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Atherosclerosis is a chronic inflammatory disease characterized by a subendothelial accumulation of lipids and the formation of a plaque which rupture is the principal cause of cardiovascular events. This process is largely driven by the immune system and high circulating low-density lipoprotein (LDL) levels. Although many studies have demonstrated the effects of hypercholesteremia on inflammatory pathways, only a few studies specifically investigated the effects of immunity on lipid metabolism. PCSK9 is a key target for the treatment of hypercholesterolemia. PCSK9 inhibitors have been shown to reduce LDL and diminish atherosclerosis through LDL receptor (LDLR) regulation. However, the specific mechanisms regulating LDLR endosomal recycling are not completely revealed. Toll-interacting protein (Tollip) is an adaptor protein, initially described as an NF-κB signaling regulator, controlling the turnover of ubiquitinated receptors through endosomal trafficking. The present thesis revealed that Tollip controls LDL levels through posttranslational modulation of LDLR. Bone marrow-derived macrophages and hepatocytes from ApoE-/-Tollip-/- mice exhibited lower LDLR expression, whereas ApoE-/-Tollip-/- mice fed high cholesterol diet (HCD) had significantly elevated cholesterol levels and increased atherosclerotic plaques in comparison with ApoE-/- mice. These findings point that LDLR expression regulation is a key process involved in the atheroprotective effects of Tollip. Moreover, the present work demonstrated that Tollip regulates the recycling of LDLR from the endosome back to the cell surface and/or directs LDLR to autophagy-mediated degradation. Taken together our data highlight the role of Tollip, a mediator of low-grade inflammation, as an autophagic regulator of LDLR expression. The second aspect of this thesis aims to reveal how TGF-β-producing B (BTGFβ1-/-) cells direct the immune response in atherosclerosis and impact cholesterol metabolism. Several studies have demonstrated that BTGFβ1-/- cells can suppress the immune responses in various diseases. However, the role of BTGFβ1-/- cells in atherosclerosis is largely unexplored. ApoE-/-BTGFβ1-/- mice fed HCD exhibited a pronounced increase of plasma B cells in the spleen, lymph nodes, and aorta, while immunoglobulins IgG1-oxLDL-specific levels raised significantly compared to ApoE-/- mice. In addition to direct immune-mediated effects, ApoE-/-BTGFβ1-/- mice had lower LDL and total cholesterol plasma levels, smaller atherosclerotic plaque size, and improved plaque stability compared to ApoE-/- mice. This atheroprotective effect could be partially explained by increased expression of ABCG1 in foam cells and in the liver, essential for reverse cholesterol transport; and by the reduction of scavenger receptors expression, promoting a decrease in foam cell formation. This is the first study to demonstrate that TGF-β-specific B cell deficiency in ApoE-/- mice has a beneficial effect on atherosclerotic disease and regulates plasma levels of cholesterol. The present work demonstrates how immunity affects lipid metabolism, resulting in pronounced effects on atherosclerosis severity.

Com o crescimento urbano, torna-se necessário definir as formas de atendimento à necessidade humana por água, em qualidade e quantidade adequadas. O presente artigo busca identificar como os gradientes de densidades populacionais podem contribuir na definição de soluções sustentáveis para o suprimento de água e tratamento de esgoto em pequenas municipalidades. Partiu-se da definição das áreas estratégicas, em termos de sustentabilidade, buscando-se determinar, com base em dados gratuitos e publicamente disponíveis, a densidade urbana do município de Feliz/RS, bem como a distribuição do abastecimento de água e destinação dos efluentes domésticos. A partir desse diagnóstico, que considera as particularidades do município, foram propostas soluções alternativas e descentralizadas para as áreas avaliadas. Os resultados mostram que a avaliação integrada e espacial pode conduzir a soluções mais sustentáveis, que envolvam e empoderem a comunidade local quanto ao uso e cuidado com a água e como potencial de suporte à tomada de decisão. As cities grow, it becomes necessary to define ways of meeting the human need for water in adequate quality and quantity. In this article, it was identified how population densities gradients can contribute to the definition of sustainable solutions for water supply and sewage treatment in small municipalities. Strategic areas were defined in terms of sustainability, seeking to determine, based on free and public data, the urban density of the municipality of Feliz/RS and the distribution of water supply and solutions for domestic effluents. Based on this diagnosis, which considers the particularities of the municipality, alternative and decentralized solutions were proposed for the assessed areas. The results show that the integrated and spatial assessment can lead to more sustainable solutions, which involve and empower the local community regarding the use and care of water and with the potential to support decision making

