Aberrant JNK signaling can result in two main forms of disease in humans: 1) neurological, coronary, hepatobiliary, and respiratory diseases and 2) autoimmune, inflammatory, and cancer conditions. Enantiomers of the lignan zuonin A, (-)-zuonin A and (+)-zuonin A, have been shown to bind to JNK isoforms with similar affinity and disrupt protein-protein interactions at JNK's D-recruitment site, making them a good candidate for specific non-ATP competitive inhibitors. However, (-)-zuonin A inhibits 80% of JNK catalyzed reactions at saturating levels, while (+)-zuonin A only inhibits 15%. Molecular docking and molecular dynamics simulations were performed to gain a better understanding of how these inhibitors interact JNK. The results of this study provide an alternative binding mode for (-)-zuonin A, compared to one proposed in a previous study, that shows (-)-zuonin A interacting with JNK via an induced fit mechanism by forming a larger pocket for itself near the highly conserved [phi]A-X-[phi]B recognition site, a dynamic move not seen in (+)-zuonin A simulations, and may help explain their different inhibition patterns. / text

We present the details of the optical design, corrector system, mechanical layout, tolerances, pointing requirements, and overall performance of the sub-millimeter wavelength Large Balloon Reflector telescope (LBR).

Class of 2012 Abstract / Specific Aims: Autologous stem cell transplant (ASCT) is the current gold standard following induction therapy to improve survival of multiple myeloma (MM). Lenalidomide (LEN) is used for treatment of MM before ASCT, but exposure may impair autologous peripheral blood stem cell (PBSC) mobilization. Chemomobilization with cyclophosphamide (CTX) has not been evaluated in this setting. CTX + filgrastim was investigated to determine if LEN-associated mobilization impairment can be abrogated. Methods: 36 pts (group A=12 pts who received ≥2 cycles of LEN and group B=24 pts without LEN) were analyzed retrospectively. Baseline characteristics were matched (p>0.05 for all variables). All pts received CTX (median group B, 1.5g/m2; median group A, 3gm/m2(p=0.18)) and filgrastim 10μg/kg/day. Primary outcomes include number of CD34+ cells collected and number of leukapheresis sessions. Secondary outcomes include failure to collect CD34+ cells and total CD34+ cells collected after second leukapheresis. Main Results: Total median number of CD34+ cells collected in group B=9.15x106/kg CD34+ cells and group A=7.43x106/kg CD34+ cells (p=0.159). Median number of apheresis sessions in group B=2 and group A=3 (p=0.42). Two of 12 pts with antecedent LEN usage failed to collect while no patient without previous LEN exposure failed to collect (p=0.105). Total number of CD34+ cells collected after 2 apheresis sessions for group B=8.13x106/kg CD34+ cells and group A=3.34x106/kg CD34+ cells (p=0.06). Conclusions: Chemomobilization with CTX + filgrastim yields robust PBSC collections irrespective of antecedent lenalidomide. There was a trend towards lesser PBSC collection in LEN-treated pts.

No description available.

<pre>Finite mixture models have been successfully used in many applications, such as classification, clustering, and many others. As opposed to classical parametric mixture models, nonparametric and semiparametric mixture models often provide more flexible approaches to the description of inhomogeneous populations. As an example, in the last decade a particular two-component semiparametric density mixture model with a known component has attracted substantial research interest. Our thesis provides an innovative way of estimation for this model based on minimization of a smoothed objective functional, conceptually similar to the log-likelihood. The minimization is performed with the help of an EM-like algorithm. We show that the algorithm is convergent and the minimizers of the objective functional, viewed as estimators of the model parameters, are consistent. </pre><pre><br></pre><pre>More specifically, in our thesis, a semiparametric mixture of two density functions is considered where one of them is known while the weight and the other function are unknown. For the first part, a new sufficient identifiability condition for this model is derived, and a specific class of distributions describing the unknown component is given for which this condition is mostly satisfied. A novel approach to estimation of this model is derived. That approach is based on an idea of using a smoothed likelihood-like functional as an objective functional in order to avoid ill-posedness of the original problem. Minimization of this functional is performed using an iterative Majorization-Minimization (MM) algorithm that estimates all of the unknown parts of the model. The algorithm possesses a descent property with respect to the objective functional. Moreover, we show that the algorithm converges even when the unknown density is not defined on a compact interval. Later, we also study properties of the minimizers of this functional viewed as estimators of the mixture model parameters. Their convergence to the true solution with respect to a bandwidth parameter is justified by reconsidering in the framework of Tikhonov-type functional. They also turn out to be large-sample consistent; this is justified using empirical minimization approach. The third part of the thesis contains a series of simulation studies, comparison with another method and a real data example. All of them show the good performance of the proposed algorithm in recovering unknown components from data.</pre>

