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A two-time-scale system involves both fast and slow dynamics. This paper studies the design of nonlinear observers for general nonlinear two-time-scale systems and presents a reduced-order observer design approach. The reduced-order observer is derived based on a lower dimensional model to reconstruct the slow states, along with the algebraic slow-motion invariant manifold function to reconstruct the fast states. Through an error analysis, it is shown that even though the observer is designed based on the reduced model by neglecting the fast dynamics, it is capable of providing accurate estimation of the states of the original detailed system. It will render a vanishing estimation error, with exponential convergence rate governed by the subsystem of fast dynamics and the chosen observer design parameters.

Due to the increasing occurrence of drought events, drought recovery has become equally important as drought resistance for long-term growth and survival of plants. However, information regarding the mechanism that controls growth recovery of herbaceous perennials is not available. In this study, perennial ryegrass (Lolium perenne) was rewatered after eight-day exposure to three drought intensities simulated by polyethylene glycol-6000. The growth, nonstructural carbohydrates (NSC, i.e. sucrose, glucose, fructose and starch), shoot δ13C, and activities of enzymes for sucrose conversion were monitored for 24 days after rewatering, allowing investigation of the dynamic of NSCs and its relation with growth in the recovery phase. In response to drought, growth and NSC content decreased mainly in shoot rather than root, and the total dry matter was negatively correlated to shoot δ13C. After rewatering, the growth of drought-treated groups still lagged behind that of control (CK) group for more than 16 days, but it was no longer correlated to shoot δ13C, suggesting that the limited growth is caused by non-stomatal factors related to photosynthesis. On day 24 after rewatering, the final growth of drought-treated groups caught up or even exceeded that of CK group, and was accompanied by higher dry weight root to shoot ratio (R/S) and root NSC content, which may facilitate water and nutrient acquisition and emergency of new tillers, respectively. During drought and subsequent recovery, the variation of R/S and root NSC content mainly attributed to root acid invertase rather than leaf sucrose phosphate synthase activity.

This article studies the problem of stabilizing a two-stage continuous bioreactor system. A simple dynamic model of the system is first introduced based on a detailed mass balance model, and then used to derive a constant-yield controller to stabilize the system at given design steady state conditions. Using Lyapunov stability analysis, this control law is proved to guarantee stability of the closed loop system over the entire positive orthant. Simulation results show the successful performance of the controller. The control law is proved to be robust with respect to errors in the kinetic parameters and in the inlet feed concentration, in the sense of preserving its stability region. Performance of the control system can be enhanced if a feed-forward measurement of the inlet feed concentration can be incorporated in the control law. © 2017 American Institute of Chemical Engineers AIChE J, 64: 1295–1304, 2018

Background/Aims: FK506 is an immunosuppressive drug and a calcineurin inhibitor that has been widely used in kidney disease in recent years. FK506 shows a wide range of biological and pharmaceutical effects; however, the mechanism of its anti- proliferative effect has not been well elucidated. An IgA nephropathy (IgAN) model was used to generate a mesangial cell proliferation model. This study aims to examine the effect of FK506 on IgAN rats and the underlying mechanisms. Methods: Hematuria, proteinuria and renal function were measured. To observe the pathological conditions, we performed HE (hematoxylin - eosin) and PAS (periodic acid - schiff) staining. Transcription and protein expression levels were detected by qRT - PCR (quantitative real-time polymerase chain reaction) and Wb (western blotting). The location and semi-quantitative expression levels of TRPCs, CaN (Calcineurin) and α-SMA were examined by IHC (Immunohistochemical staining). Results: We found that FK506 could improve hematuria, proteinuria and renal function, especially in the HF (high-dose FK506) groups. Renal pathological changes were ameliorated in the treatment groups. FK506 could significantly decrease TRPCs, CaN, phosphorylation of ERK1/2 and α-SMA expression. Conclusion: Taken together, these results suggest that the therapeutic effect of FK506 on IgAN might be partially associated with the down-regulated expression of TRPC channels, CaN and phosphorylation of ERK1/2.

