In vitro and ex vivo effect of hyaluronic acid on erythrocyte flow properties

<p>Abstract</p> <p>Background</p> <p>Hyaluronic acid (HA) is present in many tissues; its presence in serum may be related to certain inflammatory conditions, tissue damage, sepsis, liver malfunction and some malignancies. In the present work, our goal was to investigate the significance of hyaluronic acid effect on erythrocyte flow properties. Therefore we performed <it>in vitro </it>experiments incubating red blood cells (RBCs) with several HA concentrations. Afterwards, in order to corroborate the pathophysiological significance of the results obtained, we replicated the <it>in vitro </it>experiment with <it>ex vivo </it>RBCs from diagnosed rheumatoid arthritis (RA) patients, a serum HA-increasing pathology.</p> <p>Methods</p> <p>Erythrocyte deformability (by filtration through nucleopore membranes) and erythrocyte aggregability (EA) were tested on blood from healthy donors additioned with purified HA. EA was measured by transmitted light and analyzed with a mathematical model yielding two parameters, the aggregation rate and the size of the aggregates. Conformational changes of cytoskeleton proteins were estimated by electron paramagnetic resonance spectroscopy (EPR).</p> <p>Results</p> <p><it>In vitro</it>, erythrocytes treated with HA showed increased rigidity index (RI) and reduced aggregability, situation strongly related to the rigidization of the membrane cytoskeleton triggered by HA, as shown by EPR results. Also, a significant correlation (r: 0.77, p < 0.00001) was found between RI and serum HA in RA patients.</p> <p>Conclusions</p> <p>Our results lead us to postulate the hypothesis that HA interacts with the erythrocyte surface leading to modifications in erythrocyte rheological and flow properties, both <it>ex vivo </it>and <it>in vitro</it>.</p

Structural characterization of copper(II) binding to α-Synuclein: Insights into the bioinorganic chemistry of Parkinson's disease

The aggregation of α -synuclein (AS) is characteristic of Parkinson’s disease and other neurodegenerative synucleinopathies. We demonstrate here that Cu(II) ions are effective in accelerating AS aggregation at physiologically relevant concentrations without altering the resultant fibrillar structures. By using numerous spectroscopic techniques (absorption, CD, EPR, and NMR), we have located the primary binding for Cu(II) to a specific site in the N terminus, involving His-50 as the anchoring residue and other nitrogen oxygen donor atoms in a square planar or distorted tetragonal geometry. The carboxylate-rich C terminus, originally thought to drive copper binding, is able to coordinate a second Cu(II) equivalent, albeit with a 300-fold reduced affinity. The NMR analysis of AS–Cu(II) complexes reveals the existence of conformational restrictions in the native state of the protein. The metallobiology of Cu(II) in Parkinson’s disease is discussed by a comparative analysis with other Cu(II)-binding proteins involved in neurodegenerative disorders

Evolution and role of mergers in the BCG-cluster alignment. A view from cosmological hydrosimulations

Contradictory results have been reported on the time evolution of the alignment between clusters and their brightest cluster galaxy (BCG).We study this topic by analysing cosmological hydrosimulations of 24 massive clusters with M200|z=0 ≥ 1015M⊙, plus 5 less massive with 1 × 1014 ≤ M200|z=0≤ 7 × 1014M⊙, which have already proven to produce realistic BCG masses.We compute the BCG alignment with both the distribution of cluster galaxies and the dark matter (DM) halo. At redshift z = 0, the major axes of the simulated BCGs and their host cluster galaxy distributions are aligned on average within 20?. The BCG alignment with the DM halo is even tighter. The alignment persists up to z ≤ 2 with no evident evolution. This result continues, although with a weaker signal, when considering the projected alignment. The cluster alignment with the surrounding distribution of matter (3R200) is already in place at z ~ 4 with a typical angle of 35?, before the BCG-cluster alignment develops. The BCG turns out to be also aligned with the same matter distribution, albeit always to a lesser extent. These results taken together might imply that the BCG-cluster alignment occurs in an outside-in fashion. Depending on their frequency and geometry, mergers can promote, destroy or weaken the alignments. Clusters that do not experience recent majormergers are typically more relaxed and aligned with their BCG. In turn, accretions closer to the cluster elongation axis tend to improve the alignment as opposed to accretions closer to the cluster minor axis.Fil: Ragone Figueroa, Cinthia Judith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Astronomía Teórica y Experimental. Universidad Nacional de Córdoba. Observatorio Astronómico de Córdoba. Instituto de Astronomía Teórica y Experimental; ArgentinaFil: Granato, Gian Luigi. Istituto Nazionale di Astrofisica; ItaliaFil: Borgani, S.. Istituto Nazionale di Astrofisica; ItaliaFil: De Propris, R.. University of Turku; FinlandiaFil: Garcia Lambas, Diego Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Astronomía Teórica y Experimental. Universidad Nacional de Córdoba. Observatorio Astronómico de Córdoba. Instituto de Astronomía Teórica y Experimental; ArgentinaFil: Murante, G.. Istituto Nazionale di Astrofisica; ItaliaFil: Rasia, E.. Istituto Nazionale di Astrofisica; ItaliaFil: West, M.. Lowell Observatory; Estados Unido

