Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization

The hERG voltage-gated potassium channel mediates the cardiac I(Kr) current, which is crucial for the duration of the cardiac action potential. Undesired block of the channel by certain drugs may prolong the QT interval and increase the risk of malignant ventricular arrhythmias. Although the molecular determinants of hERG block have been intensively studied, not much is known about its stereoselectivity. Levo-(S)-bupivacaine was the first drug reported to have a higher affinity to block hERG than its enantiomer. This study strives to understand the principles underlying the stereoselectivity of bupivacaine block with the help of mutagenesis analyses and molecular modeling simulations. Electrophysiological measurements of mutated hERG channels allowed for the identification of residues involved in bupivacaine binding and stereoselectivity. Docking and molecular mechanics simulations for both enantiomers of bupivacaine and terfenadine (a non-stereoselective blocker) were performed inside an open-state model of the hERG channel. The predicted binding modes enabled a clear depiction of ligand-protein interactions. Estimated binding affinities for both enantiomers were consistent with electrophysiological measurements. A similar computational procedure was applied to bupivacaine enantiomers towards two mutated hERG channels (Tyr652Ala and Phe656Ala). This study confirmed, at the molecular level, that bupivacaine stereoselectively binds the hERG channel. These results help to lay the foundation for structural guidelines to optimize the cardiotoxic profile of drug candidates in silico.

Monitoring and Modeling of the Hydraulic and Sediment Processes at In-Stream Restoration Structures in the Vicinity of a Bridge Crossing

The long-term performance of infrastructure depends on reliable and sustainable designs. Many of Pennsylvania’s streams experience sediment transport problems that increase maintenance costs and lower structural integrity of bridge crossings. A stream restoration project is one common mitigation measure used to correct such problems at bridge crossings. Specifically, in an attempt to alleviate aggradation problems with the Old Route 15 Bridge crossing on White Deer Creek, in White Deer, PA, two in-stream structures (rock cross vanes) and several bank stabilization features were installed along with a complete channel redevelopment. The objectives of this research were to characterize the hydraulic and sediment transport processes occurring at the White Deer Creek site, and to investigate, through physical and mathematical modeling, the use of instream restoration structures. The goal is to be able to use the results of this study to prevent aggradation or other sediment related problems in the vicinity of bridges through improved design considerations. Monitoring and modeling indicate that the study site on White Deer Creek is currently unstable, experiencing general channel down-cutting, bank erosion, and several local areas of increased aggradation and degradation of the channel bed. An in-stream structure installed upstream of the Old Route 15 Bridge failed by sediment burial caused by the high sediment load that White Deer Creek is transporting as well as the backwater effects caused by the bridge crossing. The in-stream structure installed downstream of the Old Route 15 Bridge is beginning to fail because of the alignment of the structure with the approach direction of flow from upstream of the restoration structure.

Experimental and modeling study of the filtration and oxidation characteristics of a diesel oxidation catalyst and a catalyzed particulate filter

