O Distrito Aurífero de Lourenço, localizado na região centro-norte do Estado do Amapá, insere-se na Província Geocronológica Maroni-Itacaíunas, de idade Paleoproterozóica, onde ocorrem rochas supracrustais que foram afetadas por metamorfismo de alto grau e parcialmente migmatizadas, bem como complexos cálcio-alcalinos. O depósito de Salamangone hospeda-se em granitóides de composição tonalítica a granodiorítica, de caráter cálcio-alcalino, metaluminosos a levemente peraluminosos. Exibem concentrações relativamente elevadas de LILE e TR leves e baixas taxas de Nb, Ta, Ti e Zr, indicando que teriam sido gerados em ambiente de arco vulcânico. Análises U-Pb (zircão) em tonalito forneceram idade de cristalização de 2,16Ga, enquanto dados de Sm/Nd indicam idades modelo (\'T IND. DM\') da ordem de 2,34Ga (granodiorito) e 2,24Ga (tonalito), com valores positivos de \'\'épsilon\' IND. Nd\'(\'T IND. DM\'), +2,88 (granodiorito) e +3,02 (tonalito), permitindo interpretar que os protólitos desses granitóides foram diferenciados diretamente do manto, com pequena residência crustal, e estariam relacionados a arco juvenil Paleoproterozóico. A isócrona de referência Rb/Sr (rocha total) dos granitóides apontou uma razão inicial em torno de 0,702, indicando uma fonte mantélica (juvenil) para o magma gerador dessas rochas, corroborando os dados de geoquímica. A mineralização aurífera consiste em um sistema de veios de quartzo epigenéticos, enriquecidos em Au e As, controlado por uma zona de cisalhamento dúctil-rúptil. O sistema filoniano compreende três corpos principais, designados de Capa, Principal e Lapa, considerados como sendo veios de cisalhamento ou veios em falhas, tipificados por uma estrutura laminada ou em ribbon, a indicar episódios repetidos de fraturamentos e deposição mineral. A paragênese dos veios comporta 2 fases principais de mineralização: a Fase I, de maior deposição de quartzo, associada a processos de interação rocha-fluido, que provocou a sulfetação intensa na rocha tonalítica encaixante, e, predominantemente, em ribbons dentro dos veios, originando arsenopirita, lollingita, pirrotita e calcopirita, ressalvando-se que o ouro ocorre, principalmente, nos limites da arsenopirita e lollingita. Esta fase de mineralização se formou num intervalo de temperaturas, entre 400° e 565°C, estas calculadas por meio do geotermômetro arsenopirita. Datação Pb/Pb em cristais de arsenopirita desta Fase I forneceram uma isócrona Pb-Pb de referência de 2002 \'+ OU -\' 61 Ma e a composição isotópica sugere um reservatório crustal mais profundo para o Pb, entre as curvas, de evolução da crosta superior e de ambiente orogênico; a Fase II de mineralização constitui o episódio principal de deposição do ouro. Este ocorre sob a forma livre e associado à arsenopirita, pirita e galena e resultou de processos de remobilização, a partir de soluções aquosas de alta salinidade, atuantes ao longo da zona de cisalhamento. Os processos de alteração hidrotermal envolveram, principalmente, silicificação, sulfetação, saussuritização e cloritização da rocha tonalítica encaixante, desenvolvendo uma zona distal com pouca influência da mineralização, e uma zona proximal onde o balanço químico indica ganhos acentuados em As e Au, com pequena participação de MgO e CaO e perdas de \'Al IND. 2\'\'O IND. 3\', \'K IND. 2\'O e \'Na IND. 2\'O. Inclusões fluidas primárias, contendo soluções responsáveis pela Fase I de mineralização, não foram preservadas, tendo sido destruídas por vários episódios superpostos de deformação, responsáveis pela grande quantidade de planos de inclusões fluidas secundárias, observados nas amostras de quartzo. Uma solução aquosa complexa, contendo Ca \'+ OU -\' As(?), extremamente salina, aprisionada em inclusões fluidas, contidas em um conjunto de trilhas com direção entre N5° - 35°W, pode ter sido responsável pela remobilização e precipitação do ouro primário, durante a Fase II de mineralização. A recorrência de episódios de deformação com aporte e circulação de novos fluidos dentro da zona de cisalhamento, que hospeda o depósito de Salamangone, é demonstrada pela presença flagrante de soluções, essencialmente aquosas e com salinidades variadas, que indicam um amplo processo de mistura, envolvendo um fluido extremamente salino que evolui para termos com composições de salinas cada vez mais baixas. A origem dessas soluções pode, provavelmente, ser atribuída a uma mistura de salmouras profundas de natureza metamórfica, com fluidos hidatogênicos. Os dados isotópicos, disponíveis para a área de Lourenço e regiões vizinhas, na