Halogenases are enzymes with the ability to regioselectively and stereoselectively form carbon-halogen bonds, transferring a halogen onto various carbon scaffolds forming organohalogens. These organohalogens have many biological properties, for example, antibacterial, antifungal, anti-inflammatory, anti-proliferative, anti-fouling, anti-feedant, cytotoxic, ichthyotoxic and insecticidal activity. Additionally, the halogen is highly important for biological activity and consequently pharmaceutical and agrochemical industries are interested in environmentally sustainable and economically viable methods to selectively halogenate various organic scaffolds used during organic synthesis. One such method is to use nonheme iron halogenases, which are structurally and biochemically similar to nonheme iron hydroxylases. Common to both groups is the reactive intermediate, the iron(IV)-oxo, which abstracts a hydrogen atom from a substrate. Post hydrogen atom abstraction the catalytic cycle bifurcates, producing either hydroxylated or halogenated products. Of current debate are the factors separating halogenation and hydroxylation and in this thesis we have investigated the mechanisms of the nonheme iron halogenase (HctB) and hydroxylase (P4H) using a combination of density functional theory (DFT) and quantum mechanics/molecular mechanics (QM/MM) to gain further insight into the bifurcation factors. The QM/MM and DFT studies on the hectochlorin biosynthesis enzyme HctB revealed that substrate binding and positioning are key for optimal substrate halogenation. Additionally, key residues (Glu223) were found to influence the charge density on the chloride ligand pushing the mechanism toward halogenation. Furthermore, the influence of substrate binding and positioning was explored further in a QM/MM and MD study on the nonheme iron hydroxylase, P4H, which hydroxylates proline residues to produce 4-hydroxyproline. The QM/MM and MD study identified that mutations to either Trp243 or Tyr140 disrupted both long and short-range interactions resulting in alterations to the enzymes regioselectivity and stereoselectivity. This study also revealed that Arg161 and Glu127 formed key interactions with the substrate, which became the focus of the next study on P4H. Together these two studies on P4H, highlighted the importance of substrate positioning and selective hydrogen bonding between the protein and substrate for correct product outcome. Additionally, we were able to explore several mutations to Trp243, Tyr140, Arg161 and Glu127, identifying mutations which resulted in changes to the enzyme’s regioselectivity and stereoselectivity. Finally, in this thesis we also investigated the ability of a nonheme iron halogenase to transfer groups other than a halogen, such as nitrate and azide, using the biomimetic system , [FeIV(O)(TPA)X]+, TPA = tris(2-pyridylmethy1)amine whereby X = Cl, NO2, N3. The reaction of TPA with ethyl benzene revealed that the product distributions vary with the nature of the equatorial ligand at the metal centre. The results of this study also predict the effect of other substituents potentially opening up the application of halogenases to transferring groups other than halogens. Altogether, the studies in this thesis have looked at the different factors influencing substrate halogenation from various perspectives and have revealed the fascinating biochemistry of these enzyme’s and models to perform regioselective and stereoselective reactions with potential future industrial application.

