Poly(2-propylacrylic acid)/poly(lactic-co-glycolic acid) blend microparticles as a targeted antigen delivery system to direct either CD4+ or CD8+ T cell activation.

Poly(lactic-co-glycolic acid) (PLGA) based microparticles (MPs) are widely investigated for their ability to load a range of molecules with high efficiency, including antigenic proteins, and release them in a controlled manner. Micron-sized PLGA MPs are readily phagocytosed by antigen presenting cells, and localized to endosomes. Due to low pH and digestive enzymes, encapsulated protein cargo is largely degraded and processed in endosomes for MHC-II loading and presentation to CD4+ T cells, with very little antigen delivered into the cytosol, limiting MHC-I antigenic loading and presentation to CD8+ T cells. In this work, PLGA was blended with poly(2-propylacrylic acid) (PPAA), a membrane destabilizing polymer, in order to incorporate an endosomal escape strategy into PLGA MPs as an easily fabricated platform with diverse loading capabilities, as a means to enable antigen presentation to CD8+ T cells. Ovalbumin (OVA)-loaded MPs were fabricated using a water-in-oil double emulsion with a 0% (PLGA only), 3 and 10% PPAA composition. MPs were subsequently determined to have an average diameter of 1 µm, with high loading and a release profile characteristic of PLGA. Bone marrow derived dendritic cells (DCs) were then incubated with MPs in order to evaluate localization, processing, and presentation of ovalbumin. Endosomal escape of OVA was observed only in DC groups treated with PPAA/PLGA blends, which promoted high levels of activation of CD8+ OVA-specific OT-I T cells, compared to DCs treated with OVA-loaded PLGA MPs which were unable activate CD8+ T cells. In contrast, DCs treated with OVA-loaded PLGA MPs promoted OVA-specific OT-II CD4+ T cell activation, whereas PPAA incorporation into the MP blend did not permit CD4+ T cell activation. These studies demonstrate PLGA MP blends containing PPAA are able to provide an endosomal escape strategy for encapsulated protein antigen, enabling the targeted delivery of antigen for tunable presentation and activation of either CD4+ or CD8+ T cells

The population of propellers in Saturn's A Ring

We present an extensive data set of ~150 localized features from Cassini images of Saturn's Ring A, a third of which are demonstrated to be persistent by their appearance in multiple images, and half of which are resolved well enough to reveal a characteristic "propeller" shape. We interpret these features as the signatures of small moonlets embedded within the ring, with diameters between 40 and 500 meters. The lack of significant brightening at high phase angle indicates that they are likely composed primarily of macroscopic particles, rather than dust. With the exception of two features found exterior to the Encke Gap, these objects are concentrated entirely within three narrow (~1000 km) bands in the mid-A Ring that happen to be free from local disturbances from strong density waves. However, other nearby regions are similarly free of major disturbances but contain no propellers. It is unclear whether these bands are due to specific events in which a parent body or bodies broke up into the current moonlets, or whether a larger initial moonlet population has been sculpted into bands by other ring processes.Comment: 31 pages, 10 figures; Accepted at A

Exposure to Nickel, Chromium, or Cadmium Causes Distinct Changes in the Gene Expression Patterns of a Rat Liver Derived Cell Line

Many heavy metals, including nickel (Ni), cadmium (Cd), and chromium (Cr) are toxic industrial chemicals with an exposure risk in both occupational and environmental settings that may cause harmful outcomes. While these substances are known to produce adverse health effects leading to disease or health problems, the detailed mechanisms remain unclear. To elucidate the processes involved in the toxicity of nickel, cadmium, and chromium at the molecular level and to perform a comparative analysis, H4-II-E-C3 rat liver-derived cell lines were treated with soluble salts of each metal using concentrations derived from viability assays, and gene expression patterns were determined with DNA microarrays. We identified both common and unique biological responses to exposure to the three metals. Nickel, cadmium, chromium all induced oxidative stress with both similar and unique genes and pathways responding to this stress. Although all three metals are known to be genotoxic, evidence for DNA damage in our study only exists in response to chromium. Nickel induced a hypoxic response as well as inducing genes involved in chromatin structure, perhaps by replacing iron in key proteins. Cadmium distinctly perturbed genes related to endoplasmic reticulum stress and invoked the unfolded protein response leading to apoptosis. With these studies, we have completed the first gene expression comparative analysis of nickel, cadmium, and chromium in H4-II-E-C3 cells

