Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models

Classical receptor theory is largely built on assumptions of monomeric receptors. In this thesis, we contribute to receptor theory by considering the now widely accepted cases of dimeric receptors. The implications of dimerisation for drug discovery and therapeutics remain unclear. Therefore, a theoretical consideration of ligand binding and signalling via receptor dimers is warranted. Here, we develop mathematical models for ligand bind-ing at dimerised and dimerising receptors. A key factor in developing these theoretical models is cooperativity across the dimer, whereby binding of a ligand to one protomer affects the binding of a ligand to the other protomer. The effects of cooperativity on binding dynamics are a primary point of interest.The first models we present focus on G protein-coupled receptors, where we assume that all receptors are pre-dimerised. Ligand binding models give linear systems of differ-ential equations which we use to analyse time course behaviours. At equilibrium, these models may exhibit multi-phasic log dose response curves, critically depending on co-operativity factors. When considering receptor activation, we see dose response curves that are indicative of non-standard ligand-receptor interactions, giving a quantitative and qualitative platform for analysing and interpreting data when dimers are suspected. A ligand induced model for vascular endothelial growth factor receptors is developed, whereby receptors exist constitutively as monomers and dimerise in response to ligand binding. The resulting nonlinear system of differential equations is investigated using numerical computations and perturbation methods. We see an excellent fit to published data, validating the model.The utility of our models in parameter estimation is explored theoretically using structural identifiability analysis. This determines which parameters can be theoretically estimated from fitting. This analysis is valuable but often overlooked when fitting to ligand-receptor interaction models. We explore the identifiability of some canonical lig-and binding models, and our dimer binding models, providing a tutorial and results to contribute to the receptor theory toolbox

AUDIOLOGISTS’ KNOWLEDGE, ATTITUDES, AND PRACTICES REGARDING PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND HEARING LOSS

ABSTRACT White, Carla M. Audiologists’ Knowledge, Attitudes, and Practices Regarding Patients with Systemic Lupus Erythematosus and Hearing Loss. Unpublished Doctor of Audiology capstone research project, University of Northern Colorado, 2020. Patients diagnosed with systemic lupus erythematosus (SLE) have a moderate to high risk of developing a sensorineural hearing loss. The purpose of this study was to identify the knowledge, the degree of confidence, and the clinical practices of audiologists and graduate students when providing audiological care to this population. An opportunity for the respondents to share clinical experiences and knowledge was also provided. A sample of 77 respondents, 24 licensed audiologists and 53 graduate students, represented that audiologists are generally aware of the disease and that SLE can cause sensorineural hearing loss. Graduate students were more likely to learn about SLE from personal relationships, while licensed audiologists first learned of SLE from another health care professional. Outcomes also revealed that additional resources, such as a clinical protocol and a list of SLE support groups, are needed and have been requested by both respondent groups. Both licensed audiologists and graduate students are knowledgeable with SLE but are currently interested in clinical resources. There is an opportunity for additional research to create a more formal and finite protocol to be utilized when an audiologist sees a patient with SLE. Further research should identify the appropriate actions an audiologist must complete in order to ensure that sufficient long-term audiologic care can be provided to patients diagnosed with systemic lupus erythematosus

A Foreign Affair: A Phenomenological Study of Barriers to Adult Liberian Refugees\u27 Success in the American College Classroom

Liberia has survived a fourteen-year civil war. Within this time, many Liberians were forced to flee their countries and seek refuge. The United States and Liberia have held a long-standing friendly relationship; hence, there are thousands of Liberian refugees living within the United States. The educational issues of refugees worldwide is lacking in research. Consequently, the purpose of this dissertation is to gain an understanding of the lived experiences of adult Liberian refugees matriculating within American college classrooms. Through phenomenological methodology, the lived experiences of ten Liberian refugees enrolled within American college classrooms produced valuable results. Three major themes were found that described the perceptions and barriers to Liberian refugees academic success

