The human prion protein (PrP) gene (PRNP) codon 129 (M/V) polymorphism is a susceptibility factor for variant Creutzfeldt-Jakob Disease (vCJD) and a major determinant of clinico-pathological phenotype in sporadic CJD. The role of codon 129 in defining susceptibility and strain transmission properties has been investigated in three lines of transgenic mice that express human PrP. The human PRNP gene has directly replaced the murine version, by gene targeting, and variation at codon 129 has given the three genotype lines (HuMM, HuMV, and HuVV). The genetics of these three mouse lines are otherwise identical, and therefore differences in transmission properties can be directly attributable to the codon 129 genotype. vCJD inoculation has shown that all three codon 129 genotype mice are susceptible with a ranking of transmission efficiency of HuMM>HuMV>HuVV. HuMM mice develop the most widespread neuropathology with features similar to human vCJD. Subclinical infection was noted in each mouse line. These data suggest that the vCJD strain is transmissible to humans of each of the three codon 129 genotypes, implying that non-MM cases of human infection with bovine spongiform encephalopathy (BSE) may exist but with long subclinical incubation periods. Inoculation of material from blood transfusion associated vCJD showed no change in transmission properties suggesting that the threat of a future epidemic of human-to-human vCJD infection has not been increased by adaptation of the vCJD strain. However the route of infection, for example via blood transfusion or surgery, may be more efficient that the original oral route of BSE infection. sCJD is classified into six subgroups according to clinico-pathological features, and defined by codon 129 genotype and electrophoretic mobility type (1 or 2) of disease associated PrPSc (MM1, MM2, MV1, MV2, VV1, VV2). Typical cases from each subgroup have shown specific transmission properties suggesting that the subgrouping is defining separate disease strains. The commonest subgroup (MM1) was the most transmissible and the HuVV mouse line the most susceptible host. These data outline the transmission risk from all sCJD types to recipients of each codon 129 genotype should an infection event occur, and show the significant role of recipient codon 129 genotype in defining the clinical or subclinical state and the success or failure of transmission. This is important for determining individual risk following known exposure, and for modelling the potential of iatrogenic infection from sCJD patients.

No description available.

Cytomegalovirus (CMV) is a significant cause of mortality and morbidity in immunocompromised patients and an important cause of birth defects if acquired in utero. The licensed CMV antivirals, ganciclovir, cidofovir and foscarnet, all target the viral DNA polymerase. For each drug prolonged use is associated with significant toxicities and development of drug resistance. None are approved for use during pregnancy. Therefore, development of new anti-CMV drugs that target different pathways would be beneficial. All herpesviruses encode an alkaline nuclease. That genetic disruption of the CMV alkaline nuclease, UL98, reduces CMV replication by 1,000-fold suggests that UL98 may be a useful target for development of novel anti-CMV drugs. Moreover, using herpes simplex virus type 1 Hsiang and Ho found that the anthraquinone emodin inhibits activity of the viral alkaline nuclease, blocks viral replication in cell culture, and reduces viral pathogeneses in a mouse model (Brit. J. of Pharm., 2008). Earlier studies also showed that anthraquinone derivatives including emodin have anti-CMV activity (Barnard et al., Antiviral Research 1992 & 1995), although the mechanism of CMV inhibition has not been further studied. We therefore sought to confirm the anti-CMV activities of emodin and related anthraquinone derivatives, to characterize their mechanisms of action, and to determine specifically if they act through inhibition of UL98. Using a luciferase-based CMV yield reduction assay emodin inhibited CMV replication (IC50 = 4.9 μM); however, that the TD50 for cytotoxicity (determined using an luciferase-based cell viability assay) was only 2-fold higher suggested that emodin may act non-specifically. Two additional anthraquinone derivatives (acid blue 40 and alizarin violet R) inhibited CMV only at high concentrations (IC50 = 238; 265 μM) that were also cytotoxic. Atanyl blue PRL, however, exhibited anti-CMV activity (IC50 = 6.3 μM) with low cytotoxicity (TD50 = 216 μM). Thus, characterization of atanyl blue PRL (impact on gene expression, GFP expression, viral spread, infectivity, time of addition studies, and inhibition of UL98 nuclease activity) should be informative. Atanyl blue PRL appears to block immediate-early gene expression and reduce early and late gene expression. Atanyl blue PRL also blocked GFP expression, reduced viral spread, and also lowered the infectivity of CMV. Finally, atanyl blue PRL inhibits UL98 alkaline nuclease activity at an IC50 of 5.7 μM. This suggests that atanyl blue PRL may inhibit CMV through inhibition of UL98. Thus, atanyl blue PRL represents a novel class of anti-herpesvirals and provides a lead structure for structure based drug discovery.

