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Ovarian cancer is the deadliest gynecologic cancer. Although human epidermal growth factor receptor-2 (HER2) overexpression, a poor prognostic molecular marker in ovarian cancer, is found in almost 30% of ovarian cancer cases, there are no established therapies for HER2-overexpressing ovarian cancer. In this study, we investigated the efficacy of combined samfenet, a biosimilar compound of trastuzumab, and natural killer (NK) cells in preclinical model of HER2-overexpressing ovarian cancer. Firstly, we screened the HER2 expression in three ovarian cancer cell lines and eight ovarian cancer patient-derived tumor xenograft (PDTX) samples. Then, immunohistochemistry and silver in situ hybridization (SISH) were performed following clinical criteria. HER2-overexpressing cells exhibited the highest sensitivity to samfenet compared with low-HER2-expressing cells. In addition, the combination of samfenet with natural killer (NK) cells resulted in significantly enhanced sensitivity to HER2-overexpressing cells and showed a significant antitumor effect on PDTX mice compared with monotherapy. It is known that anti-HER2-humanized IgG1 monoclonal antibodies, including trastuzumab, induce antibody-dependent cellular cytotoxicity (ADCC). Consequently, the combination of samfenet with NK cells demonstrated NK cell-mediated ADCC, as confirmed using an in vitro NK cytotoxicity assay and in vivo antitumor efficacy. A transferase dUTP nick end labeling (TUNEL) assay using xenografted tumors further supported the ADCC effects based on the increase in the number of apoptotic cells in the combination group. Furthermore, high HER2 expression was associated with shorter progression-free survival and overall survival based on public mRNA expression data. In this study, we demonstrated that the combination of samfenet and NK cell therapy could be a promising treatment strategy for patients with HER2-overexpressing ovarian cancer, through ADCC effects. Therefore, this study supports a rationale for further clinical studies of the combination of samfenet and NK cells as a therapy for patients with HER2-overexpressing ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Sunken upper eyelids, characterized by hollowing in the upper orbital region, can contribute to an aged or fatigued appearance. We aim to report on the surgical technique and its effects, involving the release of the arcus marginalis of the upper eyelid and the precise distribution of orbital fat. Methods: From December 2021 to March 2023, a total of 84 eyelids from 42 patients who underwent surgical correction for sunken upper eyelids, utilizing the upper arcus marginalis release and precision fat distribution technique, were included in this study. Preoperative and postoperative sunken depths were measured and statistically analyzed. Aesthetic satisfaction was assessed through patient questionnaires. Results: Preoperative and postoperative sunken depths measured 9.2 ± 2.2 mm and 5.9 ± 2.3 mm, respectively. The mean improvement was 3.3 mm, a change of statistical significance. Aesthetic outcomes and patient satisfaction yielded favorable results. No major complications were observed during the follow‐up period. Conclusion: The upper arcus marginalis release and orbital fat distribution technique demonstrated favorable outcomes in correcting sunken upper eyelids. This procedure ensures stable placement of orbital fat at the deepest sunken point, resulting in aesthetically pleasing and enduring results. This technique serves as a valuable alternative for patients with moderate to severe sunken eyelids. [ABSTRACT FROM AUTHOR]

Waiting impulsivity is a risk factor for many psychiatric disorders including alcohol use disorder (AUD). Highly impulsive individuals are vulnerable to alcohol abuse. However, it is not well understood whether chronic alcohol use increases the propensity for impulsive behavior. Here, we establish a novel experimental paradigm demonstrating that continuous binge-like ethanol exposure progressively leads to maladaptive impulsive behavior. To test waiting impulsivity, we employed the 5-choice serial reaction time task (5-CSRTT) in C57BL/6J male mice. We assessed premature responses in the fixed and variable intertrial interval (ITI) 5-CSRTT sessions. We further characterized our ethanol-induced impulsive mice using Open Field, y-maze, two-bottle choice, and an action-outcome task. Our results indicate that continuous binge-like ethanol exposure significantly increased premature responses when mice were tested in variable ITI sessions even during a prolonged abstinent period. Ethanol-induced impulsive mice exhibited anxiety-like behavior during chronic exposures. This behavior was also observed in a separate cohort that was subjected to 20 days of abstinence. Ethanol-treated mice were less motivated for a sucrose reward compared with air-exposed control mice, while also demonstrating reduced responding during action-outcome testing. Overall, ethanol-treated mice demonstrated increased impulsive behavior, but a reduced motivation for a sucrose reward. Although waiting impulsivity has been hypothesized to be a trait or risk factor for AUD, our findings indicate that maladaptive impulse control can also be potentiated or induced by continuous chronic ethanol exposure in mice. [ABSTRACT FROM AUTHOR]

Habitual reward-seeking behavior is a hallmark of addictive behavior. The role of the dorsomedial striatum (DMS) in regulating goal-directed reward-seeking behavior has been long appreciated. However, it remains unclear how the astrocytic activities in the DMS differentially affect the behavioral shift. To investigate the astrocytic activity-driven neuronal synaptic events and behavioral consequences, we chemogenetically activated astrocytes in the DMS using GFAP promoter–driven expression of hM3Dq, the excitatory DREADDs (designer receptors exclusively activated by designer drugs). First, we confirmed the chemogenetically induced cellular activity in the DMS astrocytes using calcium imaging. Then, we recorded electrophysiological changes in the synaptic activity of the two types of medium spiny neurons (MSNs): direct and indirect pathway MSNs. To evaluate the behavioral consequences, we trained mice in nose-poking operant chambers that developed either habitual or goal-directed reward-seeking behaviors. The activation of DMS astrocytes reduced the frequency of spontaneous excitatory postsynaptic currents in the direct pathway MSNs, whereas it increased the amplitude of the spontaneous excitatory postsynaptic currents and decreased the frequency of spontaneous inhibitory postsynaptic currents in the indirect pathway MSNs. Interestingly, astrocyte-induced DMS neuronal activities are regulated by adenosine metabolism, receptor signaling, and transport. Importantly, mice lacking an astrocytic adenosine transporter, ENT1 (equilibrative nucleoside transporter 1; Slc29a1), show no transition from habitual to goal-directed reward-seeking behaviors upon astrocyte activation, while restoring ENT1 expression in the DMS facilitated this transition. Our findings reveal that DMS astrocyte activation differentially regulates MSNs' activity and facilitates shifting from habitual to goal-directed reward-seeking behavior. [ABSTRACT FROM AUTHOR]

