Aims Protein Phosphatase Inhibitor 1 (I-1) functions as an amplifier of the β-adrenergic cascade in cardiomyocytes. Once activated via PKA, I-1 specifically blocks PP-1-mediated dephosphorylation of phospholamban and the ryanodine receptor-1. In heart failure I-1 activity as well as its expression is significantly reduced. It is still unclear whether this adaptation is protective or detrimental. This work aims at examining the impact of I-1 depletion on the course of pressure-induced heart failure, more precisely on acute and long-term mortality, on cardiac morphology and function and on expression levels of hypertrophy markers. Results may help evaluating the benefit of putative I-1 inhibiting substances in the therapy of heart failure. Methods and Results 25 I-1KO and 28 WT mice (C57Bl/6J, age- and sex-matched) underwent transverse aortic constriction (TAC). Cardiac function was assessed via transthoracic echocardiography prior to the intervention and weekly afterwards. Additionally, mice were exposed to β-adrenergic stimulation by injection of dobutamine once prior to TAC and two times afterwards, each controlled by echocardiography. For male mice acute survival was significantly increased in WT compared to I-1KO, whereas the mortality of surviving animals did not differ during the investigation period. For female mice no difference was seen in acute mortality after TAC, but during heart failure progression I-1KO revealed a significantly better survival. Prior to TAC contractility in I-1KO after application of dobutamine was significantly lower than in WT. This effect was mainly induced by female mice. Overall female mice of both WT and I-1KO showed smaller increases in heart rate (HR) and stroke volume (SV) when stimulated. In contrast, following TAC neither line- nor sex-dependent differences were found according to β-adrenergic stimulation. The comparison of hypertrophy markers in control groups revealed clearly decreased levels for I-1KO compared to WT. Conclusion In pressure-induced heart failure, I-1 knockout alters cardiac contractility and modulates mortality in a phase- and sex-dependent way. The depletion is detrimental for male mice in the acute phase of cardiac stress, whereas it is protective for female mice during heart failure progression. The increased mortality in the acute phase might result from the loss of I-1 as an amplifier of β-adrenergic signaling as this leads to a restriction of contractile adaptation. The increased survival in heart failure progression might be caused by a reduced transmission of pathologically increased sympathetic activity on the SR due to the depletion of I-1. Additionally, hypertrophy marker analyses point to differences in expression levels even under non-pathological conditions. / Ziel Der Proteinphosphatase-Inhibitor I-1 wirkt als ein Verstärker der β-adrenergen Kaskade in Kardiomyozyten. Nach PKA-abhängiger Phosphorylierung hemmt er spezifisch die Dephosphorylierung von PLB und RYR-2 durch die Proteinphosphatase-1. Im Rahmen einer Herzinsuffizienz sind sowohl Aktivität als auch Expression von I-1 deutlich reduziert. Hierbei ist unklar, ob dies eine protektive oder eine schädliche Adaption der β-adrenergen Kaskade darstellt. Diese Arbeit untersucht den Einfluss einer Depletion des I-1 (I-1KO) im Rahmen der druckinduzierten Herzinsuffizienz auf die akute bzw. auf die langfristige Mortalität, auf die kardiale Morphologie und Funktion sowie auf die Expression typischer Hypertrophiemarker. Hieraus sollen Erkenntnisse über den Nutzen der Verwendung putativ I-1 inhibierender Substanzen in der Behandlung der Herzinsuffizienz gewonnen werden. Methoden und Resultate 25 I-1KO- sowie 28 WT-Mäuse (C57Bl/6J, age and sex matched) erhielten eine Transverse Aortic Constriction (TAC). Die kardiale Funktion wurde einmalig vor der Intervention sowie danach wöchentlich mittels TTE untersucht. Zusätzlich wurden die Tiere einmalig vor TAC und zweimalig danach unter echokardiographischer Kontrolle mittels Dobutamin β-adrenerg stimuliert. Für