Petrology and mineral chemistry of some Jan Mayen volcanics

The island of Jan Mayen is the northernmost active volcano on the Mid-Atlantic Ridge. The rocks of Jan Mayen belong to the potassic series of the alkaline rocks and appear to belong to the straddle type association. The ankaramites and alkali olivine basalts are characterized by the presence of large xenocrysts of rimmed chromium diopside, titaniferous salite, olivine (Fo83 to Fo88), magnetite and sometimes plagioclase (bytownite rimmed by labradorite). Phenocrysts of olivine (Fo74) and plagioclase (andesine) are present in several rocks. These and phenocrysts lie in a matrix composed of` titaniferous salite, olivine (Fo58), plagioclase (andesine), magnetite, biotite and sometimes ilmenite. Latite andesites contain large crystals of plagioclase of an andesine-oligoclase composition rimmed by oligoclase or alkali feldspar, magnetite, biotite, hornblende and sometimes highly altered clinopyroxene. The trachytes are characterized by phenocrysts of aegirine-augite, anorthoclase, magnetite, biotite and sometimes andesine rimmed by an alkali feldspar. The phenccrysts of the latite andesites and trachyte lie in a groundmass consisting of andesine, alkali feldspar, magnetite, hematite and biotite. Trace element whole rock geochemistry indicates that the rocks of Jan Mayen were probably derived from the mantle from slightly different source regions based on different Rb/Sr ratios for the mafic rocks of Nord Jan and Sor Jan. The rocks formed by the partial accumulation of titaniferous salite, plagioclase, olivine and magnetite from an alkali basalt magma followed by the intrusion and capture of xenoliths and xenocrysts of ultramafic or mafic rocks, which may have been in the process of accumulation. This accumulation process is supported by the results of least squares magma mixing models and Rayleigh fractionation curves

Reassembled Art and History: The San Michele in Africisco (Ravenna)Mosaics

Mosaic art gives the appearance of immutability and endurance. The materials and designs often echo or emphasize the architectural forms upon which they are fixed. Mosaics have an aura of permanence that is lacking in drawings, paintings, and frescoes. However, these same materials that present an appearance of solid form are mere fragments of stone or glass set into a base of concrete. As an art dependent on architecture, they are subject to the vicissitudes of time and weather. In the nineteenth century, human intervention in the form of invasive and unenlightened restoration practices arguably halted the deterioration of important mosaics. The result, however, was often irreversible changes to the iconography of the images and to the period style of the original. This paper discusses the church of San Michele in Africisco, Ravenna, highlighting its cultural importance as a sixth-century Byzantine monument. The recounting of its history, followed by two case studies of mosaics workshops in Venice, explain common restorations practices for buildings and their mosaics in the nineteenth century. At that time, foreign interests involved with political and social movements in Germany and England, recognized the crucial need for conservation of Byzantine heritage represented by mosaics and pressed for the establishment of more strenuous regulation and preservation

Building Community Across Colleges

When you include community, nonprofit organizations and university collaboration, students enrich their lives in and out of the classroom. My mission has been to bring community to my colleagues and JWU students university wide. Due to Covid-19, SunRise Forever, Inc. has focused on helping RI residents. As Board Chair of this nonprofit, I have been actively involved in launching a fresh fish project, called “SunRise Fuels with Fish”. A collaboration with the Rhode Island Food Policy Council, the Commercial Fisheries Center of Rhode Island and the African Alliance of Rhode Island to distribute fresh fish to over 300 families weekly

A Study of the Implementation of a Middle School Math Program and Student Achievement

Students who are entering the workplace are required to have middle or high school level skills. Graduates must develop skills in problem -solving and real-world mathematics. The purpose of this study was to determine (a) the extent to which teachers are using Carnegie Learning® for instructional planning, direct instruction, and assessment of students; (b) the extent to which there a statistically significant difference in spring MAP scores of students from spring 2016 to spring 2017 with teachers indicating they frequently use Carnegie Learning®; and (c) the impact of Carnegie Learning® on student achievement in Grades 6, 7, and 8. The theory of Gagne (1985) formed the theoretical foundation for this study. The school district in this study is a suburban school district that includes 27 schools with nearly 18,000 students. Fifty-four percent are Caucasian, 35% are African-American, 6% are Hispanic, 1.5% are Asian, 1.5% are American Indian, and 2% are other. The five middle schools within the school district were included in this study. Thirty middle school mathematics teachers participated in this mixed-method study. There were two phases of this study. Phase 1 included survey Likert scale question responses, and open-end questions were analyzed descriptively. Phase 2 included a paired t test implemented by the researcher using SPSS Statistics software. The final results verified positive correlations and the increased academic achievement of students measured by spring 2016 to spring 2017 MAP scores with teachers indicating they frequently use Carnegie Learning® for instructional planning, direct instruction in the classroom, and assessment of students. This study provides insight to school administrators, policy makers, and mathematics educators in choosing a mathematics program that will enhance student academic performance

