Amyotrophe Lateralsklerose (ALS) ist eine neurodegenerative Erkrankung, bei welcher speziell erste (kortikospinal) und zweite (spinal) Motorneurone (MN) von Neurodegeneration betroffen sind. Gegenwärtig bleibt ALS eine unheilbare Erkrankung. Der Tod tritt durchschnittlich 2 bis 5 Jahre nach Auftreten der Symptome ein. Circa 90% der Fälle treten sporadisch auf (sALS), während 10% familiär sind (fALS). Es ist von großem Interesse monogenetische Formen der fALS zu untersuchen um zugrundeliegende Pathologien und Mechanismen zu verstehen. Bislang wurden über 20 Gene mit ALS in Verbindung gebracht, einschließlich Fused in sarcoma (FUS) und Chromsosome 9 open reading frame (C9ORF72). Circa 4% der fALS Fälle sind durch dominante Mutationen in FUS verursacht und repräsentieren damit die dritthäufigste Form der fALS in Deutschland. Die G4C2 hexanucleotide repeat expansion (HRE) in C9ORF72 ist die häufigste Ursache für ALS und Frontotemporale Demenz (FTD). ALS Patienten unterscheiden sich erheblich in der Präsentation ihrer klinischen Symptome wie Ausbruchsort, Progressionsrate und Auftreten kognitiver Störungen. Diese Faktoren sind auch stark abhängig von der zugrundeliegenden Mutation in fALS. Ziel dieser Doktorarbeit ist die Modellierung von FUS- und C9ORF72-assozierter ALS in einem krankheits-relevanten in vitro Model von speziell kortikaler Neuropathologie mit Hilfe von Patienten-spezifischen iPSZs. Die Hypothese der vorliegenden Arbeit ist das in einer Zelltyp-abhängigen Art und Weise zugrundeliegende Erkrankungsmechanismen in kortikalen vs. spinalen Neuronen unterschiedlich betroffen sind. Humane iPSZ, generiert von gesunden Kontrollen und ALS Patienten mit FUS oder C9ORF72 Mutation, wurden für die gerichtete kortikale und spinale Differenzierung genutzt. Zusätzlich wurden zwei neue FUS-WT- und FUS-P525L-EGFP-markierte isogene Linien mittels CRISPR/Cas9n Technik generiert. Methoden basierend auf Immunfluoreszenz Färbungen und Lebendzell-Mikroskopie wurden angewendet um Krankheits-relevante Proteine, DNA Schäden und axonale Organell-Mobilität zu analysieren. In diesem Projekt konnte ein deutlicher Zelltyp-abhängiger Effekt auf analysierte Phänotypen beobachtet werden, während ALS-assoziierte Mutationen scheinbar nur geringfügige Effekte zeigten. Dementsprechend wurde ein Zelltyp-abhängiger Anstieg des basalen DNA Schadens in kortikalen Astrozyten vs. Neuronen und spinalen vs. kortikalen Neuronen detektiert. Jedoch konnte in FUS oder C9ORF72 mutierten kortikalen Zellen kein erhöhter DNA Schaden nachgewiesen werden, wie es zuvor in spinalen MN beobachtet wurde. Des Weiteren beeinflussen FUS Mutationen die Rekrutierung von FUS zu DNA-geschädigten Stellen, die Organell-Mobilität und die zytoplasmatische Fehllokalisation des Proteins in Abhängigkeit vom Zelltyp. In kortikalen Neuronen wurde in Bezug auf die Rekrutierung von mutiertem FUS und Organell-Mobilität nur leichte Mutations-abhängige und wesentlich schwächer ausgeprägte Effekte beobachtet als in spinalen MN. Zusammenfassend kann gesagt werden, dass Patienten-spezifische Zellmodelle ein wichtiges Instrument in der ALS Forschung sind und das vor allem Unterschiede zwischen kortikalen und spinalen MN weiter untersucht werden müssen, um zugrundeliegende Krankheits-relevante Mechanismen zu entschlüsseln und wie diese zum Fortschreiten der Erkrankung beitragen / Amyotrophic lateral sclerosis (ALS) is a of neurodegenerative diseases, in which neurodegeneration specifically affects upper (corticospinal) and lower (spinal) motor neurons (MNs). At present, ALS remains an incurable disease. Death occurs on average 2 to 5 years after symptom onset. About 90% are sporadic cases (sALS) and 10% are familial cases (fALS). It is of great interest to investigate monogenetic forms causing fALS to understand its underlying disease pathologies and mechanisms. Over 20 genes have been linked to ALS until now, including Fused in sarcoma (FUS) and Chromosome 9 open reading frame 72 (C9ORF72). About 4% of fALS cases are caused by dominant mutations within FUS, representing the third most common fALS form in Germany. The G4C2 hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common cause for ALS and Frontotemporal dementia (FTD). ALS patients differ significantly in their presentation of clinical symptoms, including site of onset, rate of progression, and presence of cognitive dysfunction. Those factors were also