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Purpose To evaluate the anticancer activities of lenvatinib in ICC and its possible molecular mechanisms. Methods Patients-derived xenograft (PDX) model and cell line-derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyze the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism. Results In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G0/G1 phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC. Conclusion Our work first found that lenvatinib exerted an excellent antitumor effect on ICC, mainly via inducing Gadd45a-mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC.

BACKGROUND Many patients with primary membranous nephropathy have severe proteinuria unresponsive to optimized renin-angiotensin-aldosterone system inhibitors (RAASi). We evaluated the efficacy and safety of hydroxychloroquine as an adjunctive agent in membranous nephropathy (MN) treatments. METHODS We prospectively recruited 126 patients with biopsy-proven primary membranous nephropathy and urinary protein 1-8 g/day while receiving optimized RAASi treatment for ≥ 3 months and well-controlled blood pressure. Forty-three patients received hydroxychloroquine and RAASi (hydroxychloroquine-RAASi group), and 83 patients received RAASi alone (RAASi group). Treatment responses, including proteinuria reduction, complete and partial remission rates, and autoantibody against phospholipase A2 receptor (anti-PLA2R) levels, were compared between the two groups at 6 months and over the long term. RESULTS At 6 months, the effective response rate (proteinuria reduction > 30%) (57.5% vs. 28.9%, P = 0.002), clinical remission rate (35.0% vs. 15.7%, P = 0.015), and percentage change in proteinuria (- 51.7% vs. - 21.9%, P

Universal challenge lies in torque feedback accuracy for steer-by-wire systems, especially on uneven and low-friction road. Therefore, this paper proposes a fusion method based on Kalman filter that combines a dynamics-reconstruction method and disturbance observer-based method. The dynamics- reconstruction method is designed according to the vehicle dynamics and used as the prediction model of the Kalman filter. While the disturbance observer-based method is performed as an observer model of the Kalman filter. The performance of all three methods is comprehensively evaluated in a hardware-in-the-loop system. Experimental results show that the proposed fusion method outperforms dynamics reconstruction method and disturbance observer-based method. Specifically, compared with the dynamics-reconstruction method, the root mean square error is reduced by 36.58% at the maximum on the flat road. Compared with the disturbance observer-based method, the root mean square error is reduced by 39.11% at the maximum on different-friction and uneven road.

This paper reported a wine-derived lactic acid bacterium, Lactiplantibacillus plantarum XJ25, which exhibited higher cell viability under acid stress upon methionine supplementation. Cellular morphology and the composition of the cytomembrane phospholipids revealed a more solid membrane architecture presented in the acid-stressed cells treated with methionine supplementation. Transcriptional analysis showed L. plantarum XJ25 reduced methionine transport and homocysteine biosynthesis under acid stress. Subsequent overexpression assays proved that methionine supplementation could alleviate the cell toxicity from homocysteine accumulation under acid stress. Finally, L. plantarum XJ25 employed energy allocation strategy to response environmental changes by balancing the uptake methionine and adjusting saturated fatty acids (SFAs) in membrane. These data support a novel mechanism of acid resistance involving methionine utilization and cellular energy distribution in LAB and provide crucial theoretical clues for the mechanisms of acid resistance in other bacteria.

Container slot allocation for liner shipping services is to allocate the limited container slots of ships to different segments of demands in order to maximize the total revenue over a shipping network. This study focuses on a planning-level container slot allocation problem with uncertain demand, which is essential in container shipping revenue management. Due to the challenge of calibrating/formulating a specific probability distribution of uncertain container slot demand, we can rely on its fundamental descriptive statistics, namely, mean, upper/lower bounds as well as variance to tackle the container slot allocation problem. We, therefore, develop a robust optimization model using the fundamental descriptive statistics, which is approximated by a solvable second-order cone programming model. A numerical example based on a real shipping network demonstrates that the optimal solution from the second-order cone programming model outperforms the models using the expectation of uncertain demand data and the normally distributed demand. The numerical results indicate that the robust optimization model can well deal with the large fluctuations of uncertain container slot demand.

