Os receptores acoplados à proteína G (GPCRs), também chamados de receptores 7TM, são conhecidos por regular virtualmente todos os processos fisiológicos em mamíferos e cerca de 40% de todas as drogas comerciais agem através destes receptores. A sinalização mediada por eles é classicamente atribuída à proteína G, que é ativada pela troca de GDP por GTP, promovendo a separação das subunidades G e G, e leva à produção de mensageiros secundários como cAMP, Ca2+ e DAG. Após a resposta os GPCRs são fosforilados pelas quinases de GPCRs (GRKs), sinalizando para recrutamento das -arrestinas citoplasmáticas, que por sua vez desencadeiam a formação de endossomos internalizando e dessensibilizando o receptor. Entretanto, estudos mostram que este endossomo, contendo o complexo ligante-receptor--arrestina, pode interagir com proteínas sinalizadoras no citoplasma desencadeando vias de sinalização independentes de proteína G. Recentemente foram descritos para diferentes receptores, ligantes capazes de ativar seletivamente uma das duas vias, proteína G ou -arrestina, chamados agonistas seletivos. O receptor AT1 é um GPCR particularmente interessante no estudo do agonismo seletivo, tanto por sua vasta expressão em tecidos quanto pelo conhecimento de agonistas seletivos já estabelecidos, tais como os ligantes SII e TRV120027. O objetivo deste trabalho foi analisar comparativamente os perfis de sinalização decorrente da ativação de AT1 por SII ou TRV120027 através do uso de arranjos de quinases e da modulação de genes relacionados a sinalização de GPCRs. Ang II que é ligante natural e total (ativa via dependente de proteína G e de -arrestina) neste receptor foi usada como controle para fins de comparação. Nossos dados mostraram que o perfil da sinalização mediada pelo receptor AT1 varia não só entre AngII e os agonistas seletivos, mas também entre os dois ligantes seletivos SII e TRV120027, mostrando que a interação receptor-ligante pode influenciar a sinalização em um grau mais refinado, além da ativação dependente de -arrestina ou proteína G. Estes dados mostram que existem perspectivas para o desenvolvimento futuro de ligantes com ainda maior grau de seletividade. / G protein coupled receptors (GPCRs), also known as 7TM receptors, are known to regulate virtually all physiological processes in mammals and approximately 40% of all current clinical drugs act by modulating such receptors. The signaling mediated by them is classically by coupling to G protein, which is activated by exchanging bound GDP for GTP, dissociation of G and G subunits, then leading to production of second messengers such as cAMP, Ca2+, and DAG. After the signal transduction, GPCR are phosphorylated by GPCR kinases (GRKs), followed by recruitment of cytoplasmic -arrestins, which initiate the endosome formation with consequent internalization and desensitization of the receptor. However, is has been demonstrated that the endosome assembling the ligand-receptor--arrestin complex can interact with cytoplasmic signaling proteins, therefore activating signaling pathways independently of G protein coupling. Recently, for different receptors, it has been described ligands capable of selectively activating one of these signaling pathways, G protein or -arrestin, called biased agonists. The AT1 receptor is a particularly interesting GPCR for the study of biased agonism, either due to its wide tissue expression as well as also due the existence of known and established biased ligands, such as SII and TRV120027. The aim of our study was to comparatively analyze the AT1 receptor signaling pathways profiles after activation by SII or TRV120027, using kinases arrays, and expression modulation of genes related to GPCRs signaling. AngII is the natural and full agonist of this receptor (activates both G protein and -arrestin signaling pathways) was used for comparison. Our data show that the signaling profile mediated by AT1 receptor can be distinct not only when comparing the profiles from AngII and the biased agonists, but also when comparing the profiles from the two biased ligands SII and TRv120027; revealing that the complex ligand-receptor can influence the downstream signaling pathways in a fine-tune way, further to the activation of -arrestin or G-protein. This data show that there are perspectives for the future development of ligands with even higher degree of selectivity.

