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The aryl hydrocarbon receptor (AhR) carboxyl terminal transcriptional activation domain was cloned, purified in denatured conditions from bacteria, refolded via limited dialysis, and analyzed for proper refolding via co-immunoprecipitation with the known binding partner SRC-1. This AhR NΔ515 transactivation domain construct was used, along with amino terminal AhR deletion constructs AhR CΔ274 and AhR CΔ553, to attempt to elucidate the nature of the interaction between AhR and p23 in vitro.

At the intersection between autoimmune disease and cancer lies a disruption in the balance of our body’s critically important immune system, and, specifically, in its regulation. While autoimmune diseases are the result of overactivation and a failure to regulate improper responses to the body’s own tissues, cancer is the result of improper suppression and a failure to recognize and eradicate transformed malignant cells. Although they are fundamentally different conditions, overlap can be found in the pathways which are critical to disease progression and which may represent important therapeutic targets. One such pathway implicated in both autoimmunity and cancer is the aryl hydrocarbon receptor (AhR). AhR activation suppresses immune cell activation through the modulation of T cell differentiation and antigen presenting cell (APC) function. AhR activation shows a beneficial therapeutic effect in models of autoimmune disease, but has also been implicated in driving cancer progression and tumor-mediated immunosuppression. While it is clear that the AhR plays an important role in the immune response, the mechanisms behind AhR regulation of the immune system and the effects of its modulation in autoimmunity and cancer are still not fully understood. Thus, in this work, we investigated the effect of targeting the AhR in models of autoimmunity and cancer, using the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) and the murine oral cancer (MOC) model of oral squamous cell carcinoma (OSCC). We demonstrated that AhR activation using the endogenous ligand 2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induced a tolerogenic transcriptional response in mouse and human dendritic cells (DCs) associated with the induction of immunoregulatory/immunosuppressive mechanisms. We further showed that targeting the AhR using a nanoliposome (NLP) delivery platform, which co-encapsulated a MS autoantigen, suppressed the development of EAE in multiple models, both in preventative and therapeutic contexts. This disease suppression was associated with the expansion of antigen-specific FoxP3+ regulatory T cells (Treg cells) and IL10+ type 1 regulatory T cells (Tr1 cells), and a reduction in CNS-infiltrating effector T cells (Teff cells). Using the MOC1 model of OSCC we demonstrated that deletion of the AhR in MOC1 malignant cells completely blocks in vivo tumor growth in an immune system-dependent manner and renders mice completely immune to either local or systemic re-challenge with wildtype MOC1 cells. Suppression of tumor growth was associated with a decrease in the expression of suppressive immune checkpoint markers including PD-L1 and CD39 on macrophages, dendritic cells, and Ly6G+ myeloid cells, and PD-1, CTLA4, Lag3, and CD39 on CD4+ T cells. Further, the AhR was found to control expression of chemokines and immunosuppressive IDO and PD-L1 in malignant cells themselves, suggesting that AhR activity in tumor cells may simultaneously regulate multiple immune checkpoints. Taken together, these results provide new insight into the critical role for the AhR in both autoimmunity and cancer, and confirm it as a valid therapeutic target for both diseases. / 2022-03-05T00:00:00Z

This research studies the use of class=SpellE>titania (titanium dioxide, TiO2) as a catalyst for deoxygenation of class=SpellE>syngas derived oxygenates. These oxygenates are formed as byproducts when biomass derived syngas (CO & H2) is converted to ethanol on Rhodium or Molybdenum based catalysts. Conversion of these oxygenates to hydrocarbon would enhance the viability of class=SpellE>syngas to gasoline technology. This study revealed that class=SpellE>titania can indeed be used to convert syngas derived oxygenates to hydrocarbon at high temperature and pressure. Acetone condensation to mesitylene was studied very closely. The study revealed that the acid-base dual nature of class=SpellE>titania is key for the success of this reaction. When titaniawas combined with the zeolite H+/ZSM-5, a broad range of gasoline type hydrocarbon could be produced. Ethanol conversion to higher alcohols was studied as part of a partial deoxygenation of ethanol research. While this conversion was possible on class=GramE>titania, zirconia proved to be a better catalyst. Ethanol could be converted to 1-butanol and other higher alcohols at high temperature and pressure. The mechanism by which this occurs was studied as well.

Laminar flat flame combustion has been studied with molecular-beam mass-spectrometry (MBMS) for a fuel-rich cyclohexane (Ф = 2.003) flame, a fuel-lean toluene (Ф = 0.895), and a fuel-rich toluene (Ф = 1.497) flame. Different hydrocarbon species in these flames were identified, and their mole fraction profiles were measured. The information can be used to propose reaction mechanisms for the different hydrocarbon flames. One MBMS apparatus located at Advanced Light Source (ALS) at Lawrence Berkeley National Laboratory was used to identify and measure the mole-fraction profiles of different species in these flames. The MBMS apparatus located at University of Massachusetts Amherst was used to measure the temperature profile of the cyclohexane flame. The temperature profile of two different fuel-rich toluene flames (Ф= 2.02 , Ф = 3.94) and a fuel-lean (Ф=0.452) methane flame were also measured with the UMass apparatus.