Rivaroxaban, an oral anticoagulant, undergoes the metabolism mediated by human cytochrome P450 (CYP). The present study is to quantitatively analyze and compare the contributions of multiple CYPs in the metabolism of rivaroxaban to provide new information for medication safety. The metabolic stability of rivaroxaban in the presence of human liver microsomes (HLMs) and recombinant CYPs was systematically evaluated to estimate the participation of various CYP isoforms. Furthermore, the catalytic efficiency of CYP isoforms was compared via metabolic kinetic studies of rivaroxaban with recombinant CYP isoenzymes, as well as via CYP-specific inhibitory studies. Additionally, docking simulations were used to illustrate molecular interactions. Multiple CYP isoforms were involved in the hydroxylation of rivaroxaban, with decreasing catalytic rates as follows: CYP2J2 > 3A4 > 2D6 > 4F3 > 1A1 > 3A5 > 3A7 > 2A6 > 2E1 > 2C9 > 2C19. Among the CYPs, 2J2, 3A4, 2D6, and 4F3 were the four major isoforms responsible for rivaroxaban metabolism. Notably, the intrinsic clearance of rivaroxaban catalyzed by CYP2J2 was nearly 39-, 64-, and 100-fold that catalyzed by CYP3A4, 2D6, and 4F3, respectively. In addition, rivaroxaban hydroxylation was inhibited by 41.1% in the presence of the CYP2J2-specific inhibitor danazol, which was comparable to the inhibition rate of 43.3% by the CYP3A-specific inhibitor ketoconazole in mixed HLMs. Furthermore, molecular simulations showed that rivaroxaban is principally bound to CYP2J2 by π-alkyl bonds, carbon-hydrogen bonds, and alkyl interactions. CYP2J2 dominated the hydroxylation of rivaroxaban, which may provide new insight into clinical drug interactions involving rivaroxaban.

Mitochondrial dysfunction is closely related to the occurrence of epilepsy. Homeostasis of mitochondrial fusion and division can alleviate mitochondrial dysfunction. The trafficking kinesin protein 1 (TRAK1) is a key regulator of mitochondrial movement and regulates mitochondrial fusion-fission balance. The pathogenic variants in TRAK1 result in the severe neurodevelopmental disorders. However, the role of TRAK1 in epilepsy remains unclear. In the present study, we report that TRAK1 has a crucial function in regulation of epileptogenesis in temporal lobe epilepsy (TLE). TRAK1 expression is decreased in the patient specimens and animal model of TLE. Knockdown of TRAK1 causes an increase in mitochondrial fission factor (MFF) in vitro and the susceptibility to seizures in vivo. Exogenous overexpression of TRAK1 can rescue the dysfunction caused by TRAK1 knockdown. These findings provide new insights into the fundamental mechanisms of TRAK1 in TLE and have important implications for understanding and treating TLE via targeting mitochondrion.

Characterizing the response of temperature variables to agricultural irrigation is expected to be an important challenge for understanding the full impact of water management on regional climate change. In this paper, the trend analysis and abrupt change test were applied to detect the global warming effect. Then, the quantitative irrigation-induced cooling effects on temperature variables between April and August from 1970 to 2010 in the Lhasa River basin were estimated using historical time series of gridded meteorological records and a map of the area equipped for irrigation. Trends in the maximum temperature (Tmax) were statistically positive, and a significant increasing trend for the minimum temperature (Tmin) was detected at the 0.01 and 0.05 confidence levels. No abrupt changing point of warming was detected in the time series for Tmax. The abrupt changes in Tmin in the irrigation concentration period took place in 1995, 5 years later than the corresponding change in April. Affected by global warming, the increase in temperature was the largest in July and August, when the irrigation-induced cooling effect was also the most significant. The irrigation-induced cooling effect for Tmax and Tmin in April–August (except for June) ranged from − 0.017 to − 0.009 °C/decade and from − 0.011 to − 0.001 °C/decade, respectively, and the cooling effect for diurnal temperature range (DTR) ranged from − 0.011 to 0 °C/decade. The cooling effect on temperature reached above 0.01 °C in July and August, but for the growing seasons, the effect was weak, only 0.001 °C. The Tmax and Tmin trends during the whole growing seasons decreased by both 0.002 °C/decade, respectively, with a 10% increase in irrigation land proportion. Even in July and August, the trends were expected to decrease by about 0.005 °C/decade with a 10% increase in irrigation land proportion. The irrigation-induced cooling effect could partially slow global warming.

The rapid development of autonomous vehicles (AV) in recent years has drawn the attention of numerous countries in terms of its feasibility for use and deployment as individually-owned vehicles or for large-scale fleet planning and deployment as a mobility-on-demand (MOD) service. Singapore is no exception to this global trend and in her pursuit to be smart and car-lite, numerous efforts are made to have AV trials in place and test out their potential deployment in the city state. As one of the many prerequisites of AV planning, public perception on AV plays a vital role when designing any potential AV deployment scheme. As such, a stated preference survey comprising both online survey and field interviews/surveys, was performed island-wide to understand how commuters in Singapore perceive about different AV-based MOD modes. The logit kernel model is adopted to determine how different preference attributes and key demographic indicators can affect the use of AV-based MOD services over other existing first- and last-mile connection modes. The model results have identified how demographics such as gender, age, housing type, education level and income level can influence the travel mode choice. Also, the impacts brought by individuals’ stated preferences over convenience, privacy and familiarity of ride-hailing apps are also investigated. Such findings can provide useful insight in planning future car-lite towns and implementing AV-based MOD services in these towns.

Although there are many studies involving influence of runaway truck entry speed and longitudinal grade on stopping distance, focusing on aggregate properties is scarce. This paper investigates the influence of the aggregate properties such as types of aggregate and river gravel radius on stopping distance through numerical analysis of particle flow code in two dimensions (PFC2D). The software is used to generate stopping distance data for two aggregate types and four group gravel radii under various approaching speeds and grades. The generated data are compared with the testing results of full-scale arrester bed. The simulated finding of this paper implies that types of aggregates and river gravel radii have a significant impact on the stopping distance for runaway truck on escape ramps.

This study aimed to investigate the complications and recurrence rates of the different surgical procedures implemented in recent years for the treatment of grade III and IV hemorrhoids using a network meta-analysis approach. A systematic literature search was conducted for randomized clinical trials (RCTs) published from January 2013 to August 2018, via PubMed, Embase, the Cochrane Library, and Web of Science. Data related to anal stenosis, fecal incontinence, hemorrhoids thrombosis, and recurrence rates were extracted from the included studies, which were selected based on associations with surgical procedures for grade III and IV hemorrhoids. A network meta-analysis was conducted by using the automated software Aggregate Data Drug Information System (ADDIS) 1.16.8 to evaluate and rank the safety and efficacy of the different surgical methods. Twenty-one studies with 2799 participants involving nine surgical procedures for grade III and IV hemorrhoids were ultimately analyzed. Transanal hemorrhoidal dearterialization (THD) and stapled hemorrhoidectomy (SH) exhibited fewer anal stenosis than open hemorrhoidectomy (OH) and Harmonic scalpel (Harmonic). SH presented the highest fecal incontinence rates. OH and Harmonic presented lower hemorrhoids thrombosis than SH and THD. Importantly, SH and THD exhibited the highest recurrence rates, when compared with the other hemorrhoidectomy surgical procedures. In summary, THD and SH were found to be associated with more complications and higher recurrence rates. In addition, the use of OH treatments resulted in less hemorrhoids thrombosis rate but higher recurrence rate. The use of Harmonic resulted in higher anal stenosis rate but lower recurrence rate.

Hyperhomocysteinemia (HHCY) has been recognized as an independent risk factor for atherosclerosis and plays a vital role in the development of atherosclerosis. Catalpol, an iridoid glucoside extracted from the root of Rehmannia glutinosa, can produce anti-inflammatory, anti-oxidant, anti-tumor, and dopaminergic neurons protecting effects. This study aimed to determine the protecting effects of catalpol against homocysteine (HCY)-induced injuries in human aortic endothelial cells (HAECs) and uncover the underlying mechanisms: 1. HAECs were cultured with different concentrations of HCY (3 mM) and catalpol (7.5 μΜ, 15 μΜ, 30 μΜ) for 24 h. (1) The level of MDA and GSH as well as LDH release was measured with colorimetric assay. (2) Reactive oxygen species (ROS) were detected by flow cytometry analysis. (3) Western blotting analysis was performed to detect the expression of Nox4, p22phox, ICAM-1, MCP-1, VCAM-1, IκB, nucleus p65, p65 phosphorylation, caspase-3, −9, bax, bcl-2, and ER stress-related proteins. (4) The expressions of CHOP, ATF4 were measured by qRT-PCR. (5) Mitochondrial membrane potential in HCY-treated HAECs was measured by rhodamine 123 staining, and the samples were observed by confocal laser scanning microscopy. 2. DPI, PDTC, and TUDCA were used to determine the interaction among Nox4/ROS, NF-κB, and endoplasmic reticulum stress. 3. TUDCA or Nox4 siRNA were used to investigate whether the effect of catalpol inhibiting the over-production of ROS were associated with inhibiting ER stress and Nox4 expression. Catalpol significantly suppressed LDH release, MDA level, and the reduction of GSH. Catalpol reduced HCY-stimulated ROS over-generation, inhibited the NF-κB transcriptional activation as well as the protein over-expressions of Nox4, ICAM-1, VCAM-1, and MCP-1. Catalpol elevated bcl-2 protein expression and reduced bax, caspase-3, −9 protein expressions in the HCY-treated HAECs. Simultaneously, catalpol could also inhibit the activation of ER stress-associated sensors GRP78, IRE1α, ATF6, P-PERK, P-eIF2α, CHOP, and ATF4 induced by HCY. In addition, the extent of catalpol inhibiting ROS over-generation and NF-κB signaling pathway was reduced after inhibiting Nox4 or ER stress with DPI or TUDCA. The inhibitor of NF-κB PDTC also reduced the effects of catalpol inhibiting the expressions of Nox4 and GRP78. Furthermore, the effect of catalpol inhibiting the over-generation of ROS was reduced by Nox4 siRNA. Catalpol could ameliorate HCY-induced oxidation, cells apoptosis and inflammation in HAECs possibly by inhibiting Nox4/NF-κB and ER stress.

