Comparison of the anticatabolic effects of leucine and Ca-β-hydroxy-β-methylbutyrate in experimental models of cancer cachexia

Objective: Loss of skeletal muscle is the most debilitating feature of cancer cachexia, and there are few treatments available. The aim of this study was to compare the anticatabolic efficacy of L-leucine and the leucine metabolite β-hydroxy-β-methylbutyrate (Ca-HMB) on muscle protein metabolism, both invitro and invivo. Methods: Studies were conducted in mice bearing the cachexia-inducing murine adenocarcinoma 16 tumor, and in murine C2 C12 myotubes exposed to proteolysis-inducing factor, lipopolysaccharide, and angiotensin II. Results: Both leucine and HMB were found to attenuate the increase in protein degradation and the decrease in protein synthesis in murine myotubes induced by proteolysis-inducing factor, lipopolysaccharide, and angiotensin II. However, HMB was more potent than leucine, because HMB at 50 μM produced essentially the same effect as leucine at 1 mM. Both leucine and HMB reduced the activity of the ubiquitin-proteasome pathway as measured by the functional (chymotrypsin-like) enzyme activity of the proteasome in muscle lysates, as well as Western blot quantitation of protein levels of the structural/enzymatic proteasome subunits (20 S and 19 S) and the ubiquitin ligases (MuRF1 and MAFbx). Invivo studies in mice bearing the murine adenocarcinoma 16 tumor showed a low dose of Ca-HMB (0.25 g/kg) tobe 60% more effective than leucine (1 g/kg) in attenuating loss of body weight over a 4-d period. Conclusion: These results favor the clinical feasibility of using Ca-HMB over high doses of leucine for the treatment of cancer cachexia. © 2014 Elsevier Inc.

Nemlineáris dinamika klasszikus növekedési modellekben (Nonlinear dynamics in classical economic growth models)

Ebben a tanulmányban a klasszikus Harrod növekedési modellt nemlineáris kiterjesztéssel, keynesi és schumpeteri tradíciók bevezetésével reprezentatív ügynök modellbe alakítjuk. A híres Lucas kritika igazolásaként megmutatjuk, hogy az intrinsic gazdasági növekedési ütemek trajektóriái vagy egy turbulens káoszba szóródnak szét, vagy egy nagyméretű rendhez vezetnek, ami elsődlegesen a megfelelő fogyasztási függvény típusától függ, s bizonyos paraméterek piaci értékei, pedig csak másodlagos szerepet játszanak. A másik meglepő eredmény empirikus, ami szerint külkereskedelmi többlet, a hazai valuta bizonyos devizapiaci értékei mellett, különös attraktorokat generálhat. _____ In this paper the classical Harrodian growth model is transformed into a representative agent model by its nonlinear extensions and the Keynesian and Schumpeterian traditions. For the proof of the celebrated Lucas critique it is shown that the trajectories of intrinsic economic growth rates either are scattered into a turbulent chaos or lead to a large scale order. It depends on the type of the appropriate consumption function, and the market values of some parameters are playing only secondary role.Another surprising result is empirical: the international trade su±cit may generate strange attractors under some exchange rate values.

Adaptability of nonlinear equilibrum models to central planning

Linear multisectoral models have for long been applied in the Hungarian national economic planning. Price-quantity correspondences and interaction, however, cannot easily be taken into account in the traditional linear framework. Computable general equilibrium modelers in the West have developed techniques which use extensively price-quantity interdependences. However, since they are usually presented with the controversial strict neoclassical interpretation, the possibility of their adaptation to socialist planning models has been concaled. This paper reflects on some results of a research investigating the possible adaptation of eqailibrium modeling techniques to central planning models.