This paper deals with the development, analysis and reduction of a two-stage anaerobic digestion process model. A two-stage model based on a two-step mass-balance model is first developed. The model incorporates two stages as two similar CSTRs, with acidogenesis in the first stage and mainly methanogenesis in the second. Steady state optimization validates the benefits of two-stage operation compared to the traditional one-stage process. Using reaction invariants, the dynamics of the fast modes is neglected by projecting the overall system dynamics on the slow-motion invariant manifold, and the original 7-state model is reduced to a 5th order system. By neglecting the nearly unobservable modes, the model is further reduced to 3rd order. Simulation results show excellent accuracy of the reduced model compared to the detailed one. At the same time, they indicate the necessity of process control for stabilization of the system.

Vascular calcification (VC) is a major contributor of cardiovascular dysfunction in chronic renal failure (CRF). Citrate binds calcium and inhibits the growth of calcium crystals. This present study intends to evaluate the effect of citrate on VC in adenine-induced CRF rats. The rats were randomly divided into five groups: the control group, the citrate control group, model group, model rats with low-dose treatment of citrate (216 mg/kg) and model rats with high-dose treatment of citrate (746 mg/kg). The rats were euthanized at 5 weeks with their blood and aorta in detection. The results showed that serum level of blood urea nitrogen, serum creatinine, phosphorus, calcium, and related renal failure function marker were elevated in the model group. Furthermore, the aortic calcium accumulation and alkaline phosphatase activity were significantly increased in the model group compared with control groups. Additionally, hematoxylin-eosin staining results demonstrated that the vascular calcification in aorta is significantly increased in the model group. Finally, the expression of VC-related proteins including bone morphogenetic protein and osteocalcin were increased in the model group, whereas alpha-smooth muscle actin was decreased in the model group compared with the control group. However, treatment with citrate caused a reversal effect of all the above events in a dose-dependent manner. In conclusion, citrate may attenuate vascular calcification in adenine-induced CRF rats.

Macrophages in the kidney play different roles in renal interstitial fibrosis (RIF) depending on their phenotypes. M2 phenotype macrophages are believed to protect the kidney against RIF. Free fatty acid receptor GPR120 is expressed in macrophages, and its activation induces macrophage transition to M2 phenotype. In this study, the effects of GPR120 agonist-programmed macrophages on RIF were investigated. The peritoneal macrophages collected from rats were incubated with GPR120 agonist TUG891 in vitro for 24 h, and then they were transplanted autologously to the kidney with ureteral obstruction by intrarenal injection for 7 days on the same day following unilateral ureteral obstruction (UUO) operation. RIF was identified by Masson trichrome histological staining, and the expression of RIF-related proteins was analyzed by immunohistochemistry and western blot. It was observed that TUG891-programmed macrophages up-regulated the expression of CD206 and arginase-1 while the expression of interleukin-6 and tumor necrosis factor-α were down-regulated. RIF in rats was significantly increased following UUO, which was markedly alleviated by TUG891-programmed macrophages but not untreated macrophages. TUG891-programmed macrophages inhibited the abnormal expression of TGF-β1 and SMAD2. The abnormal expression of epithelial-mesenchymal transition (EMT)-related proteins including vimentin, α-SMA and β-catenin was also significantly decreased in rats with transplantation of TUG891-programmed macrophages as compared to UUO rats. This study suggests that autologous administration of peritoneal macrophages programmed in vitro by GPR120 agonist to kidney has a protective effect against RIF following UUO.

Background/Aims The imbalance of T helper 17 (Th17) and regulatory T (Treg) cells exists in the occurrence and development of various diseases. Endoplasmic reticulum stress (ERS) is an important self-protective cellular response to harmful stimuli, such as uremic environment. The objective of this study was to investigate the Th17/Treg cell balance and ERS in a uremic environment and analyze the relationship between them. Methods (1) The rat spleen lymphocytes were extracted and treated with thapsigargin (inducer of ERS) and sodium citrate. The proportion of Th17 and Treg cells were then detected. (2) The uremic serum-cultured lymphocytes were used and divided into three groups: non-uremic serum group, uremic serum group, and uremic serum + sodium citrate group. Afterward, the proportion of Th17/Treg cells and the expression of ERS-related proteins (GRP78 and CHOP) were detected. Results Thapsigargin had no significant effect on the proportion of Th17 cells within a limited concentration range, but it could reduce the proportion of Treg cells, sodium citrate had a negative influence on the deviation of Th17/Treg cells treated with thapsigargin. Uremic serum treatment reduced the proportion of Treg cells, resulting in an increase of the Th17/Treg ratio. However, sodium citrate had no influence on the deviation of Th17/Treg cells treated by uremic serum. Sodium citrate reduced the elevation of ERS-related proteins induced by uremic serum. Conclusions Uremic serum can lead to the imbalance of Th17/Treg cells as well as ERS, suggesting that ERS is one of the mechanisms of the imbalance of Th17/Treg cells induced by uremic serum. Sodium citrate can inhibit ERS induced by uremic serum.

