SURROGATE SEARCH: A SIMULATION OPTIMIZATION METHODOLOGY FOR LARGE-SCALE SYSTEMS

For certain settings in which system performance cannot be evaluated by analytical methods, simulation models are widely utilized. This is especially for complex systems. To try to optimize these models, simulation optimization techniques have been developed. These attempt to identify the system designs and parameters that result in (near) optimal system performance. Although more realistic results can be provided by simulation, the computational time for simulator execution, and consequently, simulation optimization may be very long. Hence, the major challenge in determining improved system designs by incorporating simulation and search methodologies is to develop more efficient simulation optimization heuristics or algorithms. This dissertation develops a new approach, Surrogate Search, to determine near optimal system designs for large-scale simulation problems that contain combinatorial decision variables. First, surrogate objective functions are identified by analyzing simulation results to observe system behavior. Multiple linear regression is utilized to examine simulation results and construct surrogate objective functions. The identified surrogate objective functions, which can be quickly executed, are then utilized as simulator replacements in the search methodologies. For multiple problems containing different settings of the same simulation model, only one surrogate objective function needs to be identified. The development of surrogate objective functions benefits the optimization process by reducing the number of simulation iterations. Surrogate Search approaches are developed for two combinatorial problems, operator assignment and task sequencing, using a large-scale sortation system simulation model. The experimental results demonstrate that Surrogate Search can be applied to such large-scale simulation problems and outperform recognized simulation optimization methodology, Scatter Search (SS). This dissertation provides a systematic methodology to perform simulation optimization for complex operations research problems and contributes to the simulation optimization field

Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase.

Gamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC) hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH). In addition, Propylthiouracil (PTU), beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we investigated the possible involvement of gamma-secretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotaline-induced PAH, PTU therapy improved pulmonary arterial hypertrophy and hemodynamics. In vitro, treatment of PASMCs from monocrotaline-treated rats with PTU inhibited their proliferation and migration. Immunocyto, histochemistry, and western blot showed that PTU treatment attenuated the activation of Notch3 signaling in PASMCs from monocrotaline-treated rats, which was mediated via inhibition of gamma-secretase expression especially its presenilin enhancer 2 (Pen-2) subunit. Furthermore, over-expression of Pen-2 in PASMCs from control rats increased the capacity of migration, whereas knockdown of Pen-2 with its respective siRNA in PASMCs from monocrotaline-treated rats had an opposite effect. Transfection of PASMCs from monocrotaline-treated rats with Pen-2 siRNA blocked the inhibitory effect of PTU on PASMC proliferation and migration, reflecting the crucial role of Pen-2 in PTU effect. We present a novel cell-signaling paradigm in which overexpression of Pen-2 is essential for experimental pulmonary arterial hypertension to promote motility and growth of smooth muscle cells. Propylthiouracil attenuates experimental PAH via suppression of the gamma-secretase-mediated Notch3 signaling especially its presenilin enhancer 2 (Pen-2) subunit. These findings provide a deep insight into the pathogenesis of PAH and a novel therapeutic strategy

Parameters Affecting the Antimicrobial Properties of Cold Atmospheric Plasma Jet

Using the Taguchi method to narrow experimental parameters, the antimicrobial efficiency of a cold atmospheric plasma jet (CAPJ) treatment was investigated. An L9 array with four parameters of CAPJ treatments, including the application voltage, CAPJ-sample distance, argon (Ar) gas flow rate, and CAPJ treatment time, were applied to examine the antimicrobial activity against Escherichia coli (E. coli). CAPJ treatment time was found to be the most influential parameter in its antimicrobial ability by evaluation of signal to noise ratios and analysis of variance. 100% bactericidal activity was achieved under the optimal bactericidal activity parameters including the application voltage of 8.5 kV, CAPJ-sample distance of 10 mm, Ar gas flow rate of 500 sccm, and CAPJ treatment time of 300 s, which confirms the efficacy of the Taguchi method in this design. In terms of the mechanism of CAPJ’s antimicrobial ability, the intensity of hydroxyl radical produced by CAPJ positively correlated to its antimicrobial efficiency. The CAPJ antimicrobial efficiency was further evaluated by both DNA double-strand breaks analysis and scanning electron microscopy examination of CAPJ treated bacteria. CAPJ destroyed the cell wall of E. coli and further damaged its DNA structure, thus leading to successful killing of bacteria. This study suggests that optimal conditions of CPAJ can provide effective antimicrobial activity and may be grounds for a novel approach for eradicating bacterial infections

Characteristics of the experimental study groups.