die männlichen Tiere zeigte sich in den ersten Tagen nach TAC eine signifikant erhöhte Überlebensrate des WT gegenüber I-1KO. Die Mortalität der überlebenden männlichen Tiere unterschied sich hingegen nicht über den Versuchszeitraum. Für die weiblichen Tiere bestand kein Unterschied in der akuten Sterblichkeit nach TAC, während sich im Verlauf eine signifikant bessere Überlebensrate der weiblichen I-1KO gegenüber WT zeigte. Vor TAC wurde eine signifikant herabgesetzte Kontraktilität (FAS) des I-1KO unter Dobutamin festgestellt, der im Wesentlichen durch die weiblichen Tiere bewirkt wird. Insgesamt zeigten die weiblichen Tiere beider Linien unter β-adrenerger Stimulation eine geringere Zunahme von Herzfrequenz (HR) und Schlagvolumen (SV). Hingegen waren nach TAC keine linien- oder geschlechtsabhängigen Unterschiede unter Dobutamingabe feststellbar. Ein Vergleich der Hypertrophiemarker in der Kontrollgruppe zeigte für I-1KO ein deutlich vermindertes Niveau der Marker gegenüber WT. Ergebnis Der I-1-Knockout verändert die kardiale Kontraktilität und wirkt sowohl in phasen- als auch in geschlechtsabhängiger Weise auf die Mortalität infolge druckinduzierter Herzinsuffizienz. Er ist nachteilig für männliche Tiere in der akuten Phase kardialer Belastung, während er für weibliche Tiere im weiteren Verlauf protektive Wirkung entfaltet. Eine erhöhte Mortalität in der akuten Phase kann durch den Ausfall der Verstärkerfunktion des I-1 erklärt werden, da hiermit eine Einschränkung der akut notwendigen kontraktilen Adaptionsfähigkeit einhergeht. Ein Überlebensvorteil bei chronischer kardialer Belastung könnte darauf zurückzuführen sein, dass die pathologisch erhöhte sympathische Aktivierung der β-adrenergen Kaskade infolge der I-1-Depletion eine geringere Auswirkung auf die Zielstrukturen des aktivierten I-1 am Sarkoplasmatischen Retikulum hat. Darüber hinaus lassen die Analysen der Hypertrophiemarker eine veränderte Genexpression zwischen I-1KO und WT auch unter nicht-pathologischen Bedingungen vermuten.

Aims Protein Phosphatase Inhibitor 1 (I-1) functions as an amplifier of the β-adrenergic cascade in cardiomyocytes. Once activated via PKA, I-1 specifically blocks PP-1-mediated dephosphorylation of phospholamban and the ryanodine receptor-1. In heart failure I-1 activity as well as its expression is significantly reduced. It is still unclear whether this adaptation is protective or detrimental. This work aims at examining the impact of I-1 depletion on the course of pressure-induced heart failure, more precisely on acute and long-term mortality, on cardiac morphology and function and on expression levels of hypertrophy markers. Results may help evaluating the benefit of putative I-1 inhibiting substances in the therapy of heart failure. Methods and Results 25 I-1KO and 28 WT mice (C57Bl/6J, age- and sex-matched) underwent transverse aortic constriction (TAC). Cardiac function was assessed via transthoracic echocardiography prior to the intervention and weekly afterwards. Additionally, mice were exposed to β-adrenergic stimulation by injection of dobutamine once prior to TAC and two times afterwards, each controlled by echocardiography. For male mice acute survival was significantly increased in WT compared to I-1KO, whereas the mortality of surviving animals did not differ during the investigation period. For female mice no difference was seen in acute mortality after TAC, but during heart failure progression I-1KO revealed a significantly better survival. Prior to TAC contractility in I-1KO after application of dobutamine was significantly lower than in WT. This effect was mainly induced by female mice. Overall female mice of both WT and I-1KO showed smaller increases in heart rate (HR) and stroke volume (SV) when stimulated. In contrast, following TAC neither line- nor sex-dependent differences were found according to β-adrenergic stimulation. The comparison of hypertrophy markers in control groups revealed clearly decreased levels for I-1KO compared to WT. Conclusion In pressure-induced