shown to highly depend on the underlying mutation in fALS cases. Aim of this thesis work is the modeling of FUS- and C9ORF72-associated ALS in a disease-related in vitro model of particularly cortical neuropathology using patient-derived iPSCs. The hypothesis of the current work is that underlying disease mechanisms do differentially affect cortical vs. spinal neurons and act in a cell type-dependent manner. Human iPSCs derived from healthy controls and ALS patients carrying mutations within FUS or C9ORF72 were used for directed cortical and spinal differentiation. Additionally, two new FUS-WT- and FUS-P525L-EGFP-tagged isogenic iPSC lines were generated by CRISPR/Cas9n gene editing. Immunofluorescence staining and live cell imaging approaches were implemented to analyze disease-associated proteins, DNA damage, and axonal trafficking. Within this project, a clear cell type-dependent effect on analyzed phenotypes was observed, while ALS-associated mutations seemed to have only minor effects. Accordingly, cell type-dependent increased basal DNA damage levels in cortical astrocytes vs. neurons and spinal vs. cortical neurons were detected. However, FUS or C9ORF72 mutant cortical cells do not recapitulate increased DNA damage levels as they have been observed in spinal MNs. Furthermore, FUS mutation affected recruitment to DNA damage sites, axonal trafficking, and cytoplasmic mislocalization differentially, depending on the analyzed cell type. In cortical neurons, recruitment and trafficking of mutant FUS showed only slight mutation-dependent effects and also less pronounced phenotypes than observed in spinal MNs. In conclusion, patient-specific cellular models are an important tool in ALS research and particularly differences between cortical and spinal MNs need to be further investigated to decipher underlying disease mechanisms, the interplay of cell types affected by the disease, and how they participate in disease progression.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons, generally leading to paralysis and death within 3-5 years of onset. Over 50 different mutations in the gene encoding FUS/TLS (or FUS) will result in ALS, accounting for ~4% of all inherited cases. FUS is a multifunctional protein with important functions in DNA/RNA processing and stress response. How these mutations affect the structure or function of FUS protein and ultimately cause ALS is not known. The fact that mutations cause the protein to mislocalize from the nucleus to the cytoplasm of cells suggests that ALS pathogenesis may occur through a loss of nuclear function, gain of toxic cytoplasmic function, or both. Several FUS knockout animal models have been utilized for investigating a loss of function hypothesis and show phenotypes such as early lethality, reduced lifespan, and locomotor defects. To uncover cellular pathways affected by loss of FUS function, I have characterized the knockdown of FUS in a motor neuron-like cell line, NSC-34. In NSC-34 cells, the depletion of FUS severely impacts cellular proliferation and potentially causes increased levels of DNA damage. A quantitative proteomics analysis performed on cells undergoing various degrees of FUS knockdown revealed protein expression changes for known RNA targets of FUS, consistent with a loss of FUS function with respect to RNA processing. Proteins that changed in expression as a function of FUS knockdown were associated with vii multiple processes, some of which influence cell proliferation including cell-cycle regulation, cytoskeletal organization, oxidative stress and energy homeostasis. Importantly, cellular proliferation could be rescued by the re-expression of FUS and by treatment with the small-molecule, rolipram, indicative of potential therapeutic approaches. Collectively, the work presented in this dissertation demonstrates the importance of FUS for cell health and homeostasis, is suggestive of a role for FUS in DNA damage repair and identifies additional cellular pathways influenced by FUS depletion. Overall, this work provides mechanistic insight into ALS pathogenesis through loss of FUS/TLS function.