Fifteen years ago, the Steroid receptor RNA activator (SRA) was identified as a functional non-coding RNA able to increase the activity of the estrogen receptor (ER), a critical player mediating the mitogenic role of estradiol in breast cancer. Interestingly, four years later, SRA appeared to be the first ever discovered functional RNA also able to encode a protein (SRAP). As such, the products of the SRA1 gene delineate a fascinating bi-faceted system involving both a functional RNA and a protein. Since its discovery, the non-coding aspect of this system has been widely investigated, with multiple groups gathering information on SRA structure and related functions. Overall, the non-coding SRA transcript is thought to act as a broad co-regulator modulating the activity of different transcription factors. Conversely, limited information has been obtained on the coding aspect (SRAP) of this system，even though SRA/SRAP is currently believed as a whole to be involved in several mechanisms including tumourigenesis, tumour progression, myogenesis and adipogenesis. In this body of work, I have attempted to define the clinical relevance of SRAP to breast cancer and extend the understanding of the cellular processes potentially regulated by this protein. I have first established that SRAP had the potential to become a new prognostic and predictive factor in specific groups of patients. Indeed, I have demonstrated, using tissue microarray analyses (TMAs), that SRAP expression was up-regulated in some breast tumours, with high levels associated with poor prognosis in Estrogen Receptor (ER) positive breast cancer patients. Using the same technique, I have further identified a positive association between a positive response to tamoxifen treatment and a high level of SRAP expression in a large cohort of ER-α negative cases. This highlights the potential for SRAP to become a new predictive factor of response to endocrine therapy in this specific group of patients. Using RNA-seq to define the transcriptomes of cervical Hela and breast MDA-MB-231 cancer cells upon depletion or overexpression of this protein, I further identified cellular movement amongst the potential cellular processes affected by changes in SRAP expression. Using classical trans-wells assays as well as an live-cell imaging assays, I have confirmed that SRAP indeed regulates individual cancer cell motility. Overall, my results provide critical new insights into the potential functions of the protein counterpart of the intriguing SRA/SRAP bi-faceted gene system. SRAP herein appears as a potential new therapeutic target in the fight against breast cancer that remains to be further investigated. / February 2017

Sammanfattning Titel: Revisionskommittéers påverkan på hållbarhetsrapporters tillförlitlighet: En kvantitativ studie på 298 börsnoterade företag i en low-litigation kontext. Nivå: Examensarbete på grundnivå i ämnet företagsekonomi (kandidatexamen). Författare: Albin Eriksson, Philip Lindholm Handledare: Jan Svanberg Datum: 2022-05-31 Syfte: Förekomsten av hållbarhetsrapportering externt granskad av tredje part har, i tidigare studier tolkats som väsentligt hos större företag, eftersom de i dess intressenters ögon önskar framstå som tillförlitliga och legitima. Detta eftersom revisorer som granskar rapporteringen kännetecknas av ett oberoende gentemot verksamheten. Då tidigare studier endast utförts inom en institutionell kontext kännetecknad av hög risk för stämning vid felaktiga beslut blir det intressant att jämföra dessa resultat med en miljö där granskare har friare tyglar. Syftet med denna studie är därför att undersöka huruvida revisionskommittéers granskning av hållbarhetsrapporteringen påverkar dess tillförlitlighet i en annan institutionell kontext, nämligen en lägre litigationsnivå än hos den befintliga litteraturen inom ämnet.   Metod: Studien baseras på den positivistiska forskningsfilosofin med en hypotetisk-deduktiv ansats. Studien har en kvantitativ strategi där 298 börsnoterade företag ligger till grund för sekundärdata genererad från databasen Thomson Reuters Eikon. Vidare har datamaterialet bearbetats och analyserats i statistikprogrammet SPSS.     Resultat och slutsats: Studiens resultat påvisar ett positivt samband mellan revisionskommittéers förekomst och hållbarhetsrapporters tillförlitlighet. Vi finner även att finansiell expertis inom revisionskommittéer har ett positivt samband med hållbarhetsrapporters tillförlitlighet. Revisionskommittéernas oberoende inom studiens institutionella kontext indikeras ha ett negativt samband med hållbarhetsrapporters tillförlitlighet.   Examensarbetets bidrag: Studien bidrar till att fylla forskningsgapet för revisionskommittéernas påverkan på hållbarhetsrapporteringen inom en low-litigation kontext. Studien gynnar även litteraturen om sambandet mellan revisionskommittéers karaktärsdrag och hållbarhetsrapporters tillförlitlighet, samtidigt som den avser ligga till grund för framtida forskning. Resultatet bidrar med värdefull teoretisk information till den företagsekonomiska forskningen gällande sambandet mellan extern granskning och företagens legitimitet.    