Quantifying the effects of temperature and concentration on variable-density flow in numerical modeling of groundwater systems: Implications for predictive uncertainty and data collection

Groundwater systems of different densities are often mathematically modeled to understand and predict environmental behavior such as seawater intrusion or submarine groundwater discharge. Additional data collection may be justified if it will cost-effectively aid in reducing the uncertainty of a model's prediction. The collection of salinity, as well as, temperature data could aid in reducing predictive uncertainty in a variable-density model. However, before numerical models can be created, rigorous testing of the modeling code needs to be completed. This research documents the benchmark testing of a new modeling code, SEAWAT Version 4. The benchmark problems include various combinations of density-dependent flow resulting from variations in concentration and temperature. The verified code, SEAWAT, was then applied to two different hydrological analyses to explore the capacity of a variable-density model to guide data collection. ^ The first analysis tested a linear method to guide data collection by quantifying the contribution of different data types and locations toward reducing predictive uncertainty in a nonlinear variable-density flow and transport model. The relative contributions of temperature and concentration measurements, at different locations within a simulated carbonate platform, for predicting movement of the saltwater interface were assessed. Results from the method showed that concentration data had greater worth than temperature data in reducing predictive uncertainty in this case. Results also indicated that a linear method could be used to quantify data worth in a nonlinear model. ^ The second hydrological analysis utilized a model to identify the transient response of the salinity, temperature, age, and amount of submarine groundwater discharge to changes in tidal ocean stage, seasonal temperature variations, and different types of geology. The model was compared to multiple kinds of data to (1) calibrate and verify the model, and (2) explore the potential for the model to be used to guide the collection of data using techniques such as electromagnetic resistivity, thermal imagery, and seepage meters. Results indicated that the model can be used to give insight to submarine groundwater discharge and be used to guide data collection. ^

The effects of student -centered and traditional models of teaching on reading skills

A pre-test, post-test, quasi-experimental design was used to examine the effects of student-centered and traditional models of reading instruction on outcomes of literal comprehension and critical thinking skills. The sample for this study consisted of 101 adult students enrolled in a high-level developmental reading course at a large, urban community college in the Southeastern United States. The experimental group consisted of 48 students, and the control group consisted of 53 students. Students in the experimental group were limited in the time spent reading a course text of basic skills, with instructors using supplemental materials such as poems, news articles, and novels. Discussions, the reading-writing connection, and student choice in material selection were also part of the student-centered curriculum. Students in the control group relied heavily on a course text and vocabulary text for reading material, with great focus placed on basic skills. Activities consisted primarily of multiple-choice questioning and quizzes. The instrument used to collect pre-test data was Descriptive Tests of Language Skills in Reading Comprehension; post-test data were taken from the Florida College Basic Skills Exit Test. A MANCOVA was used as the statistical method to determine if either model of instruction led to significantly higher gains in literal comprehension skills or critical thinking skills. A paired samples t-test was also used to compare pre-test and post-test means. The results of the MANCOVA indicated no significant difference between instructional models on scores of literal comprehension and critical thinking. Neither was there any significant difference in scores between subgroups of age (under 25 and 25 and older) and language background (native English speaker and second-language learner). The results of the t-test indicated, however, that students taught under both instructional models made significant gains in on both literal comprehension and critical thinking skills from pre-test to post-test.

Tracking the Effects of Salt Water Encroachment on South Florida Coastal Ecotones Using Mollusks

Many coastal wetland communities of south Florida have been cut off from freshwater sheet flow for decades and are migrating landward due to salt-water encroachment. A paleoecological study using mollusks was conducted to assess the rates and effects of salt-water encroachment due to freshwater diversion and sea level rise on coastal wetland basins in Biscayne National Park. Modem mollusk distributions taken from 226 surface sites were used to determine local habitat affinities which were applied to infer past environments from mollusk distributions found in soil cores. Mollusks species compositions were found to be strongly correlated to habitat and salinity, providing reliable predictions. Wetland soils were cored to bedrock at 36locations. Mollusks were abundant throughout the cores and 15 of the 20 most abundant taxa served as bioindicators of salinity and habitat. Historic accounts coupled with mollusk based inference models indicate (1) increasing salinity levels along the coast and encroaching into the interior with mangroves communities currently migrating westward, (2) replacement of a mixed graminoid-mangrove zone by a dense monoculture of dwarf mangroves, and (3) a confinement of freshwater and freshwater graminoid marsh to landward areas between urban developments and drainage canals.