Two distinct dorsal striatum regions, dorsomedial striatum (DMS) and dorsolateral striatum (DLS), are attributed to conditioned goal‐directed and habitual reward‐seeking behaviours, respectively. Previously, our study shows that the ethanol‐sensitive adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), regulates ethanol‐drinking behaviours. Although ENT1 is expressed in both neurons and astrocytes, astrocytic ENT1 is thought to regulate adenosine levels in response to ethanol. However, the role of DMS and DLS astrocytic ENT1 in goal‐directed and habitual ethanol‐seeking is not well known. Here, we identified whether the upregulation of astrocytic ENT1 in the DMS and DLS differentially regulates operant seeking behaviours towards the 10% sucrose (10S); 10% ethanol and 10% sucrose (10E10S); and 10% ethanol (10E) in mice. Using 4 days of random interval (RI), mice exhibited habitual seeking for 10S, but goal‐directed seeking towards 10E10S. Using the same mice conditioned with 10E10S, we examined 10E‐seeking behaviour on a fixed ratio (FR) for 6 days and RI for 8 days. On the other hand, during FR and the first 4 days of RI schedules, mice showed goal‐directed seeking for 10E, whereas mice exhibited habitual seeking for 10E during the last 4 days of RI schedule. Interestingly, DMS astrocytic ENT1 upregulation promotes shift from habitual to goal‐directed reward‐seeking behaviours. By contrast, DLS astrocytic ENT1 upregulation showed no effects on behavioural shift. Taken together, our findings demonstrate that DMS astrocytic ENT1 contributes to reward‐seeking behaviours. [ABSTRACT FROM AUTHOR]

Purpose: The transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that mediates synaptic modification in the nucleus accumbens (NAc). However, no study has yet examined the mechanism of TRPV1 in the NAc on cocaine reinstatement. We investigated the mechanism of TRPV1 in NAc on cocaine reinstatement using the conditioned place preference (CPP) test in mice.Methods: We examined the effect of capsazepine (5 mg/kg, a TRPV1 antagonist, administered intraperitoneally (i.p.)), capsaicin (0.3 mg/kg, a TRPV1 agonist, administered i.p.), and genetic deletion of TRPV1 on the reinstatement of cocaine-induced CPP (15 mg/kg, administered i.p.). The expression of TRPV1 and Ca2+/calmodulin-mediated kinase II (CaMKII) in the NAc were determined after cocaine reinstatement. Microinjection of SB366791 (0.2 ng, a selective TRPV1 antagonist) in the NAc was assessed on SKF-81297 (1 µg, D1-like dopamine (DA) receptor agonist) primed cocaine reinstatement.Results: Capsazepine suppressed and capsaicin potentiated cocaine CPP in the reinstatement phase. In addition, genetic deletion of TRPV1 inhibited cocaine-priming reinstatement. Cocaine reinstatement was mediated by increased TRPV1 expression in the NAc, which involves CaMKII. Microinjection of SB366791 in the NAc prevented the cocaine reinstatement evoked by microinjection of SKF-81297 in the NAc.Conclusions: These findings suggest that activation of TRPV1 mediates the stimulation of D1-like DA receptors and CaMKII in the NAc, resulting in the facilitation of cocaine reinstatement behaviors. Thus, our findings reveal a previously unknown TRPV1 mechanism in the reinstatement to drugs of abuse. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that the transient receptor potential vanilloid type 1 channel (TRPV1) is a novel target for the treatment of drug addiction, such as cocaine and morphine. Previously we reported that TRPV1 inhibition reduced morphine reward in the dorsal striatum (DSt) of mice and morphine self-administration through a decrease in accumbal activity in rats. However, the role of TRPV1 on morphine-conditioned reward in addiction-related brain regions, such as the nucleus accumbens (NAc), has not been previously established. Here, we investigated the effects of TRPV1 on morphine conditioned place preference (CPP) and intracellular mechanisms of TRPV1 using Western blot analysis and immunohistochemistry (IHC) in morphine-administered mice. TRPV1 knockout mice did not exhibit morphine reward responses, and both i.p. and intra-NAc injections of SB366791, a selective TRPV1 antagonist, reduced morphine-induced CPP in wild-type mice. Furthermore, i.p. injection of SB203580, a selective p38 MAPK inhibitor, also dampened morphine-induced CPP. To determine the molecular mechanisms of the TRPV1/p38 MAPK pathway in morphine CPP, we investigated the expression of adenylyl cyclase type 1 (AC1) and phospho-p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) in the NAc. Either SB366791 or SB203580 decreased the protein expression levels of phospho-p38 MAPK, phosphor-NF-κB, and AC1 in the NAc of morphine CPP mice. Taken together, our findings suggest that TRPV1 may modulate morphine-induced conditioned reward effects via the p38 MAPK signaling pathway in the NAc. Therefore, blockade of TRPV1 may provide a novel therapeutic approach for the prevention and treatment of opioid addiction. [ABSTRACT FROM AUTHOR]

This paper compares five numerical methods for calculating drift forces in time domain analysis of moored bodies. The first method is the most basic one. It uses all terms of QTF (quadratic transfer function) matrix based on double summation. It is the most correct due to no approximation but needs large memory and cpu time. The second method uses diagonal terms of QTF matrix with Newman approximation. It reduces memory but still uses double summation. When the wave spectrum is narrow banded, the third and fourth methods with more approximated single summation are applicable. Those methods are much approximated but fast due to single summation. One uses fixed local frequency and the other uses time variant local frequency in calculating QTF. The fifth method uses interpolated local frequency of the third and fourth methods. A turret moored FPSO and a spread moored DTV (deck transportation vessel) are analyzed as numerical examples and the accuracy and cpu time are compared for each method. [ABSTRACT FROM AUTHOR]

As reconstructive transplantation is gaining popularity as a viable alternative for upper limb amputees, it is becoming increasingly important for plastic surgeons to renew surgical skills and knowledge of this area. Forelimb allotransplantation research has been performed previously in rodent and swine models. However, preclinical canine forelimb allotransplantation studies are lacking in the literature. The purpose of this paper is to provide an overview of the surgical skills necessary to successfully perform forelimb transplantation in canines as a means to prepare for clinical application. A total of 18 transplantation operations on canines were performed. The recipient limb was shortened at the one-third proximal forearm level. The operation was performed in the following order: bones (two reconstructive plates), muscles and tendons (separately sutured), nerves (median, ulnar, and radial nerve), arteries (two), and veins (two). The total mean time of transplantation was 5 hours ± 30 minutes. All of the animals that received transplantation were treated with FK-506 (tacrolimus, 2 mg/kg) for 7 days after surgery. Most allografts survived with perfect viability without vascular problems during the early postoperative period. The canine forelimb allotransplantation model is well qualified to be a suitable training model for standard transplantation and future research work. [ABSTRACT FROM AUTHOR]

