The hyperglycemia induced by angiotensin II in rats is mediated by AT1 receptors

We have shown that the renin-angiotensin system (RAS) is involved in glucose homeostasis during acute hemorrhage. Since almost all of the physiological actions described for angiotensin II were mediated by AT1 receptors, the present experiments were designed to determine the participation of AT1 receptors in the hyperglycemic action of angiotensin II in freely moving rats. The animals were divided into two experimental groups: 1) animals submitted to intravenous administration of angiotensin II (0.96 nmol/100 g body weight) which caused a rapid increase in plasma glucose reaching the highest values at 5 min after the injection (33% of the initial values, P<0.01), and 2) animals submitted to intravenous administration of DuP-753 (losartan), a non-peptide antagonist of angiotensin II with AT1-receptor type specificity (1.63 µmol/100 g body weight as a bolus, iv, plus a 30-min infusion of 0.018 µmol 100 g body weight-1 min-1 before the injection of angiotensin II), which completely blocked the hyperglycemic response to angiotensin II (P<0.01). This inhibitory effect on glycemia was already demonstrable 5 min (8.9 ± 0.28 mM, angiotensin II, N = 9 vs 6.4 ± 0.22 mM, losartan plus angiotensin II, N = 11) after angiotensin II injection and persisted throughout the 30-min experiment. Controls were treated with the same volume of saline solution (0.15 M NaCl). These data demonstrate that the angiotensin II receptors involved in the direct and indirect hyperglycemic actions of angiotensin II are mainly of the AT1-type.

Effect of all-trans retinoic acid on newly diagnosed acute promyelocytic leukemia patients: results of a Brazilian center

Thirty-seven patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA). Patients received 45 mg m-2 day-1 po of ATRA until complete remission (CR) was achieved, defined as: a) presence of less than 5% blasts in the bone marrow, with b) white blood cells >103/mm3, c) platelets >105/mm3 and d) hemoglobin concentration >8 g/dl, with no blood or platelet transfusions. Thirty-one (83.7%) patients achieved CR by day 50, and 75% of these before day 30. Correction of the coagulopathy, achieved between days 2 and 10 (mean, 3 days), was the first evidence of response to treatment. Only one patient had been previously treated with chemotherapy and three had the microgranular variant M3 form. Dryness of skin and mucosae was the most common side effect observed in 82% of the patients. Thrombosis, hepatotoxicity and retinoid acid syndrome (RAS) were observed in 7 (19%), 6 (16%) and 4 (11%) patients, respectively. Thirteen (35%) patients had to be submitted to chemotherapy due to hyperleukocytosis (above 40 x 103/mm3) and six of these presented with new signs of coagulopathy after chemotherapy. Four (11%) patients died secondarily to intracerebral hemorrhage (IH) and two (5.4%) dropped out of the protocol due to severe ATRA side effects (one RAS and one hepatotoxicity). RAS and IH were related strictly to hyperleukocytosis. The reduced use of platelets and fresh frozen plasma probably lowered the total cost of treatment. We conclude that ATRA is an effective agent for inducing complete remission in APL patients.

Angiotensin II-mediated vascular smooth muscle cell growth signaling

The mechanism by which Ang II stimulates the growth of vascular smooth muscle cells was investigated by measuring the phosphorylation of mitogen-activated protein kinases ERK 1 and ERK 2. Ca2+ ionophore was found to have effects practically analogous to Ang II. We found that the signaling pathway involves the activation of epidermal growth factor receptor (EGFR) kinase, activation of the adaptor proteins Shc and Grb2, and the small G-protein Ras. Although the mechanism of AT1- (or Ca2+)-induced activation of EGFR is not yet clear, we have found that calcium-dependent protein kinase CAKß/PYK2 and c-Src are involved in this process. These studies indicate a transactivation mechanism that utilizes EGFR as a bridge between a Gq-coupled receptor and activation of phosphotyrosine generation.

The effect of porphyrins on normal and transformed mouse cell lines in the presence of visible light

Photodynamic therapy consists of the uptake of a photosensitizing dye, often a porphyrin, by tumor tissue and subsequent irradiation of the tumor with visible light of an appropriate wavelength matched to the absorption spectrum of the photosensitizing dye. This class of molecules produces reactive oxygen species when activated by light, resulting in a direct or indirect cytotoxic effect on the target cells. Photodynamic therapy has been used in the treatment of cancer but the technology has a potential for the treatment of several disease conditions mainly because of its selectivity. However, it is not clear why the porphyrins are retained preferentially by abnormal tissue. This paper describes a study of the effect of the association of porphyrin and visible light on two mouse fibroblast cell lines: A31, normal cells and B61, an EJ-ras transformed variant of A31. Two water-soluble porphyrins were used, a positively charged one, tetra(N-methyl-4-pyridyl)porphyrin chloride, and a negatively charged one, tetra(4-sulfonatophenyl)porphyrin-Na salt (TPPS4) in order to assess the effect on cell survival. The results suggest that the B61 cell line is more sensitive to incubation with the anionic porphyrin (TPPS4) followed by light irradiation and that the anionic porphyrin is more efficient in killing the cells than the cationic porphyrin.