A diesel oxidation catalyst (DOC) with a catalyzed diesel particulate filter (CPF) is an effective exhaust aftertreatment device that reduces particulate emissions from diesel engines, and properly designed DOC-CPF systems provide passive regeneration of the filter by the oxidation of PM via thermal and NO2/temperature-assisted means under various vehicle duty cycles. However, controlling the backpressure on engines caused by the addition of the CPF to the exhaust system requires a good understanding of the filtration and oxidation processes taking place inside the filter as the deposition and oxidation of solid particulate matter (PM) change as functions of loading time. In order to understand the solid PM loading characteristics in the CPF, an experimental and modeling study was conducted using emissions data measured from the exhaust of a John Deere 6.8 liter, turbocharged and after-cooled engine with a low-pressure loop EGR system and a DOC-CPF system (or a CCRT® - Catalyzed Continuously Regenerating Trap®, as named by Johnson Matthey) in the exhaust system. A series of experiments were conducted to evaluate the performance of the DOC-only, CPF-only and DOC-CPF configurations at two engine speeds (2200 and 1650 rpm) and various loads on the engine ranging from 5 to 100% of maximum torque at both speeds. Pressure drop across the DOC and CPF, mass deposited in the CPF at the end of loading, upstream and downstream gaseous and particulate emissions, and particle size distributions were measured at different times during the experiments to characterize the pressure drop and filtration efficiency of the DOCCPF system as functions of loading time. Pressure drop characteristics measured experimentally across the DOC-CPF system showed a distinct deep-bed filtration region characterized by a non-linear pressure drop rise, followed by a transition region, and then by a cake-filtration region with steadily increasing pressure drop with loading time at engine load cases with CPF inlet temperatures less than 325 °C. At the engine load cases with CPF inlet temperatures greater than 360 °C, the deep-bed filtration region had a steep rise in pressure drop followed by a decrease in pressure drop (due to wall PM oxidation) in the cake filtration region. Filtration efficiencies observed during PM cake filtration were greater than 90% in all engine load cases. Two computer models, i.e., the MTU 1-D DOC model and the MTU 1-D 2-layer CPF model were developed and/or improved from existing models as part of this research and calibrated using the data obtained from these experiments. The 1-D DOC model employs a three-way catalytic reaction scheme for CO, HC and NO oxidation, and is used to predict CO, HC, NO and NO2 concentrations downstream of the DOC. Calibration results from the 1-D DOC model to experimental data at 2200 and 1650 rpm are presented. The 1-D 2-layer CPF model uses a ‘2-filters in series approach’ for filtration, PM deposition and oxidation in the PM cake and substrate wall via thermal (O2) and NO2/temperature-assisted mechanisms, and production of NO2 as the exhaust gas mixture passes through the CPF catalyst washcoat. Calibration results from the 1-D 2-layer CPF model to experimental data at 2200 rpm are presented. Comparisons of filtration and oxidation behavior of the CPF at sample load-cases in both configurations are also presented. The input parameters and selected results are also compared with a similar research work with an earlier version of the CCRT®, to compare and explain differences in the fundamental behavior of the CCRT® used in these two research studies. An analysis of the results from the calibrated CPF model suggests that pressure drop across the CPF depends mainly on PM loading and oxidation in the substrate wall, and also that the substrate wall initiates PM filtration and helps in forming a PM cake layer on the wall. After formation of the PM cake layer of about 1-2 µm on the wall, the PM cake becomes the primary filter and performs 98-99% of PM filtration. In all load cases, most of PM mass deposited was in the PM cake layer, and PM oxidation in the PM cake layer accounted for 95-99% of total PM mass oxidized during loading. Overall PM oxidation efficiency of the DOC-CPF device increased with increasing CPF inlet temperatures and NO2 flow rates, and was higher in the CCRT® configuration compared to the CPF-only configuration due to higher CPF inlet NO2 concentrations. Filtration efficiencies greater than 90% were observed within 90-100 minutes of loading time (starting with a clean filter) in all load cases, due to the fact that the PM cake on the substrate wall forms a very efficient filter. A good strategy for maintaining high filtration efficiency and low pressure drop of the device while performing active regeneration would be to clean the PM cake filter partially (i.e., by retaining a cake layer of 1-2 µm thickness on the substrate wall) and to completely oxidize the PM deposited in the substrate wall. The data presented support this strategy.

Development and modeling of thermally conductive resins for fuel cell bipolar plate applications

Thermally conductive resins are a class of material that show promise in many different applications. One growing field for their use is in the area of bipolar plate technology for fuel cell applications. In this work, a LCP was mixed with different types of carbon fillers to determine the effects of the individual carbon fillers on the thermal conductivity of the composite resin. In addition, mathematical modeling was performed on the thermal conductivity data with the goal of developing predictive models for the thermal conductivity of highly filled composite resins.

Modeling mechanical response of heterogeneous materials

Heterogeneous materials are ubiquitous in nature and as synthetic materials. These materials provide unique combination of desirable mechanical properties emerging from its heterogeneities at different length scales. Future structural and technological applications will require the development of advanced light weight materials with superior strength and toughness. Cost effective design of the advanced high performance synthetic materials by tailoring their microstructure is the challenge facing the materials design community. Prior knowledge of structure-property relationships for these materials is imperative for optimal design. Thus, understanding such relationships for heterogeneous materials is of primary interest. Furthermore, computational burden is becoming critical concern in several areas of heterogeneous materials design. Therefore, computationally efficient and accurate predictive tools are highly essential. In the present study, we mainly focus on mechanical behavior of soft cellular materials and tough biological material such as mussel byssus thread. Cellular materials exhibit microstructural heterogeneity by interconnected network of same material phase. However, mussel byssus thread comprises of two distinct material phases. A robust numerical framework is developed to investigate the micromechanisms behind the macroscopic response of both of these materials. Using this framework, effect of microstuctural parameters has been addressed on the stress state of cellular specimens during split Hopkinson pressure bar test. A voronoi tessellation based algorithm has been developed to simulate the cellular microstructure. Micromechanisms (microinertia, microbuckling and microbending) governing macroscopic behavior of cellular solids are investigated thoroughly with respect to various microstructural and loading parameters. To understand the origin of high toughness of mussel byssus thread, a Genetic Algorithm (GA) based optimization framework has been developed. It is found that two different material phases (collagens) of mussel byssus thread are optimally distributed along the thread. These applications demonstrate that the presence of heterogeneity in the system demands high computational resources for simulation and modeling. Thus, Higher Dimensional Model Representation (HDMR) based surrogate modeling concept has been proposed to reduce computational complexity. The applicability of such methodology has been demonstrated in failure envelope construction and in multiscale finite element techniques. It is observed that surrogate based model can capture the behavior of complex material systems with sufficient accuracy. The computational algorithms presented in this thesis will further pave the way for accurate prediction of macroscopic deformation behavior of various class of advanced materials from their measurable microstructural features at a reasonable computational cost.

