The characterization and pharmacology of the slow afterhyperpolarization in cultured rat hippocampal pypramidal cells

Following a burst of action potentials in hippocampal pyramidal cells, a slow afterhyperpolarization (sAHP) is observed which is insensitive to the bee-venom toxin apamin (Sah, 1996). Most of the work published on this response has employed brain slices, the sAHP proving difficult to reproduce in cultured neurones (Alger et al., 1994). In this work, the use of appropriate culture conditions and perforated patch recording has allowed the sAHP to be successfully recorded in cultured neurones. The current underlying the sAHP (SIAHP) in the isolated pyramidal cells was pharmacologically characterized and proved to be similar to that recorded using slices. The SIAHP in these cells was partially inhibited by both L- and N- type calcium channel inhibitors as well as ryanodine, an inhibitor of calcium-induced calcium release. These results suggested that calcium entry via multiple pathways can contribute to the generation of the SIAHP in these cells. The pharmacology of the SIAHP in these cells, as expected, differed greatly from the pharmacology of the apamin-sensitive afterhyperpolarization. The SIAHP could be inhibited by clotrimazole, an antifungal agent which blocks intermediate conductance calcium-activated potassium channels in red blood cells. Two derivatives of clotrimazole, UCL 2027 and UCL 2077, were the most selective blockers of the SIAHP, with very little block of calcium channels. One of the cloned small conductance calcium-activated potassium channel (SK1 channel) has been suggested underlie the SIAHP However, when SK1 cDNA was expressed in mammalian cell lines, the channels formed were apamin-sensitive. UCL 2027 and UCL 2077 also had little effect on the expressed SK1 channels. These results therefore, question whether SK1 channels underlie the SIAHP. In conclusion, two novel blockers of the SIAHP have been identified which may prove useful in establishing the physiological role and in the identification of the molecular correlate of the current

Characterisation of the DNA adducts formed by cisplatin and their repair at nucleotide resolution in cells.

Following a burst of action potentials in hippocampal pyramidal cells, a slow afterhyperpolarization (sAHP) is observed which is insensitive to the bee-venom toxin apamin (Sah, 1996). Most of the work published on this response has employed brain slices, the sAHP proving difficult to reproduce in cultured neurones (Alger et al., 1994). In this work, the use of appropriate culture conditions and perforated patch recording has allowed the sAHP to be successfully recorded in cultured neurones. The current underlying the sAHP (SIAHP) in the isolated pyramidal cells was pharmacologically characterized and proved to be similar to that recorded using slices. The SIAHP in these cells was partially inhibited by both L- and N- type calcium channel inhibitors as well as ryanodine, an inhibitor of calcium-induced calcium release. These results suggested that calcium entry via multiple pathways can contribute to the generation of the SIAHP in these cells. The pharmacology of the SIAHP in these cells, as expected, differed greatly from the pharmacology of the apamin-sensitive afterhyperpolarization. The SIAHP could be inhibited by clotrimazole, an antifungal agent which blocks intermediate conductance calcium-activated potassium channels in red blood cells. Two derivatives of clotrimazole, UCL 2027 and UCL 2077, were the most selective blockers of the SIAHP, with very little block of calcium channels. One of the cloned small conductance calcium-activated potassium channel (SK1 channel) has been suggested underlie the SIAHP However, when SK1 cDNA was expressed in mammalian cell lines, the channels formed were apamin-sensitive. UCL 2027 and UCL 2077 also had little effect on the expressed SK1 channels. These results therefore, question whether SK1 channels underlie the SIAHP. In conclusion, two novel blockers of the SIAHP have been identified which may prove useful in establishing the physiological role and in the identification of the molecular correlate of the current

Moving from traditional government to new adaptive governance: the changing face of food security responses in South Africa

The food system faces increasing pressure from dynamic and interactive, environmental, political and socio-economic stressors. Tackling the complexity that arises from such interactions requires a new form of 'adaptive governance'. This paper provides a review of various conceptions of governance from a monocentric or politicotechnical understanding of governance through to adaptive governance that is based in complex adaptive systems theory. The review is grounded by a critique of the existing institutional structures responsible for food security in South Africa. The current Integrated Food Security Strategy and tasked governmental departments are not sufficiently flexible or coordinated to deal with an issue as multi-scalar and multidisciplinary as food security. However, actions taken in the non-governmental sector signal the emergence of a new type of governance. Apart from an increasing recognition of food security as an issue of concern in the country, there is also evidence of a changing governance structure including collaboration between diverse stakeholders. We review these governance trends with an understanding of the food system as a complex adaptive socio-ecological system where actors in the food system self-organize into more flexible networks that can better adapt to uncertain pressure

Rogue Aid? The Determinants of China's Aid Allocation

Foreign aid from China is often characterized as ‘rogue aid’ that is not guided by recipient need but by China’s national interests alone. However, no econometric study so far confronts this claim with data. We make use of various datasets, covering the 1956-2006 period, to empirically test to which extent political and commercial interests shape China’s aid allocation decisions. We estimate the determinants of China’s allocation of project aid, food aid, medical teams and total aid money to developing countries, comparing its allocation decisions with traditional and other so-called emerging donors. We find that political considerations are an important determinant of China’s allocation of aid. However, in comparison to other donors, China does not pay substantially more attention to politics. In contrast to widespread perceptions, we find no evidence that China’s aid allocation is dominated by natural resource endowments. Moreover, China’s allocation of aid seems to be widely independent of democracy and governance in recipient countries. Overall, denominating aid from China as ‘rogue aid’ seems unjustified.aid allocation, China’s foreign aid, new donors, donor motives

