Dopamine Uptake Inhibition Potency Fluctuations of Cocaine at the Dopamine Transporter

Cocaine and other dopamine transporter (DAT) inhibitors block synaptic dopamine uptake by binding to the DAT. Cocaine, a powerful psychostimulant, potentiates the dopamine mediated signal transduction in the reward areas of the brain resulting in physical dependence on the drug. Amphetamines are psychotomimetics that act as substrates at the DAT and potentiate dopaminergic neurotransmission leading to addiction. It was previously reported that a conservative glutamate-for-aspartate substitution in transmembrane 1 domain of the rat DAT protein (D79E) significantly decreased the binding affinities of several classical DAT inhibitors, but had little or no effect on the dopamine uptake inhibition potencies (DUIPs) of these blockers. This finding implied that different DAT sites/conformations/populations may be responsible for dopamine uptake and for high affinity binding of inhibitors. In the present study, the DUIPs of cocaine and other DAT ligands at wildtype DAT CHO cells fluctuated as a function of cell age, while their binding affinities remained static. Curiously, neither the DUIP nor the binding affinity of amphetamine fluctuated with cell age. The DUIP fluctuations of cocaine also extended to the N2A neuronal cells, demonstrating its physiological relevance. The loss of correlation between DUIP and binding affinity at DAT might be a unique property of DAT blockers that is not exhibited by DAT substrates. A plausible explanation for the DUIP fluctuations with cell age is the existence of two different DAT populations on the cell surface, the relative distribution of which changes with cell age under the influence of intracellular events such as DAT-protein interactions or alterations in the phosphorylation state. Several proteins interact with the N- and C-terminal regions of the DAT. Studies employing GFP fusion polypeptides of the DAT N- or C-terminal fragments, which would act as decoys by intercepting DAT modulators, showed that the DAT N- or C-terminal interactions with intracellular proteins do not appear to be responsible for the DUIP shift. The role of phosphorylation state changes of DAT in DUIP fluctuations was also investigated. Studies employing a mutant DAT lacking the first 20 N-terminal amino acids demonstrated that N-terminal phosphorylation of DAT, specifically involving the first five serines is not associated with the DUIP shift

Three-Dimensional Geometric Nonlinear Contact Stress Analysis of Riveted Joints

The problems associated with fatigue were brought into the forefront of research by the explosive decompression and structural failure of the Aloha Airlines Flight 243 in 1988. The structural failure of this airplane has been attributed to debonding and multiple cracking along the longitudinal lap splice riveted joint in the fuselage. This crash created what may be termed as a minor "Structural Integrity Revolution" in the commercial transport industry. Major steps have been taken by the manufacturers, operators and authorities to improve the structural airworthiness of the aging fleet of airplanes. Notwithstanding, this considerable effort there are still outstanding issues and concerns related to the formulation of Widespread Fatigue Damage which is believed to have been a contributing factor in the probable cause of the Aloha accident. The lesson from this accident was that Multiple-Site Damage (MSD) in "aging" aircraft can lead to extensive aircraft damage. A strong candidate in which MSD is highly probable to occur is the riveted lap joint

Electrochemical behavior of lithium cobalt oxide in aqueous electrolytes

Lithium-ion (Li-ion) batteries are the most popular energy devices for almost all electronics today. From cell-phones and laptops, to advanced uses in automotive and aircraft applications, lithium-ion batteries have slowly taken over the market. Unfortunately, today’s lithium-ion batteries are also highly unsafe. They rely heavily on organic solvents for electrolytes in the battery. These organic solvents are inherently flammable in nature and have caused several fires reported in batteries over the past few years. In this research, I aimed to investigate changes in the electrochemical behavior of electrodes if we replace flammable organic solvents with a safer alternative such as water. Water-based batteries may offer greatly improved safety and lower cost (from lower raw material cost to reduced manufacturing costs). In addition, water-based electrolytes may exhibit dramatically higher ionic mobility for Li ions and thus can be potentially used for faster charging batteries or batteries with thicker electrodes, which are easier and cheaper to construct. Lithium cobalt oxide (LCO) has long been proven to be an excellent material for cathodes in conventional organic electrolytes. It has shown high volumetric capacity and good stability in non-aqueous environments of commercial Li-ion batteries. Unfortunately, the flammability of organic electrolytes in combination with a propensity for batteries constructed with LCO to experience thermal runaway creates safety concerns. Due to extensive knowledge accumulated on LCO and its structural similarity with many other common cathode materials, LCO may serve as a model material for studying electrochemical interactions of layered lithium transition metal oxides with aqueous electrolytes. While LCO had previously been demonstrated to cycle for 20-100 times in aqueous environments, the causes of its degradation had not been investigated in detail. Our studies demonstrated that in certain aqueous electrolytes LCO cathodes could cycle with a remarkable stability showing only 13% fading after over 1,500 cycles. Post mortem analysis of the electrodes was conducted to understand the effect of cycling and the causes of degradation. Electrolyte composition was found to have a dramatic impact on the electrochemical performance and stability of LCO in aqueous environments. The temperature range for aqueous electrolytes at sub-zero temperatures was also investigated in detail. We showed that Li-ion batteries with aqueous electrolytes can be excellent candidates for battery applications at low temperatures. In contrast to a common misconception, aqueous Li-ion batteries can operate at several tens of degrees below the freezing point of water when high concentration electrolyte solutions are utilized. By leveraging the colligative properties of water, I demonstrated that aqueous electrolytes can function much below the freezing point of water down to -40oC. The performance of water-based electrolyte systems with three low-cost inorganic salts (LiNO3, Li2SO4, and LiCl) was extensively studied to understand the rate-limiting step in battery performance at sub-zero temperatures. It was found that the charge transfer resistance is the largest contributor to impedance at low temperatures, until the complete solidification of the aqueous electrolytes takes place. In sharp contrast, it was found that common organic electrolytes do not support any cycling below -20oC. The contributions from the various resistances that affect low temperature cycling from the perspective of the electrode as well as the electrolyte were investigated in detail.Ph.D

