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BACKGROUND: Executive function is often altered in overweight/obese children and adolescents, which has a negative impact on their learning and daily life. Furthermore, research has shown the benefits of physical exercise in improving cognitive performance. This protocol aims to define in a detailed and structured manner the procedures that will be conducted for the development of a systematic review of the literature aimed at evaluating the effects of physical exercise on the executive functions of children and adolescents (≤18 years) with overweight/obesity in comparison with peers in control groups. METHODS: The Web of Science, PubMed, Scopus, and EBSCO databases will be searched for longitudinal studies that have at least one experimental and one control group using pre- and post-intervention measures of executive function, including working memory, inhibition, and cognitive flexibility in the pediatric population who are overweight or obese. The risk of bias and certainty of evidence will be assessed using Cochrane RoB2 and GRADE, respectively. Furthermore, Der Simonian-Laird's random effects model will be employed for meta-analyses. The effect sizes will be calculated with 95% confidence intervals, and p values < 0.05 indicate statistical significance for each dimension of executive function in the different groups before and after the intervention. DISCUSSION: The results of this review may be useful for education and health professionals to design treatment plans for overweight/obese children and adolescents, offering potential benefits related to the learning and cognitive abilities of this population. PROSPERO registration number: CRD42023391420.
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INTRODUCTION: Executive functions are commonly impaired in individuals with schizophrenia spectrum disorders. Physical exercise has the potential for improving executive functions and can be easily implemented as a therapeutic method. However, there are only few systematic reviews of exercise effects in schizophrenia including cognitive outcomes, and no meta-analytical syntheses of effects on "cool" and "hot" executive functions. The purpose of this systematic review and meta-analysis will be to determine the effects of physical exercise on "cool" and "hot" executive functions of adults with schizophrenia spectrum disorders. METHODS AND ANALYSIS: This protocol was guided by PRISMA-P guidelines. Studies will be searched using combinations of keywords and medical terms in the Web of Science, PubMed, Scopus, and EBSCO databases. Inclusion criteria will be determined as per PICOS approach. The risk of bias will be assessed using the Cochrane RoB2 tool. The certainty of evidence (per outcome) will be assessed using the GRADE method. The meta-analyses will be performed using the DerSimonian and Laird random effects model. Effect sizes (Hedges' g) with 95% confidence intervals will be calculated for each main outcome. CONCLUSIONS: The results of this review may be useful for mental health professionals to design treatment plans for adults with schizophrenia spectrum disorders, offering potential benefits related to the quality of life and cognitive abilities of this population. PROSPERO REGISTRATION NUMBER: CRD42023392295.
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Função Executiva , Esquizofrenia , Humanos , Esquizofrenia/terapia , Qualidade de Vida , Revisões Sistemáticas como Assunto , Metanálise como Assunto , Exercício Físico , Literatura de Revisão como AssuntoRESUMO
Exocytosis is a fundamental process in physiology, that ensures communication between cells, organs and even organisms. Hormones, neuropeptides and antibodies, among other cargoes are packed in exocytic vesicles that need to reach and fuse with the plasma membrane to release their content to the extracellular milieu. Hundreds of proteins participate in this process and several others in its regulation. We report here a novel component of the exocytic machinery, the Drosophila transmembrane immunophilin Zonda (Zda), previously found to participate in autophagy. Zda is highly expressed in secretory tissues, and regulates exocytosis in at least three of them: the ring gland, insulin-producing cells and the salivary gland. Using the salivary gland as a model system, we found that Zda is required at final steps of the exocytic process for fusion of secretory granules to the plasma membrane. In a genetic screen we identified the small GTPase RalA as a crucial regulator of secretory granule exocytosis that is required, similarly to Zda, for fusion between the secretory granule and the plasma membrane.
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Exocitose , Imunofilinas , Autofagia , Membrana Celular , Vesículas SecretóriasRESUMO
Autophagy is an evolutionary conserved process by which eukaryotic cells undergo self-digestion of cytoplasmic components. Here we report that a novel Drosophila immunophilin, which we have named Zonda, is critically required for starvation-induced autophagy. We show that Zonda operates at early stages of the process, specifically for Vps34-mediated phosphatidylinositol 3-phosphate (PI3P) deposition. Zonda displays an even distribution under basal conditions and, soon after starvation, nucleates in endoplasmic reticulum-associated foci that colocalize with omegasome markers. Zonda nucleation depends on Atg1, Atg13, and Atg17 but does not require Vps34, Vps15, Atg6, or Atg14. Zonda interacts physically with Atg1 through its kinase domain, as well as with Atg6 and Vps34. We propose that Zonda is an early component of the autophagy cascade necessary for Vps34-dependent PI3P deposition and omegasome formation.