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by preferential motor neuron death in the brain and spinal cord. The rapid disease progression results in death due to respiratory failure, typically within 3-5 years after disease onset. While ~90% of cases occur sporadically, remaining 10% of ALS cases show familial inheritance, and the number of genes linked to ALS has increased dramatically over the past decade. FUS/TLS (Fused in Sarcoma/ Translocated to liposarcoma) is a nucleic acid binding protein that may regulate several cellular functions, including RNA splicing, transcription, DNA damage repair and microRNA biogenesis. More than 50 mutations in the FUS gene are linked to 4% of familial ALS, and many of these may disrupt the nuclear localization signal, leading to variable amounts of FUS accumulation in the cytoplasm. However, the mechanism by which FUS mutants cause motor neuron death is still unknown. The studies presented in this dissertation focused on investigating the properties of FUS mutants in the absence and presence of stress conditions. We first examined how ALS-linked FUS mutants behaved in response to imposed stresses in both cell culture and zebrafish models of ALS. We found that FUS mutants were prone to accumulate in stress granules in proportion to their degree of cytoplasmic mislocalization under conditions of oxidative stress, ER stress, and heat shock. However, many FUS missense mutants are retained predominantly in the nucleus, and this suggested the possibility that these mutants might also perturb one or more nuclear functions. In a human cell line expressing FUS variants and in human fibroblasts from an ALS patient, mutant FUS expression was associated with enlarged promyelocytic leukemia nuclear bodies (PML-NBs) under basal condition. Upon oxidative insult with arsenic trioxide (ATO), PML-NBs in control cells increased acutely in size and were turned over within 12-24 h, as expected. However, PML-NBs in FUS mutant cells did not progress through the expected turnover but instead continued to enlarge over 24 h. We also observed a persistent accumulation of the transcriptional repressor Daxx and the 11S proteasome regulator in association with these enlarged PML-NBs. Furthermore, the peptidase activities of the 26S proteasome were decreased in FUS mutant cells without any changes in the expression of proteasome subunits. These results demonstrate that FUS mutant expression may alter cellular stress responses as manifested by (i) accumulation of mutant FUS into stress granules and (ii) inhibition of PML-NB dynamics. These findings suggest a novel nuclear pathology specific to mutant FUS expression that may perturb nuclear homeostasis and thereby contribute to ALS pathogenesis.

During stress, eukaryotes regulate protein synthesis in part through formation of cytoplasmic, non-membrane-bound complexes called stress granules (SGs). SGs transiently store signaling proteins and stalled translational complexes in response to stress stimuli (e.g. oxidative insult, DNA damage, temperature shifts and ER dysfunction). The functional outcome of SGs is proper translational regulation and signaling, allowing cells to overcome stress. The fatal motor neuron disease Amyotrophic Lateral Sclerosis (ALS) develops in an age-related manner and is marked by progressive neuronal death, with cytoplasmic protein aggregation, excitotoxicity and increased oxidative stress as major hallmarks. Fused in Sarcoma/Translocated in Liposarcoma (FUS) is an RNA-binding protein mutated in ALS with roles in RNA and DNA processing. Most ALS-associated FUS mutations cause FUS to aberrantly localize in the cytoplasm due to a disruption in the nuclear localization sequence. Intriguingly, pathological inclusions in human FUSALS cases contain aggregated FUS as well as several SG-associated proteins. Further, cytoplasmic mutant FUS incorporates into SGs, which increases SG volume and number, delays SG assembly, accelerates SG disassembly, and alters SG dynamics. I posit that mutant FUS association with stress granules is a toxic gain-of-function in ALS that alters the function of SGs by interaction with SG components. Here, I show that mutant FUS incorporates in to SGs via its Cterminal RGG motifs, the methylation of which is not required for this localization. Further, I identify protein interactions specific to full-length mutant FUS under stress conditions that are potentially capable of interacting with FUS in SGs. Finally, I demonstrate a potential change in the protein composition of SGs upon incorporation of mutant FUS. These findings advance the field of ALS and SG biology, thereby providing groundwork for future investigation.