Memoria (licenciado en ciencias jurídicas y sociales) / Esta investigación tiene la intención de realizar un análisis acerca de la idoneidad de la regulación del Caudal ecológico mínimo como una norma de protección ambiental respecto de los objetivos establecidos en el art. 129 bis 1 del Código de Aguas: la preservación de la naturaleza y protección del medio ambiente. Así, en este trabajo se contextualiza la política hídrica vigente en Chile, las problemáticas que ésta enfrenta y la incorporación del Caudal ecológico mínimo dentro de este contexto como una norma destinada a la protección del desarrollo de los ecosistemas. En el primer capítulo, se efectúa un análisis de la historia de los principales cuerpos normativos que regulan las aguas en Chile (Constitución Política de la República, el Código Civil y el Código de Aguas), para luego realizar una revisión de los tratados internacionales ratificados por Chile que han abarcado la materia, con el fin de contextualizar la política hídrica nacional. En el segundo capítulo se estudia la configuración del Caudal ecológico mínimo en la regulación, la que abarca desde la discusión parlamentaria hasta la posterior formulación de norma, analizando los objetivos que esta persigue y su aplicación. Por último, en el tercer capítulo, se desarrollan críticas acerca de la idoneidad de la norma, se analiza la reforma al Código de Aguas en curso respecto del art. 129 bis 1 y, finalmente, se da una propuesta sobre consideraciones necesarias para establecer una nueva regulación.

Since the beginning of the nuclear era, starting during the 1940s, large amount of radioactivity has been released into the environment. This thesis deals with the temporal and spatial distribution of the anthropogenic radioisotope 129I (T1/2= 15.7 Myr) in northern Europe. A routine sample preparation procedure for extraction of iodine from milligram amounts of solid materials has been developed and aimed for measuring the 129I concentration by the ultra-sensitive accelerator mass spectrometry method. The technique was further used for the analysis of 129I in sediments collected from two lakes in Sweden and one lake in Finland as well as sediments from two sites in the Baltic Sea. In addition, 129I concentrations in aerosol samples from northern and southern Sweden covering the period 1983 to 2000 have been measured. The results reveal a gradual increase in the anthropogenic 129I fluxes since the 1950s that are linked to emissions from the nuclear fuel reprocessing facilities in Sellafield (UK) and La Hague (France). A sharp increase coinciding with the Chernobyl accident is identified from the Swedish lakes located in areas characterised by relatively high Chernobyl fallout. Numerical modeling of the 129I deposition predicts that >50% of the flux to the lake sediments is related to the liquid emissions from the reprocessing facilities. The modeling also reasonably simulates the contribution of the Chernobyl event to the total 129I flux. The novel time series from northern Europe on 129I in aerosols show about one order of magnitude higher concentration in northern compared to southern Sweden. Estimate of 129I dry fallout based on the aerosol data suggests <25% contribution to the total fallout. The distribution of 129I in the sediment archives demonstrates the potential of the isotope as a new time marker for chronological and environmental investigations.

L'imagerie par résonance magnétique (IRM) est une technique médicale incontournable permettant d'observer l'intérieur du corps de façon non invasive et non irradiante. L'IRM reste cependant connue pour souffrir d'une très faible sensibilité. Pour pallier cette limitation, une solution de choix est d'utiliser des espèces hyperpolarisées. Parmi les entités dont on peut augmenter la polarisation nucléaire et donc le signal RMN de plusieurs ordres de grandeur, le xénon se distingue par sa capacité à interagir avec son environnement proche, ce qui se traduit par une large gamme de déplacement chimique. L'objectif devient alors d'utiliser le xénon hyperpolarisé comme traceur. Le sujet de cette thèse porte sur le concept de sonde IRM 129Xe hyperpolarisé par laser pour la détection d'évènements biologiques. Dans cette approche, le xénon est vectorisé vers des cibles au moyen de systèmes hôtes fonctionnalisés puis détecté grâce à des séquences d'imagerie rapide. La conception et la mise au point d'un montage permettant la production de xénon hyperpolarisé par pompage optique par échange de spin sont décrites. Sont ensuite développées des études sur l'interaction du gaz rare avec de nouveaux cryptophanes susceptibles de constituer des molécules hôtes performantes. La mise en place de séquences IRM adaptées au caractère transitoire de l'hyperpolarisation et permettant l'utilisation optimale de l'échange du xénon dans les différents environnements est présentée. Des applications de biosondes IRM 129Xe pour la détection de cations métalliques et de récepteurs de surface cellulaire sont également décrites. Enfin, nos premiers résultats sur un modèle petit animal sont abordés.

