RESUMO
Survival from UV-induced DNA lesions relies on nucleotide excision repair (NER) and the Mec1ATR DNA damage response (DDR). We study DDR and NER in aging cells and find that old cells struggle to repair DNA and activate Mec1ATR. We employ pharmacological and genetic approaches to rescue DDR and NER during aging. Conditions activating Snf1AMPK rescue DDR functionality, but not NER, while inhibition of the TORC1-Sch9S6K axis restores NER and enhances DDR by tuning PP2A activity, specifically in aging cells. Age-related repair deficiency depends on Snf1AMPK-mediated phosphorylation of Sch9S6K on Ser160 and Ser163. PP2A activity in old cells is detrimental for DDR and influences NER by modulating Snf1AMPK and Sch9S6K. Hence, the DDR and repair pathways in aging cells are influenced by the metabolic tuning of opposing AMPK and TORC1 networks and by PP2A activity. Specific Sch9S6K phospho-isoforms control DDR and NER efficiency, specifically during aging.
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Senescência Celular , Reparo do DNA , Proteínas Serina-Treonina Quinases , Proteínas de Saccharomyces cerevisiae , Dano ao DNA , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosforilação , Proteína Fosfatase 2/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/fisiologia , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
Cryptococcosis is a worldwide-distributed fungal disease affecting humans and animals and is considered the most common systemic mycosis in cats. Classically, the clinical presentation of cryptococcal infection in cats consists of solitary or multiple nodules located on the planum nasale or the bridge of the nose. Bone involvement as cryptococcal osteomyelitis is a rare clinical entity of cryptococcosis. Herein, this case report describes a domestic shorthair cat with osteomyelitis of the mandibular bone resulting from Cryptococcus spp. infection. During the physical examination, a subcutaneous mass measuring approximately 6 cm in diameter was identified at the mandibular region. Cytological evaluation revealed numerous encapsulated yeasts resembling Cryptococcus spp. Histopathological examination revealed multifocal to coalescent subcutaneous granulomatous inflammation with a large number of spherical yeasts surrounded by a clear capsule. These yeasts were positive for periodic acid-Schiff (PAS) staining. The cat was successfully treated with a combination of itraconazole therapy and surgical management. To the author's knowledge, this is the first clinical report of oral cryptococcal osteomyelitis in a cat.
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Doenças do Gato , Criptococose , Cryptococcus neoformans , Cryptococcus , Osteomielite , Humanos , Gatos , Animais , Antifúngicos/uso terapêutico , Criptococose/diagnóstico , Criptococose/tratamento farmacológico , Criptococose/veterinária , Itraconazol/uso terapêutico , Osteomielite/diagnóstico , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia , Doenças do Gato/diagnóstico , Doenças do Gato/tratamento farmacológicoRESUMO
The malignant bone tumors of the calcaneus are extremely uncommon lesions. Surgical approach can consist in either an amputation or in a limb sparing procedure, depending on the width and the location of the neoplasm. Although several reconstructive options have been proposed to fulfill the bone defect in those cases that received a selective resection, to this date a consensus reconstructive approach is far from being established. Among the alternatives described in literature, 3D printed custom-made prostheses represent one of the most intriguing and promising reconstructive options. Herein, we report our experience of a spindle cell bone sarcoma of the calcaneus treated with selective resection of the anterior segment of the calcaneus and further reconstruction with a 3D printed custom-made prosthesis, based on patients' own anatomy. The posterior calcaneus and the insertion of the Achilles tendon were preserved. The resection was performed with wide margins and no major complication occurred through the intra-operative or post-operative intercourse. At her latest follow-up, our patient showed good functional results and was continuously disease free. Our outcomes therefore suggest that a partial prosthetic replacement of the anterior calcaneus with preservation of the Achilles insertion site may represent a safe and effective solution for cases that required the resection of the anterior calcaneus due to a malignant bone tumor.
