Doctor of Philosophy

dissertationThe objective of this body of research was to (1) survey current self-management skills and treatment knowledge in patients with phenylketonuria (PKU) and (2) evaluate self-efficacy, patient activation, dietary adherence, and blood phenylalanine (Phe) levels in individuals with PKU before and after a 6-month motivational interviewing (MI) intervention. Patients with PKU aged 7-30 years (n=43) completed one of three age-specific self-management questionnaires during standard metabolic clinic appointments and were invited to participate. Separately, patients with PKU aged 7-35 years (n=31) participated in a 6-month intervention including phone-based MI, goal setting, and a monthly summary. Participants completed stage of change (SOC), self-efficacy, patient activation, and food frequency questionnaires online and obtained monthly blood Phe samples. Demographic data were collected from the electronic medical record. We considered p0.01 for all) with only approximately half of adults meeting clinical recommendations. Higher self-management skills and treatment knowledge were not associated with lower blood Phe levels (R2=0.249, p=0.025), which may reflect the small sample size. Most participants were in the action/maintenance SOC for PKU treatment behaviors during the 6-month MI intervention. Self-efficacy significantly increased from baseline (7.4±1.9) to month 6 (8.6±1.3) among adolescent and adult participants (p=0.002). There was no increase in patient activation (p=0.10) or dietary adherence, though most (n=28/31) reported adherence to medical formula at baseline. Pre-intervention blood Phe slope for all participants (β=0.71) was not significantly different from the intervention slope (β=0.26, p=0.13). Higher baseline SOC (β=-61.6, p=0.005) and increasing self-efficacy (β=-64.5, p<0.001) were associated with a decreased blood Phe slope. Self-management skills were lower than clinically recommended and did not consistently increase with age. We demonstrated a significant increase in self-efficacy with MI and, in turn, higher self-efficacy was associated with a reduction in blood Phe levels. Our results suggest strategies to support self-management and increase motivation for behavior change are necessary. Phone-based MI is feasible with a PKU population has potential to increase confidence to engage in self-management behaviors

Correlation of Age-Specific Phenylalanine Levels on Intellectual Outcome in Patients with Phenylketonuria

It is widely appreciated by the medical community that subtle deficits in intellect, academic skills and executive functioning exist in early treated phenylketonuria (PKU). In this study, we described the relationship between intellectual outcome and concentration/variation in blood phenylalanine (Phe) during specific developmental periods (0-5 years, 6-10 years, \u3e10 years). We also examined the association between mean number of blood Phe samples and maintenance of Phe within treatment range (120-360 ìmol/L) and within one standard deviation (SD) of index of dietary control, defined as the mean of 12-month median Phe. Retrospective data was collected from 55 patients receiving treatment at the University of Utah Metabolic Clinic. Index of dietary control (IDC) and SD blood Phe steadily increased and mean number of samples decreased during each developmental period. The correlation between IDC during 6-10 years of life and perceptual reasoning was -.370 (p = 0.006). Using multivariate linear regression, IDC during 0-5 years and 6-10 years were associated with a 0.5-point decrease and 0.3-point decrease in perceptual reasoning scores for every 100 ìmol/L increase in blood Phe, though associations were nonsignificant (p = 0.067; 0.082). SD of Phe was not associated with any measure of intelligence. The likelihood of IDC \u3e360 ìmol/L in those 6-10 years was 32.3% lower for each additional blood Phe sample per year (p = 0.001). The present study suggests frequent blood Phe monitoring during ages 6-10 years may reduce blood Phe and prevent deficits in perceptual reasoning later in life

Specific in vivo deletion of B-cell subpopulations expressing human immunoglobulins by the B-cell superantigen protein L

Some pathogens have evolved to produce proteins, called B-cell superantigens, that can interact with human immunoglobulin variable regions, independently of the combining site, and activate B lymphocytes that express the target immunoglobulins. However, the in vivo consequences of these interactions on human B-cell numbers and function are largely unknown. Using transgenic mice expressing fully human immunoglobulins, we studied the consequences of in vivo exposure of protein L of Peptostreptococcus magnus with human immunoglobulins. In the mature pool of B cells, protein L exposure resulted in a specific reduction of splenic marginal-zone B cells and peritoneal B-1 cells. Splenic B cells exhibited a skewed light-chain repertoire consistent with the capacity of protein L to bind specific kappa gene products. Remarkably, these two B-cell subsets are implicated in innate B-cell immunity, allowing rapid clearance of pathogens. Thus, the present study reveals a novel mechanism that may be used by some infectious agents to subvert a first line of the host's immune defense

Impact behavior of injected PP/nanoclay parts

This work attempts to contribute to bridge the gap between scientific challenges and industrial stakes regarding PP/nanoclay composites. Pieces of nanocomposites were obtained by direct injection of commercial PP mixed with a commercial MB of PP with 50% of organoclay, with a double-gated hot runner mould, which produced mouldings with a weld line. The moulding microstructure was assessed by POM and XRD, while the distribution and exfoliation grade of clay was evaluated by TEM and XRD. The typical skin-core structure was found, with a skin thickness wider in bulk than in weld line zones. Regarding clay platelets mostly intercalated structures were seen. The impact properties at room temperature were assessed by means of tensile and biaxial tests. Properties were monitored at different sites of the mouldings. At the weld line zone less energy was consumed under tensile conditions and exhibited higher apparent impact toughness under biaxial conditions than the bulk zone. Visual inspection of biaxially impacted samples showed that the orientation of polymer molecules and clay platelets induced by melt flow prevailed, and the weld line was not the determinant of the toughness of the mouldings. An optimum in impact performance was found for moulding with 3% of clay, since at larger clay contents platelets agglomerated and acted as stress raisers

