Hyaluronic acid combined with mannitol to improve protection against free-radical endothelial damage: Experimental Model

Purpose: To evaluate the protective properties of combined sodium hyaluronate2% and mannitol 0.5% (Visiol) on the corneal endothelium in the presence of oxidative stress induced by hydrogen peroxide (H2O2). Setting: Instituto Oftalmolo´ gico de Alicante, Universidad Miguel Herna´ ndez, Alicante, Spain. Methods: This was an exploratory randomized controlled parallel-group, maskedassessor study of 3 sodium hyaluronate-based ophthalmic viscosurgical devices (OVDs): Visiol, Healon (sodium hyaluronate 1%), and Viscoat (sodium hyaluronate 3%–chondroitin sodium 4%). The OVDs were tested for protective effects on the endothelium following oxidative stress induced by H2O2 at increased concentrations: control (lactated Ringer’s solution), 1mM, 10mM, and 100 mM. Groups without OVD were used as controls at the same concentrations of peroxide. Each animal received the same treatment in both eyes (10 eyes per group). Endothelial cell lesion was assessed using the Janus green photometry absorbance technique. Results: At 10 mM peroxide concentration, the value of endothelial cell lesion was significantly lower in the Visiol (16.8%, P Z .0056), Healon (22.2%, P Z .0302), and Viscoat (21.6%, PZ .0336) groups than in the control group (29.4%, no OVD). There was a trend in favor of Visiol to more efficiently reduce cell lesions of the endothelium, than Healon (PZ .055) and Viscoat (P Z .1013). Values of endothelial cell lesion at peroxide concentrations of 1 mM and 100 mM showed the same trends than those observed at 10 mM. Conclusions: All of the OVDs tested efficiently reduced endothelial lesions against free radicals compared with the control group in which no OVD was used. The following sequence for the efficacy of endothelial cell protection was established: Visiol O Viscoat O Healon O no OVD

Increased plasma levels of NT-proBNP, Troponin T and GDF-15 are driven by persistent AF and associated comorbidities:Data from the AF-RISK study

Atrial fibrillation (AF) is a progressive disease, and early recognition and management may reflect an important strategy to reduce its disease burden. In this study, we evaluated plasma levels of three biomarkers - N-terminal pro-brain natriuretic peptide (NTproBNP), Troponin-T, and growth differentiation factor-15 (GDF-15) - in patients with paroxysmal AF (pAF) (≤7 days of continuous AF, n = 323) and persistent AF ((AF duration &gt; 7 days and &lt; 1 year, n = 84) using patients from AF RISK study (NCT01510210). In this AF-RISK sub-study, patients with persistent AF experienced more symptoms (higher European Heart Rhythm Association class (p &lt; 0.001)), had a higher comorbidity burden (p &lt; 0.001), and had more unfavorable echocardiographic parameters (p &lt; 0.001). All three biomarker levels were significantly higher in patients with persistent AF as compared to those with pAF (p &lt; 0.001). Multivariate linear regression analyses showed that age (beta-coefficient for NTproBNP: 0.21; GDF-15: 0.41; Troponin-T: 0.23) and CHA2DS2-VASc (beta-coefficient for NTproBNP: 0.20; GDF-15: 0.25; Troponin-T: 0.27) were determinants of all three biomarkers, and that persistent AF determined NTproBNP (beta-coefficient: 0.34), but not Troponin-T and GDF-15. More detailed analysis of CHA2DS2-VASc score showed that for all three biomarkers age, coronary artery disease and heart failure were determinants of plasma biomarkers levels, whereas sex determined NTproBNP and Troponin T, and hypertension determined NTproBNP and GDF15. Overall, this study therefore suggests that in AF, Troponin T and GDF15, and especially NTproBNP could be used to detect those patients with more persistent form of AF that may warrant more aggressive treatment of AF and concomitant comorbidities. Future studies, however, are essential to evaluate if more aggressive AF treatment and risk factor management will reduce disease progression and holds a novel therapeutic intervention to reduce the burden of AF.</p

GW150914: First search for the electromagnetic counterpart of a gravitational-wave event by the TOROS collaboration

We present the results of the optical follow-up conducted by the TOROS collaboration of the first gravitational-wave event GW150914. We conducted unfiltered CCD observations (0.35-1 micron) with the 1.5-m telescope at Bosque Alegre starting ~2.5 days after the alarm. Given our limited field of view (~100 square arcmin), we targeted 14 nearby galaxies that were observable from the site and were located within the area of higher localization probability. We analyzed the observations using two independent implementations of difference-imaging algorithms, followed by a Random-Forest-based algorithm to discriminate between real and bogus transients. We did not find any bona fide transient event in the surveyed area down to a 5-sigma limiting magnitude of r=21.7 mag (AB). Our result is consistent with the LIGO detection of a binary black hole merger, for which no electromagnetic counterparts are expected, and with the expected rates of other astrophysical transients.Comment: ApJ Letters, in pres

