THE IMPACT OF TRANSLATIONAL FIDELITY ON HUMAN HEALTH

Ribosomopathies are a class of diseases resulting from mutations in genes encoding ribosomal proteins and ribosome biogenesis factors. Pleiotropic clinical presentations of different ribosomopathies has been taken as evidence of specialized ribosomes. Alternatively, gene dosage effects have been proposed to account for the observed differences. A yeast genetics approach was used to address this issue. Due to a historical gene duplication event, S. cerevisiae cells harbor two ohnologs for most ribosomal proteins. Deletion of one yeast ribosomal protein ohnolog was used to mimic haploinsufficiency in diploid cells (i.e. pseudo-haploinsufficient yeast). Further, insertion of a second copy of the undeleted ohnolog into the locus of the deleted ohnolog enabled separation of effects due to gene dosage from those due to ribosomal protein ohnolog identity. We found that significant changes in translational fidelity in the ribosomal protein ohnolog deletion strains were corrected by ohnolog duplication. Changes in gene dosage, particularly as they may affect the abundance of an enzyme as central as the ribosome, can impart stress through far reaching effects on cellular metabolism. Thus, as an orthogonal approach, we also examined the stress profiles of cells harboring the cbf5-D95A allele (model of X-linked Dyskeratosis Congenita) and the rps23a-R69K allele (model of MacInnes Syndrome). RNA-seq analysis revealed increased expression of proteins involved in response to oxidative stress in cbf5-D95A cells. Growth curve analysis revealed a longer plateau of the cbf5-D95A cells upon reaching stationary phase, suggestive of a pre-adaptive stress response. Decreased ROS abundance, tunicamycin resistance and increased basal levels of HAC1 mRNA in the mutant cells support this hypothesis. Similar results were observed with regard to the ohnolog deletion strains. Taken as a whole, these data support the gene dosage model as opposed to the specialized ribosome hypothesis with the caveat that this conclusion is limited to yeast cells growing in rich medium

Estimulação precoce na primeira infância: incentivando a cultura de paz em pré-escolares / Early stimulation in early childhood: encouraging the culture of peace in preschoolers

O desenvolvimento infantil corresponde às habilidades cognitivas, físicas, sociais e afetivas, as quais podem sofrer interferências positivas ou negativas, dependendo de estímulos ou ausência deles. A violência é um exemplo de interferência negativa nesta fase. A Lei 13.663, de 14 de maio de 2018, dispõe a respeito da promoção de medidas de conscientização, de prevenção e de combate a todos os tipos de violência e a promoção da cultura de paz entre as incumbências dos estabelecimentos de ensino. Portanto, o presente estudo objetiva relatar a experiência de extensionistas do Projeto de Estimulação Precoce na Primeira Infância (PEPPI), na realização de atividades de estimulação precoce em crianças na Unidade de Educação Infantil Professora Telma Vitória na Universidade Federal de Alagoas. Trata-se de um estudo descritivo com abordagem qualitativa, do tipo relato de experiência em que os extensionistas realizaram atividades voltadas à Cultura de Paz, a fim de trabalhar e promover a interação social e contribuir para a conscientização da redução de atos violentos. A atividade consistiu na construção de um cartaz pelas crianças, utilizando figuras que ilustravam os bons e maus modos, e mencionando as atitudes devidas e indevidas que rodeiam a rotina, especialmente das crianças. A Estimulação Precoce visa o favorecimento ao desenvolvimento motor, cognitivo e social. Isto posto, conclui-se que a realização de atividades envolvendo a Cultura de paz são favoráveis tanto ao desenvolvimento cognitivo quanto a questões relacionadas à sociabilidade e redução da violência. Ademais, sugere-se a realização de buscas na literatura para melhor entendimento de como atividade de estimulação sobre Cultura de Paz tem ocorrido no ambiente escolar.

The germline mutational landscape of BRCA1 and BRCA2 in Brazil

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.This work was supported in part by grants from Barretos Cancer Hospital (FINEP - CT-INFRA, 02/2010), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2013/24633-2 and 2103/23277-8), Fundação de Apoio à Pesquisa do Rio Grande do Norte (FAPERN), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Ministério da Saúde, the Breast Cancer Research Foundation (Avon grant #02-2013-044) and National Institute of Health/National Cancer Institute (grant #RC4 CA153828-01) for the Clinical Cancer Genomics Community Research Network. Support in part was provided by grants from Fundo de Incentivo a Pesquisa e Eventos (FIPE) from Hospital de Clínicas de Porto Alegre, by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, BioComputacional 3381/2013, Rede de Pesquisa em Genômica Populacional Humana), Secretaria da Saúde do Estado da Bahia (SESAB), Laboratório de Imunologia e Biologia Molecular (UFBA), INCT pra Controle do Câncer and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). RMR and PAP are recipients of CNPq Productivity Grants, and Bárbara Alemar received a grant from the same agencyinfo:eu-repo/semantics/publishedVersio

Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts

Alergia e intolerância alimentar: uma revisão de literatura

A alergia e a intolerância alimentar são consideradas condições fisiopatológicas diferentes. Por isso, o objetivo do estudo foi realizar uma revisão narrativa de literatura para caracterizar a alergia e a intolerância alimentar. Foram utilizadas para o estudo, as bases de dados Periódicos Capes e livros do período entre 2000 e 2022. Quanto aos resultados obtidos, verificou-se que, a alergia a alimentos consiste em uma resposta exacerbada do organismo a proteínas alimentares mediada por mecanismos imunológicos enquanto que, a intolerância alimentar é resultante de reações não imunológicas. Sobre as alergias alimentares, a mais comum na infância é a Alergia a Proteína do Leite de Vaca (APLV) e das intolerâncias alimentares, a considerada mais comumente conhecida é a intolerância à lactose, a qual é causada pela disfunção total ou parcial da lactase, enzima responsável pela digestão do carboidrato presente nos produtos lácteos

Soroprevalência de anticorpos do vírus SARS-CoV-2 em escolares no município de São Paulo, 2020

OBJECTIVE: To estimate seroprevalence of SARS-CoV-2 antibodies in schoolchildren aged 4 to 14 years living in the city of São Paulo, according to clinical, demographic, epidemiological, and social variables, during the school closure period as a measure against covid-19 spread. METHODS: A serological survey was made in September 2020 with a random sample stratified by school system (municipal public, state public and private) type. A venous blood sample was collected using the Wondfo SARS-CoV-2 Antibody Test (lateral flow method) for detection of total SARS-CoV-2 virus antibodies. Semi-structured questionnaires were applied to collect clinical, demographic, social, and epidemiological data. RESULTS: Seroprevalence of SARS-CoV-2 antibodies in schoolchildren was of 16.6% (95%CI 15.4–17.8). The study found higher seroprevalence in the municipal (18.5%; 95%CI 16.6–20.6) and state (16.2%; 95%CI 14.4–18.2) public school systems compared to the private school system (11.7; 95%CI 10.0–13.7), among black and brown students (18.4%; 95%CI 16.8–20.2) and in the most vulnerable social stratum (18.5 %;95%CI 16.9–20.2). Lower seroprevalence was identified in schoolchildren who reported following the recommended protective measures against covid-19. CONCLUSION: Seroprevalence of SARS-CoV-2 antibodies is found mainly in the most socially vulnerable schoolchildren. This study can contribute to support public policies that reinforce the importance of suspending face-to-face classes and developing strategies aimed at protective measures and monitoring of the serological status of those who have not yet been included in the vaccination schedule.OBJETIVO: Estimar a soroprevalência de anticorpos do vírus SARS-CoV-2 em escolares de quatro a 14 anos de idade residentes no município de São Paulo, segundo variáveis clínicas, demográficas, epidemiológicas e sociais, durante o período de fechamento das escolas como medida de controle da covid-19. MÉTODOS: Realizou-se um inquérito sorológico em setembro de 2020 com amostra aleatória estratificada por tipo de rede de ensino (pública municipal, pública estadual e privada). Foi coletada amostra de sangue venoso utilizando-se o teste de imunoensaio de fluxo lateral da fabricante Wondfo para detecção de anticorpos totais contra o vírus SARS-CoV-2. Aplicaram-se questionários semiestruturados para o levantamento de dados clínicos, demográficos, sociais e epidemiológicos. RESULTADOS: A soroprevalência de anticorpos do vírus SARS-CoV-2 em escolares foi de 16,6% (IC95% 15,4–17,8). O estudo encontrou soroprevalências mais elevadas na rede pública municipal (18,5%; IC95% 16,6–20,6) e estadual (16,2%; IC95% 14,4–18,2) em relação à rede privada (11,7; IC95% 10,0–13,7) e entre escolares da raça/cor preta e parda (18,4%; IC95% 16,8–20,2) e no estrato social mais vulnerável (18,5%; IC95% 16,9–20,2). A pesquisa identificou menores soroprevalências nos escolares que relataram seguir as medidas recomendadas de proteção contra a covid-19. CONCLUSÃO: A soroprevalência de anticorpos contra o vírus SARS-CoV-2 atinge principalmente os escolares socialmente mais vulneráveis. Este estudo pode contribuir para embasar políticas públicas que reforcem a importância da suspensão das aulas presenciais e da necessidade de estratégias de medidas de proteção e acompanhamento do status sorológico daqueles que ainda não foram contemplados no calendário vacinal

SARS-CoV-2 uses CD4 to infect T helper lymphocytes

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS-CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.</p

A epidemiologia da cardiomiopatia de Takotsubo no Brasil e os principais fatores de risco da cardiomiopatia de Takotsubo: The epidemiology of Takotsubo cardiomyopathy in Brazil and the main risk factors for takotsubo cardiomyopathy

A Cardiomiopatia de Takotsubo (CTT) é uma disfunção cardíaca reversível, a qual está relacionada, diretamente, ao estresse físico ou emocional. Objetiva-se através dessa pesquisa evidenciar os principais fatores de risco da CT. Trata-se de uma revisão sistemática realizada no motor de busca Biblioteca Virtual em Saúde (BVS) na base de dados das “Ciências em Saúde em Geral” (Scielo, Medline, Lilacs). Percebeu-se que que a CT apresenta uma ocorrência maior em mulheres na fase de pós-menopausa, onde são atingidas pelo estresse emocional, bem como a inserção de marcapasso também pode desencadear a doença. Entretanto, a etiologia da CT ainda é marcada por controvérsias, mas há concordância acerca do surgimento da CT estar relacionado com a abundância de catecolaminas circulantes

SARS-CoV-2 uses CD4 to infect T helper lymphocytes

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS-CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.</p