heart failure, I-1 knockout alters cardiac contractility and modulates mortality in a phase- and sex-dependent way. The depletion is detrimental for male mice in the acute phase of cardiac stress, whereas it is protective for female mice during heart failure progression. The increased mortality in the acute phase might result from the loss of I-1 as an amplifier of β-adrenergic signaling as this leads to a restriction of contractile adaptation. The increased survival in heart failure progression might be caused by a reduced transmission of pathologically increased sympathetic activity on the SR due to the depletion of I-1. Additionally, hypertrophy marker analyses point to differences in expression levels even under non-pathological conditions. / Ziel Der Proteinphosphatase-Inhibitor I-1 wirkt als ein Verstärker der β-adrenergen Kaskade in Kardiomyozyten. Nach PKA-abhängiger Phosphorylierung hemmt er spezifisch die Dephosphorylierung von PLB und RYR-2 durch die Proteinphosphatase-1. Im Rahmen einer Herzinsuffizienz sind sowohl Aktivität als auch Expression von I-1 deutlich reduziert. Hierbei ist unklar, ob dies eine protektive oder eine schädliche Adaption der β-adrenergen Kaskade darstellt. Diese Arbeit untersucht den Einfluss einer Depletion des I-1 (I-1KO) im Rahmen der druckinduzierten Herzinsuffizienz auf die akute bzw. auf die langfristige Mortalität, auf die kardiale Morphologie und Funktion sowie auf die Expression typischer Hypertrophiemarker. Hieraus sollen Erkenntnisse über den Nutzen der Verwendung putativ I-1 inhibierender Substanzen in der Behandlung der Herzinsuffizienz gewonnen werden. Methoden und Resultate 25 I-1KO- sowie 28 WT-Mäuse (C57Bl/6J, age and sex matched) erhielten eine Transverse Aortic Constriction (TAC). Die kardiale Funktion wurde einmalig vor der Intervention sowie danach wöchentlich mittels TTE untersucht. Zusätzlich wurden die Tiere einmalig vor TAC und zweimalig danach unter echokardiographischer Kontrolle mittels Dobutamin β-adrenerg stimuliert. Für die männlichen Tiere zeigte sich in den ersten Tagen nach TAC eine signifikant erhöhte Überlebensrate des WT gegenüber I-1KO. Die Mortalität der überlebenden männlichen Tiere unterschied sich hingegen nicht über den Versuchszeitraum. Für die weiblichen Tiere bestand kein Unterschied in der akuten Sterblichkeit nach TAC, während sich im Verlauf eine signifikant bessere Überlebensrate der weiblichen I-1KO gegenüber WT zeigte. Vor TAC wurde eine signifikant herabgesetzte Kontraktilität (FAS) des I-1KO unter Dobutamin festgestellt, der im Wesentlichen durch die weiblichen Tiere bewirkt wird. Insgesamt zeigten die weiblichen Tiere beider Linien unter β-adrenerger Stimulation eine geringere Zunahme von Herzfrequenz (HR) und Schlagvolumen (SV). Hingegen waren nach TAC keine linien- oder geschlechtsabhängigen Unterschiede unter Dobutamingabe feststellbar. Ein Vergleich der Hypertrophiemarker in der Kontrollgruppe zeigte für I-1KO ein deutlich vermindertes Niveau der Marker gegenüber WT. Ergebnis Der I-1-Knockout verändert die kardiale Kontraktilität und wirkt sowohl in phasen- als auch in geschlechtsabhängiger Weise auf die Mortalität infolge druckinduzierter Herzinsuffizienz. Er ist nachteilig für männliche Tiere in der akuten Phase kardialer Belastung, während er für weibliche Tiere im weiteren Verlauf protektive Wirkung entfaltet. Eine erhöhte Mortalität in der akuten Phase kann durch den Ausfall der Verstärkerfunktion des I-1 erklärt werden, da hiermit eine Einschränkung der akut notwendigen kontraktilen Adaptionsfähigkeit einhergeht. Ein Überlebensvorteil bei chronischer kardialer Belastung könnte darauf zurückzuführen sein, dass die pathologisch erhöhte sympathische Aktivierung der β-adrenergen Kaskade infolge der I-1-Depletion eine geringere Auswirkung auf die Zielstrukturen des aktivierten I-1 am Sarkoplasmatischen Retikulum hat. Darüber hinaus lassen die Analysen der Hypertrophiemarker eine veränderte Genexpression zwischen I-1KO und WT auch unter nicht-pathologischen Bedingungen vermuten.