Investigating the Effects of Cognitive Apprenticeship-Based Instructional Coaching on Science Teaching Efficacy Beliefs

The overall purpose of this collected papers dissertation was to examine the utility of a cognitive apprenticeship-based instructional coaching (CAIC) model for improving the science teaching efficacy beliefs (STEB) of preservice and inservice elementary teachers. Many of these teachers perceive science as a difficult subject and feel inadequately prepared to teach it. However, teacher efficacy beliefs have been noted as the strongest indicator of teacher quality, the variable most highly correlated with student achievement outcomes. The literature is scarce on strong, evidence-based theoretical models for improving STEB. This dissertation is comprised of two studies. STUDY #1 was a sequential explanatory mixed-methods study investigating the impact of a reformed CAIC elementary science methods course on the STEB of 26 preservice teachers. Data were collected using the Science Teaching Efficacy Belief Instrument (STEBI-B) and from six post-course interviews. A statistically significant increase in STEB was observed in the quantitative strand. The qualitative data suggested that the preservice teachers perceived all of the CAIC methods as influential, but the significance of each method depended on their unique needs and abilities. STUDY #2 was a participatory action research case study exploring the utility of a CAIC professional development program for improving the STEB of five Bahamian inservice teachers and their competency in implementing an inquiry-based curriculum. Data were collected from pre- and post-interviews and two focus group interviews. Overall, the inservice teachers perceived the intervention as highly effective. The scaffolding and coaching were the CAIC methods portrayed as most influential in developing their STEB, highlighting the importance of interpersonal relationship aspects in successful instructional coaching programs. The teachers also described the CAIC approach as integral in supporting their learning to implement the new inquiry-based curriculum. The overall findings hold important implications for science education reform, including its potential to influence how preservice teacher training and inservice teacher professional development in science are perceived and implemented. Additionally, given the noteworthy results obtained over the relatively short durations, CAIC interventions may also provide an effective means of achieving improvements in preservice and inservice teachers’ STEB more expeditiously than traditional approaches.

Multilevel structural equation models for longitudinal data where predictors are measured more frequently than outcomes : an application to the effects of stress on the cognitive function of nurses

Funded by Chief Scientist Office, Scotland. Grant Number: CZH/4/394 Economic and Social Research Council grant as part of the National Centre for Research Methods. Grant Number: RES-576-25-0032

The Effects of Brominated Flame Retardants on Thyroid Hormone Homeostasis in Human Placenta Tissues and Cell Culture

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants (BFRs) that have been heavily used in consumer products such as furniture foams, plastics, and textiles since the mid-1970’s. BFRs are added to products in order to meet state flammability standards intended to increase indoor safety in the event of a fire. The three commercial PBDE mixtures, Penta-, Octa-, and DecaBDE, have all been banned in the United States, however, limited use of DecaBDE is still permitted. PBDEs were phased out of production and added to the Stockholm Convention due to concerns over their environmental persistence and toxicity. Human exposure to PBDEs occurs primarily through the inadvertent ingestion of contaminated house dust, as well as though dietary sources. Despite the phase-out and discontinued use of PBDEs, human exposure to this class of chemicals is likely to continue for decades due to the continued use of treated products and existing environmental reservoirs of PBDEs. Extensive research over the years has shown that PBDEs disrupt thyroid hormone (TH) levels and neurodevelopmental endpoints in rodent and fish models. Additionally, there is growing epidemiological evidence linking PBDE exposure in humans to altered TH homeostasis and neurodevelopmental impairments in children. Due to the importance of THs throughout gestation, there is a great need to understand the effects of BFRs on the developing fetus. Specifically, the placenta plays a critical role in the transport, metabolism, and delivery of THs to the fetal compartment during pregnancy and is a likely target for BFR bioaccumulation and endocrine disruption. The central hypothesis of this dissertation research is that BFRs disrupt the activity of TH sulfotransferase (SULT) enzymes, thereby altering TH concentrations in the placenta.

In the first aim of this dissertation research, the concentrations of PBDEs and 2,4,6-TBP were measured in a cohort of 102 placenta tissue samples from an ongoing pregnancy cohort in Durham, NC. Methods were developed for the extraction and analysis of the BFR analytes. It was found that 2,4,6-TBP was significantly correlated with all PBDE analytes, indicating that 2,4,6-TBP may share common product applications with PBDEs or that 2,4,6-TBP is a metabolite of PBDE compounds. Additionally, this was the first study to measure 2,4,6-TBP in human placenta tissues.

