Modern medicine is challenged continuously by the increasing prevalence of multi-drug resistant bacteria. Therefore, the development of alternatives to traditional antibiotics is an urgent necessity. Cationic antimicrobial peptides (CAMPs) are components of the innate immune defense system. Histones, generally known as proteins that package and regulate the transcription of DNA, share all of the essential antimicrobial traits of CAMPs, and could be promising alternatives to antibiotics. In this study, I investigated the antimicrobial properties of nucleated-erythrocyte-specific linker histone H5 and its derived peptides. Histone H5 was extracted and purified from chicken erythrocytes using an acid extraction followed by ion exchange chromatography using a step salt gradient; the purity (>95%) was verified by densitometry and proteomics analysis. Purified histone H5 demonstrated potent antimicrobial activity against various Gram-positive and Gram-negative planktonic bacteria, including resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), as well as anti-biofilm activity against Listeria monocytogenes and Pseudomonas aeruginosa. Furthermore, scanning electron microscopy (SEM) revealed significant damage to L. monocytogenes and P. aeruginosa bacterial cell surfaces after histone H5 treatment. The potential for histone toxicity towards mammalian cells was investigated with a hemolytic assay which determined that even at the highest concentration tested (1 mg/mL), histone H5 was non-hemolytic. An in silico analysis determined the predicted antimicrobial domain of histone H5 of which six histone H5-derived peptides with potential antimicrobial activity were identified. These six histone H5-derived peptides were synthesized and tested against bacterial pathogens to determine their antimicrobial properties. Although the H5-derived peptides were identified within the predicted antimicrobial domain of histone H5, they did not possess more potent antimicrobial activity than the full length protein. Overall, this study demonstrates that histone H5 and histone H5-derived peptides could be promising candidates in the development of novel anti-infective therapeutics.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21637号 / 医博第4443号 / 新制||医||1034(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 河本 宏, 教授 松田 道行, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Fibre-deployment of future telecommunications networks ("Next Generation Access" - NGA) is a major challenge for sector-specific regulators as well as for investing firms. Although the future socioeconomic importance of new telecommunications networks is uncontroversial, the related investment activities vary substantially in international comparison. This work identifies the most important determinants of NGA deployment, using data from the EU27 member states for the years 2005 to 2010. Our results indicate that stricter previous broadband access regulation has a negative impact on NGA deployment, while competitive pressure from broadband and mobile affects NGA deployment in an inverted U-shaped manner. We further find that there are severe adjustment costs and stickiness towards the desired long-term level of NGA infrastructure. It appears that the approach of the European Commission of strict cost-based access regulation will not elicit the huge new investment needed for a comprehensive NGA roll-out. (authors' abstract) / Series: Working Papers / Research Institute for Regulatory Economics

The work presented in this thesis focuses on the total synthesis of (-)-6,7- Dideoxysqualestatin H5. Particular emphasis was the development of a cross- coupling strategy for direct delivery of the side chain towards the end of the synthesis. Various methods investigated to perform the key Csp3-Csp2 coupling initially led to the Fu variant of the Negishi coupling at elevated temperatures and subsequent cross- electrophile coupling at rt. Key features of the asymmetric synthesis of (-)-6,7- dideoxysqualestatin H5, include: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a Î2-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalysed cyclic carbonyl ylide formation-cycloaddition by cogeneration of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalysed Csp³-Csp² cross-electrophile coupling between tricarboxylate core and unsaturated side-chain to complete the natural product. Following completion of the natural product, further work was carried out on the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyls. The scope and limitations of reacting unsaturated tosylhydrazones with O₃ followed by Et₃N for the generation of 1,4- and 1,5-diazocarbonyl systems were explored. Tosylhydrazones, from tosylhydrazide condensation with readily available Î ́- and Îμ- unsaturated α-ketoesters, led in the former case to a 2-pyrazoline whereas the latter cases led to α-diazo-Îμ-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Tosylhydrazones from cyclic enones also allowed access to 1,4- and 1,5-diazocarbonyl systems using the ozonolysis-Et₃N strategy.

