Cerebral Small Vessel Disease: Targeting Oxidative Stress as a Novel Therapeutic Strategy?

Cerebral small vessel disease (SVD) is a major contributor to stroke, and a leading cause of cognitive impairment and dementia. Despite the devastating effects of cerebral SVD, the pathogenesis of cerebral SVD is still not completely understood. Moreover, there are no specific pharmacological strategies for its prevention or treatment. Cerebral SVD is characterized by marked functional and structural abnormalities of the cerebral microcirculation. The clinical manifestations of these pathological changes include lacunar infarcts, white matter hyperintensities, and cerebral microbleeds. The main purpose of this review is to discuss evidence implicating oxidative stress in the ateriopathy of both non-amyloid and amyloid (cerebral amyloid angiopathy) forms of cerebral SVD and its most important risk factors (hypertension and aging), as well as its contribution to cerebral SVD-related brain injury and cognitive impairment. We also highlight current evidence of the involvement of the NADPH oxidases in the development of oxidative stress, enzymes that are a major source of reactive oxygen species in the cerebral vasculature. Lastly, we discuss potential pharmacological strategies for oxidative stress in cerebral SVD, including some of the historical and emerging NADPH oxidase inhibitors

Pricing European Options with a Log Student's t-Distribution: a Gosset Formula

The distribution of the returns for a stock are not well described by a normal probability density function (pdf). Student's t-distributions, which have fat tails, are known to fit the distributions of the returns. We present pricing of European call or put options using a log Student's t-distribution, which we call a Gosset approach in honour of W.S. Gosset, the author behind the nom de plume Student. The approach that we present can be used to price European options using other distributions and yields the Black-Scholes formula for returns described by a normal pdf.Comment: 12 journal pages, 9 figures and 3 tables (Submitted to Physica A

Nox2 Oxidase Activity Accounts for the Oxidative Stress and Vasomotor Dysfunction in Mouse Cerebral Arteries following Ischemic Stroke

Background and Purpose: Post-ischemic oxidative stress and vasomotor dysfunction in cerebral arteries may increase the likelihood of cognitive impairment and secondary stroke. However, the underlying mechanisms of post-stroke vascular abnormalities, as distinct from those causing primary brain injury, are poorly understood. We tested whether augmented superoxide-dependent dysfunction occurs in the mouse cerebral circulation following ischemia-reperfusion, and evaluated the role of Nox2 oxidase. Methods: Cerebral ischemia was induced in male C57Bl6/J wild-type (WT) and Nox2-deficient (Nox2 -/-) mice by middle cerebral artery occlusion (MCAO; 0.5 h), followed by reperfusion (23.5 h). Superoxide production by MCA was measured by L-012-enhanced chemiluminescence. Nitric oxide (NO) function was assessed in cannulated and pressurized MCA via the vasoconstrictor response to N ω-nitro-L-arginine methyl ester (L-NAME; 100 μmol/L). Expression of Nox2, the nitration marker 3-nitrotyrosine, and leukocyte marker CD45 was assessed in cerebral arteries by Western blotting. Results: Following ischemia-reperfusion, superoxide production was markedly increased in the MCA of WT, but not Nox2 -/- mice. In WT mice, L-NAME-induced constriction was reduced by ~50% in ischemic MCA, whereas ischemia-reperfusion had no effect on responses to L-NAME in vessels from Nox2 -/- mice. In ischemic MCA from WT mice, expression of Nox2 and 3-nitrotyrosine were ~1.4-fold higher than in the contralateral MCA, or in ischemic or contralateral vessels from Nox2 -/- mice. Vascular CD45 levels were unchanged by ischemia-reperfusion. Conclusions: Excessive superoxide production, impaired NO function and nitrosative stress occur in mouse cerebral arteries after ischemia-reperfusion. These abnormalities appear to be exclusively due to increased activity of vascular Nox2 oxidase

Crystal structures of two one-dimensional coordination polymers constructed from Mn2+ ions, chelating hexafluoro-acetylacetonate anions, and flexible bipyridyl bridging ligands

Original Russian Text © 2016 M. J. Plater, B. M. De Silva, M. R. St. J. Foreman, W. T. A. Harrison. The text was submitted by the authors in English. Zhurnal Strukturnoi Khimii, Vol. 57, No. 6, pp. 1230-1235, July-August, 2016.Peer reviewedPostprin

The effect of erythrosine-B on the structuration of poloxamer 407 and cellulose derivative blends: in silico modelling supporting experimental studies