Rationale: Phentermine is structurally similar to methamphetamine and is widely used as an anti-obesity drug in the USA and many other countries. The potential for reward of phentermine has been noted; however, the mechanisms of phentermine dependence have not been established. Objectives: Here, we investigated the rewarding and dopaminergic behavioral responses to phentermine in mice and found that phentermine produced conditioned rewarding effects through the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in the nucleus accumbens (NAc). Methods: The impact of phentermine was assessed using conditioned place preference (CPP) test, climbing behavior test, and western blot analysis. Results: Phentermine 1 and 3 mg/kg (i.p.) significantly increased CPP. Phentermine, a known dopamine releaser, boosted apomorphine-induced climbing behavior in mice, and methamphetamine (i.p.) also increased apomorphine-induced dopaminergic behavior. Phentermine and methamphetamine increased the level of expression of the dopamine transporter (DAT) and phospho-Akt proteins to a similar degree in the NAc of CPP mice. To determine whether the conditioned rewarding effects of phentermine were mediated through the PI3K/Akt pathway, we assessed the effects of the Akt inhibitor LY294002 on phentermine-induced place preference and climbing behavior. LY294002 (1 and 3 μg/site, i.c.v.) reduced phentermine-induced CPP and phentermine-increased climbing behavior. However, LY294002 did not change CPP and climbing behavior itself and also did not decrease apomorphine-induced climbing behavior in mice. Further, LY294002 decreased the phentermine-increased levels of DAT protein and phosphorylation of Akt in the NAc of CPP mice. Conclusions: Thus, these findings suggest that phentermine induces conditioned rewarding effects via activation of the PI3K/Akt signaling pathway in the NAc. [ABSTRACT FROM AUTHOR]

In this study, we investigated the mechanisms of 3′,4′,7-trihydroxyflavone (THF) protection of neuronal cells from neuronal cell death induced by the oxidative stress-related neurotoxin hydrogen peroxide (H 2 O 2 ). Pretreatment with THF significantly elevated cell viability, reduced H 2 O 2 -induced lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) production, glutathione (GSH) content, superoxide dismutase (SOD) activity, catalase (CAT) activity, and mitochondria membrane potential (MMP) loss. Western blot data demonstrated that THF inhibited the H 2 O 2 -induced up- or down-regulation of cleaved caspase-3, cleaved caspase-9, cleaved poly-ADP-ribose polymerase (PARP), Bax, Bcl-2, and Bcl-xL, and attenuated the H 2 O 2 -induced release of cytochrome c from the mitochondria to the cytosol. In addition, pretreatment with THF attenuated H 2 O 2 -induced rapid and significant phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinases (PI3K)/Akt. THF also inhibited nuclear factor-κB (NF-κB) translocation to the nucleus induced by H 2 O 2 , down-stream of H 2 O 2 -induced phosphorylation of MAPKs and PI3K/Akt. These data provide the first evidence that THF protects neuronal cells against H 2 O 2 -induced oxidative stress, possibly through ROS reduction, mitochondria protection, and NF-κB modulation via MAPKs and PI3K/Akt pathways. The neuroprotective effects of THF make it a promising candidate as a therapeutic agent for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

In this study, a series of model tests were performed to study the relative wave elevation responses around a tension leg platform (TLP) in extreme waves. It is well known that a high relative wave elevation causes a horizontal wave impact or a wave-in-deck impact which can result in a serious damage on both fixed and floating offshore structures. In particular, tension leg platform can be exposed to severe wave-in-deck impact events due to nonlinear wave amplifications inside the multiple columns. Irregular wave tests including the waves of 100-year return periods were carried out at Ocean Engineering Basin of KRISO. Focus is on the nonlinear characteristics of the relative wave elevations. Probability of exceedance as well as time series for relative wave elevation are suggested and discussion is made on the effect of location, wave and current. Also, wave-in-deck events are described based on the model test observations. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we investigated the neuroprotective effects of Lonicera japonica THUNB. extract (LJ) on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. We found that LJ significantly increased cell viability decrease, lactate dehydrogenase release (LDH), morphological changes, nuclear condensation, fragmentation, and reactive oxygen species (ROS) production induced by 6-OHDA in SH-SY5Y cells. The cytoprotection afforded by pretreatment with LJ was associated with increases of the glutathione (GSH) level, superoxide dismutase (SOD) activity, and catalase (CAT) activity in 6-OHDA-induced SH-SY5Y cells. In addition, LJ strikingly inhibited 6-OHDA-induced mitochondrial dysfunctions including reduction of mitochondria membrane potential (MMP) and activation of cleaved poly-ADP-ribose polymerase (PARP), cleaved caspase-3, cleaved caspase-9, increased Bax, as well as decreased Bcl-2 and Bcl-xL. Additionally, LJ dramatically attenuated 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK 1/2), and phosphoinositide 3-kinase (PI3K)/Akt. Meanwhile, LJ counteracted nuclear factor-κB (NF-κB) activation by blocking its translocation to the nucleus. These findings suggest that LJ has a potent anti-parkinsonism; this effect was mediated, at least in part, by inhibition of neurotoxicity, apoptotic cascade events, and oxidative stress via activation of MAPKs, PI3K/Akt, and NF-κB. [Copyright &y& Elsevier]

Abstract: We investigated the neuroprotective effects of Lonicera japonica THUNB. (Caprifoliaceae) (LJ) extract against hydrogen peroxide (H2O2), a toxin created by oxidative stress and implicated in neurodegenerative diseases, in human SH-SY5Y neuroblastoma cells. We examined the effects of LJ against H2O2-induced cytotoxicity, apoptosis, the production of reactive oxygen species (ROS), the proteolysis of cleaved poly-ADP-ribose polymerase (PARP), and the expression of Bcl-2, Bcl-xL, and cleaved caspase-3. Moreover, we attempted to determine whether LJ suppressed the phosphorylation of Akt, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 (ERK 1/2). We found that LJ improved cell viability, inhibited cytotoxicity and apoptosis, and attenuated elevations in ROS and nuclear condensation. In addition, LJ showed radical scavenging ability in 2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azinobis-(3-ethyl-benzthiazoline-6-sulfonic acid) (ABTS) assays. Western blot data revealed that LJ inhibited H2O2-induced up- and down-regulation of cleaved PARP, cleaved caspase-3, Bcl-2, and Bcl-xL. Furthermore, LJ significantly attenuated the H2O2-induced phosphorylation of Akt, JNK, p38 MAPK, and ERK1/2. These results demonstrate that LJ possesses potent neuroprotective activity. Its potential to treat neurodegenerative diseases warrants further research. [Copyright &y& Elsevier]

Abstract: This paper investigates the characteristics of bending moments, shear forces and stresses at unit connections of very large floating structures (VLFS) under wave loads. The responses of VLFS are calculated by solving multi-body motion equation considering hydroelasticity and connection stiffness. Hydroelastic responses are calculated by the direct method. Higher-order boundary element method (HOBEM) is used for fluid analysis and finite element method (FEM) is introduced for structural analysis. The equation of motion is modified to describe the unit connections by employing spring elements. Bending moments and shear forces at the connections are obtained from the dynamic equilibrium condition for pressures and inertia forces. Two types of VLFS units such as tandem arranged units and side-by-side arranged units are considered in the numerical examples. The influences of connection stiffness, wave frequency and heading angle on responses of VLFS are investigated through the numerical examples. Rigid body analysis along with hydroelastic analysis is also carried out in the numerical analysis and comparison of those two approaches is discussed. [Copyright &y& Elsevier]