Intercontinental liner shipping services transport containers between two continents. This paper forecasts the number of containers to be transported through long-haul legs for the incoming trip of an intercontinental shipping service. Considering the clear and unique container slot booking patterns in the historical data, three different forecasting models are developed, including piecewise linear regression model, autoregressive model, and artificial neural network model. These three models are further combined into an integrated model to simultaneously incorporate their merits in formulating the container slot booking patterns. Test results show satisfactory forecasting precisions of the integrated forecasting model.

In order to optimize the artificial intelligence routing algorithm, combined with the calculation of the direction of the vector space model, three strategies are proposed to optimize the A* algorithm. The A* algorithm is widely used in the fields of GIS system and game path finding system. However, with the expansion of the scale of the search map, its performance consumption has increased exponentially. First of all, the first step of A* algorithm is to move towards the target direction by using directional factors, so that the intermediate route process will approach the shortest path as soon as possible. Secondly, the direction factor is used to ensure that the path finding of A* algorithm is the priority point in the direction of the target. Finally, the fault tolerance process is carried out. When the direction factor is guided to the “dead end”, it can be traced back, to ensure that the shortest path can be found at the end. The results show that the A * optimization algorithm is effective. The performance of A * optimization algorithm is about 20–50% higher than the traditional A * algorithm. The best case reached 88.6%. Therefore, the proposed optimization method improves the efficiency of the algorithm and reduces the performance consumption of the algorithm.

Background Complement activation plays a substantial role in the pathogenesis of primary membranous nephropathy (pMN). C5b-9, C3c, MBL, and factor B have been documented in the subepithelial immune deposits. However, the changing of complement activation products in circulation and urine is not clear. Methods We measured the circulating and urinary levels of C1q, MBL, C4d, Bb, properdin, C3a, C5a, and sC5b-9, in 134 patients with biopsy-proven pMN, by enzyme-linked immunosorbent assay. All the plasma values were corrected by eGFR and all the urinary values were corrected by urinary creatinine and urinary protein excretion. Anti-PLA2R antibodies were measured in all patients. Results The plasma complement activation products were elevated both in the patients with and without anti-PLA2R antibodies. C3a levels were remarkably increased in the circulation and urine, much higher than the elevated levels of C5a. C5b-9 was in normal range in plasma, but significantly higher in urine. The urinary C5a had a positive correlation with anti-PLA2R antibody levels and urinary protein. The plasma level of C4d was elevated, but C1q and MBL were comparable to healthy controls. Positive correlations were observed between plasma C4d/MBL and urinary protein, only in the patients with positive anti-PLA2R antibodies but not in those without. The plasma level of Bb was elevated and had positive correlation with urinary protein only in the patients without anti-PLA2R antibodies. Conclusion Complement activation products were remarkable increased in pMN and may serve as sensitive biomarkers of disease activity. The complement may be activated through lectin pathway with the existence of anti-PLA2R antibodies, while through alternative pathway in the absence of antibody.