Enhanced expression of Ang-(1-7) during pregnancy

Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS). The physiological consequences of the stimulated RAS in normal pregnancy are incompletely understood, and even less understood is the question of how this system may be altered and contribute to the hypertensive disorders of pregnancy. Findings from our group have provided novel insights into how the RAS may contribute to the physiological condition of pregnancy by showing that pregnancy increases the expression of both the vasodilator heptapeptide of the RAS, angiotensin-(1-7) [Ang-(1-7)], and of a newly cloned angiotensin converting enzyme (ACE) homolog, ACE2, that shows high catalytic efficiency for Ang II metabolism to Ang-(1-7). The discovery of ACE2 adds a new dimension to the complexity of the RAS by providing a new arm that may counter-regulate the activity of the vasoconstrictor component, while amplifying the vasodilator component. The studies reviewed in this article demonstrate that Ang-(1-7) increases in plasma and urine of normal pregnant women. In preeclamptic subjects we showed that plasma Ang-(1-7) was suppressed as compared to the levels found in normal pregnancy. In addition, kidney and urinary levels of Ang-(1-7) were increased in pregnant rats coinciding with the enhanced detection and expression of ACE2. These findings support the concept that in normal pregnancy enhanced ACE2 may counteract the elevation in tissue and circulating Ang II by increasing the rate of conversion to Ang-(1-7). These findings provide a basis for the physiological role of Ang-(1-7) and ACE2 during pregnancy.

Reduced plasma levels of angiotensin-(1-7) and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

The relationship between preeclampsia and the renin-angiotensin system (RAS) is poorly understood. Angiotensin I-converting enzyme (ACE) is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II) and inactivating the vasodilator angiotensin-(1-7) (Ang-(1-7)). ACE (I/D) polymorphism is characterized by the insertion (I) or deletion (D) of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D) polymorphism was correlated with plasma Ang-(1-7) levels and several RAS components in both preeclamptic (N = 20) and normotensive pregnant women (N = 20). The percentage of the ACE DD genotype (60%) in the preeclamptic group was higher than that for the control group (35%); however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260). The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 ± 5.06 vs 27.6 ± 3.25 nmol Hip-His Leu-1 min-1 mL-1 in DD control patients; P = 0.0005). Plasma renin activity was markedly reduced in preeclampsia (0.81 ± 0.2 vs 3.43 ± 0.8 ng Ang I mL plasma-1 h-1 in DD normotensive patients; P = 0.0012). A reduced plasma level of Ang-(1-7) was also observed in preeclamptic women (15.6 ± 1.3 vs 22.7 ± 2.5 pg/mL in the DD control group; P = 0.0146). In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

A low concentration of ouabain (0.18 µg/kg) enhances hypertension in spontaneously hypertensive rats by inhibiting the Na+ pump and activating the renin-angiotensin system

We investigated the effects of low ouabain concentrations on systolic (SAP) and diastolic (DAP) arterial pressures and on pressor reactivity in 3-month-old male spontaneously hypertensive rats (SHR). Arterial blood pressure (BP) and pressor reactivity to phenylephrine (PHE) were investigated before and after 0.18 μg/kg ouabain administration (N = 6). The influence of hexamethonium (N = 6), canrenone (N = 6), enalapril (N = 6), and losartan (N = 6) on ouabain actions was evaluated. Ouabain increased BP (SAP: 137 ± 5.1 to 150 ± 4.7; DAP: 93.7 ± 7.7 to 116 ± 3.5 mmHg; P<0.05) but did not change PHE pressor reactivity. Hexamethonium reduced basal BP in control but not in ouabain-treated rats. However, hexamethonium + ouabain increased DAP sensitivity to PHE. Canrenone did not affect basal BP but blocked ouabain effects on SAP. However, after canrenone + ouabain administration, DAP pressor reactivity to PHE still increased. Enalapril and losartan reduced BP and abolished SAP and DAP responses to ouabain. Enalapril + ouabain reduced DAP reactivity to PHE, while losartan + ouabain reduced SAP and DAP reactivity to PHE. In conclusion, a small dose of ouabain administered to SHR increased BP without altering PHE pressor reactivity. Although the renin-angiotensin system (RAS), Na+ pump and autonomic reflexes are involved in the effects of ouabain on PHE reactivity, central mechanisms might blunt the actions of ouabain on PHE pressor reactivity. The effect of ouabain on SAP seems to depend on the inhibition of both Na+ pump and RAS, whereas the effect on DAP seems to depend only on RAS.

Effect of blocking Rac1 expression in cholangiocarcinoma QBC939 cells

Cholangiocarcinomas (CCs) are malignant tumors that originate from epithelial cells lining the biliary tree and gallbladder. Ras correlative C3 creotoxin substrate 1 (Rac1), a small guanosine triphosphatase, is a critical mediator of various aspects of endothelial cell functions. The objective of the present investigation was to study the effect of blocking Rac1 expression in CCs. Seventy-four extrahepatic CC (ECC) specimens and matched adjacent normal mucosa were obtained from the Department of Pathology, Inner Mongolia Medicine Hospital, between 2007 and 2009. Our results showed that the expression of Rac1 was significantly higher (53.12%) in tumor tissues than in normal tissues. Western blotting data indicated a significant reduction in Rac1-miRNA cell protein levels. Rac1-miRNA cell growth rate was significantly different at 24, 48, and 72 h after transfection. Flow cytometry analysis showed that Rac1-miRNA cells undergo apoptosis more effectively than control QBC939 cells. Blocking Rac1 expression by RNAi effectively inhibits the growth of CCs. miRNA silencing of the Rac1 gene suppresses proliferation and induces apoptosis of QBC939 cells. These results suggest that Rac1 may be a new gene therapy target for CC. Blocking Rac1 expression in CC cells induces apoptosis of these tumor cells and may thus represent a new therapeutic approach.

Alternative pathways for angiotensin II generation in the cardiovascular system

The classical renin-angiotensin system (RAS) consists of enzymes and peptides that regulate blood pressure and electrolyte and fluid homeostasis. Angiotensin II (Ang II) is one of the most important and extensively studied components of the RAS. The beneficial effects of angiotensin converting enzyme (ACE) inhibitors in the treatment of hypertension and heart failure, among other diseases, are well known. However, it has been reported that patients chronically treated with effective doses of these inhibitors do not show suppression of Ang II formation, suggesting the involvement of pathways alternative to ACE in the generation of Ang II. Moreover, the finding that the concentration of Ang II is preserved in the kidney, heart and lungs of mice with an ACE deletion indicates the important role of alternative pathways under basal conditions to maintain the levels of Ang II. Our group has characterized the serine protease elastase-2 as an alternative pathway for Ang II generation from Ang I in rats. A role for elastase-2 in the cardiovascular system was suggested by studies performed in heart and conductance and resistance vessels of normotensive and spontaneously hypertensive rats. This mini-review will highlight the pharmacological aspects of the RAS, emphasizing the role of elastase-2, an alternative pathway for Ang II generation.

Veracidade da germinação indicada nas embalagens de sementes de espécies medicinais

O comércio de sementes de plantas medicinais encontra-se em ascensão, estimulado pelo crescente consumo de ervas, seja para o preparo de infusões, ou mesmo para o preparo de fármacos industrializados. No entanto, o consumidor dessas sementes normalmente encontra dificuldades para o cultivo destas espécies. Dentre os problemas por eles enfrentados, encontra-se a baixa densidade populacional, decorrente da utilização de sementes de baixa qualidade, ou por seguirem as informações expressas nas embalagens, as quais nem sempre conferem com a realidade. Considerando estas dificuldades, desenvolveu-se o presente trabalho, com a finalidade de avaliar a qualidade das sementes de cinco espécies de plantas medicinais, verificar a autenticidade das informações impressas nas embalagens para utilização doméstica, especialmente quanto a reprodutibilidade do teste germinação e a eficiência dos métodos indicados nas Regras para Análise de Sementes (RAS), adotadas no Brasil, para a superação da dormência. Sementes de anis (Pimpinella anisum L.), funcho (Foeniculum vulgare Mill.), losna (Artemisia absinthium L.), melissa (Melissa officinalis L.) e hortelã (Mentha piperita L.) foram submetidas a tratamentos para superação de dormência sugeridos pelas RAS, avaliando-se posteriormente, a germinação e emergência em casa de vegetação. Conclui-se que: a percentagem de germinação indicada nas embalagens domésticas superestima a qualidade de todas as espécies avaliadas; o pré-esfriamento é um método eficiente para a superação da dormência de sementes de melissa; o KNO3 é apropriado para a superar da dormência de sementes de hortelã; nas embalagens de sementes de espécies medicinais, deveriam constar informações adicionais quanto a possível existência de dormência nas sementes, bem como, o método adicional a ser empregado para superá-la.

Targeting oncogenic signaling proteins : new insights using a FRET-based chemical biology approach

Cancer affects more than 20 million people each year and this rate is increasing globally. The Ras/MAPK-pathway is one of the best-studied cancer signaling pathways. Ras proteins are mutated in almost 20% of all human cancers and despite numerous efforts, no effective therapy that specifically targets Ras is available to date. It is now well established that Ras proteins laterally segregate on the plasma membrane into transient nanoscale signaling complexes called nanoclusters. These Ras nanoclusters are essential for the high-fidelity signal transmission. Disruption of nanoclustering leads to reduction in Ras activity and signaling, therefore targeting nanoclusters opens up important new therapeutic possibilities in cancer. This work describes three different studies exploring the idea of membrane protein nanoclusters as novel anti-cancer drug targets. It is focused on the design and implementation of a simple, cell-based Förster Resonance Energy Transfer (FRET)-biosensor screening platform to identify compounds that affect Ras membrane organization and nanoclustering. Chemical libraries from different sources were tested and a number of potential hit molecules were validated on full-length oncogenic proteins using a combination of imaging, biochemical and transformation assays. In the first study, a small chemical library was screened using H-ras derived FRET-biosensors. Surprisingly from this screen, commonly used protein synthesis inhibitors (PSIs) were found to specifically increase H-ras nanoclustering and downstream signalling in a H-ras dependent manner. Using a representative PSI, increase in H-ras activity was shown to induce cancer stem cell (CSC)-enriched mammosphere formation and tumor growth of breast cancer cells. Moreover, PSIs do not increase K-ras nanoclustering, making this screening approach suitable for identifying Ras isoform-specific inhibitors. In the second study, a nanoncluster-directed screen using both H- and K-ras derived FRET biosensors identified CSC inhibitor salinomycin to specifically inhibit K-ras nanocluster organization and downstream signaling. A K-ras nanoclusteringassociated gene signature was established that predicts the drug sensitivity of cancer cells to CSC inhibitors. Interestingly, almost 8% of patient tumor samples in the The Cancer Genome Atlas (TCGA) database had the above gene signature and were associated with a significantly higher mortality. From this mechanistic insight, an additional microbial metabolite screen on H- and K-ras biosensors identified ophiobolin A and conglobatin A to specifically affect K-ras nanoclustering and to act as potential breast CSC inhibitors. In the third study, the Ras FRET-biosensor principle was used to investigate membrane anchorage and nanoclustering of myristoylated proteins such as heterotrimeric G-proteins, Yes- and Src-kinases. Furthermore, Yes-biosensor was validated to be a suitable platform for performing chemical and genetic screens to identify myristoylation inhibitors. The results of this thesis demonstrate the potential of the Ras-derived FRETbiosensor platform to differentiate and identify Ras-isoform specfic inhibitors. The results also highlight that most of the inhibitors identified predominantly perturb Ras subcellular distribution and membrane organization through some novel and yet unknown mechanisms. The results give new insights into the role of Ras nanoclusters as promising new molecular targets in cancer and in stem cells.

