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Doctor of Philosophy / Department of Biochemistry and Molecular Biophysics / John M. Tomich / Branched Amphiphilic Peptide Capsules (BAPCs) are peptide nano-spheres comprised of equimolar proportions of two branched peptide sequences bis(FLIVI)-K-KKKK and bis(FLIVIGSII)-K-KKKK that self-assemble in water to form bilayer delimited poly-cationic capsules capable of trapping solutes. We examined the lipid-like properties of this system including assembly, fusion, solute encapsulation, and resizing by membrane extrusion as well as their capability to be maintained at a specific size by storage at 4˚C. These studies along with earlier work from the lab (Gudlur et al. (2012) PLOS ONE 7(9): e45374) demonstrated that the capsules, while sharing many properties with lipid vesicles, were much more robust. We next investigated the stability, size limitations of encapsulation, cellular localization, retention and, bio-distribution of the BAPCs. We demonstrated that the BAPCs are readily taken up by epithelial cells in culture, escape or evade the endocytotic pathway, and accumulate in the peri-nuclear region where they persist without any apparent degradation. The stability and persistence of the capsules suggested they might be useful in delivering radionuclides. The BAPCs encapsulated alpha particle emitting radionuclides without any apparent leakage, were taken up by cells and were retained for extended periods of time. Their potential in this clinical application is being currently pursued. Lastly we studied the temperature dependence of capsule formation by examining the biophysical characteristics of temperature induced conformational changes in BAPCs and examined the structural parameters within the sequences that contribute to their remarkable stability. A region in the nine-residue sequence was identified as the critical element in this process. The ability to prepare stable uniform nano-scale capsules of desired sizes makes BAPCs potentially attractive as delivery vehicles for various solutes/drugs.

Thesis (MSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: The binary cluster model is used to investigate the properties of exotic structures and decays in various nuclei. A simple method is described to choose the possible clusters forming within the nucleus, by assuming the nucleus consists of a mixture of up to four different core-cluster pairs. A phenomenological potential is then used, with optimized parameters, to describe the even-even 222-232Th nuclei within the binary cluster model, by calculating exotic decay half-lives, reduced electromagnetic transition probabilities, and energy spectra. After finding that all experimentally observed heavy ion emissions are predicted with the model and calculated structure observables are reproduced within good agreement of the experimentally measured values, the model was extended to include the even-even 230-234U, 236-240Pu and 222-224Ra nuclei. We found that almost all experimentally observed heavy ion emissions are predicted within the model with reasonable accuracy in the calculated halflives, and found good agreement in the other calculated structure observables. / AFRIKAANSE OPSOMMING: Die binêre bondel model is gebruik om die eienskappe van eksotiese strukture en verval in verskeie nukliedes te ondersoek. ’n Eenvoudige metode is gebruik om die moontlike bondels wat binne die nuklied vorm te kies, deur die aanname te maak dat die nuklied uit ’n mengsel van tot vier verskillende kern-bondel pare bestaan. ’n Fenomenologiese potensiaal is dan gebruik, met optimale parameters, om die ewe-ewe 222-232Th nukliedes met die binêre bondel model te beskryf, deur eksotiese verval halfleeftye, verminderde elektromagnetiese oorgangswaarskynlikhede, en energie spektra te bereken. Nadat daar gevind is dat alle vrygestelde swaar ione wat eksperimenteel waargeneem is deur die model voorspel word, en berekende struktuur waarneembares tot goeie ooreenstemming met die eksperimentele waardes produseer is, is die model uitgebrei om die ewe-ewe 230-234U, 236-240Pu en 222-224Ra nukliedes in te sluit. Daar is gevind dat byna alle vrygestelde swaar ione wat eksperimenteel waargeneem is deur die model voorspel word met redelike akkuraathied in die berekening van hul halfleeftye, asook dat daar goeie ooreenstemming tussen die berekende en eksperimentele waardes van ander struktuur waarneembares was.