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

RESUMO: A presença de Salmonella spp. em produtos de origem avícola e seus subprodutos se mostra um grande desafio para a produção comercial. Dados de prevalência, dos sorotipos circulantes e do perfil de susceptibilidade antimicrobiana de cepas de Salmonella spp. no Estado do Rio de Janeiro são escassos. Portanto, objetivou-se detectar a presença Salmonella spp. em frangos vivos e carcaças em matadouros do Estados do Rio de Janeiro, identificar os sorotipos e avaliar a susceptibilidade antimicrobiana dessas cepas para fluoroquinolonas e betalactâmicos. Foram coletadas 60 amostras cloacais de frangos vivos e 60 amostras de carcaça de seis matadouros sob Inspeção Estadual (SIE). Os isolados foram sorotipificados e testados frente a oito antimicrobianos: enrofloxacina, ciprofloxacina, norfloxacina, cefalotina, ceftiofur, cefotaxima, amoxicilina/ácido clavulânico e ampicilina pelo método de difusão em disco. Os resultados mostraram uma prevalência de Salmonella spp. de 1,66% (1/60) em amostras de suabe de cloaca e de 26,66% (16/60) em carcaças. Em amostras de suabe de cloaca, somente o sorotipo Senftenberg (1,66%) foi isolado. No total, foram isolados sete sorotipos diferentes nas carcaças: Senftenberg (15%) o mais frequente, seguido por Mbandaka (8,3%), Schwarzengrund (3,3%), Cerro (3,3%), Ohio (3,3%), Minnesota (1,66%) e Tennessee (1,66%). Em relação à susceptibilidade antimicrobiana, 29 (87,87%) isolados foram sensíveis a todos os antimicrobianos testados e 4 (12,12%) isolados foram resistentes a pelo menos três antimicrobianos betalactâmicos ou mais. Não foi observada resistência às fluoroquinolonas. Os resultados encontrados demonstram uma prevalência de Salmonella spp. acima da esperada em matadouros do Estado do Rio de Janeiro, além da presença de vários sorotipos de Salmonella spp. A resistência encontrada para betalactâmicos alerta para a disseminação dessas cepas pela cadeia alimentar. ABSTRACT: The presence of Salmonella spp. in poultry products and their by-products is a major challenge for commercial production. Data about the prevalence, the circulating serotypes and the antimicrobial susceptibility profile of Salmonella spp. strains in the State of Rio de Janeiro are scarce. Therefore, the aim of this study was to detect the presence of Salmonella spp. in live chickens and carcasses in slaughterhouses of the State of Rio de Janeiro, to identify the serotypes and to evaluate the antimicrobial susceptibility of these strains for fluoroquinolones and beta-lactams. Sixty cloacal swabs samples from broiler chickens and sixty samples of carcasses from six slaughterhouses under State Inspection were collected. The isolates were serotyped and resistance was tested to eight antimicrobials: enrofloxacin, ciprofloxacin, norfloxacin, cephalothin, ceftiofur, cefotaxime, amoxicillin/clavulanic acid and ampicillin by disc diffusion method. The results showed a prevalence of Salmonella spp. of 1.66% (1/60) in cloacal swabs samples and 26.66% (16/60) in carcasses. In cloacal swabs sample only Senftenberg (1.66%) serotype was isolated. In total, seven different serotypes were obtained from carcasses: Senftenberg (15%), followed by Mbandaka (8.3%), Schwarzengrund (3.3%), Cerro (3.3%), Ohio (3.3%), Minnesota (1.66%) and Tennessee (1.66%). Regarding antimicrobial susceptibility, 29 (87.87%) isolates were sensitive to all antimicrobials tested and 4 (12.12%) isolates were resistant to three or more beta-lactams antimicrobials. No susceptibility to fluoroquinolones was observed. These results showed a prevalence of Salmonella spp. higher than expected in slaughterhouses in the State of Rio de Janeiro, besides the presence of several serotypes of Salmonella spp. The resistance found for beta-lactams alerts to the spread of these strains through the food chain.

