Vaccination and targeted therapy using liposomes : opportunities for treatment of atherosclerosis and cancer

This thesis focuses on using liposomes in two different treatment strategies; vaccination (or immunotherapy) and delivery of a small molecule, and in two different disease models; cancer and atherosclerosis. For each of these treatment strategies, the liposomal formulation was tailored to obtain the desired therapeutic effect. Chapter 2 reviews some of the most important physicochemical properties (size, shape, and rigidity) that determine the immunological effects of liposomes and other nanoparticles. In chapter 3 we present a detailed study on the effect of the rigidity of anionic liposomes, as measured by atomic force microscopy, on antigen-specific regulatory T-cell (Treg) responses. In chapter 4, we show that our optimized anionic liposomes can induce potent antigen-specific Treg responses, and can be used to delay atherosclerosis progression in a mouse model. Chapter 5 also focuses on liposomal treatment of atherosclerosis, but here targeted liposomes were prepared to successfully deliver a small molecule to foam cells in atherosclerotic plaques. In Chapter 6, we used cationic liposomes in combination with an adjuvant for cancer immunotherapy in mice. Finally, we summarize the overall findings in chapter 7 and discuss perspectives of using liposomes for vaccination and targeted drug delivery. Drug Delivery Technolog

Oral History, Mobile Curation, and African American Memory in Cleveland\u27s Fairfax and Glenville Neighborhoods

Fairfax and Glenville are historic neighborhoods with signal importance in the African American community. Too often these neighborhoods are subjected to a simplistic declension narrative that pins their heyday in the 1920s-50s and traces their decline to the convulsive riots of the late 1960s and the subsequent loss of population to the suburbs as middle-class African Americans mirrored “white flight.” Our team conducted over 40 interviews, created story clips, and curated several new sites for the Cleveland Historical website and mobile application. Our research, rooted in oral history, exposed an important post-1968 counternarrative of resilience. Our oral histories demonstrate a continuing thread of black/white/Jewish collaborative approaches to community issues, particularly in Glenville, as well as the continuing relevance of the “old neighborhoods” for work, play, and worship long after middle-class suburban flight. They also reveal a selective memory that privileges personal connections to the neighborhood through kinship, friendship, faith, and social activism, yielding a “sense of place” that is not always tied to prevailing assumptions about the neighborhoods.https://engagedscholarship.csuohio.edu/u_poster_2014/1007/thumbnail.jp

High-precision Photometric Redshifts from Spitzer/IRAC: Extreme [3.6]-[4.5] Colors Identify Galaxies in the Redshift Range z~6.6-6.9

One of the most challenging aspects of studying galaxies in the z>~7 universe is the infrequent confirmation of their redshifts through spectroscopy, a phenomenon thought to occur from the increasing opacity of the intergalactic medium to Lya photons at z>6.5. The resulting redshift uncertainties inhibit the efficient search for [C II] in z~7 galaxies with sub-mm instruments such as ALMA, given their limited scan speed for faint lines. One means by which to improve the precision of the inferred redshifts is to exploit the potential impact of strong nebular emission lines on the colors of z~4-8 galaxies as observed by Spitzer/IRAC. At z~6.8, galaxies exhibit IRAC colors as blue as [3.6]-[4.5] ~-1, likely due to the contribution of [O III]+Hb to the 3.6 mum flux combined with the absence of line contamination in the 4.5 mum band. In this paper we explore the use of extremely blue [3.6]-[4.5] colors to identify galaxies in the narrow redshift window z~6.6-6.9. When combined with an I-dropout criterion, we demonstrate that we can plausibly select a relatively clean sample of z~6.8 galaxies. Through a systematic application of this selection technique to our catalogs from all five CANDELS fields, we identify 20 probable z~6.6-6.9 galaxies. We estimate that our criteria select the ~50% strongest line emitters at z~6.8 and from the IRAC colors we estimate a typical [O III]+Hb rest-frame equivalent width of 1085A for this sample. The small redshift uncertainties on our sample make it particularly well suited for follow-up studies with facilities such as ALMA.Comment: In submission to the Astrophysical Journal, updated in response to the referee report, 13 pages, 11 figures, 1 tabl

A Self-consistent Model for Brown Dwarf Populations

We present a self-consistent model of the Milky Way to reproduce the observed distributions (spectral type, absolute J-band magnitude, effective temperature) and total velocity dispersion of brown dwarfs. For our model, we adopt parametric forms for the star formation history and initial-mass function, published evolutionary models, and theoretical age–velocity relations. Using standard Markov Chain Monte Carlo methods, we derive a power-law index of the initial-mass function of α = −0.71 ± 0.11, which is an improvement over previous studies. We consider a gamma-function form for the star formation history, though we find that this complex model is only slightly favored over a declining exponential. We find that a velocity variance that linearly increases with age and has an initial value of km s−1 best reproduces the total velocity dispersions. Given the similarities to main-sequence stars, this suggests brown dwarfs likely form via similar processes, but we recognize that the sizable uncertainties on σ0 preclude firm conclusions. To further refine these conclusions, we suggest that wide-field infrared imaging or low-resolution spectroscopic surveys, such as with the Nancy Grace Roman Space Telescope or Euclid, could provide large samples of brown dwarfs with robust spectral types that could probe the thickness of the thin disk. In this way, the number counts and population demographics could probe the same physical processes as with the kinematic measurements, however may provide larger samples and be subject to different selection biases

Quantified H i morphology – IV. The merger fraction and rate in WHISP.