Förslag till fortsatt forskning: Förslag till framtida forskning är att utföra en liknande typ av studie i denna institutionella kontext där fler av revisionskommittéernas främsta karaktärsdrag tas i åtanke, eftersom det möjligtvis kan innebära en annorlunda påverkan på tillförlitligheten.   Nyckelord: SRA, hållbarhetsrapportering, revisionskommittéer och low-litigation / Abstract Title: Audit committee impact on the credibility of sustainability reporting: A quantitative study of 298 public companies in a low-litigation context. Level: Student thesis, final assignment for Bachelor Degree in Business Administration  Authors: Albin Eriksson, Philip Lindholm Supervisor: Jan Svanberg Date: 2022-05-31 Aim: The existence of externally assured sustainability reporting by a third party, have in previous studies been interpreted as essential by bigger companies since they, in their stakeholder’s eyes, wish to appear as reliable and legitimate. This because the auditors that review the reporting are characterized by an independence towards the company. Since previous studies have only been implemented within an institutional context characterized by greater risk in case of wrongdoings it becomes interesting to compare these results with an environment where auditors have more space to act. The purpose of this study is therefore to examine whether audit committees review of sustainability reporting affects its reliability in a different institutional context, namely a lower litigation level than in the subject's existing literature.   Method: The study is based on the positivist philosophy of research with a hypothetical-deductive approach. The study has a quantitative strategy where 298 listed companies are the basis for secondary data generated from the database Thomson Reuters Eikon. Furthermore, the data material has been processed and analyzed in the statistical program SPSS.    Result and Conclusions: The results of the study show a positive relationship between the audit committees external review and the reliability of sustainability reports. We also find that financial expertise within audit committees is positively related to the reliability of sustainability reports. The independence of the audit committees within the institutional context of the study is indicated to have a negative relationship with the reliability of sustainability reports.   Contribution of the thesis: The study fills the research gap for audit committees impact on sustainability reporting in a low-litigation context. The study also benefits the literature on the relationship between the characteristics of audit committees and the reliability of sustainability reports, at the same time as it intends to form the basis for future research. The results contribute valuable theoretical information to the business economics research regarding the connection between external review and the company’s legitimacy.   Suggestions for future research: Suggestions for further research are to carry out a similar type of study within this institutional context where several of the audit committees main characteristics are taken into account, as this may have a different impact on reliability.   Key words: SRA, sustainability reporting, audit committees and low-litigation

Pandemics of plague have reemerged multiple times throughout human history with tremendous mortality and extensive geographic spread. The First Pandemic (6th - 8th century) devastated the Mediterranean world, the Second Pandemic (14th - 19th century) swept across much of Afro-Eurasia, and the Third Pandemic (19th - 20th century) reached every continent except for Antarctica, and continues to persist in various endemic foci around the world. Despite centuries of historical research, the epidemiology of these pandemics remains enigmatic. However, recent technological advancements have yielded a novel form of evidence: ancient DNA of the plague bacterium Yersinia pestis. In this thesis, I explore how genomic data can be used to unravel the mysteries of when and where this disease appeared in the past. In particular, I focus on phylogenetic approaches to studying this 'small microbe' with 'big data' (i.e. 100s - 1000s of genomes). I begin by describing novel software I developed that supports the acquisition and curation of large amounts of DNA sequences in public databases. I then use this tool to create an updated global phylogeny of Y. pestis, which includes ~600 genomes with standardized metadata. I devise and validate a new approach for temporal modeling (i.e. molecular clock) that produces robust divergence dates in pandemic lineages of Y. pestis. In addition, I critically examine the questions that genomic evidence can and cannot address in isolation, such as whether the timing and spread of short-term epidemics can be confidently reconstructed. Finally, I apply this theoretical and methodological insight to a case study in which I reconstruct the appearance, persistence, and disappearance of plague in Denmark during the Second Pandemic. The three papers enclosed in this sandwich-thesis contribute to a larger body of work on the anthropology of plague, which seeks to understand how disease exposure and experience change over time and between human populations. Furthermore, this dissertation more broadly impacts