Theranostic Copolymers Neutralize Reactive Oxygen Species and Lipid Peroxidation Products for the Combined Treatment of Traumatic Brain Injury

Traumatic brain injury (TBI) results in the generation of reactive oxygen species (ROS) and lipid peroxidation product (LPOx), including acrolein and 4-hydroxynonenal (4HNE). The presence of these biochemical derangements results in neurodegeneration during the secondary phase of the injury. The ability to rapidly neutralize multiple species could significantly improve outcomes for TBI patients. However, the difficulty in creating therapies that target multiple biochemical derangements simultaneously has greatly limited therapeutic efficacy. Therefore, our goal was to design a material that could rapidly bind and neutralize both ROS and LPOx following TBI. To do this, a series of thiol-functionalized biocompatible copolymers based on lipoic acid methacrylate and polyethylene glycol monomethyl ether methacrylate (FW ∼950 Da) (O950) were prepared. A polymerizable gadolinium-DOTA methacrylate monomer (Gd-MA) was also synthesized starting from cyclen to facilitate direct magnetic resonance imaging and in vivo tracking of accumulation. These neuroprotective copolymers (NPCs) were shown to rapidly and effectively neutralize both ROS and LPOx. Horseradish peroxidase absorbance assays showed that the NPCs efficiently neutralized H2O2, while R-phycoerythrin protection assays demonstrated their ability to protect the fluorescent protein from oxidative damage. 1H NMR studies indicated that the thiol-functional NPCs rapidly form covalent bonds with acrolein, efficiently removing it from solution. In vitro cell studies with SH-SY5Y-differentiated neurons showed that NPCs provide unique protection against toxic concentrations of both H2O2and acrolein. NPCs rapidly accumulate and are retained in the injured brain in controlled cortical impact mice and reduce post-traumatic oxidative stress. Therefore, these materials show promise for improved target engagement of multiple biochemical derangements in hopes of improving TBI therapeutic outcomes

The effects of electrical hippocampal kindling of seizures on amino acids and kynurenic acid concentrations in brain structures

Our study demonstrated that the development of seizures during the electrically induced kindling of seizures is associated with significant changes in the concentration of kynurenic acid (KYNA) and its precursor, tryptophan (TRP). The primary finding of our study was an increase in KYNA levels and the KYNA/TRP ratio (a theoretical index of activity of the kynurenine pathway) in the amygdala and hippocampus of kindled animals. We also found decreases in the concentration of tryptophan in the hippocampus and prefrontal cortex. Changes in the concentration of KYNA and TRP in the amygdala were accompanied by a significant decrease in γ-Aminobutryic Acid (GABA) levels and an increase in the glutamate/GABA ratio. Moreover, we found a significant negative correlation between the local concentrations of KYNA and glutamate in the amygdala of kindled rats. However, there were no changes in the local concentrations of the following amino acids: glutamate, aspartate, glutamine, glycine, taurine and alanine. In conclusion, these new results suggest a modulatory influence of KYNA on the process of epileptogenesis, characterized by a negative relationship between the KYNA and glutamate systems in the amygdala

A tumor cord model for Doxorubicin delivery and dose optimization in solid tumors

<p>Abstract</p> <p>Background</p> <p>Doxorubicin is a common anticancer agent used in the treatment of a number of neoplasms, with the lifetime dose limited due to the potential for cardiotoxocity. This has motivated efforts to develop optimal dosage regimes that maximize anti-tumor activity while minimizing cardiac toxicity, which is correlated with peak plasma concentration. Doxorubicin is characterized by poor penetration from tumoral vessels into the tumor mass, due to the highly irregular tumor vasculature. I model the delivery of a soluble drug from the vasculature to a solid tumor using a tumor cord model and examine the penetration of doxorubicin under different dosage regimes and tumor microenvironments.</p> <p>Methods</p> <p>A coupled ODE-PDE model is employed where drug is transported from the vasculature into a tumor cord domain according to the principle of solute transport. Within the tumor cord, extracellular drug diffuses and saturable pharmacokinetics govern uptake and efflux by cancer cells. Cancer cell death is also determined as a function of peak intracellular drug concentration.</p> <p>Results</p> <p>The model predicts that transport to the tumor cord from the vasculature is dominated by diffusive transport of free drug during the initial plasma drug distribution phase. I characterize the effect of all parameters describing the tumor microenvironment on drug delivery, and large intercapillary distance is predicted to be a major barrier to drug delivery. Comparing continuous drug infusion with bolus injection shows that the optimum infusion time depends upon the drug dose, with bolus injection best for low-dose therapy but short infusions better for high doses. Simulations of multiple treatments suggest that additional treatments have similar efficacy in terms of cell mortality, but drug penetration is limited. Moreover, fractionating a single large dose into several smaller doses slightly improves anti-tumor efficacy.</p> <p>Conclusion</p> <p>Drug infusion time has a significant effect on the spatial profile of cell mortality within tumor cord systems. Therefore, extending infusion times (up to 2 hours) and fractionating large doses are two strategies that may preserve or increase anti-tumor activity and reduce cardiotoxicity by decreasing peak plasma concentration. However, even under optimal conditions, doxorubicin may have limited delivery into advanced solid tumors.</p

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice:Relevance to Psychotic Disorders

BACKGROUND: Kynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway-which is implicated as dysfunctional in various psychiatric disorders-toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia. METHODS: In the present study, we investigated adaptive-and possibly regulatory-changes in mice with a targeted deletion of Kmo (Kmo-/-) and characterized the kynurenine 3-monooxygenase-deficient mice using six behavioral assays relevant for the study of schizophrenia. RESULTS: Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo-/- mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo-/- mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo-/- mice showed potentiated horizontal activity in the open field paradigm. CONCLUSIONS: Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders

A Process Model for Laser Surface Treatment of Plasma Sprayed Coatings

Advanced ceramics are not easily fabricated and consolidated by the plasma spray technique because of their extremely high melting temperature. Zirconium diboride (ZrB2) has been successfully plasma sprayed, but the coatings are quite porous. The high levels of porosity are usually a result of unmelted ZrB2 particles that have been incorporated into the coating during deposition. Applying a laser surface treatment to reduce both the porosity and the coating surface roughness, and to improve the coating quality, is of great interest. A laser based surface treatment technique provides a well-controlled heat input, with minimal or no distortion. In this study, a two dimensional mathematical model is developed to investigate the effects of laser power, beam diameter and level of porosity on the coating quality, incorporating melting, solidification, and evaporation phenomena. A continuum model is used to solve Navier-Stokes equations for both solid and liquid phases. Volume-of-Fluid (VOF) is incorporated to track the free surface. The surface force is incorporated as a body force instead of a boundary condition. The porosity level and surface roughness before and after the laser surface treatment are simulated and compared with experimental results

Numerical and Experimental Analysis for Laser Surface Densification of Plasma Sprayed Coatings

Advanced ceramics, suitable to fabricate ultra-high temperature ceramic components for structural applications and thermal protection systems, are not easily prepared by the plasma spray technique due to their extremely high melting temperature. How to prepare the materials with high density is a challenging research task. In this study, applying a laser surface treatment technique for the densification of zirconium diboride, the influence of laser power and beam diameter on the microstructure and mechanical properties of the coatings are examined both numerically and experimentally. Using a two dimensional mathematical model, which was developed incorporating melting, solidification, and evaporation phenomena, the microstructural characteristics during solidification are predicted via tracking the solid-liquid interface. For the mathematical model, volume-of-fluid technique is incorporated to track the free surface, while the surface force as a body force instead of a boundary condition. Typical laser processing parameters have been obtained for the desired both porosity reduction and microstructure from the model and the predicted results are compared with the experimental results

Pressureless Sintering of Carbon Nanotube-Al₂O₃ Composites

Alumina ceramics reinforced with 1, 3, or 5 vol.% multi-walled carbon nanotubes (CNTs) were densified by pressureless sintering. Commercial CNTs were purified by acid treatment and then dispersed in water at pH 12. The dispersed CNTs were mixed with Al2O3 powder, which was also dispersed in water at pH 12. The mixture was freeze dried to prevent segregation by differential sedimentation during solvent evaporation. Cylindrical pellets were formed by uniaxial pressing and then densified by heating in flowing argon. The resulting pellets had relative densities as high as not, vert, similar99% after sintering at 1500 °C for 2 h. Higher temperatures or longer times resulted in lower densities and weight loss due to degradation of the CNTs by reaction with the Al2O3. A CNT/Al2O3 composite containing 1 vol.% CNT had a higher flexure strength (not, vert, similar540 MPa) than pure Al2O3 densified under similar conditions (not, vert, similar400 MPa). Improved fracture toughness of CNT-Al2O3 composites was attributed to CNT pullout. This study has shown, for the first time, that CNT/Al2O3 composites can be densified by pressureless sintering without damage to the CNTs

Thermal and Electrical Properties of a High Entropy Carbide (Ta, Hf, Nb, Zr) at Elevated Temperatures

The thermal and electrical properties were measured for a high entropy carbide ceramic, consisting of (Hf, Ta, Zr, Nb)C. The ceramic was produced by spark plasma sintering a mixture of the monocarbides and had a relative density of more than 97.6%. The resulting ceramic was chemically homogeneous as a single-phase solid solution formed from the constituent carbides. The thermal diffusivity (0.045-0.087 cm2/s) and heat capacity (0.23-0.44 J/g·K) were measured from room temperature up to 2000°C. The thermal conductivity increased from 10.7 W/m·K at room temperature to 39.9 W/m·K at 2000°C. The phonon and electron contributions to the thermal conductivity were investigated, which showed that the increase in thermal conductivity was predominantly due to the electron contribution, while the phonon contribution was independent of temperature. The electrical resistivity increased from 80.9 μΩ·cm at room temperature to 114.1 μΩ·cm at 800°C

Comparison Study of the Processing Methods and Properties for Zirconium Silicate Fibrous Monoliths

ZrSiO4/ZrSiO4 fibrous monoliths (FMs) have been fabricated using both ram and screw extrusion processing methods to form unidirectional [0⁰] architectures. Ram extrusion has been the traditional process for fabricating FMs, in which a controlled-geometry feedrod containing the cell and cell-boundary phases as ceramic/polymer blends is forced through a die. Conventional screw extrusion has also been used more recently to fabricate FM filaments. Both techniques resulted in FMs that exhibit graceful failure in flexure. Peak strengths are in the range of 90-100 MPa with load retention after fracture occurs

Microwave Sintering of a ZrB2-B4C Particulate Ceramic Composite

A two phase particulate ceramic composite containing ZrB2 and B4C was densified by microwave sintering a mixture of ZrB2 and 4 wt% B4C powders. The particulate composite reached \u3e98% relative density at processing temperatures as low as 1720 °C. In comparison to conventional sintering, microwave sintering promoted densification of the composite at lower temperatures without promoting rapid grain growth. Vickers\u27 hardness and fracture toughness of the microwave sintered specimens were as high as 17.5 GPa and 3.8 MPa m1/2, respectively