Teixeira V.C.M., Baptista D.Q., Carlos F.C., Menezes W.R., José D.S., Barreto M.L., Abreu D.L.C., Pereira V.L.A. & Nascimento E.R. [Epidemiological situation of avian mycoplamosis in the State of Rio de Janeiro, Brazil.] Situação epidemiológica da micoplasmose aviária no Estado do Rio de Janeiro. Revista Brasileira de Medicina Veterinária, 37(4):379-385, 2015. Departamento de Saúde Coletiva Veterinária e Saúde Pública, Faculdade de Medicina Veterinária, Universidade Federal Fluminense, Rua Vital Brasil, 64, Santa Rosa, Niterói, RJ 24320-340, Brasil. E-mail: petlela@hotmail.com This study was conducted to characterize the Mycoplasmosis epidemiological situation in Rio de Janeiro State. The state was divided into three regions considered significant in poultry production in the state and 252 samples of tracheal specimens were taken, using swabs dipped in 1.5ml of Frey medium and 2.5 ml of blood from 884 birds, in 47 flocks, from 11broiler chickens farms, 6 laying hens farms and 1 broiler breeders farm, of which were evaluated 334 broilers, 205 laying hens and 345 broilers breeders. The serums were subjected to Rapid Serum Agglutination (RSA) and ELISA for detection of antibodies against Mycoplasma gallisepticum (MG) and M. synoviae (MS) and the swabs used in the polymerase chain reaction (PCR) for those agents detection. Were obtained by SAR for MG and MS in the 884 birds studied, frequencies of 14.25% (126/884) and 13.68% (121/884), respectively. By ELISA, were btained 16.17% (143/884) for MG and 15.61% (138/884) for MS. According to the type of production, it was found in broilers chickens by SAR, 11.37% (38/334) for MG and 9.5% (32/334) for MS and in the ELISA, 9.28% (31/334) for MG and 9.88% (33/334) for MS. In laying chickens, the frequency of positive birds by SAR for MG and MS were in an amount of 42.92% (88/205) and 43.41% (89/205), respectively, and by ELISA, 54.63% (112/205) for MG and 49.75% (102/205) for MS. The broiler breeders shown to be negative for MG by SAR and by ELISA, but for MS, 0.86% (2/345) were positive only by ELISA. When comparing the frequencies for MG and MS in the flocks studied, by SAR, was obtained a total of positivity of 55.31% (26/47) for MG and 63.82% (30/47) for MS, and by ELISA, 51.06% (24/47) and 68.08% (32/47), respectively. For each type of production, was obtained for the broilers chickens a positivity to the SAR of 40% (10/25) for MG e 56% (14/25) for MS; and to the ELISA, 28% (7/25) e 60% (15/25) for MG and MS, respectively. In laying chickens was obtained values of 80% (16/20) for the MG and MS by SAR, whereas by ELISA, was obtained 85% (17/20) for MG and 75% (15/20) for MS. In breeders, by ELISA both two flocks studied were positive only for MS. By PCR, the total of positivity for MG and MS were in an amount of 1.19% (3/252) and 9.92% (25/252), respectively. For each type of production, were obtained 0.78% (1/127) of positive for MS in broilers chickens. In laying hens chickens, the results were 2.6% (3/115) positive for MG and 20.86% (24/115) for MS. About the broiler breeders, there was no positivity by PCR. The frequency of positives for MG and MS, by PCR, in the total of the flocks studied were, respectively, 2.12% (1/47) and 21.27% (10/47). By type of production, were not found positive flocks for MG, however, for MS was obtained 4% (1/25) in the broilers. In laying chickens, it was verifiedthat 5% (1/20) of the flocks were positive for MG and 45% (9/20) for MS. All flocks of broiler breeders were negative for MG and MS. Higher prevalence for MS were detected in the layeing hens farms than in the broilers farms and breeders farm, such as by serology as by PCR. The prevalence of MG was higher in broilers chickens than in broilers breeders. There was high positivity in laying hens, whose data was not considered because included vaccinated chickens. There were differences in the results obtained for the broilers flocks and laying hens flocks and in the positivity among the flocks, which can