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Neoplasias Ósseas , Procedimentos de Cirurgia Plástica , Sarcoma , Humanos , Feminino , Neoplasias Ósseas/cirurgia , Implantação de Prótese/métodos , Próteses e Implantes , Sarcoma/cirurgia , Impressão Tridimensional , Resultado do Tratamento , Estudos RetrospectivosRESUMO
A vast body of studies is available that describe age-dependent gene expression in relation to aging in a number of different model species. These data were obtained from animals kept in conditions with reduced environmental challenges, abundant food, and deprivation of natural sensory stimulation. Here, we compared wild- and captive aging in the short-lived turquoise killifish (Nothobranchius furzeri). These fish inhabit temporary ponds in the African savannah. When the ponds are flooded, eggs hatch synchronously, enabling a precise timing of their individual and population age. We collected the brains of wild fish of different ages and quantified the global age-dependent regulation of transcripts using RNAseq. A major difference between captive and wild populations is that wild populations had unlimited access to food and hence grew to larger sizes and reached asymptotic size more rapidly, enabling the analysis of age-dependent gene expression without the confounding effect of adult brain growth. We found that the majority of differentially expressed genes show the same direction of regulation in wild and captive populations. However, a number of genes were regulated in opposite direction. Genes downregulated in the wild and upregulated in captivity were enriched for terms related to neuronal communication. Genes upregulated in the wild and downregulated in captive conditions were enriched in terms related to DNA replication. Finally, the rate of age-dependent gene regulation was higher in wild animals, suggesting a phenomenon of accelerated aging.
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Ciprinodontiformes , Fundulidae , Animais , Fundulidae/genética , Envelhecimento/genética , Ciprinodontiformes/genética , Animais Selvagens/genética , EncéfaloRESUMO
This research aims to summarize the process and results of the 2022 Report Card on Physical Activity for Brazilian children and adolescents. A group of experts led by 10 PhD researchers gathered the best possible evidence on physical activity indicators. The Report Card Brazil 2022 included the top 10 indicators of physical activity and sleep, obesity, and poor mental health variables, which made up four dimensions: (I) Daily Behaviors; (II) Settings and Sources of Influence; (III) Government Strategies and Investments; and (IV) Health Outcomes. Comprehensive searches, including peer-reviewed and gray literature searches, were performed for each indicator. Data were considered from systematic reviews, local and national surveys, websites, and official information from the Brazilian Federal Government. Grades from the indicators ranged from F (Active Play) to B (School). In addition, the results found for each indicator were Overall Physical Activity (D), Organized Sport Participation (C-), Active Transportation (C), Sedentary Behaviors (D), Sleep (C), Family and Peers (C-), Community and Environment (C), Government (D+), Physical Fitness (D+), Obesity (11.7%), and Poor Mental Health (37.8%). Successfully strategies for increasing physical activity among Brazilian children and adolescents should look at the different indicators presented in this report.
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Promoção da Saúde , Jogos e Brinquedos , Adolescente , Brasil , Criança , Exercício Físico , Política de Saúde , Promoção da Saúde/métodos , Humanos , ObesidadeRESUMO
We present a workflow for clinical data analysis that relies on Bayesian Structure Learning (BSL), an unsupervised learning approach, robust to noise and biases, that allows to incorporate prior medical knowledge into the learning process and that provides explainable results in the form of a graph showing the causal connections among the analyzed features. The workflow consists in a multi-step approach that goes from identifying the main causes of patient's outcome through BSL, to the realization of a tool suitable for clinical practice, based on a Binary Decision Tree (BDT), to recognize patients at high-risk with information available already at hospital admission time. We evaluate our approach on a feature-rich dataset of Coronavirus disease (COVID-19), showing that the proposed framework provides a schematic overview of the multi-factorial processes that jointly contribute to the outcome. We compare our findings with current literature on COVID-19, showing that this approach allows to re-discover established cause-effect relationships about the disease. Further, our approach yields to a highly interpretable tool correctly predicting the outcome of 85% of subjects based exclusively on 3 features: age, a previous history of chronic obstructive pulmonary disease and the PaO2/FiO2 ratio at the time of arrival to the hospital. The inclusion of additional information from 4 routine blood tests (Creatinine, Glucose, pO2 and Sodium) increases predictive accuracy to 94.5%.