O modelo de cluster de partícula-alfa, o qual já foi bem-sucedido na descrição de dados espectroscópicos em núcleos leves próximos das duplas camadas fechadas no 16O e 40Ca, é aplicado ao núcleo 94Mo da região de massa dos meio-pesados. Para este propósito, vários estados deste núcleo são interpretados em termos de um sistema alfa + 90Zr onde um cluster-alfa interage com um caroço inerte de 90Zr através de um potencial fenomenológico local. São calculados os níveis de energia da banda do estado fundamental e as respectivas taxas de transição B(E2), havendo boa concordância com dados experimentais disponíveis. Os raios intercluster rms calculados para os níveis da banda do estado fundamental indicam que tal banda apresenta uma estrutura de cluster-alfa compacta. A comparação entre auto-funções de oscilador harmônico adaptadas ao sistema e as funções de onda radiais da banda do estado fundamental fornece a estimativa na qual há uma significativa contribuição do modelo de camadas na formação dos estados desta banda. O potencial de interação cluster-caroço faz prever a existência de uma banda de paridade negativa que se inicia a alguns MeV acima do limiar alfa + 90Zr, onde a aproximação de estado ligado é bastante apropriada. Da mesma forma, é previsto que uma banda de paridade positiva excitada se inicia logo abaixo da barreira coulombiana, mostrando uma característica típica de ressonância. / The alpha-particle cluster model, which has already been successful in describing the spectroscopic data in light nuclei near to the double shell closures at 16O and 40Ca, is applied to the 94Mo nucleus of the medium-heavy mass region. For this purpose, various states of this nucleus are interpreted in terms of an alpha + 90Zr system where an alpha-cluster interacts with an inert 90Zr core through a local phenomenological potential. The energy levels of the ground state band and the respective B(E2) transition rates are calculated, in good agreement with available experimental data. The intercluster rms radii calculated for the levels of the ground state band indicate that such band presents a compact alpha-cluster structure. The comparison between harmonic oscillator eigenfunctions adapted to the system and the radial wave functions of the ground state band provides the estimate in which there is a significant contribution of the shell model for the formation of the states of this band. The cluster-core potential predicts the existence of a negative parity band that starts at a few MeV above the alpha + 90Zr threshold, where the bound state approximation is very appropriate. In the same way, it is predicted that an excited positive parity band starts just below the Coulomb barrier, showing a typical feature of resonance.

<p>Reaction cross sections were measured for protons at 65.5 MeV, for deuterons at 37.8, 65.5, 97.4 MeV, for ³He at 96.4, 137.8, 167.3 MeV, and for ⁴He at 69.6, 117.2, 163.9 and 192.4 MeV. Targets were ⁹Be, ¹²C, ¹⁶O, ²⁸Si, ^40,48Ca, ^58,60Ni, ^{112,116,118,120,124}Sn and ²⁰⁸Pb. ⁴⁸Ca and ¹¹⁸Sn targets were used only for some of the measurements. Rest of the targets have been measured for all energies and projectiles but ⁴He at 69.6 MeV where reaction cross sections were measured for ⁹Be, ¹²C, ¹⁶O, ²⁸Si, ⁴⁰Ca targets. A modification of a standard attenuation technique was used. Details of the experimental design are presented.</p><p>Experimental uncertainties were 2-3% for p, 3% for d and 3-10% for ^3,4He. </p><p>A strong forward peaking of the reaction products was observed for ^3,4He. Therefore the standard reaction cross section measurement technique was not applicable for these projectiles. The forward peaking is also responsible for the increase of experimental uncertainties for these projectiles. The forward peaking of the reaction products is not known for other projectiles and has also not been observed with ^3,4He at different - both higher and lower - energies. Possible explanations for this phenomenon are discussed.</p><p>Optical model calculations of the reaction cross sections are in good agreement with the measured values.</p><p>The measurements were performed with beams from the Gustav Werner cyclotron at the The Svedberg Laboratory, Uppsala.</p>

Reaction cross sections were measured for protons at 65.5 MeV, for deuterons at 37.8, 65.5, 97.4 MeV, for 3He at 96.4, 137.8, 167.3 MeV, and for 4He at 69.6, 117.2, 163.9 and 192.4 MeV. Targets were 9Be, 12C, 16O, 28Si, 40,48Ca, 58,60Ni, 112,116,118,120,124Sn and 208Pb. 48Ca and 118Sn targets were used only for some of the measurements. Rest of the targets have been measured for all energies and projectiles but 4He at 69.6 MeV where reaction cross sections were measured for 9Be, 12C, 16O, 28Si, 40Ca targets. A modification of a standard attenuation technique was used. Details of the experimental design are presented. Experimental uncertainties were 2-3% for p, 3% for d and 3-10% for 3,4He. A strong forward peaking of the reaction products was observed for 3,4He. Therefore the standard reaction cross section measurement technique was not applicable for these projectiles. The forward peaking is also responsible for the increase of experimental uncertainties for these projectiles. The forward peaking of the reaction products is not known for other projectiles and has also not been observed with 3,4He at different - both higher and lower - energies. Possible explanations for this phenomenon are discussed. Optical model calculations of the reaction cross sections are in good agreement with the measured values. The measurements were performed with beams from the Gustav Werner cyclotron at the The Svedberg Laboratory, Uppsala.

