Ensinando geometria plana através de mosaicos com a ajuda de um objeto de aprendizagem no padrão RIVED

O presente artigo trata da construção de um objeto aprendizagem degeometria plana voltado aos alunos do ensino médio, através de atividades desimulação de pavimentação e da utilização de conceitos de mosaicos para oprojeto RIVED (Rede Internacional Virtual de Educação). Trata também avantagem do uso de objetos virtuais de aprendizagem nas salas de aula, bemcomo discute brevemente os conceitos e padrões dos objetos do RIVED

Novel genes and sex differences in COVID-19 severity

[EN] Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.S

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Potential contribution of translational factors to triiodo-l-hyronine-induced Insulin synthesis by pancreatic beta cells

Thyroid hormones (THs) are known to regulate protein synthesis by acting at the transcriptional level and inducing the expression of many genes. However, little is known about their role in protein expression at the post-transcriptional level, even though studies have shown enhancement of protein synthesis associated with mTOR/p70S6K activation after triiodo-l-thyronine (T3) administration. On the other hand, the effects of TH on translation initiation and polypeptidic chain elongation factors, being essential for activating protein synthesis, have been poorly explored. Therefore, considering that preliminary studies from our laboratory have demonstrated an increase in insulin content in INS-1E cells in response to T3 treatment, the aim of the present study was to investigate if proteins of translational nature might be involved in this effect. INS-1E cells were maintained in the presence or absence of T3 (10(-6) or 10(-8) M) for 12 hours. Thereafter, insulin concentration in the culture medium was determined by radioimmunoassay, and the cells were processed for Western blot detection of insulin, eukaryotic initiation factor 2 (eIF2), p-eIF2, eIF5A, EF1A, eIF4E binding protein (4E-BP), p-4E-BP, p70S6K, and p-p70S6K. It was found that, in parallel with increased insulin generation, T3 induced p70S6K phosphorylation and the expression of the translational factors eIF2, eIF5A, and eukaryotic elongation factor 1 alpha (eEF1A). In contrast, total and phosphorylated 4E-BP, as well as total p70S6K and p-eIF2 content, remained unchanged after T3 treatment. Considering that (i) p70S6K induces S6 phosphorylation of the 40S ribosomal subunit, an essential condition for protein synthesis; (ii) eIF2 is essential for the initiation of messenger RNA translation process; and (iii) eIF5A and eEF1A play a central role in the elongation of the polypeptidic chain during the transcripts decoding, the data presented here lead us to suppose that a part of T3-induced insulin expression in INS-1E cells depends on the protein synthesis activation at the post-transcriptional level, as these proteins of the translational machinery were shown to be regulated by T3226637642FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP08/56446-

Influence of Cardiorespiratory Fitness on PPARG mRNA Expression Using Monozygotic Twin Case Control

The influence of cardiorespiratory fitness (VO2max) on anthropometric variables and PPARG mRNA expression was investigated. Monozygotic twin pairs aged 11-18 years were grouped into discordant (D) and concordant (C) high and low VO2max groups. VO2max was determined by progressive maximal exercise test on treadmill with gas exchange analysis. Body mass (BM), BMI, waist circumference (WC), triceps (TR), and subscapular (SB) skinfold thicknesses were measured. Twins from the discordant group had differences in VO2max values (D-high = 45.9 +/- 10.0 versus D-low = 32.4 +/- 10.6mL.kg(-1).min(-1), P = 0.025), while no differences were found in the concordant group (C-high = 42.4 +/- 9.2 versus C-low = 38.8 +/- 9.8mL.kg(-1).min(-1), P = 0.952). In discordant group, VO2max was negatively correlated with TR + SB (r = -0.540, P = 0.021) and positively correlated with PPARG expression in leukocytes (r = 0.952, P = 0.001). Moreover, PPARG expression was directly correlated with BM (e = -0.714, P = 0.047) and height (r = -0.762, P = 0.028). In concordant twins, VO2max was inversely correlated with BM (r = -0.290, P = 0.027), BMI (r = -0.472,P = 0.001), WC (r = -0.426, P = 0.001), and TR + SB (r = -0.739, P = 0.001). Twins D-high had 1.78-fold greater PPARG expression when compared with twins D-low (P = 0.048). In conclusion, the cardiorespiratory fitness may modulate PPARG expression in childhood and adolescence, independently of the genetic background.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Metabolismo de glicose em gêmeos monozigóticos discordantes para aptidão cardiorrespiratória