Abstract: A nonlinear sloshing problem is numerically simulated. During excessive sloshing, the sloshing-induced impact load can cause a critical damage on the tank structure. Recently the problem becomes an important research topic in LNG (Liquefied Natural Gas) Tanker and FPSO (Floating Production Storage Offloading) design. In this study, the wave impact load on the structure is obtained numerically by imposing the exact nonlinear free surface conditions and compared with that predicted by Morison''s formula. As a theoretical model, a three-dimensional free surface flow in a tank is formulated in the scope of potential flow theory with the exact nonlinear free-surface conditions. A finite-element method based on Hamilton''s principle is employed as a numerical method. The problem is treated as an initial-value problem. The nonlinear problem is numerically solved through an iterative scheme at each time step. [Copyright &y& Elsevier]

Abstract: An influence of sea-bottom topography on the hydroelastic response of a Very Large Floating Structure (VLFS) is considered. When the floating structure is constructed near the shore, the sea-bottom topographical effect should be considered. In this study, the effect of sea-bottom topography is investigated for four different bottom cases. To calculate the sea-bottom effects rigorously, the finite-element method based on the variational formulation is used in the fluid domain. The pontoon-type floating structure is modeled as the Kirchhoff plate. The mode superposition method is adopted for the hydroelastic behavior of the floating structure. [Copyright &y& Elsevier]

In the striatum, two main types of GABAergic medium spiny neurons (MSNs), denoted striatonigral (or direct-pathway MSNs, dMSNs) and striatopallidal neurons (indirect-pathway MSNs, iMSNs), form circuits with distinct pallidal nuclei, which sends "GO" or "NO-GO" signals through the thalamus. These striatopallidal circuits evaluate and execute reward-seeking and taking behaviors. Especially, the dorsal striatum can be further divided into the dorsomedial striatum (DMS, equivalent to caudate in primates and humans) and dorsolateral striatum (DLS, equivalent to putamen), which orchestrates goal-directed and habitual reward-seeking and taking behaviors, respectively. Using optogenetics, chemogenetics and in vivo calcium imaging technologies combined with electrophysiology and digitalized behavior phenotyping, recent studies have revealed cell-, circuit- and context-specific functions of these microcircuits in addictive behaviors. Also, region-specific astrocytes regulate the homeostatic activities of the dMSNs and iMSNs as well as the downstream circuits, which determine the net balance of cortico-striato-pallidal activities to the thalamic neurons. This review will summarize the recent progress of striatopallidal circuits focusing on astrocyte-neuron interaction and, reward- and alcohol-seeking behaviors. Our review will also discuss the translational and clinical implications of these microcircuit studies. This article is part of the special Issue on "Neurocircuitry Modulating Drug and Alcohol Abuse". • Striatopallidal circuits are critical for goal-directed and habitual reward-seeking behaviors. • Direct- and indirect-pathway medium spiny neurons regulate reward-seeking behaviors. • Astrocyte-neuron interaction in the dorsal striatum is essential for alcohol use disorder. [ABSTRACT FROM AUTHOR]

Substituted cathinones are synthetic analogs of the active components of natural products and are widely abused worldwide. However, the rewarding properties of these agents have not yet been evaluated. In this study, we investigated the abuse potential of buphedrone [2-(methylamino)-1-phenylbutan-1-one, α-methylamino-butyrophenone] and its effects on the mesolimbic dopaminergic system in mice using conditioned place preference (CPP) analysis, a self-administration test, a locomotor activity test, a behavioral sensitization test and Western blot analysis. Treatment with buphedrone supported CPP and self-administration, enhanced locomotor activity and produced behavioral sensitization when mice were challenged with methamphetamine. SCH23390, a D1 dopamine antagonist, prevented buphedrone-induced CPP, whereas raclopride, a D2 dopamine antagonist, had no effect. SCH23390 also blocked locomotor activity increase by buphedrone, while raclopride partially attenuated locomotor activation. Western blot analysis revealed that repeated buphedrone treatment increased D1 dopamine receptor expression in the dorsal striatum and nucleus accumbens in mice. Collectively, these findings suggest the abuse potential of buphedrone and demonstrate the involvement of the dopaminergic system in the establishment of its rewarding properties. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against BRCA1/2-mutated cancers through synthetic lethality. Unfortunately, most cases ultimately develop acquired resistance. Therefore, enhancing PARP inhibitor sensitivity and preventing resistance in those cells are an unmet clinical need. Here, we investigated the ability of paraspeckle component 1 (PSPC1), as an additional synthetic lethal partner with BRCA1/2, to enhance olaparib sensitivity in preclinical models of BRCA1/2-mutated breast and ovarian cancers. In vitro, the combined olaparib and PSPC1 small interfering RNA (siRNA) exhibited synergistic anti-proliferative activity in BRCA1/2-mutated breast and ovarian cancer cells. The combination therapy also demonstrated synergistic tumor inhibition in a xenograft mouse model. Mechanistically, olaparib monotherapy increased the expressions of p-ATM and DNA-PKcs, suggesting the activation of a DNA repair pathway, whereas combining PSPC1 siRNA with olaparib decreased the expressions of p-ATM and DNA-PKcs again. As such, the combination increased the formation of γH2AX foci, indicating stronger DNA double-strand breaks. Subsequently, these DNA-damaged cells escaped G2/M checkpoint activation, as indicated by the suppression of p-cdc25C (Ser216) and p-cdc2 (Tyr15) after combination treatment. Finally, these cells entered mitosis, which induced increased apoptosis. Thus, this proves that PSPC1 inhibition enhances olaparib sensitivity by targeting DNA damage response in our preclinical model. The combination of olaparib and PSPC1 inhibition merits further clinical investigation to enhance PARP inhibitor efficacy. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the global leading cancer burden in women and the hormone receptor-positive (HR+) subtype is a major part of breast cancer. Though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are highly effective therapy for HR+ subtype, acquired resistance is inevitable in most cases. Herein, we investigated the paternally expressed gene 10 (PEG10)-associated mechanism of acquired resistance to CDK4/6 inhibitors. Methods: Palbociclib-resistant cells were generated by exposing human HR+ breast cancer cell lines to palbociclib for 7–9 months. In vitro mechanistic study and in vivo xenograft assay were performed. For clinical relevance, public mRNA microarray data sets of early breast cancer were analyzed and PEG10 immunohistochemical staining was performed using pre-CDK4/6 inhibitor tumor samples. Results: We observed that PEG10 was significantly upregulated in palbociclib-resistant cells. Ectopic overexpression of PEG10 in parental cells caused CDK4/6 inhibitor resistance and enhanced epithelial–mesenchymal transition (EMT). On the contrary, PEG10-targeting siRNA or antisense oligonucleotides (ASOs) combined with palbociclib synergistically inhibited proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice and suppressed EMT as well. The mechanistic study confirmed that high PEG10 expression suppressed p21, a natural CDK inhibitor, and SIAH1, a post-translational degrader of ZEB1, augmenting CDK4/6 inhibitor resistance. Then PEG10 siRNA combined with palbociclib suppressed cell cycle progression and EMT via activating p21 and SIAH1, respectively. Consequently, combined PEG10 inhibition and palbociclib overcame CDK4/6 inhibitor resistance. Furthermore, high PEG10 expression was significantly associated with a shorter recurrence-free survival (RFS) based on public mRNA expression data. In pre-CDK4/6 inhibitor treatment tissues, PEG10 positivity by IHC also showed a trend toward a shorter progression-free survival (PFS) with CDK4/6 inhibitor. These results support clinical relevance of PEG10 as a therapeutic target. Conclusions: We demonstrated a novel PEG10-associated mechanism of CDK4/6 inhibitor resistance. We propose PEG10 as a promising therapeutic target for overcoming PEG10-associated resistance to CDK4/6 inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: Paclitaxel-based chemotherapy is the standard front-line therapy for advanced or metastatic endometrial cancer. However, paclitaxel resistance eternally develops. Based on the high prevalence of PIK3CA mutation, reaching 50%, in endometrial cancer, we preclinically investigated the effectiveness of a combination of a PI3K inhibitor with eribulin, a post-paclitaxel therapy for breast cancer, in treating paclitaxel-resistant, PIK3CA-mutated endometrial cancer. Based on our in vitro and in vivo results, we suggest that paclitaxel resistance is associated with the activation of the PIK3/AKT pathway in PIK3CA-mutated endometrial cancer, and the combination of a PI3K inhibitor and eribulin merits further clinical investigation. Endometrial cancer stands as the predominant gynecological malignancy in developed nations. For advanced or recurrent disease, paclitaxel-based chemotherapy is the standard front-line therapy. However, paclitaxel resistance eternally develops. Based on the high prevalence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, reaching 50%, in endometrial cancer, we preclinically investigated the effectiveness of a combination of a phosphatidylinositol 3-kinase (PI3K) inhibitor with eribulin, a post-paclitaxel therapy for breast cancer, in treating paclitaxel-resistant, PIK3CA-mutated endometrial cancer. We generated paclitaxel-resistant cell lines from PIK3CA-mutated endometrial cancer cell lines by gradually increasing the concentration of paclitaxel in cell cultures. We observed that the PI3K/AKT and epithelial–mesenchymal transition (EMT) pathways in paclitaxel-resistant cells were significantly upregulated compared with those in parental cells. Then, we demonstrated that the combination of alpelisib (a PI3K inhibitor) and eribulin more effectively suppressed the cellular growth of paclitaxel-resistant cells in in vitro and in vivo xenograft models. Mechanistically, we demonstrated that the effect of the combination could be enhanced by inhibiting both the PI3K/AKT and EMT pathways. Therefore, we suggest that paclitaxel resistance is associated with the activation of the PIK3/AKT pathway in PIK3CA-mutated endometrial cancer, and the combination of a PI3K inhibitor and eribulin merits further clinical investigation. [ABSTRACT FROM AUTHOR]