Validação de metodologia para o teste de germinação em sementes de nabo forrageiro (Raphanus sativus L. var. oleiferus)

Para várias espécies vegetais, testes como o de germinação não tem seus procedimentos descritos nas Regras para Análise de Sementes (RAS) utilizadas no Brasil pela falta de padronização e validação metodológica. Dentre elas, o nabo forrageiro, que tem sido considerada uma cultura promissora para a produção de biodiesel, tem sua germinação avaliada por metodologia recomendado para a espécie Raphanus sativus , mas tem especificidade de variedade (var oleiferus) com características de plantas e sementes, que diferem das demais variedades da espécie. Para assegurar a padronização de metodologias para o comércio internacional de sementes é necessário estabelecer critérios para validação de metodologia, cuja descrição deve ser clara e completa com procedimentos que propiciem exatidão, robustez, precisão (reprodutibilidade e repetibilidade). O objetivo neste estudo foi avaliar o processo de validação de duas metodologias para o teste de germinação em sementes de nabo forrageiro, utilizando para as análises estatísticas o procedimento padrão da ISTA, bem como técnicas complementares. Os testes de germinação foram realizados em oito laboratórios com cinco lotes, utilizando substrato areia e papel em temperatura alternada 20-30 ºC. As técnicas estatísticas foram utilizadas para: verificar a homogeneidade dos lotes (teste H), identificar a presença de valores discrepantes (método de Hampel) e outliers nas variâncias (teste de Levene para média); avaliar os efeitos de laboratórios e lotes (Análise de Variância); verificar a repetibilidade, reprodutibilidade, exatidão e robustez (limites críticos de repetibilidade, reprodutibilidade, estatísticas h e k de Mandel), comparar as diferentes metodologias de germinação (testes F) e reavaliar o nível de qualidade dos lotes (Análise Discriminante). Tanto no aspecto estatístico, como fitotécnico, as metodologias para o teste de germinação em sementes de nabo forrageiro com a utilização do substrato areia e papel, temperatura alternada 20-30 ºC podem ser considerados validadas, pois apresentam exatidão, robustez e precisão adequadas.

Recueil de lettres et de pièces originales, et de copies de pièces indiquées comme telles dans le dépouillement qui suit.