Les gènes TDP-43 (TAR DNA Binding Protein 43) et FUS/TLS (Fused in Sarcoma/Translocated in Liposarcoma) sont actuellement à l’étude quant à leurs rôles biologiques dans le développement de diverses neuropathies telles que la Sclérose Latérale Amyotrophique (SLA). Étant donné que TDP-43 et FUS sont conservés au cours de l’évolution, nous avons utilisé l’organisme modèle C. elegans afin d’étudier leurs fonctions biologiques. Dans ce mémoire, nous démontrons que TDP-1 fonctionne dans la voie de signalisation Insuline/IGF pour réguler la longévité et la réponse au stress oxydatif. Nous avons développé des lignées C. elegans transgéniques mutantes TDP-43 et FUS qui présentent certains aspects de la SLA tels que la dégénérescence des motoneurones et la paralysie adulte. La protéotoxicité causée par ces mutations de TDP- 43 et FUS associées à la SLA, induit l’expression de TDP-1. À l’inverse, la délétion de tdp-1 endogène protège contre la protéotoxicité des mutants TDP-43 et FUS chez C. elegans. Ces résultats suggèrent qu’une induction chronique de TDP-1/TDP-43 sauvage propagerait la protéotoxicité liée à la protéine mutante. Nous avons aussi entrepris un criblage moléculaire pilote afin d’isoler des suppresseurs de toxicité neuronale des modèles transgéniques mutants TDP-43 et FUS. Nous avons ainsi identifié le bleu de méthylène et le salubrinal comme suppresseurs potentiels de toxicité liée à TDP-43 et FUS via réduction de la réponse au stress du réticulum endoplasmique (RE). Nos résultats indiquent que l’homéostasie de repliement des protéines dans le RE représente une cible pour le développement de thérapies pour les maladies neurodégénératives. / Two recently discovered causative genes for ALS, TDP-43 (TAR DNA Binding Protein 43) and FUS/TLS (Fused in Sarcoma/Translocated in Liposarcoma) are under further investigation regarding their biological roles in neuropathies such as Amyotrophic Lateral Sclerosis (ALS). Since TDP-43 and FUS are evolutionarily conserved we turned to the model organism C. elegans to learn more about their biological functions. Here we report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response. We have generated mutant TDP-43 and FUS transgenic lines in C. elegans that recapitulate certain aspects of ALS including motor neuron degeneration and adult-onset paralysis. Proteotoxicity caused by ALS- associated mutations in TDP-43 or FUS also induce TDP-1 expression and consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild type TDP-1/TDP-43 by proteotoxicity may actively promote neurodegeneration. We also screened for small- molecule suppressors of mutant TDP-43 and FUS neuronal toxicity in transgenic C. elegans and identified methylene blue and salubrinal as potent suppressors of TDP-43 and FUS toxicity in our models through induction of the endoplasmic reticulum (ER) stress response. Our results indicate that protein folding homeostasis in the ER may be an important target for therapeutic development in neurodegenerative diseases.

