Role of Brain Angiotensin II in Cardiovascular Regulation and Erythropoiesis

Hypertension prevalence is still growing worldwide as well as the number of drug-therapy non-responsive patients. Therefore, improving the current and developing new therapies to control blood pressure (BP) is warranted. Growing literature points to the sympathetic nerve system as the major system controlling long-term BP homeostasis, and human hypertension is often accompanied by increased sympathetic nerve activity (SNA). The renin angiotensin system (RAS) is involved in cardiovascular control and beyond due to the broad actions of the powerful hormone angiotensin II (Ang II) produced in the circulation or within organs. The project aimed to further characterize the modulatory effects of the RAS on SNA and its impact on cardiovascular control and erythropoiesis, particularly focusing on the role of brain-borne Ang II. These questions were experimentally addressed with RAS gain and loss of function mouse models in the FVB/N background strain, and complementary experiments were performed with rats and mixed background mice. A transgenic line with brain-specific angiotensinogen (Agt) expression was validated (Agt-Tg) and used to demonstrate in vivo local brain Ang II formation. FVB/N mice cardiovascular regulation revealed predicted and surprising phenotypes. As expected FVB/N mice lacking the major Ang II receptor (AT1a-KO) presented reduced BP, and Agt-Tg displayed increased BP accompanied by increased SNA. Surprisingly, adult FVB/N mice lacking Agt (Agt-KO) were normotensive contrasting previous findings in other strains. Paradoxically, the genetic brain-rescue of Agt in Agt-KO (Agt-KO-Tg) strongly reduced BP. Using integrative physiology, we identified that the normotension in Agt-KO is driven by increased vascular tone due to exaggerated sympathetic outflow and impaired nitric oxide production which is reversed by brain Ang II in Agt-KO-Tg contrasting Agt-Tg. Agt-KO-Tg also presented better renal function compared to Agt-KO despite similar renal morphological damage. In addition, brain Ang II strongly activated renal SNA in Agt-KO-Tg, and renal denervation had minimal effect on Agt-KO and Agt-KO-Tg baseline BP. A genome-wide-association-study was employed to uncover the genetic alteration causing FVB/N Agt-KO to fail in reducing BP. For this, a mixed background (FVB/N x C57BL/6N) F2 Agt-KO line was generated. Strikingly, the phenotyping data of the F2 Agt-KO strongly indicates a single recessive allele responsible for the BP phenotype in FVB/N Agt-KO once the BP in the F2 presented a clear bimodal distribution with most mice being hypotensive. However, the association analyses demonstrated that several loci likely contribute to the phenotype in FVB/N Agt-KO. Finally, we identified one central and one peripheral mechanism of erythropoiesis regulation modulated by the RAS. In the brain, Ang II favors erythropoiesis via SNA. Agt-Tg with elevated brain Ang II displayed increased erythropoiesis that was reverted by peripheral sympathectomy, and rats with depleted brain Agt presented decreased baseline erythropoiesis. In the periphery, the experiments revealed that the RAS influences the iron homeostasis because Agt-KO mice presented microcytic anemia accompanied by reduced levels of circulating and tissue-stored iron. Altogether, the data set generated within the frame of my doctoral thesis supports local formation and function of brain Ang II. Furthermore, we provided evidence that brain Ang II is involved in differential SNA regulation to different organs impacting BP homeostasis. Finally, two unprecedented mechanisms of erythropoiesis control modulated by the RAS via SNA and iron homeostasis were revealed.Die Prävalenz von Bluthochdruck nimmt weltweit weiter zu, ebenso wie die Zahl der Patienten, die nicht auf eine medikamentöse Therapie ansprechen. Daher ist die Verbesserung der derzeitigen und die Entwicklung neuer Therapien zur Kontrolle des Blutdrucks gerechtfertigt. Zunehmend weist Literatur darauf hin, dass das sympathische Nervensystem das