Sex biased expression characterizes ~1,000 genes in mammalian liver, and impart sex differences in metabolism and disease susceptibility. The sex-dependent temporal patterns of pituitary growth hormone (GH) secretion, pulsatile in males and more continuous in females, are known to sex-differentially activate transcriptional regulators (TFs), leading to widespread sex-differences in the mouse liver transcriptome. This thesis elucidates sex-biased gene expression patterns in the following studies. Gene structures, expression patterns and species conservation are characterized for ~15,000 liver-expressed intergenic long noncoding RNAs (lncRNAs), many of which are novel. Analysis of intergenic lncRNA promoters revealed unexpected high conservation and significant enrichment of TF binding compared to protein-coding promoters. A subset of intergenic lncRNAs showed strong sex-specific and GH-dependent gene expression, and whose transcription was tightly correlated with the surrounding chromatin environment and TF binding patterns. The pervasive role of genetic factors to regulate sex-biased genes was revealed by analyzing livers with matched genotype and gene expression data from Diversity Outbred (DO) mice, an outbred population with high natural allelic variance derived from eight inbred strains. Significant associations between genetic variants and gene expression (eQTLs) were identified, including many eQTLs with a strong sex-biased association. Remarkably, a large fraction of these sex-biased eQTLs were linked to either gain or loss of sex-specific gene expression in the DO founder strain predicted to be regulated by the eQTL. Thus, genetic factors are a major contributor to the variability of sex-biased genes, which has important consequences related to the individual variability of liver phenotypes with known sex-differences. Natural genetic perturbations in DO mice were leveraged to identify candidate lncRNAs that may regulate hypophysectomy (hypox) responsiveness. Co-regulated protein-coding gene clusters were discovered based on gene expression correlations across DO mouse livers, many of which are enriched for distinct hypox response classes. LncRNAs whose expression showed unexpected significant negative correlation with protein-coding gene clusters enriched for genes of the opposite-sex bias and inverse hypox class were hypothesized to play negative regulatory role. In sum, these studies expand the characterization of the sex-biased hepatic transcriptome and reveal contributions of genetic factors to the regulation of sex bias in mammalian liver. / 2020-11-27T00:00:00Z

Receptores acoplados a proteína G (GPCRs) são proteínas integrais de membrana caracterizados por possuírem sete ?-helices transmembranares e por isso também são chamados de receptores 7TM. Esta superfamília de receptores medeia um grande numero de processos fisiológicos e é alvo para aproximadamente 40% de todas as drogas no mercado. O receptor de Bradicinina de tipo 2 (B2) é o principal mediador do sistema Calicreina-Cinina e é classicamente ativado pelo nonapeptídeo Bradicinina (BK). Trabalhos recentes descreveram agonistas para diferentes GPCRs, que podem ativar seletivamente (ou pelo menos preferencialmente) vias de sinalização dependentes de proteína G ou do acoplamento de ?-arrestina, sendo este fenômeno denominado agonismo tendencioso (do inglês \"biased agonism\"). Neste trabalho estão sendo desenhados e sintetizados uma serie de análogos com o objetivo de produzir novos ligantes com distintas propriedades bioquímicas e farmacológicas. Alguns destes análogos já sintetizados apresentaram características interessantes nos perfis de ativação. Estes análogos devem ser utilizados como modelos para a síntese e caracterização de novas gerações de análogos com potenciais propriedades de agonismo tendencioso. Nos acreditamos que o desenho de novos agonistas tendenciosos pode levar ao desenvolvimentos de uma nova geração de drogas, seletivas para ativação não somente de um subtipo de receptor, mas também de uma via de sinalização especifica / G-protein coupled receptors (GPCRs) are integral membrane proteins characterized by bearing seven transmembrane ?-helices, and are therefore also known as 7TM receptors. This receptor superfamily mediates a large number of physiological processes and is subject to approximately 40% of all drugs on the market. The type 2 Bradykinin receptor (B2) is the primary mediator of the Kallikrein-Kinin System and is classically activated by the nonapeptide Bradykinin (BK). Recent studies have described different GPCRs agonists which can selectively activate (or at least preferably) dependent signaling pathways of G protein or ?-arrestin coupling, this phenomenon is called biased agonism. This work are based in design and synthesize a series of analogs with the goal of producing new ligands with different biochemical and pharmacological properties. Some of these synthesized analogs have presented interesting characteristics in activation profiles. These analogs should be used as templates for the synthesis and characterization of novel analogs with properties of biased agonism. We believe that the design of novel agonists can lead to development of a new generation of drugs, not only selective for activation of a receptor subtype but also a specific signaling pathway

The aim of this thesis is to achieve a deeper understanding of how media portrays politicians and examine whether media is gender-biased. This is done by carrying out a case study within the Swedish context, which compares print media’s portrayal of the Moderate party’s former leader Anna Kinberg Batra with their current leader Ulf Kristersson. A quantitative content analysis is applied on 330 articles from four Swedish newspapers. By examining previous literature, a theoretical framework is constructed using theories on framing, the gender system as well as media’s treatment of female and male politicians which is later operationalized. In brief, the results of the study show there are differences in certain parts of media’s portrayal of Kinberg Batra and Kristersson, however they were not always as substantial and obvious as previous literature had indicated.