A Facile Approach for the Synthesis of Monolithic Hierarchical Porous Carbons - High Performance Materials for Amine Based CO2 Capture and Supercapacitor Electrode

An ice templating coupled with hard templating and physical activation approach is reported for the synthesis of hierarchically porous carbon monoliths with tunable porosities across all three length scales (macro- meso- and micro), with ultrahigh specific pore volumes [similar]11.4 cm3 g−1. The materials function well as amine impregnated supports for CO2 capture and as supercapacitor electrodes.KUS-C1-018-02 King Abdullah University of Science and Technology (KAUST), National Science Foundation Grassroots GK-12 Program (DGE 1045513), Energy Materials Center at Cornell (EMC2) (DE-SC0001086)NSF MRSEC Program (DMR-1120296

A Hybrid Object Clustering Strategy for Large Knowledge-Based Systems

Object bases underlying knowledge-based applications tend to be complex and require management. This research aims at improving the performance of object bases underlying a class of large knowledgebased systems that utilize object-oriented technology to engineer the knowledge base. In this paper, a hybrid clustering strategy that beneficially combines semantic clustering and iterative graph-paritioning techniques has been developed and evaluated for use in knowledge bases storing information in the form of object graphs. It is demonstrated via experimentation that such a technique is useful and feasible in realistic object bases. A semantic specification mechanism similar to placement trees has been developed for specifying the clustering. The workload and the nature of object graphs in knowledge bases differ significantly from those present in conventional objectoriented databases. Therefore, the evaluation has been performed by building a new benchmark called the Granularity Benchmar..

Fluctuation of the dopamine uptake inhibition potency of cocaine, but not amphetamine, at mammalian cells expressing the dopamine transporter

Cocaine, amphetamines and other psychostimulants inhibit synaptic dopamine uptake by interfering with dopamine transporter (DAT) function. The resultant potentiation of dopaminergic neurotransmission is associated with psychostimulant addiction. Fluctuations in dopamine uptake inhibition potency (DUIP) were observed for classical DAT blockers including cocaine, mazindol, methylphenidate (Ritalin™) and benztropine in CHO cells expressing wild type DAT; cocaine potency also decreased in DAT-expressing non-neuronal COS-7 cells and neuronal N2A neuroblastoma cells. In contrast, the DAT substrate (+)-amphetamine did not display this DUIP fluctuation. In parallel experiments, no fluctuation was observed for the apparent binding affinities of these 5 drugs. The DUIP decrease appeared to correlate with an increase in cell surface DAT expression level, as measured by Bmax values and confocal microscopy. The fact that the DUIP profile of amphetamine diverged from that of the classical DAT blockers is consistent with the idea of fundamental differences between the mechanisms of abused psychostimulant DAT substrates and inhibitors. Identification of the cellular factors that underlie the DAT inhibitor DUIP fluctuation phenomenon may be relevant to anti-psychostimulant drug discovery efforts. © 2006 Elsevier B.V. All rights reserved

Mixed Metal Difluorides as High Capacity Conversion-Type Cathodes: Impact of Composition on Stability and Performance

With the most recent development of ultrahigh capacity anodes, such as Li- or Si-based anodes, metal fluorides hold promise as complementary high-capacity conversion cathode materials for next-generation energy storage devices. Despite their higher theoretical energy density compared to cells with sulfur cathodes, these materials have received dramatically less attention and little is understood about the origins of their electrochemical behavior. Here, the successful methodology to produce highly uniform size-controlled mixed metal difluoride nanocomposites is reported. It is discovered that such materials undergo reduction in a single step with a reduction potential intermediate to those for the corresponding single-metal difluorides and that a solid solution is reformed upon charging, which is advantageous for practical applications. For the first time the progressive formation of metal trifluorides upon repeated cycling of difluorides is reported. Systematic electrochemical measurements in combination with postmortem analyses lead to the conclusion that the cathode stability strongly depends on the ability to prevent formation and growth of a resistive cathode solid electrolyte interphase, which, in turn, strongly depends on the metal composition. This methodology and new findings will help to elucidate a path to developing metal fluoride?based commercial Li-ion batteries and provide guidelines for material selection. ? 2018 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimD.G. and Q.H. contributed equally to this work. This work was funded in part by a grant from the Qatar National Research Fund under its National Priorities Research Program award number NPRP7-567-2-216. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Qatar National Research Fund. The authors also wish to acknowledge fellowship support of Qiao Huang by the China Scholarship Council