In the second aim of this dissertation research, the placenta tissue concentrations of THs, as well as the endogenous activity of deiodinase (DI) and TH SULT enzymes were quantified using the same cohort of 102 placenta tissue samples. Enzyme activity was detected in all samples and this was the first study to measure TH DI and SULT activity in human placenta tissues. Enzyme activities and TH concentrations were compared with BFR concentrations measured in Aim 1. There were few statistically significant associations observed for the combined data, however, upon stratifying the data set based on infant sex, additional significant associations were observed. For example, among males, those with the highest concentrations of BDE-99 in placenta had T3 levels 0.80 times those with the lowest concentration of BDE-99 (95% confidence interval (CI): 0.59, 1.07). Whereas females with the highest concentrations of BDE-99 in placenta had T3 levels 1.50 times those with the lowest concentration of BDE-99 (95% CI: 1.10, 2.04). Additionally, all BFR analyte concentrations were higher in the placenta of males versus females and they were significantly higher for 2,4,6-TBP and BDE-209. 3,3’-T2 SULT activity was significantly higher in female placenta tissues, while type 3 DI activity was significantly higher in male placenta tissues. This research is the first to show sex-specific differences in the bioaccumulation of BFRs in human placenta tissue, as well as differences in TH concentrations and endogenous DI and SULT activity. The underlying mechanisms of these observed sex differences warrant further investigation.

In the third aim of this dissertation research, the effects of BFRs were examined in a human choriocarcinoma placenta cell line, BeWo. Michaelis-Menten parameters and inhibition curves were calculated for 2,4,6-TBP, 3-OH BDE-47, and 6-OH BDE-47. 2,4,6-TBP was shown to be the most potent inhibitor of 3,3’-T2 SULT activity with a calculated IC50 value of 11.6 nM. It was also shown that 2,4,6-TBP and 3-OH BDE-47 exhibit mixed inhibition of 3,3’-T2 sulfation in BeWo cell homogenates. Next, a series of cell culture exposure experiments were performed using 1, 6, 12, and 24 hour exposure durations. Once again, 2,4,6-TBP was shown to be the most potent inhibitor of basal 3,3’-T2 SULT activity by significantly decreasing activity at the high and medium dose (1 M and 0.5 M, respectively) at all measured time points. Interestingly, BDE-99 was also shown to inhibit basal 3,3’-T2 SULT activity in BeWo cells following the 24 hour exposure, despite exhibiting no inhibitory effects in the BeWo cell homogenate experiments. This indicates that BDE-99 must act through a pathway other than direct enzyme inhibition. Following exposures, the TH concentrations in the cell culture growth media and mRNA expression of TH-related genes were also examined. There was no observed effect of BFR treatment on these endpoints. Future work should focus on determining the downstream biological effects of TH SULT disruption in placental cells, as well as the underlying mechanisms of action responsible for reductions in basal TH SULT activity following BFR exposure.

This was one of the first studies to measure BFRs in a cohort of placenta tissue samples from the United States and the first study to measure THs, DI activity, and SULT activity in human placenta tissues. This research provides a novel contribution to our growing understanding of the effects of BFRs on TH homeostasis within the human placenta, and provides further evidence for sex-specific differences within this important organ. Future research should continue to investigate the effects of environmental contaminants on TH homeostasis within the placenta, as this represents the most critical and vulnerable stage of human development.

