The role of structure in the electrochemical performance of nanostructured metal oxides for lithium ion battery anodes

The Li-ion battery has for a number of years been a key factor that has enabled an ever increasing number of modern consumer devices, while in recent years has also been sought to power a range of emerging electric and hybrid electric vehicles. Due to their importance and popularity, a number of characteristics of Li-ion batteries have been subjected to intense work aimed at radical improvement. Although electrode material selection intrinsically defines characteristics like maximum capacity or voltage, engineering of the electrode structure may yield significant improvements to the lifetime performance of the battery, which would not be available if the material was used in its bulk form. The body of work presented in this thesis describes the relationship between the structure of electrochemically active materials and the course of the electrochemical processes occurring within the electrode. Chapter one describes the motivation behind the research presented herein. Chapter two serves to highlight a number of key advancements which have been made and detailed in the literature over recent years, pertaining to the use of nanostructured materials in Li-ion technology. Chapter three details methods and techniques applied in developing the body of work presented in this thesis. Chapter four details structural, molecular and electrochemical characteristics of tin oxide nanoparticle based electrodes, with particular emphasis on the relationship between the size distribution and the electrode performance. Chapter five presents findings of structural, electrochemical and optical study of indium oxide nanoparticles grown on silicon by molecular beam epitaxy. In chapter 6, tin oxide inverted opal electrodes are investigated for the conduct of the electrochemical performance of the electrodes under varying rate of change of potential. Chapter 7 presents the overall conclusions drawn from the results presented in this thesis, coupled with an indication of potential future work which may be explored further.

Characterisation of the role of Fas in intestinal inflammation and cancer

Background: The role of Fas (CD95) and its ligand, Fas ligand (FasL/CD95L), is poorly understood in the intestine. Whilst Fas is best studies in terms of its function in apoptosis, recent studies suggest that Fas ligation may mediate additional, non-apoptotic functions such as inflammation. Toll like Receptors (TLRs) play an important role in mediating inflammation and homeostasis in the intestine. Recent studies have shown that a level of crosstalk exists between the Fas and TLR signalling pathways but this has not yet been investigated in the intestine. Aim: The aim of this study was to evaluate potential cross-talk between TLRs and Fas/FasL system in intestinal cancer cells. Results: Treatment with TLR4 and TLR5 ligands, but not ligands for TLR2 and TLR9 increased the expression of Fas and FasL in intestinal cancer cells in vitro. Consistent with this, expression of Fas and FasL was reduced in the distal colon tissue from germ-free (GF), TLR4 and TLR5 knock-out (KO) mice but was unchanged in TLR2KO tissue, suggesting that intestinal cancer cells display a degree of specificity in their ability to upregulate Fas and FasL expression in response to TLR ligation. Expression of both Fas and FasL was significantly reduced in TRIF KO tissue, indicating that signalling via TRIF by TLR4 and TLR5 agonists may be responsible for the induction of Fas and FasL expression in intestinal cancer cells. In addition, modulating Fas signalling using agonistic anti-Fas augmented TLR4 and TLR5-mediated tumour necrosis factor alpha (TNFα) and interleukin 8 (IL)-8 production by intestinal cancer cells, suggesting crosstalk occurs between these receptors in these cells. Furthermore, suppression of Fas in intestinal cancer cells reduced the ability of the intestinal pathogens, Salmonella typhimurium and Listeria monocytogenes to induce the expression of IL-8, suggesting that Fas signalling may play a role in intestinal host defence against pathogens. Inflammation is known to be important in colon tumourigenesis and Fas signalling on intestinal cancer cells has been shown to result in the production of inflammatory mediators. Fas-mediated signalling may therefore play a role in colon cancer development. Suppression of tumour-derived Fas by 85% led to a reduction in the tumour volume and changes in tumour infiltrating macrophages and neutrophils. TLR4 signalling has been shown to play a role in colon cancer via the recruitment and activation of alternatively activated immune cells. Given the crosstalk seen between Fas and TLR4 signalling in intestinal cancer cells in vitro, suppressing Fas signalling may enhance the efficacy of TLR4 antagonism in vivo. TLR4 antagonism resulted in smaller tumours with fewer infiltrating neutrophils. Whilst Fas downregulation did not significantly augment the ability of TLR4 antagonism to reduce the final tumour volume, Fas suppression may augment the anti-tumour effects of TLR4 antagonism as neutrophil infiltration was further reduced upon combinatorial treatment. Conclusion: Together, this study demonstrates evidence of a new role for Fas in the intestinal immune response and that manipulating Fas signalling has potential anti-tumour benefit.

