APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons.

The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer's disease (AD). In contrast, APOE2 is known to lower the AD risk, while APOE3 is defined as risk neutral. APOE plays a prominent role in the bioenergetic homeostasis of the brain, and early-stage metabolic changes have been detected in the brains of AD patients. Although APOE is primarily expressed by astrocytes in the brain, neurons have also been shown as source for APOE. However, the distinct roles of the three APOE isoforms in neuronal energy homeostasis remain poorly understood. In this study, we generated pure human neurons (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4, or carrying an APOE knockout (KO) to investigate APOE isoform-specific effects on neuronal energy metabolism. We showed that endogenously produced APOE4 enhanced mitochondrial ATP production in APOE-isogenic iN cells but not in the corresponding iPS cell line. This effect neither correlated with the expression levels of mitochondrial fission or fusion proteins nor with the intracellular or secreted levels of APOE, which were similar for APOE2, APOE3, and APOE4 iN cells. ATP production and basal respiration in APOE-KO iN cells strongly differed from APOE4 and more closely resembled APOE2 and APOE3 iN cells, indicating a gain-of-function mechanism of APOE4 rather than a loss-of-function. Taken together, our findings in APOE isogenic iN cells reveal an APOE genotype-dependent and neuron-specific regulation of oxidative energy metabolism.

Light in a Heartbeat: Bond Scission by a Single Photon above 800 nm.

Photocages enable scientists to take full control over the activity of molecules using light as a biocompatible stimulus. Their emerging applications in photoactivated therapies call for efficient uncaging in the near-infrared (NIR) window, which represents a fundamental challenge. Here, we report synthetically accessible cyanine photocages that liberate alcohol, phenol, amine, and thiol payloads upon irradiation with NIR light up to 820 nm in aqueous media. The photocages display a unique chameleon-like behavior and operate via two distinct uncaging mechanisms: photooxidation and heterolytic bond cleavage. The latter process constitutes the first example of a direct bond scission by a single photon ever observed in cyanine dyes or at wavelengths exceeding 800 nm. Modulation of the beating rates of human cardiomyocytes that we achieved by light-actuated release of adrenergic agonist etilefrine at submicromolar concentrations and low NIR light doses (∼12 J cm-2) highlights the potential of these photocages in biology and medicine.

Mortes de trabalhadores durante a crise sanitária Covid-19: Minas Gerais, 2019-2021 / Worker deaths during the Covid-19 health crisis: Minas Gerais, 2019-2021

A Covid-19, doença infecciosa causada pelo vírus SARS-CoV-2, emergiu na China em dezembro de 2019 e rapidamente se espalhou por todo o mundo. A infecção foi declarada pandemia pela Organização Mundial de Saúde (OMS) em 11 de março de 2020. Desde então, o distanciamento social, entre outras medidas de proteção, foi adotado para desestruturar a cadeia de transmissão do vírus. Contudo, as desigualdades nas oportunidades para se valer dessa medida de proteção foram constatadas. O presente estudo examinou as chances de desligamento por morte de empregados celetistas em Minas Gerais, no período de 2019 a 2021, de acordo com as características sociodemográficas e ocupacionais da força de trabalho registrada no Cadastro Geral de Empregados e Desempregados (Novo - CAGED), do Ministério do Trabalho e Emprego (MTE). A hipótese central diz respeito à variação da chance de desligamento por morte em atividades consideradas essenciais no período pandêmico e pós-pandêmico. Estudo transversal utilizou dados secundários disponíveis para acesso no site do MTE. A Classificação Nacional de Atividades Econômicas (CNAE) e a Classificação Brasileira de Ocupações (CBO) foram tomadas como referência para examinar a hipótese principal. As covariáveis de interesse foram sexo, idade, escolaridade, raça/cor, renda. A distribuição do total de empregados registrados e daqueles desligados por morte, em 2019, 2020 e 2021, foi descrita de acordo com os grandes grupos e subgrupos da CBO. Modelos probabilísticos estimados por regressão logística (RL) binária foram usados para avaliar as chances de desligamento por morte. Foram desenvolvidas RL geral por natureza da ocupação e específicas por subgrupos ocupacionais de três grupos ocupacionais estruturados para fins do estudo, sendo os seguintes: setor saúde, setor essencial fora da saúde e setor não essencial. Homens, pessoas mais velhas, com menor nível de escolaridade e de raça/cor branca tiveram maior chance de desligamento por morte. Esse resultado foi mantido em todos os modelos nos três grupos ocupacionais de interesse. Em relação à natureza da ocupação, trabalhadores dos setores saúde e essencial fora da saúde tiveram maior chance de desligamento por morte. No setor saúde, médicos, trabalhadores da enfermagem e cuidadores tiveram maior chance de desligamento por morte. No setor essencial fora da saúde, a maior chance de desligamento por morte foi observada entre os operadores de utilidades (operadores de máquinas a vapor, de instalações de captação e tratamento de água, esgoto e gases) nos três períodos estudados. A taxa de variação da incidência de desligamentos por morte foi considerada marcador próximo da proporção de mortes causadas direta e indiretamente pela Covid-19. Foi observado aumento dessa taxa no período pandêmico, em relação ao período pré-pandêmico. O perfil sociodemográfico da amostra desligada por morte, em 2020 e 2021, é convergente com os estudos sobre mortalidade causada direta e indiretamente pelo SARS-CoV-2, à exceção do resultado sobre raça/cor branca. Essas evidências serão pistas tanto para fomentar o debate sobre as desigualdades nas oportunidades de proteção durante crises sanitárias, quanto impulsionar a formulação de estratégias para reverter a situação de vulnerabilidade dos trabalhadores de setores considerados essenciais.