both prospective studies of infectious disease, such as environmental surveillance and outbreak monitoring, and retrospective studies, which seek to date the emergence and spread of past pandemics. / Dissertation / Doctor of Philosophy (PhD) / The Plague is a disease that has profoundly impacted human history and is responsible for some of the most fatal pandemics ever recorded. It may surprise many to know that this disease is not a bygone of a past era, but in fact is still present in many regions of the world. Although researchers have been studying plague for hundreds of years, there are many aspects of its epidemiology that are enigmatic. In this thesis, I focus on how DNA from the plague bacterium can be used to estimate where and when this disease appeared in the past. To do so, I reconstruct the evolutionary relationships between modern and ancient strains of plague, using publicly available data and new DNA sequences retrieved from the skeletal remains of plague victims in Denmark. This work offers a new methodological framework for large-scale genetic analysis, provides a critique on what questions DNA evidence can and cannot answer, and expands our knowledge of the global diversity of plague.

No description available.

The study employed 206 entry-level, retail sales associates working for a large telecommunications company across 70 store sites. The purpose of the study was to discriminate successful performers from those with little sales potential via a valid, fair, and practical selection procedure. The experimental test set consisted of the General Ability Battery, Sales Attitude Checklist, Wonderlic Personnel Test, SRA Verbal Form, School and College Ability Test Verbal, SPA Arithmetic Index, and SRA Reading Index. Supervisory ratings and percent revenue data were used as measures of sales performance. Based on the multiple regression results, the SPA Reading Index and SRA Verbal Form were chosen to compose the final selection system for the retail sales position.

La protéine UHRF1 est impliquée dans le maintien et la transmission des modifications épigénétiques. Lors du processus de réplication, elle recrute la méthyltransférase de l’ADN Dnmt1 au niveau des sites CpG hémi-méthylés via son domaine SRA (SET and RING Associated), favorisant la duplication des profils de méthylation. La structure tridimensionnelle du complexe SRA/ADN révèle que la protéine induit un basculement de la méthylcytosine qui permet un ancrage spécifique de la protéine sur les sites hémim éthylés, facilitant le recrutement de la Dnmt1 au niveau de ces positions stratégiques. Dans ce contexte, notre projet vise à comprendre les mécanismes d’interaction du domaine SRA de UHRF1 avec l’ADN hémi-méthylé. Des oligonucléotides doubles brins ont été marqués à la 2-aminopurine, un analogue nucléosidique fluorescent sensible à l’environnement, à différentes positions au voisinage d’un unique site de reconnaissance CpG hémi-méthylé. Les mesures de spectroscopie de fluorescence à l’état stationnaire et résolues en temps de ces duplexes liés au domaine SRA nous ont permis de caractériser de manière site spécifique les changements conformationnels induits par la liaison du domaine SRA. En accord avec la structure tridimensionnelle du complexe SRA/ADN, nos données suggèrent que le domaine SRA est capable de basculer la méthylcytosine tout en préservant la structure des autres bases dans le duplexe. Le domaine SRA semble se lier selon le même mécanisme aux duplexes hémi-méthylés, bi-méthylés et non-méthylés. La protéine UHRF1 jouerait ainsi un rôle de “lecteur“ capable de scanner la séquence d’ADN à la recherche de sites hémi-méthylés. / The UHRF1 protein plays a key role in the maintenance and transmission of epigenetic modifications. Duringthe replication process, it recruits the DNA methyltransferase Dnmt1 to hemi-methylated CpG sites via itsSRA (SET and RING Associated) domain, promoting the duplication of the methylation profiles. Thetridimensional structure of the SRA/DNA complex revealed that the protein induces a base-flipping of themethylcytosine that enables a specific anchoring of the protein to hemi-methylated sites facilitating therecruitment of Dnmt1 to this strategic position. In this context, our project was aimed to further understand themechanism of interaction of the SRA domain with hemi-methylated DNA. To this end, oligonucleotideduplexes were labeled by 2-aminopurine, a fluorescent nucleoside analogue sensitive to environment, atvarious positions close to the single hemi-methylated CpG recognition site. Steady-state and time-resolvedfluorescence spectroscopy measurements of these duplexes bound to the SRA domain enabled us to sitespecificallycharacterize the conformational changes induced by the binding of this domain. In agreement withthe tridimensional structure of the SRA/DNA complex, our data suggest that the SRA domain is able to flip themethylcytosine while preserving the structure of the surrounding bases in the duplex. The SRA domain wasshown to bind with the same mechanism to hemi-methylated, fully-methylated and non-methylated duplexes.Our data suggest the UHRF1 protein plays a role of “reader” that scans the DNA sequence for hemimethylatedsites.