Les Granule de Stress (GS) sont des inclusions cytoplasmiques contenant des protéines et des ARNm qui s’assemblent en réponse à l’exposition à un stress. Leur formation fait partie intégrante de la réponse cellulaire au stress et est considérée comme une étape déterminante pour la résistance au stress et la survie cellulaire. Actuellement, les GS sont reliés à divers pathologies allant des infections virales aux maladies neurovégétatives. L’une d’entre elle, la Sclérose Latérale Amyotrophique (SLA) est particulièrement agressive, caractérisée par une perte des neurones moteurs aboutissant à la paralysie et à la mort du patient en cinq ans en moyenne. Les mécanismes de déclenchement de la pathologie restent encore à déterminer. TDP-43 (TAR DNA binding protein 43) et FUS (Fused in liposarcoma) sont deux protéines reliées à la pathologie qui présentent des similarités de structure et de fonction, suggérant un mécanisme commun de toxicité. TDP-43 et FUS sont toutes les deux recrutées au niveau des GS en condition de stress. Nous avons démontré pour la première fois que la fonction des GS est de protéger les ARNm de la dégradation induite par l’exposition au stress. Cette fonction n’était que suspectée jusqu’alors. De plus nous avons mis en évidence que G3BP1 (Ras GTPase-activating protein-binding protein 1) est l’effectrice de cette fonction via son implication dans la dynamique de formation des GS. TDP-43 étant un régulateur de G3BP1, nous prouvons ainsi que la perte de fonction de TDP-43/G3BP1 aboutit à un défaut de réponse au stress aboutissant à une vulnérabilisation cellulaire. Le mécanisme de toxicité emprunter par FUS diffère de celui de TDP-43 et ne semble pas passer par une perte de fonction dans le cadre de la réponse au stress. / Stress Granule (SGs) are cytoplasmic inclusions sequestering proteins and mRNAs following a stress exposure. Their assembly is part of the cell stress response and is considered an important step for stress resistance and cell survival. SG are currently linked to different pathogenesis from viral infection to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).ALS is an aggressive disease, characterized by neuronal death leading to paralysis and death within five years. Pathogenesis mechanisms are still not fully understood. TDP-43 (TAR DNA binding protein 43) and FUS (Fused in liposarcoma) are two proteins linked to the disease that share many structural features and functions suggesting a common toxicity mechanism. TDP-43 and FUS are both recruited to SGs in stress conditions. We demonstrate for the first time that SGs function to protect mRNA from degradation induced after stress exposure, a function that was only suspected until now. We also prove that G3BP1 (Ras GTPase-activating protein-binding protein 1) is the effector of this function via it’s implication in the dynamics of SG formation. As TDP-43 is a regulator of G3BP1, we prove that loss of TDP-43/G3BP1 function leads to a stress response defect yielding increased cellular vulnerability. Furthermore, we have discovered that the mechanism of toxicity for FUS is different from TDP-43, and does not implicate a loss of function mechanism during the cell stress response.

Made available in DSpace on 2015-12-03T18:33:08Z (GMT). No. of bitstreams: 1 Peterson_Carlos_Pirola.pdf: 1373676 bytes, checksum: ce4b7c1d993a0bd8c80f2c8bf89a8cf9 (MD5) Previous issue date: 2014-05-19 / This work sought to study the reaction of the Brazilian capital market towards announcements of Mergers & Acquisitions (M&A) processes, investigating its impact in the price of stocks negotiated on S??o Paulo Stock Exchange, Commodities and Futures Exchange (BM&FBOVESPA). With regard to the methodology applied in this work, both descriptive and quantitative researches can be observed. These were carried out by using secondary data collection and statistical analysis. The aim of the survey was to check if the announcements of M&A operations produced impact on the prices of stocks publicly negotiated on BM&FBOVESPA after the global financial crisis in 2008. An event study was carried out in order to verify the existence of statistically significant abnormal returns around the dates of the announcements of the M&A processes, based on the assumption that a link between the stock market and companies decision to join an M&A process exists. The results obtained with the segmentation of the sample between acquiring and acquired companies indicate that announcements of M&A operations did not impact on the prices of publicly traded shares on the BM&FBOVESPA, during the research period, showing evidence of the informational efficiency of the Brazilian capital market as being semi-strong. When making up the segmentation between companies that had a change in control, both the acquired companies as the acquiring firms had positive abnormal returns, a fact that repeated itself in the segmentation carried out with regard to the payment method / Este trabalho procurou estudar a rea????o do mercado de capitais Brasileiro diante do an??ncio de um processo de Fus??es e Aquisi????es (F&A), investigando seu impacto no pre??o das a????es negociadas na Bolsa de Valores, Mercadorias e Futuros de S??o Paulo (BM&FBOVESPA). Com rela????o ?? metodologia aplicada neste trabalho, podem-se observar pesquisas de natureza descritiva e quantitativa, realizadas com coleta de dados secund??rios e an??lise estat??stica. O problema estudado foi verificar se os an??ncios de opera????es de F&A produziram impacto nos pre??os das a????es negociadas publicamente na BM&FBOVESPA ap??s a crise financeira