Le muscle squelettique adulte a une importante capacité à se régénérer après une lésion. La régénération musculaire dépend de divers signaux moléculaires tels que l’activation de la signalisation Wnt dans les cellules souches musculaires, appelées cellules satellites. Les protéines R-spondins (Rspo) composent une famille de quatre protéines qui ont un rôle d’activateurs/potentialisateurs sur les voies Wnt dans les cellules souches de différents tissus. Bien qu’il soit connu que ces protéines sont importantes pour la régénération de ces tissus, leur rôle dans la myogenèse régénérative n’a pas été étudié à ce jour. L’expression génique de R-spondin1 étant sur-régulée par Pax7, le marqueur des cellules satellites, nous avons émis l’hypothèse que R-spondin1 participe à la régénération musculaire. Nous avons, tout d’abord, isolé les cellules souches musculaires des modèles murins d’invalidation constitutive pour Rspo1 et avons observé qu’une déficience de R-spondin1 n’altère pas le cycle cellulaire de ces cellules. Cependant, une altération de l’expression de Rspo1 induit un défaut global de la cinétique de différenciation myogénique. Nous montrons que R-spondin1 inhibe la fusion des cellules musculaires puisque les myotubes déficients pour R-spondin1 possèdent un plus grand nombre de noyaux. Nous avons ensuite induit la régénération du muscle squelettique Tibalis Antérieur par une injection de Cardiotoxine et nous avons analysé les muscles à différents temps de régénération. Nos données prouvent qu’en l’absence de R-spondin1, les cellules souches présentent un retard de différenciation alors qu’elles possèdent une plus grande capacité de fusion, ayant pour conséquence une hypertrophie des myofibres dans le muscle. Concordant au rôle de R-spondin dans les cellules souches intestinales ou dans le follicule pileux, la protéine R-spondin1 stimule l’expression des gènes cibles de la voie Wnt canonique dans les cellules souches musculaires. Nous avons mis en évidence que R-spondin1 potentialise la voie Wnt canonique et régule négativement l’activation de la voie non-canonique dans les cellules. Nos résultats démontrent que la protéine R-spondin1 contribue à la régénération du muscle squelettique adulte par la régulation de l’activation des voies Wnt. / Adult mammalian skeletal muscles have the remarkable ability to repair after injury. Muscle regeneration depends on various cellular and molecular responses, such as activation of Wnt signaling pathways in muscle stem cells called satellite cells. R-spondin (Rspo) proteins are able to potentiate Wnt signaling pathways in vivo in many stem cells and play important role for regeneration of several tissues. The role of R-spondin in injury-induced myogenesis has not been studied. Given that R-spondin1 gene expression is up-regulated by Pax7, the satellite cell-specific transcription factor, we explored the hypothesis that R-spondin1 plays a role during skeletal muscle regeneration. We firstly isolated primary myoblasts from Rspo1 constitutive knock-out mice and observed that a depletion of Rspo1 did not alter cell cycle of these cells. However, a lack of R-spondin1 on cells resulted in global alteration of differentiation kinetics. We found that R-spondin1 inhibits muscle cell fusion, as Rspo1 knock-out myotubes contain an higher number of myonuclei. Then, we injured the Tibialis Anterior (TA) muscle of Rspo1-null mice and littermates controls by Cardiotoxin injection and analyzed muscle regeneration at different time points following injury. Our data show that R-spondin1 removal results in a delay of stem cell differenciation. In contrast, a R-spondin1 deficiency leads to better cell capacity to fuse to dommaged myofibers, giving rise to myofiber hypertrophy. As with other tissue-specific stem cells, such as hair follicle or intestinal crypt stem cells, R-spondin1 potentiates canonical Wnt signaling target genes expression in muscle stem cells. We proved that R-spondin1 potentiates canonical Wnt signaling target genes expression and negatively regulates non-canonical signaling in muscle stem cells. Our results demonstrate that R-spondin1 is crucial for adult muscle regeneration through a tighly cross-talk regulation between Wnt signalings.

