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Early-life metabolic stress has been demonstrated to affect brain development, persistently influence brain plasticity and to exert multigenerational effects on cognitive functions. However, the impact of an ancestor's diet on the adult neurogenesis of their descendants has not yet been investigated. Here, we studied the effects of maternal high fat diet (HFD) on hippocampal adult neurogenesis and the proliferation of neural stem and progenitor cells (NSPCs) derived from the hippocampus of both the second and the third generations of progeny (F2HFD and F3HFD). Maternal HFD caused a multigenerational depletion of neurogenic niche in F2HFD and F3HFD mice. Moreover, NSPCs derived from HFD descendants showed altered expression of genes regulating stem cell proliferation and neurodifferentiation (i.e., Hes1, NeuroD1, Bdnf). Finally, ancestor HFD-related hyper-activation of both STAT3 and STAT5 induced enhancement of their binding on the regulatory sequences of Gfap gene and an epigenetic switch from permissive to repressive chromatin on the promoter of the NeuroD1 gene. Collectively, our data indicate that maternal HFD multigenerationally affects hippocampal adult neurogenesis via an epigenetic derangement of pro-neurogenic gene expression in NSPCs. [ABSTRACT FROM AUTHOR]

Metabolic dysregulation harms brain health. Early-life (pre- and perinatal) dysmetabolic stimuli have been demonstrated to affect central nervous system (CNS), multigenerationally impairing brain plasticity and cognitive functions in adult offsprings. In our previous work, we reported that maternal high fat diet (HFD) impaired synaptic plasticity, learning and memory of descendants until the third generation. Neural stem and progenitor cells (NSPCs) represent the cellular source of newborn neurons in the subgranular zone of the hippocampus, and their fate is finely modulated by metabolic signals. Epigenetic mechanisms are key factors controlling the neural fate of NSPCs and they dynamically regulate CNS development and adult neurogenesis. Here, we demonstrate that progenitor HFD altered both the proliferation of NSPCs and the hippocampal adult neurogenesis on second and third generations of progeny (F2HFD and F3HFD), leading to the depletion of neurogenic niche in the descendants. Moreover, in NSPCs isolated from the hippocampus of HFD descendants we found reduced expression of genes regulating stem cell proliferation and neuro-differentiation (i.e., Hes1, NeuroD1, Bdnf). Furthermore, maternal HFD-related metabolic stress induced a rearrangement of STAT3/5 transcription factors occurring on the regulatory sequences of NeuroD1 and Gfap genes, causing the epigenetic repression of pro-neurogenic and the activation of pro-glial differentiation genes. Collectively, our data indicate that maternal HFD multigenerationally impairs hippocampal neural stem cell niche via epigenetic inhibition of pro-neurogenic gene expression in NSPCs. [ABSTRACT FROM AUTHOR]

Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading to neurological damage has not been completely elucidated. Innovative strategies of investigation are needed to more precisely define this pathological process. By longitudinal in vivo bioluminescence imaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Luc mouse, in which light emission is restricted to the regions of active cell proliferation. We assessed that acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an increment in the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive for both luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation of microglial cells. In addition, we demonstrated that brain induction of bioluminescence was altered by pharmacological displacement of bilirubin from its albumin binding sites and by modulation of the blood-brain barrier permeability, all pivotal factors in the development of bilirubin-induced neurologic dysfunction. We also determined that treatment with minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascular endothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the study supports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring of drugs aiming at preventing acute bilirubin-induced neurological dysfunction. [ABSTRACT FROM AUTHOR]

The present work aims to identify the predictors of COVID-19 in-hospital mortality testing a set of Machine Learning Techniques (MLTs), comparing their ability to predict the outcome of interest. The model with the best performance will be used to identify in-hospital mortality predictors and to build an in-hospital mortality prediction tool. The study involved patients with COVID-19, proved by PCR test, admitted to the "Ospedali Riuniti Padova Sud" COVID-19 referral center in the Veneto region, Italy. The algorithms considered were the Recursive Partition Tree (RPART), the Support Vector Machine (SVM), the Gradient Boosting Machine (GBM), and Random Forest. The resampled performances were reported for each MLT, considering the sensitivity, specificity, and the Receiving Operative Characteristic (ROC) curve measures. The study enrolled 341 patients. The median age was 74 years, and the male gender was the most prevalent. The Random Forest algorithm outperformed the other MLTs in predicting in-hospital mortality, with a ROC of 0.84 (95% C.I. 0.78–0.9). Age, together with vital signs (oxygen saturation and the quick SOFA) and lab parameters (creatinine, AST, lymphocytes, platelets, and hemoglobin), were found to be the strongest predictors of in-hospital mortality. The present work provides insights for the prediction of in-hospital mortality of COVID-19 patients using a machine-learning algorithm. [ABSTRACT FROM AUTHOR]

Restaurants are regular eating environments for many families. Children's consumption of restaurant foods has been linked with poorer diet quality, prompting emerging research examining strategies to encourage healthier eating among children in restaurants. Although taste is a primary determinant of restaurant meal choices, there is a lack of research considering children's perspectives on the taste of different healthier kids' meal options. The current study sought to examine, via objective taste testing, children's liking of and preference for healthier kids' meal options at a quick-service restaurant (QSR) and to describe bundled kids' meals with evidence of both taste acceptability and consistency with nutrition guidelines. Thirty-seven 4-to-8-year-old children completed taste tests of ten healthier main and side dish options. Liking and preference were assessed using standard methods after children tasted each food. Children also reported their ideal kids' meal. Results show the majority of children liked and preferred three main (turkey sandwich, chicken strips, peanut butter/banana sandwich) and side dishes (yogurt, applesauce, broccoli), with rank order differing slightly by age group. Accepted foods were combined into 11 bundles meeting nutritional criteria. Results highlight healthier kids' meals with evidence of appeal among children in a QSR. Findings can inform future research and may increase the success of healthy eating interventions in these settings. [ABSTRACT FROM AUTHOR]

Overnutrition and metabolic disorders impair cognitive functions through molecular mechanisms still poorly understood. In mice fed with a high fat diet (HFD) we analysed the expression of synaptic plasticity-related genes and the activation of cAMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signalling. We found that a HFD inhibited both CREB phosphorylation and the expression of a set of CREB target genes in the hippocampus. The intranasal administration of neural stem cell (NSC)-derived exosomes (exo-NSC) epigenetically restored the transcription of Bdnf, nNOS, Sirt1, Egr3, and RelA genes by inducing the recruitment of CREB on their regulatory sequences. Finally, exo-NSC administration rescued both BDNF signalling and memory in HFD mice. Collectively, our findings highlight novel mechanisms underlying HFD-related memory impairment and provide evidence of the potential therapeutic effect of exo-NSC against metabolic disease-related cognitive decline.

Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading to neurological damage has not been completely elucidated. Innovative strategies of investigation are needed to more precisely define this pathological process. By longitudinal in vivo bioluminescence imaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Luc mouse, in which light emission is restricted to the regions of active cell proliferation. We assessed that acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an increment in the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive for both luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation of microglial cells. In addition, we demonstrated that brain induction of bioluminescence was altered by pharmacological displacement of bilirubin from its albumin binding sites and by modulation of the blood-brain barrier permeability, all pivotal factors in the development of bilirubin-induced neurologic dysfunction. We also determined that treatment with minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascular endothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the study supports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring of drugs aiming at preventing acute bilirubin-induced neurological dysfunction., Competing Interests: The authors declare no conflict of interest.