The human papillomavirus and cancer: a multiphase study investigating preventative behaviours in young males

Background: The Human Papillomavirus (HPV) is one of the world’s most common sexually transmitted infections, and a causative factor of oropharyngeal, anal and penile cancers in males. Worldwide, an estimated 39,000 HPV-associated cancers occur each year in men. The highest rates of HPV infection are found in adults aged 18 to 28 years. Clinical evidence indicates that use of a condom in addition to obtaining the HPV vaccine provides the greatest protection from HPV infections. Aim: To explore young men’s attitudes, beliefs, and behavioural intention in relation to receiving the HPV vaccine and using a condom correctly and consistently. Collectively, both behaviours are linked to the prevention of HPV transmission and associated infections with HPV. Method: A multi- phase study, underpinned by the Theory of Planned Behaviour, involving a qualitative belief elicitation, pilot, and quantitative cross-sectional study was conducted. A belief elicitation (n=12) phase was used to generate items to include in a newly developed research instrument. Post pilot the research instrument was utilised in a cross sectional online survey to explore the attitudes, beliefs, and behavioural intention of young men (n= 359) with regard to receiving the HPV vaccine, and using a condom correctly and consistently. Data Collection: Data collection took place over a three month time frame. Male participants were recruited from a university in Southern Ireland via a student email system, as well as posting advertisements on numerous health, social and sports websites. Sample: Three hundred and fifty nine male participants aged 18- 28 years completed the online questionnaire. Data Analysis: Data were analysed using SPSS. Descriptive, correlational, multiple and hierarchical regression analysis were performed on the indirect and direct variables of the Theory of Planned Behaviour i.e. attitude, subjective norm, perceived behavioural control, and intention. Status variables were also included in descriptive analysis and hierarchical regressions. Findings are presented through text and graphical representation. Results: Alarming sexual health statistics identified that only 44.3% of participants always used a condom, and 78.6% never used a condom for oral sex. Furthermore, findings reveal that the constructs of the Theory of Planned Behaviour adequately measure male’s attitudes, beliefs and behavioural intention with regard to both behaviours. The Theory of Planned Behaviour has assisted in identifying how social pressures play an influential role in relation to males receiving the HPV vaccine. Attitudes presented as the most significant predictor of male’s intentions to use a condom correctly and consistently. Intention to perform both behaviours was identified as moderate to high. Conclusion: This study has contributed to the field of HPV research, as it is the first piece of research to explore preventative HPV behaviours i.e. receiving the HPV vaccine, and condom use, amongst young males, utilising the Theory of Planned Behaviour. A deeper understanding of young male’s attitudes, beliefs, and behavioural intention on this topic has been achieved. Additionally, a new robust research instrument has been constructed. Findings from this study will undoubtedly help in the implementation of the HPV vaccine in Ireland, as well as influence health promotion campaigns aimed at young males, addressing the topic of condom use.