A lesão granulomatosa é caracterizada como um agregado compacto de fagócitos maduros formado em resposta à um estímulo persistente. Os mediadores pró-inflamatórios da família da IL-1, ao promoverem a ativação da imunidade inata e o remodelamento tecidual descontrolados, geram a fisiopatologia da paracoccidioidomicose, doença pulmonar granulomatosa causada pelo fungo P. brasiliensis. A principal via inflamatória envolvida na secreção de IL-1?, IL-18 e IL-1? é a ativação dos inflammasomas, complexos protéicos conhecidos pela sua capacidade de ativar proteoliticamente a enzima caspase-1. Neste estudo abordamos os mecanismos subjacentes às vias canônica e não canônica do inflamassoma, avaliando a importância funcional das caspases 1, 11 e 8 na resistência do hospedeiro durante a infecção por P. brasiliensis. Demonstramos que a resposta imunológica protetora mediada pelo IFN-?, após a liberação de IL-18 pela via da caspase-1, é o principal mecanismo responsável pelo controle fúngico quando o dano celular desencadeado pelo fungo é reconhecido pelo inflamassoma de NLRP3. No entanto, apesar do papel importante da caspase-1 na maturação da IL-1?, a falta de caspase-1 apenas reduz parcialmente os níveis de IL-1? durante a infecção por P. brasiliensis. Ao contrário do esperado, a deficiência de caspase-11 não prejudicou a produção de IL-1?, mas em vez disso, preveniu, na célula, a morte por piroptose e a secreção IL-1?, citocina importante para restringir o crescimento fúngico através da síntese de IL-17. Por fim, observamos que a ativação de caspase-8 pela sinalização de dectina-1 / Syk, além de mediar a maturação da IL-1?, que acontece de maneira independente de caspase-1 e 11, é necessária também para o funcionamento eficiente da via canônica de caspase-1, demonstrando uma rede interligada entre as vias canônica de caspse-1 e não canônica de caspase-8 para coordenar o processamento da IL-1?. Em conjunto, nossos resultados mostram contribuições distintas das vias canônica e não canônica do inflamassoma na produção de citocinas da família da IL-1, enfatizam a versatilidade desta plataforma em recrutar várias proteínas efetoras para adequar a resposta imunológica antifúngica e evidenciam a complexidade envolvida nas interações patógeno-hospedeiro. / Granuloma is a lesion characterized by a compact aggregate of mature phagocytes arising in response to a persistent stimulus. By driving uncontrolled innate immunity and tissue remodelling, IL-1 family pro-inflammatory mediators govern the pathophysiology of paracoccidioidomycosis, a granulomatous lung disorders caused by Paracocccidioides brasiliensis. A major inflammatory pathway involved in IL-1?, IL-18 e IL-1? secretion is the activation of inflammasomes, large multimolecular complexes best known for their ability to control activation of the proteolytic enzyme caspase-1. In this study we addressed the mechanisms that underlie canonical and non-canonical inflammasome pathways, assessing the functional importance of caspase-1, caspase-11 and caspase-8 in the regulation of inflammasome-mediated host resistance during P. brasiliensis infection. We found that IFN-?-mediated protective immune response following by caspase-1- dependent IL-18 release after is the key mechanism responsible for the fungal control after P. brasiliensis-induced cell damage recognition by NLRP3 canonical inflammasome pathway. Nonetheless, despite the important role of caspase-1 in the IL-1? maturation, the lack of caspase-1 only partially reduced IL-1? levels during P. brasiliensis infection. Unlike caspase-1, caspase-11 deficiency did not impair IL-1? production, cytokine strictly secreted by canonical caspase-1 inflammasome pathway. Instead, P. brasiliensis-triggered caspase-11 activation in an ill-defined manner leads to a rapid pore-mediated cell lysis and is required for IL-1? production during P. brasiliensis infection. IL-1?, in turn, is important for promoting the restriction of fungal growth trough IL-17-based inflammation. Finally, the caspase-8 induction by dectin-1/Syk signaling besides playing a role in mediating the caspase-1/11-independent IL-1? maturation is also required to efficient canonical caspase-1 inflammasome pathway, demonstrating a connected network between non-canonical caspase-8 and canonical caspase-1 inflammasome pathways to coordinate IL-1?. Taken together, our results revealed distincts contributions of both canonical and non-canonical inflammasome pathways in IL-1 family cytokine production and emphasizes the versatility of this platform to recruit several effector proteins to tailor the antifungal immune response, sheding new light on the complexity of this hostpathogen interaction.

