Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage.

BACKGROUND: Injury to cells adjacent to an intracerebral hemorrhage (ICH) is likely mediated at least in part by toxins released from the hematoma that initiate complex and interacting injury cascades. Pharmacotherapies targeting a single toxin or pathway, even if consistently effective in controlled experimental models, have a high likelihood of failure in a variable clinical setting. Nuclear factor erythroid-2 related factor 2 (Nrf2) regulates the expression of heme oxygenase-1 (HO-1) and multiple other proteins with antioxidant and antiinflammatory effects, and may be a target of interest after ICH. METHODS: Studies that tested the effect of HO and Nrf2 in models relevant to ICH are summarized, with an effort to reconcile conflicting data by consideration of methodological limitations. RESULTS: In vitro studies demonstrated that Nrf2 activators rapidly increased HO-1 expression in astrocytes, and reduced their vulnerability to hemoglobin or hemin. Modulating HO-1 expression via genetic approaches yielded similar results. Systemic treatment with small molecule Nrf2 activators increased HO-1 expression in perivascular cells, particularly astrocytes. When tested in mouse or rat ICH models, Nrf2 activators were consistently protective, improving barrier function and attenuating edema, inflammation, neuronal loss and neurological deficits. These effects were mimicked by selective astrocyte HO-1 overexpression in transgenic mice. CONCLUSION: Systemic treatment with Nrf2 activators after ICH is protective in rodents. Two compounds, dimethyl fumarate and hemin, are currently approved for treatment of multiple sclerosis and acute porphyria, respectively, and have acceptable safety profiles over years of clinical use. Further development of these drugs as ICH therapeutics seems warranted

Project SLOPE - Study of Lunar Orbiter Photographic Evaluation Final report

Quantitative measurement methods for evaluating ability of Lunar Orbiter photographs to detect topographic feature

Apotransferrin Protects Cortical Neurons from Hemoglobin Toxicity

The protective effect of iron chelators in experimental models of intracerebral hemorrhage suggests that nonheme iron may contribute to injury to perihematomal cells. Therapy with high affinity iron chelators is limited by their toxicity, which may be due in part to sequestration of metals in an inaccessible complex. Transferrin is unique in chelating iron with very high affinity while delivering it to cells as needed via receptor-mediated endocytosis. However, its efficacy against iron-mediated neuronal injury has never been described, and was therefore evaluated in this study using an established cell culture model of hemoglobin neurotoxicity. At concentrations similar to that of CSF transferrin (50-100 micrograms/ml), both iron-saturated holotransferrin and apotransferrin were nontoxic per se. Overnight exposure to 3 μM purified human hemoglobin in serum-free culture medium resulted in death, as measured by lactate dehydrogenase release assay, of about three-quarters of neurons. Significant increases in culture iron, malondialdehyde, protein carbonyls, ferritin and heme oxygenase-1 were also observed. Holotransferrin had no effect on these parameters, but all were attenuated by 50-100 micrograms/ml apotransferrin. The effect of apotransferrin was very similar to that of deferoxamine at a concentration that provided equivalent iron binding capacity, and was not antagonized by concomitant treatment with holotransferrin. Transferrin receptor-1 expression was localized to neurons and was not altered by hemoglobin or transferrin treatment. These results suggest that apotransferrin may mitigate the neurotoxicity of hemoglobin after intracerebral hemorrhage. Increasing its concentration in perihematomal tissue may be beneficial

Effect of Iron Chelators on Methemoglobin and Thrombin Preconditioning.

