The Brain Epigenome Goes Drunk: Alcohol Consumption Alters Histone Acetylation and Transcriptome.

Recent studies demonstrated that alcohol consumption can induce epigenetic changes in the brain, although the exact mechanism underlying such changes remained unclear. Now, a report by Mews et al. shows a direct link between alcohol consumption and histone acetylation changes in the brain, which are mediated by the neuronal acetyl-CoA synthase, ACSS2.

Risk Factors of Serious Bacterial Infection in Previously Healthy Children Older Than 90 Days Old With Fever and Neutropenia.

BACKGROUND: The main objective was to determine the clinical or analytical factors that independently predict risk of serious bacterial infection (RSBI) in immunocompetent patients older than 90 days given a diagnosis of fever and for whom neutropenia was an incidental finding. The secondary objective was to describe the prevalence of serious bacterial infections (SBIs). METHODS: This is a 3-year-long, multicenter, prospective analytical and observational study carried out at 6 pediatric emergency departments. Data for epidemiological, clinical, and analytical variables were collected. RESULTS: One hundred forty patients with febrile neutropenia (60.7% mild, 39.3% moderate to severe) were recruited. Serious bacterial infection incidence was 15.0% (95% confidence interval [CI], 9-21): 1 Invasive Bacterial Infection (Staphylococcus epidermidis bacteremia), 10 urinary tract infections, 8 pneumonias, and 2 cellulitis. Median total neutrophil counts per microliter showed no statistically significant differences (P = 0.512; 1000 [750-1200] in SBI patients vs 1100 [800-1300] in non-SBI patients). Higher RSBI was observed in patients with neutrophils less than 20% relative to total leukocytes (SBI, 15, 26.3%) than in those with neutrophils of 20% or greater (SBI, 6, 7.2%) (odds ratio, 4.6; 95% CI, 1.7-12.7). In patients with greater than 5000 leukocytes/µL, a percentage of neutrophils less than 20% was related to a greater RSBI with a trend toward statistical significance (odds ratio, 6.1; 95% CI, 0.7-51.1; P = 0.066). The clinical variables did not show a significant association with RSBI. CONCLUSIONS: None of the clinical or analytical variables assessed were associated with the RSBI. However, according to a post hoc analysis, in patients with greater than 5000 leukocytes/µL, a neutrophil percentage less than 20% could be an independent risk factor for SBI. A thorough physical examination and basic diagnostic tests (urinalysis and chest x-ray) may help to establish a diagnosis of SBI in the vast majority of cases.

Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse.

Suitable animal models are essential for translational research, especially in the case of complex, multifactorial conditions, such as obesity. The non-inbred mouse (Mus musculus) line Titan, also known as DU6, is one of the world's longest selection experiments for high body mass and was previously described as a model for metabolic healthy (benign) obesity. The present study further characterizes the geno- and phenotypes of this non-inbred mouse line and tests its suitability as an interventional obesity model. In contrast to previous findings, our data suggest that Titan mice are metabolically unhealthy obese and short-lived. Line-specific patterns of genetic invariability are in accordance with observed phenotypic traits. Titan mice also show modifications in the liver transcriptome, proteome, and epigenome linked to metabolic (dys)regulations. Importantly, dietary intervention partially reversed the metabolic phenotype in Titan mice and significantly extended their life expectancy. Therefore, the Titan mouse line is a valuable resource for translational and interventional obesity research.

The role of lipids in aging-related metabolic changes.

Fat is historically associated with poor health and obesity. However, the continuous use of lipidomics and genetic studies in model organisms revealed that specific lipid profiles and signals might delay aging. In order to identify and quantify the lipid species, researchers are taking advantage of the recent developments in the area of lipidomics that is mainly done by mass spectrometry and further techniques, such as NMR spectroscopy and chromatographic separations. This review will emphasize the role of lipid composition and metabolism during aging. We review the molecular and physiological changes during the progression of aging with a special focus on the role of lipids. Interventions to modulate life span in a variety of organisms such caloric restriction, show a significant extension of their maximum life-span and a decrease in the onset of age-related diseases. In particular, the influence of dietary restriction in lipid metabolism will be a major point of this review.

Telomerase Is Essential for Zebrafish Heart Regeneration.

After myocardial infarction in humans, lost cardiomyocytes are replaced by an irreversible fibrotic scar. In contrast, zebrafish hearts efficiently regenerate after injury. Complete regeneration of the zebrafish heart is driven by the strong proliferation response of its cardiomyocytes to injury. Here we show that, after cardiac injury in zebrafish, telomerase becomes hyperactivated, and telomeres elongate transiently, preceding a peak of cardiomyocyte proliferation and full organ recovery. Using a telomerase-mutant zebrafish model, we found that telomerase loss drastically decreases cardiomyocyte proliferation and fibrotic tissue regression after cryoinjury and that cardiac function does not recover. The impaired cardiomyocyte proliferation response is accompanied by the absence of cardiomyocytes with long telomeres and an increased proportion of cardiomyocytes showing DNA damage and senescence characteristics. These findings demonstrate the importance of telomerase function in heart regeneration and highlight the potential of telomerase therapy as a means of stimulating cell proliferation upon myocardial infarction.

Genetic inactivation of dopamine D1 but not D2 receptors inhibits L-DOPA-induced dyskinesia and histone activation.

BACKGROUND: Pharmacologic studies have implicated dopamine D1-like receptors in the development of dopamine precursor molecule 3,4-dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesias and associated molecular changes in hemiparkinsonian mice. However, pharmacologic agents for D1 or D2 receptors also recognize other receptor family members. Genetic inactivation of the dopamine D1 or D2 receptor was used to define the involvement of these receptor subtypes. METHODS: During a 3-week period of daily L-DOPA treatment (25 mg/kg), mice were examined for development of contralateral turning behavior and dyskinesias. L-DOPA-induced changes in expression of signaling molecules and other proteins in the lesioned striatum were examined immunohistochemically. RESULTS: Chronic L-DOPA treatment gradually induced rotational behavior and dyskinesia in wildtype hemiparkinsonian mice. Dyskinetic symptoms were associated with increased FosB and dynorphin expression, phosphorylation of extracellular signal-regulated kinase, and phosphoacetylation of histone 3 (H3) in the lesioned striatum. These molecular changes were restricted to striatal areas with complete dopaminergic denervation and occurred only in dynorphin-containing neurons of the direct pathway. D1 receptor inactivation abolished L-DOPA-induced dyskinesias and associated molecular changes. Inactivation of the D2 receptor had no significant effect on the behavioral or molecular response to chronic L-DOPA. CONCLUSIONS: Our results demonstrate that the dopamine D1 receptor is critical for the development of L-DOPA-induced dyskinesias in mice and in the underlying molecular changes in the denervated striatum and that the D2 receptor has little or no involvement. In addition, we demonstrate that H3 phosphoacetylation is blocked by D1 receptor inactivation, suggesting that inhibitors of H3 acetylation and/or phosphorylation may be useful in preventing or reversing dyskinesia.