Receptores acoplados a proteína G (GPCRs) são proteínas integrais de membrana caracterizados por possuírem sete ?-helices transmembranares e por isso também são chamados de receptores 7TM. Esta superfamília de receptores medeia um grande numero de processos fisiológicos e é alvo para aproximadamente 40% de todas as drogas no mercado. O receptor de Bradicinina de tipo 2 (B2) é o principal mediador do sistema Calicreina-Cinina e é classicamente ativado pelo nonapeptídeo Bradicinina (BK). Trabalhos recentes descreveram agonistas para diferentes GPCRs, que podem ativar seletivamente (ou pelo menos preferencialmente) vias de sinalização dependentes de proteína G ou do acoplamento de ?-arrestina, sendo este fenômeno denominado agonismo tendencioso (do inglês \"biased agonism\"). Neste trabalho estão sendo desenhados e sintetizados uma serie de análogos com o objetivo de produzir novos ligantes com distintas propriedades bioquímicas e farmacológicas. Alguns destes análogos já sintetizados apresentaram características interessantes nos perfis de ativação. Estes análogos devem ser utilizados como modelos para a síntese e caracterização de novas gerações de análogos com potenciais propriedades de agonismo tendencioso. Nos acreditamos que o desenho de novos agonistas tendenciosos pode levar ao desenvolvimentos de uma nova geração de drogas, seletivas para ativação não somente de um subtipo de receptor, mas também de uma via de sinalização especifica / G-protein coupled receptors (GPCRs) are integral membrane proteins characterized by bearing seven transmembrane ?-helices, and are therefore also known as 7TM receptors. This receptor superfamily mediates a large number of physiological processes and is subject to approximately 40% of all drugs on the market. The type 2 Bradykinin receptor (B2) is the primary mediator of the Kallikrein-Kinin System and is classically activated by the nonapeptide Bradykinin (BK). Recent studies have described different GPCRs agonists which can selectively activate (or at least preferably) dependent signaling pathways of G protein or ?-arrestin coupling, this phenomenon is called biased agonism. This work are based in design and synthesize a series of analogs with the goal of producing new ligands with different biochemical and pharmacological properties. Some of these synthesized analogs have presented interesting characteristics in activation profiles. These analogs should be used as templates for the synthesis and characterization of novel analogs with properties of biased agonism. We believe that the design of novel agonists can lead to development of a new generation of drugs, not only selective for activation of a receptor subtype but also a specific signaling pathway

Emotional events are often better preserved in memory than events without an emotional component. Emotional stimuli benefit from capturing and holding the attention of a perceiver to a higher degree than more emotion-neutral stimuli. Arousal associated with experiencing emotionally valenced stimuli or situations affects every major stage in creating, maintaining and retrieving lasting memories. Presented in this thesis were models delineating the behavioral and neurological mechanisms that might explain arousal-induced effects on subsequent memory outcome. Based on a study of relevant literature, findings were presented in this thesis that highlight amygdala activation as crucial for the enhancement of memory generally associated with emotional arousal. The amygdala modulates processing in other areas of the brain involved in memory. Heightened levels of norepinephrine, stemming from sympathetic nervous system activation, underlies observable arousal-induced memory effects and seem to be a crucial component in enabling glucocorticoid augmentation of memory. Arousal seems to further amplify the biased competition between stimuli that favors the neural representation of motivationally relevant stimuli and stimuli of a sensory salient nature. The aim of this thesis was to outline the impact of emotional arousal on different stages of memory processing, including processes for memory formation, strengthening of memory traces, and eventual subsequent retrieval.