MULTISCALE EXAMINATION AND MODELING OF ELECTRON TRANSPORT IN NANOSCALE MATERIALS AND DEVICES

For half a century the integrated circuits (ICs) that make up the heart of electronic devices have been steadily improving by shrinking at an exponential rate. However, as the current crop of ICs get smaller and the insulating layers involved become thinner, electrons leak through due to quantum mechanical tunneling. This is one of several issues which will bring an end to this incredible streak of exponential improvement of this type of transistor device, after which future improvements will have to come from employing fundamentally different transistor architecture rather than fine tuning and miniaturizing the metal-oxide-semiconductor field effect transistors (MOSFETs) in use today. Several new transistor designs, some designed and built here at Michigan Tech, involve electrons tunneling their way through arrays of nanoparticles. We use a multi-scale approach to model these devices and study their behavior. For investigating the tunneling characteristics of the individual junctions, we use a first-principles approach to model conduction between sub-nanometer gold particles. To estimate the change in energy due to the movement of individual electrons, we use the finite element method to calculate electrostatic capacitances. The kinetic Monte Carlo method allows us to use our knowledge of these details to simulate the dynamics of an entire device— sometimes consisting of hundreds of individual particles—and watch as a device ‘turns on’ and starts conducting an electric current. Scanning tunneling microscopy (STM) and the closely related scanning tunneling spectroscopy (STS) are a family of powerful experimental techniques that allow for the probing and imaging of surfaces and molecules at atomic resolution. However, interpretation of the results often requires comparison with theoretical and computational models. We have developed a new method for calculating STM topographs and STS spectra. This method combines an established method for approximating the geometric variation of the electronic density of states, with a modern method for calculating spin-dependent tunneling currents, offering a unique balance between accuracy and accessibility.

The Genesis Solar Wind Concentrator: Flight and Post-Flight Conditions and Modeling of Instrumental Fractionation

The Genesis mission Solar Wind Concentrator was built to enhance fluences of solar wind by an average of 20x over the 2.3 years that the mission exposed substrates to the solar wind. The Concentrator targets survived the hard landing upon return to Earth and were used to determine the isotopic composition of solar-wind—and hence solar—oxygen and nitrogen. Here we report on the flight operation of the instrument and on simulations of its performance. Concentration and fractionation patterns obtained from simulations are given for He, Li, N, O, Ne, Mg, Si, S, and Ar in SiC targets, and are compared with measured concentrations and isotope ratios for the noble gases. Carbon is also modeled for a Si target. Predicted differences in instrumental fractionation between elements are discussed. Additionally, as the Concentrator was designed only for ions ≤22 AMU, implications of analyzing elements as heavy as argon are discussed. Post-flight simulations of instrumental fractionation as a function of radial position on the targets incorporate solar-wind velocity and angular distributions measured in flight, and predict fractionation patterns for various elements and isotopes of interest. A tighter angular distribution, mostly due to better spacecraft spin stability than assumed in pre-flight modeling, results in a steeper isotopic fractionation gradient between the center and the perimeter of the targets. Using the distribution of solar-wind velocities encountered during flight, which are higher than those used in pre-flight modeling, results in elemental abundance patterns slightly less peaked at the center. Mean fractionations trend with atomic mass, with differences relative to the measured isotopes of neon of +4.1±0.9 ‰/amu for Li, between -0.4 and +2.8 ‰/amu for C, +1.9±0.7‰/amu for N, +1.3±0.4 ‰/amu for O, -7.5±0.4 ‰/amu for Mg, -8.9±0.6 ‰/amu for Si, and -22.0±0.7 ‰/amu for S (uncertainties reflect Monte Carlo statistics). The slopes of the fractionation trends depend to first order only on the relative differential mass ratio, Δ m/ m. This article and a companion paper (Reisenfeld et al. 2012, this issue) provide post-flight information necessary for the analysis of the Genesis solar wind samples, and thus serve to complement the Space Science Review volume, The Genesis Mission (v. 105, 2003).

Making minimally invasive THR safe: conclusions from biomechanical simulation and analysis.

The use of smaller surgical incisions has become popularized for total hip arthroplasty (THR) because of the potential benefits of shorter recovery and improved cosmetic appearance. However, an increased incidence of serious complications has been reported. To minimize the risks of minimally invasive approaches to THR, we have developed an experimental approach which enables us to evaluate risk factors in these procedures through cadaveric simulations performed within the laboratory. During cadaveric hip replacement procedures performed via posterior and antero-lateral mini-incisions, pressures developed between the wound edges and the retractors were approximately double those recorded during conventional hip replacement using Charnley retractors (p < 0.01). In MIS procedures performed via the dual-incision approach, lack of direct visualisation of the proximal femur led to misalignment of broaches and implants with increased risk of cortical fracture during canal preparation and implant insertion. Cadaveric simulation of surgical procedures allows surgeons to measure variables affecting the technical success of surgery and to master new procedures without placing patients at risk.