Background The clinical outcome varies considerably in primary membranous nephropathy (pMN). Risk factors for kidney prognosis include ageing, male gender, persistent heavy proteinuria, decreased eGFR at presentation, persistent elevation of anti-PLA2R antibodies, no remission, and so on. It was controversial whether the histopathological features of pMN could predict treatment response and kidney outcome. Methods A retrospective study was conducted in 371 patients with biopsy-proven pMN. Pathological parameters included immunofluorescence staining, membranous Churg’s stages, sclerosis, crescent, focal segmental sclerosis lesion, chronic and acute tubulointerstitial injury. The fluorescence intensity was determined: 0, negative; 1, weak; 2, moderate; 3, strong; 4, glaring. Chronic tubulointerstitial injury was graded by the involved area: 0, 0–5%; 1, 6–25%; 2, 26–50%; 3, > 50%. Results We found that patients with higher intensity of C3 staining, advanced membranous stage, and more severe chronic tubulointerstitial injury presented with higher positivity rate of anti-PLA2R antibodies, higher levels of urinary protein excretion and serum creatinine, and lower level of serum albumin. Univariate Cox regression analysis showed that severe (grade = 3) chronic tubulointerstitial injury was a risk factor to the kidney outcome of ESKD (HR = 61.02, 95%CI, 7.75–480.57, P 0.05). Conclusions We found the prognostic role of chronic tubulointerstitial injury to the kidney outcome of pMN. This study highlighted the value of kidney biopsy under the widespread usage of anti-PLA2R antibodies for diagnosis and prognosis. Electronic supplementary material The online version of this article (10.1186/s12882-018-1011-5) contains supplementary material, which is available to authorized users.

Friction-stir processing (FSP) is used to prepare Ti-35Nb-2Ta-3Zr alloys via different processing routes. Dislocation walls and tangles, deformation-induced α″ martensite, and deformation-induced ω phase are observed. The dominant deformation mechanisms are altered from deformation-induced α″ martensitic transformation and dislocation walls to twinning upon increasing the FSP passes. A reverse deformation-induced ω to β transformation and de-twinning process are observed together with grain refinement to the nanoscale. Meanwhile, compressive distortions along [0001]ω direction are favorable for the transformation from ω to β.

To investigate protective effects of alisol B 23-acetate (AB23A) against hepatotoxity and cholestasis induced by 17α-ethinylestradiol (EE) in association with farnesoid X receptor (FXR) activation in vivo and in vitro. The cholestatic liver injury model was established by subcutaneous injections of EE in C57BL/6 mice. Serum biomarkers, bile flow assay and H&E staining were used to identify the amelioration of cholestasis after AB23A treatment. Mice primary hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying AB23A hepatoprotection. AB23A treatment protected against liver injury induced by EE through increasing hepatic efflux and reducing uptake of bile acid via an induction in efflux transporters (Bsep and Mrp2) and an inhibition in hepatic uptake transporter (Ntcp) expression. AB23A also reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrated that the changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo and were abrogated after FXR was silenced in vitro. AB23A produces protective effects against EE-induced cholestasis, due to FXR-mediated gene regulation.

A Rapid Life Cycle Assessment (RLCA) method based on Green features is proposed in order to solve the inherent limitations of conventional Life Cycle Assessment (LCA), such as long period, massive data requirement, which result in difficulties in supporting product conceptual design. Firstly, Green Feature is proposed in supporting the LCA in conceptual design, where a mapping relationship is established between green feature and design information to achieve the transformation from the design information to green features. Secondly, product conceptual design model is proposed based on modular configuration. The approximate products program will be obtained through retrieval and matching of each module of product using the knowledge base and case base. Thirdly, Intuitionistic Fuzzy theory and Monte Carlo method are respectively used to process the qualitative and quantitative uncertain information of green features in order to ensure the accuracy of the evaluation results. Besides, the appropriate life cycle impact assessment method is selected to complete the life cycle impact assessment and obtain the LCA results. Consequently, the RLCA of product design program is completed to support product green design. Finally, a fan of a ventilation system is studied as an example to verify the proposed RLCA theory.

Investigating the hepatoprotective effect of calycosin against acute liver injury in association with FXR activation and STAT3 phosphorylation. The acute liver injury model was established by intraperitoneal injection of CCl4 in C57BL/6 mice. Serum alanine aminotransferase, aspartate aminotransferase, HE staining and TUNEL assay were used to identify the amelioration of the liver histopathological changes and hepatocytes apoptosis after calycosin treatment. ELISA kit and 5-bromo-2-deoxyuridine immunohistochemistry were used to measure the liver bile acid concentration and hepatocyte mitotic rate in vivo. The relation between calycosin and activation of FXR and STAT3 was comfirmed using the Luciferase assay, Molecular docking, Real-time PCR and Western Blot in vitro. The liver histopathological changes, hepatocytes apoptosis, liver bile acid overload and hepatocyte mitosis showed significant changes after calycosin treatment. Calycosin promoted the expression of FXR target genes such as FoxM1B and SHP but the effect was reversed by FXR suppressor guggulsterone. Molecular docking results indicated that calycosin could be embedded into the binding pocket of FXR, thereby increasing the expressions of STAT3 tyrosine phosphorylation and its target genes, Bcl-xl and SOCS3. Calycosin plays a critical role in hepatoprotection against liver injury in association with FXR activation and STAT3 phosphorylation.