OBJETIVO: Verificar se as concentrações de glicose e insulina em jejum são reguladas pela aptidão cardiorrespiratória (VO2máx), independentemente dos efeitos genéticos. MÉTODOS: Dados de 38 pares de gêmeos monozigóticos (11 a 18 anos) foram analisados transversalmente. Os participantes foram submetidos a um teste de esforço máximo com ergoespirometria aberta (MedGraphics VO2000® - Medical Graphics Corp., St. Paul, MN) e à coleta de sangue para estimar a concentração de glicose e insulina em jejum. A zigosidade foi determinada por intermédio da investigação de concordância dos gêmeos em relação a 15 marcadores genéticos polimórficos. Nove pares demonstraram diferença média intrapar para o consumo máximo de oxigênio ≥10mL.kg-1.min-1 e foram divididos em dois grupos, de alta e baixa aptidão. Os grupos foram comparados a partir do teste pareado de Wilcoxon, tendo em vista a assimetria dos dados. RESULTADOS: em média, os gêmeos do grupo de alta aptidão apresentaram consumo máximo de oxigênio 17% superior (13,5±3,7mL.kg-1.min-1) a seus irmãos menos aptos. Não houve diferença entre os grupos para as concentrações de insulina (36,5±34,6 versus 25,3±13,7mg/dL; p<0,813), porém, os gêmeos mais aptos demonstraram menor concentração de glicose do que seus contrapares menos aptos (82,9±7,3 versus 86,7±7,6mg/dL; p<0,010). CONCLUSÕES: Neste estudo, caracterizado como caso-controle (gêmeos monozigóticos discordantes), o irmão com menor aptidão cardiorrespiratória apresentou maior concentração de glicose em jejum, sugerindo que a baixa aptidão cardiorrespiratória está associada a distúrbios no metabolismo de glicose.OBJETIVO: Verificar si las concentraciones de glucosa e insulina en ayuno son reguladas por la aptitud cardiorrespiratoria (VO2máx), independiente de los efectos genéticos. MÉTODOS: Datos de 38 pares de gemelos monocigóticos (11 a 18 años) fueron analizados transversalmente. Los participantes fueron sometidos a una prueba de esfuerzo máximo con ergoespirometría abierta (MedGraphics VO2000® Medical Graphics Corp., St. Paul, MN) y a la recolección de sangre para estimar la concentración de glucosa e insulina en ayuno. La cigosidad fue determinada por medio de la investigación de concordancia de los gemelos respecto a 15 marcadores genéticos polimórficos. Nueve pares demostraron diferencia mediana intrapares para el consumo máximo de oxígeno ≥10mL.kg-1.min-1 y fueron divididos en dos grupos, de alta y baja aptitud. Los grupos fueron comparados a partir de la prueba pareada de Wilcoxon, teniendo en vista la asimetría de los datos. RESULTADOS: En promedio, los gemelos del grupo de alta aptitud presentaron consumo máximo de oxígeno el 17% superior (13,5±3,7mL.kg-1.min-1) a sus hermanos menos aptos. No hubo diferencia entre los grupos para las concentraciones de insulina (36,5±34,6 versus 25,3±13,7mg/dL; p<0,813), pero los gemelos más aptos demostraron menor concentración de glucosa que sus contrapares menos aptos (82,9±7,3 versus 86,7±7,6mg/dL; p<0,010, respectivamente). CONCLUSIONES: En este estudio, caracterizado como caso-control (gemelos monocigóticos discordantes), el hermano con menor aptitud cardiorrespiratoria presentó mayor concentración de glucosa en ayuno, sugiriendo que la baja aptitud cardiorrespiratoria está asociada a disturbios en el metabolismo de glucosa.OBJECTIVE: To determine if glucose and insulin concentrations are regulated by cardiorespiratory fitness (VO2max) regardless of their genetic effects. METHODS: This cross-sectional study enrolled 38 pairs of young monozygotic twins (11 to 18 years-old). All subjects underwent a progressive maximal exercise test on a treadmill to determine the VO2max with gas exchange analysis (MedGraphics VO2000® - Medical Graphics Corp., St. Paul, MN). Blood samples were drawn after fasting to determine glucose and insulin levels. Monozygosity was confirmed by genotyping 15 informative genetic markers. Nine pairs had at least 10mL.kg-1.min-1 difference in VO2max and were divided into the more and less active group, according to their VO2max. Mean differences between more and less active groups were evaluated by Wilcoxon's test for paired data. RESULTS: on average, twins from the more active group presented a 17% (13.5±3.7mL.kg-1.min-1) higher VO2max compared to their less active siblings. No significant differences were observed between the groups for fasting insulin (36.5±34.6 versus 25.3±13.7mg/dL; p<0.813). However, the more active twins had lower fasting glucose than the less active ones (82.9±7.3 versus 86.7±7.6mg/dL; p<0.010). CONCLUSIONS: In this case-control study (discordant monozygotic twins), the less active co-twins were characterized by higher fasting plasma glucose levels. This implies that poor cardiorespiratory fitness can be associated with defective glucose metabolism regardless of genetic factors

Potential Contribution of Translational Factors to Triiodo-L-Thyronine-Induced Insulin Synthesis by Pancreatic Beta Cells