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This dissertation provides a model for understanding the relation between shifting imperial and post-imperial geopolitics and cultural change in diverse local communities. Specifically, I offer a new perspective on the debate in ancient history regarding “Hellenization,” i.e., the adoption and adaptation of Greek cultural idioms by non-Greek communities. Despite recent advances in emphasizing local communities’ agency in the “Hellenization” process, scholars tend to maintain a rigid dichotomy of monolithic “Greek” vs. “local” culture, and do not offer a comprehensive model accounting for variations in changes, and continuity, by region or time. I propose such a model for the late- and post-Seleucid Levant, and offer significant insights into Hellenistic, Phoenician and Jewish history. I argue that following the Seleucid conquest in the early second century BCE, diverse local communities began competing against each other for imperial favor by often resorting to a form of particularistic ethnic discourse, which emphasized claims to ancestral, pre-Hellenistic identities. In a paradoxical process, however, competing communities often adopted Greek cultural idioms to support these particularistic claims. While it is shown how the specific Greek cultural idioms adapted, varied according to sub-region and period, leadership, and geopolitical situation, it is argued that the idiosyncratic competitive dynamic, fostered by Seleucid power, incentivizing both particularistic discourse and the adoption of new Greek cultural idioms, proved pivotal in allowing diverse communities to develop a Greek cultural “infrastructure.” The political-cultural analysis allows us to broaden and nuance our understanding of subsequent Seleucid disintegration. By better integrating the literary and epigraphical sources with a fresh approach to the numismatic evidence (including the study of some unpublished collections) and taking into account the dramatic archaeological advances of the past two decades, I propose a new model for Seleucid decline. The “concessionist” dynamic outlined by recent scholarship, according to which local elites exploited Seleucid dynastic rivalries to extract privileges, needs to be qualified. While describing well the situation in some communities, such as Hasmonaean Judaea, it is not adequate for cities on the Phoenician coast. Rather, I propose an alternative “loyalist-secessionist” model, stressing the greater importance of external actors, especially the underappreciated role of the Ptolemies and a new understanding of Rome’s indirect involvement. The cultural implications for this novel political-historical model come to the fore following a watershed in Seleucid political history, the death of King Antiochus VII in 129 BCE. In an anarchic late-Hellenistic world, smaller cities, such as Tyre and Sidon, upon becoming independent, sought new alliances by re-utilizing their Greek cultural “infrastructure” towards greater institutional and cultic homology with Greek peer polities. In the absence of Seleucid pressure towards particularism, by contrast, traditional elements were rendered obsolete or even counterproductive to these new efforts. Thus, only at this stage of independence from Hellenistic empire non-Greek cultural elements atrophied, explaining the loss of Phoenician language in this period and the decline in sites of native cult. In other words, it was not a long, linear process of “Hellenization” but concrete, largely contingent, historical factors that explain this development in the specific time and place. In the neighboring Hasmonaean kingdom, by contrast, a series of contingent events (e.g., the “Judaization” of the Idumaeans) created a power-multiplier that put the kingdom onto a different trajectory. Prioritizing imperialistic ambitions, and shifting their own Greek “infrastructure” accordingly, they were not incentivized to similarly abandon traditional language and cult. Rather, by adopting a new ethos of a Hellenistic court, the kingdom facilitated the coalescing of newly-Judaized elites around the Hasmonaean dynasty and Jerusalem, fostering a metrocentric imperialistic outlook which paradoxically complemented and cemented rather than replaced the Yahwistic cult and a sense of Jewish particularism. This, I argue, is a key, hitherto overlooked, factor in the continuity of particularistic Jewish identity, which may help historicize and elucidate the seeming Jewish “exceptionalism” in the region. Put differently, the observed cultural divergence between Levantine communities, clearly apparent by the Roman period, can, in fact, be traced to, and elucidated by a specific historical moment, the common experiences of Seleucid imperial domination and the contingent effects of it collapse in the course of the 2nd century BCE.

Psalms using the language of enmity present a challenge for Christians who wish to use these psalms as prayer. This study investigates the language of enmity in Psalms 110, 119, 129, 137, 139 and 149 as Christian prayer and beyond the normal form category of lament or complaint of the individual. An argument is proposed to understand Book V of the Psalter as an integral unit, which editors have arranged to represent the post-exilic early restoration period. The study begins with an exegesis of each psalm and seeks to determine the perceived suffering of the psalmist(s) at the hands of enemies and the meaning of the responses to these adversaries. It then moves to a limited historical survey of how commentators through Church history have perceived the suffering and responses in these psalms which use language of enmity. This historical survey is used to correct or clarify the findings in the exegesis. In the third movement of this thesis, the results of the individual exegesis and historical survey of Psalms 110, 119, 129, 137, 139 and 149 are compared in order to elucidate the meaning of the language of enmity. The findings suggest that the language of enmity represents images of judgment on a recalcitrant adversary. The psalms are also investigated as prayers and as normative scripture. The use of the language of enmity in these psalms suggests a use of language that differs from normal use. In this regard the rhetorical device of synecdoche is most helpful in explaining how the texts function. The basis for the language of enmity seems to be the unchanging nature of moral evil. The study then investigates the psalms as canonical, normative prayer in order to move towards developing a theology of God’s just dealing with people and his people in particular. In this regard the psalms are approached as prayer, regardless of the voice in which they were composed. It is suggested that the text as normative prayer allows the psalmist, God, and the pray-er to inhabit and celebrate the same sacred time and space. Of particular concern is how each psalm speaks to the issue of how God engages with moral evil and the question of what can be known about moral evil. The findings suggest that these psalms are an invaluable spiritual resource for the church and should remain unaltered in their use as Christian private and public prayer. / PhD (Old Testament), North-West University, Potchefstroom Campus in cooperation with Greenwich School of Theology, 2015