The role of transformative thinking and practice in a property entrepreneur's response to the funding crisis since 2008

This portfolio of exploration explores the role of transformative thinking and practice in a property entrepreneur’s response to the financial crisis which swept over Ireland from 2008. The complexity of this challenge and the mental capacity to meet its demands is at the core of the exploration. This inquiry emerged from the challenges the financial crisis presented to my values, beliefs, assumptions, and theories, i.e. the interpretive lens through which I make meaning of my experiences. Given the issue identified, this inquiry is grounded in aspects of theories of constructive developmental psychology, applied developmental science, and philosophy. Integrating and linking these elements to business practice is the applied element of the Portfolio. As the 2008 crisis unfolded I realised I was at the limits of my way of knowing. I came to understand that the underlying structure of a way of knowing is the ‘subject-object relationship’ i.e. what a way of knowing can reflect upon, look at, have perspective on, in other words, make object, as against what is it embedded in, attached to, identified within, or subject to. My goal became enhancing my awareness of how I made meaning and how new insights, which would transform a way of knowing, are created. The focus was on enhancing my practice. This Portfolio is structured into three essays. Essay One reported on my self-reflection and external evaluation out of which emerged my developmental goals. In Essay Two I undertake a reading for change programme in which different meaning making systems were confronted in order to challenge me as a meaning maker. Essay Three reported on my experiment which concerned the question whether it was possible for me as a property entrepreneur, and for others alike, to retain bank finance in the face of the overwhelming objective of the bank to deleverage their balance sheet of property loans. The output of my research can be grouped into General Developmental and Specific Business Implications. Firstly I address those who are interested in a transformational-based response to the challenges of operating in the property sector in Ireland during a crisis. I outline the apparatus of thought that I used to create insight, and thus transform how I thought, these are Awareness, Subject-object separation, Exploring other’s perspectives from the position of incompleteness, Dialectical thinking and Collingwood’s Questioning activity. Secondly I set out my learnings from the crisis and their impact on entrepreneurial behaviour and the business of property development. I identify ten key insights that have emerged from leading a property company through the crisis. Many of these are grounded in common sense, however, in my experience these were, to borrow Shakespeare’s words, “More honor'd in the breach than the observance” in pre Crisis Ireland. Finally I set out a four-step approach for forging a strategy. This requires my peer practitioners to identify (i) what they are subject to, (ii) Assess the Opportunity or challenge in a Systemic Context, (iii) Explore Multiple Perspectives on the opportunity or Challenge with an Orientation to change how you know and (iv) Using the Questioning Activity to create Knowledge. Based on my experience I conclude that transformative thinking and practice is a key enabler for a property entrepreneur, in responding to a major collapse of traditional (bank debt) funding.

Dose-effect of interleukin-10 and its immunoregulatory role in Crohn's disease.

BACKGROUND: Interleukin-10 (IL-10) is currently being extensively studied in clinical trials for the treatment of Crohn's disease (CD). Only marginal effects have, however, been reported, and the dose-response curve was bell-shaped contrasting with the reported data from in vitro experiments. AIM: To use another in vitro model to analyze the effect of rhIL-10 and rhIL-4 on the spontaneous mucosal TNF-alpha secretion in patients with CD, and to characterize the phenotype of the cells targeted by rhIL-10. METHODS: Non-inflamed colon biopsies from CD patients were cultured for 16 hours in presence of different concentrations of rhIL-10 or rhIL-4. The numbers of TNF-alpha-secreting cells among isolated lamina propria mononuclear cells (LPMNC) were estimated by Elispot. RESULTS: Both rhIL-10 and rhIL-4 down-regulate TNF-alpha secretion by LPMNC from CD patients, with a more pronounced effect with rhIL-10. These effects were closely linked to the cytokine concentrations used, with a bell-shaped dose-response curve. Residual TNF-alpha secretion, in the presence of optimal rhIL-10 concentration was mainly attributable to CD3+ T cells. In contrast, at higher rhIL-10 concentrations, CD3- cells contributed significantly to the TNF-alpha secretion. CONCLUSIONS: The in vitro model we used, demonstrates that IL-4, but mostly IL-10, efficiently suppresses TNF-alpha secretion in LPMNC from CD patients, with a dose-response curve similar to results obtained in vivo. Resistance at high rhIL-10 concentrations was associated with a change in the phenotype of TNF-alpha-secreting cells.