Uni- and biaxial impact behavior of double-gated nanoclay-reinforced polypropylene injection moldings

Polypopylene/nanoclay three-dimensional parts were produced without intermediate steps by direct injection molding to explore the influence of flow features and nanoclay incorporation in their impact performance. The nanocomposite was obtained by direct compounding of commercial PP with nanoclay masterbatch. The as-molded morphology was analyzed by X-ray and TEM analyses in terms of skin-core structure and nanoclay particle dispersion. The nanoclay particles induced the reduction of b-form spherulites, a known toughener. The impact behavior was assessed in tensile and biaxial modes. The PP nanocomposite molding toughness was practically unaffected by the processing melt temperature and flow rate. Conversely the nanoclay presence is influent in the impact performance. Under biaxial stress impact, the regions close to weld lines are tougher than the bulk and the fracture develops with main crack paths along the flow direction and the weld line. Cracking along the weld line results from less macromolecular interpenetration and chain entanglement, and unfavorable nanoparticle orientation. It seems that a failure mechanism which involves nanoclay delamination and multiple matrix crazing explains the toughening of PP in the directions where the nanoparticle orientation with respect to loading is adequate.Contract grant sponsors: CONICET, ANPCyT from Argentina, MINCyT (Argentina) - FCT (Portugal), Universities Nacional de Mar del Plata and Minho

Radiative transfer and the energy equation in SPH simulations of star formation

We introduce and test a new and highly efficient method for treating the thermal and radiative effects influencing the energy equation in SPH simulations of star formation. The method uses the density, temperature and gravitational potential of each particle to estimate a mean optical depth, which then regulates the particle's heating and cooling. The method captures -- at minimal computational cost -- the effects of (i) the rotational and vibrational degrees of freedom of H2, H2 dissociation, H0 ionisation, (ii) opacity changes due to ice mantle melting, sublimation of dust, molecular lines, H-, bound-free and free-free processes and electron scattering; (iv) external irradiation; and (v) thermal inertia. The new algorithm reproduces the results of previous authors and/or known analytic solutions. The computational cost is comparable to a standard SPH simulation with a simple barotropic equation of state. The method is easy to implement, can be applied to both particle- and grid-based codes, and handles optical depths 0<tau<10^{11}.Comment: Submitted to A&A, recommended for publicatio

Tuning complex shapes in Pt(0) nanoparticles : from cubic dendrites to five-fold stars

A platinum star performance: Quasi-single-crystalline Pt nanoparticles with peculiar morphologies—cubic dendrites, planar tripods, and fivefold stars—were synthesized in high yield. Shape selectivity was achieved by finely tuning the growth kinetics under a dihydrogen atmosphere

Impacts of the Last Glacial Cycle on ground surface temperature reconstructions over the last millennium

Borehole temperature profiles provide robust estimates of past ground surface temperature changes, in agreement with meteorological data. Nevertheless, past climatic changes such as the Last Glacial Cycle (LGC) generated thermal effects in the subsurface that affect estimates of recent climatic change from geothermal data. We use an ensemble of ice sheet simulations spanning the last 120 ka to assess the impact of the Laurentide Ice Sheet on recent ground surface temperature histories reconstructed from borehole temperature profiles over North America. When the thermal remnants of the LGC are removed, we find larger amounts of subsurface heat storage (2.8 times) and an increased warming of the ground surface over North America by 0.75 K, both relative to uncorrected borehole estimates

Stat3 controls tubolointerstitial communication during CKD

Functional Genomics of Systemic Disorder

Tuning the 3D microenvironment of reprogrammed tubule cells enhances biomimetic modeling of polycystic kidney disease

Renal tubular cells frequently lose differentiation markers and physiological properties when propagated in conventional cell culture conditions. Embedding cells in 3D microenvironments or controlling their 3D assembly by bioprinting can enhance their physiological properties, which is beneficial for modeling diseases in vitro. A potential cellular source for modeling renal tubular physiology and kidney diseases in vitro are directly reprogrammed induced renal tubular epithelial cells (iRECs). iRECs were cultured in various biomaterials and as bioprinted tubular structures. They showed high compatibility with the embedding substrates and dispensing methods. The morphology of multicellular aggregates was substantially influenced by the 3D microenvironment. Transcriptomic analyses revealed signatures of differentially expressed genes specific to each of the selected biomaterials. Using a new cellular model for autosomal-dominant polycystic kidney disease, Pkd1$^{-/-}$ iRECs showed disrupted morphology in bioprinted tubules and a marked upregulation of the Aldehyde dehydrogenase 1a1 (Aldh1a1). In conclusion, 3D microenvironments strongly influence the morphology and expression profiles of iRECs, help to unmask disease phenotypes, and can be adapted to experimental demands. Combining a direct reprogramming approach with appropriate biomaterials will facilitate construction of biomimetic kidney tubules and disease models at the microscale