Abstract Bow-flare slamming is issue that must be considered in ship design because it affects the local strength and fatigue life of a ship. In this paper, the experimental study of the spatial distribution of slamming load was conducted, which acts on the bow flares of ultra-large containerships. For a model test, 10,000 TEU container ship model with 1/60-scale ratio divided into six segments was applied. Fifteen force sensors were placed on the bow flare surface to measure slamming load. The slamming loads were measured in regular and irregular waves at various ship speeds, wave lengths, wave heights, and heading angles. In a regular wave test, the slamming load was larger in oblique sea than in head sea because the relative angle of the wave and bow flare is smaller in oblique sea. In an irregular wave test, extremely large slamming loads were measured at the centre line at the bow, which is influenced by the horizontal relative velocity such as the ship speed and surge. In an analysis of the slamming load of the ship, the direction of wave and forward speed of the ship should be carefully considered. These are difficult to consider in 2D analysis. Highlights • The measured slamming impact loads on the bow flare of ultra-large containership are presented. • Various ship speeds, heading angles, wave heights, and wave lengths were applied in regular and irregular waves. • It is known that the slamming load of the ship is mainly determined by the vertical relative velocity, but it was found that abnormal large slamming load occurs due to horizontal relative velocity as well as the vertical relative velocity in the model test of irregular wave. • The slamming load in oblique sea can be larger than that in head sea because the relative angle between the bow the wave surface decreases in oblique sea. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid type 1 (TRPV1), the archetypal member of the vanilloid TRP family, was initially identified as the receptor for capsaicin, the pungent ingredient in hot chili peppers. We previously demonstrated that TRPV1 in the dorsal striatum significantly contributes to morphine reward by using the conditioned place preference paradigm in mice; however, it is unknown whether TRPV1 has the same effect in other reward models. In this study, we investigated the role of TRPV1 in morphine reward by using a self-administration paradigm in rats. We found that treatment with a selective TRPV1 antagonist, SB366791, significantly decreased morphine self-administration on a fixed-ratio 1 schedule or a progressive ratio schedule of reinforcement. In addition, treatment with another selective TRPV1 antagonist, AMG9810, not only significantly prevented morphine self-administration but also prevented morphine-induced c-fos expression in the nucleus accumbens. Furthermore, administration of SB366791 decreased an anxiolytic-like effect during the morphine abstinence period. Moreover, treatment with SB366791 significantly decreased morphine-priming reinstatement. Taken together, our findings suggest that blockade of TRPV1 receptors could provide an approach to limiting morphine addiction. [ABSTRACT FROM AUTHOR]

Cathinone derivatives are new recreational drugs known to produce psychostimulant effects. However, unlike other psychostimulants, the addictive potential of cathinone derivatives has not been widely studied. Here, we investigated the effects of pentedrone, a type of cathinone derivative, on the dopaminergic system using reverse transcription polymerase chain reaction and Western blot. We also evaluated the addictive potential of pentedrone using conditioned place preference and self-administration. We found that pentedrone increased the mRNA expression of dopamine 1 receptor, dopamine 2 receptor and dopamine transporter, as well as induced phosphorylation of cAMP response element-binding protein in PC-12 cells. Additionally, pentedrone at 3 and 10 mg/kg significantly increased conditioned place preference in mice, while pentedrone at 0.3 mg/kg/infusion significantly increased self-administration in rats. Finally, we found that acute administration of pentedrone enhanced locomotor activity in a dose-dependent manner. Collectively, these data suggest that the addictive properties of pentedrone may be due to its effects on the dopaminergic system. [ABSTRACT FROM AUTHOR]