Ligand binding dynamics for pre-dimerised G protein-coupled receptor homodimers: Linear models and analytical solutions

Evidence suggests that many G protein-coupled receptors (GPCRs) are bound together forming dimers. The implications of dimerisation for cellular signalling outcomes, and ultimately drug discovery and therapeutics, remain unclear. Consideration of ligand binding and signalling via receptor dimers is therefore required as an addition to classical receptor theory, which is largely built on assumptions of monomeric receptors. A key factor in developing theoretical models of dimer signalling is cooperativity across the dimer, whereby binding of a ligand to one protomer affects the binding of a ligand to the other protomer. Here, we present and analyse linear models for one-ligand and two-ligand binding dynamics at homodimerised receptors, as an essential building block in the development of dimerised receptor theory. For systems at equilibrium, we compute analytical solutions for total bound labeled ligand, and derive conditions on the cooperativity factors underwhich multiphasic log-dose-response curves are expected. This could help explain data extracted from pharmacological experiments that does not fit to the standard Hill curves that are often used in this type of analysis. For the time-dependent problems, we also obtain analytical solutions. For the single-ligand case, the construction of the analytical solution is straightforward; it is bi-exponential in time, sharing a similar structure to the well known monomeric competition dynamics of Motulsky-Mahan. We suggest that this model is therefore practically usable by the pharmacologist towards developing insights into the potential dynamics and consequences of dimerised receptors

Performance of formulae based estimates of glomerular filtration rate for carboplatin dosing in stage 1 seminoma

<b>Background:</b> Single cycle carboplatin, dosed by glomerular filtration rate (GFR), is standard adjuvant therapy for stage 1 seminoma. Accurate measurement of GFR is essential for correct dosing. Isotopic methods remain the gold standard for the determination of GFR. Formulae to estimate GFR have improved the assessment of renal function in non-oncological settings. We assessed the utility of these formulae for carboplatin dosing.<p></p> <b>Methods:</b> We studied consecutive subjects receiving adjuvant carboplatin for stage 1 seminoma at our institution between 2007 and 2012. Subjects underwent 51Cr-ethylene diamine tetra-acetic acid (EDTA) measurement of GFR with carboplatin dose calculated using the Calvert formula. Theoretical carboplatin doses were calculated from estimated GFR using Chronic Kidney Disease-Epidemiology (CKD-EPI), Management of Diet in Renal Disease (MDRD) and Cockcroft–Gault (CG) formulae with additional correction for actual body surface area (BSA). Carboplatin doses calculated by formulae were compared with dose calculated by isotopic GFR; a difference <10% was considered acceptable.<p></p> <b>Results:</b> 115 patients were identified. Mean isotopic GFR was 96.9 ml/min/1.73 m2. CG and CKD-EPI tended to overestimate GFR whereas MDRD tended to underestimate GFR. The CKD-EPI formula had greatest accuracy. The CKD-EPI formula, corrected for actual BSA, performed best; 45.9% of patients received within 10% of correct carboplatin dose. Patients predicted as underdosed (13.5%) by CKD-EPI were more likely to be obese (p = 0.013); there were no predictors of the 40.5% receiving an excess dose.<p></p> <b>Conclusions:</b> Our data support further evaluation of the CKD-EPI formula in this patient population but clinically significant variances in carboplatin dosing occur using non-isotopic methods of GFR estimation. Isotopic determination of GFR should remain the recommended standard for carboplatin dosing when accuracy is essential.<p></p&gt

A Review of Contemporary Diversity Literature in Pharmacy Education

Objective. To review and categorize published educational research concerning diversity within colleges and schools of pharmacy