© 2021 Elsevier B.V. All rights reserved. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1016/j.msec.2021.112440Erythrosine is a dye approved for medical use that has shown promising photodynamic activity, allowing for the inactivation of microorganisms and activity against malignant cells. Despite the great photodynamic potential, erythrosine exhibits hydrophilicity, negatively impacting its action in biological membranes. Therefore, the incorporation of erythrosine in micellar polymeric systems, such as poloxamers, may overcome this limitation. Moreover, using bioadhesive and thermoresponsive polymers to combine in situ gelation and bioadhesion may enhance retention of this topically applied drug. In this work, mucoadhesive and thermoresponsive micellar systems were prepared containing erythrosine in two states: the native form (ERI) and the disodium salt (ERIs). The systems were evaluated based on the effect of ERI/ERIs on the micellar structure of the binary polymer mixtures. Optimised combinations of poloxamer 407 (polox407) and mucoadhesive sodium carboxymethylcellulose (NaCMC) or hydroxypropyl methylcellulose (HPMC) were used as micellar systems for ERI or ERIs delivery. The systems were studied with respect to theoretical interactions, qualitative composition, morphology, and micellar properties. In silico modelling indicated a higher interaction of the drug with poly(ethylene oxide) (PEO) than poly(propylene oxide) (PPO) fragments of polox407. Systems containing NaCMC displayed a repulsive effect in the presence of erythrosine, due to the polymer's charge density. Both systems could convert the photosensitizer in its monomeric form, ensuring photodynamic activity. In these mixtures, crystallinity, critical micellar temperature and enthalpy of polox407 micellisation were reduced, and micellar size, evaluated by transmission electron microscopy (TEM), showed low impact of ERI/ERIs in HPMC preparations. Aiming toward photodynamic applications, the findings showed how ERI or ERIs can affect the micellar formation of gels composed of 17.5% (w/w) polox407 and 3% (w/w) HPMC or 1% (w/w) NaCMC, important for understating their behaviour and future utilisation as erythrosine delivery systems.Peer reviewe

Evaluating Impacts of Anthropogenic Disturbance to Wetland Water Quality Functions

Wetland ecosystems play fundamental roles in regulating our freshwater resources, yet they are not comprehensively protected from degradation and loss. West Virginia, USA has wetlands across diverse landscapes and geography that feed into both the Chesapeake Bay and Gulf of Mexico. The state is also comprised of diverse anthropogenic land-use practices. We are assessing 200 wetlands over 2 years to evaluate how anthropogenic disturbance impact wetland water quality functions. Select water quality parameters (20), and relative diversity and abundance of vegetation and macroinvertebrates will be used as bioindicators. They will be compared with GIS assessments of watershed land cover/ land-use practices and climate data to evaluate relationships and determine how they impact a wetland’s ability to carry out select water quality functions. Preliminary results after one year of sampling indicate that wetlands at higher elevation with fewer watershed land-use practices generally had lower E. Coli, heavy metal (Lead and Zinc), and nutrient (Phosphorus and Nitrogen) concentrations relative to wetlands at lower elevations with greater watershed land-use practices. Seasonal conductivity readings increased following precipitation events. Conductivity and salinity readings also decreased along its drainage gradient, indicative of the wetland performing its water quality functions. We also observed that conductivity and nutrient concentrations were highest during the winter and lowest during the summer, coinciding with the bottom and peak periods of primary productivity. The results of this project will be used to develop wetland water quality standards for West Virginia and help advance more comprehensive wetland regulations

Ages and Metallicities of Hickson Compact Group Galaxies

Hickson Compact Groups (HCGs) constitute an interesting extreme in the range of environments in which galaxies are located, as the space density of galaxies in these small groups are otherwise only found in the centres of much larger clusters. The work presented here uses Lick indices to make a comparison of ages and chemical compositions of galaxies in HCGs with those in other environments (clusters, loose groups and the field). The metallicity and relative abundance of `$\alpha$-elements' show strong correlations with galaxy age and central velocity dispersion, with similar trends found in all environments. However, we show that the previously reported correlation between $\alpha$-element abundance ratios and velocity dispersion disappears when a full account is taken of the the abundance ratio pattern in the calibration stars. This correlation is thus found to be an artifact of incomplete calibration to the Lick system. Variations are seen in the ranges and average values of age, metallicity and $\alpha$-element abundance ratios for galaxies in different environments. Age distributions support the hierarchical formation prediction that field galaxies are on average younger than their cluster counterparts. However, the ages of HCG galaxies are shown to be more similar to those of cluster galaxies than those in the field, contrary to the expectations of current hierarchical models. A trend for lower velocity dispersion galaxies to be younger was also seen. This is again inconsistent with hierarchical collapse models, but is qualitatively consistent with the latest N-body-SPH models based on monolithic collapse in which star formation continues for many Gyr in low mass halos.Comment: 18 pages. Submitted for publication in MNRA