In this study, the Hopf bifurcation problem with regard to the nonlinear dynamics of a towed vessel was numerically investigated. A time-domain simulation method based on three degrees-of-freedom maneuvering equations of motion was applied to study the nonlinear dynamic responses of a towed vessel in calm water, wind and waves. In the towing operation, it is assumed that a vessel is passively towed by a tug via a towline with a constant towing speed following a straight line. In the case of wind or wave conditions, the steady wind or wave drift forces are considered as additional external force components. The hydrodynamic forces acting on the towed vessel are modeled as a modular-type hull force model, and the towline force is simply modeled as a linear spring. First, for the validation, the motion trajectories of the towed vessel were compared between the experimental data and numerical simulation results under the calm water condition. Discussions are provided on the effect of skegs on the dynamics of the towed vessel and related Hopf bifurcation according to the skeg size. Next, the wind speed was changed, and the resulting limit cycles were studied. It can be observed that the Hopf bifurcation can be delayed according to the wind speed and direction. Finally, the dynamic characteristics of the towed vessel in regular waves were investigated via numerical simulations. The stability of the towed vessel with no skegs increases owing to the mean wave drift forces for both the model test and numerical simulation. The effects of the wave height and period on the Hopf bifurcation were studied based on numerical simulations. It was found that the occurrence of Hopf bifurcation for nonlinear dynamics of a towed vessel is sensitive to the conditions of wave height and period. • Hopf bifurcation problem with regard to the nonlinear dynamics of a towed vessel is numerically investigated based on a time-domain simulation method. • Discussions are provided on the effect of skeg on the dynamics of the towed vessel and related Hopf bifurcation according to the skeg size. • The effects of wind and wave on the Hopf bifurcation are studied based on numerical simulations. [ABSTRACT FROM AUTHOR]

In this study, the berthing problem in waves is numerically investigated by a time-domain simulation method based on a potential flow model. The boundary value problem for a berthing operation is formulated with respect to an earth-fixed coordinate system. The Laplace equation of a moving boundary problem is solved using the finite element method by adopting an efficient re-mesh algorithm. The developed numerical method is applied to investigate the berthing problem between two rectangular barges, with particular focus on the hydrodynamic forces acting on the barges during the berthing process. It is assumed that the two barges correspond to installation and transportation barges. To simplify the berthing problem, the transportation barge is assumed to approach the installation barge along a straight path at constant speed. The hydrodynamic force responses during berthing operation are investigated via a series of numerical computations. Further, the effects of wave heading and wave frequency are investigated. To validate present numerical results, model tests were conducted in the Ocean Engineering Basin of KRISO. The berthing tests were performed using two barge models under the head and beam sea conditions. Fairly good agreement is observed between the numerical simulation and experimental results. [ABSTRACT FROM AUTHOR]

In the current study, we evaluated the anti-inflammatory effects of Lonicera japonica THUNB. (LJ) and its underlying molecular mechanism in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Our results indicated that LJ significantly inhibits LPS-stimulated production of nitric oxide (NO) and prostaglandin E2 (PGE2). In addition, LJ inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at both the protein and mRNA levels. In LPS-stimulated BV-2 microglial cells, LJ inhibited proinflammatory cytokines and chemokines, tumor necrosis factor- α (TNF- α), interleukin-1 β (IL-1 β), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) enzymatic activities, and/or mRNA expression, as well as reactive oxygen species (ROS) production. LJ significantly suppressed activation of nuclear factor- κB (NF- κB) and its translocation from the cytosol to the nucleus and suppressed the DNA-binding activity of NF- κB. Furthermore, LJ significantly inhibited phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK 1/2), p38 mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinases (PI3K)/Akt, and Janus kinase 1 (JAK1)/signal transducer and activator of transcription (STAT)1/3. Collectively, our findings indicated that the antineuroinflammatory properties of LJ in LPS-induced BV-2 microglial cells is due to downregulation of proinflammatory cytokines and chemokines downstream of inhibition of NF- κB activation. [ABSTRACT FROM AUTHOR]

In the current study, we evaluated the anti-inflammatory effects of Lonicera japonica THUNB. (LJ) and its underlying molecular mechanism in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Our results indicated that LJ significantly inhibits LPS-stimulated production of nitric oxide (NO) and prostaglandin E2 (PGE2). In addition, LJ inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at both the protein and mRNA levels. In LPS-stimulated BV-2 microglial cells, LJ inhibited proinflammatory cytokines and chemokines, tumor necrosis factor- α (TNF- α), interleukin-1 β (IL-1 β), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) enzymatic activities, and/or mRNA expression, as well as reactive oxygen species (ROS) production. LJ significantly suppressed activation of nuclear factor- κB (NF- κB) and its translocation from the cytosol to the nucleus and suppressed the DNA-binding activity of NF- κB. Furthermore, LJ significantly inhibited phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK 1/2), p38 mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinases (PI3K)/Akt, and Janus kinase 1 (JAK1)/signal transducer and activator of transcription (STAT)1/3. Collectively, our findings indicated that the antineuroinflammatory properties of LJ in LPS-induced BV-2 microglial cells is due to downregulation of proinflammatory cytokines and chemokines downstream of inhibition of NF- κB activation. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid type 1 (TRPV1), a nonselective cation channel, is a well-known pain-related receptor. TRPV1 involvement in morphine-induced antinociception, tolerance, and withdrawal symptoms has been previously reported. Emerging evidence indicates that TRPV1 may be related to both the cellular and behavioral effects of addictive drugs. In the present study, we investigated the role of TRPV1 in morphine reward using the conditioned place preference (CPP) paradigm in mice. Repeated morphine treatments upregulated TRPV1 expression in the dorsal striatum (DSt). Treatment with a TRPV1 agonist potentiated morphine reward, and pretreatment with TRPV1 antagonists attenuated these effects. Microinjection of a selective TRPV1 antagonist into the DSt significantly inhibited morphine-CPP. In addition, treatment with a TRPV1 antagonist suppressed morphine-induced increases in μ-opioid receptor binding, adenylyl cyclase 1 (AC1), p38 mitogen-activated protein kinase (p38 MAPK), and nuclear factor kappa B (NF-κB) expression in the DSt. Administering a p38 inhibitor not only prevented morphine-CPP, but also prevented morphine-induced NF-κB and TRPV1 activation in the DSt. Furthermore, injecting an NF-κB inhibitor significantly blocked morphine-CPP. Our findings suggest that TRPV1 in the DSt contribute to morphine reward via AC1, p38 MAPK, and NF-κB. Brain TRPV1 may serve as a novel therapeutic target to treat morphine-addictive disorders. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Eucommia ulmoides Oliv. Bark. (EUE) has commonly been used to fortify the muscles and lungs, lower blood pressure, prevent miscarriage, improve liver and kidney tone, and promote longevity as a traditional tonic medicine in Korea, China, and Japan. Aim of the study: In this study, we investigated the mechanisms by which EUE protects neuronal cells from apoptosis induced by the Parkinson's disease (PD)-related neurotoxin, 6-hydroxydopamine (6-OHDA). Materials and methods: We determined the neuroprotective effects of EUE on 6-OHDA-induced neuronal cell death, cytotoxicity, reactive oxygen species (ROS) production, and mitochondrial membrane dysfunction. Moreover, we examined whether EUE suppressed phosphorylation of c-Jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K)/Akt, and glycogen synthase kinase-3 beta (GSK-3β). Furthermore, the neuroprotective effects of EUE on 6-OHDA-induced activation of nuclear factor-kappa B (NF-κB) was studied in SH-SY5Y cells. Results: Pretreatment of SH-SY5Y cells with EUE significantly reduced 6-OHDA-induced cell death and cytotoxicity. EUE inhibited 6-OHDA-induced generation of ROS, which conferred cytoprotection against 6-OHDA-induced oxidative injury. EUE treatment also strikingly inhibited 6-OHDA-induced mitochondrial dysfunction. In addition, EUE suppressed phosphorylation of JNK, PI3K/Akt, and GSK-3β. Furthermore, EUE blocked 6-OHDA-induced NF-κB nuclear translocation, an event downstream from JNK, PI3K/Akt, and GSK-3β phosphorylation. Moreover, chlorogenic acid (CGA), one of the active constituents of EUE, was also able to reduce 6-OHDA-induced toxicity in SH-SY5Y cells. Conclusion: Taken together, these results suggest that EUE attenuates oxidative stress through activation of JNK, PI3K/Akt, GSK-3β, and NF-κB pathways, thereby protecting cells from neuronal cell death. [Copyright &y& Elsevier]