wichtigste System für die Steuerung langfristiger Blutdruckhomöostase ist, außerdem wird Bluthochdruck oft von einer erhöhten sympathischen Nervenaktivität (SNA) begleitet. Das Renin-Angiotensin-System (RAS) ist an der Kontrolle des Herz-Kreislauf-Systems beteiligt. Das potente Hormon Angiotensin-II (Ang-II) des RAS wird im Blutkreislauf oder in den Organen gebildet und besitzt vielfältige physiologische Effekte. Das Projekt zielte darauf ab, die modulatorischen Wirkungen des RAS auf die SNA und entsprechenden Folgen auf die kardiovaskuläre Kontrolle und die Erythropoese weiter zu charakterisieren, wobei der Schwerpunkt auf der Rolle des im Gehirn gebildeten Ang II lag. Dieses Ausgangsinteresse wurde experimentell mit RAS Gain und Loss-of-Function-Mausmodellen im FVB/N Hintergrundstamm untersucht. Ergänzend wurden Versuche mit Ratten und Mäusen mit gemischtem genetischen Hintergrund durchgeführt. Eine transgene Linie mit gehirnspezifischer Angiotensinogen-Expression (Agt) wurde validiert (Agt-Tg) und verwendet, um die lokale Ang-II-Bildung im Gehirn in vivo zu demonstrieren. Die Ergebnisse zur kardiovaskulären Regulation von FVB/N-Mäusen ergaben die vermuteten und überraschende Phänotypen. Wie erwartet hatten FVB/N-Mäuse, denen der wichtigste Ang-II-Rezeptor (AT1a-KO) fehlte, einen verminderten Blutdruck. Außerdem zeigte Agt-Tg einen erhöhten Blutdruck im Zusammenhang mit erhöhter SNA. Im Gegensatz zu früheren Befunden bei anderen Stämmen, waren erwachsene FVB/N-Mäuse ohne Agt (Agt-KO), überraschenderweise normotensiv. Paradoxerweise senkte die spezifische Wiederherstellung der Agt Genexpression im Gehirn von Agt-KO (Agt-KO-Tg) den Blutdruck dramatisch. Mithilfe von integrativer Physiologie konnten wir feststellen, dass die Normotonie bei Agt-KO durch einen erhöhten Gefäßtonus aufgrund eines übermäßigen Sympathikotonus und einer beeinträchtigten Stickoxidproduktion verursacht wird. Diese werden bei Agt-KO-Tg im Gegensatz zu Agt-Tg durch Ang II im Gehirn umgekehrt. Agt-KO-Tg wies im Vergleich zu Agt-KO trotz ähnlicher morphologischer Nierenschäden eine bessere Nierenfunktion auf. Des Weiteren aktivierte Ang II im Gehirn die renale SNA in Agt-KO-Tg stark, wohingegen eine renale Denervierung nur minimale Auswirkungen auf den Basisblutdruck von Agt-KO und Agt-KO-Tg hatte. Eine genomweite Assoziationsstudie wurde implementiert um die genetische Veränderung, die zu der Normotonie bei FVB/N Agt-KO führt, aufzudecken. Für diesen Zweck wurde eine F2 Agt-KO-Linie mit gemischtem Hintergrund (FVB/N x C57BL/6N) erzeugt. Bemerkenswerterweise wiesen die Phänotypisierungsdaten durch eine klare bimodale Verteilung des Basisblutdrucks in der F2 Agt-KO stark auf ein einzelnes rezessives Allel hin, das für den Blutdruck-Phänotyp in FVB/N Agt-KO verantwortlich ist, wobei die meisten Mäuse hypoton waren. Die Assoziationsanalysen zeigten jedoch, dass wahrscheinlich mehrere Loci zum Phänotyp bei FVB/N Agt-KO beitragen. Im letzten Teil der Arbeit identifizierten wir zwei Regulationsmechanismen der Erythropoese- (zentraler und peripherer), die durch das RAS moduliert werden. Im Gehirn begünstigt Ang II die Erythropoese über SNA, da Agt-Tg mit gesteigertem Ang-II im Gehirn eine erhöhte Erythropoese zeigte, die durch periphere Sympathektomie rückgängig gemacht wurde. Außerdem zeigten Ratten mit verminderter Agt-Expression im Gehirn eine verringerte Erythropoese. In der Peripherie zeigten die Experimente, dass das RAS die Eisenhomöostase beeinflusst, da Agt-KO-Mäuse eine mikrozytäre Anämie aufwiesen, die mit reduzierten Konzentrationen von zirkulierendem und im Gewebe gespeichertem Eisen einherging. Zusammenfassend zeigen die im Rahmen meiner Doktorarbeit erhobenen Daten die lokale Bildung und Funktion von Ang II im Gehirn. Darüber hinaus konnten wir nachweisen, dass Ang II im Gehirn an der differenzierten SNA-Regulierung in verschiedenen Organen beteiligt ist, was sich auf die Homöostase des Blutdrucks auswirkt. Schließlich wurden zwei neue Mechanismen der Erythropoese Kontrolle aufgedeckt, die durch das RAS über SNA und Eisenhomöostase moduliert werden