Owing to the increasing demand for large scale and high efficiency in manufacturing processes, computer aided tools for process operation and control are rapidly gaining popularity. An important state variable in aerobic processes is the dissolved oxygen, which can be easily measured online and is an important indicator of the metabolic activity. However, due to the fast kinetics of the oxygen transfer, dynamical models describing aerobic bioprocesses tend to be highly stiff. This can lead to significant numerical problems hampering its use for fixed step discretization methods and computationally costly applications such as computer fluid dynamics. In this work we use the slow-motion invariant manifold and the quasi steady state assumption methods to eliminate the differential equation describing the dissolved oxygen (the fast mode). By doing this, the tractability of the model is significantly increased with a neglectable loss in description power. The reduced model is also useful for simplifying the observer design problems, which is demonstrated by a state and parameter estimation example at the end of the work.

This thesis consists of three journal papers that I have been worked on during my PhD program of study. The first paper presents heuristic algorithms that are designed to be implemented and executed in parallel with an existing algorithm in order to overcome its two limitations. Computational experiments show that implementing the heuristic algorithm on one auxiliary processor in parallel with the existing algorithm on the main processor significantly improves its computational efficiency, in addition to providing a series of improving feasible upper bound solutions. In the second paper, we present two interactive models to jointly forecast PEV sales and the diurnal recharging load curve in the U.S. between 2012 and 2020. A case study is conducted for the Midwest ISO region. Compared to the sales forecasts from the literature, our results turn out to be less optimistic. Our recharging load forecast results also suggest that, if appropriately managed, the impact of PEVs on electricity load would not be overwhelming in the next decade. The third paper focuses on assessing and mitigating the potential impact of PEVs recharging load on power systems, Case study show that electricity rates with higher flexibility induces PEVs to have less impact on the power systems in terms of both generation cost and uncertainties. Also, PEV users higher recharging behavior responsiveness will improve the effectiveness of price incentives and the control ability of the power utilities under all types of TOU rates mechanisms.

Citrate is commonly used as an anticoagulant in hemodialysis for chronic renal failure (CRF) and for the regulation of the immune dysfunction in CRF patients. The objective of this study was to investigate the effect of citrate on the balance of T helper 17 (Th17) and regulatory T (Treg) cells in CRF. The levels of blood urea nitrogen (BUN) and serum creatinine (Scr) were significantly increased in the CRF model group compared to the control group, and were decreased in the citrate-treated groups. Citrate treatment inhibited the viability of Th17 cells while elevating the viability of Treg cells in CRF rats. Moreover, Th17-related cytokines significantly decreased while the Treg-related cytokines significantly increased with citrate treatment. Moreover, citrate had a negative influence on the deviation of Th17/Treg cells in CRF rats. Therefore, our study suggests that citrate had an anti-inflammatory effect on CRF through the modulation of the Th17/Treg balance.