Serotonin was first discovered in the late 1940s as a vasotonic factor and is now considered a principal neurotransmitter in the nervous system. 5-HT6 receptors are one of the most recently identified members of the serotonin receptor family which consists of seven classes (5-HT1-5-HT7). 5-HT6 receptors are G-protein coupled, positively coupled to an adenylate cyclase second messenger system and are primarily found in the central nervous system (CNS). The exact functional role of 5-HT6 receptors has not been determined, but is implicated to have possible involvement in certain neuropsychiatric disorders and cognition. To investigate the functional role of these receptors, it is useful to identify 5-HT6 selective ligands as pharmacological tools. Our laboratory identified one of the first 5-HT6 receptor antagonists: the arylsulfonamide MS-245 (14a). It has been assumed that a sulfonyl (i.e., SO2) moiety is important for the binding of arylsulfonamides at 5-HT6 receptors. We now have identified benzyl analog 33 (R=H) as a single example of a non-sulfonyl analog that retains affinity. This questions the importance of the SO2 group and whether an aryl moiety or other hydrophobic groups (of equal or greater hydrophibicity) is required for binding. The purpose of the present investigation was to determine if the SO2, and the aryl moieties are required for high affinity binding. N1-Alkylsulfonyl- 78, and N1-benzyl-substituted tryptamines 33 were synthesized and affinities compared with their corresponding N1-benzenesulfonyl-substituted counterparts 31 at h5-HT6 receptors. None of the alkylsulfonyl or benzyl analogs displayed and/or retained the affinity of the simple benzenesulfonyl tryptamine analog (31a) (Ki = 4.1 nM). The results show that an arylsulfonyl group at the tryptamine N1 position is optimal, relative to an alkylsulfonyl group, for 5-HT6 receptor affinity. In a comparative analysis utilizing six pairs of tryptamines, it was found that there was little correspondence (r2 = 0.048) between the 5-HT6 receptor affinities of the examined benzyl and benzenesulfonyl pairs. Current findings indicate that an aryl (or substituted aryl)sulfonyl (rather than benzyl) moiety is optimal for high affinity binding, and further suggest that N1-benzenesulfonyl- and their corresponding N1-benzyltryptamine counterparts bind in a different fashion.

Η παρούσα διπλωματική εργασία πραγματεύεται τη μελέτη και την κατασκευή ενός μονοφασικού αντιστροφέα Η5, ο οποίος χρησιμοποιείται ευρέως σε τοπολογίες αντιστροφέων χωρίς μετασχηματιστή για τη διασύνδεση φωτοβολταϊκών πλαισίων με το δίκτυο χαμηλής τάσης. Η εργασία αυτή εκπονήθηκε στο Εργαστήριο Ηλεκτρομηχανικής Μετατροπής Ενέργειας του Τμήματος Ηλεκτρολόγων Μηχανικών και Τεχνολογίας Υπολογιστών της Πολυτεχνικής Σχολής του Πανεπιστημίου Πατρών. Σκοπός της διπλωματικής αυτής εργασίας είναι να καταστεί σαφής η λειτουργία του αντιστροφέα Η5 μέσω της θεωρητικής ανάλυσής του. Ακόμη, σκοπός της εργασίας αυτής είναι να γίνει κατανοητός ο λόγος για τον οποίο ο αντιστροφέας Η5 βρίσκει μεγάλη εφαρμογή και προτιμάται έναντι άλλων τοπολογιών αντιστροφέων στα φωτοβολταϊκά συστήματα ισχύος της τάξης των 5-20 kW. Αρχικά, παρουσιάζεται η ανάγκη εκμετάλλευσης της ηλιακής ενέργειας και περιγράφονται εν συντομία τα φωτοβολταϊκά στοιχεία που αποτελούν καθοριστικό ρόλο στον τομέα αυτό. Στη συνέχεια, περιγράφονται τα φωτοβολταϊκά συστήματα, οι τρόποι διασύνδεσής τους με το δίκτυο χαμηλής τάσης καθώς και οι τοπολογίες αντιστροφέων χωρίς μετασχηματιστή. Ακολούθως, παρατίθεται η θεωρητική ανάλυση και η προσομοίωση του αντιστροφέα Η5 καθώς και η σύγκρισή του με την τοπολογία πλήρους γέφυρας. Τέλος, αναλύεται η διαδικασία υλοποίησης κάθε σταδίου του μονοφασικού αντιστροφέα τύπου Η5 και παρατίθενται παλμογραφήματα και μετρήσεις που προέκυψαν από τα πειράματα που διενεργήθηκαν μετά την ολοκλήρωση της κατασκευής σε εργαστηριακό περιβάλλον. / This thesis deals with the design and construction of a single-phase H5 inverter, which is widely used in transformerless inverter topologies to interconnect PV modules to the low voltage grid. The study was prepared in the Laboratory of Electromechanical Energy Conversion, Department of Electrical and Computer Engineering, University of Patras. The aim of this thesis is to clarify the operation of the H5 inverter through theoretical analysis. Moreover, the aim of this work is to illustrate the reason why the H5 inverter finds wide application and is preferred over other transformerless inverter topologies in photovoltaic power systems in the range of 5-20 kW. Initially, is presented the need to exploit solar energy and are described shortly PV modules which form a key role in this area. Then, takes place a description of photovoltaic systems, the interconnection ways to the low voltage grid as well different transformerless topologies. Thereafter,is presented the theoretical analysis and simulation of H5 inverter and its comparison with the full-bridge topology. Finally, is analyzed the implementation process of every step of the single-phase H5 inverter,while some graphs and measurements obtained from the experiments carried out after the copletion of H5 inverter's construction in a lab environment are cited.

