Glucocorticoids promote structural and functional maturation of foetal cardiomyocytes: a role for PGC-1α

Glucocorticoid levels rise dramatically in late gestation to mature foetal organs in readiness for postnatal life. Immature heart function may compromise survival. Cardiomyocyte glucocorticoid receptor (GR) is required for the structural and functional maturation of the foetal heart in vivo, yet the molecular mechanisms are largely unknown. Here we asked if GR activation in foetal cardiomyocytes in vitro elicits similar maturational changes. We show that physiologically relevant glucocorticoid levels improve contractility of primary-mouse-foetal cardiomyocytes, promote Z-disc assembly and the appearance of mature myofibrils, and increase mitochondrial activity. Genes induced in vitro mimic those induced in vivo and include PGC-1α, a critical regulator of cardiac mitochondrial capacity. SiRNA-mediated abrogation of the glucocorticoid induction of PGC-1α in vitro abolished the effect of glucocorticoid on myofibril structure and mitochondrial oxygen consumption. Using RNA sequencing we identified a number of transcriptional regulators, including PGC-1α, induced as primary targets of GR in foetal cardiomyocytes. These data demonstrate that PGC-1α is a key mediator of glucocorticoid-induced maturation of foetal cardiomyocyte structure and identify other candidate transcriptional regulators that may play critical roles in the transition of the foetal to neonatal heart

Hereditary breast cancer in Middle Eastern and North African (MENA) populations: identification of novel, recurrent and founder BRCA1 mutations in the Tunisian population

Germ-line mutations in BRCA1 breast cancer susceptibility gene account for a large proportion of hereditary breast cancer families and show considerable ethnic and geographical variations. The contribution of BRCA1 mutations to hereditary breast cancer has not yet been thoroughly investigated in Middle Eastern and North African populations. In this study, 16 Tunisian high-risk breast cancer families were screened for germline mutations in the entire BRCA1 coding region and exon–intron boundaries using direct sequencing. Six families were found to carry BRCA1 mutations with a prevalence of 37.5%. Four different deleterious mutations were detected. Three truncating mutations were previously described: c.798_799delTT (916 delTT), c.3331_3334delCAAG (3450 delCAAG), c.5266dupC (5382 insC) and one splice site mutation which seems to be specific to the Tunisian population: c.212 + 2insG (IVS5 + 2insG). We also identified 15 variants of unknown clinical significance. The c.798_799delTT mutation occurred at an 18% frequency and was shared by three apparently unrelated families. Analyzing five microsatellite markers in and flanking the BRCA1 locus showed a common haplotype associated with this mutation. This suggests that the c.798_799delTT mutation is a Tunisian founder mutation. Our findings indicate that the Tunisian population has a spectrum of prevalent BRCA1 mutations, some of which appear as recurrent and founding mutations

Pore-scale simulations of gas displacing liquid in a homogeneous pore network using the lattice Boltzmann method

A lattice Boltzmann high-density-ratio model, which uses diffuse interface theory to describe the interfacial dynamics and was proposed originally by Lee and Liu (J Comput Phys 229:8045–8063, 2010), is extended to simulate immiscible multiphase flows in porous media. A wetting boundary treatment is proposed for concave and convex corners. The capability and accuracy of this model is first validated by simulations of equilibrium contact angle, injection of a non-wetting gas into two parallel capillary tubes, and dynamic capillary intrusion. The model is then used to simulate gas displacement of liquid in a homogenous two-dimensional pore network consisting of uniformly spaced square obstructions. The influence of capillary number (Ca), viscosity ratio ( M M ), surface wettability, and Bond number (Bo) is studied systematically. In the drainage displacement, we have identified three different regimes, namely stable displacement, capillary fingering, and viscous fingering, all of which are strongly dependent upon the capillary number, viscosity ratio, and Bond number. Gas saturation generally increases with an increase in capillary number at breakthrough, whereas a slight decrease occurs when Ca is increased from 8.66×10−4 8.66 × 10 - 4 to 4.33×10−3 4.33 × 10 - 3 , which is associated with the viscous instability at high Ca. Increasing the viscosity ratio can enhance stability during displacement, leading to an increase in gas saturation. In the two-dimensional phase diagram, our results show that the viscous fingering regime occupies a zone markedly different from those obtained in previous numerical and experimental studies. When the surface wettability is taken into account, the residual liquid blob decreases in size with the affinity of the displacing gas to the solid surface. Increasing Bo can increase the gas saturation, and stable displacement is observed for Bo >1 because the applied gravity has a stabilizing influence on the drainage process