Background/Aims: Endoplasmic reticulum stress (ERS) is an important self-protective cellular response to harmful stimuli that contribute to various diseases, including chronic renal failure (CRF). Sodium citrate plays an important role in antioxidant and cellular immunity, but whether it improves ERS in CRF is unclear. Methods: The rats were randomly divided into five groups: the control group, the sodium citrate control group, the model group, model rats with low dose sodium citrate (216 mg/kg), and model rats with a high dose of sodium citrate (746 mg/kg). The rats were euthanized at 6, 8, 12, and 16 weeks with their blood and renal tissue in detection. Results: The increased concentrations of blood urea nitrogen and serum creatinine in the model group were significantly decreased by sodium citrate treatment. Hematoxylin-eosin and Masson staining showed that sodium citrate treatment apparently improved renal pathological changes in CRF rats. Western blot analysis showed that sodium citrate treatment decreased the protein levels of transforming growth factor-beta 1 and collagen type IV, which were increased in model rats. Moreover, immunohistochemical staining demonstrated that sodium citrate could effectively reduce the protein expression of glucose-regulated protein 78 kDa and CCAAT/enhancer-binding protein homologous protein in the model rats, which was consistent with western blot results. Additionally, the high dose of sodium citrate had a stronger protective effect in CRF rats than the low dose of sodium citrate. Conclusions: Sodium citrate has a protective effect on CRF through its effects on ERS.

The two-stage continuous bioreactor system is an advanced configuration that could improve process production and system performance. Our paper studies the problem of feedback stabilization of this system. Based on a simple dynamic model, a constant-yield controller is derived to stabilize the system. Using Lyapunov stability analysis, this control law is proved to be able to regulate the system at the design steady state with stability basin the entire positive orthant. The control law is also proved to be robust to errors in influent concentration, in the sense of preserving the stability region.

Suppressor of cytokine signaling 1 (SOCS1) participates in renal fibrosis by downregulating Janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1)-mediated cytokine signalling. Recently, it was found that anti-double stranded DNA (dsDNA) IgG induces the synthesis of profibrotic cytokines by renal cells. To explore the potential effect of anti-dsDNA IgG on SOCS1-mediated renal fibrosis, kidney tissues were collected from patients with lupus nephritis as well as MRL/lpr lupus-prone mice. The SOCS1 expression was evaluated in tissue samples. In addition, SCID mice were injected with anti-dsDNA IgG, followed by evaluation of SOCS1 levels. Renal resident cells were cultured in vitro, receiving the stimulation of anti-dsDNA IgG and then the measurement of SOCS1, JAK2, STAT1α, and profibrotic cytokines. Moreover, the binding of anti-dsDNA IgG to SOCS1-kinase inhibitory region (KIR) peptide was analyzed by surface plasmon resonance. We found that SOCS1 expression was inhibited, but JAK2/STAT1 activation was prominent in the kidney tissues of patients with lupus nephritis, MRL/lpr mice, or anti-dsDNA IgG-injected SCID mice. The cultured renal cells also showed SOCS1 downregulation, JAK2/STAT1 activation, and profibrotic cytokine promotion upon anti-dsDNA IgG stimulation. Surprisingly, anti-dsDNA IgG showed high affinity to KIR peptide, and competed with JAK2 loop for KIR. Additionally, a DNA-mimicking peptide (ALW) blocked the binding of anti-dsDNA IgG to KIR, and even partially abrogated the activation of JAK2/STAT1α signals and the expression of profibrotic cytokines in SCID mice. In conclusion, anti-dsDNA IgG downregulates SOCS1 expression, activates JAK2/STAT1 signals, and contributes to renal fibrosis; its peptide blockade may restore the SOCS1 inhibitory effect on the production of profibrotic cytokines, and finally ameliorate renal fibrosis in lupus nephritis.

Reversible addition&ndash, fragmentation chain&ndash, transfer (RAFT) polymerization of methyl methacrylate (MMA) is modeled and monitored using a multi-rate multi-delay observer in this work. First, to fit the RAFT reaction rate coefficients and the initiator efficiency in the model, in situ 1 H nuclear magnetic resonance (NMR) experimental data from small-scale (&lt, 2 mL) NMR tube reactions is obtained and a least squares optimization is performed. 1 H NMR and size exclusion chromatography (SEC) experimental data from large-scale (&gt, 400 mL) reflux reactions is then used to validate the fitted model. The fitted model accurately predicts the polymer properties of the large-scale reactions with slight discordance at late reaction times. Based on the fitted model, a multi-rate multi-delay observer coupled with an inter-sample predictor and dead time compensator is designed, to account for the asynchronous multi-rate measurements with non-constant delays. The multi-rate multi-delay observer shows perfect convergence after a few sampling times when tested against the fitted model, and is in fair agreement with the real data at late reaction times when implemented based on the experimental measurements.