Contient : 1 Lettre du roi « CHARLES » IX au « Sr de Montmorency, mareschal de France... A Thoulouse, le VIIIe jour de fevrier 1565 » ; 2 Lettre du roi « CHARLES » IX au « duc de Nevers, pair de France... A Chaune, le XVIIIe jour de aoust 1567 » ; 3 Lettre du roi « CHARLES » IX au « duc de Nevers,... lieutenant general delà les montz... A Chaune, le XVIIIe jour de aoust 1567 » ; 4 Lettre de « CATERINE » DE MEDICIS au duc de Nevers, « A Chaune, le XXme jour de aoust 1567 » ; 5 Lettre de « CATERINE [DE MEDICIS]... à monseigneur l'evesque de Conserans [Menaud de Martres]... A Nogent sur Seine, le VIIe jour d'avril M. V.C. XLVIII, apres Pasques » ; 6 Lettre du roi « CHARLES » IX au « duc de Nevers,... A Paris, le cinquiesme jour de juing 1572 » ; 7 Lettre de « FRANÇOYS [DE CLEVES]... à monseigneur de Rasay, cappitaine et gouverneur de Maisieres... A Chaallons, ce XVIIe jour d'apvril 1548 » ; 8 Lettre d'ANNE DE « MONTMORENCY [connétable de France]... à monseigneur [l'évêque] de Conserans... De Amboise, le IIIIe jour d'avril » ; 9 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur l'evesque de Conserans... D'Amboise, le XIIIe jour d'avril » ; 10 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur de Conserans,... De Fere en Tardenois, ce XXIIIe avril » ; 11 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur l'evesque de Conserans... De Chantilly, le XIIIe jour de may » ; 12 Copie d'une lettre d'ANNE DE « MONTMORENCI » à « monseigneur de Conserans,... A Paris, ce VIIIe de may mil V.C. XLVII » ; 13 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur de Conserans,... De Chantilly, le XXIe jour de juillet » ; 14 Lettre d'ANNE DE « MONTMORENCY » à « monseigneur de Conserans,... De Berryseau, le XXIIIIe juillet » ; 15 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur de Conserans,... A Braye Conte Robert, le XVIIe jour de juillet » ; 16 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur [l']evesque de Conserans,... De Charenton, ce jour de Nostre Dame de septembre » ; 17 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur l'evesque de Conserans,... De Fontainebleau, ce XXVIIe jour de septembre 1547 » ; 18 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur de Conserans,... De Chantilly, ce dernier jour de septembre » ; 19 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur de Conserans,... De Chantilly, ce XXIIIe jour d'octobre » ; 20 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur l'evesque de Conserans,... De Poissy, ce XXIIIIe octobre » ; 21 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur de Cozerans,... De Fontainebleau, ce dernier jour d'octobre » ; 22 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur de Conserans,... D'Escouen, le IIIe jour de novembre » ; 23 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur de Conserans,... A Chantilly, ce VIe jour de novembre » ; 24 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur l'evesque de Conserans,... De Yere lez Nonnains, le VIIe jour de novembre » ; 25 Lettre de « JEHAN [DE BUZ], e[vêque] de Meaulx... à monseigneur de Coserans,... De Villemarueil, ce quatriesme jour de may mil cinq cens quarante deux » ; 26 Lettre de « GUY [XVII, comte] DE LAVAL,... à monseigneur... de Coserans,... A Paris, ce VIe de febvrier M.V.C.XLI » ; 27 Lettre de « GUY [XVII, comte] DE LAVAL,... à monseigneur de Coserans,... A Vitré, le XXIXe jour de mars mil V.C. quarente et ung » ; 28 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur de Conserans,... De Fontaynebleau, le Xe jour de novembre V.C.XL » ; 29 Lettre de « GUY [XVII, comte] DE LAVAL,... à monseigneur de Conserans,... A Paris, le XVe jour de febvrier » ; 30 Lettre de « GUY DE LAVAL,... à monseigneur de Coserans,... A Bloys, ce VIIIe jour de mars, l'an mil V.C.XL » ; 31 Reçu délivré par « GUY, conte DE LAVAL », à « Menault de Marthory, evesque de Coserans,... A Coloummiers en Brye, le dernier jour de mars, l'an mil cinq cens quarante trois, apres Pasques » ; 32 Lettre de « GUY DE LAVAL,... à monseigneur de Coserans,... A Bloys, ce VIIIme jour de mars » ; 33 Lettre de « GUY DE LAVAL,... à monseigneur de Coserans,... A Bloys, ce XIe jour de mars » ; 34 Lettre de « GUY DE LAVAL,... à monseigneur de Coserans,... A Villanche, ce XXVIIIme jour de mars » ; 35 Lettre de « GUY DE LAVAL,... à monseigneur de Conserans,... A Vitré, le IIIe jour de may » ; 36 Lettre de « GUY DE LAVAL,... à monseigneur de Conserans,... A Vitré, le Xe de may » ; 37 Lettre de « GUY DE LAVAL,... à monseigneur de Coserans,... A Chastellerault, ce quatriesme juing » ; 38 Lettre de « GUY DE LAVAL,... à monseigneur de Coserans,... A Chastellerault, ce XVe juing » ; 39 Lettre de « GUY DE LAVAL,... à monseigneur de Coserans,... A l'abbaye de Trouare, ce XXVe juung M. V.C.XLV » ; 40 Lettre de « GUY DE LAVAL,... à monseigneur de Conserans,... A Longjumeau, ce XVIe juillet » ; 41 Lettre de « GUY DE LAVAL,... à monseigneur