Submitted by Valquíria Barbieri (kikibarbi@hotmail.com) on 2018-05-11T20:59:15Z No. of bitstreams: 1 DISS_2015_Karen Janones da Rocha.pdf: 4327569 bytes, checksum: 1207959001ffdfc221d56edf601d488a (MD5) / Approved for entry into archive by Jordan (jordanbiblio@gmail.com) on 2018-05-24T14:50:15Z (GMT) No. of bitstreams: 1 DISS_2015_Karen Janones da Rocha.pdf: 4327569 bytes, checksum: 1207959001ffdfc221d56edf601d488a (MD5) / Made available in DSpace on 2018-05-24T14:50:15Z (GMT). No. of bitstreams: 1 DISS_2015_Karen Janones da Rocha.pdf: 4327569 bytes, checksum: 1207959001ffdfc221d56edf601d488a (MD5) Previous issue date: 2015-02-06 / CAPES / O objetivo geral do presente estudo foi caracterizar um fragmento secundário de Floresta Estacional Semidecidual localizado em Tapurah-MT, quanto a sua estrutura e composição florestal, verificar a formação de grupos florísticos e, ainda, explorar possíveis relações com o ambiente. Aplicou-se o método de área fixa com conglomerados retangulares de dimensões de 10 x 250 m, foram alocados e medidos cinco conglomerados com cinco subunidades cada de 10 X 50 m. Em cada subunidade amostral foi considerada todas as espécies arbóreas e arbustivas com diâmetro à altura do peito (DAP) superior ou igual a 10 cm. A composição florística foi analisada quanto ao número de famílias, gêneros e espécies botânicas encontradas no levantamento do componente arbóreo e a suficiência amostral do levantamento florístico foi verificada pelo procedimento Bootstrap. A similaridade florística entre as subunidades amostrais foi obtida através do Índice de Jaccard e a diversidade de espécies nas subunidades amostrais foi medida pelo Índice de Shannon (H’) e pelo Índice de Equabilidade de Pielou (J’). A caracterização da estrutura horizontal da vegetação foi feita a partir dos parâmetros fitossociológicos e a estrutura diamétrica pelo procedimento de Spiegel. A presença de grupos florísticos foi verificada pelo método de associação das espécies e o número de grupos foi estabelecido pelo coeficiente de concordância de Kendall, onde para cada grupo florístico foi analisada a estrutura horizontal, o padrão de distribuição espacial das espécies pelo índice de Payandeh e a estrutura diamétrica dos indivíduos pelo procedimento de Spiegel. A construção da matriz das variáveis edáficas foi realizada através de uma análise preliminar para identificar variáveis semelhantes entre as subunidades amostrais, as quais não apresentaram influência foram retiradas. A correlação entre os dados de vegetação e dados ambientais foi realizada por meio da Análise de Correlação Canônica, que permitiu confirmar se os nutrientes do solo influenciam na presença das espécies e pela Análise de Redundância Canônica para avaliar quais as variáveis ambientais apresentaram maior influência sobre os indivíduos. No fragmento foi verificada uma alta variabilidade florística e estrutural, que pode ser explicada pelos históricos de perturbação local a que este fragmento foi submetido no passado. De uma forma geral, a vegetação corresponde a de florestas secundárias jovens e apresenta uma comunidade estável e autorregenerativa, além de preservar características da estrutura original. Através da análise de agrupamento foi verificado que as características autoecológicas das espécies assim como os DAP’s médios de cada espécie foram os principais responsáveis pela associação e similaridade entre os grupos. Também foi verificada que apesar das perturbações no ambiente que salientam a saturação do sítio florestal, o fragmento está se recuperando. A heterogeneidade das variáveis edáficas relacionadas influencia no comportamento florístico-estrutural do fragmento secundário de Floresta Estacional Semidecidual. Sendo, as espécies das famílias Fabaceae, Lauraceae, Moraceae e Vochysiaceae as mais influentes para o presente estudo. Destacando a Qualea paraensis Ducke quanto à importância ecológica e a sua adaptabilidade ao ambiente. / The general objective of this study was to characterize a secondary fragment of semideciduous forest located in Tapurah-MT, as its structure and forest composition, verify the formation of floristic groups and also explore possible relationships with the environment. Was applied the fixed area method with five rectangular clusters of 10 x 250 m, they were measured and allocated to five subunits of 10 x 50 m each. In each sample subunit was considered all tree and shrub species with diameter at breast height (DBH) greater than or equal to 10 cm. The floristic composition was analyzed for the number of families, genera and plant species found in the survey of the tree component and sampling sufficiency of floristic survey was tested by bootstrap procedure. The floristic similarity between plots was obtained through the Jaccard index and the diversity of species in the sample subunits was