The morphology of the atomic hydrogen (H I) disc of a spiral galaxy is the first component to be disturbed by a gravitational interaction such as a merger between two galaxies. We use a simple parametrization of the morphology of H I column density maps of the Westerbork observations of neutral Hydrogen in Irregular and SPiral galaxies (WHISP) project to select those galaxies that are likely undergoing a significant interaction. Merging galaxies occupy a particular part of parameter space defined by Asymmetry (A), the relative contribution of the 20 per cent brightest pixels to the second-order moment of the column density map (M20) and the distribution of the second-order moment over all the pixels (GM). Based on their H I morphology, we find that 13 per cent of the WHISP galaxies are in an interaction (Concentration–M20) and only 7 per cent are based on close companions in the data cube. This apparent discrepancy can be attributed to the difference in visibility time-scales: mergers are identifiable as close pairs for 0.5 Gyr but are identifiable for ∼1 Gyr by their disturbed H I morphology. Expressed as volume merger rates, the two estimates agree very well: 7 and 6.8 × 10−3 mergers Gyr−1 Mpc−3 for paired and morphologically disturbed H I discs, respectively. The consistency of our merger fractions with those published for bigger surveys such as the Sloan Digital Sky Survey shows that H I morphology can be a very viable way to identify mergers in large H I surveys. The relatively high value for the volume merger rate may be a bias in the selection or WHISP volume. The expected abundance in high-resolution H I data by the planned South African Karoo Array Telescope (MeerKAT), Australian SKA Pathfinder (ASKAP) and Westerbork Synthesis Radio Telescope/APERture Tile In Focus instrument (WSRT/APERTIF) radio observatories will reveal the importance of mergers in the local Universe and, with the advent of the Square Kilometer Array (SKA), over cosmic times

Atomic force microscopy measurements of anionic liposomes reveal the effect of liposomal rigidity on antigen-specific regulatory T cell responses

Regulatory T cells (Tregs) are vital for maintaining a balanced immune response and their dysfunction is oftenassociated with auto-immune disorders. We have previously shown that antigen-loaded anionic liposomescomposed of phosphatidylcholine (PC) and phosphatidylglycerol (PG) and cholesterol can induce strong antigenspecificTreg responses. We hypothesized that altering the rigidity of these liposomes while maintaining theirsize and surface charge would affect their capability of inducing Treg responses. The rigidity of liposomes isaffected in part by the length and saturation of carbon chains of the phospholipids in the bilayer, and in part bythe presence of cholesterol. We used atomic force microscopy (AFM) to measure the rigidity of anionic OVA323-containing liposomes composed of different types of PC and PG, with or without cholesterol, in a molar ratio of4:1(:2) distearoyl (DS)PC:DSPG (Young's modulus (YM) 3611 ± 1271 kPa), DSPC:DSPG:CHOL(1498 ± 531 kPa), DSPC:dipalmitoyl (DP)PG:CHOL (1208 ± 538), DPPC:DPPG:CHOL (1195 ± 348 kPa),DSPC:dioleoyl (DO)PG:CHOL (825 ± 307 kPa), DOPC:DOPG:CHOL (911 ± 447 kPa), and DOPC:DOPG(494 ± 365 kPa). Next, we assessed if rigidity affects the association of liposomes to bone marrow-deriveddendritic cells (BMDCs) in vitro. Aside from DOPC:DOPG liposomes, we observed a positive correlation betweenliposomal rigidity and cellular association. Finally, we show that rigidity positively correlates with Treg responsesin vitro in murine DCs and in vivo in mice. Our findings underline the suitability of AFM to measureliposome rigidity and the importance of this parameter when designing liposomes as a vaccine delivery system

The brightest of reionizing galaxies survey : constraints on the bright end of the z ~ 8 luminosity function.

