Loss of the Wnt/β-catenin pathway in microglia of the developing brain drives pro-inflammatory activation leading to white matter injury

Microglia-mediated neuroinflammation is key in numerous brain diseases including encephalopathy of the preterm born infant. Microglia of the still-developing brain have unique properties but little is known of how they regulate their inflammatory activation. This is important information as every year 9 million preterm born infants acquire persisting neurological injuries associated with encephalopathy and we lack strategies to prevent and treat these injuries. Our study of activation state regulators in immature brain microglia found a robust down-regulation of Wnt/β-catenin pathway receptors, ligands and intracellular signalling members in pro-inflammatory microglia. We undertook our studies initially in a mouse model of microglia-mediated encephalopathy including the clinical hallmarks of oligodendrocyte injury and hypomyelination. We purified microglia from this model and applied a genome-wide transcriptomics analysis validated with quantitative profiling. We then verified that down-regulation of the Wnt/β-catenin signalling cascade is sufficient and necessary to drive microglia into an oligodendrocyte-damaging phenotype using multiple pharmacological and genetic approaches in vitro and in vivo in mice and in humans and zebrafish. We also demonstrated that genomic variance in the WNT/β-catenin pathway is associated with the anatomical connectivity phenotype of the human preterm born infant. This integrated analysis of genomics and connectivity, as a surrogate for oligodendrocyte function/myelination, is agnostic to cell type. However, this data indicates that the WNT pathway is relevant to human brain injury and specifically that WNT variants may be useful clinically for injury stratification and prognosis. Finally, we performed a translational experiment using a BBB penetrant microglia-specific targeting 3DNA nanocarrier to deliver a Wnt agonist specifically and directly to microglia in vivo. Increasing the activity of the Wnt/β-catenin pathway specifically in microglia in our model of microglia-mediated encephalopathy was able to reduce microglial pro-inflammatory activation, prevent the typical hypomyelination and also prevent the long-term memory deficit associated with this hypomyelination. In summary, the canonical Wnt/β-catenin pathway regulates microglial activation and up-regulation of this pathway could be a viable neurotherapeutic strategy

Ribonucleotide reductase regulation in response to genotoxic stress in Arabidopsis.

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Body mass index and B-lines on lung ultrasonography in chronic and acute heart failure

Aims Increased body mass index (BMI) is common in heart failure (HF) patients and is associated with lower levels of N‐terminal pro‐brain natriuretic peptide (NT‐proBNP). We evaluated the influence of BMI on lung ultrasonography (LUS) findings indicative of pulmonary congestion (i.e. B‐lines) in patients with chronic and acute HF (AHF). Methods and results We analysed ambulatory chronic HF (n = 118) and hospitalized AHF (n = 177) patients (mean age 70 years, 64% men, mean BMI 29 kg/m2, mean ejection fraction 42%) undergoing echocardiography and LUS in eight chest zones. B‐lines and chest wall thickness (skin to pleura) on ultrasound were quantified offline and blinded to clinical findings. NT‐proBNP was available in AHF patients (n = 167). In chronic HF, B‐line number decreased by 18% per 5 unit increase in BMI [95% confidence interval (CI) −35% to +5%, P = 0.11]. In AHF, the number of B‐lines decreased by 12% per 5 unit increase in BMI (95% CI −19% to −5%, P = 0.001), whereas NT‐proBNP concentration decreased by 28% per 5 unit increase in BMI (95% CI −40% to −16%, P 6 B‐lines were observed in half of AHF patients with severe obesity. There was an inverse relationship between B‐line number and chest wall thickness, and this association varied by chest region. Conclusions Despite an inverse relationship between B‐lines and BMI, B‐lines declined to a lesser degree than NT‐proBNP with increasing BMI. These data suggest that LUS may be useful in patients with HF despite obesity