measured by the Shannon Index (H') and equability index of Pielou (J'). The characterization of the horizontal structure of vegetation was made from the phytosociological parameters and the structure diameter by Spiegel procedure. The presence of floristic groups was verified by the association method of species and the number of groups was established by Kendall concordance coefficient, where for each floristic group was analyzed horizontal structure, the pattern of spatial distribution of species by Payandeh index and the diameter distribution of individuals by Spiegel procedure. The construction of the matrix of the soil variables was performed in a preliminary analysis to identify variables similar to the sample subunits, which showed no influence were dropped. The correlation between the data of vegetation and environmental data was performed by Canonical Correlation Analysis, which allowed confirm that soil nutrients influence the presence of the species and the Canonical Redundancy Analysis to evaluate which environmental variables had the greatest influence on the individuals. In the studied fragment was observed high variability floristic and structural, which can be explained by historical local disturbance that this fragment was in the past. In general, the vegetation corresponds to young secondary forests and presents a stable and self-regenerative community, besides preserving the original structure characteristics. Through cluster analysis it was found that the ecological self characteristics of the species as well as the average DBH of each species were mainly responsible for the association and similarity between the groups. We also observed that despite the disturbances in the environment that emphasize the saturation of forest site, the fragment is recovering. The soil variables heterogeneity related influence the floristic-structural behavior of the secondary fragment of semideciduous forest. Being, the species of the families: Fabaceae, Lauraceae, Moraceae and Vochysiaceae the most influential for the present study. Highlighting the Qualea paraensis Ducke about its ecological significance and adaptability to the environment.

Reliability prediction of components operating in complex systems has historically been conducted in a statistically isolated manner. Current physics-based, i.e. mechanistic, component reliability approaches focus more on component-specific attributes and mathematical algorithms and not enough on the influence of the system. The result is that significant error can be introduced into the component reliability assessment process. The objective of this study is the development of a framework that infuses the influence of the system into the process of conducting mechanistic-based component reliability assessments. The formulated framework consists of six primary steps. The first three steps, identification, decomposition, and synthesis, are qualitative in nature and employ system reliability and safety engineering principles for an appropriate starting point for the component reliability assessment. The most unique steps of the framework are the steps used to quantify the system-driven local parameter space and a subsequent step using this information to guide the reduction of the component parameter space. The local statistical space quantification step is accomplished using two newly developed multivariate probability tools: Multi-Response First Order Second Moment and Taylor-Based Inverse Transformation. Where existing joint probability models require preliminary statistical information of the responses, these models combine statistical information of the input parameters with an efficient sampling of the response analyses to produce the multi-response joint probability distribution. Parameter space reduction is accomplished using Approximate Canonical Correlation Analysis (ACCA) employed as a multi-response screening technique. The novelty of this approach is that each individual local parameter and even subsets of parameters representing entire contributing analyses can now be rank ordered with respect to their contribution to not just one response, but the entire vector of component responses simultaneously. The final step of the framework is the actual probabilistic assessment of the component. Variations of this final step are given to allow for the utilization of existing probabilistic methods such as response surface Monte Carlo and Fast Probability Integration. The framework developed in this study is implemented to conduct the finite-element based reliability prediction of a gas turbine airfoil involving several failure responses. The framework, as implemented resulted in a considerable improvement to the accuracy of the part reliability assessment and an increased statistical understanding of the component failure behavior.