Enumeration And Bit-encoded Values For Use With IEEE 1278.1-1994, Distributed Interactive Simulation: Application Protocols

Report specifies the numerical values and associated definitions for those distributed interactive simulation protocol data unit fields which are identified as enumerations in IEEE 1278.1-1994

Weak States, strong elites and acquiescent donors: State-building and aid relationships in the Democratic Republic of Congo 2006-2016

This thesis contributes to theories about aid negotiations by researching how development assistance for state-building has been negotiated in a fragile state, the Democratic Republic of Congo (DRC). Using qualitative methods, mainly in the form of semi-structured interviews, I explore how, in the context of the various structural factors that surround the negotiations, the different actors have tried to influence these factors to their advantage and what strategies the donors and the government have used to reach their objectives. In contrast to countries such as Rwanda and Uganda, I found that the Congolese government hasn’t tried to use image management to ‘sell’ itself to the donors. Instead, its strategy has been to increase its negotiation capital by taking an aggressive approach in discourse with the donors. Donors have struggled to have a constructive dialogue with the government and have been reluctant, due to international norms of ownership and previous experiences, to use conditionality as a negotiating strategy. To see how the strategies employed by donors and the government varied depending on the sector and level (central – district) at which engagement was taking place, I reviewed two large donor-funded programmes; one in the health sector, the other in the justice sector. I found that the strategies used in the two sectors did indeed vary quite substantially, with the consequence that the donors had more influence in the health than in the justice sector. To add to the complexity, Congo is what researchers have described as an archetype for a hybrid state, where the state is sharing its authority and legitimacy with a large number of non-state actors, such as customary chiefs and faithbased organisations. In this thesis I explored what this meant for donor efforts to build state-capacity and how it affects aid negotiations. I conclude with the recommendation that donors would benefit from working more closely with nonstate actors in their efforts to build state-capacity

A Qualitative Exploration of Parenting Experiences with Health Conditions

This thesis examines the experiences of parenting with health conditions, specifically that of cancer and Parkinson’s disease. Paper one is a systematic literature review and meta-synthesis of 20 papers which explore the experiences of persons with cancer when informing their children about their parental cancer. The research identified one superordinate theme of ‘protection’ and four themes of ‘deciding’, ‘telling’, ‘impact’ and ‘support’ that described the process of informing. The findings, recommendations for clinical practice and for future research are discussed at the end of this review. The second paper is a qualitative study that explores the experience of persons with Parkinson’s when parenting adolescents and young adults. Data were generated using semi-structured interviews and analysed using reflexive thematic analysis. The findings identified four themes of: ‘disclosing’, ‘holding on to the parent I was’, ‘changing as a parent’ and ‘an uncertain future’. These themes captured how the changes parents were subject to, began to impact their parental functioning and identity, leaving them worried about the future for their children. Recommendations for clinical practice and future research are also discussed for this paper. The final paper is a critical review of the above papers, comparing the two sets of findings and discussing the methodology in more detail. It considers the meaning of the work for the researcher and their role in their research process

Characterisation of immune responses to the E5 protein of the human papillomavirus type 16

A thesis submitted to the University of Luton for the degree of Doctor of PhilosophyHigh-risk mucosal human papillomaviruses (HPVs) are major aetiological agents for the development of cervical cancer. Thus, the current goal of cervical cancer treatment is to develop vaccines against HPV s. Such vaccines would either prevent cervical cancer by eliminating HPV infection or be useful for treating established lesions by the destruction of cells displaying HPV proteins. The aim of this thesis was to characterise immune responses to the E5 protein of HPV -16, one of several antigens with possible use in vaccination. To determine whether immune responses to HPV -16 E5 existed and whether they could be correlated with disease severity or with the presence of HPV -16 DNA, both cell mediated (Chapter Two) and humoral (Chapter Three) immunity was investigated in women with and without cervical disease. Cellular responses in a minority of women were inversely correlated with disease severity. However, E5 specific antibodies were negatively correlated with the absence of HPV -16 DNA. Thus, although some immune responses were evident, these were generally limited to a small number of subjects and were not associated with the detection of HPV-16 E5 mRNA or DNA sequence variants. Due to the immune responses in women, E5 was further investigated to determine if the absence of HPV -16 E5 specific immune responses was due to the poor antigenicity of HPV -16. Mice were immunised with synthetic peptides corresponding to full length HPV -16 E5 (Chapter Four). As with the human data, cellular responses and weak antibody responses were detected in mice. Some mice also exhibited cytotoxic T -lymphocyte responses and when E5/major histocompatibility class I (MHC-I) interactions were investigated, a number of peptides showed a high percentage of binding. The E5/MHC-I interactions were further investigated (Chapter Five). The surface expression of MHC-I on cells containing HPV-16 or -18 DNA was found to be lower than on HPV DNA negative cell lines even after stimulation with interferon-gamma. Stimulation with E5 synthetic peptides increased expression of cell surface MHC-I molecules on cell lines negative for HPV DNA. Furthermore, the presence of the E5 gene reduced the expression of the ovalbumin gene in normal human keratinocytes. In conclusion, the data contained within this thesis indicate that HPV-16 E5 CMI is inversely correlated with disease status. It is possible to induce cell mediated responses to HPV -16 E5 and low-titre antibody responses. The presence of HPV16 E5 DNA may impair normal cellular function