Characterization of the degradation of wild-type and mutant HFE proteins during stress signalling in the endoplasmic reticulum

HFE is a transmembrane protein that becomes N-glycosylated during transport to the cell membrane. It acts to regulate cellular iron uptake by interacting with the Type 1 transferrin receptor and interfering with its ability to bind iron-loaded transferrin. There is also evidence that HFE regulates systemic iron levels by binding to the Type II transferrin receptor although the mechanism by which this occurs is still not well understood. Mutations to HFE that disrupt this function, or physiological conditions that decrease HFE protein levels, are associated with increased iron uptake, and its accumulation in tissues and organs. This is exemplified by the point mutation that results in conversion of cysteine residue 282 to tyrosine (C282Y), and gives rise to the majority of HFE-related hemochromatoses. The C282Y mutation prevents the formation of a disulfide bridge and disrupts the interaction with its co-chaperone β2-microglobulin. The resulting misfolded protein is retained within the endoplasmic reticulum (ER) where it activates the Unfolded Protein Response (UPR) and is subjected to proteasomal degradation. The absence of functional HFE at the cell surface leads to unregulated iron uptake and iron loading. While the E3 ubiquitin ligase involved in the degradation of HFE-C282Y has been identified, the mechanism by which it is targeted for degradation remains relatively obscure. The primary objective of this project was to further our understanding of how the iron regulatory HFE protein is targeted for degradation. Our studies suggest that the glycosylation status, and the active process of deglycosylation, are central to this process. We identified a number of additional factors that can contribute towards degradation and explored their regulation during ER stress conditions.

Leisure and surveillance in Irish childhoods: A cross-class study of Cork city

This research provides an interpretive cross-class analysis of the leisure experience of children, aged between six and ten years, living in Cork city. This study focuses on the cultural dispositions underpinning parental decisions in relation to children’s leisure activities, with a particular emphasis on their child-surveillance practices. In this research, child-surveillance is defined as the adult monitoring of children by technological means, physical supervision, community supervision, or adult supervised activities (Nelson, 2010; Lareau, 2003; Fotel and Thomsen, 2004). This research adds significantly to understandings of Irish childhood by providing the first in-depth qualitative analysis of the surveillance of children’s leisure-time. Since the 1990s, international research on children has highlighted the increasingly structured nature of children’s leisure-time (Lareau, 2011; Valentine & McKendrick, 1997). Furthermore, research on child-surveillance has found an increase in the intensive supervision of children during their unstructured leisure-time (Nelson, 2010; Furedi, 2008; Fotel and Thomsen, 2004). This research bridges the gap between these two key bodies of literature, providing a more integrated overview of children’s experience of leisure in Ireland. Using Bourdieu’s (1992) model of habitus, field and capital, the dispositions that shape parents’ decisions about their children’s leisure time are interrogated. The holistic view of childhood adopted in this research echoes the ‘Whole Child Approach’ by analysing the child’s experience within a wider set of social relationships including family, school, and community. Underpinned by James and Prout’s (1990) paradigm on childhood, this study considers Irish children’s agency in negotiating with parents’ decisions regarding leisure-time. The data collated in this study enhances our understanding of the micro-interactions between parents and children and, the ability of the child to shape their own experience. Moreover, this is the first Irish sociological research to identify and discuss class distinctions in children’s agentic potential during leisure-time.

Exploring the relationship between social network sites and the consumption of cultural goods through the lens of affordances

This thesis presents research theorising the use of social network sites (SNS) for the consumption of cultural goods. SNS are Internet-based applications that enable people to connect, interact, discover, and share user-generated content. They have transformed communication practices and are facilitating users to present their identity online through the disclosure of information on a profile. SNS are especially effective for propagating content far and wide within a network of connections. Cultural goods constitute hedonic experiential goods with cultural, artistic, and entertainment value, such as music, books, films, and fashion. Their consumption is culturally dependant and they have unique characteristics that distinguish them from utilitarian products. The way in which users express their identity on SNS is through the sharing of cultural interests and tastes. This makes cultural good consumption vulnerable to the exchange of content and ideas that occurs across an expansive network of connections within these social systems. This study proposes the lens of affordances to theorise the use of social network sites for the consumption of cultural goods. Qualitative case study research using two phases of data collection is proposed in the application of affordances to the research topic. The interaction between task, technology, and user characteristics is investigated by examining each characteristic in detail, before investigating the actual interaction between the user and the artifact for a particular purpose. The study contributes to knowledge by (i) improving our understanding of the affordances of social network sites for the consumption of cultural goods, (ii) demonstrating the role of task, technology and user characteristics in mediating user behaviour for user-artifact interactions, (iii) explaining the technical features and user activities important to the process of consuming cultural goods using social network sites, and (iv) theorising the consumption of cultural goods using SNS by presenting a theoretical research model which identifies empirical indicators of model constructs and maps out affordance dependencies and hierarchies. The study also provides a systematic research process for applying the concept of affordances to the study of system use.