global de 2008. Tendo como pressuposto a liga????o existente entre o mercado de capitais e a decis??o das empresas em ingressar num processo de F&A, foi realizado um estudo de evento com o intuito de verificar a exist??ncia de retornos anormais estatisticamente significantes em torno e na data do an??ncio de um processo de F&A. Os resultados obtidos com a segmenta????o da amostra entre empresas adquirentes e adquiridas indicam que os an??ncios de opera????es de F&A n??o produziram impacto nos pre??os das a????es negociadas publicamente na BM&FBOVESPA, durante o per??odo pesquisado, demostrando ind??cios da efici??ncia informacional do mercado de capitais Brasileiro na forma semiforte. Ao efetuar-se a segmenta????o entre empresas que tiveram mudan??a de controle, tanto as empresas adquiridas quanto as empresas adquirentes obtiveram retornos anormais positivos. Fato que se repetiu na segmenta????o efetuada com rela????o ?? forma de pagamento

Submitted by Elba Lopes (elba.lopes@fecap.br) on 2017-12-19T22:59:36Z No. of bitstreams: 2 Adriano Dantas Lima Rodrigues.pdf: 683093 bytes, checksum: 5e76ca0b2e0469af0f0484640b8755c6 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-12-19T22:59:36Z (GMT). No. of bitstreams: 2 Adriano Dantas Lima Rodrigues.pdf: 683093 bytes, checksum: 5e76ca0b2e0469af0f0484640b8755c6 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-06-05 / The objetive of this work was to analyze which motivating factors could positively be associated with the level of disclosure of business combination in Brazilian public companies that trade in S??o Paulo city stock exchange (B3). To fulfill such aim, it was developed a Business Combination index ??? INDCOMBADAPT, based on Nakayama & Salotti (2014) and Shalev (2009) researches. Instead of developing a disclosure index based on a checklist model, described by the technical pronouncement CPC 15 - Business Combinations as mandatory, in this research, some itens (subcategories) that could be repetitive were removed. Therefore, it was considered only information about one relevante criterion, that is, if missing, could cause problems to understand the procedure On the basis of previous researches, we selected factors that could positively impact the level of disclosure of business combination. We analyzed: companies?? size, listing segment in B3, subjection to regulatory agencies, free float shares, internationalization, audit firms, bond issuance, performance and indebtedness. We investigated the annual financial statements of 2015, from Brazilian companies that trade in S??o Paulo city stock exchange (B3), which described information concerning business combinations in these statements. We identified 28 acquirer companies involved in 53 procedures characterized as combinations, according to IFRS 03 (CPC-15 R1). In the studied period, the business combination disclosure index was 0,4082 (maximum 0,8095, and minimum 0,0479), indicating low disclosure level. Positive correlations concerning the combination index for the variable Indebteness were found. Moreover, after the regression analyzis the only conformed hyphotesis was that there is a positive relationship among financial statements audited by big audit firms and the level of disclosure of business combination. This confirms the works of Taplin, Zhao, & Brown (2014), Nakayama (2012) and Murcia (2009). / O objetivo desta pesquisa foi analisar quais fatores motivadores poderiam estar associados positivamente ao n??vel de divulga????o de combina????o de neg??cios em empresas brasileiras de capital aberto, na bolsa de valores de S??o Paulo (B3). Para alcan????-lo, foi desenvolvido um ??ndice de Combina????o de Neg??cios, o INDCOMBADPT, adaptado de Nakayama & Salotti (2014) e Shalev (2009). Em vez de desenvolver um ??ndice de divulga????o baseado em um modelo checklist do que o pronunciamento t??cnico CPC-15 R1 (IFRS 03) de combina????o de neg??cios descreve como conformidade da norma, nesta pesquisa, foram retirados itens (subcategorias) que poderiam ser repetitivos. Desse modo, considerou-se somente informa????es sobre um crit??rio de relev??ncia. Assim, foram observadas somente informa????es que partem do pressuposto de que, na falta, podem causar problemas no entendimento da opera????o. Com base em pesquisas anteriores, foram selecionados fatores que poderiam impactar positivamente o n??vel de combina????o de neg??cios. Foram analisados: porte das companhias, segmento de listagem, sujei????o ??s ag??ncias reguladoras, percentual das a????es em circula????o no mercado, internacionaliza????o, firmas de auditoria, emiss??o de t??tulos, desempenho e endividamento. Foram analisadas as demonstra????es financeiras anuais de 2015, das companhias brasileiras com a????es negociadas na bolsa de valores de S??o Paulo (B3), que descreveram informa????es referentes a combina????es de neg??cios nessas demonstra????es. Foram identificadas 28 companhias adquirentes envolvidas em 53 opera????es caracterizadas como combina????o, conforme o CPC-15 R1 (2011). No per??odo analisado, o ??ndice de divulga????o de combina????o de neg??cios ficou em 0,4082 (m??ximo 0,8095 e m??nimo 0,0476), indicando baixo n??vel de divulga????o. A pesquisa apresentou correla????o positiva quanto ao ??ndice de combina????o para a vari??vel Endividamento. E ap??s an??lise de regress??o, a ??nica hip??tese confirmada foi que existe rela????o positiva entre demonstra????es financeiras auditadas por grandes empresas de auditoria e o n??vel e divulga????o de combina????o de neg??cios, corroborando Taplin, Zhao, & Brown (2014), Nakayama (2012) e Murcia (2009).