Guiana Francesa e Guiana, sugerem um modelo de evolução crustal geodinâmico, baseado no desenvolvimento de um arco magmático cálcio-alcalino, entre 2250 e 2000Ma. Este fato pode ser interpretado admitindo-se a subducção de uma litosfera oceânica, pré-colisão, entre massas continentais representadas, à época, pela Província Central Amazônica (Bloco Carajás-Iricoumé) e pelo Craton do Oeste Africano. Os períodos mais importantes de formação de depósitos de ouro orogênicos do Paleoproterozóico correlacionam-se, muito bem, com os episódios de crescimento da crosta continental juvenil, notando-se que os eventos de concentração de ouro se posicionam entre 2,1 e 1,8 Ga, incluindo a geração de importantes depósitos nos cratons do Oeste Africano e Amazônico e no Orógeno Trans-Hudsoniano (Goldfarb et al. 2001). Deste modo, Salamangone constituiria um depósito aurífero orogênico mesozonal, originado durante processos de deformações compressional a transpressional, em orógenos de acresção, associados à margem convergente Paleoproterozóica. / The Lourenço Au-District is located in the central portion of the State of Amapá, within the Maroni-Itacaiúnas Province, 2.2 - 1.95 Ga (Teixeira et al. 1989), of the Amazonian Craton. The Lourenço region is included within a Paleoproterozoic suite of high-grade partially migmatized metamorphic supracrustal rocks and calc-alkaline complexes. The Salamangone gold deposit lies within a calc-alkaline, metaluminous to slightly peraluminous tonalite to granodiorite pluton. It is characterized by high contents of incompatible trace elements and LREE, showing a geochemical signature of volcanic-arc granites. Zircons extracted from the tonalite were analyzed by the U-Pb method, and analytical points are plotted on a concordia diagram. The discordia calculated for 14 data points has an upper intersection at 2.16 \'+ OU -\' 0.13Ga, the inferred crystallization age of the tonalite, and a lower intercept 0.48 \'+ OU -\' 0.13Ga, respectively. The \'\'épsilon\' IND. Nd\' values were corrected using 2.16Ga age determined for the tonalite. The \'\'épsilon\' IND. Nd (2.16Ga)\' values vary from +2.88 to +3.02, which suggest that the magmatic source region was mainly a depleted mantle with little or no contamination from Archean crust. The low initial \'Sr ANTPOT. 87\'/\'Sr ANTPOT. 86\' ratios obtained for both contemporaneous granodiorite and tonalite vary from 0.702 to 0.703, in agreement with the Sm-Nd isotope data. The deposit, clearly related to the epigenetic style of mineralisation, mainly encompass tree ore bodies, named: Filão Principal, Filão Capa and Filão Lapa. A ductile-brittle shear zone striking N50°-60°W and dipping 55° to 70°NE controls all of these veins. The primary mineralisation consists of ribbon banded quartz veins enriched in Au and As, exhibiting relatively low enrichment of Ag, Pb, Cu, Bi. On the basis of the internal structure and texture, the veins can be classified as laminated. The alteration processes so far recognized are represented by silicification, sulphidation, saussuritization and chloritization of the host tonalite, producing a proximal alteration zone marked by enrichment in As and Au and a poorly mineralized distal zone. The textural and chronological relationships between the most common sulfide minerals, associated with the gold mineralisation, indicate a distinct paragenetic sequence, Stage I: arsenopyrite, pyrrotite, löllingite and chalcopyrite. Gold, located at grain boundaries between arsenopyrite and löllingite, is related to sulphidation hydrothermal processes. Temperatures yielded by the arsenopyrite thermometer are about 400 to 565°C. For directly date the ore minerals, age determinations were made on samples of arsenopyrite by stepwise leaching technique using Pb-Pb systematic. The analytical points define an isochron, which yield an age of 2002 \'+ OU -\' 61 Ma, consistent with the mineralisation stage I. The radiogenic Pb- Pb isotopic composition suggests a deep orogenic crustal source for the Pb. Stage II: arsenopyrite, pyrite and minor galena. It was the predominant period of gold deposition, which is related to remobilization processes. The primary stage I minerarization fluid inclusions are not at all preserved and recognized in the studied quartz samples, because they were destroyed by superposed episodes of deformation. However, abundant secondary aqueous healed fluid inclusions planes were observed. More complex N5°-35°W trending Ca \'+ OU -\' As (?) high salinity aqueous fluids, active during later stages of deformation within shear zone, are