First principles simulation of amorphous silicon bulk, interfaces, and nanowires for photovoltaics

Amorphous silicon has become the material of choice for many technologies, with major applications in large area electronics: displays, image sensing and thin film photovoltaic cells. This technology development has occurred because amorphous silicon is a thin film semiconductor that can be deposited on large, low cost substrates using low temperature. In this thesis, classical molecular dynamics and first principles DFT calculations have been performed to generate structural models of amorphous and hydrogenated amorphous silicon and interfaces of amorphous and crystalline silicon, with the ultimate aim of understanding the photovoltaic properties of core-shell crystalline amorphous Si nanowire structures. We have shown, unexpectedly, from the simulations, that our understanding of hydrogenated bulk a-Si needs to be revisited, with our robust finding that when fully saturated with hydrogen, bulk a-Si exhibits a constant optical energy gap, irrespective of the hydrogen concentration in the sample. Unsaturated a-Si:H, with a lower than optimum hydrogen content, shows a smaller optical gap, that increases with hydrogen content until saturation is reached. The mobility gaps obtained from an analysis of the electronic states show similar behavior. We also obtained that the optical and mobility gaps show a volcano curve as the H content is varied from 7% (undersaturation) to 18% (mild oversaturation). In the case of mild over saturation, the mid-gap states arise exclusively from an increase in the density of strained Si-Si bonds. Analysis of our structures shows the extra H atoms in this case form a bridge between neighboring silicon atoms which increases the corresponding Si-Si distance and promotes bond length disorder in the sample. That has the potential to enhance the Staebler-Wronski effect. Planar interface models of amorphous-crystalline silicon have been generated in Si (100), (110) and (111) surfaces. The interface models are characterized by structure, RDF, electronic density of states and optical absorption spectrum. We find that the least stable (100) surface will result in the formation of the thickest amorphous silicon layer, while the most stable (110) surface forms the smallest amorphous region. We calculated for the first time band offsets of a-Si:H/c-Si heterojunctions from first principles and examined the influence of different surface orientations and amorphous layer thickness on the offsets and implications for device performance. The band offsets depend on the amorphous layer thickness and increase with thickness. By controlling the amorphous layer thickness we can potentially optimise the solar cell parameters. Finally, we have successfully generated different amorphous layer thickness of the a-Si/c-Si and a-Si:H/c-Si 5 nm nanowires from heat and quench. We perform structural analysis of the a-Si-/c-Si nanowires. The RDF, Si-Si bond length distributions, and the coordination number distributions of amorphous regions of the nanowires reproduce similar behaviour compared to bulk amorphous silicon. In the final part of this thesis we examine different surface terminating chemical groups, -H, - OH and –NH2 in (001) GeNW. Our work shows that the diameter of Ge nanowires and the nature of surface terminating groups both play a significant role in both the magnitude and the nature of the nanowire band gaps, allowing tuning of the band gap by up to 1.1 eV. We also show for the first time how the nanowire diameter and surface termination shifts the absorption edge in the Ge nanowires to longer wavelengths. Thus, the combination of nanowire diameter and surface chemistry can be effectively utilised to tune the band gaps and thus light absorption properties of small diameter Ge nanowires.