No description available.

Les gènes TDP-43 (TAR DNA Binding Protein 43) et FUS/TLS (Fused in Sarcoma/Translocated in Liposarcoma) sont actuellement à l’étude quant à leurs rôles biologiques dans le développement de diverses neuropathies telles que la Sclérose Latérale Amyotrophique (SLA). Étant donné que TDP-43 et FUS sont conservés au cours de l’évolution, nous avons utilisé l’organisme modèle C. elegans afin d’étudier leurs fonctions biologiques. Dans ce mémoire, nous démontrons que TDP-1 fonctionne dans la voie de signalisation Insuline/IGF pour réguler la longévité et la réponse au stress oxydatif. Nous avons développé des lignées C. elegans transgéniques mutantes TDP-43 et FUS qui présentent certains aspects de la SLA tels que la dégénérescence des motoneurones et la paralysie adulte. La protéotoxicité causée par ces mutations de TDP- 43 et FUS associées à la SLA, induit l’expression de TDP-1. À l’inverse, la délétion de tdp-1 endogène protège contre la protéotoxicité des mutants TDP-43 et FUS chez C. elegans. Ces résultats suggèrent qu’une induction chronique de TDP-1/TDP-43 sauvage propagerait la protéotoxicité liée à la protéine mutante. Nous avons aussi entrepris un criblage moléculaire pilote afin d’isoler des suppresseurs de toxicité neuronale des modèles transgéniques mutants TDP-43 et FUS. Nous avons ainsi identifié le bleu de méthylène et le salubrinal comme suppresseurs potentiels de toxicité liée à TDP-43 et FUS via réduction de la réponse au stress du réticulum endoplasmique (RE). Nos résultats indiquent que l’homéostasie de repliement des protéines dans le RE représente une cible pour le développement de thérapies pour les maladies neurodégénératives. / Two recently discovered causative genes for ALS, TDP-43 (TAR DNA Binding Protein 43) and FUS/TLS (Fused in Sarcoma/Translocated in Liposarcoma) are under further investigation regarding their biological roles in neuropathies such as Amyotrophic Lateral Sclerosis (ALS). Since TDP-43 and FUS are evolutionarily conserved we turned to the model organism C. elegans to learn more about their biological functions. Here we report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response. We have generated mutant TDP-43 and FUS transgenic lines in C. elegans that recapitulate certain aspects of ALS including motor neuron degeneration and adult-onset paralysis. Proteotoxicity caused by ALS- associated mutations in TDP-43 or FUS also induce TDP-1 expression and consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild type TDP-1/TDP-43 by proteotoxicity may actively promote neurodegeneration. We also screened for small- molecule suppressors of mutant TDP-43 and FUS neuronal toxicity in transgenic C. elegans and identified methylene blue and salubrinal as potent suppressors of TDP-43 and FUS toxicity in our models through induction of the endoplasmic reticulum (ER) stress response. Our results indicate that protein folding homeostasis in the ER may be an important target for therapeutic development in neurodegenerative diseases.