From Pampas to Pixels: Fine-Tuning Diffusion Models for Ga\'ucho Heritage

Generative AI has become pervasive in society, witnessing significant advancements in various domains. Particularly in the realm of Text-to-Image (TTI) models, Latent Diffusion Models (LDMs), showcase remarkable capabilities in generating visual content based on textual prompts. This paper addresses the potential of LDMs in representing local cultural concepts, historical figures, and endangered species. In this study, we use the cultural heritage of Rio Grande do Sul (RS), Brazil, as an illustrative case. Our objective is to contribute to the broader understanding of how generative models can help to capture and preserve the cultural and historical identity of regions. The paper outlines the methodology, including subject selection, dataset creation, and the fine-tuning process. The results showcase the images generated, alongside the challenges and feasibility of each concept. In conclusion, this work shows the power of these models to represent and preserve unique aspects of diverse regions and communities

A CONSENSUALIDADE ABUSIVA NO DIREITO ADMINISTRATIVO

O Direito Administrativo tem apostado na adoção de formas consensuais de atuação administrativa. Não obstante, há casos em que a Administração Pública celebra acordos administrativos, com particulares, com suposto lastro na consensualidade, mas que, na essência, escondem imposições unilaterais de vontade do Estado. Isso ocorre em situações nas quais o particular se vê circunstancialmente premido a celebrar o acordo e a aceitar determinadas cláusulas que sejam desproporcionais. O objeto deste artigo será explorar esse fenômeno, o qual passaremos a chamar de consensualidade abusiva, apontando casos concretos nos quais ele teria ocorrido na prática do Direito Administrativo brasileiro e tentando delimitar adequadamente os seus contornos jurídicos, bem como possíveis formas de lidar com o problema

Um estudo da produção acadêmica nacional sobre gestão do conhecimento através da teoria do conhecimento de Habermas

The purpose of this study is to challenge the academic production on Knowledge Management (KM) recently published by the Brazilian academy. A total of 6,096 published articles in the Proceedings of the National Meeting of Postgraduate Management Programs, named ENANPAD, from 1997 to 2007, were compiled. Habermas' knowledge theory has great relevance for the critical debate on the area of knowledge management (KM) in three types of knowledge: technical, practical and emancipatory. Through the documental research it was possible to identify the absolute predominance of the technical interest as a characteristic of the instrumental reason directed to constant prediction and control in the area of KM. Approximately 75% of these empirical studies did not address the question of power relations and knowledge nor did it address human consciousness emancipation towards a critical reflection of oppressive practices or political and ideological social approaches

Late recurrence of Burkitt’s lymphoma in the jaw: numb chin syndrome as the only symptom

The Numb Chin Syndrome (NCS) is defined as facial and oral numbness restricted to the mental nerve’s distribution involving the lower lip, skin of the chin, or gingiva of the lower anterior teeth. Hypoesthesia can occur unilaterally or bilaterally. Although this syndrome is rare, its importance is related to the fact that it represents the clinical manifestations of malignant diseases. Breast cancer and non-Hodgkin lymphoma are the most common cause of NCS. The patient, a 58-year-old woman, treated for a Burkitt Lymphoma (BL) nine years ago, described a two-week history of change in sensitivity and pain in the chin region, without relief with the use of analgesics. She had no headache, speech disturbance, dysphagia, visual disturbance, or other neurological symptoms. No surgical intervention has been performed recently. The intraoral examination revealed a healthy oral mucosa and a small area adjacent to the right mental nerve region that was uncomfortable to palpation. No changes were found in the bone trabeculae at cone-beam computed tomography. The contrasted magnetic resonance features made it possible to identify a change in the mandibular body extending to the entire right side, coinciding with the patient’s complaint, indicating a probable mandibular medullary invasion. The patient was submitted to a biopsy to rule out a possible recurrence of BL. The microscopic findings were consistent with the diagnosis of BL. The present report described a very unusual presentation of late recurrent BL nine years after the first treatment, which manifested as an NCS