be attributed to differences in farm building and structures, in the ambience and manger inherent to each type of production. In this research for MG and MS in poultry production, was obtained higher frequency of positive by ELISA than by SAR, with a low agreement between the tests., Realizou-se um estudo para caracterizar a situação epidemiológica da Micoplasmose no Estado do Rio de Janeiro, o qual foi dividido em três regiões consideradas expressivas em produção avícola no Estado. Foram realizadas coletas de 252 espécimes de traqueia, utilizando suabes imersos em 1,5ml de meio de Frey e 2,5 ml de sangue de 884 aves, em 47 lotes, provenientes de 11 propriedades de criação de frangos de corte, 6 de postura e em 1 de matrizes pesadas, das quais foram avaliados 334 frangos de corte, 205 galinhas de postura e 345 matrizes pesadas. Os soros foram submetidos à Soroaglutinação rápida (SAR) e ao ELISA para detec- ção de anticorpos contra MG e MS e os suabes utilizados na reação em cadeia pela polimerase (PCR), para detecção desses agentes. Foram obtidas à SAR para Mycoplasma gallisepticum (MG) e M. synoviae (MS) nas 884 aves estudadas, frequências de 14,25% (126/884) e 13,68% (121/884), respectivamente. Ao ELISA, foram obtidos 16,17% (143/884) para MG e 15,61% (138/884) para MS. De acordo com o tipo de produção, verificou-se nos frangos de corte pela SAR 11,37% (38/334) para MG e para MS, 9,5% (32/334) e no ELISA, 9,28%(31/334) para MG e 9,88% (33/334) para MS. Em galinhas de postura, as frequências de aves positivas à SAR para MG e MS foram de 42,92% (88/205) e 43,41% (89/205), respectivamente, e ao ELISA, 54,63% (112/205) para MG e 49,75% (102/205) para MS. As matrizes pesadas apresentaram-se negativas para MG à SAR e ao ELISA, mas para MS, 0,86% (2/345) foram positivas apenas ao ELISA. Quando comparadas as frequências para MG e para MS nos lotes estudados, à SAR, obtive-se um total de positividade de 55,31% (26/47) para MG e 63,82% (30/47) para MS, e ao ELISA, 51,06% (24/47) e 68,08% (32/47), respectivamente. Por tipos de produção, obteve-se para os frangos de corte uma positividade à SAR de 40% (10/25) para MG e 56% (14/25) para MS; e ao ELISA, 28% (7/25) e 60% (15/25) para MG e MS, respectivamente. Em galinhas de postura, obteve- -se valores de 80% (16/20) para MG e MS à SAR, enquanto que ao ELISA, obteve-se 85% (17/20) para MG e 75% (15/20) para MS. Nas matrizes, ao ELISA os dois lotes estudados foram positivos apenas para MS. À PCR, os coeficientes de positividade total das aves para MG e MS foram de 1,19% (3/252) e 9,92% (25/252), respectivamente. Por tipos de produção, foram obtidos 0,78% (1/127) de positividade para MS em frangos de corte. Nas galinhas de postura, os resultados foram 2,6% (3/115) positivos para MG e 20,86% (24/115) para MS. Quanto as matrizes, não houve positividade à PCR. A frequência de positivos para MG e MS, à PCR, no total de lotes estudados foi, respectivamente, 2,12% (1/47) e 21,27% (10/47). Por tipo de produção, não foram encontrados lotes positivos para MG, entretanto para MS obteve-se 4% (1/25) nos frangos. Na postura comercial, verificou-se que 5% (1/20) dos lotes foram positivos para MG e 45%(9/20), para MS. Todos os lotes de matrizes pesadas foram negativos para MG e MS. Foi detectada maior prevalência para MS nas criações de postura que nas criações de frangos de corte e reprodução tanto pela sorologia como pela PCR. A prevalência de MG foi maior em frangos de corte que nas matrizes pesadas. Houve alta positividade em poedeiras comerciais, não sendo considerados esses dados porque incluíam galinhas vacinadas. Houve diferença nos resultados obtidos para as criações de frangos de corte e de postura comercial e na positividade entre os lotes, o que pode ser atribuído às diferenças nas instalações, na ambiência e no manejo inerentes ao tipo de produção. Na pesquisa para MG e MS nas criações avícolas, foi obtida maior frequência de positivos ao ELISA que à SAR, com uma fraca concordância entre os testes.