Cell loss immediately adjacent to an intracerebral hemorrhage may be mediated in part by the toxicities of extracellular hemoglobin (Hb) and thrombin. However, at low concentrations, these proteins induce tolerance to hemin and iron that may limit further peri-hematomal injury as erythrocyte lysis progresses. The mechanisms mediating these preconditioning effects have not been completely defined, but increased expression of both heme oxygenase (HO)-1 and iron binding proteins likely contributes. In the present study, we hypothesized that iron chelator therapy would attenuate this protective response. Pretreatment of cortical glial cultures (\u3e 90 % GFAP+) with 3 μM methemoglobin (metHb) or 5 units/ml thrombin for 24 h was nontoxic per se, and increased HO-1 and ferritin expression. When challenged with a toxic concentration of hemin, the increase in cellular redox-active iron was attenuated in preconditioned cultures and cell survival was increased. However, if cultures were pretreated with metHb or thrombin plus deferoxamine or 2,2\u27-bipyridyl, ferritin induction was prevented and cellular redox-active iron increased with hemin treatment. Preconditioning-mediated cytoprotection was consistently reduced by deferoxamine, while 2,2\u27-bipyridyl had a variable effect. Neither chelator altered HO-1 expression. A cytoprotective response was preserved when chelator therapy was limited to 11 hours of the 24 h preconditioning interval. These results suggest a potentially deleterious effect of continuous iron chelator therapy after ICH. Intermittent therapy may remove peri-hematomal iron without negating the benefits of exposure to low concentrations of Hb or thrombin

Hemin uptake and release by neurons and glia.

Hemin accumulates in intracerebral hematomas and may contribute to cell injury in adjacent tissue. Despite its relevance to hemorrhagic CNS insults, very little is known about hemin trafficking by neural cells. In the present study, hemin uptake and release were quantified in primary murine cortical cultures, and the effect of the hemin-binding compound deferoxamine (DFO) was assessed. Net uptake of (55)Fe-hemin was similar in mixed neuron-glia, neuron, and glia cultures, but was 2.6-3.6-fold greater in microglia cultures. After washout, 40-60% of the isotope signal was released by mixed neuron-glia cultures into albumin-containing medium within 24 h. Inhibiting hemin breakdown with tin protoporphyrin IX (SnPPIX) had minimal effect, while release of the fluorescent hemin analog zinc mesoporphyrin was quantitatively similar to that of (55)Fe-hemin. Isotope was released most rapidly by neurons (52.2 ± 7.2% at 2 h), compared with glia (15.6 ± 1.3%) and microglia (17.6 ± 0.54%). DFO did not alter (55)Fe-hemin uptake, but significantly increased its release. Mixed cultures treated with 10 μM hemin for 24 h sustained widespread neuronal loss that was attenuated by DFO. Concomitant treatment with SnPPIX had no effect on either enhancement of isotope release by DFO or neuroprotection. These results suggest that in the presence of a physiologic albumin concentration, hemin uptake by neural cells is followed by considerable extracellular release. Enhancement of this release by DFO may contribute to its protective effect against hemin toxicity

On the Structure of Style Space for Documents

We identify three aspects of style pertaining to documents. The first of these we call literary style and it includes the word and sentence constructions and choice of illustrations traditionally associated with authorship. The second we call informative style and it includes formatting and iconic choices that convey additional information such as the document\u27s genre or corporate identity. The third aspect of style covers the degrees of freedom remaining for the author and is used to convey the author\u27s intent. Literary style is the realm of academic scholarship and discourse and is beyond the scope of the present article. But corporate and intent style can be quantified by measuring many different attributes. For example, density of text, colorfulness of images, regularity of positioning of images, diversity of font and typeface, all contribute to the document\u27s overall style. Indeed, we have identified more than 150 different value functions, each of which can be measured, and each of which can contribute to a document\u27s overall stylistic appearance. Measurement of these value functions effectively places a document as a point in a style space. But the 150 value functions are not independent. A heuristic approach is described for investigating the possibility of finding basis vectors for intent space

Controlling molecular mobility and ductile–brittle transitions of polycarbonate copolymers

To control molecular mobility and study its effects on mechanical properties, we synthesized two series of poly(ester carbonate) and polycarbonate copolymers with different linkages: (B x t) n ( x = 3, 5, 7, 9) and (B x T) n ( x = 1, 3, 5, 7, 9), where t represents the terephthalate, T represents the tetramethyl bisphenol A carbonate linkages, and B is the conventional bisphenol-A (BPA) carbonate. These two series of materials have distinct differences in their relaxation behaviors and chain mobility, as indicated by the Π-flip motion of the phenylene rings in the B x blocks. Uniaxial tensile tests of the copolymers indicate that the brittle–ductile transition (BDT) temperatures of the copolymers are correlated to whether the Γ-relaxation peaks due to the B x sequence is fully established. The materials possessing more fully established low-temperature Γ peaks give rise to a lower BDT. Also, the locations of the Γ peaks are correlated to the ring flips of the B x blocks of polymer chains. © 2001 John Wiley & Sons, Inc. J Polym Sci Part B: Polym Phys 39: 1730–1740, 2001Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35007/1/1146_ftp.pd