Metabolism of host-derived carbohydrates by Bifidobacterium breve UCC2003

Bifidobacteria are Gram positive, anaerobic, typically Y-shaped bacteria which are naturally found in the digestive tract of certain mammals, birds and insects. Bifidobacterium breve strains are numerically prevalent among the gut microbiota of many healthy breast-fed infants. The prototypical B. breve strain UCC2003 has previously been shown to utilise numerous carbohydrates of plant origin. Various aspects of host-derived carbohydrate metabolism occurring in this bacterium will be described in this thesis. Chapter II describes B. breve UCC2003 utilisation of sialic acid, a nine-carbon monosaccharide, which is found in human milk oligosaccharides (HMOs) and the mucin glycoprotein. B. breve UCC2003 was also shown to cross-feed on sialic acid released from 3’ sialyllactose, a prominent HMO, by the extracellular sialidase activity of Bifidobacterium bifidum PRL2010. Chapter III reports on the transcriptional regulation of sialic acid metabolism in B. breve UCC2003 by a transcriptional repressor encoded by the nanR gene. NanR belongs to the GntR-family of transcriptional regulators and represents the first bifidobacterial member of this family to be characterised. Chapter IV investigates B. breve UCC2003 utilisation of mucin. B. breve UCC2003 was shown to be incapable of degrading mucin; however when grown in co-culture with B. bifidum PRL2010 it exhibits enhanced growth and survival properties. A number of methods were used to investigate and identify the mucin components supporting this enhanced growth/viability phenotype. Chapter V describes the characterisation of two sulfatase-encoding gene clusters from B. breve UCC2003. The transcriptional regulation of both sulfatase-encoding gene clusters was also investigated. The work presented in this thesis represents new information on the metabolism of host-derived carbohydrates in bifidobacteria, thus increasing our understanding of how these gut commensals are able to colonise and persist in the gastrointestinal tract.

Cancer associated malnutrition: prevalence of cachexia, sarcopenia and impact on treatment outcomes, survival and health related quality of life

Malnutrition, sarcopenia and cancer cachexia (CC) are prevalent among cancer patients and can have detrimental effects on clinical outcomes such as quality of life (QoL) and overall survival. Cachexia is associated with lower tolerance for chemotherapy, which limits the total dose that can be delivered, the number of symptomatic responses and any survival advantage that might be accrued. Moreover, for the majority who do not respond, cachexia may be exacerbated by systemic chemotherapy, thus increasing the net symptom burden experienced by patients. The multitude of interactions between cancer location, treatments, nutritional status and QoL has never been thoroughly explored in an Irish cancer cohort. The objectives of this thesis were to further understand nutritional status, especially body composition in ambulatory cancer patients and determine the relationship between nutritional status using different assessment criteria and QoL, chemotherapy toxicity and survival among cancer patients undergoing chemotherapy. Results aimed to identify baseline factors that may be predictive of poor outcome, toxicities to chemotherapy and disease-free and overall survival. This thesis broadly divides into two sections. The first section (Chapters 3 & 4) focuses on improving our knowledge of the nutritional status of Irish cancer outpatients using a cross sectional study design. A study of 517 patients referred for chemotherapy was conducted using computed tomography (CT) imaging (body composition) and a survey that documented oncologic data, weight loss (WL) data and QoL data. We revealed that a significant proportion of Irish cancer patients undergoing chemotherapy experience unintentional WL over the previous 6 months (62%), sarcopenia (45%) and CC (43%), and the distribution of WL and nutritional risk were associated with site of primary tumour and treatment intent. Patients that had sarcopenia, nutritional risk, or CC had significantly reduced functional abilities, more symptoms and adverse global QoL. In the second section of this thesis (Chapters 5 & 6) the potential link between developing toxicity to antineoplastic regimens in patients with sarcopenia was conducted by way of retrospective studies. A retrospective serial CT analysis defined the prevalence of sarcopenia in patients with metastatic renal cell carcinoma (mRCC) and metastatic castrate resistant prostate cancer (mCRPC), which was then correlated with dose limiting toxicities of sunitinib and docetaxel respectively. Sarcopenia was prevalent in patients with mRCC and mCRPC, was an occult condition in patients with normal/high BMI, was associated with less treatment days, was a significant predictor of DLT in patients receiving sunitinib and a significant predictor of neutropenia and neurosensory toxicities in patients receiving docetaxel. This thesis attempted to address the underlying research deficiencies in Irish oncology nutritional data at national level. The findings from this thesis have implications for the planning of cancer care interventions and indicate that further research is required to improve nutritional screening, in particular for CC and sarcopenia, in the hope that timely intervention can improve both patient-centered and oncologic outcomes.