Abstract: Various artificial damping schemes for progressive water waves were evaluated in a three-dimensional numerical wave tank (3D NWT). Five types of damping schemes were applied to the end of a computational domain and their damping capabilities were compared to find an optimum artificial damping scheme. The 3D NWT was based on a nine-node, bi-quadratic, higher-order boundary element method (HOBEM). A semi-Lagrangian approach known as the Mixed-Eulerian–Lagrangian (MEL) method was used to capture the nonlinear free surface fluctuation. A Runge–Kutta fourth-order time integration scheme was used for time marching to produce a time history of water surface elevations. For efficient damping performance, four different ramping functions were introduced and applied to the damping coefficients, and their influences were evaluated in order to select an optimal ramping shape along the artificial damping zone. The conservation of total energy in the computational domain was ensured to verify wave dissipation in the artificial damping zone. The wave elevations at different locations in the damping zone were also compared in order to appraise the damping capabilities of the respective damping schemes. The optimal numerical damping scheme associated with a proper damping shape over a range of damping zones was proposed for an efficient numerical beach. [Copyright &y& Elsevier]

Abstract: Previously we reported that the 50% EtOH extract of Cinnamomum cassia (C. cassia) possesses anxiolytic-like activity in the mouse elevated plus maze (EPM) test. This activity was blocked by the 5-HT1A receptor antagonist, WAY 100635. Therefore, in order to investigate the effect of C. cassia on 5-HT1A receptor binding, quantitative autoradiography of 5-HT1A receptors was carried out in brains of mice treated acutely and repeatedly with C. cassia. Binding of [3H]8-OH-DPAT to the 5-HT1A receptor was investigated in the mouse brain. After a single treatment of C. cassia (750mg/kg, p.o.), [3H]8-OH-DPAT binding showed a significant increase in the dorsal raphe nucleus (DRN). After repeated treatment with C. cassia (100mg/kg, once a day for 5days, p.o.), [3H]8-OH-DPAT binding showed no significant change in any brain region. Taken together, the anxiolytic-like effect of the 50% EtOH extract of C. cassia might be mediated by region specific change of 5-HT1A receptors in the dorsal raphe nucleus. [Copyright &y& Elsevier]

Abstract: We investigated the mechanisms underlying the protective effects of loganin against hydrogen peroxide (H2O2)-induced neuronal toxicity in SH-SY5Y cells. The neuroprotective effect of loganin was investigated by treating SH-SY5Y cells with H2O2 and then measuring the reduction in H2O2-induced apoptosis using 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays. Following H2O2 exposure, Hoechst 33258 staining indicated nuclear condensation in a large proportion of SH-SY5Y cells, along with an increase in reactive oxygen species (ROS) production and an intracellular decrease in mitochondria membrane potential (MMP). Loganin was effective in attenuating all the above-stated phenotypes induced by H2O2. Pretreatment with loganin significantly increased cell viability, reduced H2O2-induced LDH release and ROS production, and effectively increased intracellular MMP. Pretreatment with loganin also significantly decreased the nuclear condensation induced by H2O2. Western blot data revealed that loganin inhibited the H2O2-induced up-regulation of cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspase-3, increased the H2O2-induced decrease in the Bcl-2/Bax ratio, and attenuated the H2O2-induced release of cytochrome c from mitochondria to the cytosol. Furthermore, pretreatment with loganin significantly attenuated the H2O2-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 (ERK 1/2). These results suggest that the protective effects of loganin against H2O2-induced apoptosis may be due to a decrease in the Bcl-2/Bax ratio expression due to the inhibition of the phosphorylation of JNK, p38, and ERK 1/2 MAPKs. Loganin''s neuroprotective properties indicate that this compound may be a potential therapeutic agent for the treatment of neurodegenerative diseases. [Copyright &y& Elsevier]

Numerical analyses were performed to investigate the characteristics of the slamming impact loads on the bow-flare of a ship-type floating production storage and offloading (FPSO) model under breaking waves. To estimate the slamming impact load, a series of breaking wave simulations was performed. From 2D wave flume tests, the grid aspect ratio, convection scheme, turbulence model, effect of surface tension, and grid dependencies were investigated. Through a series of numerical simulations, the grid system and numerical schemes were determined, and the slamming impact load simulations were conducted. It could be observed that the slamming impact loads and motions of the FPSO model in the numerical simulations were in good agreement with the experimental results. In order to investigate the relation between the slamming impact load and free motion of the FPSO model, the breaking impact simulations were performed under fixed positions and the free motion of the FPSO model. From the results, the relation between the relative angle and slamming impact load, as well as the relation between the position of the FPSO model and impulse response, are discussed. • For the purpose of generating high-intensity breaking waves in Computational Fluid Dynamics (CFD), various case studies were conducted, including turbulent models, the effect of surface tension, grid aspect ratios, mesh resolutions and discretization techniques for convection terms. • To accurately simulate breaking waves, a grid system with an aspect ratio of approximately 2 is necessary, along with a second-order convection scheme. Turbulence models and surface tension effects are found to be insignificant in breaking wave simulations. However, in deep-water conditions, additional meshes under the free surface are crucial to capture the distribution of wave velocity to greater depths. • In analyzing slamming impact loads under breaking wave conditions, the highest impact loads shifted in location based on changes in wave headings, influenced by relative angles between the wave and the FPSO model's bow. Trends in numerical simulations closely mirrored experimental observations. • This study identified the relative angle between the breaking wave and the FPSO model's bow as the primary factor influencing breaking impact loads. Accurate prediction of wave characteristics and relative angle enables the estimation of slamming impact load magnitude. Additionally, under fixed FPSO model conditions, impulse responses are greater compared to free motion conditions due to prolonged wave interaction. Precise estimation of impulse responses requires accurate prediction of floating body motion. [ABSTRACT FROM AUTHOR]