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Autofagia/fisiologia , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Imunofilinas/metabolismo , Animais , Proteínas Relacionadas à Autofagia , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Imunofilinas/genética , Fagossomos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Transdução de SinaisRESUMO
Hypoxia-inducible factors (HIFs) are a family of evolutionary conserved alpha-beta heterodimeric transcription factors that induce a wide range of genes in response to low oxygen tension. Molecular mechanisms that mediate oxygen-dependent HIF regulation operate at the level of the alpha subunit, controlling protein stability, subcellular localization, and transcriptional coactivator recruitment. We have conducted an unbiased genome-wide RNA interference (RNAi) screen in Drosophila cells aimed to the identification of genes required for HIF activity. After 3 rounds of selection, 30 genes emerged as critical HIF regulators in hypoxia, most of which had not been previously associated with HIF biology. The list of genes includes components of chromatin remodeling complexes, transcription elongation factors, and translational regulators. One remarkable hit was the argonaute 1 (ago1) gene, a central element of the microRNA (miRNA) translational silencing machinery. Further studies confirmed the physiological role of the miRNA machinery in HIF-dependent transcription. This study reveals the occurrence of novel mechanisms of HIF regulation, which might contribute to developing novel strategies for therapeutic intervention of HIF-related pathologies, including heart attack, cancer, and stroke.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Drosophila melanogaster/genética , Hipóxia/genética , Interferência de RNA , Transcrição Gênica , Animais , Proteínas Argonautas , Linhagem Celular , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Fatores de Iniciação em Eucariotos/genética , Estudo de Associação Genômica Ampla , Hipóxia/metabolismoRESUMO
The Drosophila HIFalpha homologue, Sima, is localized mainly in the cytoplasm in normoxia and accumulates in the nucleus upon hypoxic exposure. We have characterized the mechanism governing Sima oxygen-dependent subcellular localization and found that Sima shuttles continuously between the nucleus and the cytoplasm. We have previously shown that nuclear import depends on an atypical bipartite nuclear localization signal mapping next to the C-terminus of the protein. We show here that nuclear export is mediated in part by a CRM1-dependent nuclear export signal localized in the oxygen-dependent degradation domain (ODDD). CRM1-dependent nuclear export requires both oxygen-dependent hydroxylation of a specific prolyl residue (Pro850) in the ODDD, and the activity of the von Hippel Lindau tumor suppressor factor. At high oxygen tension rapid nuclear export of Sima occurs, whereas in hypoxia, Sima nuclear export is largely inhibited. HIFalpha/Sima nucleo-cytoplasmic localization is the result of a dynamic equilibrium between nuclear import and nuclear export, and nuclear export is modulated by oxygen tension.
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Transporte Ativo do Núcleo Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Oxigênio/metabolismo , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/citologia , Drosophila melanogaster/embriologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Dados de Sequência Molecular , Sinais de Exportação Nuclear , Pró-Colágeno-Prolina Dioxigenase/genética , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transgenes , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismoRESUMO
Drosophila tracheal terminal branches are plastic and have the capacity to sprout out projections toward oxygen-starved areas, in a process analogous to mammalian angiogenesis. This response involves the upregulation of FGF/Branchless in hypoxic tissues, which binds its receptor Breathless on tracheal cells. Here, we show that extra sprouting depends on the Hypoxia-Inducible Factor (HIF)-alpha homolog Sima and on the HIF-prolyl hydroxylase Fatiga that operates as an oxygen sensor. In mild hypoxia, Sima accumulates in tracheal cells, where it induces breathless, and this induction is sufficient to provoke tracheal extra sprouting. In nontracheal cells, Sima contributes to branchless induction, whereas overexpression of Sima fails to attract terminal branch outgrowth, suggesting that HIF-independent components are also required for full induction of the ligand. We propose that the autonomous response to hypoxia that occurs in tracheal cells enhances tracheal sensitivity to increasing Branchless levels, and that this mechanism is a cardinal step in hypoxia-dependent tracheal sprouting.