As metas de universalização do novo marco do saneamento básico e os desafios para assegurar o equilíbrio econômico-financeiro dos contratos de programa

[Purpose] The Sanitation's New Legal Framework promoted significant changes in Federal Law No. 11,445/2007, among which the duty of the contracts for the provision of sanitation services to set targets that ensure that 99% of the population is served with drinking water and 90% of the population with sewage collection and treatment by December 31st, 2033. For state companies, which today are responsible for providing water and sewage services in approximately 77% of Brazilian cities, the assessment of economic capacity and the addition of contracts to incorporate the new goals represents a challenge both for service holders and for the companies themselves, considering its peculiarities and the contracts peculiarities, such as the practice of cross subsidy and a single tariff structure for different providers. [Methodology/approach/design] This context must be considered in order to analyze the possibility of incorporating the new universalization targets, as well as overcoming the obstacles related to the prohibition of extending their validity and the political criterion in tariffs definition to ensure the contracts economic balance and serve the public interest by providing an efficient, universal service at adequate rates. [Findings] An uncertain and very difficult scenario is envisioned for the existing program contracts and for the state companies themselves.[Purpose] The Sanitation's New Legal Framework promoted significant changes in Federal Law No. 11,445/2007, among which the duty of the contracts for the provision of sanitation services to set targets that ensure that 99% of the population is served with drinking water and 90% of the population with sewage collection and treatment by December 31st, 2033. For state companies, which today are responsible for providing water and sewage services in approximately 77% of Brazilian cities, the assessment of economic capacity and the addition of contracts to incorporate the new goals represents a challenge both for service holders and for the companies themselves, considering its peculiarities and the contracts peculiarities, such as the practice of cross subsidy and a single tariff structure for different providers. [Methodology/approach/design] This context must be considered in order to analyze the possibility of incorporating the new universalization targets, as well as overcoming the obstacles related to the prohibition of extending their validity and the political criterion in tariffs definition to ensure the contracts economic balance and serve the public interest by providing an efficient, universal service at adequate rates. [Findings] An uncertain and very difficult scenario is envisioned for the existing program contracts and for the state companies themselves.[Propósito] O Novo Marco Legal do Saneamento Básico promoveu alterações significativas na Lei Federal nº 11.445/2007, dentre as quais previu-se o dever de os contratos de prestação de serviços de saneamento básico definirem metas que assegurem o atendimento de 99% da população com água potável e de 90% da população com coleta e tratamento de esgotos até 31 de dezembro de 2033. Para as empresas estatais, que hoje são responsáveis pela execução dos serviços de água e esgoto em aproximadamente 77% dos municípios brasileiros, a aferição da capacidade econômico-financeira e o aditamento dos contratos de programa para incorporação das novas metas representa um desafio tanto para os titulares dos serviços quanto para as próprias empresas, tendo em vista as peculiaridades dessa forma de prestação e dos contratos de programa, os quais estão, em regra, inseridos em uma prestação regionalizada dos serviços, com a prática do subsídio cruzado e de uma estrutura tarifária única para diversos municípios. [Metodologia/abordagem/design] Para analisar a possibilidade de incorporação das novas metas de universalização, deverá ser levado em conta o contexto em que os contratos de programa estão inseridos, bem como a superação dos entraves relacionados às medidas de reequilíbrio econômico-financeiro, como a vedação da prorrogação da vigência dos contratos de programa e a resistência política na definição de novos valores tarifários, de modo que a incorporação das novas metas de universalização seja concomitante à garantia do equilíbrio contratual, atendendo ao público com a prestação de um serviço eficiente, universal e com tarifas adequadas. [Resultados] Vislumbra-se um cenário incerto e de muita dificuldade para os contratos de programa existentes e para as próprias empresas estatai