The general public is at risk of ionising-radiation exposure. The development of high-throughput methods to triage exposures is warranted. Current biodosimetry techniques are low-throughput and encumbered by time and technical expertise. Although there has been an emergence of gene-profiling tools for the purpose of photon biodosimetry, similar capacities do not exist for alpha-particle radiation. Herein is the first genomic study useful for alpha-particle radiation biodosimetric triage. This work has identified robust alpha-particle induced gene-based biomarkers in isolated, ex-vivo irradiated leukocytes from multiple donors. It was found that alpha-particle and photon radiation elicited similar transcriptional responses, which could potentially be distinguished by aggregate-signature analysis. Although no distinct genes were sole indicators of exposure type, clustering algorithms and principal component analysis were able to demarcate radiation type with some success. By comparing the biological effects elicited by photon and alpha-particle radiation, significant contributions have been made to the field of radiation biodosimetry.

O modelo de cluster de partícula-alfa, o qual já foi bem-sucedido na descrição de dados espectroscópicos em núcleos leves próximos das duplas camadas fechadas no 16O e 40Ca, é aplicado ao núcleo 94Mo da região de massa dos meio-pesados. Para este propósito, vários estados deste núcleo são interpretados em termos de um sistema alfa + 90Zr onde um cluster-alfa interage com um caroço inerte de 90Zr através de um potencial fenomenológico local. São calculados os níveis de energia da banda do estado fundamental e as respectivas taxas de transição B(E2), havendo boa concordância com dados experimentais disponíveis. Os raios intercluster rms calculados para os níveis da banda do estado fundamental indicam que tal banda apresenta uma estrutura de cluster-alfa compacta. A comparação entre auto-funções de oscilador harmônico adaptadas ao sistema e as funções de onda radiais da banda do estado fundamental fornece a estimativa na qual há uma significativa contribuição do modelo de camadas na formação dos estados desta banda. O potencial de interação cluster-caroço faz prever a existência de uma banda de paridade negativa que se inicia a alguns MeV acima do limiar alfa + 90Zr, onde a aproximação de estado ligado é bastante apropriada. Da mesma forma, é previsto que uma banda de paridade positiva excitada se inicia logo abaixo da barreira coulombiana, mostrando uma característica típica de ressonância. / The alpha-particle cluster model, which has already been successful in describing the spectroscopic data in light nuclei near to the double shell closures at 16O and 40Ca, is applied to the 94Mo nucleus of the medium-heavy mass region. For this purpose, various states of this nucleus are interpreted in terms of an alpha + 90Zr system where an alpha-cluster interacts with an inert 90Zr core through a local phenomenological potential. The energy levels of the ground state band and the respective B(E2) transition rates are calculated, in good agreement with available experimental data. The intercluster rms radii calculated for the levels of the ground state band indicate that such band presents a compact alpha-cluster structure. The comparison between harmonic oscillator eigenfunctions adapted to the system and the radial wave functions of the ground state band provides the estimate in which there is a significant contribution of the shell model for the formation of the states of this band. The cluster-core potential predicts the existence of a negative parity band that starts at a few MeV above the alpha + 90Zr threshold, where the bound state approximation is very appropriate. In the same way, it is predicted that an excited positive parity band starts just below the Coulomb barrier, showing a typical feature of resonance.

The general public is at risk of ionising-radiation exposure. The development of high-throughput methods to triage exposures is warranted. Current biodosimetry techniques are low-throughput and encumbered by time and technical expertise. Although there has been an emergence of gene-profiling tools for the purpose of photon biodosimetry, similar capacities do not exist for alpha-particle radiation. Herein is the first genomic study useful for alpha-particle radiation biodosimetric triage. This work has identified robust alpha-particle induced gene-based biomarkers in isolated, ex-vivo irradiated leukocytes from multiple donors. It was found that alpha-particle and photon radiation elicited similar transcriptional responses, which could potentially be distinguished by aggregate-signature analysis. Although no distinct genes were sole indicators of exposure type, clustering algorithms and principal component analysis were able to demarcate radiation type with some success. By comparing the biological effects elicited by photon and alpha-particle radiation, significant contributions have been made to the field of radiation biodosimetry.

The purpose of this project was to design, construct, and evaluate an alpha spectrometer based on an inexpensive p-i-n photodiode as a radiation detector. The BPX-61 p-i-n photodiode was selected and calculated to have a 93 µm wide sensitive volume at 25 V reverse bias. Electronics consisting of a charge-sensitive preamplifier, a pole-zero canceling CR-(RC)4 pulse shaping amplifier, and an adjustable detector bias voltage supply were devised and assembled. Several alpha spectra were recorded from different alpha radiation sources to determine the performance of the alpha spectrometer. The results show that the alpha spectrometer could successfully and accurately measure alpha spectra, which could then be used to identify radioactive materials present in the sources. An FWHM resolution of about 230 keV was measured for 5.486 MeV alpha particles from Am-241. This resolution is inferior to most alpha spectrometers that measure under vacuum. However, because the device does not require a vacuum pump and uses USB for power and data acquisition, it is a convenient and compact option for field measurements. The low cost and reasonable performance of commercial p-i-n photodiodes as radiation detectors could be appealing for future alpha spectroscopy applications.