Spatial Curvature Falsifies Eternal Inflation

Inflation creates large-scale cosmological density perturbations that are characterized by an isotropic, homogeneous, and Gaussian random distribution about a locally flat background. Even in a flat universe, the spatial curvature measured within one Hubble volume receives contributions from long wavelength perturbations, and will not in general be zero. These same perturbations determine the Cosmic Microwave Background (CMB) temperature fluctuations, which are O(10^-5). Consequently, the low-l multipole moments in the CMB temperature map predict the value of the measured spatial curvature \Omega_k. On this basis we argue that a measurement of |\Omega_k| > 10^-4 would rule out slow-roll eternal inflation in our past with high confidence, while a measurement of \Omega_k < -10^-4 (which is positive curvature, a locally closed universe) rules out false-vacuum eternal inflation as well, at the same confidence level. In other words, negative curvature (a locally open universe) is consistent with false-vacuum eternal inflation but not with slow-roll eternal inflation, and positive curvature falsifies both. Near-future experiments will dramatically extend the sensitivity of \Omega_k measurements and constitute a sharp test of these predictions.Comment: 16+2 pages, 2 figure

Coronary Artery Calcification (CAC) and Post-Trial Cardiovascular Events and Mortality Within the Women's Health Initiative (WHI) Estrogen-Alone Trial.

BackgroundAmong women aged 50 to 59 years at baseline in the Women's Health Initiative (WHI) Estrogen-Alone (E-Alone) trial, randomization to conjugated equine estrogen-alone versus placebo was associated with lower risk of myocardial infarction and mortality, and, in an ancillary study, the WHI-CACS (WHI Coronary Artery Calcification Study) with lower CAC, measured by cardiac computed tomography ≈8.7&nbsp;years after baseline randomization. We hypothesized that higher CAC would be related to post-trial coronary heart disease (CHD), cardiovascular disease (CVD), and total mortality, independent of baseline randomization or risk factors.Methods and resultsWHI-CACS participants (n=1020) were followed ≈8&nbsp;years from computed tomography scan in 2005 (mean age=64.4) through 2013 for incident CHD (myocardial infarction and fatal CHD, n=17), CVD (n=69), and total mortality (n=55). Incident CHD and CVD analyses excluded women with CVD before scan (n=89). Women with CAC=0 (n=54%) had very low age-adjusted rates/1000&nbsp;person-years of CHD (0.91), CVD (5.56), and mortality (3.45). In comparison, rates were ≈2-fold higher for women with any CAC (&gt;0). Associations were not modified by baseline randomization to conjugated equine estrogen-alone versus placebo. Adjusted for baseline randomization and risk factors, the hazard ratio (95% confidence interval) for CAC &gt;100 (19%) was 4.06 (2.11, 7.80) for CVD and 2.70 (1.26, 5.79) for mortality.ConclusionsAmong a subset of postmenopausal women aged 50 to 59 years at baseline in the WHI E-Alone Trial, CAC at mean age of 64 years was strongly related to incident CHD, CVD, and to total mortality over ≈8&nbsp;years, independent of baseline randomization to conjugated equine estrogen-alone versus placebo or CVD risk factors.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00000611

Evaluating the role of a galanin enhancer genotype on a range of metabolic, depressive and addictive phenotypes

Funded by •ERC. Grant Number: 284167 •NIH. Grant Number: 1RO1DK0921127-01 •NWO. Grant Numbers: 463-06-001, 451-04-034Peer reviewedPublisher PD