Thesis (DTh)--Stellenbosch University, 2006. / ENGLISH ABSTRACT: This dissertation seeks to develop further the theological interpretation of the books of Samuel, by examining I Samuel I: 1-2:10 in the context of fertility and barrenness as blessing and curse. This reading was related to the Karanga understanding of fertility and barrenness. The contribution shows how the Biblical narrative can become a resource for ethical reflection in African communities such as the Karanga women. The hypotheses that guided this study, were that: a-Fertility and barrenness in the Old Testament should be understood in close conjunction with blessing and cursing as theological concepts in ancient Israel. b-Fertility and barrenness could also be examined in a relevant and contextual manner by relating it to the culture and understanding of the Karanga people. In order to achieve this, two major tasks were attempted. One: An exegesis of I Samuel I: 12: 10 in which Vernon Robbins' method of Socio- Rhetorical criticism was used. The method helped to identify that the text is a narrative, and that the author might have been the Deuteronomistic historian, who wrote in the period of the decline of the Judean monarchy and when the Jews were in exile. The narrative is used to tell about the despair of the Jews, and to inform the Jews that there was hope for restoration if they obeyed God. This ideology is woven in the story of a barren woman Hannah who suffered the despair of barrenness and was later blessed with a child because of her prayer and obedience to God. In the narrative God is described as one who cares for the marginalised, and one who changes the lives of his people, from curse to blessing. The method also helped to realise tbe culture and context of Hannah, and made it possible to relate this culture and context to other cultures that are similar. Secondly an empirical survey was conducted amongst one hundred Karanga women. The findings were that Karanga consider fertility as blessing and barrenness as curse. The curse is experienced in the suffering of the barren women. Barrenness is used to inflict pain, to marginalise women, and has become a major cause of divorce and death through the spread of HIV and Aids. A reading of the story of Hannah helped the Karanga women to identify their barren problems with Hannah, and to find a new way of understanding their own problem in terms of hope. This study was able to prove its hypothesis both through the exegesis and the discussions of the research findings. It was found that the narrative form of the text appealed effectively to the understanding of Karanga women. This was possible because narrative is one of the methods of communication that is used effectively by the Karanga in their language. Through using Hannah as a paradigm of curse and blessing in relation to barrenness and fertility, Karanga women were challenged to view their barren situations in a different way that is open to accept change from curse to blessing. The study has also contributed to see how an old text of the time of Hannah could in the present day contextually influence Karanga women's barren experiences through holding the same culture and also by having similar experiences barren of women. / AFRIKAANSE OPSOMMING: Hierdie dissertasie poog om die teologiese interpretasie van die boeke van Samuel verder te ontwikkel by wyse van 'n ondersoek van I Samuel 1:1-2:10 in die konteks van vrugbaarheid en onvrugbaarheid as 'n seën en as 'n vervloeking. Hierdie ondersoek verwys na die Karangabevolking se begrip van vrugbaarheid en onvrugbaarheid. Die bydrae toon aan hoe die Bybelse verhaal 'n bron vir etiese nadenke onder Afrika-gemeenskappe, soos die Karangavroue, kan word. Die hipoteses wat hierdie studie gerig het, was dat: a-Vrugbaarheid en onvrugbaarheid in die Ou Testament behoort begryp te word in 'n noue verbintenis met seën en vervloeking as teologiese begrippe in antieke Israel. b-Vrugbaarheid en onvrugbaarheid kan ook ondersoek word in 'n relevante en kontekstuele wyse deur dit te verbind met die kultuur en begrip van die Karanga-mense. Om dit te vermag, is twee hooftake onderneem. Die eerste was 'n eksegese van I Samuel 1: 12: 10 waarin Vernon Robbins se metode van sosioretoriese kritiek aangewend is. Hierdie metode het gehelp om die teks as 'n narratief te identifiseer en dat die skrywer die Deuteronomiese historikus kon gewees het, wat in die periode van die monargie van Juda geskryf het en ook tydens die Jode se ballingskap. Die narratief word gebruik