We report the discovery of 33 Lyman-break galaxy candidates at z ∼ 8 detected in Hubble Space Telescope Wide Field Camera 3 (WFC3) imaging as part of the Brightest of Reionizing Galaxies (BoRG) pure-parallel survey. The ongoing BoRG survey currently has the largest area (274 arcmin2) with Y098 (or Y105), J125, and H160 band coverage needed to search for z ∼ 8 galaxies, about three times the current CANDELS area, and slightly larger than what will be the final CANDELS wide component with Y105 data (required to select z ∼ 8 sources). Our sample of 33 relatively bright Y098-dropout galaxies have J125-band magnitudes between 25.5 and 27.4 mag. This is the largest sample of bright (J125 27.4) z ∼ 8 galaxy candidates presented to date. Combining our data set with the Hubble Ultra-Deep Field data set, we constrain the rest-frame ultraviolet galaxy luminosity function at z ∼ 8 over the widest dynamic range currently available. The combined data sets are well fitted by a Schechter function, i.e., φ(L) = φ∗(L/L∗) α e−(L/L∗) , without evidence for an excess of sources at the bright end. At 68% confidence, for h = 0.7 we derive φ∗ = (4.3+3.5 −2.1) × 10−4 Mpc−3, M∗ = −20.26+0.29 −0.34, and a very steep faint-end slope α = −1.98+0.23 −0.22. While the best-fit parameters still have a strong degeneracy, especially between φ∗ and M∗, our improved coverage at the bright end has reduced the uncertainty of the faint-end power-law slope at z ∼ 8 compared to the best previous determination at ±0.4. With a future expansion of the BoRG survey, combined with planned ultradeep WFC3/IR observations, it will be possible to further reduce this uncertainty and clearly demonstrate the steepening of the faint-end slope compared to measurements at lower redshift, thereby confirming the key role played by small galaxies in the reionization of the universe

Assessment of the Energy Impacts of Outside Air in the Commercial Sector

The enormous quantity of energy consumed by U.S. commercial buildings places a significant burden on the energy supply and is a potential source of economic strain. To address this, the DOE Building Technologies Program has established the goal of developing market-viable zero energy buildings by 2025. This study focuses on the effects of outside air, and considers various outside air sources, types of building construction, building subsectors, and climates. Based on the information about energy consumption attributed to outside air, it identifies topics for further research that have the greatest potential to achieve energy savings

Atomic force microscopy measurements of anionic liposomes reveal the effect of liposomal rigidity on antigen-specific regulatory T cell responses

Regulatory T cells (Tregs) are vital for maintaining a balanced immune response and their dysfunction is oftenassociated with auto-immune disorders. We have previously shown that antigen-loaded anionic liposomescomposed of phosphatidylcholine (PC) and phosphatidylglycerol (PG) and cholesterol can induce strong antigenspecificTreg responses. We hypothesized that altering the rigidity of these liposomes while maintaining theirsize and surface charge would affect their capability of inducing Treg responses. The rigidity of liposomes isaffected in part by the length and saturation of carbon chains of the phospholipids in the bilayer, and in part bythe presence of cholesterol. We used atomic force microscopy (AFM) to measure the rigidity of anionic OVA323-containing liposomes composed of different types of PC and PG, with or without cholesterol, in a molar ratio of4:1(:2) distearoyl (DS)PC:DSPG (Young's modulus (YM) 3611 ± 1271 kPa), DSPC:DSPG:CHOL(1498 ± 531 kPa), DSPC:dipalmitoyl (DP)PG:CHOL (1208 ± 538), DPPC:DPPG:CHOL (1195 ± 348 kPa),DSPC:dioleoyl (DO)PG:CHOL (825 ± 307 kPa), DOPC:DOPG:CHOL (911 ± 447 kPa), and DOPC:DOPG(494 ± 365 kPa). Next, we assessed if rigidity affects the association of liposomes to bone marrow-deriveddendritic cells (BMDCs) in vitro. Aside from DOPC:DOPG liposomes, we observed a positive correlation betweenliposomal rigidity and cellular association. Finally, we show that rigidity positively correlates with Treg responsesin vitro in murine DCs and in vivo in mice. Our findings underline the suitability of AFM to measureliposome rigidity and the importance of this parameter when designing liposomes as a vaccine delivery system

Reproducible k-means clustering in galaxy feature data from the GAMA survey

A fundamental bimodality of galaxies in the local Universe is apparent in many of the features used to describe them. Multiple sub-populations exist within this framework, each representing galaxies following distinct evolutionary pathways. Accurately identifying and characterizing these sub-populations requires that a large number of galaxy features be analysed simultaneously. Future galaxy surveys such as LSST and Euclid will yield data volumes for which traditional approaches to galaxy classification will become unfeasible. To address this, we apply a robust k-means unsupervized clustering method to feature data derived from a sample of 7338 local-Universe galaxies selected from the Galaxy And Mass Assembly (GAMA) survey. This allows us to partition our sample into k clusters without the need for training on pre-labelled data, facilitating a full census of our high-dimensionality feature space and guarding against stochastic effects. We find that the local galaxy population natively splits into 2, 3, 5, and a maximum of six sub-populations, with each corresponding to a distinct ongoing evolutionary mechanism. Notably, the impact of the local environment appears strongly linked with the evolution of low-mass (M* \u3c 1010 M⊙) galaxies, with more massive systems appearing to evolve more passively from the blue cloud on to the red sequence. With a typical run time of ~3 min per value of k for our galaxy sample, we show how k-means unsupervized clustering is an ideal tool for future analysis of large extragalactic data sets, being scalable, adaptable, and providing crucial insight into the fundamental properties of the local galaxy population