probably responsible for remobilization of gold from deeper levels, during stage II mineralization. The wide range of salinities recorded in the aqueous fluid inclusions might be referred to the mixture of high-salinity aqueous fluids with low-salinity fluids. These fluids were probably derived from a mixture of deep metamorphic brines with shallow meteoric waters of deep circulation. The isotopic data available for the Lourenço Au-District and neighboring regions in French Guiana and Guiana, strongly suggest a geodynamic crustal evolution model, based on the development of a calc-alkaline magmatic arc in the time interval (2.25-2.0 Ga). This can be explained by subduction of oceanic lithosphere in the beginning of the collision between two continental masses composed at that time by the Central Amazonian Province-Carajás-Iricoumé Block and the West African craton. The important periods of Archean and Paleoproterozoic orogenic gold-deposit formation correlate well with episodes of growth of juvenile continental crust, where the gold-forming events concentrated between 2.1 and 1.8 Ga, including deposition of the important ores, mainly, in the West Africa craton, Amazonian craton and Trans-Hudson orogen. In this way, the Salamangone gold deposit represents an orogenic mesozonal gold deposit, which was formed during compressional to transpressional deformation processes at Paleoproterozoic convergent plate margins in accretionary orogens.

Introduction AP2α is a 52 kDa retinoic acid inducible and developmentally regulated activator of transcription, which binds to the DNA in a sequence-specific manner. Transcription factor AP-2α was isolated from HeLa cells by affinity chromatography using specific binding sites with in SV40 and human metallothionein promoters. Further screening of HeLa cDNA library with oligonucleotide probes predicted partial peptide sequence which led to the isolation of AP-2α cDNA and subsequently it was mapped to chromosome 6 near HLA locus. A differentially spliced version of AP-2α, which lacks most of the C-terminus, encodes a dominant negative protein (AP-2B). Subsequent studies led to the identification of four more isoforms: AP-2β, AP-2γ, AP-2δ and AP-2ε. AP-2 family members can form homo or hetero dimers among themselves through the unique C-terminal helix span helix motif and bind DNA through basic domain lies N-terminus of DNA binding domain. Several evidences suggest that AP-2α can act as a tumor suppressor gene. It has been shown that AP-2α can activate growth suppressor genes like p21WAF1/CIP1. Transforming viral oncogenes like adenovirus E1A and SV40 large T antigen have been shown to alter AP-2α function. In addition, reduced expression of AP-2α has been reported in human breast, ovary, colon, skin, brain and prostate cancers. Further, supporting evidences suggest that more invasiveness and tumorogenicity was observed when dominant negative mutant of AP-2α was expressed in melanoma cells. In this work, we have carried out a systematic study to find the various signal transduction pathways which regulate AP-2 activity as well as we attempted to demonstrate the importance of DNA binding domain in the growth inhibitory functions of AP-2α. HDAC inhibitors (HDIs) activate AP-2 activity through spleen tyrosine kinase (Syk) In the literature, ample evidences are available that genotoxic drugs such as adriamycin, induce tumor suppressors like p53 and p73. In this study, we have screened pharmacological drugs which damage DNA and specific inhibitors of various signal transduction pathways for their ability to activate AP-2 activity. AP-2 specific reporter, 3Χ-AP2-CAT was used in this study to measure the AP-2 activity. Of all the compounds studied, we found that Histone Deacetylase Inhibitors (HDIs) efficiently activated AP-2 activity and was found to be specific as they failed to activate 3X-AP2 mut CAT, which contains mutated AP-2 binding sites as well as pGL tk Luc, which contains thymidine kinase minimal promoter and no AP-2 binding sites. To understand the mechanism of HDI-mediated of AP-2 activation, AP-2 isoforms and its coactivators transcript and protein levels were analyzed. We found significant change in transcript levels of the some of the molecules tested. While the endogenous protein levels of various AP-2 isoforms were undetectable, we found stabilization of AP-2α protein expressed from exogenous source in cells treated with HDIs. HDI stabilized AP-2α was found to be functionally active as it showed increased sequence-specific DNA-binding as well as increased