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Discovering some of the impact of the hidden curriculum (HC) while doing a postgraduate diploma in pediatric palliative care (PPC) in South Africa (SA), six graduates reflected on their formal and informal learning. To navigate the HC the transformative learning theory is used as a bridge connecting the formal and informal learning between interprofessional education where diversity is an enabler to enhance learning outcomes and shift perspectives to enhance patient care. The graduates were guided through the stages of the competency model to reflect on their learning experience. The authors believe that the experiential lessons reflected on, both clinical and psychosocial, can assist with not only strengthening the particular multidisciplinary needs of students, but also to align the HC and formal curricula. These lessons can also aid toward upscaling the need for PPC education in the SA context.
Assuntos
Currículo , Educação de Pós-Graduação em Medicina , Cuidados Paliativos , Pediatria , Humanos , África do Sul , Pediatria/educação , Masculino , Feminino , Competência Clínica , AdultoRESUMO
Recent studies have implicated impaired Parvalbumin Fast-Spiking Interneuron (PVIN) function as a precipitating factor underlying abnormalities in network synchrony, oscillatory rhythms, and cognition associated with Alzheimer's disease (AD). However, a complete developmental investigation of potential gamma deficits, induced by commonly used carbachol or kainate in ex vivo slice preparations, within AD model mice is lacking. We examined gamma oscillations using field recordings in acute hippocampal slices from 5xFAD and control mice, through the period of developing pathology, starting at 3 months of age, when there is minimal plaque presence in the hippocampus, through to 12+ months of age, when plaque burden is high. In addition, we examined PVIN participation in gamma rhythms using targeted cell-attached recordings of genetically-reported PVINs, in both wild type and mutant mice. In parallel, a developmental immunohistochemical characterisation probing the PVIN-associated expression of PV and perineuronal nets (PNNs) was compared between control and 5xFAD mice. Remarkably, this comprehensive longitudinal evaluation failed to reveal any obvious correlations between PVIN deficits (electrical and molecular), circuit rhythmogenesis (gamma frequency and power), and Aß deposits/plaque formation. By 6-12 months, 5xFAD animals have extensive plaque formation throughout the hippocampus. However, a deficit in gamma oscillatory power was only evident in the oldest 5xFAD animals (12+ months), and only when using kainate, and not carbachol, to induce the oscillations. We found no difference in PV firing or phase preference during kainate-induced oscillations in younger or older 5xFAD mice compared to control, and a reduction of PV and PNNs only in the oldest 5xFAD mice. The lack of a clear relationship between PVIN function, network rhythmicity, and plaque formation in our study highlights an unexpected resilience in PVIN function in the face of extensive plaque pathology associated with this model, calling into question the presumptive link between PVIN pathology and Alzheimer's progression.
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Medulloblastoma is the most common pediatric brain cancer, and sequencing studies identified frequent mutations in DDX3X, a DEAD-box RNA helicase primarily implicated in translation. Forty-two different sites were identified, suggesting that the functional effects of the mutations are complex. To investigate how these mutations are affecting DDX3X cellular function, we constructed a full set of equivalent mutant alleles in DED1, the Saccharomyces cerevisiae ortholog of DDX3X, and characterized their effects in vivo and in vitro. Most of the medulloblastoma-associated mutants in DDX3X/DED1 (ded1-mam) showed substantial growth defects, indicating that functional effects are conserved in yeast. Further, while translation was affected in some mutants, translation defects affecting bulk mRNA were neither consistent nor correlated with the growth phenotypes. Likewise, increased formation of stress granules in ded1-mam mutants was common but did not correspond to the severity of the mutants' growth defects. In contrast, defects in translating mRNAs containing secondary structure in their 5' untranslated regions (UTRs) were found in almost all ded1-mam mutants and correlated well with growth phenotypes. We thus conclude that these specific translation defects, rather than generalized effects on translation, are responsible for the observed cellular phenotypes and likely contribute to DDX3X-mutant medulloblastoma. Examination of ATPase activity and RNA binding of recombinant mutant proteins also did not reveal a consistent defect, indicating that the translation defects are derived from multiple enzymatic deficiencies. This work suggests that future studies into medulloblastoma pathology should focus on this specific translation defect, while taking into account the wide spectrum of DDX3X mutations.
