Assessing the Contribution Antiretroviral Therapy to Neuronal Damage and Death as a Mediator of Cognitive Decline in HIV-Associated Neurocognitive Disorders

The advent of combination antiretroviral therapy (ART) in 1996 revolutionized the treatment of HIV/AIDS and significantly decreased the incidence of HIV-associated neurocognitive disorders (HAND), a spectrum of HIV-related CNS dysfunctions ranging from mild cognitive deficits to severe dementia. Although the long-term prognosis for ART-treated, HIV-positive individuals continues to improve, the life-expectancy for this population remains 10-30 years less than that of uninfected individuals. Additionally, the clinical and pathologic presentation of HAND has evolved from a subacute, subcortical encephalitic condition, to a prolonged, cortical, neurodegenerative disease with pathological features that resemble those found in Alzheimer Disease (AD). The specific mechanisms driving these pathological changes remain unknown, although emerging evidence suggests that antiretroviral neurotoxicity may be a significant contributing factor. Here, we examined mechanisms by which antiretroviral drugs induce stress in neurons leading to changes in amyloid precursor protein (APP) processing. Utilizing in vitro models of acute ART exposure, we observed that HIV protease inhibitor (PI)-class ART drugs robustly active the unfolded protein response in primary neurons leading to translational de-repression of beta-site cleaving enzyme 1 (BACE1) by phosphorylated eIF2alpha; and augmented amyloidogenic cleave of APP. These results were corroborated in ART-treated, SIV-infected macaques were we saw increased hippocampal expression of BACE1 AND IN HAND patients where we also found similar increases in BACE1 expression in CA1 and CA3 hippocampal regions accompanied by accumulation of intraneuronal oligomeric Abeta;. Finally, we demonstrate that inhibition of neuronal BACE1 activity in vitro protects cells from hydrogen peroxide and antiretroviral drug-mediated toxicity. From this body of work, we conclude that PI-class antiretroviral drugs play a prominent role in stress activation of CNS neurons leading to aberrant changes in APP processing and potentially contributing to neuronal damage and death in HAND. Lastly, we have identified BACE1 as an important adjunctive therapeutic target in the treatment of chronic cognitive decline in ART-medicated, HIV-positive individuals

Candidates for the Redemption Machine

This collection takes the concept of the "stunted individual" from grotesque fiction and applies it to surrealist prose poetry, where only traces of standard logic can be found; through this, the contrast between impossible events and innately human behavior becomes exaggerated. The melding of these forms forces the struggling individuals in these poems to represent humanity, where it is found wanting, despite artificial hope

Nitrogen Cycle Chemistry with Metal-Pincer Complexes Relevant to Electrochemical Nitrogen Fixation

The large-scale industrial fixation of N2 to NH3 through the Haber-Bosch process has cemented itself as the primary means to provide N for fertilizer and commodity chemicals globally. However, our dependence on this process is unsustainable in the long term due to its reliance on fossil fuels to generate H2 and to provide the substantial energy input for the reaction, paired with high infrastructure requirements that necessitate centralized synthesis plants and sophisticated transportation networks. As an alternative, electrochemical fixation of N2, coupling water oxidation to provide proton (H+) and electron (e–) equivalents with the N2 reduction reaction (NRR) to achieve the 6H+/6e– reduction of N2 to 2 NH3, could operate on a smaller, localized scale while utilizing renewable sources to generate electrical energy to drive the reaction. A key challenge in achieving electrochemical N2 fixation is the development of catalysts for electrochemical NRR. Existing heterogeneous catalysts for NRR suffer from poor activity, selectivity, and robustness. Insights that aid the development of better NRR catalysts may be found by studying molecular systems that can reduce N2. This thesis probes potential N2 functionalization pathways that could be involved in electrochemical NRR by studying molecular model systems in which N2 binds to, or is cleaved by, reduced metal-pincer complexes. Chapter 1 describes electrochemical N2 fixation as an alternative to the Haber-Bosch process. A molecular approach towards understanding electrochemical NRR is proposed, especially through bimetallic N2 cleavage to form metal nitrides. Strategies for the subsequent functionalization of the metal nitride are discussed, primarily via proton-coupled electron transfer (PCET) reduction of the nitride into NH3. Challenges involved in PCET nitride reduction, as well as opportunities inspired by molecular N2 reduction catalysts and recent discoveries of potent PCET reagents, are identified and applied to a hypothetical system for electrochemical NRR. Chapter 2 describes the protonation and electrochemical reduction of Ir- and Rh-pincer complexes that can strongly bind N2. The potential utility of these complexes in an electrochemical NRR system are assessed by complimentary electrochemical and spectroscopic studies exploring their stepwise protonation and electrochemical reduction. Protonation was found to be a prerequisite for electrochemical reduction of the N2 complexes, with protonation occurring at the metal center to form metal hydrides. Protonation triggers release of the N2 ligand, preventing reductive N2 functionalization with these complexes. Chapter 3 investigates the possibility of oxidative functionalization of an N2-derived Re nitride in order to form NOx species. Although no N–O bond formation was achieved at the nitride, a series of Re nitrides was synthesized and characterized in which the metal center is oxidized by 1e– and/or the supporting pincer ligand is oxidized to a nitroxide. The Re-nitride interaction was monitored over the series using NMR and IR spectroscopies, X-ray crystallography, and computational methods. Cooperative oxidation of both the metal center and the supporting ligand results in the weakest Re-nitride interaction, more localization of the LUMO at the nitride ligand, and an umpolung in nitride reactivity. Chapter 4 applies PCET methods to N2-derived Re nitrides in an attempt to reduce the nitride to NH3, thus closing the cycle of N2 to NH3. Stepwise PCET mechanisms were prohibited by high-energy intermediates in both systems; however, the combination of SmI2 and H2O to generate a strong concerted PCET reagent resulted in formation of 74% yield of NH4+ in one system, but exclusive production of H2 in the other. Other PCET methods, such as pairing organic H-atom transfer reagents with SmI2, are also assessed for PCET nitride reduction. Chapter 5 studies the conversion of NH3 to a nitride in a Re system that can also cleave N2. Re-ammine and Re-amide intermediates were isolated, and the mechanisms of H atom removal from these to form the nitride were identified. Experimental determination of the N–H bond enthalpies in the Re-amide were used to benchmark computational studies elucidating the thermodynamics of N–H bond cleavage (and formation, the microscopic reverse). The putative Re-imide intermediate in the PCET reduction pathway was found to feature a particularly weak N–H bond, representing a thermodynamic bottleneck to PCET nitride reduction in this system

