Selective agonists of estrogen receptor isoforms : new perspectives for cardiovascular disease

The cloning of estrogen receptors (ERs) and generation of ER-deficient mice have increased our understanding of the molecular mechanisms underlying the cardiovascular effects of estrogen. It is conceivable that clinical trials of estrogens so far failed to improve cardiovascular health because of the poor ER isoform selectivity and tissue specificity of endogenous hormones as well as incorrect treatment timing and regimens. Tissue-selective ER modulators (SERMs) may be safer agents than endogenous estrogens for cardiovascular disease. Yet, designing isoform-selective ER ligands (I-SERMs) with agonist or antagonist activity is required to pursue improved pharmacological control of ERs, especially taking into account emerging evidence for the beneficial role of vascular ER alpha activation. Ideally, the quest for unique ER ligands targeted to the vascular wall should lead to compounds that merge the pharmacological profiles of SERM and I-SERM agents. This review highlights the current bases for and approaches to selective ER modulation in the cardiovascular system

Acetyl Phosphate as a Primordial Energy Currency at the Origin of Life

Metabolism is primed through the formation of thioesters via acetyl CoA and the phosphorylation of substrates by ATP. Prebiotic equivalents such as methyl thioacetate and acetyl phosphate have been proposed to catalyse analogous reactions at the origin of life, but their propensity to hydrolyse challenges this view. Here we show that acetyl phosphate (AcP) can be synthesised in water within minutes from thioacetate (but not methyl thioacetate) under ambient conditions. AcP is stable over hours, depending on temperature, pH and cation content, giving it an ideal poise between stability and reactivity. We show that AcP can phosphorylate nucleotide precursors such as ribose to ribose-5-phosphate and adenosine to adenosine monophosphate, at modest (~2%) yield in water, and at a range of pH. AcP can also phosphorylate ADP to ATP in water over several hours at 50 °C. But AcP did not promote polymerization of either glycine or AMP. The amino group of glycine was preferentially acetylated by AcP, especially at alkaline pH, hindering the formation of polypeptides. AMP formed small stacks of up to 7 monomers, but these did not polymerise in the presence of AcP in aqueous solution. We conclude that AcP can phosphorylate biologically meaningful substrates in a manner analogous to ATP, promoting the origins of metabolism, but is unlikely to have driven polymerization of macromolecules such as polypeptides or RNA in free solution. This is consistent with the idea that a period of monomer (cofactor) catalysis preceded the emergence of polymeric enzymes or ribozymes at the origin of life

Expression analysis of HLA-E and NKG2A and NKG2C receptors points at a role for natural killer function in ankylosing spondylitis

Background. Ankylosing Spondylitis (AS) is a complex chronic inflammatory disease strongly associated with the majority of HLA-B27 alleles. HLA-E are non-classical MHC class I molecules that specifically interact with the natural killer receptors NKG2A (inhibitory) and NKG2C (activating), and have been recently proposed to be involved in AS pathogenesis. Objectives: To analyze the expression of HLA-E and the CD94/NKG2 pair of receptors in HLA-B27 positive AS patients and healthy controls (HC) bearing the AS-associated, B*2705 and the non-AS-associated, B*2709 allele. Methods: The level of surface expression of HLA-E molecules on CD14 positive peripheral blood mononuclear cell was evaluated in 21 HLA-B*2705 patients with AS, 12 HLA-B*2705 HC, 12 HLA-B*2709 HC and 6 HLA-B27 negative HC, using the monoclonal antibody MEM-E/08 by quantitative cytofluorimetric analysis. The percentage and density of expression of HLA-E ligands NKG2A and NKG2C were also measured on CD3-CD56+ NK cells. Results. HLA-E expression in CD14 positive cells was significantly higher in AS patients (587.0 IQR 424-830) compared to B*2705 HC (389 IQR 251.3-440.5, p=0.0007), B*2709 HC (294.5 IQR 209.5-422, p=0.0004) and HLA-B27 negative HC (380 IQR 197.3-515.0, p=0.01). A higher number of NK cells expressing NKG2A compared to NKG2C was found in all cohort analysed as well as a higher cell surface density. Conclusion: The higher surface level of HLA-E molecules in AS patients compared to HC, concurrently with a prevalent expression of NKG2A, suggests that the crosstalk between these two molecules might play a role in AS pathogenesis accounting for the previously reported association between HLA-E and AS

Phase shifts of synchronized oscillators and the systolic/diastolic blood pressure relation

We study the phase-synchronization properties of systolic and diastolic arterial pressure in healthy subjects. We find that delays in the oscillatory components of the time series depend on the frequency bands that are considered, in particular we find a change of sign in the phase shift going from the Very Low Frequency band to the High Frequency band. This behavior should reflect a collective behavior of a system of nonlinear interacting elementary oscillators. We prove that some models describing such systems, e.g. the Winfree and the Kuramoto models offer a clue to this phenomenon. For these theoretical models there is a linear relationship between phase shifts and the difference of natural frequencies of oscillators and a change of sign in the phase shift naturally emerges.Comment: 8 figures, 9 page

