Epigenetic repression of Wnt receptors in AD: a role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters

Growing evidence supports a role for deficient Wnt signalling in Alzheimer’s disease (AD). First, the Wnt antagonist DKK1 is elevated in AD brains and is required for amyloid-β-induced synapse loss. Second, LRP6 Wnt co-receptor is required for synapse integrity and three variants of this receptor are linked to late-onset AD. However, the expression/role of other Wnt signalling components remain poorly explored in AD. Wnt receptors Frizzled1 (Fzd1), Fzd5, Fzd7 and Fzd9 are of interest due to their role in synapse formation/plasticity. Our analyses showed reduced FZD1 and FZD7 mRNA levels in the hippocampus of human early AD stages and in the hAPPNLGF/NLGF mouse model. This transcriptional downregulation was accompanied by reduced levels of the pro-transcriptional histone mark H4K16ac and a concomitant increase of its deacetylase Sirt2 at Fzd1 and Fzd7 promoters in AD. In vitro and in vivo inhibition of Sirt2 rescued Fzd1 and Fzd7 mRNA expression and H4K16ac levels at their promoters. In addition, we showed that Sirt2 recruitment to Fzd1 and Fzd7 promoters is dependent on FoxO1 activity in AD, thus acting as a co-repressor. Finally, we found reduced levels of SIRT2 inhibitory phosphorylation in nuclear samples from human early AD stages with a concomitant increase in the SIRT2 phosphatase PP2C. This results in hyperactive nuclear Sirt2 and favours Fzd1 and Fzd7 repression in AD. Collectively, our findings define a novel role for nuclear hyperactivated SIRT2 in repressing Fzd1 and Fzd7 expression via H4K16ac deacetylation in AD. We propose SIRT2 as an attractive target to ameliorate AD pathology

Brain 3T magnetic resonance imaging in neonates:features and incidental findings from a research cohort enriched for preterm birth

BACKGROUND AND OBJECTIVES: The survival rate and patterns of brain injury after very preterm birth are evolving with changes in clinical practices. Additionally, incidental findings can present legal, ethical and practical considerations. Here, we report MRI features and incidental findings from a large, contemporary research cohort of very preterm infants and term controls.METHODS: 288 infants had 3T MRI at term-equivalent age: 187 infants born &lt;32 weeks without major parenchymal lesions, and 101 term-born controls. T1-weighted, T2-weighted and susceptibility-weighted imaging were used to classify white and grey matter injury according to a structured system, and incidental findings described.RESULTS: Preterm infants: 34 (18%) had white matter injury and 4 (2%) had grey matter injury. 51 (27%) infants had evidence of intracranial haemorrhage and 34 (18%) had punctate white matter lesions (PWMLs). Incidental findings were detected in 12 (6%) preterm infants. Term infants: no term infants had white or grey matter injury. Incidental findings were detected in 35 (35%); these included intracranial haemorrhage in 22 (22%), periventricular pseudocysts in 5 (5%) and PWMLs in 4 (4%) infants. From the whole cohort, 10 (3%) infants required referral to specialist services. CONCLUSIONS: One-fifth of very preterm infants without major parenchymal lesions have white or grey matter abnormalities at term-equivalent age. Incidental findings are seen in 6% of preterm and 35% of term infants. Overall, 3% of infants undergoing MRI for research require follow-up due to incidental findings. These data should help inform consent procedures for research and assist service planning for centres using 3T neonatal brain MRI for clinical purposes.</p

Feature similarity gradients detect alterations in the neonatal cortex associated with preterm birth

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multi-modal MRI and is unbound by arbitrary parcellations has proven elusive, which hampers efforts to uncover the perinatal origins of cortical health. Here, we use the Vogt-Bailey index to provide a fine-grained description of regional homogeneities and sharp variations in cortical microstructure based on feature gradients, and we investigate the impact of being born preterm on cortical development at term-equivalent age. Compared to term-born controls, preterm infants have a homogeneous microstructure in temporal and occipital lobes, and the medial parietal, cingulate, and frontal cortices, compared with term infants. These observations replicated across two independent datasets and were robust to differences that remain in the data after matching samples and alignment of processing and quality control strategies. We conclude that cortical microstructural architecture is altered in preterm infants in a spatially distributed rather than localised fashion.Keywords: feature similarity gradients, neonatal brain, preterm birth, MRI, neonatal corte

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion