Impact of viral vectors on vaccine design: IL-13Ra2 in DC regulation

Studies in our laboratory have established that the route of vaccination, viral vector and the cytokine milieu, specifically IL-13 can critically impact the vaccine-specific adaptive immune outcomes. Recent efforts in understanding which cells at the vaccination site produced IL-13 revealed that innate lymphoid cells (ILC)2 were the major source of this cytokine at the vaccination site 24h post delivery. Knowing that manipulating IL-13 levels at the vaccination site also significantly altered resident lung dendritic cell (DC) recruitment, this study focused on dissecting the underlying mechanisms by which ILCs and DCs regulated vaccine-specific immunity at the lung mucosae following intranasal vaccination. Poxviral and non-poxviral vaccine vectors induced uniquely different ILC-derived cytokine and DC profiles at the lung mucosae, 24 h post vaccination. For example, rFPV priming known to induce high avidity T cells, exhibited low ILC2-derived IL-13, high ILC1/ILC3-derived IFN-g and enhanced recruitment of CD11b+ CD103- conventional DCs (cDC). Whereas, rMVA, rVV and Influenza A vector priming, linked to low avidity T cells, induced opposing ILC-derived cytokine profiles, together with enhanced CD11b- CD103+ cross-presenting DCs and reduced cDCs. Interestingly, Rhinovirus (RV) and Adenovius type 5 (Ad5) vectors, also showed different ILC-derived cytokine profiles and predominant recruitment of CD11b- B220+ plasmacytoid DCs (pDC). Knowing that cDCs are associated with high avidity CD8 T cell priming and pDCs are involved in antibody differentiation, these findings showed that vaccine derived early ILC/DC profiles directly impact the downstream adaptive immune outcomes. When trying to unravel how IL-13 signalling modulated these vaccine-specific adaptive immune outcomes, unlike IL-13Ra1, IL-13Ra2 was found to be the major sensor and regulator of early IL-13 mediated DC activity. For the first time a dual role of IL-13Ra2 was unraveled on lung cDC, where low IL-13 was associated with IL-13Ra2 signalling via STAT3 activating TGF-b1, whilst, high IL-13 triggered sequestration by the same receptor. Interestingly, in this study differential IL-13 receptor mediated STAT3/STAT6 paradigms were observed, regulated collaboratively or independently by TGF-b1 and IFN-g. Low IL-13 driven early IL-13Ra2/STAT3 responses were regulated primarily by TGF-b1, whereas, high IL-13 driven IL-13Ra1/STAT6 responses were associated with IFN-gR expression bias. Moreover, inherent properties of viral vaccine vectors (host tropism, replication status and presence or absence of immunomodulatory genes), were also found to significantly alter the IL-4/IL-13 receptor regulation on lung DCs, in a time dependent manner. Specifically, the generation of a balanced adaptive immune outcome was associated with early regulation of IL-13Ra2, succeeded by IL-13Ra1/ IL-4Ra on lung DCs, as observed with rFPV vaccination unlike the other poxviral vectors tested. Collectively, findings of this thesis for the first time demonstrated the importance of understanding the mechanisms of IL-13 mediated DC regulation, at the vaccination site. Therefore, knowing these innate mechanisms associated with ILC/DC regulation may help design more efficacious vaccines and therapeutics against IL-13 related disease conditions

Adsorptive removal of nitrogen from coal-based needle coke feedstocks using activated carbon

A low percentage of nitrogen in needle coke feedstocks is desired for the reduction of puffing during the process of graphitization of needle coke. The purpose of the present study is to investigate the removal of nitrogen species from a coal-based needle coke feedstock, when treated with both commercial activated carbon, Nuchar SA 20 and coal-derived activated carbon, WVUAC 900-15. Koppers coal tar distillate (CTD), which has 1.1% wt starting nitrogen content, is selected as the needle coke feedstock. A series of experiments was performed to establish a standard procedure for the removal of nitrogen species. Using the established experimental procedure, experiments were conducted to determine the effect of solvent, time and amount of activated carbon on the adsorption capacity of nitrogen for both Nuchar and WVUAC 900-15 activated carbons. Also, the surface properties of both the activated carbons were modified via oxidation with nitric acid and air. The oxidized activated carbons were then tested as adsorbents for the de-nitrogenation of CTD. From the pH test results, it is observed that oxidation modification has improved acidic surface functional groups on activated carbons. In an experiment it is observed that 92% of the nitrogen was removed from the CTD with 9 g of Nuchar SA20. Unfortunately the result was not repeatable. No reasonable explanations were found for this but it is suspected that aging of the CTD which may change the nitrogen compounds in CTD and error in the sampling technique are possible reasons. Oxidized activated carbons performed 10--15% better than unoxidized activated carbon in removing nitrogen species. The coefficient of thermal expansion (CTE) of the graphite test specimen prepared with de-nitrogenated CTD is measured as 0.209 ppm/°C while CTE of the graphite test specimen prepared with a petroleum-based needle-coke feedstock, decant oil, is 0.250 ppm/°C

Design of Nano-satellite Cluster Formations for Bi-Directional Reflectance Distribution Function (BRDF) Estimations

The bidirectional reflectance distribution function (BRDF) of the Earth’s surface describes the directional and spectral variation of reflectance of a surface element. It is required for precise determination of important geophysical parameters such as albedo. BRDF can be estimated using reflectance data acquired at large 3D angular spread of solar illumination and detector directions and visible/near infrared (VNIR) spectral bands. This paper proposes and evaluates the use of nanosatellite clusters in formation flight to achieve large angular spreads for cheaper, faster and better estimations that will complement existing BRDF data products. In this paper, the technical feasibility of this concept is assessed in terms of various formation flight geometries available to achieve BRDF requirements and multiple tradespaces of solutions proposed at three levels of fidelity – Hill’s equations, full sky spherical relative motion and global orbit propagation. Preliminary attitude control requirements, as constrained by cluster geometry, are shown to be achievable using CubeSat reaction wheels

Comparative Impact Of Network Adequacy Standard Strategies On Medicaid Recipient Cvd Outcomes: A Computer Simulation Modeling Study

Context: Medicaid managed care network adequacy standards vary widely across states and are not typically informed by scientific evidence. The comparative efficacy of these standards for protecting the health of the Medicaid population has not yet been comprehensively researched.Objective: The aims of this study are to construct simulation modeling methods to approach this policy problem and to determine which numeric values for network adequacy standards are most effective for producing favorable health outcomes for Medicaid recipients who develop CVD. Design and Setting: A continuous-time Markov model was used to simulate the natural history of cardiovascular disease, using a cohort that is representative of the Medicaid population over 40, under different provider appointment wait times and CVD emergency travel time delays. Input and Output Measures: Medicaid claims data from Tennessee in 2019, Social Security life expectancy data, the Centers for Disease Control and Prevention\u27s Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database, and values pulled from existing literature were used to inform input parameters. Survival time, age at death, number of lifetime hospital visits, number of lifetime provider visits, time spent in recovery, time spent waiting for an appointment, lifetime healthcare costs, and lifetime healthcare costs attributable to hospitalization were collected as simulation outputs. Results: It was found that the strategy with a 45-day appointment wait time and 0-minute emergency travel time delay yielded the most favorable health outcomes for individuals with CVD: mean age at death of 83.79 (83.10, 84.47) and mean survival time of 32.08 (31.09, 33.07). When the strategies hypothesized to be the “best” (7-day wait times and no travel delay) and “worst” (90-day wait times and 90-min travel delay for emergencies) were run in comparison to one another, statistically significant differences were found for time spent in recovery, time spent waiting for an appointment, provider visit quantity, and healthcare system cost burden. Statistically significant differences were not found for life expectancy, hospital visit quantity, and costs attributable to hospitalization. Conclusion: There is not enough evidence of robustness in these results to recommend that policy decisions should be made using them; further complexities and calibration should be incorporated into the model before doing so

Coherent state-based approaches to quantum dynamics: application to thermalization in finite systems

We investigate thermalization in finite quantum systems using coherent state-based approaches to solve the time-dependent Schr\'odinger equation. Earlier, a lot of work has been done in the quantum realm, to study thermalization in spin systems, but not for the case of continuous systems. Here, we focus on continuous systems. We study the zero temperature thermalization i.e., we consider the ground states of the bath oscillators (environment). In order to study the quantum dynamics of a system under investigation, we require numerical methods to solve the time-dependent Schr\'odinger equation. We describe different numerical methods like the split-operator fast fourier transform, coupled coherent states, static grid of coherent states, semiclassical Herman-Kluk propagator and the linearized semiclassical initial value representation to study the quantum dynamics. We also give a comprehensive comparison of the most widely used coherent state based methods. Starting from the fully variational coherent states method, after a first approximation, the coupled coherent states method can be derived, whereas an additional approximation leads to the semiclassical Herman-Kluk method. We numerically compare the different methods with another one, based on a static rectangular grid of coherent states, by applying all of them to the revival dynamics in a one-dimensional Morse oscillator, with a special focus on the number of basis states (for the coupled coherent states and Herman-Kluk methods the number of classical trajectories) needed for convergence. We also extend the Husimi (coherent state) based version of linearized semiclassical theories for the calculation of correlation functions to the case of survival probabilities. This is a case that could be dealt with before only by use of the Wigner version of linearized semiclassical theory. Numerical comparisons of the Husimi and the Wigner case with full quantum results as well as with full semiclassical ones is given for the revival dynamics in a Morse oscillator with and without coupling to an additional harmonic degree of freedom. From this, we see the quantum to classical transition of the system dynamics due to the coupling to the environment (bath harmonic oscillator), which then can lead ultimately to our final goal of thermalization for long-time dynamics. In regard to thermalization in quantum systems, we address the following questions--- is it enough to increase the interaction strength between the different degrees of freedom in order to fully develop chaos which is the classical prerequisite for thermalization, or if, in addition, the number of those degrees of freedom has to be increased (possibly all the way to the thermodynamic limit) in order to observe thermalization. We study the ``toppling pencil'' model, i.e., an excited initial state on top of the barrier of a symmetric quartic double well to investigate thermalization. We apply the method of coupled coherent states to study the long-time dynamics of this system. We investigate if the coupling of the central quartic double well to a finite, environmental bath of harmonic oscillators in their ground states will let the central system evolve towards its uncoupled ground state. This amounts to thermalization i.e., a cooling down to the bath ``temperature'' (strictly only defined in the thermodynamic limit) of the central system. It is shown that thermalization can be achieved in finite quantum system with continuous variables using coherent state-based methods to solve the time-dependent Schr\'odinger equation. Also, here we witness thermalization by coupling the system to a bath of only few oscillators (less than ten), which until now has been seen for more than ten to twenty bath oscillators