Made available in DSpace on 2015-07-22T20:49:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-05-26 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A angiotensina II (Ang II), um dos mais relevantes peptídeos angiotensinérgicos, tem um importante papel na fisiologia e na fisiopatologia dos tecidos renal e cardíaco. Existem diversas enzimas capazes de gerar Ang II. Uma delas é a tonina, capaz de formar a Ang II a partir da angiotensina I (Ang I) ou diretamente do AGT. Nosso objetivo foi caracterizar o RAS no rim e no coração do camundongo transgênico que expressa tonina de rato (TGM(rTon)). Foram utilizados camundongos machos C57bl/6 (grupo controle, CT) e camundongos transgênicos [TGM(rTon)]. Vinte e quatro horas após o implante de cânulas, animais acordados, com 12 semanas de idade, foram submetidos a procedimentos de avaliação hemodinâmica. Os dados mostraram que não existem diferenças estatísticas entre os grupos quanto aos parâmetros hemodinâmicos. Após determinação da pressão arterial, os camundongos foram sacrificados por decapitação e os órgãos (rim e coração) foram retirados. O coração foi dividido em átrios (AT) [direito + esquerdo], ventrículo direito (VD) e ventrículo esquerdo (VE). Usando o tetradecapeptídeo sintético como substrato, a atividade tonina foi avaliada nos rins e nas estruturas cardíacas. A atividade da enzima conversora de angiotensina (ECA) foi determinada usando os substratos ZPhe-His-Leu (específico para o domínio N da ECA) e Hip-His-Leu (específico para o domínio C). Tanto a atividade da tonina, quanto da ECA nos rins e no AT foram significantemente maiores no grupo TGM(rTon) quando comparado ao dos camundongos CT. Já entre as estruturas cardíacas o AT mostrou atividade significantemente maior em ambos os grupos, quando comparados aos ventrículos. A expressão da isoforma de 65 kDa da ECA foi significantemente maior no grupo TGM(rTon) nos rins e no AT. Apenas no rim foi analisada a expressão de ECA e não foi observada diferença estatística entre os grupos. As concentrações da angiotensina 1-7 [Ang-(1-7)] e da Ang I foram significantemente diminuídas no grupo TGM(rTon) quando comparadas ao CT. Entretanto, não foi observada diferença estatística nos níveis da Ang II entre os grupos. Sugerimos que o ambiente com abundância em tonina pode aumentar a atividade N-domínio da ECA por meio de uma secretase, explicando os baixos níveis da Ang-(1-7) encontrados no grupo transgênicoPela primeira vez foi mostrado um importante papel fisiológico da tonina comomodulador do SRA renal e cardíaco. / Angiotensin II (Ang II), one of the most relevant angiotensinergic peptides, has an important role in the renal and cardiac physiology. There are many enzymes that generate Ang II. One of them is tonin, that is able to liberate AII from angiotensin I (Ang I) or directly from angiotensinogen (AGT). Our goal was to characterize the RAS in the kidney and heart of transgenic mouse that express rat tonin [TGM(rTon)]. Twenty-four hours after implantation of cannulas, 12 weeks old awake animals were subjected to hemodynamic evaluation. Data showed no statistical differences for the hemodynamic parameters analyzed between transgenic and the wild-type (control, CT). After that mice were sacrificed by decapitation and their organs (kidney and heart) removed. Heart was separated into atria [right plus left (AT)], right ventricle (RV), and left ventricle (LV)]. Using the synthetic tetradecapeptide renin substrate, tonin activity was evaluated in the kidney and cardiac structures. The angiotensin converting enzyme (ACE) activity was determined using the substrates Z-Phe- His-Leu (specific for N-domain ACE active site) and Hip-His-Leu (specific for Cdomain active site). Both the activity of tonin and the ACE, in the kidneys and AT were significantly higher in TGM(rTon) when compared with CT mice. Among