Growth factor erv1-like modulates Drp1 to preserve mitochondrial dynamics and function in mouse embryonic stem cells.

The relationship of mitochondrial dynamics and function to pluripotency are rather poorly understood aspects of stem cell biology. Here we show that growth factor erv1-like (Gfer) is involved in preserving mouse embryonic stem cell (ESC) mitochondrial morphology and function. Knockdown (KD) of Gfer in ESCs leads to decreased pluripotency marker expression, embryoid body (EB) formation, cell survival, and loss of mitochondrial function. Mitochondria in Gfer-KD ESCs undergo excessive fragmentation and mitophagy, whereas those in ESCs overexpressing Gfer appear elongated. Levels of the mitochondrial fission GTPase dynamin-related protein 1 (Drp1) are highly elevated in Gfer-KD ESCs and decreased in Gfer-overexpressing cells. Treatment with a specific inhibitor of Drp1 rescues mitochondrial function and apoptosis, whereas expression of Drp1-dominant negative resulted in the restoration of pluripotency marker expression in Gfer-KD ESCs. Altogether, our data reveal a novel prosurvival role for Gfer in maintaining mitochondrial fission-fusion dynamics in pluripotent ESCs.

MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy.

Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E-binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy.

Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.

Neurodegenerative diseases such as Huntington disease are devastating disorders with no therapeutic approaches to ameliorate the underlying protein misfolding defect inherent to poly-glutamine (polyQ) proteins. Given the mounting evidence that elevated levels of protein chaperones suppress polyQ protein misfolding, the master regulator of protein chaperone gene transcription, HSF1, is an attractive target for small molecule intervention. We describe a humanized yeast-based high-throughput screen to identify small molecule activators of human HSF1. This screen is insensitive to previously characterized activators of the heat shock response that have undesirable proteotoxic activity or that inhibit Hsp90, the central chaperone for cellular signaling and proliferation. A molecule identified in this screen, HSF1A, is structurally distinct from other characterized small molecule human HSF1 activators, activates HSF1 in mammalian and fly cells, elevates protein chaperone expression, ameliorates protein misfolding and cell death in polyQ-expressing neuronal precursor cells and protects against cytotoxicity in a fly model of polyQ-mediated neurodegeneration. In addition, we show that HSF1A interacts with components of the TRiC/CCT complex, suggesting a potentially novel regulatory role for this complex in modulating HSF1 activity. These studies describe a novel approach for the identification of new classes of pharmacological interventions for protein misfolding that underlies devastating neurodegenerative disease.

Gender differences in the risk of HIV infection among persons reporting abstinence, monogamy, and multiple sexual partners in northern Tanzania.

BACKGROUND: Monogamy, together with abstinence, partner reduction, and condom use, is widely advocated as a key behavioral strategy to prevent HIV infection in sub-Saharan Africa. We examined the association between the number of sexual partners and the risk of HIV seropositivity among men and women presenting for HIV voluntary counseling and testing (VCT) in northern Tanzania. METHODOLOGY/ PRINCIPAL FINDINGS: Clients presenting for HIV VCT at a community-based AIDS service organization in Moshi, Tanzania were surveyed between November 2003 and December 2007. Data on sociodemographic characteristics, reasons for testing, sexual behaviors, and symptoms were collected. Men and women were categorized by number of lifetime sexual partners, and rates of seropositivity were reported by category. Factors associated with HIV seropositivity among monogamous males and females were identified by a multivariate logistic regression model. Of 6,549 clients, 3,607 (55%) were female, and the median age was 30 years (IQR 24-40). 939 (25%) females and 293 (10%) males (p<0.0001) were HIV seropositive. Among 1,244 (34%) monogamous females and 423 (14%) monogamous males, the risk of HIV infection was 19% and 4%, respectively (p<0.0001). The risk increased monotonically with additional partners up to 45% (p<0.001) and 15% (p<0.001) for women and men, respectively with 5 or more partners. In multivariate analysis, HIV seropositivity among monogamous women was most strongly associated with age (p<0.0001), lower education (p<0.004), and reporting a partner with other partners (p = 0.015). Only age was a significant risk factor for monogamous men (p = 0.0004). INTERPRETATION: Among women presenting for VCT, the number of partners is strongly associated with rates of seropositivity; however, even women reporting lifetime monogamy have a high risk for HIV infection. Partner reduction should be coupled with efforts to place tools in the hands of sexually active women to reduce their risk of contracting HIV.

Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice.

BACKGROUND: Inflammatory bowel disease (IBD) is hypothesized to result from stimulation of immune responses against resident intestinal bacteria within a genetically susceptible host. Mast cells may play a critical role in IBD pathogenesis, since they are typically located just beneath the intestinal mucosal barrier and can be activated by bacterial antigens. METHODOLOGY/PRINCIPAL FINDINGS: This study investigated effects of mast cells on inflammation and associated neoplasia in IBD-susceptible interleukin (IL)-10-deficient mice with and without mast cells. IL-10-deficient mast cells produced more pro-inflammatory cytokines in vitro both constitutively and when triggered, compared with wild type mast cells. However despite this enhanced in vitro response, mast cell-sufficient Il10(-/-) mice actually had decreased cecal expression of tumor necrosis factor (TNF) and interferon (IFN)-gamma mRNA, suggesting that mast cells regulate inflammation in vivo. Mast cell deficiency predisposed Il10(-/-) mice to the development of spontaneous colitis and resulted in increased intestinal permeability in vivo that preceded the development of colon inflammation. However, mast cell deficiency did not affect the severity of IBD triggered by non-steroidal anti-inflammatory agents (NSAID) exposure or helicobacter infection that also affect intestinal permeability. CONCLUSIONS/SIGNIFICANCE: Mast cells thus appear to have a primarily protective role within the colonic microenvironment by enhancing the efficacy of the mucosal barrier. In addition, although mast cells were previously implicated in progression of sporadic colon cancers, mast cells did not affect the incidence or severity of colonic neoplasia in this inflammation-associated model.

Direct TLR2 signaling is critical for NK cell activation and function in response to vaccinia viral infection.

Natural killer (NK) cells play an essential role in innate immune control of poxviral infections in vivo. However, the mechanism(s) underlying NK cell activation and function in response to poxviruses remains poorly understood. In a mouse model of infection with vaccinia virus (VV), the most studied member of the poxvirus family, we identified that the Toll-like receptor (TLR) 2-myeloid differentiating factor 88 (MyD88) pathway was critical for the activation of NK cells and the control of VV infection in vivo. We further showed that TLR2 signaling on NK cells, but not on accessory cells such as dendritic cells (DCs), was necessary for NK cell activation and that this intrinsic TLR2-MyD88 signaling pathway was required for NK cell activation and played a critical role in the control of VV infection in vivo. In addition, we showed that the activating receptor NKG2D was also important for efficient NK activation and function, as well as recognition of VV-infected targets. We further demonstrated that VV could directly activate NK cells via TLR2 in the presence of cytokines in vitro and TLR2-MyD88-dependent activation of NK cells by VV was mediated through the phosphatidylinositol 3-kinase (PI3K)-extracellular signal-regulated kinase (ERK) pathway. Taken together, these results represent the first evidence that intrinsic TLR signaling is critical for NK cell activation and function in the control of a viral infection in vivo, indicate that multiple pathways are required for efficient NK cell activation and function in response to VV infection, and may provide important insights into the design of effective strategies to combat poxviral infections.

Response decision processes and externalizing behavior problems in adolescents.