Fireworks on Independence Day have been identified as a nationwide but short-term source of particulate matter in the U.S. No study has specifically examined their impacts on ambient polycyclic aromatic hydrocarbons (PAHs). Based on data between 1990 and 2019 in the Air Quality System, we identified 76 unique events that had PAH measurements on both July 4th days and control days (within 15 days before and after July 4th). We compared concentrations and diagnostic ratios of 16 priority PAHs between event and control days using Wilcoxon signed-rank tests and multivariable regressions. A local PAH monitoring campaign was conducted at eight sites in Memphis, Tennessee, to obtain a close observation of PAH changes. The national geometric mean (GM) concentrations of summed 16 PAHs (ΣPAHs) were similar between event and control days (48.1 ng/m3 vs. 52.8 ng/m3, p = 0.98). About a quarter of events had elevated PAH concentrations compared with control days. Higher diagnostic ratios were found on event days, suggesting more contributions from fireworks sources. PAHs on July 4th were unlikely to cause acute or chronic health effects. While the local monitoring showed a 15% increase of ΣPAHs on July 4th, the difference was not significant (p = 0.62). Elevated PAH concentrations occurred at sites near fireworks sources and without major traffics, but did not occur at those in remote areas or near major interstate highways. In conclusion, this study finds that Independence Day fireworks have negligible impacts on atmospheric PAHs at the national level, and are unlikely to pose significant health risks. The firework effect is localized within a limited geographic scale, suggesting potential needs for local monitoring and control programs.

Polycyclic aromatic hydrocarbons (PAH) are important environmental pollutants generally formed during incomplete combustion of organic matter containing carbon and hydrogen. Introduced into the human body by adsorption through the skin, ingestion or inhalation, the biotransformation processes of PAH lead to the formation of multiple metabolites. Due to the short elimination lifetime from the body, the quantitative determination of monohydroxy-PAH (OH-PAH) in urine samples provides accurate information on recent exposure to environmental PAH. Urine analysis of OH-PAH with established methodology relies on sample clean-up and pre-concentration followed by chromatographic separation and quantification. Although chromatographic techniques provide reliable results in the analysis of OH-PAH, their experimental procedures are time consuming and expensive. Additional problems arise when laboratory procedures are scaled up to handle thousands of samples under mass screening conditions. Under the prospective of a sustainable environment, the large usage of organic solvents is one of the main limitations of current chromatographic methodology. It is within this context that new analytical approaches based on easy-to-use and cost-effective methodology become extremely relevant. This dissertation focuses on the development of screening methodology for the routine analysis of PAH metabolites in numerous samples. It explores the room-temperature fluorescence properties of six metabolites originating from parent PAH included in the Environmental Protection Agency priority pollutants list. 1- hydroxyfluorene, 1-hydroxypyrene, 6-hydroxychrysene, 9-hydroxyphenanthrene, 3- hydroxybenzo[a]pyrene and 4-hydroxybenzo[a]pyrene are used as model biomarkers to investigate the analytical potential of new methods based on solid-phase extraction (SPE) and iii room-temperature fluorescence (RTF) spectroscopy. Quantitative determination of metabolites is carried out either in the eluent extract[1, 2] or on the surface of extraction membranes[3, 4] . The direct determination – i.e., no chromatographic separation - of the six metabolites is based on the collection of excitation-emission matrices and synchronous fluorescence spectra.

<p> A two stage chromatographic separation method was adapted to the separation of nitrogen-containing compounds from heavy syncrude oils. Crude oil samples were first chromatographed on alumina to obtain an aliphatic fraction A1 (70 wt% of oil, <1% of total nitrogen), a polycyclic aromatic hydrocarbon fraction A2 (20%, 16%N) and a nitrogenous fraction A3 (3%, 80%N). The nitrogenous fraction was further separated on silicic acid into three fractions: a secondary-PANH fraction S1 (61% total N), an amino-PAH and tertiary-PANH fraction S2 (4%N) and a tertiary-PANH fraction S3 (9%N). One Tar Sand and two oil residue samples, provided by Shell Canada Ltd, were taken through this procedure.</p> <p> The nitrogen-containing fractions were analyzed by mass spectrometry (electron impact, methane chemical ionization and ammonia chemical ionization) and by two chromatographic methods (gas and reverse phase liquid chromatography). Further analyses were performed using gas chromatography/mass spectrometry, liquid chromatography/mass spectrometry and nuclear magnetic resonance (1H and 13C) spectroscopy.</p> <p> The nitrogenous components in the S1 fractions were shown to be alkylated carbazoles, containing from one to twenty carbons attached to the carbazole nucleus, in varying degrees of unsaturation ranging from zero to five degrees of unsaturation. The distribution of carbon substitution maximized in the C5 to C8 range for the different series of alkylcarbazoles. The distribution of the degrees of unsaturation in the Tar Sand oil sample was: saturated carbazoles, 32%, 1-degree unsaturates, 23%, 2-degree, 9%, 3-degree, 16%, 4-degree, 12% and 5-degree, 8%. In the processed Peace River residue, the ratio between the saturated, 1-, 2-, 3-, 4- and 5-degree unsaturated carbazoles was 28%:39%:18%:6%:6%:3%. From the 1H NMR spectrum the ratio of benzylic to aliphatic resonances was 1:1.25 which was interpreted to mean that the alkyl chains attached to the carbazole nucleus were short on average. A complete lack of vinyl proton absorption indicated that few alkene bonds if any were present; thus, the degrees of unsaturations must be accommodated by rings or benzo-annulations.</p> <p> Of all the analytical methods used, ammonia chemical ionization mass spectrometry (NH3 CIMS) was found to be a most useful and selective method and was used in probe MS, GC/MS and LC/MS experiments. Reverse phase liquid chromatography (RPLC) was more useful in this work than capillary column gas chromatography (CCGC). A combination of nuclear magnetic resonance (NMR) experiments (1H, 13C, 13C spectral editing, 1H-13C shift correlation and 13C T1 ) was found to be extremely useful for these samples because of the unique information these experiments provided.</p> / Thesis / Master of Science (MSc)

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