the cardiac structures AT showed significantly greater activity in both groups when compared to the ventricles.The expression of the 65 kDa ACE isoform was significantly higher in TGM(rTon) in the kidney and AT when compared with CT. ACE2 expression was determined only in the kidney and there was not statistic differences between groups. The levels of angiotensin 1- 7 [Ang-(1-7)] and Ang I was significantly decreased in TGM(rTon) when compared with CT. However, the levels of Ang II were not statistically different between groups. We suggest that the environment of tonin abundance may increase N-domain ACE activity by a secretase activity, which could explain the low levels of Ang-(1-7) in the transgenic animal. Our data show, for the first time, the physiologic role of tonin as an important modulator of renal and cardiac RAS. / FAPESP: 2009/03261-04 / TEDE / BV UNIFESP: Teses e dissertações

The SRA-10 is a tactile instrument which provides hearing impaired subjects with acoustic transforms that can be easily discriminated on the skin. Whether or not the SRA-10 is an effective means of training speech-language skills in profoundly hearing impaired subjects was the focus of this investigation. Two profoundly hearing impaired subjects were trained on phonetic reception/production tasks and on discrimination of multisyllabic words. Each subject served as his own control, wearing the SRA-10 for 14, 30 minute sessions, and a Bioacoustics 70-B auditory training unit for the same period of time. Results indicated a greater correct performance gain function with the SRA-10 than with the 70-B, suggesting that speech perception/production training using the SRA-10 or similar device would be superior to training using acoustic amplification.

A restrição de sal na dieta está associada com resistência à ação da insulina e obesidade. O mecanismo molecular pelo qual a dieta hipossódica (HO) pode induzir resistência à insulina e obesidade não está totalmente compreendido. O objetivo do presente estudo foi avaliar a influência da ingestão crônica de sal sobre o peso corporal (PC), sinalização da insulina no fígado, músculo e tecido adiposo branco (TAB) e sua associação com adiposidade e resistência à insulina. Com esta finalidade, ratos Wistar foram alimentados com dieta HO, normossódica (NR) ou hipersódica (HR) desde o desmame. O PC foi avaliado desde o desmame. Ao completarem 12 semanas de vida, foram avaliados pressão arterial, balanço energético, consumo de ração, glicemia, angiotensina II (ANGIO II) plasmática e perfil hormonal. A atividade motora espontânea foi estudada em ratos com 8 e 12 semanas. A sensibilidade à insulina foi analisada pelo índice de HOMA. A expressão da proteína desacopladora mitocondrial 1 (UPC-1) foi quantificada no tecido adiposo marrom (TAM) e o conteúdo de ANGIO II no TAM, TAB e hipotálamo. As etapas iniciais da sinalização da insulina foram avaliadas por imunoprecipitação e immunoblotting das proteínas envolvidas como o receptor da insulina (IR), substrato 1 e 2 do IR (IRS-1 e IRS-2), enzima fosfatidilinositol 3 – quinase (PI-3q), proteína quinase B (Akt/PKB), ativação da proteína c-jun NH2-terminal quinase (JNK) e fosforilação em serina 307 do IRS-1. O PC no desmame foi semelhante entre os grupos de dieta. No entanto, na idade adulta os ratos em dieta HO apresentaram maior PC, adiposidade visceral, glicemia e insulinemia de jejum, concentração de ANGIO II plasmática e aumento do conteúdo de ANGIO II no TAM. Por outro lado, nestes mesmos animais a dieta HO diminuiu o consumo de ração, o gasto energético, a expressão da proteína UCP-1, adiponectina plasmática e o conteúdo de ANGIO II no TAB. A atividade motora não foi diferente entre os grupos estudados. A dieta HO diminuiu a via IR/PI-3q/Akt/Foxo1 de sinalização da insulina no fígado e músculo. Por outro lado, parte desta via (IRS-2/Akt/Foxo1) mostrou-se