High Contrast Imaging in the Visible: First Experimental Results at the Large Binocular Telescope

In February 2014, the SHARK-VIS (System for High contrast And coronography from R to K at VISual bands) Forerunner, a high contrast experimental imager operating at visible wavelengths, was installed at LBT (Large Binocular Telescope). Here we report on the first results obtained by recent on-sky tests. These results show the extremely good performance of the LBT ExAO (Extreme Adaptive Optics) system at visible wavelengths, both in terms of spatial resolution and contrast achieved. Similarly to what was done by (Amara et al. 2012), we used the SHARK-VIS Forerunner data to quantitatively assess the contrast enhancement. This is done by injecting several different synthetic faint objects in the acquired data and applying the ADI (angular differential imaging) technique. A contrast of the order of $5 \times 10^{-5}$ is obtained at 630 nm for angular separations from the star larger than 100 mas. These results are discussed in light of the future development of SHARK-VIS and compared to those obtained by other high contrast imagers operating at similar wavelengths.Comment: Astronomical Journal - Accepted for publicatio

Tools to discriminate between targets of CK2 vs PLK2/PLK3 acidophilic kinases

While the great majority of Ser/Thr protein kinases are basophilic or proline directed, a tiny minority is acidophilic. The most striking example of such "acidophilic" kinases is CK2, whose sites are specified by numerous acidic residues surrounding the target one. However PLK2 and PLK3 kinases recognize an acidic consensus similar to CK2 when tested on peptide libraries. Here we describe optimal buffer conditions for PLK2 and 3 kinase activity assays and tools such as using GTP as a phosphate donor and the specific inhibitors CX-4945 and BI 2536, useful to discriminate between acidic phosphosites generated either by CK2 or by PLK2/PLK

Fabrication of nanoporous al by vapor-phase dealloying: Morphology features, mechanical properties and model predictions

The physical and chemical properties shown by nanoporous metals, related to their unique structure, make them very promising for application in several fields. Recently, vapor-phase dealloying has been reported as a method for the preparation of several non-noble nanoporous metals, alternatively to dealloying in aqueous solutions. Using this approach, we have successfully fabricated nanoporous Al starting from an Al20Zn80 nanocomposite obtained by ball milling. The nanocomposite was annealed at 550◦C under high-vacuum conditions, and the difference in the vapor pressures allowed the selective removal of Zn by vapor-phase dealloying. The morphology of the resulting nanoporous material was analyzed by Scanning Electron Microscopy showing pores from few to thousands of nm; moreover, the nanoporous 3D structure was observed through Serial Block Face-Scanning Electron Microscopy. A specific surface area as high as 73 m2 g−1 was estimated by N2 physisorption measurements. In addition, a fractal model able to well reproduce the morphology of nanoporous Al was built. This model has been used for predicting mechanical properties which are in good agreement with experimental data obtained by nanoindentation

Study of macular and optic disk blood flow by angio‐OCT in Glucose‐6‐Phosphate Dehydrogenase (G6PD) deficient men and age‐related G6PD‐normal subjects

Purpose: The reported prevalence of Glucose‐6‐Phosphate Dehydrogenase (G6PD) deficiency in Sardina, Italy, ranges from 8% to 15%. Hemizygous males have totally deficient erythrocytes. Evidence indicates that patients with G6PD deficiency are protected against ischemic heart and cerebrovascular disease, colorectal cancer, retinal vein occlusion, and nonarteritic anterior ischemic optic neuropathy. The purpose of this study was to study the macular and optic disk blood flow by angio‐OCT in G6PD‐deficient men and age‐related G6PD‐normal subjects and ascertain whether, or not, there are statistically significant differences between the two groups Methods: 22 G6PD‐deficient men and 22 perfectly age‐matched G6PD‐normal controls were examined at the Ophthalmology Unit, University of Sassari, Sassari, Italy. A complete review of the medical history and a complete ophthalmological examination, including ETDRS best corrected visual acuity, slit‐lamp biomicroscopy of the anterior segment, applanation tonometry, and fundus examination, was carried out. An HD 6‐mm Angio‐Retina and a 4.5‐mm Angio Disk (RT‐Vue, Optovue XR‐100 with Angio Vue, CA) examination were also performed Results: Only 1 eye per patients was included in the analysis, for a total of 22 eyes in each group. All the exported parameters about retinal and disk flow were evaluated. No statistical differences between the two groups were found, even after controlling for the effects of age, hypertension and hypercholesterolemia (p = 0.9). Conclusions: Results suggest that G6PD‐deficient and G6PD‐normal men have similar macular and optic disk blood flow. Larger scale studies are necessary to confirm these findings