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COVID-19 , Teorema de Bayes , Causalidade , Hospitalização , HumanosRESUMO
Abstract The aim of this study is to describe the prevalence of sports participation in Brazilian children and adolescents through a systematic literature review. A search was carried out in the following electronic databases: MEDLINE, WEB OF SCIENCE, BIREME, SCIELO, and SCOPUS for manuscripts published until 2020, combining the keywords: "children", "adolescents", "prevalence", and "sports participation", in Portuguese and English. Twenty-six articles published between 2003 and 2020 were included in the review, with the aim of estimating the prevalence of participation in organized sports in Brazilian children and adolescents. Considering the regions where the studies were carried out, the majority were developed in the south (57.7%; n=15), followed by the southeast (19.2%; n=05), and northeast (15.4%; n=04), in addition to 7.7% (n=02) in all regions of the country. The data showed prevalence of sports participation ranging from 15.0% to 73.2% (mean of 44.8%) among children and adolescents, being higher in males (63.1%). From the results found, the need to develop public policies is evident, in order to favor adherence and maintenance of young people to sports practice, especially among those of the female sex.
Resumo O objetivo deste estudo foi descrever a prevalência de participação esportiva em crianças e adolescentes brasileiros por meio de uma revisão sistemática de literatura. A busca foi realizada nas seguintes bases de dados eletrônicas: MEDLINE, WEB OF SCIENCE, BIREME, SCIELO e SCOPUS de manuscritos publicados até o ano de 2020, por meio da combinação das palavras-chave: "crianças", "adolescentes", "prevalência" e "participação esportiva", em português e inglês. Foram incluídos na revisão 26 artigos publicados no período de 2003 a 2020, com objetivo de estimar a prevalência de crianças e adolescentes brasileiros acerca da participação em esportes organizados. Quanto a região de realização do estudo, a maioria foi desenvolvido no sul (57.7%; n=15), seguido do sudeste (19.2%; n=05) e nordeste (15.4; n=04), além de 7.7% (n=02) em todas as regiões do país. Os dados mostraram prevalências de participação esportiva que variaram entre 15.0% a 73.2% (média de 44.8%) entre crianças e adolescentes, sendo superior no sexo masculino (63.1%). A partir dos resultados encontrados evidencia-se a necessidade do desenvolvimento de políticas públicas para favorecera aderência e manutenção de jovens para a prática esportiva, principalmente entre aqueles do sexo feminino.
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The first purpose of this study was to verify the association between Instability Severity Index Score (ISIS) and Recurrent Shoulder Dislocation (RSD) after a first episode treated conservatively. The second aim is to identify the risk factors associated with RSD after a primary acute shoulder anterior dislocation treated conservatively. A total of 111 patients with first traumatic anterior shoulder dislocation treated at a single trauma centre between January 2014 and March 2016 were enrolled. The main predictive variables of risk factors and the ISIS score were calculated. Among the 85 patients included, 26 cases of RSD were observed (30.6%). Considering the whole population, no significant association between ISIS and RSD were reported. Regarding other risk factors, high-risk working activities and rotator cuff injury had a significantly higher RSD risk. Sex, dominant limb, familiar history, hyperlaxity, contact or overhead sports, competitive sport, post-reduction physiokinesitherapy, return to sports activity time, Hill-Sachs lesion, bony Bankart lesion and great tuberosity fracture did not seem to influence the risk of RSD. No correlation between ISIS score and RSD in patients treated conservatively after a first episode of shoulder dislocation were reported. The only risk factors with a significant association to RSD were high-risk working activities and rotator cuff injury.