The three hundred project. A machine learning method to infer clusters of galaxy mass radial profiles from mock Sunyaev–Zel’dovich maps

We develop a machine learning algorithm to infer the three-dimensional cumulative radial profiles of total and gas masses in galaxy clusters from thermal Sunyaev–Zel’dovich effect maps. We generate around 73 000 mock images along various lines of sight using 2522 simulated clusters from THE THREE HUNDRED project at redshift z &lt; 0.12 and train a model that combines an auto-encoder and a random forest. Without making any prior assumptions about the hydrostatic equilibrium of the clusters, the model is capable of reconstructing the total mass profile as well as the gas mass profile, which is responsible for the Sunyaev–Zel’dovich effect. We show that the recovered profiles are unbiased with a scatter of about 10 per cent, slightly increasing towards the core and the outskirts of the cluster. We selected clusters in the mass range of 1013.5 ≤ M200/(h−1 M) ≤ 1015.5, spanning different dynamical states, from relaxed to disturbed haloes. We verify that both the accuracy and precision of this method show a slight dependence on the dynamical state, but not on the cluster mass. To further verify the consistency of our model, we fit the inferred total mass profiles with a Navarro–Frenk–White model and contrast the concentration values with those of the true profiles. We note that the inferred profiles are unbiased for higher concentration values, reproducing a trustworthy mass–concentration relation. The comparison with a widely used mass estimation technique, such as hydrostatic equilibrium, demonstrates that our method recovers the total mass that is not biased by non-thermal motions of the gas

Iron in x-cop: Tracing enrichment in cluster outskirts with high accuracy abundance profiles

We present the first metal abundance profiles for a representative sample of massive clusters. Our measurements extend to R500 and are corrected for a systematic error plaguing previous outskirt estimates. Our profiles flatten out at large radii, admittedly not a new result, however the radial range and representative nature of our sample extends its import well beyond previous findings. We find no evidence of segregation between cool-core and non-cool-core systems beyond 3c0.3\ue2 R500, implying that, as was found for thermodynamic properties, the physical state of the core does not affect global cluster properties. Our mean abundance within R500 shows a very modest scatter, < 15%, suggesting the enrichment process must be quite similar in all these massive systems. This is a new finding and has significant implications for feedback processes. Together with results from the thermodynamic properties presented in a previous X-COP paper, it affords a coherent picture in which feedback effects do not vary significantly from one system to another. By combining intra-cluster medium with stellar measurements we have found the amount of Fe diffused in the intra-cluster medium to be about ten times higher than that locked in stars. Although our estimates suggest, with some strength, that the measured iron mass in clusters is well in excess of the predicted one, systematic errors prevent us from making a definitive statement. Further advancements will only be possible when systematic uncertainties, principally those associated with stellar masses, both within and beyond R500, can be reduced

Substructure of the galaxy clusters in the REXCESS sample: observed statistics and comparison to numerical simulations

We study the substructure statistics of a representative sample of galaxy clusters by means of two currently popular substructure characterisation methods, power ratios and centroid shifts. We use the 31 clusters from the REXCESS sample, compiled from the southern ROSAT All-Sky cluster survey REFLEX with a morphologically unbiased selection in X-ray luminosity and redshift, all of which have been reobserved with XMM-Newton. We investigate the uncertainties of the substructure parameters and examine the dependence of the results on projection effects, finding that the uncertainties of the parameters can be quite substantial. Thus while the quantification of the dynamical state of individual clusters with these parameters should be treated with extreme caution, these substructure measures provide powerful statistical tools to characterise trends of properties in large cluster samples. The centre shift parameter, w, is found to be more sensitive in general. For the REXCESS sample neither the occurence of substructure nor the presence of cool cores depends on cluster mass. There is a significant anti-correlation between the existence of substantial substructure and cool cores. The simulated clusters show on average larger substructure parameters than the observed clusters, a trend that is traced to the fact that cool regions are more pronounced in the simulated clusters, leading to stronger substructure measures in merging clusters and clusters with offset cores. Moreover, the frequency of cool regions is higher in the simulations than in the observations, implying that the description of the physical processes shaping cluster formation in the simulations requires further improvement.Comment: Mauscript submitted to Astronomy and Astrophysics, 20 figure