In order to study the effect of plastic deformation on the banded texture and flashes in friction stir welding process, a three-dimensional Lagrangian incremental finite element model was developed. The plastic deformation of friction stir welding and the forming and healing of transient keyhole during the welding process were studied visually by numerical simulation and validated by corresponding experiments. The simulation results were acceptably in good agreement with the experimental data. As shown in the numerical and experimental results, the flash of FSW joint which could be divided into two layers was mainly distributed on the retreating side. The forming and healing process of transient state keyhole includes outflow of weld materials from the beginning to 1/3 rotation period and backflow into the keyhole after 2/3 period. The distribution of plastic deformation was inhomogeneous upon the transverse cross-section, while the large deformation region was near the top surface and close to the advancing side.

Background Eprosartan is an angiotensin II receptor antagonist, used in the treatment of hypertension and heart failure in clinical patients. The objective of this study was to clarify the mechanism underlying hepatic uptake and biliary excretion of eprosartan in rats and humans. Methods Perfused rat liver in situ , rat liver slices, isolated rat hepatocytes and human organic anion-transporting polypeptide (OATP)-transfected cells in vitro were used in this study. Results Extraction ratio of eprosartan was decreased by rifampicin in perfused rat livers. Uptake of eprosartan in rat liver slices and isolated rat hepatocytes was significantly inhibited by Oatp modulators such as ibuprofen, digoxin, rifampicin and cyclosporine A, but not by tetraethyl ammonium or p -aminohippurate. Uptake of eprosartan in rat hepatocytes indicated a saturable process. Although uptake of eprosartan in OATP1B3-human embryonic kidney cells (HEK) 293 cells was not observed, significant differences in cellular accumulations of eprosartan between vector- and OATP1B1-Madin–Darby canine kidney strain (MDCK) II cells were found in transcellular transport study. Moreover, cumulative biliary excretion rate of eprosartan in the presence of probenecid (Multidrug resistance-associated protein 2 (Mrp2) inhibitor) was significantly decreased in perfused rat livers. Vectorial basal-to-apical transport of eprosartan was also observed in OATP1B1/MRP2 double transfectants. Conclusions Eprosartan was transported by multiple Oatps (at least Oatp1a1 and Oatp1a4)/Mrp2 in rat and OATP1B1/MRP2, at least, in human.

Efflux of monocaroxylates like lactate, pyruvate, and ketone bodies from astrocytes through monocarboxylate transporter 4 (MCT4) supplies the local neuron population with metabolic intermediates to meet energy requirements under conditions of increased demand. Disruption of this astroglial-neuron metabolic coupling pathway may contribute to epileptogenesis. We measured MCT4 expression in temporal lobe epileptic foci excised from patients with intractable epilepsy and in rats injected with pilocarpine, an animal model of temporal lobe epilepsy (TLE). Cortical MCT4 expression levels were significantly lower in TLE patients compared with controls, due at least partially to MCT4 promoter methylation. Expression of MCT4 also decreased progressively in pilocarpine-treated rats from 12 h to 14 days post-administration. Underexpression of MCT4 in cultured astrocytes induced by a short hairpin RNA promoted apoptosis. Knockdown of astrocyte MCT4 also suppressed excitatory amino acid transporter 1 (EAAT1) expression. Reduced MCT4 and EAAT1 expression by astrocytes may lead to neuronal hyperexcitability and epileptogenesis in the temporal lobe by reducing the supply of metabolic intermediates and by allowing accumulation of extracellular glutamate.