A mineração de dados é um processo computacionalmente caro, que se apoia no pré-processamento dos dados para aumentar a sua eficiência. As técnicas de redução de elementos do conjunto de dados, principalmente a amostragem de dados se destacam no pré-processamento. Os dados reais são caracterizados pela não uniformidade da distribuição, grande quantidade de atributos e presença de elementos considerados ruídos. Para esse tipo de dado, a amostragem uniforme, na qual cada elemento tem a mesma probabilidade de ser escolhido, é inefiiente. Os dados nos últimos anos, vem passando por transformações. Assim, não só o seu volume tem aumentado significantemente, mas também a maneira de como eles são representados. Os dados usualmente são divididos apenas em dados tradicionais (número e pequenas cadeias de caracteres) e dados complexos (imagens, cadeias de DNA, vídeos, etc). Entretanto, uma representação mais rica, na qual não só os elementos do conjunto são representados mas também a suas ligações, vem sendo amplamente utilizada. Esse novo tipo de dado, chamado rede complexa, fez surgir uma nova área de pesquisa chamada mineração de redes complexas ou de grafos, já que estes são utilizados na representação das redes complexas. Para esta nova área é necessário o desenvolvimento de técnicas que permitam a mineração de grandes redes complexas, isto é, redes com centenas de milhares de elementos(nós) e ligações(arestas). Esta tese teve como objetivo explorar a redução de elementos em conjuntos de dados chamados desbalanceados, isto é, que possuem agrupamentos ou classes de tamanhos bastantes distintos, e que também possuam alta quantidade de atributos e presença de ruídos. Além disso, esta tese também explora a mineração de redes complexas com a extração de padrões e propriedades e o desenvolvimento de algoritmos eficientes para a classificação das redes em reais e sintéticas. Também é proposto a mineração de redes complexas utilizando gerenciadores de base de dados para a mineração de cliques de tamanho 4 e 5 e a apresentação da extensão do coeficiente de clusterização / Data mining is an expensive computational process speeded up by data preprocessing. Data reduction techniques, as data sampling are useful during the data preprocessing. Real data are known for presenting non-uniform data distribution, a large amount of attributes and noise. For this type of data, uniform sampling, which selects elements with the same probability, is inefficient. Over the past years, the data available to mining have been changed. Not only have their volume increased but also data format. Data are usually divided into traditional (number and small chains of character) and complex (images, DNA, videos, etc). However, a rich representation, in which not only elements but also the connections among the elements have been used, is necessary. This new data type, which is called complex network and is usually modeled as a graph, has created a new research area, called graph mining or complex network mining, which requires the development of new mining techniques to allow mining large networks, that is, networks with hundreds of thousands of nodes and edges. The present thesis aims to explore the data reduction in unbalanced data, that is, data that have clusters with very different sizes, a large amount of attributes and noise. It also explores complex network mining with two basic findings: useful new patterns, which allow distinguishing real from synthetic networks and mining cliques of sizes 4 and 5 using database systems, discovering interesting power laws and presenting a new cluster coefficient formula