No description available.

Which matrices can be written as sums or products of square-zero matrices? This question is the central premise of this dissertation. Over the past 25 years a signi - cant body of research on products and linear combinations of square-zero matrices has developed, and it is the aim of this study to present this body of research in a consolidated, holistic format, that could serve as a theoretical introduction to the subject. The content of the research is presented in three parts: rst results within the broader context of sums and products of nilpotent matrices are discussed, then products of square-zero matrices, and nally sums of square-zero matrices. / Mathematical Sciences / M. Sc. (Mathematics)

The study was aimed at exploring the relationship between poverty and aggravated robbery in Limpopo Province. Sampled secondary data of aggravated robbery of- fenders, obtained from the South African Police (SAPS), Polokwane, was used in the analysis. From empirical researches on poverty and crime, there are some deductions that vulnerability to crime is increased by poverty. Poverty set was categorised by gender, employment status, marital status, race, age and educational attainment. Variables for aggravated robbery were house robbery, bank robbery, street/common robbery, carjacking, truck hijacking, cash-in-transit and business robbery. Canonical correlation analysis was used to make some inferences about the relationship of these two sets. The results revealed a signi cant positive correlation of 0.219(p-value = 0.025) between poverty and aggravated robbery at ve per cent signi cance level. Of the thirteen variables entered into the poverty-aggravated model, ve emerged as sta- tistically signi cant. These were gender, marital status, employment status, common robbery and business robbery. / Mathematical Sciences / M. Sc. (Statistics)

A lesão granulomatosa é caracterizada como um agregado compacto de fagócitos maduros formado em resposta à um estímulo persistente. Os mediadores pró-inflamatórios da família da IL-1, ao promoverem a ativação da imunidade inata e o remodelamento tecidual descontrolados, geram a fisiopatologia da paracoccidioidomicose, doença pulmonar granulomatosa causada pelo fungo P. brasiliensis. A principal via inflamatória envolvida na secreção de IL-1?, IL-18 e IL-1? é a ativação dos inflammasomas, complexos protéicos conhecidos pela sua capacidade de ativar proteoliticamente a enzima caspase-1. Neste estudo abordamos os mecanismos subjacentes às vias canônica e não canônica do inflamassoma, avaliando a importância funcional das caspases 1, 11 e 8 na resistência do hospedeiro durante a infecção por P. brasiliensis. Demonstramos que a resposta imunológica protetora mediada pelo IFN-?, após a liberação de IL-18 pela via da caspase-1, é o principal mecanismo responsável pelo controle fúngico quando o dano celular desencadeado pelo fungo é reconhecido pelo inflamassoma de NLRP3. No entanto, apesar do papel importante da caspase-1 na maturação da IL-1?, a falta de caspase-1 apenas reduz parcialmente os níveis de IL-1? durante a infecção por P. brasiliensis. Ao contrário do esperado, a deficiência de caspase-11 não prejudicou a produção de IL-1?, mas em vez disso, preveniu, na célula, a morte por piroptose e a secreção IL-1?, citocina importante para restringir o crescimento fúngico através da síntese de IL-17. Por fim, observamos que a ativação de caspase-8 pela sinalização de dectina-1 / Syk, além de mediar a maturação da IL-1?, que acontece de maneira independente de caspase-1 e 11, é necessária também para o funcionamento eficiente da via canônica de caspase-1, demonstrando uma rede interligada entre as vias canônica de caspse-1 e não canônica de caspase-8 para coordenar o processamento da IL-1?. Em conjunto, nossos resultados mostram contribuições distintas das vias canônica e não canônica do inflamassoma na produção de citocinas da família da IL-1, enfatizam a versatilidade desta plataforma em recrutar várias proteínas efetoras para adequar a resposta imunológica antifúngica e evidenciam a complexidade envolvida nas interações patógeno-hospedeiro. / Granuloma is a lesion characterized by a compact aggregate of mature phagocytes arising in response to a persistent stimulus. By driving uncontrolled innate immunity and tissue remodelling, IL-1 family pro-inflammatory mediators govern the pathophysiology of paracoccidioidomycosis, a granulomatous lung disorders caused by Paracocccidioides brasiliensis. A major inflammatory pathway involved in IL-1?, IL-18 e IL-1? secretion is the activation of inflammasomes, large multimolecular complexes best known for their ability to control activation of the proteolytic enzyme caspase-1. In this study we addressed the mechanisms that underlie canonical and non-canonical inflammasome pathways, assessing the functional importance of caspase-1, caspase-11 and caspase-8 in the regulation of inflammasome-mediated host resistance during P. brasiliensis infection. We found that IFN-?