To conduct in vivo and in vitro experiments to investigate puerarin (PUR), an isoflavone C-glyoside, and elucidate its ability to alter methotrexate (MTX) transport and pharmacokinetics.In vivo absorption studies, in vitro everted intestinal sac preparation, kidney slices in rats and bi-directional transport assay with mock-/MDCK-MDR1 cells, uptake studies in HEK293-OAT1/3 cells were employed to evaluate the interaction.In vivo and in vitro MTX absorption in rats were enhanced in combination with PUR. PUR inhibited digoxin efflux transport in MDCK-MDR1 monolayers with an IC50 value of 1.6 ± 0.3 μM, suggesting that the first target of drug interaction was MDR1 in the intestine during the absorption process. MTX renal clearance decreased significantly after simultaneous intravenous administration. MTX uptake in rat kidney slices and HEK293-OAT1/3 cells were markedly inhibited by PUR, suggesting that the second target of drug interaction was OATs located in the kidney. Moreover, concomitant administration of PUR reduced renal MTX accumulation and plasma levels of creatinine and BUN.Co-administration of PUR enhanced MTX exposure by inhibition of intestinal MDR1 and renal OAT1/3. Although the renal damage of MTX was improved by PUR, the high level exposure of MTX should be cautious in the clinical usage.

Background Acyclovir is acyclic guanosine derivative. Benzylpenicillin (PCG) is a β-lactam antibiotic. The purpose of this study was to investigate the pharmacokinetic drug-drug interaction (DDI) between PCG and acyclovir. Method When acyclovir and PCG were co-administered, plasma concentration of acyclovir, urinary excretion of acyclovir in vivo, uptake of acyclovir in kidney slices and uptake of acyclovir in human (h) OAT1/hOAT3- HEK293 cells were determined to examine the effect of PCG on urinary excretion of acyclovir. Results The plasma concentration of acyclovir was increased markedly and accumulative renal excretion and renal clearance of acyclovir were decreased significantly after intravenous administration of acyclovir in combination with PCG. PCG could decrease the uptake of acyclovir in kidney slices and in hOAT1-/hOAT3-human embryonic kidney (HEK293) cells. Conclusions It indicates that acyclovir is a substrate for OAT1 and OAT3. PCG inhibits the renal excretion of acyclovir by inhibiting renal transporters OAT1 and OAT3 in vivo and in vitro . These results suggest important information for DDI between PCG and acyclovir in kidney.

The chronic mild stress (CMS) protocol is widely used to evoke depression-like behaviors in the laboratory. Some animals exposed to CMS are resistant to the development of anhedonia, whereas the remaining are responsive, CMS-resilient and CMS-sensitive, respectively. The aim of this study was to examine the effects of chronic stress on oxidative parameters in the rat brain. The consumption of sweet food, protein and lipid oxidation levels and superoxide dismutase and catalase activities in the rat hippocampus, cortex and cerebellum were assessed. We found a significant increase in protein peroxidation (hippocampus and cortex), a significant increase in catalase activity (cortex, hippocampus and cerebellum) and a decrease in superoxide dismutase activity (cortex, hippocampus and cerebellum) in the CMS-sensitive group compared to the CMS-resilient group and normal controls as well as an increase in lipid peroxidation (cerebellum) in the CMS-sensitive and CMS-resilient groups compared to normal controls. However, there was no significant difference in protein peroxidation (cerebellum) and lipid peroxidation (cortex and hippocampus) among the three groups. In conclusion, our results indicate that the segregation into CMS-sensitive and -resilient groups based on sucrose intake is paralleled by significant differences in oxidative parameters. CMS induces oxidative damage and alterations in the activity of antioxidants which may lead to increased oxidative damage, irrespective of the anhedonia-like status of the stressed animals.

We study numerically the phase diagram for s and d-wave fermionic superfluidity/superconductivity with spin-dependent bandwidth imbalance on a two-dimensional square-lattice. We also investigate the spontaneous space symmetry breaking states at low temperatures by solving the Bogoliubov-de Gennes equations. It is found that, the spatial configuration of the order parameter, both the uni-directional Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) states and the two-dimensional FFLO state may show up in the presence of finite spin-dependent bandwidth imbalance. Moreover, we calculate the spectra of local density of states, and the experimental proposals of observing such FFLO states are therefore suggested.

A toll pattern that can restrict link flows on the tolled links to some predetermined thresholds is named as effective toll solution, which can be theoretically obtained by solving a side-constraint traffic assignment problem. Considering the practical implementation, this paper investigates availability of an engineering-oriented trial-and-error method for the effective toll pattern of cordon-based congestion pricing scheme, under side-constrained probit-based stochastic user equilibrium (SUE) conditions. The trial-and-error method merely requires the observed traffic counts on each entry of the cordon. A minimization model for the side-constrained probit-based SUE problem with elastic demand is first proposed and it is shown that the effective toll solution equals to the product of value of time and optimal Lagrangian multipliers with respect to the side constraints. Then, employing the Lagrangian dual formulation of the minimization method, this paper has built a convergent trial-and-error method. The trial-and-error method is finally tested by a numerical example developed from the cordon-based congestion pricing scheme in Singapore.