Atherosclerosis is a chronic inflammatory disease involving the infiltration of immune cells, such as monocytes/macrophages, neutrophils, T cells, and B cells, into the inner layer of vessel walls. T and B cell functions in the process of atherogenesis, as well as their mutual regulation, have been investigated but several aspects remain to be clarified. In the present review, we give a brief overview of the functions of follicular regulatory T cell (Tfr) on follicular T (Tfh) and B cell regulation related to atherosclerosis pathogenesis, including their influence on lymphangiogenesis and lipoprotein metabolism. We will also discuss their potential therapeutics properties in the resolution of established atherosclerotic lesions.

Structural plasticity in the somatosensory cortex is maintained throughout life. In adult animals structural changes occur at the level of dendritic spines and axonal boutons in response to alterations in sensory experience. The causal relationship between synaptic activity and structural changes, however, is not clear. Hebbian-plasticity models predict that synapses will be stabilized at the nodes of neuronal networks that display high levels of coincident activity. Here, we aim at studying the effects of a targeted increase in coincident activity between segregated inputs on pyramidal cell synapses of the mouse somatosensory barrel cortex in vivo. Supragranular layers of the barrel cortex receive anatomically distinct inputs from two thalamic pathways: the ‘lemniscal’ pathway that originates in the ventral posteromedial (VPM) nucleus and projects in a whisker-specific fashion to the barrel columns, and the ‘paralemniscal’ pathway that originates in the posteromedial (POm) nucleus and projects to the cortex in a non-specific manner. Previous work from our lab shows that rhythmic (8Hz) whisker stimulation-evoked LTP (RWS-LTP) in layer (L) 2/3 pyramidal cells relies on the combined activity of lemniscal and paralemniscal pathways. Here, we targeted ChR2 expression to POm neurons using AAV-mediated gene transfer in order to optically control the activity of those inputs. As a first step, we show that photostimulation of the POm nucleus induces NMDA-dependent, sub-threshold responses in L2/3 pyramidal cells similar to those that are required for the induction of RWS-LTP. In addition, simultaneous photostimulation of POm neurons together with whisker stimulation at low frequencies (1Hz) can also elicit LTP, suggesting that coincident lemniscal and paralemniscal input can drive LTP induction. Next, we combined the ChR2-tdTomato expression in POm neurons with sparse AAV-mediated eGFP expression in L2/3 pyramidal cells in order to study the effects of coincident activity on dendritic spines. Preliminary data suggest that simultaneous photostimulation of the POm nucleus together with whisker stimulation may also affect spine dynamics. Taken together, these results indicate that the coincident activity of the convergent lemniscal and paralemniscal inputs onto L2/3 pyramidal cells may potentiate synapses and affect their stability.

O presente relatório, tem por finalidade descrever os aspectos relativos a uma experiência de estágio académico onde se colocou o enfoque fundamental numa reflexão acerca de uma condição portuguesa no design, indústria, artesanato e mercado. Foi efectuado na Menina Design Group, no Porto, em que os inovadores e esclarecidos processos de investigação, análise, argumentação e criação se revelaram especialmente eficientes na configuração de produtos “globais”, contemporâneos, com evidente sucesso nos mais diversos mercados, sublinhando e enfatizando os recursos técnicos e tecnológicos existentes. Partindo da identidade portuguesa no mobiliário, dos processos de globalização e do mercado internacional, desenvolveram-se duas abordagens projectuais que pretendem interpretar o discurso de cada marca, seus valores e conteúdo narrativo e formal, destinados a “target’s” bem definidos, em mercado global, sem que com isso se deixasse de introduzir força identitária, a qualidade original e preponderantemente retórica aos artefactos de tradição portuguesa. O objectivo seria contribuir para a produção e disseminação de conhecimento sobre as relações existentes entre artesanato e design no mobiliário, para servir de suporte ao desenvolvimento projectual na MDG e testar os variados recursos disponíveis para descrever e analisar a implementação de soluções experimentalistas nas variadas áreas de intervenção da instituição.

Direito e Justiça, n. Especial (2012): Direito comercial e das sociedades

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Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

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Submitted by Ana Costa (apcosta@porto.ucp.pt) on 2021-05-19T14:30:58Z No. of bitstreams: 1 00645_02_joao-andre-goncalves-344918011-dissertacao-integral.pdf: 597947 bytes, checksum: ee159106ce3132e250ee4acfd07212ee (MD5) Approved for entry into archive by Maria Helena Ribeiro (helena.ribeiro@lisboa.ucp.pt) on 2021-06-16T15:06:43Z (GMT) No. of bitstreams: 1 00645_02_joao-andre-goncalves-344918011-dissertacao-integral.pdf: 597947 bytes, checksum: ee159106ce3132e250ee4acfd07212ee (MD5) Made available in DSpace on 2021-06-16T15:06:43Z (GMT). No. of bitstreams: 1 00645_02_joao-andre-goncalves-344918011-dissertacao-integral.pdf: 597947 bytes, checksum: ee159106ce3132e250ee4acfd07212ee (MD5) Previous issue date: 2020-09-11