As Southern Africa faces new urban drought challenges, who is heeding the wake-up call?

As experts forecast the likelihood of El Nino in southern Africa over the next few months, Kate Gannon, Patrick Curran and Declan Conway examine the impact of drought-related water and electricity supply disruption on businesses in southern Africa during the 2015/16 El Niño

DYNAMIC KNOWLEDGE MANAGEMENT CAPABILITY FOR THE SMALL TOURISM FIRM

Strategic management theory has largely and traditionally focused on the external environment in which a firm can achieve competitive advantage (Bounfour, 2003). Increasingly literature has redirected their focus towards the more controllable internal resources within the firm (Barney, 1991). An increasing amount of literature has recognised that the potential for competitive advantage arises from Intellectual Capital (IC) in the form of human, social and structural resources (Teece, 1998). Previous IC literature has tended to focus mostly on the measurement of individual components of IC and IC components collectively (Mayo, 2000; Tsai and Ghoshal, 1998; Stewart, 1997). Essentially IC amalgamates to a firm’s knowledge assets. Although it makes sense to redirect IC theory towards Knowledge Management (KM) thinking, it has traditionally remained as two distinct areas (Bounfour, 2003). The scant literature that does link KM with IC has been produced purely on a theoretical basis (Moustaghfir, 2008) and the tendency has been to focus on larger firms with case studies and little research has taken place in the tourism industry (Engstrom et al, 2003; Roos and Roos, 1997b) or SME sector. Key authors in the area are calling for the integration of academics and management practitioners to form a practice based model (Grant, 1997). This article therefore seeks to create this link between IC and KM in the Irish tourism sector, by identifying the IC resources of importance, and leveraging these resources through knowledge management capability. Further this paper identifies and distinguishes between the cognitive based aspects of knowledge management and the action based area of organisational learning that will enhance the tourism firm’s competitive advantage

FRAMEWORK FOR ENHANCING COMPETITIVENESS IN CULTURE AND HERITAGE ORGANISATIONS IN THE IRISH TOURISM INDUSTRY

The culture and heritage sector of the tourism industry has become a major economic sector of enterprise and of wealth creation (Failte Ireland, 2009a). However, as the National Development Plan (2007-2013) notes, the landscape is changing and the tourism industry is at a significant turning point in its evolution due to the economic downturn. Creating a stronger competitive capacity within Irish tourism companies is a challenging issue (National Development Plan, 2007-2013) and a core focus of this research. This research will particularly focus on cultural and heritage organisations where the industry is predominantly made up of micro and small to medium sized organisations. Given these organisation‟s are small they have limited resource pools. However, as outlined in the „New Horizons for Irish Tourism‟ report (Failte Ireland, 2009b), the cultural and heritage sector has „core assets‟ which if leveraged and deployed to maximum capacity, it could result in a competitive advantage. Strategic management theory has largely and traditionally focused on the external environment in which a firm can achieve competitive advantage (Bounfour, 2003). Increasingly literature has redirected its focus towards the more controllable internal resources within the firm (Barney, 1991). Indeed, an increasing amount of literature has recognised that if small cultural and tourism organisations can strategically utilise their limited resources to maximum capacity, competitiveness should increase (Sundbo et al. 2006). Drawing on the resource based (Barney, 1991) and dynamic capabilities views of the firm (Teece et al., 1997), this paper will make a unique contribution to a very significant gap in the capabilities and business strategy literature by analysing how tourism organisations are utilising and maximising their intangible resource stocks as a means of gaining competitive advantage. Due to the scarcity of research and interest in this area, it is perceived that our ongoing study will contribute substantially to academic knowledge and practice and should highlight key areas warranting investigation going forward