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Padronização Corporal , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/embriologia , Drosophila melanogaster/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Larva/anatomia & histologia , Oxigênio/metabolismo , Fenótipo , Pró-Colágeno-Prolina Dioxigenase/genética , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismoRESUMO
Hypoxia-inducible factor alpha (HIF-alpha) proteins are regulated by oxygen levels through several different mechanisms that include protein stability, transcriptional coactivator recruitment, and subcellular localization. It was previously reported that these transcription factors are mainly nuclear in hypoxia and cytoplasmic in normoxia, but so far the molecular basis of this regulation is unclear. We show here that the Drosophila melanogaster HIF-alpha protein Sima shuttles continuously between the nucleus and the cytoplasm. We identified the relevant nuclear localization signal and two functional nuclear export signals (NESs). These NESs are in the Sima basic helix-loop-helix (bHLH) domain and promote CRM1-dependent nuclear export. Site-directed mutagenesis of either NES provoked Sima nuclear retention and increased transcriptional activity, suggesting that nuclear export contributes to Sima regulation. The identified NESs are conserved and probably functional in the bHLH domains of several bHLH-PAS proteins. We propose that rapid nuclear export of Sima regulates the duration of cellular responses to hypoxia.
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Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Carioferinas/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transporte Ativo do Núcleo Celular , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Sequência Conservada , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Evolução Molecular , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Carioferinas/genética , Modelos Biológicos , Dados de Sequência Molecular , Sinais de Exportação Nuclear/genética , Sinais de Localização Nuclear/química , Sinais de Localização Nuclear/genética , Processamento de Proteína Pós-Traducional , Receptores Citoplasmáticos e Nucleares/genética , Homologia de Sequência de Aminoácidos , Transcrição Gênica , Proteína Exportina 1RESUMO
The fruit fly Drosophila melanogaster, a widely utilized genetic model, is highly resistant to oxygen starvation and is beginning to be used for studying physiological, developmental, and cellular adaptations to hypoxia. The Drosophila respiratory (tracheal) system has features in common with the mammalian circulatory system so that an angiogenesis-like response occurs upon exposure of Drosophila larvae to hypoxia. A hypoxia-responsive system homologous to mammalian hypoxia-inducible factor (HIF) has been described in the fruit fly, where Fatiga is a Drosophila oxygen-dependent HIF prolyl hydroxylase, and the basic helix-loop-helix Per/ARNT/Sim (bHLH-PAS) proteins Sima and Tango are, respectively, the Drosophila homologues of mammalian HIF-alpha (alpha) and HIF-beta (beta). Tango is constitutively expressed regardless of oxygen tension and, like in mammalian cells, Sima is controlled at the level of protein degradation and subcellular localization. Sima is critically required for development in hypoxia, but, unlike mammalian model systems, it is dispensable for development in normoxia. In contrast, fatiga mutant alleles are all lethal; however, strikingly, viability to adulthood is restored in fatiga sima double mutants, although these double mutants are not entirely normal, suggesting that Fatiga has Sima-independent functions in fly development. Studies in cell culture and in vivo have revealed that Sima is activated by the insulin receptor (InR) and target-of-rapamycin (TOR) pathways. Paradoxically, Sima is a negative regulator of growth. This suggests that Sima is engaged in a negative feedback loop that limits growth upon stimulation of InR/TOR pathways.
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Adaptação Fisiológica , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Modelos Animais , Oxigênio/metabolismo , Animais , Hipóxia Celular/genética , Tamanho Celular , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/farmacologia , Drosophila melanogaster/genética , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Proteína Tirosina Quinases/farmacologiaRESUMO
The Drosophila adult male terminalia originate from the genital disc. During the pupal stages, the external parts of terminalia evert from two ventral stalks; the everted left and right dorsal halves fuse at the dorsal midline. At the same time the male terminalia perform a 360 clockwise rotation. Several mutations are known to affect the rotation of the male terminalia, while none is known to affect dorsal closure. We show here that the Pvf1 gene, encoding one of the three Drosophila homologues of the mammalian VEGF/PDGF growth factors, is required for both processes. Males either mutant for Pvf1 or bearing a dominant negative form of Pvr or stasis (stai), the unique PVF receptor, do not complete either rotation or dorsal closure. Pvf1 expression in the genital disc is restricted to the A8 cells. However, PVF1/PVR signaling influences A8, A9 and A10 cells, suggesting that the PVF1 protein diffuses from its source. Flies hemizygous for the apoptotic genes hid, reaper and grim, or mutant for puckered which encodes a phosphatase that down-regulates the n-Jun-N terminal kinase pathway, lead to the same phenotypes as mutations in PVF1/PVR. Our results indicate that PVF1/PVR signaling functions not only in apoptotic phenomena but are also required during rotation and dorsal closure of the Drosophila male genital disc.