Genetic Risk and Atrial Fibrillation in Patients with Heart Failure

Aims: To study the association between an atrial fibrillation (AF) genetic risk score with prevalent AF and all-cause mortality in patients with heart failure. Methods and results: An AF genetic risk score was calculated in 3759 European ancestry individuals (1783 with sinus rhythm, 1976 with AF) from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) by summing 97 single nucleotide polymorphism (SNP) alleles (ranging from 0–2) weighted by the natural logarithm of the relative SNP risk from the latest AF genome-wide association study. Further, we assessed AF risk variance explained by additive SNP variation, and performance of clinical or genetic risk factors, and the combination in classifying AF prevalence. AF was classified as AF or atrial flutter (AFL) at baseline electrocardiogram and/or a history of AF or AFL. The genetic risk score was associated with AF after multivariable adjustment. Odds ratio for AF prevalence per 1-unit increase genetic risk score was 2.12 (95% confidence interval 1.84–2.45, P = 2.15 × 10−24) in the total cohort, 2.08 (1.72–2.50, P = 1.30 × 10−14) in heart failure with reduced ejection fraction (HFrEF) and 2.02 (1.37–2.99, P = 4.37 × 10−4) in heart failure with preserved ejection fraction (HFpEF). AF-associated loci explained 22.9% of overall AF SNP heritability. Addition of the genetic risk score to clinical risk factors increased the C-index by 2.2% to 0.721. Conclusions: The AF genetic risk score was associated with increased AF prevalence in HFrEF and HFpEF. Genetic variation accounted for 22.9% of overall AF SNP heritability. Addition of genetic risk to clinical risk improved model performance in classifying AF prevalence

Quantitative phase microscopy enables precise and efficient determination of biomolecular condensate composition

Many compartments in eukaryotic cells are protein-rich biomolecular condensates demixed from the cyto- or nucleoplasm. Although much has been learned in recent years about the integral roles condensates play in many cellular processes as well as the biophysical properties of reconstituted condensates, an understanding of their most basic feature, their composition, remains elusive. Here we combined quantitative phase microscopy (QPM) and the physics of sessile droplets to develop a precise method to measure the shape and composition of individual model condensates. This technique does not rely on fluorescent dyes or tags, which we show can significantly alter protein phase behavior, and requires 1000-fold less material than traditional label-free technologies. We further show that this QPM method measures the protein concentration in condensates to a 3-fold higher precision than the next best label-free approach, and that commonly employed strategies based on fluorescence intensity dramatically underestimate these concentrations by as much as 50-fold. Interestingly, we find that condensed-phase protein concentrations can span a broad range, with PGL3, TAF15(RBD) and FUS condensates falling between 80 and 500 mg/ml under typical in vitro conditions. This points to a natural diversity in condensate composition specified by protein sequence. We were also able to measure temperature-dependent phase equilibria with QPM, an essential step towards relating phase behavior to the underlying physics and chemistry. Finally, time-resolved QPM reveals that PGL3 condensates undergo a contraction-like process during aging which leads to doubling of the internal protein concentration coupled to condensate shrinkage. We anticipate that this new approach will enable understanding the physical properties of biomolecular condensates and their function

Simulations of COMPASS vertical displacement events with a self-consistent model for halo currents including neutrals and sheath boundary conditions

The understanding of the halo current properties during disruptions is key to design and operate large scale tokamaks in view of the large thermal and electromagnetic loads that they entail. For the first time, we present a fully self-consistent model for halo current simulations including neutral particles and sheath boundary conditions. The model is used to simulate vertical displacement events (VDEs) occurring in the COMPASS tokamak. Recent COMPASS experiments have shown that the parallel halo current density at the plasma-wall interface is limited by the ion saturation current during VDE-induced disruptions. We show that usual magneto-hydrodynamic boundary conditions can lead to the violation of this physical limit and we implement this current density limitation through a boundary condition for the electrostatic potential. Sheath boundary conditions for the density, the heat flux, the parallel velocity and a realistic parameter choice (e.g. Spitzer's resistivity and Spitzer-Harm parallel thermal conductivity) extend present VDE simulations beyond the state of the art. Experimental measurements of the current density, temperature and heat flux profiles at the COMPASS divertor are compared with the results obtained from axisymmetric simulations. Since the ion saturation current density (Jsat) is shown to be essential to determine the halo current profile, parametric scans are performed to study its dependence on different quantities such as the plasma resistivity and the particle and heat diffusion coefficients. In this respect, the plasma resistivity in the halo region broadens significantly the Jsat profile, increasing the halo width at a similar total halo current

Synthetic inhibitors of bacterial cell division targeting the GTP-binding site of FtsZ

Cell division protein FtsZ is the organizer of the cytokinetic Z-ring in most bacteria and a target for new antibiotics. FtsZ assembles with GTP into filaments that hydrolyze the nucleotide at the association interface between monomers and then disassemble. We have replaced FtsZ's GTP with non-nucleotide synthetic inhibitors of bacterial division. We searched for these small molecules among compounds from the literature, from virtual screening (VS), and from our in-house synthetic library (UCM), employing a fluorescence anisotropy primary assay. From these screens we have identified the polyhydroxy aromatic compound UCM05 and its simplified analogue UCM44 that specifically bind to Bacillus subtilis FtsZ monomers with micromolar affinities and perturb normal assembly, as examined with light scattering, polymer sedimentation, and negative stain electron microscopy. On the other hand, these ligands induce the cooperative assembly of nucleotide-devoid archaeal FtsZ into distinct well-ordered polymers, different from GTP-induced filaments. These FtsZ inhibitors impair localization of FtsZ into the Z-ring and inhibit bacterial cell division. The chlorinated analogue UCM53 inhibits the growth of clinical isolates of antibiotic-resistant Staphylococcus aureus and Enterococcus faecalis. We suggest that these interfacial inhibitors recapitulate binding and some assembly-inducing effects of GTP but impair the correct structural dynamics of FtsZ filaments and thus inhibit bacterial division, possibly by binding to a small fraction of the FtsZ molecules in a bacterial cell, which opens a new approach to FtsZ-based antibacterial drug discovery.This work was supported by grants from Plan Nacional de Investigación BFU 2011-23416 (J.M.A.), BFU2099-09552 (P.C.), and SAF2010-22198 (M.L.L.-R.), grant CM S2010/BMD-2353 (M.L.L.-R, P.C., J.M.A.), and fellowships FPI (L.B.R.-A.), FPU (M.A.) and CSIC-JAE (E.R.-A.)