<p>MCT = monocrotaline; PTU = propylthiouracil; PA = pulmonary artery; T3 = triiodothyronine</p><p>All data are presented as mean ± SE; *p-value<0.05, ^✝p-value<0.01, ǂp-value<0.001versus MCT</p><p>Characteristics of the experimental study groups.</p

Effect of PTU on serum-induced PASMC proliferation and migration.

<p>After 24 hours of serum deprivation, PASMCs from MCT rats were treated with indicated conditions for 24 hours. Translocation of proliferating cell nuclear antigen (PCNA, red staining; scale bar: 75μm) into the nucleus <b>(A)</b> and BrdU incorporation <b>(B)</b> were used to represent proliferative activities of PASMCs. Each value (mean±SE [n = 6]) is expressed as fold change of BrdU incorporation in control cells with 0.1% FBS. (<b>C)</b> Migratory activity of PASMC was assessed by migration assay chamber. After treatment with indicated conditions for 6 hours, PASMCs from MCT rats at the lower aspect of filter membrane was fixed and stained with Liu’s stain (pink staining; magnification 100X). (<b>D)</b> Each value (mean±SE [n = 6]) is determined by cell number at the lower aspect of filter membrane, and expressed as a percentage of control. *p<0.05, **p<0.01, ***p<0.001 versus 10% FBS without PTU, one-way ANOVA, bonferroni’s post test.</p

Effect of PTU on pulmonary hemodynamics and pulmonary arterial hypertrophy.

<p>(A) Right ventricle systolic pressure (RVSP) in 4 different groups is shown. Pulmonary hypertension (indicated by elevated RVSP) was established 28 days after MCT injection and PTU treatment (5 mg/100g/day by gavage from day 14 to 28) reduced RVSP in MCT-treated rats. (B) Ratio of RV to LV plus septum weight (RV/LV+S) is shown. (C) Medial wall thickness of small pulmonary arteries (25–50μm) identified by α-SM-actin staining (brown staining) is shown. (D) The degree of medial wall thickness was compared among 4 groups. Each value (mean±SE [n = 6–7]) is expressed. ***p<0.001 versus control or MCT group, one-way ANOVA, bonferroni's post-test.</p

Effect of PTU on gamma-secretase subunit expression in cultured PASMCs.

<p>(A, C) After 24 hours of serum deprivation, PASMCs from control or MCT rats were treated with indicated conditions for 24 hours. Western blot shows gamma-secretase subunit expression in whole cell extraction. (B, D, F) The relative expression level of each protein is quantified by densitometry and normalized to GAPDH. (E) PASMCs from control rats were treated with indicated conditions for 24 hours. Western blot shows gamma-secretase subunit expression in whole cell extraction. Each value represents the mean±SE of 4 independent experiments. *P<0.05, **p<0.01, ***p<0.001 versus control PASMCs without PTU or scrambled peptide or Normaxia, one-way ANOVA, bonferroni’s post test.</p

Effect of PTU on Notch3 and gamma-secretase subunit expression in proximal and distal pulmonary arteries.

<p>Immuohistochemistry shows Notch3 expression in the proximal part (A) (scale bar: 20μm; L: vascular lumen) and the distal part of pulmonary arteries (B) (scale bar: 20μm). Notch3 in medial layer of pulmonary arteries was identified by α-SM-actin double staining for vascular SMC. The picture is a representative of 4 independent experiments.</p

Effect of Pen-2 over-expression on PASMC proliferation and migration.

<p><b>(A)</b> After transfection with indicated plasmids for 24 hours, PASMCs from control rats were treated with or without 10mmol/L PTU for 24 hours. Immunocytochemistry shows Pen-2 localization (green staining; nuclear staining with DAPI in blue, rhodamine-phalloidin staining in red, and Pen-2/phalloidin merging in yellow; scale bar: 75 and 20μm). The picture is a representative of 4 independent experiments. After transfection with indicated plasmids for 24 hours, PASMCs from control rats were treated with or without 10mmol/L PTU for 24 hours. Migration chamber assay <b>(B)</b> and BrdU incorporation <b>(C)</b> were used to assess migratory and proliferative activities of PASMCs, respectively. Each value represents the mean±SE of 4 independent experiments. ***p<0.001 PTU versus vehicle; ¶¶¶ p<0.001 Pen-2/vehicle versus control vector/vehicle. (<b>D)</b> After transfection with indicated plasmids for 24 hours, western blot shows over-expression of Pen-2 in PASMCs from control rats. Lower panel: The relative expression level of each protein is quantified by densitometry and normalized to GAPDH. Each value represents the mean ± SE of 4 independent experiments. **p<0.01 versus control vector</p