aumentada no TAB. No fígado e músculo houve um aumento da fosforilação da proteína JNK associada com maior fosforilação do IRS-1ser307 no grupo HO. Em conclusão, a restrição ou sobrecarga crônica de sal altera a evolução ponderal associada com modificações no balanço energético e no perfil hormonal na idade adulta. A resistência à insulina induzida pela dieta HO é tecido-específico e foi acompanhada por uma ativação da proteína JNK e um aumento da fosforilação dos resíduos de serina 307 do IRS-1. / Restriction of sodium chloride intake has been associated with insulin resistance (INS-R) and obesity. The molecular mechanisms by which the low salt diet (LSD) can induce INS-R and obesity have not yet been established.The aim of the present study was to evaluate the influences of salt intake on body weight (BW) and on insulin signaling in liver, muscle and white adipose tissue (WAT). Wistar rats were fed a LSD, normal (NSD), or high (HSD) salt diet since weaning. At 12 weeks of age, BW, blood pressure(BP),energy balance, food intake, plasma glucose and angiotesin II (ANGIO II), and hormonal profile were evaluated. Afterward, motor activity, HOMA index, uncoupling protein 1 expression (UCP-1) and tissue adipose ANGIO II content was determined. The early steps of insulin signaling (IR: insulin receptor, IRS-1 and IRS-2: IR substrate 1 and 2, PI-3K: phosphatidylinositol 3-kinase), Akt (protein kinase B) phosphorylation, JNK (c-jun NH2-terminal kinase) activation and IRS-1ser307 (serine 307 of IRS-1) phosphorylation were evaluated by immunoprecipitation and immunoblotting. LSD increased BW, visceral adiposity, blood glucose, insulin, leptin, plasma ANGIO II and its content in BAT. Otherwise, LSD decreased food intake, energy expenditure, UCP-1 expression, adiponectin and ANGIO II content in WAT. Motor activity was not influenced by the dietary salt content. In LSD, a decreasing in IR/PI-3K/Akt/Foxo1 was observed in liver and muscle and an increase in this pathway was showed in adipose tissue. JNK activity and IRS-1ser307 phosphorylation were higher in liver and muscle. In conclusion, LSD induced obesity and insulin resistance due to changes in energy expenditure, SRA and insulin signaling. The INS-R is tissuespecific and is accompanied by JNK activation and IRS-1ser307 phosphorylation.

La thèse étudie l'évolution sous contraintes du milieu que se donnent les élèves dans les cadres des premiers moments d'une activité d'étude et de recherche sur les équations du premier degré à une inconnue en classe de 4°. Le dispositif d'observation - analyses mathématique et didactique a priori soutenant la proposition d'activité, mise en place de groupes au sein des classes, films des interactions au sein du processus de recherche - recourt à une méthodologie de type clinique. Elle autorise une analyse micro-didactique qui, utilisant les récents développements de la théorie Anthropologique du didactique, conclut à la différenciation des milieux, des temporalités et des fonctions au sein des groupes observés et un enrichissement du concept de mémoire didactique. / The thesis studies the evolution under constraints of the milieu that pupils give themselves in the frames of the first moments of an activity of study and research on single-unknown equations of the first degree in class of 4 °.The observation device - a priori mathematical and didactical analyzes supporting the activity proposal, setting up groups within the classes, films of the interactions within the research process - resorts to a methodology of the clinical type. It allows a micro-didactic analysis which, using the most recent developments of the anthropological theory of didactics, concludes with the differentiation of the environments, the temporalities and the functions within the groups observed and an enrichment of the concept of didactic memory.