Assuntos
Luxação do Ombro , Articulação do Ombro , Artroscopia , Humanos , Recidiva , Estudos Retrospectivos , Luxação do Ombro/terapiaRESUMO
Atg6Beclin 1 mediates autophagy and endosomal trafficking. We investigated how Atg6 influences replication stress. Combining genetic, genomic, metabolomic, and proteomic approaches, we found that the Vps34-Vps15-Atg6Beclin 1-Vps38UVRAG-phosphatydilinositol-3 phosphate (PtdIns(3)P) axis sensitizes cells to replication stress by favoring the degradation of plasma membrane amino acid (AA) transporters via endosomal trafficking and ESCRT proteins, while the PtdIns(3)P phosphatases Ymr1 and Inp53 promote survival to replication stress by reversing this process. An impaired AA uptake triggers activation of Gcn2, which attenuates protein synthesis by phosphorylating eIF2α. Mec1Atr-Rad53Chk1/Chk2 activation during replication stress further hinders translation efficiency by counteracting eIF2α dephosphorylation through Glc7PP1. AA shortage-induced hyperphosphorylation of eIF2α inhibits the synthesis of 65 stress response proteins, thus resulting in cell sensitization to replication stress, while TORC1 promotes cell survival. Our findings reveal an integrated network mediated by endosomal trafficking, translational control pathways, and checkpoint kinases linking AA availability to the response to replication stress.
Assuntos
Autofagia/fisiologia , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA/fisiologia , Endossomos/metabolismo , Proteína Beclina-1/metabolismo , Fosforilação , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , LevedurasRESUMO
O objetivo do presente estudo foi verificar se há associação entre o conhecimento tático declarativo e o nível de ansiedade, de acordo com o sexo, de jovens praticantes de futsal. Participaram do estudo raticantes de futsal em nível escolar. Para análise do conhecimento tático declarativo (CTD) foi utilizado o Teste de Conhecimento Tático Declarativo - Futsal 2. Para análise do nível de ansiedade foi aplicado o Inventário de Ansiedade Traço-Estado. O sexo masculino apresentou melhor pontuação para melhor decisão e escore total no CTD em relação ao sexo feminino. Para ansiedade, não foram observadas diferenças significativas para os escores obtidos entre os grupos, assim como não foram observadas correlações significativas entre ansiedade-traço e ansiedade-estado com os escores obtidos no CTD. Conclui-se que meninos apresentam maiores níveis de CTD do que as meninas, porém, o nível de ansiedade parece não influenciar no CTD dos escolares.
The aim of this study was to verify whether there is an association between declarative tactical knowledge and the level of anxiety, according to gender of young futsal practitioners. 25 boys and 11 girls who practice futsal at school participated in the study. Declararative Tactical Knowledge Test Futsal 2 was used to analyze the declarative tactical knowledge (DTK). For the analysis of the level of anxiety, State-Trait Anxiety Inventory was applied. Boys had better score for better decision and total score on the DTK compared to girls. For anxiety, no significant difference were observed for the scores obtained between the groups, as well no significant correlations between trait-anxiety and state-anxiety with the scores obtained in the DTK. It is concluded that boys have higher levels of DTK than girls, however, the level of anxiety does not seem to influence the students' DTK.
El objetivo de este estudio fue verificar si existe asociación entre el conocimiento táctico declarativo y el nivel de ansiedad, según lo género, de los jóvenes practicantes de fútbol sala. Participaron 25 ninõs y 11 ninãs que practican fútbol sala en la escuela. Para el análisis del conocimiento táctico declarativo (CTD) se utilizó el Test de Conocimiento Táctico Declarativo Futsal 2. Para análisis del nivel de ansiedad se aplicó el Inventario de Ansiedad Estado-Rasgo. Los niños obtuvieron mejores puntajes para una mejor decisión y total en el CTD en comparación con las niñas. Para la ansiedad, no se observaron diferencias significativas para las puntuaciones obtenidas entre los grupos, así como tampoco correlaciones significativas entre rasgo-ansiedad y estado-ansiedad con las puntuaciones del CTD. Se concluye que los niños tienen niveles más altos de CTD que las niñas, sin enbargo, el nivel de ansiedad no parece influir en el CTD de ellos.
