infrared instrument mounted on the Large Binocular Telescope (LBT). We fit lens models to the rest-frame optical images and find the galaxy has an intrinsic effective radius of 7.4 kpc with a lens magnification factor of about 5 for the A and B components. We also discovered a new arc belonging to another lensed high-z source galaxy, which makes this lens system a potential double Einstein ring system. Using the high S/N rest-frame optical spectra covering H+K band, we detected Hbeta, OIII, Halpha, NII and SII emission lines. Detailed physical properties of this high-z galaxy were derived. The extinction towards the ionized HII regions (E_g(B-V)) is computed from the flux ratio of Halpha and Hbeta and appears to be much higher than that towards stellar continuum (E_s(B-V)), derived from the optical and NIR broad band photometry fitting. The metallicity was estimated using N2 and O3N2 indices. It is in the range of 1/5-1/3 solar abundance, which is much lower than the typical z~2 star-forming galaxies. From the flux ratio of SII 6717 and 6732, we found that the electron number density of the HII regions in the high-z galaxy were >1000 cm^-3, consistent with other z~2 galaxies but much higher than that in local HII regions. The star-formation rate was estimated via the Halpha luminosity, after correction for the lens magnification, to be about 365\pm69 Msun/yr. Combining the FWHM of Halpha emission lines and the half-light radius, we found the dynamical mass of the lensed galaxy is 5.8\pm0.9x10^10 Msun. The gas mass is 5.1\pm1.1x10^10~Msun from the H\alpha flux surface density by using global Kennicutt-Schmidt Law, indicating a very high gas fraction of 0.79\pm0.19 in J0900+2234.Comment: 11 pages, 6 figures accepted by ApJ, revised based on referee repor

Examining the development environments of elite English Football Academies: the players’ perspective.

As a preliminary investigation, we examined elite youth football academy players' perceptions of the quality of their developmental environment, at a crucial stage in their progression to a professional level. With institutional ethics approval, the Talent Development Environment Questionnaire (TDEQ)[1]was used to survey 50 elite players aged 16-18 (m17.1,±s=0.6 years)recruited from the academies of Premier League and Championship clubs in England. Overall, the results suggest that elite player development environments are perceived to be of a good quality. However, while academies appeared strong in areas related to coaching, organisation, and sport-related support; they were somewhat deficient in areas related to athlete understanding, links to senior progression, and key stakeholder relationships. In addition to the importance of establishing well-integrated youth and senior teams and positive working relationships with parents; the findings underline the necessity for academies to pay close attention to the psychosocial environments they create for developing players. Theoretical considerations and applied implications for those involved in elite player development are discussed

The Marco Polo mission: a sample return from a low-albedo Near Earth Object in the ESA Cosmic Vision Program 2015-2025

Marco Polo is a sample return mission to a Near-Earth Object (NEO) which was originally proposed as a joint European-Japanese mission for the scientific program Cosmic Vision 2015-2025 of the European Space Agency (ESA) in June 2007 and selected for an assessment study until fall 2009. The main goal of this mission is to return a sample from a dark taxonomic type (low albedo) NEO for detailed laboratory analysis in order to answer questions related to planetary formation, evolution and the origin of Life. In addition, it will provide detailed information on the physical and chemical properties of a body belonging to the population of potential Earth impactors, and therefore it is also directly relevant to the problems of risk assessment and mitigation. We review basic information on NEOs, potential targets for a sample return mission and the Marco Polo mission, with emphasis on their relevance to impact risk assessment and mitigation. More details on the Marco Polo mission and scientific objectives can be found in [1]

A UV Ultra-luminous Lyman Break Galaxy at Z=2.78 in NDWFS Bootes Field

We present one of the most ultraviolet (UV) luminous Lyman Break Galaxies (LBGs) (J1432+3358) at z=2.78, discovered in the NOAO Deep Wide-Field Survey (NDWFS) Bootes field. The R-band magnitude of J1432+3358 is 22.29 AB, more than two magnitudes brighter than typical L* LBGs at this redshift. The deep z-band image reveals two components of J1432+3358 separated by 1.0" with flux ratio of 3:1. The high signal-to-noise ratio (S/N) rest-frame UV spectrum shows Lya emission line and interstellar medium absorption lines. The absence of NV and CIV emission lines, the non-detection in X-ray and radio wavelengths and mid-infrared (MIR) colors indicate no or weak active galactic nuclei (AGN) (<10%) in this galaxy. The galaxy shows broader line profile with the full width half maximum (FWHM) of about 1000 km/s and larger outflow velocity (~500 km/s) than those of typical z~3 LBGs. The physical properties are derived by fitting the spectral energy distribution (SED) with stellar synthesis models. The dust extinction, E(B-V)=0.12, is similar to that in normal LBGs. The star formation rates (SFRs) derived from the SED fitting and the dust-corrected UV flux are consistent with each other, ~300 Msun/yr, and the stellar mass is 1.3e11 Msun. The SFR and stellar mass in J1432+3358 are about an order of magnitude higher than those in normal LBGs. The SED-fitting results support that J1432+3358 has a continuous star formation history with the star formation episode of 630 Myr. The morphology of J1432+3358 and its physical properties suggest that J1432+3358 is in an early phase of 3:1 merger process. The unique properties and the low space number density (~1e-7 Mpc^{-3})are consistent with the interpretation that such galaxies are either found in a short unobscured phase of the star formation or that small fraction of intensive star-forming galaxies are unobscured.Comment: 9 pages, 5 figures, and 2 tables, accepted for publication in Ap

Therapeutic targeting of integrin αvβ6 in breast cancer

BACKGROUND: Integrin ?v?6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of ?v?6 has yet to be elucidated in breast cancer.METHODS: Protein expression of integrin subunit beta6 (?6) was measured in breast cancers by immunohistochemistry (n &gt; 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of ?6 in breast cell lines, the role of ?v?6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ? 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.RESULTS: High expression of either the mRNA or protein for the integrin subunit ?6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of ?6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P &lt; .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.CONCLUSIONS: Targeting ?v?6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.<br/