Today, groups considered Hispanic in the United States consist of populations whose complex genetic structures reflect intermixed diverse groups of people who came in contact during Spanish colonization in Latin America. After coming in contact and wiping out most of the Native Americans who occupied North and Latin America, the Spanish also introduced West African individuals for labor to begin developing crops to be shipped back to Europe, resulting in the Trans-Atlantic African slave trade. These migration events and differential gene flow among males and females that occurred throughout Latin America have led to populations that have been genetically transformed from what they were prior to Spanish arrival (Madrigal, 2006). Genetic research commonly refers to individuals considered Hispanic as "tri-hybrids" of Native American, European, and African ancestry (Bertoni et al., 2003; Gonz[aacute]lez-Andrade et al., 2007). This research focuses on populations from present-day Mexico, Puerto Rico, and Cuba, all of whom experienced various population histories as these three ancestral groups came in contact. Published genetic research demonstrates that individuals from Mexico tend to have the highest mean proportion of Native American ancestry, while Puerto Rican individuals have the highest mean proportion of European ancestry, and Cuban individuals have the highest mean proportion of African ancestry (Bonilla et al., 2005; Lisker et al., 1990; Mendizabal et al., 2008; Tang et al., 2007; Via et al., 2011). The present research utilizes craniometric data from these three groups to determine whether the cranial morphology reflects similar population relationships and mean ancestry proportions as found in genetic research through Mahalanobis distance (D2), canonical discriminant function, and normal mixture cluster analyses. Sex-biased ancestry asymmetry was also tested by separating each group by sex and running the same analyses. The results show that all three groups considered Hispanic (Mexico, Puerto Rico, and Cuba) are significantly different from each other; however, when proxy ancestral groups are included (Guatemalan Mayan, Indigenous Caribbean, Spanish, and West African), the Mexican and Guatemalan Mayan samples are the most similar, followed by the Mexican and Indigenous Caribbean samples and the Puerto Rican and Cuban samples. The results of the normal mixture analyses indicate that Mexico has the highest mean ancestry proportion of Native American (Guatemalan Mayan) (72.9%), while the Puerto Rican and Cuban samples both have a higher mean European ancestry proportion, with 81.34% and 73.6% respectively. While the Cuban sample is not reflective of the genetic research in regards to ancestry proportion results, with the highest proportion of African ancestry over European and Native American ancestry, it does have the highest proportion of African ancestry among the three groups (18.4%). When separated by sex, the results indicate that the Mexican and Puerto Rican samples may show some evidence in sex-biased ancestry proportions, with the male individuals having a larger proportion of European ancestry and the female individuals having a larger proportion of Native American or African ancestry. Cuba, on the other hand, does not follow this trend and instead displays a higher proportion of European ancestry in females and a higher proportion of Native American and African ancestry in the males. Techniques in the field of forensic anthropology in the United States are constantly being reanalyzed and restructured based on the changing demographics of the population, especially with the arrival of individuals from Latin America (Ennis et al., 2011). Recent samples of American Black and White individuals were included in the Mahalanobis distance (D2) and canonical discriminant function analyses in place of the ancestral proxy groups to determine the craniometric relationship of the groups within the United States. The results show that the Mexico and Guatemala samples are the most similar (D2=2.624), followed by the Cuba and American Black samples (D2=3.296) and the Puerto Rico and American White samples (D2=4.317), which each cluster together in pairs. These results reflect the population histories that took place during colonialism, with the largest amount of slave trade occurring in Cuba over the other two countries. From an applied perspective, clarification is needed in the biological definition of Hispanic and the degree of heterogeneity in each social group, as well as the relationship among groups, in order to accurately develop techniques in forensic anthropology for human identification.

當我們在應用迴歸分析法時，往往會遇到兩個或多個自變數間存在著線性 關係的問題，即所謂多重共線性(multicollinearity)； 多重共線性的存 在會使得一般被廣泛運用的最小平方估計式 (least square estimator) 出現不穩定的情形。此估計式之總變異(total variance)會因共線性之程 度愈高而發散，呈現出不穩定的現象，進而影響其預測模式的能力。因此 相繼有學者提出改良共線性模式的方法，以期達到較精確且穩健的預測結 果。脊迴歸分析法(Ridge regression analysis) 便是其中之一；對於有 共線性存在之模式，若使用傳統脊估式，其總變異會較最小平方估計式穩 定。但傳統脊估式為一個偏量估計式(biased estimator)，故本文考慮採 用Jackknife 取一法以求降低脊迴歸估計式之偏量(bias)，此二法併用所 產生之一個新的估計式即本文所謂改良式脊迴歸估計式。本文將應用線性 模式Jackknife 估計式，配合脊迴歸分析法導出改良式脊迴歸估計式。並 另外利用電腦模擬出不同程度之共線性資料以比較分析傳統脊迴歸係數與 改良式脊迴歸係數，此二者於預測模式上之表現。結果顯示：改良式脊迴 歸估計係數對於降低估計偏差方面有顯著之改善，其預測能力亦優於傳統 脊迴歸係數，因此改良式脊迴歸估計式較傳統脊迴歸估計式更加穩定、精 確。迴歸分析是目前應用最廣泛之統計工具，不論是經濟模型、商業方面 以及醫學上之應用等均以求精求準之預測為主要目的，本文提出之改良式 脊迴歸係數，於共線性存在之迴歸模式下兼備了傳統脊迴歸係數穩定估計 式變異以求精，降低估計偏量以求準之優點，因此改良式脊迴歸係數於預 測模式上之貢獻是值得肯定的。

<p>In this thesis I present and discuss the phenomenon of ethical fading, and its association with biased assessment of a fair action. Ethical fading is an intuitive, self-deceptive, unconscious mechanism by which even morally competent agents are lead to disregard the ethical consequences of a particular choice. In engaging in this psychological mechanism, I argue, agents are also presupposing a biased assessment of entitlement. This biased assessment of fairness is intentionally dubious, and to be found in decision frames and reinforced by contexts. In the final part of the work I present an applied ethics case to show how ethical fading may be a quite prevalent pattern of behavior.</p>