Liner ship fleet deployment is the assignment of ships to liner service routes for delivering containers in a planning horizon. This paper first reformulates the maximum number of voyages that can be completed in the planning horizon, which is incorrectly defined by the existing studies on liner ship fleet deployment. It proceeds to remedy a constraint in Gelareh and Meng (Transp Res 46E:76–89 2010) such that the nonlinear programming model proposed by Gelareh and Meng (Transp Res 46E:76–89 2010) is equivalent to its linear formulation. Finally, a reformulation of the fleet deployment model is presented to eliminate the combinatorial behavior of the model proposed by Gelareh and Meng (Transp Res 46E:76–89 2010). Computational study demonstrates significant efficiency improvement of the reformulated model.

A rapid and selective liquid chromatographic/tandem mass spectrometric method for the determination of JBP485 was developed and validated. Following protein precipitation, the analyte and internal standard (JBP923) were separated from human plasma using an isocratic mobile phase on an Elite Kromasil C18 column. An API 3200 tandem mass spectrometer equipped with a Turbo ionSpray ionization source was used as the detector and operated in the positive ion mode. Multiple reaction monitoring using the precursor to product ion combinations of m/z 201.2 → 86.2 and m/z 219.2 → 86.2 was performed to quantify JBP485 and JBP923, respectively. The method was linear in the concentration range of 0.10–50.00 μg mL−1 using 100 μL of plasma. The lower limit of quantification was 0.10 μg mL−1. The intra- and inter-day relative standard deviations over the entire concentration range were less than 6.65%. Accuracy determined at three concentrations (0.25, 4.00 and 25.00 μg mL−1 for JBP485) ranged from −0.78 to 2.74% in terms of relative error. Each plasma sample was chromatographed within 2.0 min. The method was successfully applied to characterize the pharmacokinetic profiles of JBP485 in rats after an intravenous injection of 6.25 mg kg−1 JBP485.

Micro total analysis systems (-TAS) or labs-on-a-chip, have been spreading rapidly due to their desirable characteristics, including reductions in reagent consumption, space requirements and analysis time. This work aimed at establishing an integrated microfluidic system which can supply the cells with fresh medium of oxygen and nutrition continuously at a control flow rate mimicking the microenvironment in vivo. Human non-small cell lung cancer cell line SPCA1 was seeded in a microchip supplied with fresh medium at a constant rate of 15 mm/24 h controlled by a pump. The expression of P-gp for verapamil-pretreated or non-pretreated cells was assayed with immunofluorescence. Both groups cells were exposed to anticancer drug VP-16 at 30 μM for 6 h before the apoptosis analysis online. The results indicated that the cells could grow and spread well for 4 days in the microfluidic system successively furnished with fresh medium. Immunofluorescence assay showed that the intensity of the fluorescence for the verapamil-pretreated cells was obvious weak compared with that of non-pretreated cells. Apoptosis analysis demonstrated that the percentage of apoptotic cells for verapamil-pretreated group increased around twofold compared with that of non-verapamil pretreated group (26.5 ± 2.5% versus 10.9 ± 0.85%, p < 0.05), showing a similar results as by flow cytometry analysis. All these indicate that P-gp plays an important role in the resistance to VP-16 in SPCA1, the microfluidic system provides a suitable environment for cells survival and is valuable in long time cell culture and bioassays mimicking the microenvironment in vivo and deserved to be studied further.

Based on the analysis of several familiar large integer modular multiplication algorithms, this paper proposes a new Scalable Hybrid modular multiplication (SHyb) algorithm which has scalable operands, and presents an RSA algorithm model with scalable key size. Theoretical analysis shows that SHyb algorithm requires m2n/2 + 2m iterations to complete an mn-bit modular multiplication with the application of an n-bit modular addition hardware circuit. The number of the required iterations can be reduced to a half of that of the scalable Montgomery algorithm. Consequently, the application scope of the RSA cryptosystem is expanded and its operation speed is enhanced based on SHyb algorithm.

In this paper, we present a modified Goldstein-Levitin-Polyak projection method for asymmetric strongly monotone variational inequality problems. A practical and robust stepsize choice strategy, termed self-adaptive procedure, is developed. The global convergence of the resulting algorithm is established under the same conditions used in the original projection method. Numerical results and comparison with some existing projection-type methods are given to illustrate the efficiency of the proposed method.