apoptosis. While HDIs known for their ability to modulate the gene activities by chromatin remodeling, it is also known that they alter various signal transduction pathways. In an effort to find pathway(s) by which HDIs activate AP-2 activity, we found that HDIs failed to activate AP-2 reporter in the presence of staurosporine suggesting the involvement a staurosporine sensitive pathway(s) in this process. Stauosporine is a non-specific kinase inhibitor of different signaling pathways. Further studies using different pathway specific inhibitors identified that spleen tyrosine kinase (Syk) is essential for HDIs mediated activation of AP-2 activity. Syk is a non receptor tyrosine kinase which is known to be activated in stress conditions. Syk is considered to be a tumor suppressor since Syk over expression leads to growth suppression of breast cancer cells and is also inactivated in a subset of breast cancers. These results suggest that HDI mediated activation of AP-2 involves AP-2α stabilization through Syk pathway. Regulation of AP-2 by MAP kinase pathway Cell growth, differentiation, and apoptosis are mediated by the activation of mitogenactivated protein kinase (MAPK) pathways. These kinases constitute MAP kinase cascades mainly regulated through phosphorylation status. In mammalian cells, at least four MAPKs, namely, extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs), p38 and ERK5/big MAP kinase have been identified. The ERKs are usually activated by mitogenic stimuli which in turn increase the proliferation and survival. Over expression of any activator of this signaling cascade lead to the unregulated proliferation of cells. In many cancers, ERK pathways are known to be up regulated. In this study, we found that MEK (MEK is the immediate upstream regulator of ERK) inhibitors - PD98059 and U0126 activate 3X-AP2-CAT suggesting that AP-2 activity is repressed by activated MAP kinase pathway. MEK inhibitor mediated activation was found to be specific because they failed to activate transcription from pGL tk Luc which contains thymidine kinase minimal promoter and no AP-2 binding sites. To understand the mechanism of MEK inhibitor-mediated of AP-2 activation, AP-2 isoforms and its coactivators transcript and protein levels were analyzed. We found significant change in transcript levels of the some of the molecules tested. The endogenous protein levels of various AP-2 isoforms were undetectable. When AP-2α was exogenously expressed, while no change in protein levels and DNA-binding ability was seen, we found evidence for appearance of post-ranslationally modified AP-2α protein in U0126 treated cells. We also found CITED2 (CBP/p300-interacting transactivator 2, co-activator of AP-2α) transcript levels were up regulated in UO126 treated cells. Post translational modifications of AP-2α and increased and increased CITED2 levels may be responsible for MEK inhibitor mediated AP-2 activation. Thus we conclude that ERK pathway, which is an oncogenic MAP kinase pathway, inhibits AP-2 activity thereby suggesting the importance of down regulation of AP-2 activity during transformation. Essential role of DNA-binding domain of AP-2α for its growth inhibitory functions Transcription factor AP-2α has three distinct domains, N-terminal transactivation domain (52-108 aa), C-terminal DNA binding domain (204-408 aa) and dimerization domain (277-395 aa) which lies within the DNA binding domain. AP-2α exerts its effects through binding to specific DNA sequence in the promoter of its target genes leading to either repression or activation. Recent evidences suggest that AP-2α represses many genes through its competitive binding to overlapping AP-2 and other transcription factor binding sites. This suggests an important role exclusively for the DNA binding domain in AP-2α mediated functions. To address the importance of DNA binding domain for AP-2α mediated apoptosis, we have tested the ability different deletion/point mutants of AP-2α with varying DNA binding and transactivation capability to perform growth suppressor function and ability to induce apoptosis. Replication-deficient recombinant adenoviruses expressing different mutants were used in this study. We found that an intact DNA-binding domain alone even in the absence of activation domain is sufficient for AP-2α to inhibit colony formation and to induce significant levels of apoptosis. These results suggest an important role for DNA binding domain growth inhibitory functions of AP-2α and thereby implying the importance of transcriptional repression in AP-2α functions.