The expected market penetration of plug-in electric vehicles has drawn much attention to the potential impact on power systems, which to a large extent depends on the number of electric vehicles on the road and the fleet's diurnal recharging load curve. We present two interactive models to jointly forecast plug-in electric vehicle sales and the diurnal recharging load curve in the U.S. between 2012 and 2020. The sales forecasting model is based on information about consumer preferences between hybrid electric vehicles and internal combustion engine vehicles, which can be extracted from historical data. The recharging load forecasting model is based on the assumption that electric vehicle users' recharging behavior will demonstrate a gradual transition from a convenience driven mode in 2012 to a cost driven mode in 2020. A case study is conducted for the Midwest ISO region. Compared to the sales forecasts from the literature, our results turn out to be less optimistic. Our recharging load forecast results also suggest that, if appropriately managed, the impact of plug-in electric vehicles on electricity load would not be overwhelming in the next decade.

Ghrelin can act as a signal for mealtime hunger and meal initiation. Amygdala is indispensable in appetitive behavior motivated by learned emotions. This study was to investigate the alteration of ghrelin in the amygdala of rats with chronic renal failure (CRF) and its relation with uremic anorexia.SD rats were randomly classified into CRF group and control group (n=16 per group). The CRF model was constructed using 5/6 nephrectomy. When plasma creatinine (PCr) and blood urea nitrogen (BUN) in the CRF group were twice more than the normal level, food intake (g/24h) was measured and then all rats were killed for detection of ghrelin protein expression in the amygdala using immunohistochemical analysis and mRNA expression using RT-PCT. Statistics was conducted with one-way analysis of variance, Student-Newman-Keuls-q test and correlation analysis.By the 8th week after the surgery, the BUN and PCr of CRF rats exceeded double the normal level, and their food intake was obviously decreased compared with the controls (P0.05). The protein and mRNA expression of ghrelin in the amygdala of CRF group were significantly reduced, and there was a positive correlation between this reduction and the decrease in food intake (P0.05).The reduction of amygdala's ghrelin in CRF rats may be associated with uremic anorexia.

Comprehensive and revealing performance measures are critical for the assessment of long-term investment plans. In this paper are defined three performance measures for long-term investment planning in integrated energy and transportation infrastructures: cost, sustainability, and resiliency. Whereas the first measure can be defined relatively straightforwardly, there exist significant ambiguity and discrepancy in the definitions of the last two in the existing literature. Different qualitative descriptions have been made in various research contexts, yet few studies have provided quantifiable definitions. This paper provides quantitative definitions of sustainability and resiliency measures that are appropriate for assessing long-term investment decisions in an integrated energy and transportation system. Sustainability is defined using the time duration for which the system will be able to satisfy operational and environmental requirements. Resiliency is measured as the cost to transition from a precontingency state to a postrecovery state. A case study using representative U.S. coal transportation and electricity transmission networks is conducted to demonstrate the assessment methods.

To investigate the relationship between the regulatory immune network and endoplasmic reticulum stress (ERS) in patients with different stages of chronic kidney disease (CKD). A total of 91 patients diagnosed with CKD were divided into different groups according to the stage of disease and treatment with hemodialysis (HD) or peritoneal dialysis (PD). Routine blood and biochemical tests were performed in patients in the different CKD groups and in healthy controls (n = 20). The frequencies of T helper type 17 (Th17) and regulatory T (Treg) cells in the overall T cell population were measured by flow cytometric analysis. Levels of Th17 cell (IL-17) and Treg cell (IL-10) cytokines and the ERS markers CCAAT-enhancer-binding protein homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) were measured by enzyme-linked immunosorbent assay in serum samples collected from controls and patients. Correlations between each parameter and serum creatinine were analyzed by Spearman rank correlation and regression test. CKD stage showed a positive correlation with serum creatinine level, and increased and decreased percentages of Th17 and Treg cells, respectively, reflected in an increased Th17/Treg cell ratio. Consistent with this, CKD stage was positively correlated with serum concentrations of IL-17 and negatively correlated with serum IL-10 levels. Moreover, serum levels of CHOP and GRP78 increased with advancing CKD stage. These correlations were most pronounced in patients in the CKD5 group, who also had the poorest response to HD and PD treatment, compared with CKD5 patients in the nondialysis group. Correlation analysis showed that serum levels of CHOP and GRP78 were independently and positively correlated with the ratio of Th17/Treg cells. We have found that an increased Th17/Treg cell ratio and increased serum levels of ERS markers correlate with the progression of CKD. Our results indicate that the interplay between regulation of the immune network and management of ERS is closely associated with the pathogenesis of CKD. Although HD and PD treatment manage chronic kidney conditions and prevent further deterioration of renal function, they have limited effects on improving the immune disorder and relieving ERS. Our study suggests a potential new direction for development of therapeutic strategies in CKD.