WorldMap – A Geospatial Framework for Collaborative Research

WorldMap is a web-based, map-centric data exploration system built on open-source geospatial technology at Harvard University. It is designed to serve collaborative research and teaching, but is also accessible to the general public. This article explains WorldMap's basic functions through several historical research projects, demonstrating its flexible scale (from neighborhood to continent) and diverse research themes (social, political, economic, cultural, infrastructural, etc.). Also shared in this article are our experiences in handling technical and institutional challenges during system development, such as synchronization of software components being developed by multiple organizations; juggling competing priorities for serving individual requests and developing a system that will enable users to support themselves; balancing promotion of the system usage with constraints on infrastructure investment; harnessing volunteered geographic information while managing data quality; as well as protecting copyrights, preserving permanent links and citations, and providing long-term archiving.East Asian Languages and Civilization

Tribolium beetles as a model system in evolution and ecology

Flour beetles of the genus Tribolium have been utilised as informative study systems for over a century and contributed to major advances across many fields. This review serves to highlight the significant historical contribution that Tribolium study systems have made to the fields of ecology and evolution, and to promote their use as contemporary research models. We review the broad range of studies employing Tribolium to make significant advances in ecology and evolution. We show that research using Tribolium beetles has contributed a substantial amount to evolutionary and ecological understanding, especially in the fields of population dynamics, reproduction and sexual selection, population and quantitative genetics, and behaviour, physiology and life history. We propose a number of future research opportunities using Tribolium, with particular focus on how their amenability to forward and reverse genetic manipulation may provide a valuable complement to other insect models

On the miscibility of cardiolipin with 1,2-diacyl phosphoglycerides: Binary mixtures of dimyristoylphosphatidylethanolamine and tetramyristoylcardiolipin

The thermotropic phase behavior and organization of model membranes composed of binary mixtures of the quadruple-chained, anionic phospholipid tetramyristoylcardiolipin (TMCL) with the double-chained zwitterionic phospholipid dimyristoylphosphatidylethanolamine (DMPE) were examined by a combination of differential scanning calorimetry (DSC) and Fourier-transform infrared (FTIR) spectroscopy. After equilibration at low temperature, DSC thermograms exhibited by binary mixtures of TMCL and DMPE containing < 80 mol DMPE exhibit a fairly energetic lower temperature endotherm and a highly energetic higher temperature endotherm. As the relative amount of TMCL in the mixture decreases, the temperature, enthalpy and cooperativity of the lower temperature endotherm also decreases and is not calorimetrically detectable when the TMCL content falls below 20 mol%. In contrast, the temperature of the higher temperature endotherm increases as the proportion of TMCL decreases, but the enthalpy and cooperativity both decrease and the transition endotherms become multimodal. The FTIR spectroscopic results indicate that the lower temperature endotherm corresponds to a lamellar crystalline (Lc) to lamellar gel (Lβ) phase transition and that the higher temperature transition involves the conversion of the Lβ phase to the lamellar liquid-crystalline (Lα) phase. Moreover, the FTIR spectroscopic signatures observed at temperatures below the onset of the Lc/Lβ phase transitions are consistent with the coexistence of structures akin to a TMCL-like Lc phase and the L β phase, and with the relative amount of the TMCL-like L c phase increasing progressively as the TMCL content of the mixture increases. These latter observations suggest that the TMCL and DMPE components of these mixtures are poorly miscible at temperatures below the L β/Lα phase transition temperature. Poor miscibility of these two components is also suggested by the complexity of the DSC thermograms observed at the Lβ/Lα phase transitions of these mixtures and with the complex relationship between their Lβ/Lα phase transition temperatures and the composition of the mixture. Overall, our data suggests that TMCL and DMPE may be intrinsically poorly miscible across a broad composition range, notwithstanding the homogeneity of the fatty acid chains of the two components and the modest (~ 10 °C) difference between their Lβ/Lα phase transition temperatures.Fil: Frías, María de los Ángeles. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Benesch, Matthew G. K.. University of Alberta; CanadáFil: Lewis, Ruthven N. A. H.. University of Alberta; CanadáFil: McElhaney, Ronald N.. University of Alberta; Canad