This thesis examines the impacts of inclement weather days on AP exam scores in public schools, specifically low socioeconomic districts, and the assessment of their current closure procedures. By investigating the potential disruption in scores by inclement weather days, I can create a new dataset in analyzing a field that has yet to be studied through this lens, in addition to advising future policy for district superintendents and state government officials. The areas studied include Massachusetts and Georgia, representing states that are properly prepared for inclement weather closures and are under-prepared for inclement weather, respectively. I use two research methods to fully understand the quantitative and qualitative effects of inclement weather closures. The first is a quantitative analysis of district-level data on inclement weather days and AP exam scores over the past five years. To accomplish this, I contacted public-school districts in the two states involved in the case study to get raw data on school closures and combine this with already available datasets on AP exam score performance. The second is a qualitative account of inclement weather days from teachers and superintendents from districts across both states to establish their opinions regarding school closures and investigate the decision-making process in canceling school. In this qualitative assessment, I observe the roles that socioeconomic status and public transportation, among other factors, play in cancelations. This thesis seeks to challenge the argument proposed by previous research that snow days have no effect on test performance. Previously, this was measured by looking at state-wide exams. By using AP exams as a performance measure instead, a more direct impact on exam scores is expected due to the immovable testing dates and content- specific nature of the exams. Policy recommendations are given to accommodate the negative relationship between closures and test scores, given socioeconomic status.

We have recently reported that antioxidant liposomes can be used as antidotes for mustard gas induced lung injury in guinea pigs. The maximum protection was achieved with a liposome composed of tocopherols (α, γ, δ) and N-acetylcysteine (NAC) when administered after 5 min of exposure of 2-chloroethyl ethyl sulfide (CEES), a half sulfur mustard gas. We also reported an association of mustard gas-induced lung injury with an activation of MAPK/AP-1 signaling pathway and cell proliferation. The objective of the present study was to investigate whether CEES-induced MAPKs/AP-1 signaling pathway is influenced by antioxidant liposome therapy. A single dose (200 μl) of the antioxidant liposome was administered intratracheally after 5 min of exposure of CEES (0.5 mg/kg). The animals were sacrificed after 1 h and 30 days of CEES exposure. Although the liposome treatment did not have any significant effect on the activation of the MAPKs family (ERK1/2, p38 and JNK1/2), it significantly counteracted the CEES-induced activation of AP-1 transcription factors and corresponding increase in the protein levels of Fos, ATF and Jun family members. The liposome treatment significantly blocked the CEES-induced increase in the protein levels of cyclin D1, a cell cycle protein and PCNA, a cell differentiation marker. Furthermore, it protected lung against CEES-induced inflammation and infiltration of neutrophils, eosinophils and erythrocytes in the alveolar space. This suggests that the protective effect of antioxidant liposome against CEES-induced lung damage is mediated via control of AP-1 signaling.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21135号 / 農博第2261号 / 新制||農||1057(附属図書館) / 学位論文||H30||N5109(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 松井 徹, 教授 久米 新一, 教授 廣岡 博之 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