This dissertation proposes novel solutions for important drawbacks of antenna arrays. One of the main contributions of the presented work is size reduction and nulling performance improvement of traditionally large anti-jam global positioning system (GPS) arrays using miniature antennas and electrically small resonators emulating an engineered metamaterial. Specifically, a miniaturized coupled double loop (CDL) dual band antenna is first introduced as a small antenna element of the compact GPS array. The loops that are capacitively coupled using lumped element capacitor, and employ metallic pins around their perimeter to improve the radiation efficiency by achieving a volumetric current distribution. This design is employed for the implementation of a compact 2x2 GPS array by reducing the inter-element spacing between the adjacent elements. However, having the antenna elements in close proximity of each other yields to a high mutual coupling and potentially degrades the nulling performance. The mutual coupling is performed by observing the magnetic field distribution within the array. It is noticed that the mutual coupling can be reduced by using metamaterial resonators. The right hand circular polarization (RHCP) radiation nature of the array complicates the mutual coupling suppression as compared to linear arrays. It is determined that split ring resonator (SRRs) are effective to mitigate the mutual coupling problem if placed strategically around the antenna elements. The study is verified experimentally where the mutual coupling is reduced by more than 10 dB. Lowering the mutual coupling improved the array's nulling capability by increasing the nulls depth by 8 dB as well as enhancing the accuracy of the nulls' locations. The second major contribution of the presented work is to introduce a novel microfluidic based beam-scanning technique for the implementation of low cost mm-wave antenna arrays. Traditionally, beam scanning capability is obtained using mechanical steering of the entire antenna structure or electronic components such as switches or phase shifters. The former is bulky, whereas the latter technique requires integrating substantial and expensive hardware in the array's feed network. For instance, a beam-scanning 1x8 focal plane array (FPA) would employ 7 single pole double through (SPDT) switches in its feed network. If an 8x8 FPA is desired, then 8x7+8 switches are required that results in an efficient design in terms of power loss and cost. In this dissertation, the microfluidic principles are introduced for designing and implementing affordable beam scanning antenna array with high gain radiation. Specifically, a microfluidic-based focal plane array 1x8 (MFPA) is designed and implemented at 30 GHz. The proposed MFPA consists of microfluidic channels connecting reservoirs. Both of the channels and reservoirs are filled with a low loss dielectric solution, and the antenna is formed by using a small volume of liquid metal. The beam scanning capability is obtained by placing the array at the focal point of a microwave lens and moving the antenna among the reservoirs using a micropump. Therefore, the feed network is extremely simplified by avoiding using SPDT switches. In addition, a strategic design methodology for a completely passive resonant based corporate feed network is discussed. The array is characterized numerically and verified experimentally. The simulated and measured performances are in a very good agreement with ±300 FoV and > 21 dB realized gain. However, the array's radiation pattern exhibits high side lobe level (SLL) due to the resonant nature of the introduced corporate feed network. Consequently, new resonant and non-resonant straight based feed networks are introduced to alleviate the high SLL issue. Moreover, they are modeled with appropriate equivalent circuits in order to analyze the array's performance analytically in terms of -10 dB |S11| bandwidth and power loss. The analytical solution is based on the transmission line theory and two ports network analysis. It is verified with the full wave simulations and a very good agreement is observed. Using the straight feed network reduces the SLL to more than 20 dB relative the pattern's peak. This enhancement in the performance is verified experimentally as well by designing, fabricating and testing a 30 GHz MFPA fed using a resonant based straight network. A ±250 FoV is obtained with a SLL < -20 dB and 4% -10 dB |S11| bandwidth.

This thesis encloses quantum chemical calculations performed in the framework of density functional response theory for evaluating electron paramagnetic resonance (EPR) spin Hamiltonian parameters of various spin-labels in different environments. These parameters are the well known electronic g-tensor and the nitrogen hyperfine coupling constants, which are extensively explored in this work for various systems. A special attention was devoted to the relationships that form between the structural and spectroscopic properties that can be accounted for as an environmental inuence. Such environmental effects were addressed either within a fully quantum mechanical formalism, involving simplified model structures that still capture the physical properties of the extended system, or by employing a quantum mechanics/molecular mechanics (QM/MM) approach. The latter implies that the nitroxide spin label is treated quantum mechanically, while the environment is treated in a classical discrete manner, with appropriate force fields employed for its description. The state-of- the art techniques employed in this work allow for an optimum accounting of the environmental effects that play an important role for the behaviour of EPR properties of nitroxides spin labels. One achievement presented in this thesis includes the first theoretical con_rmation of an empirical assumption that is usually made for inter-molecular distance measurement experiments in deoxyribonucleic acid (DNA), involving pulsed electron-electron double resonance (PELDOR) and site-directed spin labeling (SDSL) techniques. This refers to the fact that the EPR parameters of the spin-labels are not affected by their interaction with the nucleobases from which DNA is constituted. Another important result presented deals with the inuence of a supramolecular complex on the EPR properties of an encapsulated nitroxide spin-label. The enclusion complex affects the hydrogen bonding topology that forms around the R2NO moiety of the nitroxide. This, on the other hand has a major impact on its structure which further on governs the magnitude of the spectroscopic properties. The projects and results presented in this thesis offer an example of successful usage of modern quantum chemistry techniques for the investigation of EPR parameters of spin-labels in complex systems. / <p>QC 20130318</p>