Outlier effects on robust joint modelling of longitudinal and survival data

Robust joint modelling is an emerging field of research. Through the advancements in electronic patient healthcare records, the popularly of joint modelling approaches has grown rapidly in recent years providing simultaneous analysis of longitudinal and survival data. This research advances previous work through the development of a novel robust joint modelling methodology for one of the most common types of standard joint models, that which links a linear mixed model with a Cox proportional hazards model. Through t-distributional assumptions, longitudinal outliers are accommodated with their detrimental impact being down weighed and thus providing more efficient and reliable estimates. The robust joint modelling technique and its major benefits are showcased through the analysis of Northern Irish end stage renal disease patients. With an ageing population and growing prevalence of chronic kidney disease within the United Kingdom, there is a pressing demand to investigate the detrimental relationship between the changing haemoglobin levels of haemodialysis patients and their survival. As outliers within the NI renal data were found to have significantly worse survival, identification of outlying individuals through robust joint modelling may aid nephrologists to improve patient's survival. A simulation study was also undertaken to explore the difference between robust and standard joint models in the presence of increasing proportions and extremity of longitudinal outliers. More efficient and reliable estimates were obtained by robust joint models with increasing contrast between the robust and standard joint models when a greater proportion of more extreme outliers are present. Through illustration of the gains in efficiency and reliability of parameters when outliers exist, the potential of robust joint modelling is evident. The research presented in this thesis highlights the benefits and stresses the need to utilise a more robust approach to joint modelling in the presence of longitudinal outliers.

Investigation of the effects of flow conditions at rotor inlet on mixed flow turbine performance for automotive applications

Current trends in the automotive industry have placed increased importance on engine downsizing for passenger vehicles. Engine downsizing often results in reduced power output and turbochargers have been relied upon to restore the power output and maintain drivability. As improved power output is required across a wide range of engine operating conditions, it is necessary for the turbocharger to operate effectively at both design and off-design conditions. One off-design condition of considerable importance for turbocharger turbines is low velocity ratio operation, which refers to the combination of high exhaust gas velocity and low turbine rotational speed. Conventional radial flow turbines are constrained to achieve peak efficiency at the relatively high velocity ratio of 0.7, due the requirement to maintain a zero inlet blade angle for structural reasons. Several methods exist to potentially shift turbine peak efficiency to lower velocity ratios. One method is to utilize a mixed flow turbine as an alternative to a radial flow turbine. In addition to radial and circumferential components, the flow entering a mixed flow turbine also has an axial component. This allows the flow to experience a non-zero inlet blade angle, potentially shifting peak efficiency to a lower velocity ratio when compared to an equivalent radial flow turbine.
This study examined the effects of varying the flow conditions at the inlet to a mixed flow turbine and evaluated the subsequent impact on performance. The primary parameters examined were average inlet flow angle, the spanwise distribution of flow angle across the inlet and inlet flow cone angle. The results have indicated that the inlet flow angle significantly influenced the degree of reaction across the rotor and the turbine efficiency. The rotor studied was a custom in-house design based on a state-of-the-art radial flow turbine design. A numerical approach was used as the basis for this investigation and the numerical model has been validated against experimental data obtained from the cold flow turbine test rig at Queen’s University Belfast. The results of the study have provided a useful insight into how the flow conditions at rotor inlet influence the performance of a mixed flow turbine.

Big bang bifurcations in von Bertalanffy’s dynamics with strong and weak Allee effects

The main purpose of this work was to study population dynamic discrete models in which the growth of the population is described by generalized von Bertalanffy's functions, with an adjustment or correction factor of polynomial type. The consideration of this correction factor is made with the aim to introduce the Allee effect. To the class of generalized von Bertalanffy's functions is identified and characterized subclasses of strong and weak Allee's functions and functions with no Allee effect. This classification is founded on the concepts of strong and weak Allee's effects to population growth rates associated. A complete description of the dynamic behavior is given, where we provide necessary conditions for the occurrence of unconditional and essential extinction types. The bifurcation structures of the parameter plane are analyzed regarding the evolution of the Allee limit with the aim to understand how the transition from strong Allee effect to no Allee effect, passing through the weak Allee effect, is realized. To generalized von Bertalanffy's functions with strong and weak Allee effects is identified an Allee's effect region, to which is associated the concepts of chaotic semistability curve and Allee's bifurcation point. We verified that under some sufficient conditions, generalized von Bertalanffy's functions have a particular bifurcation structure: the big bang bifurcations of the so-called box-within-a-box type. To this family of maps, the Allee bifurcation points and the big bang bifurcation points are characterized by the symmetric of Allee's limit and by a null intrinsic growth rate. The present paper is also a significant contribution in the framework of the big bang bifurcation analysis for continuous 1D maps and unveil their relationship with the explosion birth and the extinction phenomena.