Covid-19, an infectious disease caused by the SARS-CoV-2 virus, emerged in China in December 2019 and quickly spread worldwide. The infection was declared a pandemic by the World Health Organization (WHO) on March 11, 2020. Since then, several protective measures have been recommended in order to decrease the transmission of the virus. Among the measures recommended by the WHO, social distancing was adopted to disrupt the virus transmission chain. However, inequalities in opportunities to avail of the protective measure have been documented. The present study examined the odds of shutdown due to death of celetal employees in Minas Gerais, in the period from 2019 to 2021, according to the sociodemographic and occupational characteristics of the population registered in the General Cadastre for the Employed and Unemployed (Novo - CAGED), of the Ministry of Labor and Employment (MTE). The central hypothesis concerns the greater odds of shutdown due to death in activities considered essential. This cross-sectional study used secondary data available for access on the MTE website. The National Classification of Economic Activities (CNAE) and the Brazilian Classification of Occupations (CBO) were used as reference to examine the main hypothesis. The covariates of interest were gender, age, education, race/color, and income. The distribution of total registered employees and those dismissed due to death in 2019, 2020, and 2021 was described according to the major groups and subgroups of the CBO. Probabilistic models estimated by binary logistic regression (LR) were used to assess the odds of shutdown due to death. General RL were developed by nature of occupation and specific by occupational subgroups of three occupational groups structured for the purposes of the study, as follows: health sector, essential sector outside of health and non-essential sector. Men, older people, with a lower level of and people of white race/color had a higher odd of shutdown due to death. This result was maintained in all models in the three occupational groups of interest. Regarding the nature of the occupation, workers in the health and non-health essential sectors had a higher odd of shutdown due to death. In the health sector, physicians, nursing workers, and caregivers had the highest odds of being dismissed due to death. In the non-health essential sector, the highest odds of shutdown due to death was evidenced among utility operators (steam machine operators, water, sewage and gas capture and treatment facilities) in the three periods studied. The rate of change in the incidence of shutdown due to death was considered a marker close to the proportion of deaths directly and indirectly caused by Covid-19. An increase in this rate was observed in the pandemic period, in relation to the pre-pandemic period. The sociodemographic profile of the sample shutdowned due to death, in 2020 and 2021, is consistent with studies on mortality directly and indirectly caused by SARS-CoV-2, with the exception of the result on white race/color. This evidence will be clues both to foment the debate on inequalities in protection opportunities during health crises, and to boost the formulation of strategies to reverse the vulnerable situation of workers in sectors considered essential.