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Machine learning (ML) approaches have been widely applied to medical data in order to find reliable classifiers to improve diagnosis and detect candidate biomarkers of a disease. However, as a powerful, multivariate, data-driven approach, ML can be misled by biases and outliers in the training set, finding sample-dependent classification patterns. This phenomenon often occurs in biomedical applications in which, due to the scarcity of the data, combined with their heterogeneous nature and complex acquisition process, outliers and biases are very common. In this work we present a new workflow for biomedical research based on ML approaches, that maximizes the generalizability of the classification. This workflow is based on the adoption of two data selection tools: an autoencoder to identify the outliers and the Confounding Index, to understand which characteristics of the sample can mislead classification. As a study-case we adopt the controversial research about extracting brain structural biomarkers of Autism Spectrum Disorders (ASD) from magnetic resonance images. A classifier trained on a dataset composed by 86 subjects, selected using this framework, obtained an area under the receiver operating characteristic curve of 0.79. The feature pattern identified by this classifier is still able to capture the mean differences between the ASD and Typically Developing Control classes on 1460 new subjects in the same age range of the training set, thus providing new insights on the brain characteristics of ASD. In this work, we show that the proposed workflow allows to find generalizable patterns even if the dataset is limited, while skipping the two mentioned steps and using a larger but not well designed training set would have produced a sample-dependent classifier.
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Transtorno do Espectro Autista , Transtorno do Espectro Autista/diagnóstico , Encéfalo/diagnóstico por imagem , Humanos , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Curva ROCRESUMO
The DNA damage response (DDR) coordinates DNA metabolism with nuclear and non-nuclear processes. The DDR kinase Rad53CHK1/CHK2 controls histone degradation to assist DNA repair. However, Rad53 deficiency causes histone-dependent growth defects in the absence of DNA damage, pointing out unknown physiological functions of the Rad53-histone axis. Here we show that histone dosage control by Rad53 ensures metabolic homeostasis. Under physiological conditions, Rad53 regulates histone levels through inhibitory phosphorylation of the transcription factor Spt21NPAT on Ser276. Rad53-Spt21 mutants display severe glucose dependence, caused by excess histones through two separable mechanisms: dampening of acetyl-coenzyme A-dependent carbon metabolism through histone hyper-acetylation, and Sirtuin-mediated silencing of starvation-induced subtelomeric domains. We further demonstrate that repression of subtelomere silencing by physiological Tel1ATM and Rpd3HDAC activities coveys tolerance to glucose restriction. Our findings identify DDR mutations, histone imbalances and aberrant subtelomeric chromatin as interconnected causes of glucose dependence, implying that DDR kinases coordinate metabolism and epigenetic changes.
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Proteínas de Ciclo Celular/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Glucose/metabolismo , Histonas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/genética , Quinase do Ponto de Checagem 2/genética , Dano ao DNA , Reparo do DNA , Inativação Gênica , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Serina/genética , Serina/metabolismo , Telômero/genética , Fatores de Transcrição/genéticaRESUMO
Portulaca oleracea is a C4 herb capable of performing CAM under drought stress. It is distributed worldwide and is either considered a polymorphic species or a complex of subspecies, due to its numerous morphological variations. We evaluated CAM plasticity within P. oleracea genotypes since the complexity surrounding this species may be reflected in intraspecific variations in photosynthetic behavior. Eleven subspecies of P. oleracea from distant geographical locations and one cultivar were morphologically and physiologically characterized. C4 and CAM photosynthesis were monitored in plants exposed to well-watered, droughted and rewatered treatments, and data obtained were compared among individual genotypes. All subspecies expressed CAM in a fully-reversible manner. Transcript abundance of C4-CAM signature genes was shown to be a useful indicator of the C4-CAM-C4 switches in all genotypes. C4-related genes were down-regulated and subsequently fully expressed upon drought and rewatering, respectively. CAM-marker genes followed the opposite pattern. A gradient of morphological traits and drought-induced nighttime malate accumulation was observed across genotypes. Therefore, different combinations of CAM expression levels, plant sizes and shapes are available within the P. oleracea complex, which can be a valuable tool in the context of C4/CAM photosynthesis research.