om aan te toon hoe wanhopig die Jode was en om hulle in te lig dat daar hoop op hul herstel was indien hulle God gehoorsaam. Hierdie ideologie is verweef in die verhaal van die onvrugbare vrou, Hanna, wat aan die wanhoop van onvrugbaarheid gely het en later met 'n kind geseën is op grond van haar gebede en gehoorsaamheid aan God. In die narratief word God as die een beskryf wat na die gemarginaliseerdes omsien en wat die lewens van sy mense vanaf vervloeking tot seën omvorm. Die metode het ook meegehelp om die kultuur en konteks van Hanna te begryp en dit moontlik gemaak om hierdie kultuur en konteks te verklaar ingevolge die van ander soortgelyke kulture. Tweedens is 'n empiriese studie onder 'n honderd Karanga-vroue onderneem. Die bevindinge was dat Karanga-vroue vrugbaarheid as 'n seën en onvrugbaarheid as 'n vervloeking beskou. Die vervloeking word in die lyding van die onvrugbare vroue ervaar. Onvrugbaarheid word aangewend om pyn en lyding te veroorsaak, om vroue te marginaliseer en het 'n belangrike bron van egskeiding en dood deur die verspreiding van HIV en Vigs geword. Deur die verhaal van Hanna te lees, het die Karanga-vroue gehelp om hul eie onvrugbaarheidsprobleme met die van Hanna te identifiseer en om nuwe wyses te vind om hul eie probleme te verstaan in terme van hoop. Hierdie studie was in staat om sy hipoteses te bewys sowel by wyse van die eksegese en ook deur die bespreking van die navorsingsbevindings. Dit is bevind dat die narratiewe vorm van die teks duidelik tot die begrip van die Karanga-vroue gespreek het. Dit was moontlik aangesien 'n verhalende trant een van die kommunikasiewyses is wat doeltreffend deur Karanga-vroue aangewend word in hul taal. Deur Hanna as 'n paradigma van vervloeking en as seën te gebruik met verwysing tot onvrugbaarheid en vrugbaarheid, is Karanga-vroue uitgedaag om hul beskouing van hul onvrugbare toestand op verskillende wyses te betrag wat oop is om 'n verandering te aanvaar vanaf vervloeking tot seën. Die studie het ook daartoe bygedra om te sien hoe 'n ou teks uit die tyd van Hanna tans kontekstueel die Karanga-vroue se onvrugbaarheidservarings kan beinvloed waar hulle uit 'n soortgelyke kultuur kom en ook soortgelyke ervarings as Hanna het as onvrugbare vroue.

Thesis (MPhil (Ancient Studies. Centre for Bible Interpretation and Translation in Africa))--University of Stellenbosch, 2007. / Reading the creation narratives in Genesis 1 and 2, one encounters two totally different renditions. The two creation narratives agree that God created the universe and that God blesses his creation in abundance. But why did the Hebrews need two creation stories so different in style? Gen. 1-2:4a seized my interest and I wanted to explore not only the milieu in which it was written, but also to read it against the creation narratives of the ancient Near East. The research was done religioushistorically. An insight had to be gained in the function and role of mythology within a cultural system and after distinguishing between folk sagas, legends and myths, different types of myths, as well as some perspectives on myths had to be investigated. Creation themes such as creation by birth, by struggle or victory, by action or activity as well as creation through the spoken word were encountered in the various creation narratives studied. Ancient Near East cosmogonies such as the variety of Egyptian cosmogonies, as well as Mesopotamian creation epics have been considered. Hittite myths were also considered, but here the result was the discovery of an extended pantheon with virtually no creation references. Thereafter I have concentrated on the cosmogony of the Hebrew Bible and the position, structure and understanding of Gen. 1-2:4a. Most creation stories revert to bloody violence between the gods. The God of the Hebrews is a God of order – from chaos he creates more than order, he creates beauty. The subsequent survey of the conception of humankind in the near Ancient East, proved to be varied as well as interesting, some with remarkable parallels. My interest was extended to placing the creation narrative of Gen. 1-2:4a in the modern era, by attempting to gain insight into the “Big Bang” theory, as well as Creationism and Evolution movements. Many motives were deducted by the research, but the idea of God creating in a “Godly” manner (bārā') and not merely give order to pre-created creations through struggle was unique. Human beings were created as the pinnacle of creation, and made to live in a relationship with their Creator.