Submitted by Ana Costa (apcosta@porto.ucp.pt) on 2021-05-20T15:52:46Z No. of bitstreams: 1 00768_02_patricia-pereira-faria-344918007-dissertação-integral.pdf: 705830 bytes, checksum: ba037e1555fed5df78736f2c658c1e6b (MD5) Approved for entry into archive by Maria Helena Ribeiro (helena.ribeiro@lisboa.ucp.pt) on 2021-06-17T09:46:21Z (GMT) No. of bitstreams: 1 00768_02_patricia-pereira-faria-344918007-dissertação-integral.pdf: 705830 bytes, checksum: ba037e1555fed5df78736f2c658c1e6b (MD5) Made available in DSpace on 2021-06-17T09:46:21Z (GMT). No. of bitstreams: 1 00768_02_patricia-pereira-faria-344918007-dissertação-integral.pdf: 705830 bytes, checksum: ba037e1555fed5df78736f2c658c1e6b (MD5) Previous issue date: 2020-09-11

Submitted by Ana Costa (apcosta@porto.ucp.pt) on 2021-05-19T16:14:13Z No. of bitstreams: 1 00225_02_joao-marcelo-brandao-344918012-dissertacao-integral.pdf: 678795 bytes, checksum: 31f0762923246b14521ed08dc2620846 (MD5) Approved for entry into archive by Maria Helena Ribeiro (helena.ribeiro@lisboa.ucp.pt) on 2021-06-16T15:57:08Z (GMT) No. of bitstreams: 1 00225_02_joao-marcelo-brandao-344918012-dissertacao-integral.pdf: 678795 bytes, checksum: 31f0762923246b14521ed08dc2620846 (MD5) Made available in DSpace on 2021-06-16T15:57:08Z (GMT). No. of bitstreams: 1 00225_02_joao-marcelo-brandao-344918012-dissertacao-integral.pdf: 678795 bytes, checksum: 31f0762923246b14521ed08dc2620846 (MD5) Previous issue date: 2020-10-09

Submitted by Cristina Afonso (cac@lisboa.ucp.pt) on 2018-12-19T14:18:10Z No. of bitstreams: 1 TESE-VASCOLEMOS.pdf: 1125412 bytes, checksum: 65f35e533a2e521962a493e1e84168c1 (MD5) Approved for entry into archive by Cristina Afonso (cac@lisboa.ucp.pt) on 2018-12-19T14:18:25Z (GMT) No. of bitstreams: 1 TESE-VASCOLEMOS.pdf: 1125412 bytes, checksum: 65f35e533a2e521962a493e1e84168c1 (MD5) Made available in DSpace on 2018-12-19T14:18:25Z (GMT). No. of bitstreams: 1 TESE-VASCOLEMOS.pdf: 1125412 bytes, checksum: 65f35e533a2e521962a493e1e84168c1 (MD5) Previous issue date: 2018-12-30

Submitted by Cristina Afonso (cac@lisboa.ucp.pt) on 2018-12-19T09:41:59Z No. of bitstreams: 1 Sofia Pereira Barros 340112099.pdf: 917049 bytes, checksum: e9ecb5c2a62db46dd1f5fe0c0885ea40 (MD5) Approved for entry into archive by Cristina Afonso (cac@lisboa.ucp.pt) on 2018-12-19T09:42:10Z (GMT) No. of bitstreams: 1 Sofia Pereira Barros 340112099.pdf: 917049 bytes, checksum: e9ecb5c2a62db46dd1f5fe0c0885ea40 (MD5) Made available in DSpace on 2018-12-19T09:42:10Z (GMT). No. of bitstreams: 1 Sofia Pereira Barros 340112099.pdf: 917049 bytes, checksum: e9ecb5c2a62db46dd1f5fe0c0885ea40 (MD5) Previous issue date: 2018-10-30

Submitted by Cristina Afonso (cac@lisboa.ucp.pt) on 2018-12-18T10:05:11Z No. of bitstreams: 1 Rita Mota - 340120023.pdf: 558941 bytes, checksum: 3a516ee6e20e4a419df9b70d34559b6d (MD5) Approved for entry into archive by Cristina Afonso (cac@lisboa.ucp.pt) on 2018-12-18T10:05:26Z (GMT) No. of bitstreams: 1 Rita Mota - 340120023.pdf: 558941 bytes, checksum: 3a516ee6e20e4a419df9b70d34559b6d (MD5) Made available in DSpace on 2018-12-18T10:05:26Z (GMT). No. of bitstreams: 1 Rita Mota - 340120023.pdf: 558941 bytes, checksum: 3a516ee6e20e4a419df9b70d34559b6d (MD5) Previous issue date: 2018-10-16