Type 2 diabetic nephropathy (DN) is a serious end-stage kidney disease worldwide. Multiple studies demonstrate that resveratrol (RSV) has a beneficial effect on DN. However, whether RSV-induced improvement in kidney function in diabetes is due to the regulation of autophagy remains unclear. Here, we investigated the mechanisms underlying RSV-mediated protection against DN in diabetic rats, with a special focus on the role of NAD-dependent deacetylase sirtuin 1 (Sirt1) in regulating autophagy. We found that long-term RSV treatment in rats promoted Sirt1 expression and improved related metabolic levels in the diabetic kidney. Our study showed that, in cultured NRK-52E cells, Sirt1 knockdown inhibited the autophagy levels of proteins Atg7, Atg5, and LC3 and impaired the RSV amelioration of dysfunctional autophagy under hypoxic condition. Furthermore, exposed to 1% O2 over time induced autophagy dysfunction and apoptosis in NRK-52E cells, which could be improved by RSV treatment. Our data highlight the role of the Sirt1-mediated pathway in the effects of RSV on autophagy in vivo and in vitro, suggesting RSV could be a potential new therapy for type 2 DN.

OBJECTIVE:This study was to investigate whether sorafenib can inhibit the progression of renal fibrosis and to study the possible mechanisms of this effect. METHODS:Eight-week-old rats were subjected to unilateral ureteral obstruction (UUO) and were intragastrically administered sorafenib, while control and sham groups were administered vehicle for 14 or 21 days. NRK-52E cells were treated with TGF-β1 and sorafenib for 24 or 48 hours. HE and Masson staining were used to visualize fibrosis of the renal tissue in each group. The expression of α-SMA and E-cadherin in kidney tissue and NRK-52E cells were performed using immunohistochemistry and immunofluorescence. The apoptosis rate of NRK-52E cells was determined by flow cytometry analysis. The protein levels of Smad3 and p-Smad3 in kidney tissue and NRK-52E cells were detected by western blot analysis. RESULTS:HE staining demonstrated that kidney interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration in the sorafenib-treated-UUO groups were significantly decreased compared with the vehicle-treated-UUO group (p

Aims To clarify whether activation of adenosine monophosphate-activated protein kinase (AMPK) by metformin inhibits transforming growth factor beta (TGF-β)-induced collagen production in primary cultured mouse renal fibroblasts and further to address the molecular mechanisms. Main methods Primary cultured mouse renal fibroblasts were stimulated with TGF-β1 and the sequence specific siRNA of Smad3 or connective tissue growth factor (CTGF) was applied to investigate the involvement of these molecular mediators in TGF-β1-induced collagen type I production. Cells were pre-incubated with AMPK agonist metformin or co-incubated with AMPK agonist metformin and AMPK inhibitor Compound C before TGF-β1 stimulation to clarify whether activation of AMPK inhibition of TGF-β1-induced renal fibroblast collagen type I expression. Key findings Our results demonstrate that TGF-β1 time- and dose-dependently induced renal fibroblast collagen type I production; TGF-β1 also stimulated Smad3-dependent CTGF expression and caused collagen type I generation; this effect was blocked by knockdown of Smad3 or CTGF. Activation of AMPK by metformin reduced TGF-β1-induced collagen type I production by suppression of Smad3-driven CTGF expression. Significance This study suggests that activation of AMPK might be a novel strategy for the treatment of chronic kidney disease (CKD) partially by inhibition of renal interstitial fibrosis (RIF).