Self-organized vegetation patterning as a fingerprint of climate and human impact on semi-arid ecosystems

Spatially periodic vegetation patterns are well known in arid and semi-arid regions around the world. Mathematical models have been developed that attribute this phenomenon to a symmetry-breaking instability. Such models are based on the interplay between competitive and facilitative influences that the vegetation exerts on its own dynamics when it is constrained by arid conditions, but evidence for these predictions is still lacking. Moreover, not all models can account for the development of regularly spaced spots of bare ground in the absence of a soil prepattern. We applied Fourier analysis to high-resolution, remotely sensed data taken at either end of a 40-year interval in southern Niger. Statistical comparisons based on this textural characterization gave us broad-scale evidence that the decrease in rainfall over recent decades in the sub-Saharan Sahel has been accompanied by a detectable shift from homogeneous vegetation cover to spotted patterns marked by a spatial frequency of about 20 cycles km-1. Wood cutting and grazing by domestic animals have led to a much more marked transition in unprotected areas than in a protected reserve. Field measurements demonstrated that the dominant spatial frequency was endogenous rather than reflecting the spatial variation of any pre-existing heterogeneity in soil properties. All these results support the use of models that can account for periodic vegetation patterns without invoking substrate heterogeneity or anisotropy, and provide new elements for further developments, refinements and tests. This study underlines the potential of studying vegetation pattern properties for monitoring climatic and human impacts on the extensive fragile areas bordering hot deserts. Explicit consideration of vegetation self-patterning may also improve our understanding of vegetation and climate interactions in arid areas. © 2006 The Authors.

Corporate Bond Market in the Transition Economy of Vietnam, 1990-2010

Corporate bond appeared early in 1992-1994 in Vietnamese capital markets. However, it is still not popular to both business sector and academic circle. This paper explores different dimensions of Vietnamese corporate bond market using a unique, and perhaps, most complete dataset. State not only intervenes in the bond markets with its powerful budget and policies but also competes directly with enterprises. The dominance of SOEs and large corporations also prevents SMEs from this debt financing vehicle. Whenever a convertible term is available, bondholders are more willing to accept lower fixed income payoff. But they would not likely stick to it. On one hand, prospective bondholders could value the holdings of equity when realized favorably ex ante. On the other hand, the applicable coupon rate for such bond could turn out negative inflationadjusted payoff when tight monetary policy is exercised and the corresponding equity holding turns out valueless, ex post. Given the weak primary market and virtually nonexistent secondary market, the corporate bond market in Vietnam reflects our perception of the relationship-based and rent-seeking behavior in the financial markets. For the corporate bonds to really work, they critically need a higher level of liquidity to become truly tradable financial assets.

A mathematical theory of stochastic microlensing. II. Random images, shear, and the Kac-Rice formula

Continuing our development of a mathematical theory of stochastic microlensing, we study the random shear and expected number of random lensed images of different types. In particular, we characterize the first three leading terms in the asymptotic expression of the joint probability density function (pdf) of the random shear tensor due to point masses in the limit of an infinite number of stars. Up to this order, the pdf depends on the magnitude of the shear tensor, the optical depth, and the mean number of stars through a combination of radial position and the star's mass. As a consequence, the pdf's of the shear components are seen to converge, in the limit of an infinite number of stars, to shifted Cauchy distributions, which shows that the shear components have heavy tails in that limit. The asymptotic pdf of the shear magnitude in the limit of an infinite number of stars is also presented. All the results on the random microlensing shear are given for a general point in the lens plane. Extending to the general random distributions (not necessarily uniform) of the lenses, we employ the Kac-Rice formula and Morse theory to deduce general formulas for the expected total number of images and the expected number of saddle images. We further generalize these results by considering random sources defined on a countable compact covering of the light source plane. This is done to introduce the notion of global expected number of positive parity images due to a general lensing map. Applying the result to microlensing, we calculate the asymptotic global expected number of minimum images in the limit of an infinite number of stars, where the stars are uniformly distributed. This global expectation is bounded, while the global expected number of images and the global expected number of saddle images diverge as the order of the number of stars. © 2009 American Institute of Physics.

Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.

The computational detection of regulatory elements in DNA is a difficult but important problem impacting our progress in understanding the complex nature of eukaryotic gene regulation. Attempts to utilize cross-species conservation for this task have been hampered both by evolutionary changes of functional sites and poor performance of general-purpose alignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolution in multiple related genomes, based on phylogenetic pair hidden Markov models which explicitly model the gain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatory regions and the inference of precise binding-site locations within those regions. As the underlying formalism is a stochastic, generative model, it can also be used to simulate the evolution of regulatory elements. Our implementation is scalable in terms of numbers of species and sequence lengths and can produce alignments and binding-site predictions with accuracy rivaling or exceeding current systems that specialize in only alignment or only binding-site prediction. We demonstrate the validity and power of various model components on extensive simulations of realistic sequence data and apply a specific model to study Drosophila enhancers in as many as ten related genomes and in the presence of gain and loss of binding sites. Different models and modeling assumptions can be easily specified, thus providing an invaluable tool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolution of gene regulation.

Global fire emissions and the contribution of deforestation, savanna, forest, agricultural, and peat fires (1997-2009)

New burned area datasets and top-down constraints from atmospheric concentration measurements of pyrogenic gases have decreased the large uncertainty in fire emissions estimates. However, significant gaps remain in our understanding of the contribution of deforestation, savanna, forest, agricultural waste, and peat fires to total global fire emissions. Here we used a revised version of the Carnegie-Ames-Stanford-Approach (CASA) biogeochemical model and improved satellite-derived estimates of area burned, fire activity, and plant productivity to calculate fire emissions for the 1997-2009 period on a 0.5° spatial resolution with a monthly time step. For November 2000 onwards, estimates were based on burned area, active fire detections, and plant productivity from the MODerate resolution Imaging Spectroradiometer (MODIS) sensor. For the partitioning we focused on the MODIS era. We used maps of burned area derived from the Tropical Rainfall Measuring Mission (TRMM) Visible and Infrared Scanner (VIRS) and Along-Track Scanning Radiometer (ATSR) active fire data prior to MODIS (1997-2000) and estimates of plant productivity derived from Advanced Very High Resolution Radiometer (AVHRR) observations during the same period. Average global fire carbon emissions according to this version 3 of the Global Fire Emissions Database (GFED3) were 2.0 PgC year-1 with significant interannual variability during 1997-2001 (2.8 Pg Cyear-1 in 1998 and 1.6 PgC year-1 in 2001). Globally, emissions during 2002-2007 were rela-tively constant (around 2.1 Pg C year-1) before declining in 2008 (1.7 Pg Cyear-1) and 2009 (1.5 PgC year-1) partly due to lower deforestation fire emissions in South America and tropical Asia. On a regional basis, emissions were highly variable during 2002-2007 (e.g., boreal Asia, South America, and Indonesia), but these regional differences canceled out at a global level. During the MODIS era (2001-2009), most carbon emissions were from fires in grasslands and savannas (44%) with smaller contributions from tropical deforestation and degradation fires (20%), woodland fires (mostly confined to the tropics, 16%), forest fires (mostly in the extratropics, 15%), agricultural waste burning (3%), and tropical peat fires (3%). The contribution from agricultural waste fires was likely a lower bound because our approach for measuring burned area could not detect all of these relatively small fires. Total carbon emissions were on average 13% lower than in our previous (GFED2) work. For reduced trace gases such as CO and CH4, deforestation, degradation, and peat fires were more important contributors because of higher emissions of reduced trace gases per unit carbon combusted compared to savanna fires. Carbon emissions from tropical deforestation, degradation, and peatland fires were on average 0.5 PgC year-1. The carbon emissions from these fires may not be balanced by regrowth following fire. Our results provide the first global assessment of the contribution of different sources to total global fire emissions for the past decade, and supply the community with an improved 13-year fire emissions time series. © 2010 Author(s).

Mechanisms of specificity in neuronal activity-regulated gene transcription.