This thesis is an unconventional history of the interpretation of Day One, Genesis 1.1-5, in Hebrew and Greek texts up to c. 200 CE. Using the concept of ‘intertextuality’ as developed by Kristeva, Derrida, and others, the method for this historical exploration looks at the dynamic interconnectedness of texts. The results reach beyond deliberate exegetical and eisegetical interpretations of Day One to include intertextual, and therefore not necessarily deliberate, connections between texts. The purpose of the study is to gain a glimpse into the textual possibilities available to the ancient reader / interpreter. Central to the method employed is the identification of the intertexts of Day One. This is achieved, at least in part, by identifying and tracing flags that may draw the reader from one text to another. In this study these flags are called ‘intertextual markers’ and may be individual words, word-pairs, or small phrases that occur relatively infrequently within the corpus of texts being examined. The thesis first explores the intertextuality of Genesis 1.1-5 in the confines of the Hebrew Bible and the Septuagint. The second half of the thesis identifies and explores the intertexts of Day One in other Hebrew texts (e.g. the Dead Sea Scrolls, Sirach) and other Greek texts (e.g. Philo, the New Testament) up to c. 200 CE. The thesis concludes with a summation of some of the more prominent and surprising threads in this intertextual ‘tapestry’ of Day One. These summary threads include observations within the texts in a given language and a comparative look at the role of language in the intertextual history of Day One.

In this dissertation, the affinities between the Prologue of the Fourth Gospel and the Maronite Prayer of the Faithful especially the use of light metaphor are examined and new hypothetic proposals are suggested: the former has influenced the latter; both of them might have shared the same milieu or have been influenced by an existent Antiochene liturgical hymn. These proposals are discussed according to reflections on the Fourth Gospel, the Antiochene Syriac Maronite Church, the light metaphor, the work done on the Prologue from a socio-rhetorical perspective and the study conducted on the first English edition of the Maronite Prayer of the Faithful. / New Testament / M.Th. (New Testament)

This study attempts to offer an ecological interpretation of Genesis 1: 1-2:4a in view of the question as to what extent this passage bears footprints of anthropocentrism, on the one hand, and/or ecological wisdom, on the other hand. Extant ecological readings of this text tend to either recover its ecofriendliness, or they criticise the text on the basis of its dominion and subdual language in Genesis 1:26-28 which seems to go against the grain of ecological sensibilities. In resonance with revisionist readings, this study shows that the only way to mollify the dominion language of Genesis I :26-28 is to read this section as part of the whole Priestly creation account. Elements of the exilic context and many literary features of Genesis I: l-2:4a present humans as a member of a world of interdependences. Hence, accusing Genesis I: l-2:4a of lying at the root of modern indifference towards nature, is not the whole story. / Old Testament & Ancient Near Eastern Studies / M. A. (Biblical Studies)

In this dissertation, the affinities between the Prologue of the Fourth Gospel and the Maronite Prayer of the Faithful especially the use of light metaphor are examined and new hypothetic proposals are suggested: the former has influenced the latter; both of them might have shared the same milieu or have been influenced by an existent Antiochene liturgical hymn. These proposals are discussed according to reflections on the Fourth Gospel, the Antiochene Syriac Maronite Church, the light metaphor, the work done on the Prologue from a socio-rhetorical perspective and the study conducted on the first English edition of the Maronite Prayer of the Faithful. / New Testament / M.Th. (New Testament)

This study attempts to offer an ecological interpretation of Genesis 1: 1-2:4a in view of the question as to what extent this passage bears footprints of anthropocentrism, on the one hand, and/or ecological wisdom, on the other hand. Extant ecological readings of this text tend to either recover its ecofriendliness, or they criticise the text on the basis of its dominion and subdual language in Genesis 1:26-28 which seems to go against the grain of ecological sensibilities. In resonance with revisionist readings, this study shows that the only way to mollify the dominion language of Genesis I :26-28 is to read this section as part of the whole Priestly creation account. Elements of the exilic context and many literary features of Genesis I: l-2:4a present humans as a member of a world of interdependences. Hence, accusing Genesis I: l-2:4a of lying at the root of modern indifference towards nature, is not the whole story. / Biblical and Ancient Studies / M. A. (Biblical Studies)