Previous studies from our lab have shown that the Activating Protein- 2 (AP-2) transcription factors, AP-2α and AP-2β, are important in retinal development. It was discovered that these are co-expressed in developing horizontal cells and postmitotic amacrine cells. To understand their role in retinogenesis, and the impact of their deletion on the adult retina, a double mutant mouse model was created, AP-2αKI/flox/AP-2β-/flox. The neural retina of the AP-2αKI/flox/AP-2β-/flox mice was examined in the current study using histological, immunofluorescent and electron microscopy (EM) techniques at embryonic, post-natal and adult stages. These double mutants displayed a variety of abnormalities in the inner retina. Loss of AP-2α and AP-2β at E10.5 led to a complete absence of developing and mature horizontal cells. This loss was associated with changes in the outer plexiform layer, which diminished from two to four months of age. There were also defects with photoreceptor ribbons in which triad synapses failed to form, and instead led to rudimentary, spherical-shaped ribbons. There was also significant retraction of photoreceptor axons. Furthermore, this study was able to infer a role of AP-2α and AP-2β as acting upstream of the Onecut-1 protein, which targets Lim1 and Prox1 to direct horizontal cell genesis. Examining amacrine cells of the double mutants shows evidence that AP-2α and AP-2β are involved in the mosaic arrangement pattern of amacrine cell bodies and axons. Previous work on embryonic double mutants displayed clustering of amacrine cells. This study observed abnormalities in the dendrites of the inner plexiform layer, which consists of amacrine cell processes. Taken together, the work presented in this thesis implicates the redundant requirement of both AP-2α and AP-2β in development of horizontal cells and patterning of amacrine cells in the neural retina. / Thesis / Master of Health Sciences (MSc)

To increase student engagement as well as cover the content of Ancient Rome, the author developed a game named Civitas for an AP Art History course. The question driving this research project was, "Will incorporating a game into this Ancient Rome unit increase engagement without sacrificing the academic integrity of the class?" Research about engagement as well as others' success incorporating games into the classroom was examined to determine the benefits and difficulties. Much of the work for this unit came before any teaching occurred: designing all aspects of the game as well as carefully determining how it would contribute to measurable learning objectives. The researcher video recorded three AP History courses, with a total of 8 students, over a period of one week. Data collection measures used to determine engagement included a video-recording of the class, keeping a log of engaged behaviors, personal observations, and student free-response questions. Data collection measures to determine evidence of learning content about Ancient Rome included analysis of students' homework, discussions in the class, a multiple-choice test, and an essay test. Upon analysis, it was concluded that playing Civitas greatly increased engagement as well as contributed to the academic integrity of the unit. However, it also took twice as long to engage with the same subject matter, was expensive to produce, and many hours of preparation, which limits the ability to share this learning strategy with others.

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The software environment for power electronics design is comprised of tools that address many interrelated disciplines including circuits design, physical layout, thermal management, structural mechanics, and electromagnetics. This usually results in a number of separate models that provide various views of a design, each of which is usually stored separately in proprietary formats. The problem is that the relationships between views (e.g., the circuit design that defines the functional connectivity between components, and the physical layout that provides physical paths to implement connections), are not explicitly captured. This makes it difficult to synchronize and maintain data consistency across all models as changes are made to the respective views. This thesis addresses this problem by describing power electronics modules using STEP AP210, the STandard for the Exchange of Product data, Application Protocol 210; which has been designated as ISO 10303-210. A multidisciplinary model was implemented for an integrated power electronics module (IPEM). It consists of two views of the IPEM: a functional network definition of the IPEM, and a physical implementation that satisfies the functional connectivity requirements. The relationships between these two views are explicitly recorded in the model. These relationships allow for the development of a method which verifies whether the connectivity data in both views are consistent. Finally, this thesis provides guidance for deploying STEP AP210 to unify multidisciplinary data resources during the design of integrated power electronics. / Master of Science