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Metabolismo Ácido das Crassuláceas/fisiologia , Fotossíntese/fisiologia , Portulaca/metabolismo , Dióxido de Carbono/metabolismo , Secas , Folhas de Planta/metabolismo , Portulaca/fisiologia , Estresse Fisiológico/fisiologiaRESUMO
Over the years, there has been growing interest in using machine learning techniques for biomedical data processing. When tackling these tasks, one needs to bear in mind that biomedical data depends on a variety of characteristics, such as demographic aspects (age, gender, etc.) or the acquisition technology, which might be unrelated with the target of the analysis. In supervised tasks, failing to match the ground truth targets with respect to such characteristics, called confounders, may lead to very misleading estimates of the predictive performance. Many strategies have been proposed to handle confounders, ranging from data selection, to normalization techniques, up to the use of training algorithm for learning with imbalanced data. However, all these solutions require the confounders to be known a priori. To this aim, we introduce a novel index that is able to measure the confounding effect of a data attribute in a bias-agnostic way. This index can be used to quantitatively compare the confounding effects of different variables and to inform correction methods such as normalization procedures or ad-hoc-prepared learning algorithms. The effectiveness of this index is validated on both simulated data and real-world neuroimaging data.
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Pesquisa Biomédica/métodos , Fatores de Confusão Epidemiológicos , Aprendizado de Máquina , HumanosRESUMO
No univocal and reliable brain-based biomarkers have been detected to date in Autism Spectrum Disorders (ASD). Neuroimaging studies have consistently revealed alterations in brain structure and function of individuals with ASD; however, it remains difficult to ascertain the extent and localization of affected brain networks. In this context, the application of Machine Learning (ML) classification methods to neuroimaging data has the potential to contribute to a better distinction between subjects with ASD and typical development controls (TD). This study is focused on the analysis of resting-state fMRI data of individuals with ASD and matched TD, available within the ABIDE collection. To reduce the multiple sources of heterogeneity that impact on understanding the neural underpinnings of autistic condition, we selected a subgroup of 190 subjects (102 with ASD and 88 TD) according to the following criteria: male children (age range: 6.5-13 years); rs-fMRI data acquired with open eyes; data from the University sites that provided the largest number of scans (KKI, NYU, UCLA, UM). Connectivity values were evaluated as the linear correlation between pairs of time series of brain areas; then, a Linear kernel Support Vector Machine (L-SVM) classification, with an inter-site cross-validation scheme, was carried out. A permutation test was conducted to identify over-connectivity and under-connectivity alterations in the ASD group. The mean L-SVM classification performance, in terms of the area under the ROC curve (AUC), was 0.75 ± 0.05. The highest performance was obtained using data from KKI, NYU and UCLA sites in training and data from UM as testing set (AUC = 0.83). Specifically, stronger functional connectivity (FC) in ASD with respect to TD involve (p < 0.001) the angular gyrus with the precuneus in the right (R) hemisphere, and the R frontal operculum cortex with the pars opercularis of the left (L) inferior frontal gyrus. Weaker connections in ASD group with respect to TD are the intra-hemispheric R temporal fusiform cortex with the R hippocampus, and the L supramarginal gyrus with L planum polare. The results indicate that both under- and over-FC occurred in a selected cohort of ASD children relative to TD controls, and that these functional alterations are spread in different brain networks.