Quantum Mechanics in Space--Time: the Feynman Path Amplitude Description of Physical Optics, de Broglie Matter Waves and Quark and Neutrino Flavour Oscillations

Feynman's laws of quantum dynamics are concisely stated, discussed in comparison with other formulations of quantum mechanics and applied to selected problems in the physical optics of photons and massive particles as well as flavour oscillations. The classical wave theory of light is derived from these laws for the case in which temporal variation of path amplitudes may be neglected, whereas specific experiments, sensitive to the temporal properties of path amplitudes, are suggested. The reflection coefficient of light from the surface of a transparent medium is found to be markedly different to that predicted by the classical Fresnel formula. Except for neutrino oscillations, good agreement is otherwise found with previous calculations of spatially dependent quantum interference effects.Comment: 89 pages, 12 figures, 3 table

Application of activated barrier hopping theory to viscoplastic modeling of glassy polymers

YesAn established statistical mechanical theory of amorphous polymer deformation has been incorporated as a plastic mechanism into a constitutive model and applied to a range of polymer mechanical deformations. The temperature and rate dependence of the tensile yield of PVC, as reported in early studies, has been modeled to high levels of accuracy. Tensile experiments on PET reported here are analyzed similarly and good accuracy is also achieved. The frequently observed increase in the gradient of the plot of yield stress against logarithm of strain rate is an inherent feature of the constitutive model. The form of temperature dependence of the yield that is predicted by the model is found to give an accurate representation. The constitutive model is developed in two-dimensional form and implemented as a user-defined subroutine in the finite element package ABAQUS. This analysis is applied to the tensile experiments on PET, in some of which strain is localized in the form of shear bands and necks. These deformations are modeled with partial success, though adiabatic heating of the instability causes inaccuracies for this isothermal implementation of the model. The plastic mechanism has advantages over the Eyring process, is equally tractable,and presents no particular difficulties in implementation with finite elements.F. Boutenel acknowledges an Erasmus Programme Scholarshi

Anisotropic rate-dependent mechanical behavior of Poly(Lactic Acid) processed by Material Extrusion Additive Manufacturing

The strain-rate dependence of the yield stress for Material Extrusion Additive Manufacturing (ME-AM) polylactide samples was investigated. Apparent densities of the ME-AM processed tensile test specimens were measured and taken into account in order to study the effects of the ME-AM processing step on the material behavior. Three different printing parameters were changed to investigate their influence on mechanical properties, i.e. infill velocity, infill orientation angle, and bed temperature. Additionally, compression molded test samples were manufactured in order to determine bulk properties, which have been compared to the ME-AM sample sets. Anisotropy was detected in the strain-rate dependence of the yield stresses. ME-AM samples with an infill angle of 0° have a higher strain-rate dependence than specimens with αor = 90°. Remarkably, the strain-rate dependence manifested by the ME-AM samples is considerably lower than that displayed by compression molded test specimens. The Ree-Eyring modification of the Eyring flow rule is able to accurately describe the strain-rate dependence of the yield stresses, taking two molecular deformation processes into account to describe the yield kinetics. The results from this paper further show a change from a brittle behavior in case of compression molded samples to a semi-ductile behavior for some of the ME-AM sample sets. This change is attributed to the processing phase and stresses the importance that the temperature profile (initial fast cooling combined with successive heating cycles) and the strain profile during ME-AM processing have on the resulting mechanical properties. Both these profiles are significantly different from the thermo-mechanical history that material elements experience during conventional processing methods, e.g. injection or compression molding. This paper can be seen as initial work that can help to further develop predictive numerical tools for Material Extrusion Additive Manufacturing, as well as for the design of structural components