de Conserans,... A Paris, le dernier jour d'octobre » ; 42 Lettre de « GUY DE LAVAL,... à monseigneur de Conserans,... A Fere, ce dymanche VIe jour de novembre » ; 43 Lettre de « GUY DE LAVAL,... à monseigneur de Coserans,... A Paris, ce XIXe novembre » ; 44 Copie d'une lettre du connétable ANNE DE « MONTMORENCY,... à monseigneur le conte de Laval,... D'Amboyse, ce XIIe avril 1540 » ; 45 Copie d'une lettre de l'évêque de « Coserans [MENAUD DE MARTRES]... à madame de Laval,... A Colomyers, ce XXVIe séptembre mil V.C.XLVII » ; 46 Lettre de « GUY DE LAVAL,... à monseigneur le duc de Nyvernoys,... A Lorriz, ce Xe jour de may 1554 » ; 47 Lettre de « RENEE DE LORRAINE [abbesse de Saint-Pierre de Reims]... à monsieur le duc de Nevers,... De Reims, ce XIXe de jeung 1554 » ; 48 Lettre de « JEHAN DE BRETAYGNE [duc d'Étampes]... à monsieur le duc de Nyvernoys,... De Maulepvrier, ce IIIIe jour de novembre 1554 » ; 49 Lettre de « MADELENE DE MAILLY,... à madame la duchesse de Nevers,... De Roucy, ce XVe jour de febvrier 1558 » ; 50 Lettre de « RENE DE MAILLY,... à monseigneur le duc de Nivernois,... De Monstreul, le XVIIe de febvrier 1558 » ; 51 Lettre de « CHANTEREAU,... à monseigneur le duc de Nevers,... De Villiers Costeretz, ce VIIIe de mars 1558 » ; 52 Lettres des gens de « conseil aux comptes à Nevers... à monseigneur » le duc de Nevers. « De Nevers, ce penultime jour de mars 1559 » ; 53 Lettre de « CHARLES DE ROUCY, e[vêque] de Soissons... à monseigneur le duc de Nivernois,... A Reims, ce XXIIe de septembre 1559 » ; 54 Lettre de « DE ROCHECHOUART,... à monseigneur le duc de Nyvernoys,... De Rems, ce XXIIIe jour de septembre V.C.LIX » ; 55 Lettre de « CHARLES DU MOLIN,... à monseigneur le duc de Nyvernoys,... De Paris, ce Xe janvier 1560 » ; 56 Lettre de « D'ESTAMPLE,... à monseigneur de La Herbaudure,... receveur general des finances de monseigneur [le duc de Nevers]... De Annet, le XXe jour de janvier 1560 » ; 57 Lettre de « GUILLAUME DE CROY,... à madame la marquise de Rynel,... A Chierves, le XXVIIe de janvyer 1560 » ; 58 Lettre de « KATERINE DE CLAI[VES]... à madame la comtesse de Senighan,... De Joinville, ce XIIIe jour de febvrier 1560 » ; 59 Lettre d'« ANTHOINETTE [DE BOURBON]... à madame la contesse de Senighan,... De Joinville, ce XIIIIe jour de febvrier 1560 » ; 60 Lettre des gens du « conseil aux comptes à Nevers... à monseigneur [le duc de Nevers]... De Nevers, ce XXIXe jour de may 1560 » ; 61 Lettre des gens du « conseil et des comptes à Nevers... à monsieur le bailly de Nivernoys... De Nevers, ce XXIXe jour de may 1560 » ; 62 Lettre de « LAMOIGNON,... à monseigneur [le duc de Nevers]... De Paris, ce XXVIIe janvier » ; 63 Lettre des gens du conseil des « comptes à Nevers... à monseigneur [le duc de Nevers]... De Nevers, ce VIe jour de jung 1561 » ; 64 Lettre de « HAVIRLET,... à monsieur Lamaignon,... A Hambye, ce XIe de juing 1561 » ; 65 État des revenus du roi d'Espagne, « Don Felipe », en l'année 1562. En espagnol ; 66 Lettre de « FRANÇOYS [II DE NEVERS]... à La Herbaudure,... A St Germain, le XIIIIe jour d'aoust 1562 » ; 67 Lettre de « FRANÇOYS [II DE NEVERS]... à La Herbaudure,... De St Germain en Laye, le penultime jour d'aoust 1562 » ; 68 Lettre de « FRANÇOYS [II DE NEVERS]... à La Herbaudure,... A St Germain en Laye, le Ve jour de septembre 1562 » ; 69 Lettre d'ANNE DE « MONTMORENCY,... à monseigneur le prince de Portian,... De Troyes, le dernier jour de mars 1563 » ; 70 Lettre de « ROBERT DE LA MARK [duc DE BOUILLON]... à... monsieur le prince de Portian,... De Chaallons, ce XIXe apvril 1564 » ; 71 Lettre d'« ANTHOINE DE CROY,... à monsieur de Sturmes,... De Chasteau Porcian, ce XXIe jour d'avril 1564 » ; 72 Lettre de « JEHAN DE BRETAYGNE [duc d'Étampes]... à monseigneur [l'évêque] de Conserans... De Boussac, ce VIIIe jour de fevrier » ; 73 Lettre de « JEHAN DE BRETAYGNE,... à monsieur l'evesque de Conserans... De Boussac, ce XXVIe jour de fevrier » ; 74 Lettre de « JEHAN DE BRETAYGNE,... à monsieur l'evesque de Conserans... D'Estampes, ce jour de Pasques » ; 75 Lettre de « CHARLES DE LUXEMBOURG,... à monseigneur l'evesque de Conserans... De Boussac, ce XXVe jour de febvrier » ; 76 Lettre de « CHARLES DE LUXEMBOURG,... à... monseigneur l'evesque de Conzerans... De Boussac, ce XXVe jour de febvrier » ; 77 Lettre de « CHARLES DE LUXEMBOURG,... à monseigneur [l'évêque] de Conserans... De Boussac, ce VIIIe de mars » ; 78 Lettre de « CHARLES DE LUXEMBOURG,... à... monseigneur [l'évêque] de Conserans... De Boussac, ce IXe de mars » ; 79 Lettre de « DE THOU,... à monseigneur de Coserans » ; 80 Fragment de lettre de « MARTIN DE JOUY,... De Paris, ce premier lundi de caresme XIIe febvrier » ; 81 Lettre de « F[RANÇOIS, cardinal] DE TOURNON, ar[chevêque] de Bourges... De Yvry, ce XXIIIIe de fevrier » ; 82 Lettre de « DE THOU,... à monseigneur de Coserans,... A Boisdaulphin, ce Vme may » ; 83 Lettre de « F[RANÇOIS], cardinal