Sunyaev-Zel'dovich clusters in millennium gas simulations

Large surveys using the Sunyaev–Zel’dovich (SZ) effect to find clusters of galaxies are now starting to yield large numbers of systems out to high redshift, many of which are new dis- coveries. In order to provide theoretical interpretation for the release of the full SZ cluster samples over the next few years, we have exploited the large-volume Millennium gas cosmo- logical N-body hydrodynamics simulations to study the SZ cluster population at low and high redshift, for three models with varying gas physics. We confirm previous results using smaller samplesthattheintrinsic(spherical)Y500–M500relationhasverylittlescatter(σlog10Y ≃0.04), is insensitive to cluster gas physics and evolves to redshift 1 in accordance with self-similar expectations. Our preheating and feedback models predict scaling relations that are in excel- lent agreement with the recent analysis from combined Planck and XMM–Newton data by the Planck Collaboration. This agreement is largely preserved when r500 and M500 are derived using thehydrostaticmassproxy,YX,500,albeitwithsignificantlyreducedscatter(σlog10Y ≃0.02),a result that is due to the tight correlation between Y500 and YX,500. Interestingly, this assumption also hides any bias in the relation due to dynamical activity. We also assess the importance of projection effects from large-scale structure along the line of sight, by extracting cluster Y500 values from 50 simulated 5 × 5-deg2 sky maps. Once the (model-dependent) mean signal is subtracted from the maps we find that the integrated SZ signal is unbiased with respect to the underlying clusters, although the scatter in the (cylindrical) Y500–M500 relation increases in the preheating case, where a significant amount of energy was injected into the intergalactic medium at high redshift. Finally, we study the hot gas pressure profiles to investigate the origin of the SZ signal and find that the largest contribution comes from radii close to r500 in all cases. The profiles themselves are well described by generalized Navarro, Frenk & White profiles but there is significant cluster-to-cluster scatter. In conclusion, our results support the notion that Y500 is a robust mass proxy for use in cosmological analyses with clusters

Benznidazole biotransformation and multiple targets in <i>Trypanosoma</i> cruzi revealed by metabolomics

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; The first line treatment for Chagas disease, a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, involves administration of benznidazole (Bzn). Bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active, although its mode of action is not fully understood. In the present work we used a non-targeted MS-based metabolomics approach to study the metabolic response of T. cruzi to Bzn.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methodology/Principal findings&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Parasites treated with Bzn were minimally altered compared to untreated trypanosomes, although the redox active thiols trypanothione, homotrypanothione and cysteine were significantly diminished in abundance post-treatment. In addition, multiple Bzn-derived metabolites were detected after treatment. These metabolites included reduction products, fragments and covalent adducts of reduced Bzn linked to each of the major low molecular weight thiols: trypanothione, glutathione, γ-glutamylcysteine, glutathionylspermidine, cysteine and ovothiol A. Bzn products known to be generated in vitro by the unusual trypanosomal nitroreductase, TcNTRI, were found within the parasites, but low molecular weight adducts of glyoxal, a proposed toxic end-product of NTRI Bzn metabolism, were not detected.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions/significance&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Our data is indicative of a major role of the thiol binding capacity of Bzn reduction products in the mechanism of Bzn toxicity against T. cruzi

The GALAH survey: accurate radial velocities and library of observed stellar template spectra

GALAH is a large-scale magnitude-limited southern stellar spectroscopic survey. Its second data release (GALAH DR2) provides values of stellar parameters and abundances of 23 elements for 342 682 stars (Buder et al.). Here we add a description of the public release of radial velocities with a typical accuracy of 0.1 km s−1 for 336 215 of these stars, achievable due to the large wavelength coverage, high resolving power, and good signal-to-noise ratio of the observed spectra, but also because convective motions in stellar atmosphere and gravitational redshift from the star to the observer are taken into account. In the process we derive medians of observed spectra that are nearly noiseless, as they are obtained from between 100 and 1116 observed spectra belonging to the same bin with a width of 50 K in temperature, 0.2 dex in gravity, and 0.1 dex in metallicity. Publicly released 1181 median spectra have a resolving power of 28 000 and trace the well-populated stellar types with metallicities between −0.6 and +0.3. Note that radial velocities from GALAH are an excellent match to the accuracy of velocity components along the sky plane derived by Gaia for the same stars. The level of accuracy achieved here is adequate for studies of dynamics within stellar clusters, associations, and streams in the Galaxy. So it may be relevant for studies of the distribution of dark matter.TZ, GT, and KC acknowledge financial support of ˇ the Slovenian Research Agency (research core funding No. P1-0188 and project N1-0040). TZ acknowledges the grant from the distinguished visitor programme of the RSAA at the Australian National University. JK is supported by a Discovery Project grant from the Australian Research Council (DP150104667) awarded to J. BlandHawthorn and T. Bedding. ARC acknowledges support through the Australian Research Council through grant DP160100637. LD, KF, and Y-ST are grateful for support from Australian Research Council grant DP160103747. SLM acknowledges support from the Australian Research Council through grant DE140100598. LC is the recipient of an ARC Future Fellowship (project number FT160100402). Parts of this research were conducted by the Australian Research Council Centre of Excellence for All Sky Astrophysics in 3 Dimensions (ASTRO 3D), through project number CE17010001