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Tumor cells may adapt to metabolic challenges by alternating between glycolysis and oxidative phosphorylation (OXPHOS). To target this metabolic plasticity, we combined intermittent fasting, a clinically feasible approach to reduce glucose availability, with the OXPHOS inhibitor metformin. In mice exposed to 24-h feeding/fasting cycles, metformin impaired tumor growth only when administered during fasting-induced hypoglycemia. Synergistic anti-neoplastic effects of the metformin/hypoglycemia combination were mediated by glycogen synthase kinase 3ß (GSK3ß) activation downstream of PP2A, leading to a decline in the pro-survival protein MCL-1, and cell death. Mechanistically, specific activation of the PP2A-GSK3ß axis was the sum of metformin-induced inhibition of CIP2A, a PP2A suppressor, and of upregulation of the PP2A regulatory subunit B56δ by low glucose, leading to an active PP2A-B56δ complex with high affinity toward GSK3ß.
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Jejum/metabolismo , Hipoglicemia/metabolismo , Metformina/administração & dosagem , Neoplasias/terapia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicólise/efeitos dos fármacos , Células HCT116 , Células HeLa , Humanos , Hipoglicemia/etiologia , Metformina/farmacologia , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neoplasias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
RATIONALE & OBJECTIVE: Although primary atypical hemolytic uremic syndrome (aHUS) is associated with abnormalities in complement genes and antibodies to complement factor H, the role of complement in secondary aHUS remains debatable. We evaluated the usefulness of an ex vivo test to: (1) detect complement activation within the endothelium in primary and secondary aHUS, (2) differentiate active disease from remission, (3) monitor the effectiveness of eculizumab therapy, and (4) identify relapses during eculizumab dosage tapering and after discontinuation of treatment. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 121 patients with primary aHUS and 28 with secondary aHUS. Serum samples were collected during acute episodes, following remission, and during eculizumab treatment and were assessed using a serum-induced ex vivo C5b-9 endothelial deposition test. RESULTS: Serum-induced C5b-9 deposition on cultured microvascular endothelium was quantified by calculating the endothelial area covered by C5b-9 staining; values were expressed as percentage of C5b-9 deposits induced by a serum pool from healthy controls. Testing with adenosine diphosphate-activated endothelium demonstrated elevated C5b-9 deposits for all untreated patients with aHUS independent of disease activity, while testing with unstimulated endothelium demonstrated deposits only in active disease. Similar findings were observed in secondary aHUS. Serum-induced C5b-9 deposits on activated and unstimulated endothelium normalized during eculizumab treatment. 96% (22/23) of patients receiving eculizumab at extended 3- or 4-week dosing intervals demonstrated normal C5b-9 deposits on activated endothelium, despite most patients having CH50Eq (serum complement activity) > 20 UEq/mL, indicating that adequate complement control was achieved even with incomplete blockade of circulating C5. During eculizumab dosage tapering or after treatment discontinuation, all patients experiencing relapses versus only 6% (1/17) of those in stable remission had elevated C5b-9 deposits on unstimulated endothelium. LIMITATIONS: The C5b-9 endothelial deposition test can be performed in only specialized laboratories. Findings on eculizumab dosage tapering need to be confirmed with longitudinal monitoring of C5b-9 deposition. CONCLUSIONS: The C5b-9 endothelial deposition assay may represent an advance in our ability to monitor aHUS activity and individualize therapy.