Background: Thyroid hormones (THs) are known to regulate protein synthesis by acting at the transcriptional level and inducing the expression of many genes. However, little is known about their role in protein expression at the post-transcriptional level, even though studies have shown enhancement of protein synthesis associated with mTOR/p70S6K activation after triiodo-l-thyronine (T3) administration. On the other hand, the effects of TH on translation initiation and polypeptidic chain elongation factors, being essential for activating protein synthesis, have been poorly explored. Therefore, considering that preliminary studies from our laboratory have demonstrated an increase in insulin content in INS-1E cells in response to T3 treatment, the aim of the present study was to investigate if proteins of translational nature might be involved in this effect. Methods: INS-1E cells were maintained in the presence or absence of T3 (10(-6) or 10(-8) M) for 12 hours. Thereafter, insulin concentration in the culture medium was determined by radioimmunoassay, and the cells were processed for Western blot detection of insulin, eukaryotic initiation factor 2 (eIF2), p-eIF2, eIF5A, EF1A, eIF4E binding protein (4E-BP), p-4E-BP, p70S6K, and p-p70S6K. Results: It was found that, in parallel with increased insulin generation, T3 induced p70S6K phosphorylation and the expression of the translational factors eIF2, eIF5A, and eukaryotic elongation factor 1 alpha (eEF1A). In contrast, total and phosphorylated 4E-BP, as well as total p70S6K and p-eIF2 content, remained unchanged after T3 treatment. Conclusions: Considering that (i) p70S6K induces S6 phosphorylation of the 40S ribosomal subunit, an essential condition for protein synthesis; (ii) eIF2 is essential for the initiation of messenger RNA translation process; and (iii) eIF5A and eEF1A play a central role in the elongation of the polypeptidic chain during the transcripts decoding, the data presented here lead us to suppose that a part of T3-induced insulin expression in INS-1E cells depends on the protein synthesis activation at the post-transcriptional level, as these proteins of the translational machinery were shown to be regulated by T3.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP: 08/56446-9]Fundacao de Amparo a Pesquisa do Estado de Sao Paul

Evidences of a Role for Eukaryotic Translation Initiation Factor 5A (eIF5A) in Mouse Embryogenesis and Cell Differentiation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Eukaryotic translation initiation factor 5A (eIF5A) has a unique character: the presence of an unusual amino acid, hypusine, which is formed by post-translational modifications. Even before the identification of hypusination in eIF5A, the correlation between hypusine formation and protein synthesis, shifting cell proliferation rates, had already been observed. Embryogenesis is a complex process in which cellular proliferation and differentiation are intense. In spite of the fact that many studies have described possible functions for eIF5A, its precise role is under investigation, and to date nothing has been reported about its participation in embryonic development. In this study we show that eIF5A is expressed at all mouse embryonic post-implantation stages with increase in eIF5A mRNA and protein expression levels between embryonic days E10.5 and E13.5. Immunohistochemistry revealed the ubiquitous presence of eIF5A in embryonic tissues and organs at E13.5 day. Interestingly, stronger immunoreactivity to eIF5A was observed in the stomodeum, liver, ectoderm, heart, and eye, and the central nervous system; regions which are known to undergo active differentiation at this stage, suggesting a role of eIF5A in differentiation events. Expression analyses of MyoD, a myogenic transcription factor, revealed a significantly higher expression from day E12.5 on, both at the mRNA and the protein levels suggesting a possible correlation to eIF5A. Accordingly, we next evidenced that inhibiting eIF5A hypusination in mouse myoblast C2C12 cells impairs their differentiation into myotubes and decreases MyoD transcript levels. Those results point to a new functional role for eIF5A, relating it to embryogenesis, development, and cell differentiation. J. Cell. Physiol. 225: 500-505, 2010. (C) 2010 Wiley-Liss, Inc.2252500505Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)LTPS`sFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Evidences of a role for eukaryotic translation initiation factor 5A (eIF5A) in mouse embryogenesis and cell differentiation

Eukaryotic translation initiation factor 5A (eIF5A) has a unique character: the presence of an unusual amino acid, hypusine, which is formed by post-translational modifications. Even before the identification of hypusination in eIF5A, the correlation between hypusine formation and protein synthesis, shifting cell proliferation rates, had already been observed. Embryogenesis is a complex process in which cellular proliferation and differentiation are intense. In spite of the fact that many studies have described possible functions for eIF5A, its precise role is under investigation, and to date nothing has been reported about its participation in embryonic development. In this study we show that eIF5A is expressed at all mouse embryonic post-implantation stages with increase in eIF5A mRNA and protein expression levels between embryonic days E10.5 and E13.5. Immunohistochemistry revealed the ubiquitous presence of eIF5A in embryonic tissues and organs at E13.5 day. Interestingly, stronger immunoreactivity to eIF5A was observed in the stomodeum, liver, ectoderm, heart, and eye, and the central nervous system; regions which are known to undergo active differentiation at this stage, suggesting a role of eIF5A in differentiation events. Expression analyses of MyoD, a myogenic transcription factor, revealed a significantly higher expression from day E12.5 on, both at the mRNA and the protein levels suggesting a possible correlation to eIF5A. Accordingly, we next evidenced that inhibiting eIF5A hypusination in mouse myoblast C2C12 cells impairs their differentiation into myotubes and decreases MyoD transcript levels. Those results point to a new functional role for eIF5A, relating it to embryogenesis, development, and cell differentiation2252500505FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP00/11397-