DE TOURNON,... à monseigneur de Conserans,... De Bayonne, le XIXe jour de may » ; 84 Lettre de « DE ROCHECHOUART,... à monseigneur le president Seguier et à monseigneur de La Mongnon,... De Lyon, ce XVIe juing » ; 85 Lettre de « JEHAN DE LAVAL,... à monseigneur... [l']evesque de Conserans... De Maysdon, ce XVme jour d'aoust » ; 86 Lettre de « F[BANÇOIS], cardinal DE TOURNON,... à monseigneur de Conzerans,... De Villiers Costeretz, ce XIIIe de septembre » ; 87 Lettre d' « ODET DE FOYX » à « monseigneur de Coserans,... A Parme, le XVe jour de novembre » ; 88 Lettre de « HENRY DE FOIX,... à... monseigneur de Coserans,... A Conches, le XXVIe jour d'avril » ; 89 Lettre de « HENRY DE FOIX,... à... monseigneur de Conserans,... De Fontainebleau, ce XXVIII may » ; 90 Lettre de « HENRY DE FOIX,... à... monseigneur de Coserans,... A Fontainebleau, le dernier jour de may » ; 91 Lettre de « HENRY DE FOIX,... à... monseigneur de Coserans,... De Paris, ce XIIIIe de juing » ; 92 Lettre de « HENRY DE FOIX,... à... monseigneur de Conserans,... A Villiers Costerez, ce IIe de septembre » ; 93 Lettre de « HENRY DE FOIX,... à... monseigneur de Conserans,... De Milly, ce XIIIIe novembre » ; 94 Lettre de « CLAUDE DE FOIX,... à... monseigneur de Conzerans,... A Parys, ce XIIIe de may » ; 95 Lettre de « CLAUDE DE FOIX,... à... monseigneur de Conzerans,... A Laval, ce XXIe de decenbre » ; 96 Lettre de « CLAUDE DE FOIX,... à... monseigneur de Conzerans,... A Laval, ce Xe de mars » ; 97 Lettre de « CLAUDE DE FOIX,... à... monseigneur de Conzerans,... A Estempes, ce IIIIme d'abvyr » ; 98 Lettre de « CLAUDE DE FOIX,... à... monseigneur de Conzerans,... A Parys, ce XXVIme d'oubz » ; 99 Lettre de « CLAUDE DE FOIX,... à monseigneur de Conserant,... A Vitré, ce XXVIme de janvyer » ; 100 Lettre de « CLAUDE DE FOIX,... à monseigneur de Conserans,... A Monjaut, ce XIXe d'apvirl » ; 101 Lettre de « CLAUDE DE FOIX,... à monseigneur de Conzerant,... A Laval, ce XVIIIIe de janvyer » ; 102 Lettre de « CLAUDE DE FOIX,... à monseigneur de Conserans,... A Laval, le IIIIe jour d'aoust » ; 103 Lettre de « CLAUDE DE FOIX,... à monseigneur de Conserans,... A Laval, le XXme octobre » ; 104 Lettre de « HENRY DE FOIX,... à... monseigneur de Conserans,... A Evreux, ce sabmedy premier jour de may » ; 105 Lettre de « CLAUDE DE FOIX,... à... monseigneur de Conserans,... A Laval, le Vme septembre » ; 106 Lettre de « CLAUDE DE FOIX,... à monseigneur de Conserans,... A Laval, le XXIIe jour d'octobre » ; 107 Lettre de « CLAUDE DE FOIX.... à... monseigneur de Conzerans,... De Tours, ce XV de desanbre » ; 108 Lettre de « CLAUDE DE FOYS,... à monseigneur de Conserans,... A Chasteaubriant, ce XXVIIIe jour d'octobre » ; 109 Lettre de « CLAUDE DE FOIX,... à monseigneur de Conserans,... A Vitré, ce VIe jour d'aoust » ; 110 Lettre de « DE ROUGIER, Sr DE MARL RAS,... à monseigneur le prince de Pourcian,... A Lyon, le XXVIIIe may 1563 » ; 111 Lettre de « FEUQUERES,... à monsieur le prince de Porcian,... Du Boys de Vincennes, se IIIe de jung » ; 112 Lettre de « JAQUES DE CLEVES,... à monsieur le prince de Porcian,... De Vitry, le XXVIIe avril 1563 » ; 113 Lettre de « JAQUES [DE CLEVES]... à messieurs les president Seguyer et Lamongnon, conseiller du roy en sa court de parlement à Paris... De Lion, ce XXVe jour de jung 1564 » ; 114 Lettre de « DUBROC,... à messeigneurs Seguyer,... et Lamoignon,... D'Aucerre, ce Vme aoust V.C.LXIIII » ; 115 Extrait d'une « lettre missive envoyée en la chambre des comptes à Nevers par Me Edme Vincent, bailly de Beauche, en datte du XIXe jour de juillet 1564 » ; 116 Lettre des « gens du conseil et des comptes à Nevers... à messrs Seguyer,... president, et Lamoignon, conseiller en la cour de parlemant... De Nevers, ce tiers jour d'aoust 1564 » ; 117 Vidimus donné le « 20 mars 1566 » des « lectres des franchises de l'isle de Ré », octroyées par le roi CHARLES VI en 1408 ; 118 Lettre de « GUILLAUME RABOT,... à la royne... De Metz, ce VIIIe d'avril 1567 » ; 119 Minute de « lectres de la royne [CATHERINE DE MEDICIS] au lantgrave de Hessen, du XIIe jour d'avril 1567 » ; 120 Minute de « lectres du roy [CHARLES IX] au lantgrave de Hessen, du XIIe jour d'avril 1567 » ; 121 Lettre de « BILLIAR,... à monseigneur le duc de Nivernoys,... De Lyon, le XXIIIIe jour de may 1567 » ; 122 « Coppie d'une lectre escripte de la main de monseigneur... le cardinal [CHARLES] DE BOURBON,... Orleans, 1573, 7 janvier » ; 123 Formules de médicaments. En italien ; 124 Lettre, en italien, de « GASPAR BARCHINO,... Di Milano, l'otto d'aprile 1569 » ; 125 Fragment d'un acte, en latin, daté du 4 novembre 1566, relatif à certains arrangements avec un débiteur et ses créanciers ; 126 « Chifre pour faire de nuit entendre ce que l'on veult... par M. ANTONIO DONI,... 1569 » ; 127 « Extret des monstres faittes cejourduy des compagnies tant italienes que françoieses... Belleville, 1561, 10 novembre »