-mediated protective immune response following by caspase-1- dependent IL-18 release after is the key mechanism responsible for the fungal control after P. brasiliensis-induced cell damage recognition by NLRP3 canonical inflammasome pathway. Nonetheless, despite the important role of caspase-1 in the IL-1? maturation, the lack of caspase-1 only partially reduced IL-1? levels during P. brasiliensis infection. Unlike caspase-1, caspase-11 deficiency did not impair IL-1? production, cytokine strictly secreted by canonical caspase-1 inflammasome pathway. Instead, P. brasiliensis-triggered caspase-11 activation in an ill-defined manner leads to a rapid pore-mediated cell lysis and is required for IL-1? production during P. brasiliensis infection. IL-1?, in turn, is important for promoting the restriction of fungal growth trough IL-17-based inflammation. Finally, the caspase-8 induction by dectin-1/Syk signaling besides playing a role in mediating the caspase-1/11-independent IL-1? maturation is also required to efficient canonical caspase-1 inflammasome pathway, demonstrating a connected network between non-canonical caspase-8 and canonical caspase-1 inflammasome pathways to coordinate IL-1?. Taken together, our results revealed distincts contributions of both canonical and non-canonical inflammasome pathways in IL-1 family cytokine production and emphasizes the versatility of this platform to recruit several effector proteins to tailor the antifungal immune response, sheding new light on the complexity of this hostpathogen interaction.

Einer der bestimmenden Faktoren moderner Gesellschaften ist die fortlaufende Digitalisierung von Informationen und Resourcen. Dieser Trend spiegelt sich in heutiger Forschung wider und hat starken Einfluss auf akademische und industrielle Projekte. Es ist nahezu unmöglich, ein modernes Projekt aufzusetzen, welches keinerlei digitale Aspekte beinhaltet und viele Projekte werden mit dem alleinigen Zweck der Digitalisierung eines Teils der Welt ins Leben gerufen. Dieser Trend führt zur Entstehung neuer Forschungsfelder an den Schnittstellen zwischen der analogen Welt -- beispielsweise den Geisteswissenschaften -- und der Digitalen -- beispielsweise der Informatik. Eine davon ist das für diese Arbeit interessante Gebiet der Digital Humanities. Dabei werden komplexe Forschungsfragen, -techniken und -prinzipien verbunden, die sich unabhängig voneinander entwickelten. Viel Mühe ist nötig, um die Kommunikation zwischen deren Konzepte zu definieren um Missverständnisse und Fehleinschätzungen zu vermeiden. Dieser Prozess der Brückenbildung ist eine zentrale Aufgabe der neu entstehenden Forschungsfelder. Diese Arbeit schlägt eine solche Brücke für die textorientierten Digital Humanities vor. Diese Lösung basiert auf einem Referenzsystem für digitalen Text, welches in den Geisteswissenschaften spezifiziert und im Rahmen dieser Arbeit zu einem Datenkommunikationsprotokoll für die Informatik uminterpretiert wurde: dem Canonical Text Service (CTS) Protokoll. / One of the defining factors of modern societies is the ongoing digitization of information, resources and in many ways even life itself. This trend is obviously also reflected in today's research environments and heavily influences the direction in which academic and industrial projects are headed. It is borderline impossible to set up a modern project without including digital aspects and many projects are even set up for the sole purpose of digitizing a specific part of the world. One of the side effects of this trend is the emergence of new research fields at the intersection points between the analog world -- represented for example by the humanities -- and the digital world -- represented for example by computer science. One set of such research fields are the digital humanities, the area of interest for this work. In the process of this development, complex research questions, techniques, and principles are aligned next to each other that were developed independently from another. A lot of work has to go into defining communication between the concepts to prevent misunderstandings and misconceptions on both sides. This bridge building process is one of the major tasks that must be done by the newly developed research fields. This work proposes such a bridge for the text-oriented digital humanities based on a digital text reference system that was previously developed in the humanities and is in this work reinterpreted as a data communication protocol for computer science: The Canonical Text Service (CTS) protocol.