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Anticorpos Monoclonais Humanizados , Síndrome Hemolítico-Urêmica Atípica , Ativação do Complemento/efeitos dos fármacos , Complexo de Ataque à Membrana do Sistema Complemento/análise , Monitoramento de Medicamentos/métodos , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Síndrome Hemolítico-Urêmica Atípica/sangue , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Fator H do Complemento/análise , Fator H do Complemento/genética , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/farmacocinética , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Feminino , Humanos , Técnicas In Vitro/métodos , Masculino , Reprodutibilidade dos Testes , Prevenção Secundária/métodos , Prevenção Secundária/estatística & dados numéricosRESUMO
Objective: analyze the prevalence of dissatisfaction with body image and concordance and reliability of the printed version and the electronic version of a body image instrument in university students. Method: A total of 117 university students of both sexes were evaluated. The validated questionnaire was the body figure scale. Data were compared using a t-test for paired samples, concordance between versions was tested by the kappa index, and reliability by the intraclass correlation coefficient and the percentage of agreement, using the Statistical Package for the Social Sciences 15.0 software. Results: The percent agreement and intraclass correlation coefficient values ranged from low to high according to version, sex and the item analyzed. The kappa index was higher than 0.60, indicating good correlation. Conclusions: The version of the questionnaire does not modify the assessment of body image
Objetivo: Analizar la prevalencia de insatisfacción con la imagen corporal y la concordancia y confiabilidad de la versión impresa y de la versión electrónica de un instrumento de imagen corporal en universitarios. Método: Se evaluaron un total de 117 estudiantes universitarios de ambos sexos. El cuestionario validado fue la escala de figuras corporales. Los datos fueron comparados utilizando la prueba t para muestras pareadas, la concordancia entre las versiones fue probada por el índice kappa y la confiabilidad por el coeficiente de correlación intraclase y el porcentaje de concordancia, utilizando el software Statistical Package for the Social Sciences 15.0 . Resultados: El porcentaje de concordancia y los valores del coeficiente de correlación intraclase varían de abajo a alto de acuerdo con la versión, el sexo y el ítem analizado. El índice kappa fue superior a 0.60, indicando buena correlación. Conclusiones: La versión del cuestionario no modifica la evaluación de la imagen corporal
Objetivo: Analisar a prevalência de insatisfação com a imagem corporal e a concordância e confiabilidade da versão impressa e da versão eletrônica de um instrumento de imagem corporal em universitários. Método: Um total de 117 estudantes universitários de ambos os sexos foram avaliados. O questionário validado foi a escala de figuras corporais. Os dados foram comparados utilizando-se o teste t para amostras pareadas, a concordância entre as versões foi testada pelo índice kappa e a confiabilidade pelo coeficiente de correlação intraclasse e o percentual de concordância, utilizando-se do software Statistical Package for the Social Sciences 15.0. Resultados: O percentual de concordância e os valores do coeficiente de correlação intraclasse variaram de baixo o alto de acordo com a versão, o sexo e o item analisado. O índice kappa foi superior a 0.60, indicando boa correlação. Conclusões: A versão do questionário não modifica a avaliação da imagem corporal
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Autoimagem , Imagem Corporal , Pesos e Medidas Corporais/estatística & dados numéricos , Estudantes/estatística & dados numéricos , Autorrelato/estatística & dados numéricos , Inquéritos e Questionários/estatística & dados numéricos , Reprodutibilidade dos TestesRESUMO
The aim of our study is a retrospective analysis of the 2 most common surgical treatments of symptomatic juvenile flat foot: different arthroereisis techniques. Exosinotarsal arthroereisis with metallic screw and endosinotarsal with bioabsorbable devices were compared. In total, 402 feet were examined for a median follow-up of 130 months. Only symptomatic (plantar or calcaneus pain), flexible, and idiopathic flat feet were included in our study. Congenital (fibrous/bone tarsal coalitions), neurologic, and posttraumatic flat feet were excluded. During clinical examination, the feet were categorized according to the Viladot classification, which took into consideration the plantar impression: only grades 3 and 4 were included (complete medial longitudinal arch collapse). Evaluation was determined by taking into consideration 3 parameters: clinical evaluation, pain, and variation of the radiologic angles. No statistical differences were found between the 2 techniques; the choice can be determined mostly by the surgeon's preference.