Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion

Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients

Identification of a Chlamydomonas plastidial 2-lysophosphatidic acid acyltransferase and its use to engineer microalgae with increased oil content

Despite a strong interest in microalgal oil production, our understanding of the biosynthetic pathways that produce algal lipids and the genes involved in the biosynthetic processes remains incomplete. Here, we report that Chlamydomonas reinhardtii Cre09.g398289 encodes a plastid-targeted 2-lysophosphatidic acid acyltransferase (CrLPAAT1) that acylates the sn-2 position of a 2-lysophosphatidic acid to form phosphatidic acid, the first common precursor of membrane and storage lipids. In vitro enzyme assays showed that CrLPAAT1 prefers 16:0-CoA to 18:1-CoA as an acyl donor. Fluorescent protein-tagged CrLPAAT1 was localized to the plastid membrane in C.reinhardtii cells. Furthermore, expression of CrLPAAT1 in plastids led to a>20% increase in oil content under nitrogen-deficient conditions. Taken together, these results demonstrate that CrLPAAT1 is an authentic plastid-targeted LPAAT in C.reinhardtii, and that it may be used as a molecular tool to genetically increase oil content in microalgae.11114Nsciescopu

A novel micropump droplet generator for aerosol drug delivery: Design simulations

One challenge of generating a liquid aerosol is finding an efficient way to break up bulk amounts of the compound into micron-sized droplets. Traditional methods of aerosol generation focus on the principle of creating the liquid droplets by blowing air at high speed over or through a liquid. In this study, a novel micropump droplet generator (MDG) is proposed based on a microfluidics device to produce monodisperse droplets on demand (DoD). The micropump design was employed to both pump the fluid into the air and to encourage droplet breakup and aerosol formation. Computational simulation modeling of the new MDG was developed and validated with comparisons to experimental data for current generators. The device was found to produce an aerosol similar to a vibrating orifice DoD device. Most importantly, the input power required by the newly proposed device (MDG) was several orders of magnitude below existing DoD generators for a similar droplet output. Based on the simulation results obtained in comparison with current DoD generators, the MDG device performed effectively at higher frequencies, smaller nozzle diameters, and regardless of the liquid viscosity of the solution

Structure and properties of (1-x)(0.6Pb(Zn1/3Nb 2/3)O3-0.4Pb (Mg1/3Nb2/3)O 3)-xPbTiO3 thin films with perovskite phase promoted by polyethylene glycol

10.1007/s10971-007-0744-6Journal of Sol-Gel Science and Technology423357-364JSGT