Assuntos
Neoplasias Cerebelares/genética , RNA Helicases DEAD-box/genética , Meduloblastoma/genética , Biossíntese de Proteínas , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Regiões 5' não Traduzidas , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Substituição de Aminoácidos , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Sequência Conservada , RNA Helicases DEAD-box/metabolismo , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Mutagênese Sítio-Dirigida , Mutação , Fenótipo , Ligação Proteica , RNA/genética , RNA/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteína Vermelha FluorescenteRESUMO
BACKGROUND: Late preterm infants, previously considered low risk, have been identified to be at risk of developmental problems in infancy and early childhood. There is limited information on the outcome of these infants in low and middle income countries. METHODS: Bayley scales of infant and toddler development, version III, were done on a group of late preterm infants in Johannesburg, South Africa. The mean composite cognitive, language and motor sub-scales were compared to those obtained from a group of typically developed control infants. Infants were considered to be "at risk" if the composite subscale score was below 85 and "disabled" if the composite subscale score was below 70. Infants identified with cerebral palsy were also reported. RESULTS: 56 of 73 (76.7%) late preterm infants enrolled in the study had at least one Bayley assessment at a mean age of 16.5 months (95% CI 15.2-17.6). The mean birth weight was 1.9 kg (95%CI 1.8-2.0) and mean gestational age 33.0 weeks (95% CI 32.56-33.51). There was no difference in the mean cognitive subscales between late preterm infants and controls (95.4 9, 95% CI 91.2-99.5 vs 91.9.95% CI 87.7-96.0). There was similarly no difference in mean language subscales (94.5, 95% CI 91.3-97.7 vs 95.9, 95% CI 92.9-99.0) or motor subscales (96.2, 95% CI 91.8-100.7 vs 97.6, 95% CI 94.7-100.5). There were four late preterm infants who were classified as disabled, two of whom had cerebral palsy. None of the control group was disabled. CONCLUSIONS: This study demonstrates that overall developmental outcome, as assessed by the Bayley scales of infant and toddler development, was not different between late preterm infants and a group of normal controls. However, 7.1% of the late preterm infants, had evidence of developmental disability. Thus late preterm infants in low and middle income countries require long term follow up to monitor developmental outcome. In a resource limited setting, this may best be achieved by including a parental screening questionnaire, such as the Ages and Stages Questionnaire, in the routine well baby clinic visits.
Assuntos
Deficiências do Desenvolvimento/diagnóstico , Disfunção Cognitiva/diagnóstico , Feminino , Seguimentos , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Masculino , Transtornos Motores/diagnóstico , Estudos Prospectivos , Fatores de Risco , África do SulRESUMO
DEAD-box proteins (DBPs) are required in gene expression to facilitate changes to ribonucleoprotein complexes, but the cellular mechanisms and regulation of DBPs are not fully defined. Gle1 is a multifunctional regulator of DBPs with roles in mRNA export and translation. In translation, Gle1 modulates Ded1, a DBP required for initiation. However, DED1 overexpression causes defects, suggesting that Ded1 can promote or repress translation in different contexts. Here we show that GLE1 expression suppresses the repressive effects of DED1 in vivo and Gle1 counteracts Ded1 in translation assays in vitro Furthermore, both Ded1 and Gle1 affect the assembly of preinitiation complexes. Through mutation analysis and binding assays, we show that Gle1 inhibits Ded1 by reducing its affinity for RNA. Our results are consistent with a model wherein active Ded1 promotes translation but inactive or excess Ded1 leads to translation repression. Gle1 can inhibit either role of Ded1, positioning it as a gatekeeper to optimize Ded1 activity to the appropriate level for translation. This study suggests a paradigm for finely controlling the activity of DEAD-box proteins to optimize their function in RNA-based processes. It also positions the versatile regulator Gle1 as a potential node for the coordination of different steps of gene expression.