A review of the chemistry of poly(lactic acid) was carried out with a focus on techniques and applications of PLA polymer and copolymers with reference to some of the work that has been accomplished over the last 20 years or so. A review of the characterisation techniques used to analyse PLA polymers and copolymers was also carried out giving reference to the equipment and methods used herein. An investigation into the potential of PLA as the hydrophilic portion of a polymeric surfactant was carried out. To develop PLA based surfactants, the ring opening polymerisation of lactide was carried out in a melt in the presence of a long chain alcohol (C₇ to C₂₀) or diol (C₄ & C₆) to produce AB or ABA type polymers that follow the traditional surfactant template. Stannous octanoate and 4-dimethylaminopyridine were typically used as catalysts due to their high activity and relative cheapness. PLA only shows good hydrophilicity with up to 12 lactic acid units in the chain. Above this the electrostatic interactions between polymer chains reduced water solubility. It was also noted that D,L-lactide produced more water soluble polymers (syndiotactic) than the enantiomerically pure L-lactide (isotactic polymer chains). An investigation of the hydrophobic properties of PLA was carried out to evaluate their usefulness for other biodegradable surfactant applications. To this end an investigation of sugars as the hydrophilic portion of the molecule was carried out. Due to problems with solubilising sugars, they were deemed unsuitable for use as initiatiors within the scope of this research. Choline chloride was then investigated as a potential hydrophilic initiator and indeed has produced some of the most water soluble of PLA polymers. Choline chloride presented several challenges as an initiator, its high melting point resulted in polar solvents such as t-butanol being employed. Alternatively, more success was achieved by preparation of a choline chloride eutectic mixture prior to the polymerisation. It was discovered that a choline chloride/urea eutectic mixture was capable of self initiation, thus required no further addition of catalyst, this result shows a potential step forward in PLA green chemistry. A final investigation into producing surface-active PLA in a one-pot process that required only a hydroxycarboxylate initiator was carried out. The production of PLA sodium or potassium salts was carried out in a melt polymerisation and the results show some promise. Initiators that have been employed include a range of a, b and g-hydroxycarboxylic acids. These work through tautomerisation to the alkoxide, which then initiates a living type polymerisation of lactide to produce surface-active polymers. As well as the synthesis of these polymers some analysis of the physical and aqueous properties of these materials was carried out. PLA sodium salts were shown to have reasonable surfactant ability (~45 mNm⁻¹) and low CMC values of around 5x10⁻⁹ mol cm⁻³. They were also shown to have some properties as emulsifiers, and in some cases showed non-Newtonian fluid behaviour such as shear-thinning (thixotropy) and shear-thickening (dilatant). The thermal characteristics of the polymers such as T[subscript]g and stability were assessed as well as their ability to retain water.

This paper responds to the development policy debate involving the World Bank and the IMF on the use of fiscal policy not only for economic stabilization but also to promote economic growth and increase per capita income. A key issue in this debate relates to the effect of the composition of public expenditure on economic growth. Policy makers and some researchers have argued that expenditure on growth-enhancing functions could enhance future revenue and justify the provision of "fiscal space" in the budget. But there are no simple ways to identify the growth-maximizing composition of public expenditure. The current paper lays out a research strategy to explore the effects of fiscal policy, including the composition of public expenditure, on economic growth, using a time series approach. Based on the modeling strategy of Greiner, Semmler and Gong (2005) we develop a general model that features a government that undertakes public expenditure on (a) education and health facilities which enhance human capital, (b) public infrastructure such as roads and bridges necessary for market activity, (c) public administration to support government functions, (d) transfers and public consumption facilities, and (e) debt service. The proposed model is numerically solved, calibrated and the impact of the composition of public expenditure on the long-run per capita income explored for low-, lower-middle- and uppermiddle-income countries. Policy implications and practical policy rules are spelled out, the extension to an estimable model indicated, a debt sustainability test proposed, and the out-of-steady-state dynamics studied.

Fiber-deployment of telecommunications networks is currently a great challenge for sector-specific regulators, national governments, as well as for investing operators. One of the most controversial regulatory issues in Europe (and elsewhere) is whether the emerging next generation access (NGA) infrastructure should be subjected to cost-based access regulation or whether at least a temporary removal of ex ante obligations ("regulatory holidays") should be granted. In answering this question we examine the current and foreseeable EU regulatory framework and show that it does not provide positive incentives for NGA deployment and increasing penetration rates. On the basis of an international comparison with the most recent data on NGA deployment and penetration, it appears, in turn, that deregulatory and/or state aid driven approaches targeted at the demand (subscribers) and supply side (coverage) are more promising. (author's abstract) / Series: Working Papers / Research Institute for Regulatory Economics

Fibre deployment of next-generation high-speed broadband networks is considered to be a decisive development for any information-based society, yet investment activities and especially the adoption of fibre-based broadband services take place only very gradually in most countries. This work identifies the most important determinants of the adoption of fibre-based broadband services, using the most recent panel data from the European Union member states (EU27) for the years from 2004 to 2012. The results show that the stricter previous broadband access regulation has a negative impact on adoption, while competitive pressure from mobile networks affects adoption in a non-linear manner. It appears that the approach of strict cost-based access regulation embedded in the EU regulatory framework is at odds with the targets outlined in the European Commission's "Digital Agenda". Finally, we also find strong evidence for network effects underlying the adoption process. (author's abstract) / Series: Working Papers / Research Institute for Regulatory Economics