Cultural adaptation and reliability analysis of the early clinical assessment of balance / Adaptação cultural e análise da confiabilidade da early clinical assessment of balance

ABSTRACT Objective: To translate the Early Clinical Assessment of Balance (ECAB), an assessment scale developed specifically for children and adolescents with cerebral palsy into Brazilian Portuguese, evaluate semantic, idiomatic, experiential and conceptual equivalences, and to examine the face validity and the reliability within and between examiners of the Brazilian version. Methods: The following steps were done: translation by two independent translators; synthesis of translations; back translation into English; analysis of back-translations by a multidisciplinary committee and the author of the test to develop the final version of the test; test application training; administration of the translated version of ECAB (videotaped) in 60 children and adolescents with cerebral palsy; intra and inter-examiner reliability assessment. Reability was assessed by intraclass correlation coefficient (CCI). Results: The discrepancies found were related mainly to semantic equivalence and, therefore, there was no need to make cultural adaptations in any of the 13 items on the scale. The rate of agreement was greater than 90% and the reliability of the ECAB-Portuguese total score was excellent both for the intra-rater test (CCI=1.00) and for the inter-rater test (CCI=0.998). Likewise, the reliability evaluation of each of the scale items was also excellent. Conclusions: The translated version of the ECAB into Portuguese provides a tool for the evaluation of the specific balance for children and adolescents with cerebral palsy with different levels of functioning.

RESUMO Objetivo: Traduzir a Early Clinical Assessment of Balance (ECAB), escala de avaliação do equilíbrio desenvolvida especificamente para crianças e adolescentes com paralisia cerebral (PC) para a língua portuguesa do Brasil; avaliar as equivalências semânticas, idiomáticas, experiencial e conceituais; e examinar a validade de face e a confiabilidade intra e interavaliadores da versão brasileira. Métodos: Estudo envolveu tradução do instrumento por dois tradutores independentes; síntese das traduções; retrotradução para o inglês; análise das retrotraduções por um comitê multidisciplinar; treinamento; administração da versão traduzida da ECAB (gravadas em vídeo) em 60 crianças e adolescentes com PC; e avaliação da confiabilidade intra e interexaminadores. A confiabilidade foi avaliada por meio do coeficiente de correlação intraclasse (CCI). Resultados: As discrepâncias encontradas foram referentes principalmente à equivalência semântica e, portanto, não houve necessidade da realização de adaptações culturais em nenhum dos 13 itens da escala. A taxa de concordância foi maior que 90%, e a confiabilidade do escore total da ECAB-português foi excelente tanto para o teste intra-avaliador (CCI=1,00) quanto para interavaliadores (CCI=0,998). Da mesma forma, a avaliação da confiabilidade de cada um dos itens da escala também foi excelente. Conclusões: A versão traduzida da ECAB para o português disponibiliza, para os profissionais da reabilitação infantil, um instrumento confiável de avaliação do equilíbrio específico para crianças e adolescentes com PC com diferentes níveis de funcionalidade.

CULTURAL ADAPTATION AND RELIABILITY ANALYSIS OF THE EARLY CLINICAL ASSESSMENT OF BALANCE.

OBJECTIVE: To translate the Early Clinical Assessment of Balance (ECAB), an assessment scale developed specifically for children and adolescents with cerebral palsy into Brazilian Portuguese, evaluate semantic, idiomatic, experiential and conceptual equivalences, and to examine the face validity and the reliability within and between examiners of the Brazilian version. METHODS: The following steps were done: translation by two independent translators; synthesis of translations; back translation into English; analysis of back-translations by a multidisciplinary committee and the author of the test to develop the final version of the test; test application training; administration of the translated version of ECAB (videotaped) in 60 children and adolescents with cerebral palsy; intra and inter-examiner reliability assessment. Reability was assessed by intraclass correlation coefficient (CCI). RESULTS: The discrepancies found were related mainly to semantic equivalence and, therefore, there was no need to make cultural adaptations in any of the 13 items on the scale. The rate of agreement was greater than 90% and the reliability of the ECAB-Portuguese total score was excellent both for the intra-rater test (CCI=1.00) and for the inter-rater test (CCI=0.998). Likewise, the reliability evaluation of each of the scale items was also excellent. CONCLUSIONS: The translated version of the ECAB into Portuguese provides a tool for the evaluation of the specific balance for children and adolescents with cerebral palsy with different levels of functioning.