The long-term trends of PM10, O3 and NOx concentrations were analyzed using Holland model (without meteorological-adjusted) and MM-Regression model (with meteorological-adjusted) based on the data of ten EPA air quality stations from 1997 to 2006 in Kao-Ping area. The aim of this study was to determine the impact of meteorological factors on the trends of these pollutants in Kao-Ping. The annual variations (AV) of O3 was −0.496 % in Kaohsiung county, −0.200 in Pingtung county, and 0.277 % in Kaohsiung city, showing different characteristics in Kao-Pin area. On average, the annual variations (AV) influenced by meteorological factors were: PM10: 0.205 %, O3: −0.127 %, and NOx: 0.338 %. After being adjusted by meteorological factors, the seasonal variations (SV) were about 1, indicating little seasonal change. In Kao-Ping region, the influence by meteorological factors was 9.566 %, 8.026 % and 7.351 % in PM10, O3, NOx, respectively. In total, the average influence was 8.314% in Kao-Ping region, with 7.791% in Kaohsiung city (8.481% at Cianjin, the most influenced area), 9.439% in Kaohsiung County (10.368% at Linyuan, the most influenced area), and 7.110% in Pingtung County (7.516% at Chaojhou, the most influenced area). PM10 was influenced most by meteorological factors (PM10: 9.566 %, O3: 8.026 %, NOx: 7.351 %) in Kao-Ping area.. In Kao-Ping region, the contributions by individual meteorological factors were 70.78% in wind speed, 38.23% in total cloudiness, 36.56% in sunshine hour, 19.86% in temperature, 12.40% in atmospheric pressure, 5.96% in relative humidity and 1.27% in wind direction. The influences by the wind speed were 66.62 %, 72.35 % and 72.31 % on the concentrations of PM10, O3, NOx, respectively. Wind speed was the most important factor controlling concentration trends in Kao-Ping area.

The trends of PM10, O3, NOX and NMHC concentrations were analyzed by the Holland model (without meteorological-adjusted) and the MM-Regression model (with meteorological-adjusted) base on the data of eight EPA air quality stations from 1997 to 2006 in Kaohsiung. The aim of this study was to evaluate the influence of meteorological factors on the pollutants (PM10 and O3) trends. The trends of PM10 concentrations in Kaohsiung city analyzed without meteorological-adjusted were 7.18 % at Tzuo-Yin, 3.20 % at Chien-Chin and 9.72 % at Nan-Chie. After eliminating the meteorological factors, the percent of gradual trends were 1.91 % at Tzuo-Yin, 2.92 % at Chien-Chin and 2.02 % at Nan-Chie. The trends of O3 concentrations without meteorological-adjusted were 11.42 % at Tzuo-Yin, 20.92 % at Hsiung-Kong, 42.08 % at Chien-Chin and 13.69 % at Nan-Chie. The trends of PM10 concentrations in Kaohsiung County analyzed without meteorological-adjusted were 14.96 % at Lin-yuan and 3.24 % at Jen-wu. After meteorological factors eliminating, the trend was 3.15 % at Jen-wu but the trend was -2.53 % at Lin-yuan. Meteorological factor was a primary reason that influences the PM10 concentration in recent years. The trends of O3 in Kaohsiung County without meteorological-adjusted were 18.89 % at Da-liao, 4.40 % at Jen-wu, 35.16 % at Lin-yuan and 29.98 % at Mei-nung. After meteorological factors eliminating, the trends were 1.99 % at Da-liao, 2.23 % at Jen-wu, 1.16 % at Lin-yuan and -1.16 % at Mei-nung. The results show that the influence of meteorological factors for O3 trends was more sensitive in Kaohsiung county than in Kaohsiung city. The concentration of PM10 has no significant difference (64.8 ¡V 92.3 %) in Kaohsiung city. For the concentration of O3, the similarity (78 ¡V 100 %) was extensive in Kaohsiung city because O3 could diffuse easily. O3 episodes has no significant difference as PM10 episodes in Kaohsiung city. As above-mentioned, the results show that the contributions of ambient PM10 were individually but the contributions of ambient O3 were uniform extensively.