Externalizing behavior problems of 124 adolescents were assessed across Grades 7-11. In Grade 9, participants were also assessed across social-cognitive domains after imagining themselves as the object of provocations portrayed in six videotaped vignettes. Participants responded to vignette-based questions representing multiple processes of the response decision step of social information processing. Phase 1 of our investigation supported a two-factor model of the response evaluation process of response decision (response valuation and outcome expectancy). Phase 2 showed significant relations between the set of these response decision processes, as well as response selection, measured in Grade 9 and (a) externalizing behavior in Grade 9 and (b) externalizing behavior in Grades 10-11, even after controlling externalizing behavior in Grades 7-8. These findings suggest that on-line behavioral judgments about aggression play a crucial role in the maintenance and growth of aggressive response tendencies in adolescence.

Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity.

Recently, we identified a GTPase-activating protein for the ADP ribosylation factor family of small GTP-binding proteins that we call GIT1. This protein initially was identified as an interacting partner for the G protein-coupled receptor kinases, and its overexpression was found to affect signaling and internalization of the prototypical beta(2)-adrenergic receptor. Here, we report that GIT1 overexpression regulates internalization of numerous, but not all, G protein-coupled receptors. The specificity of the GIT1 effect is not related to the type of G protein to which a receptor couples, but rather to the endocytic route it uses. GIT1 only affects the function of G protein-coupled receptors that are internalized through the clathrin-coated pit pathway in a beta-arrestin- and dynamin-sensitive manner. Furthermore, the GIT1 effect is not limited to G protein-coupled receptors because overexpression of this protein also affects internalization of the epidermal growth factor receptor. However, constitutive agonist-independent internalization is not regulated by GIT1, because transferrin uptake is not affected by GIT1 overexpression. Thus, GIT1 is a protein involved in regulating the function of signaling receptors internalized through the clathrin pathway and can be used as a diagnostic tool for defining the endocytic pathway of a receptor.

A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins.

The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor. Mutagenesis studies of the beta2 receptor tail revealed that the optimal C-terminal motif for binding to the first PDZ domain of NHERF is D-S/T-x-L, a motif distinct from those recognized by other PDZ domains. The first PDZ domain of NHERF-2, a protein that is 52% identical to NHERF and also known as E3KARP, SIP-1, and TKA-1, exhibits binding preferences very similar to those of the first PDZ domain of NHERF. The delineation of the preferred binding motif for the first PDZ domain of the NHERF family of proteins allows for predictions for other proteins that may interact with NHERF or NHERF-2. For example, as would be predicted from the beta2 receptor tail mutagenesis studies, NHERF binds to the tail of the purinergic P2Y1 receptor, a seven-transmembrane receptor with an intracellular C-terminal tail ending in D-T-S-L. NHERF also binds to the tail of the cystic fibrosis transmembrane conductance regulator, which ends in D-T-R-L. Because the preferred binding motif of the first PDZ domain of the NHERF family of proteins is found at the C termini of a variety of intracellular proteins, NHERF and NHERF-2 may be multifunctional adaptor proteins involved in many previously unsuspected aspects of intracellular signaling.

beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein.

G protein-coupled receptor activation leads to the membrane recruitment and activation of G protein-coupled receptor kinases, which phosphorylate receptors and lead to their inactivation. We have identified a novel G protein-coupled receptor kinase-interacting protein, GIT1, that is a GTPase-activating protein (GAP) for the ADP ribosylation factor (ARF) family of small GTP-binding proteins. Overexpression of GIT1 leads to reduced beta2-adrenergic receptor signaling and increased receptor phosphorylation, which result from reduced receptor internalization and resensitization. These cellular effects of GIT1 require its intact ARF GAP activity and do not reflect regulation of GRK kinase activity. These results suggest an essential role for ARF proteins in regulating beta2-adrenergic receptor endocytosis. Moreover, they provide a mechanism for integration of receptor activation and endocytosis through regulation of ARF protein activation by GRK-mediated recruitment of the GIT1 ARF GAP to the plasma membrane.