It is widely agreed among scholars that the third part of the Hebrew canon, the Writings, is a miscellaneous collection of materials, as its name would seem to suggest. My thesis re-examines this assumption. The introduction sets out the critical issues, outlines the thesis and charts the larger picture from which the thesis makes a limited contribution. Chapter one explains my approach. In critical conversation with Brevard Childs and his adherents, I examine the need for contours within the canonical context that respect the discrete voice of each book, while understanding it in relationship to the larger collection in which it is located. The canon is not like a street map, rather, it is more like a topographical map providing contour and depth to the canonical terrain. Taking Childs’ approach one step further; I examine the formation of the Twelve Minor prophets and the Psalter in order to develop a redaction critical grammar for the compilation of texts into collections that serves as a methodological check for the project. This grammar includes the use of catchwords or phrases to bind adjacent books near their seams, the juxtaposition of similar or contrasting themes, framing devices, and superscriptions to provide an overall structure. Chapter two analyzes the formation of the Writings in antiquity. There were a number of different conceptions of sacred literature within Judaism, but probably within temple circles the canon of the Jews was closed prior to the end of the first century C.E. The Prologue to Ben Sira testifies to a tripartite arrangement of the Jewish canon, and 4 Ezra, which provides solid evidence that the canon was closed sometime prior to the end of the first century C.E., confirms the antiquity of a tripartite arrangement. Chapter three explores the various orders for the Writings. Within the conceptual world of Judaism, the concern with the order of the books is not the result of the invention of the codex or long scroll, but rather arises from the holiness attributed to these books in association with their strong connection to the temple and its sacred space. Despite the consensus that there are a vast number of orders for the collection, in fact there is only evidence that the Masoretic (Leningrad Codex) and the Talmudic (Baba Batra 14b) orders existed prior to the twelfth century C.E. The grouping of the Megilloth in the Masoretic tradition is probably not the result of liturgical practices within Judaism, as is commonly thought, which leaves room to re-examine the antiquity of this order. Both arrangements reveal a similar logic of association among the books of the Writings with the possible exception of Ruth. Chapter four explores the location of Ruth in the Former Prophets between Judges and Samuel and in the Writings after Proverbs and before the Psalter. Ruth has been purposefully figured into the Former Prophets and then later was integrated into the Writings after Proverbs as a wisdom book. In this case, different orders bear witness to the search for meaningful associations within the canon. Chapter five probes Esther’s position as part of the sub-collection of Lamentations, Esther, Daniel and Ezra-Nehemiah, in which it always follows Lamentations and is juxtaposed to Daniel. Within this canonical frame I explore Esther’s links to Daniel 1-6 and Lamentations 5 and the way this sets in relief Esther’s theology. Chapter six briefly observes some compilational phenomena in Song of Songs, Ecclesiastes and Lamentations. I also examine the structure of the Megilloth as a whole and the forces at work in this sub-collection. The thesis concludes, due to historical and exegetical reasons, that the codification of the Megilloth into a collection is an integral part of the canonical process rather than a formal feature that is the result of some supposed effort to close the canon.