The MUSIC of CLASH: predictions on the concentration-mass relation

We present the results of a numerical study based on the analysis of the MUSIC-2 simulations, aimed at estimating the expected concentration-mass relation for the CLASH cluster sample. We study nearly 1400 halos simulated at high spatial and mass resolution, which were projected along many lines-of-sight each. We study the shape of both their density and surface-density profiles and fit them with a variety of radial functions, including the Navarro-Frenk-White, the generalised Navarro-Frenk-White, and the Einasto density profiles. We derive concentrations and masses from these fits and investigate their distributions as a function of redshift and halo relaxation. We use the X-ray image simulator X-MAS to produce simulated Chandra observations of the halos and we use them to identify objects resembling the X-ray morphologies and masses of the clusters in the CLASH X-ray selected sample. We also derive a concentration-mass relation for strong-lensing clusters. We find that the sample of simulated halos which resemble the X-ray morphology of the CLASH clusters is composed mainly by relaxed halos, but it also contains a significant fraction of un-relaxed systems. For such a sample we measure an average 2D concentration which is ~11% higher than found for the full sample of simulated halos. After accounting for projection and selection effects, the average NFW concentrations of CLASH clusters are expected to be intermediate between those predicted in 3D for relaxed and super-relaxed halos. Matching the simulations to the individual CLASH clusters on the basis of the X-ray morphology, we expect that the NFW concentrations recovered from the lensing analysis of the CLASH clusters are in the range [3-6], with an average value of 3.87 and a standard deviation of 0.61. Simulated halos with X-ray morphologies similar to those of the CLASH clusters are affected by a modest orientation bias.Comment: 21 pages, 16 figures, 3 tables, submitted to Ap

Structural variability of E. coli thioredoxin captured in the crystal structures of single-point mutants

Thioredoxin is a ubiquitous small protein that catalyzes redox reactions of protein thiols. Additionally, thioredoxin from E. coli (EcTRX) is a widely-used model for structure-function studies. In a previous paper, we characterized several single-point mutants of the C-terminal helix (CTH) that alter global stability of EcTRX. However, spectroscopic signatures and enzymatic activity for some of these mutants were found essentially unaffected. A comprehensive structural characterization at the atomic level of these near-invariant mutants can provide detailed information about structural variability of EcTRX. We address this point through the determination of the crystal structures of four point-mutants, whose mutations occurs within or near the CTH, namely L94A, E101G, N106A and L107A. These structures are mostly unaffected compared with the wild-type variant. Notably, the E101G mutant presents a large region with two alternative traces for the backbone of the same chain. It represents a significant shift in backbone positions. Enzymatic activity measurements and conformational dynamics studies monitored by NMR and molecular dynamic simulations show that E101G mutation results in a small effect in the structural features of the protein. We hypothesize that these alternative conformations represent samples of the native-state ensemble of EcTRX, specifically the magnitude and location of conformational heterogeneity

Tracing cosmic evolution with clusters of galaxies

The most successful cosmological models to date envision structure formation as a hierarchical process in which gravity is constantly drawing lumps of matter together to form increasingly larger structures. Clusters of galaxies currently sit atop this hierarchy as the largest objects that have had time to collapse under the influence of their own gravity. Thus, their appearance on the cosmic scene is also relatively recent. Two features of clusters make them uniquely useful tracers of cosmic evolution. First, clusters are the biggest things whose masses we can reliably measure because they are the largest objects to have undergone gravitational relaxation and entered into virial equilibrium. Mass measurements of nearby clusters can therefore be used to determine the amount of structure in the universe on scales of 10^14 to 10^15 solar masses, and comparisons of the present-day cluster mass distribution with the mass distribution at earlier times can be used to measure the rate of structure formation, placing important constraints on cosmological models. Second, clusters are essentially ``closed boxes'' that retain all their gaseous matter, despite the enormous energy input associated with supernovae and active galactic nuclei, because the gravitational potential wells of clusters are so deep. The baryonic component of clusters therefore contains a wealth of information about the processes associated with galaxy formation, including the efficiency with which baryons are converted into stars and the effects of the resulting feedback processes on galaxy formation. This article reviews our theoretical understanding of both the dark-matter component and the baryonic component of clusters. (Abridged)Comment: 54 pages, 15 figures, Rev. Mod. Phys. (in press