Dynamic Knowledge Management Capability (DKMC): From Resources to Capital (RIKON Group)

Strategic management theory has largely and traditionally focused on the external environment in which a firm can achieve competitive advantage (Bounfour, 2003). Increasingly literature has redirected their focus towards the more controllable internal resources within the firm (Barney, 1991). An increasing amount of literature has recognised that the potential for competitive advantage arises from Intellectual Capital (IC) in the form of human, relational and structural resources (Teece, 1998). However, transforming these resources in to Intellectual Capital has received scant attention within the literature and remains a central dilemma for most firms. Utilising the tourism industry as a context, this paper presents a conceptual model that details how the cultural and heritage organisation can effectively deploy and reconfigure resources to deliver sustained competitive advantage through cognitive and action orientated processes. The model proposes that the transformative process involves the integration of a firm’s knowledge and learning capability. The knowledge management capability engages the firm’s capital and transforms its inert state through the acquisition, storage, retrieval and distribution of knowledge within the firm (Crossan et al, 1999), while the application of knowledge takes place through learning within the firm (Chatzkel, 2000)

DOES SUSTAINABLE COMPETITIVE ADVANTAGE EXIST? AND, IF SO, HOW CAN IT BE ACHIEVED?

Strategists and economists have spent years studying firms and organisations that have been successful. The questions that arose back then remain unanswered today. Why are some organisations more successful than others? What is different about these successful firms? How did they achieve this competitive advantage (CA)? And is it sustainable? Many theories have been put forward in an effort to solve this matter, but not one particular theory has been acknowledged as the means of gaining this competitive advantage (Cockburn, Henderson and Stern, 2000). Strategy within the 1980s mainly focused on the management of external factors as the source of competitive advantage (Porter, 1985). In the context of tourism, this is even more apparent. Many authors within the tourism literature have researched competitiveness in relation to the external environment (Yasin, Alavi, Sobral, Lisboa, 2003; Go, Pine and Yu, 1994). However, in the early nineties there was a significant shift in focus when strategists began to recognise that CA came from resources within the firm (Mahoney and Pandian, 1992; Barney, 1991; Grant, 1991). Policy makers have recognised the significant role that the Irish tourism sector plays within the Irish economy as well as its lack of competitiveness, hence they are eager to instil competitiveness in Irish tourism organisations (Dept of Arts, Sports and Tourism, 2010; Tourism Renewal Group, 2009). However, the dynamic nature of the tourism industry has made competition difficult to sustain. The problem with Sustainable Competitive Advantage (SCA) is that nobody really knows how to achieve it or whether it can even exist (Useem, 2000). There has been significant debate about this issue in strategic literature for quite some time and is still ongoing today (Fiol, 2001; Coyne, 1986). This paper will look comprehensively at whether it is possible for a tourism organisation to attain a competitive advantage. If it is possible, then how can the tourism organisation‟s internal resources be utilised to gain this level of competitiveness. Furthermore, this paper will discuss whether tourist practitioners can transform this advantage into a sustainable competitive advantage

Congruence and similarity of 3-manifolds

Let f be an integer greater than one. We study three progressively finer equivalence relations on closed 3-manifolds generated by Dehn surgery with denominator f: weak f-congruence, f-congruence, and strong f-congruence. If f is odd, weak f-congruence preserves the ring structure on cohomology with Z_f-coefficients. We show that strong f-congruence coincides with a relation previously studied by Lackenby. Lackenby showed that the quantum SU(2) invariants are well-behaved under this congruence. We strengthen this result and extend it to the SO(3) quantum invariants. We also obtain some corresponding results for the coarser equivalence relations, and for quantum invariants associated to more general modular categories. We compare S^3, the Poincare homology sphere, the Brieskorn homology sphere Sigma(2,3,7) and their mirror images up to strong f-congruence. We distinguish the weak f-congruence classes of some manifolds with the same Z_f-cohomology ring structure.Comment: 24 pages,5 figure