The brain is a highly adaptable organ that is capable of converting sensory information into changes in neuronal function. This plasticity allows behavior to be accommodated to the environment, providing an important evolutionary advantage. Neurons convert environmental stimuli into long-lasting changes in their physiology in part through the synaptic activity-regulated transcription of new gene products. Since the neurotransmitter-dependent regulation of Fos transcription was first discovered nearly 25 years ago, a wealth of studies have enriched our understanding of the molecular pathways that mediate activity-regulated changes in gene transcription. These findings show that a broad range of signaling pathways and transcriptional regulators can be engaged by neuronal activity to sculpt complex programs of stimulus-regulated gene transcription. However, the shear scope of the transcriptional pathways engaged by neuronal activity raises the question of how specificity in the nature of the transcriptional response is achieved in order to encode physiologically relevant responses to divergent stimuli. Here we summarize the general paradigms by which neuronal activity regulates transcription while focusing on the molecular mechanisms that confer differential stimulus-, cell-type-, and developmental-specificity upon activity-regulated programs of neuronal gene transcription. In addition, we preview some of the new technologies that will advance our future understanding of the mechanisms and consequences of activity-regulated gene transcription in the brain.

The environmental justice dimensions of climate change

Nations around the world are considering strategies to mitigate the severe impacts of climate change predicted to occur in the twenty-first century. Many countries, however, lack the wealth, technology, and government institutions to effectively cope with climate change. This study investigates the varying degrees to which developing and developed nations will be exposed to changes in three key variables: temperature, precipitation, and runoff. We use Geographic Information Systems (GIS) analysis to compare current and future climate model predictions on a country level. We then compare our calculations of climate change exposure for each nation to several metrics of political and economic well-being. Our results indicate that the impacts of changes in precipitation and runoff are distributed relatively equally between developed and developing nations. In contrast, we confirm research suggesting that developing nations will be affected far more severely by changes in temperature than developed nations. Our results also suggest that this unequal impact will persist throughout the twenty-first century. Our analysis further indicates that the most significant temperature changes will occur in politically unstable countries, creating an additional motivation for developed countries to actively engage with developing nations on climate mitigation strategies. © 2011, Mary Ann Liebert, Inc.

Human dimensions of bycatch reduction technology: Current assumptions and directions for future research

Bycatch reduction technology (BRT) modifies fishing gear to increase selectivity and avoid capture of non-target species, or to facilitate their non-lethal release. As a solution to fisheries-related mortality of non-target species, BRT is an attractive option; effectively implemented, BRT presents a technical 'fix' that can reduce pressure for politically contentious and economically detrimental interventions, such as fisheries closures. While a number of factors might contribute to effective implementation, our review of BRT literature finds that research has focused on technical design and experimental performance of individual technologies. In contrast, and with a few notable exceptions, research on the human and institutional context of BRT, and more specifically on how fishers respond to BRT, is limited. This is not to say that fisher attitudes are ignored or overlooked, but that incentives for fisher uptake of BRT are usually assumed rather than assessed or demonstrated. Three assumptions about fisher incentives dominate: (1) economic incentives will generate acceptance of BRT; (2) enforcement will generate compliance with BRT; and (3) 'participation' by fishers will increase acceptance and compliance, and overall support for BRT. In this paper, we explore evidence for and against these assumptions and situate our analysis in the wider social science literature on fisheries. Our goal is to highlight the need and suggest focal areas for further research. © Inter-Research 2008.

Institutional and ecological interplay for successful self-governance of community-based fisheries

The goal of this paper is to improve our understanding of the role of institutional arrangements and ecological factors that facilitate the emergence and sustainability of successful collective action in small-scale fishing social-ecological systems. Using a modified logistic growth function, we simulate how ecological factors (i.e. carrying capacity) affect small-scale fishing communities with varying degrees of institutional development (i.e. timeliness to adopt new institutions and the degree to which harvesting effort is reduced), in their ability to avoid overexploitation. Our results show that strong and timely institutions are necessary but not sufficient to maintain sustainable harvests over time. The sooner communities adopt institutions, and the stronger the institutions they adopt, the more likely they are to sustain the resource stock. Exactly how timely the institutions must be adopted, and by what amount harvesting effort must be diminished, depends on the ecological carrying capacity of the species at the particular location. Small differences in the carrying capacity between fishing sites, even under scenarios of similar institutional development, greatly affects the likelihood of effective collective action. © 2009 Elsevier B.V. All rights reserved.