Learning experience and identity development as a research assistant /

What research learning experiences do current students have as research assistants (RAs) in the Faculty of Education at Brock University? How do the experiences of research assistants contribute to the formation of a researcher identity and influence future research plans? Despite the importance of these questions, there seems to be very little research conducted or written about the experiences of research assistants as they engage in the research process. There are few resources to which research assistants or their advisors can refer regarding graduate student research learning experiences. The purpose of this study was to understand the kinds of learning experiences that 4 RAs (who are enrolled in the Faculty of Education at Brock University, St. Catharines, Ontario) have and how those experiences contribute to their identities as researchers. Through interviews with participants, observations of participants, and textual documents produced by participants, I have (a) discovered what 4 RAs have learned while engaged in one or more research assistantships and (b) explored how these 4 RAs' experiences have shaped their identities as new researchers. My research design provided a separate case study for each participant RA, including myself as a research participant. Then as a collective, I studied all 4 cases as a case study in itself in the form of a cross-analysis to identify similarities and differences between cases. Using a variety of writing forms and visual narratives, I analyzed and interpreted the experiences of my participants utilizing arts-based literature to inform my analysis and thesis format. The final presentation includes electronic diagrams, models, poetry, a newsletter, a website presentation, and other representational arts-based forms.This thesis is a resource for current and future research assistants who can learn from the research assistant experiences presented in the research. Faculty members who hire research assistants to assist them with their research will also benefit from reading about RAs' learning experiences from the RAs' perspective. The information provided in this thesis document is a resource to inform future policies and research training initiatives in faculty departments and offices at universities. Consequently, this thesis also informs researchers (experienced and inexperienced) about how to conduct research in ways that benefit all parties and provide insight into potential ways to improve research assistantship practices.

Hydraulic and fluvial geomorphological models for a bedrock channel reach of the Twenty Mile Creek /

Bedrock channels have been considered challenging geomorphic settings for the application of numerical models. Bedrock fluvial systems exhibit boundaries that are typically less mobile than alluvial systems, yet they are still dynamic systems with a high degree of spatial and temporal variability. To understand the variability of fluvial systems, numerical models have been developed to quantify flow magnitudes and patterns as the driving force for geomorphic change. Two types of numerical model were assessed for their efficacy in examining the bedrock channel system consisting of a high gradient portion of the Twenty Mile Creek in the Niagara Region of Ontario, Canada. A one-dimensional (1-D) flow model that utilizes energy equations, HEC RAS, was used to determine velocity distributions through the study reach for the mean annual flood (MAF), the 100-year return flood and the 1,000-year return flood. A two-dimensional (2-D) flow model that makes use of Navier-Stokes equations, RMA2, was created with the same objectives. The 2-D modeling effort was not successful due to the spatial complexity of the system (high slope and high variance). The successful 1 -D model runs were further extended using very high resolution geospatial interpolations inherent to the HEC RAS extension, HEC geoRAS. The modeled velocity data then formed the basis for the creation of a geomorphological analysis that focused upon large particles (boulders) and the forces needed to mobilize them. Several existing boulders were examined by collecting detailed measurements to derive three-dimensional physical models for the application of fluid and solid mechanics to predict movement in the study reach. An imaginary unit cuboid (1 metre by 1 metre by 1 metre) boulder was also envisioned to determine the general propensity for the movement of such a boulder through the bedrock system. The efforts and findings of this study provide a standardized means for the assessment of large particle movement in a bedrock fluvial system. Further efforts may expand upon this standardization by modeling differing boulder configurations (platy boulders, etc.) at a high level of resolution.