Caracterização de depressões fechadas no vão do Paranã, a oeste da Serra Geral de Goiás

This paper presents the characteristics of the dolines, uvalas and other closed depressions present in Vão do Paranã, located to the west of Serra Geral de Goiás. The methodology includes bibliographic review, interpretation of Sentinel 2 satellite images, identification of closed depressions, morphological characterization and fieldwork. The results show that the dolines and uvalas are predominantly concentrated in the Paranã river depression, while the caves are located mainly in the cliffs of Serra Geral de Goiás. There is a random pattern of rounded, elliptic and irregular dolines and uvalas. The dolinas and uvalas with smaller areas and perimeters are located mainly in the southern and also to the north of the area, between Iaciara and Nova Roma. The largest area and volume are in the features located in the central portion of the Paranã depression. The studied geoforms are developed directly in: i) laterites, where limestones of the Paraopeba Subgroup with underlying ithology; ii) limestones of the Paraopeba Subgroup and the Sete Lagoas Formation. The obtained results indicate that all these features originated by dissolution processes.Este trabalho apresenta as características das dolinas, uvalas e outras depressões fechadas presentes no Vão do Paranã, que está situado a oeste da Serra Geral de Goiás. Os procedimentos metodológicos utilizados incluem revisão bibliográfica, interpretação de imagens de satélites Sentinel 2, identificação e vetorização das depressões fechadas, caracterização morfológica e trabalho de campo. Os resultados demonstram que as dolinas e uvalas estão concentradas, predominantemente, na depressão do rio Paranã, enquanto as cavidades naturais subterrâneas estão localizadas principalmente nas escarpas da Serra Geral de Goiás. Verifica-se a ocorrência de padrão aleatório de dolinas e uvalas arredondadas, elípticas e irregulares. As dolinas e uvalas com menores áreas e perímetros estão localizadas principalmente no extremo sul da área de estudo e também ao norte, entre Iaciara e Nova Roma. Os maiores índices de área e volume estão nas feições situadas na porção central da depressão do Paranã. As geoformas estudadas desenvolvem-se diretamente em: i) coberturas detrito lateríticas ferruginosas, onde ocorrem calcários do subgrupo Paraopeba como litologia subjacente; ii) calcários do subgrupo Paraopeba indiviso e da Formação Sete Lagoas. Ratifica-se que os resultados obtidos sinalizam que todas essas feições originaram-se a partir de processos de dissolução

BIOESTIMULANTE APLICADO NA SEMENTE E VIA FOLIAR NA PRODUÇÃO DE REPOLHO

O objetivo foi avaliar o efeito de doses do bioestimulante ácido 4-indol-3-ilbutírico + ácido giberélico + cinetina no crescimento, desenvolvimento e produtividade do repolho hibrido cultivar Musashi. Conduziu-se dois experimentos com doses de bioestimulante (0, 3, 5, 7 e 9 ml) no delineamento inteiramente casualizado com 5 repetições. O bioestimulante ácido 4-indol-3-ilbutírico + ácido giberélico + cinetina não influencia o crescimento, o desenvolvimento, e a produtividade de repolho

Response Surface Methodology and Genetic Algorithms Applied to Model and Optimize the Dyeing of Cotton Process with the Reactive Black 5 Dyestuff

This work aimed to combine response surface methodology and genetic algorithms to model and optimize the dyeing process to show the influences of each component in the dyeing of cotton knit to optimize its dyeing conditions. A 26 design of central composite and rotational (DCCR) was used as support to execute seventy-eight dyeings with Reactive Black 5 dyestuff (RB5) on 100% knitted cotton substrate. The impacts of various dyeing process parameters were also investigated. The concentrations of [RB5] (percent), [NaCl] (g/L), [Na2CO3] (g/L), and [NaOH] (mL/L), as well as processing time (min) and temperature (°C), were employed. The K S-1 coefficient and the costs of each experiment were calculated as a result. The objective function was derived from the fitting of the experimental points using the least-squares method and analysis of variance (ANOVA). The findings revealed that both techniques can be efficiently applied to model and optimize the cotton dyeing, with the goal of lowering the cost and environmental impact