We propose a knowledge representation and operators for large, diverse model libraries. The knowledge representation distinguishes between model types that are classes of models defined by a collection of assumptions and model templates and instances that instantiate model types through decomposition and specialization of components. Underlying the knowledge representation are inheritance to represent the level of generalization and multiple levels of instantiation to represent the level of details among models. For inheritance, we define partial order relations for models and their components including domains, classes, units, assumptions, metrics, and constraints. For instantiation, we define constraints on transformations between model types, templates, and instances. The inexact search operators support content-based retrieval especially when it is difficult for a user to exactly specify the characteristics of models of interest. The operators use similarity functions to measure the closeness of a match between a search atom and the value of a model attribute. The explanation operators are designed to enhance users' understanding about the symbols, assumptions, components, and relationships among models. A prototype system has been implemented in Prolog to demonstrate the essential features of the model library system. [ABSTRACT FROM AUTHOR]

Ultraviolet photoelectron spectroscopy and atomic force microscopy (AFM) were used to investigate the energy level alignment and growth morphology of pentacene (Pn) films deposited on a PMMA derivative-based dielectric surface with and without ultraviolet/ozone treatment. The treated surface exhibited higher offset values for the highest occupied molecular orbital levels between Pn and the polymer, which would result in higher threshold voltages for the device. However, aligned vacuum levels of the treated surface and the Pn at the interface were observed, suggesting that the dipole field would be reduced in the Pn film on the treated surface. The hydrophilic nature of the treated surface, observed by water contact angle measurement, allowed for a larger grain size of the Pn film, as confirmed by the AFM measurements, which will also favorably contribute to device mobility. [ABSTRACT FROM AUTHOR]

This study conducted an experimental investigation into the characteristics of the sidewall green water problem of a ship-type floating production storage and offloading (FPSO) under irregular waves. The study applied three different irregular waves and two different heading angles. Relative wave elevations were measured using 12 wave probes on the deck and side of the FPSO model, along with the forces acting on pillars during the green water event. The process of the sidewall green water event was studied, investigating variations in relative wave elevations and forces acting on the pillars based on the heading angle. The experimental results examined correlations between the vertical motions of the FPSO model and relative wave elevations. Bow green water events at heading angles of 165° and 150° were mainly affected by the pitch and roll motions of the FPSO model, respectively. Additionally, it was found that the side green water event is affected by the heave motion of the FPSO model. • In order to investigate the characteristics of bow and sidewall green water phenomena under irregular wave conditions, the experiments were conducted using the FPSO of ship-type with 12 wave probes and 2-components loadcells. • Regular waves were generated to investigate the phenomena of sidewall green water, and the phenomena of sidewall green water were as following. (i) The wave propagated along the FPSO sidewall, while the bow green water passed on the deck of the FPSO; (ii) during the wave propagation, the wave was progressing higher on the sidewall of FPSO. (iii) The relative wave elevation rised and exceeded the freeboard of the FPSO when the wave arrived near the midship of the FPSO. • In the irregular wave test, the roll motion of FPSO in heading = 165° was relatively smaller than that of heading = 150°. So, the forces on Pillars for heading = 150° gradually increased from Pillar#1 to Pillar#3. For heading = 165°, relatively small green water loads occurred on Pillar#2, and there were relatively large bow side and sidewall green water loads on Pillar#1 and Pillar#3, respectively. • From the irregular wave tests, correlations between the relative wave elevations and vertical motions attributable to the bow and sidewall green water events were investigated. Bow green water events mainly occurred by the pitch and roll motions for heading conditions of 165° and 150°, respectively. Side wall green water events could occur by not only the developed wave on the sidewall of FPSO, but also the heave motion of the FPSO. [ABSTRACT FROM AUTHOR]

Experimental and numerical studies were performed on the hand-over operation of a riser between an installation vessel and an FPSO. A series of model tests were conducted in the Ocean Engineering Basin of KRISO. In the model test, a riser truncation model was introduced considering the limited depth of the basin and pit diameter. In addition, a nonlinear time-domain numerical simulation was performed considering two-body interaction effects. The experimental data were directly compared with the simulation results in terms of vessel motion and wire tension under two load transfer conditions. The results show that two floating bodies during the riser hand-over operation experience significant hydrodynamic interaction. Under the low load transfer condition, the snapping phenomenon was clearly observed in the PIW tension. The discussion focuses on the effects of the two-body interaction, riser truncation, load transfer stages, and wave conditions. • A series of model tests were performed on the hand-over operation of a riser between an installation vessel and an FPSO. • Truncation riser modeling was successfully applied in the model test. • The discussion focuses on the effects of the two-body interaction, riser truncation, load transfer stages, and wave conditions. [ABSTRACT FROM AUTHOR]

Abstract: This paper compares the dynamic coupled behavior of floating structure and mooring system in time domain using two numerical methods for the mooring lines such as the linear spring method and the nonlinear FEM (Finite Element Method). In the linear spring method, hydrodynamic coefficients and forces on the floating body are calculated using BEM (Boundary Element Method) and the time domain equation is derived using convolution. The coupled solution is obtained by simply adding the pre-determined spring constants of the mooring lines into the floating body equation. In FEM, the minimum energy principle is applied to formulate the nonlinear dynamic equation of the mooring system with a discrete numerical model. The ground contact model and Morison formula for drag forces are also included in the formulation. The coupled solution is obtained by iteratively solving the floating body equation and the FEM equation of the mooring system. Two example structures such as weathervane ship and semi-submersible structure are analyzed using linear spring and nonlinear FEM methods and the difference of those two methods are presented. By analyzing the cases with or without surge-pitch or sway-roll coupling stiffness of mooring lines in the linear spring method, the effect of coupling stiffness of the mooring system is also discussed. [Copyright &y& Elsevier]

Abstract: Julibroside C1 is a saponin-containing compound isolated from Albizzia julibrissin Durazz. In this study, we investigated the putative anxiolytic effects of Julibroside C1 using the elevated plus maze (EPM) in mice. Julibroside C1 at doses of 0.5 and 1mg/kg significantly increased the time spent in the open arms and the number of entries into the open arms of the EPM compared to the control group. Moreover, the anxiolytic-like effects of Julibroside C1 (0.5mg/kg) were blocked by WAY-100635 (5-HT1A receptor antagonist), bicuculline (GABAA receptor antagonist), and flumazenil (antagonist of the GABAA receptor benzodiazepine site). However, Julibroside C1 did not change locomotor activity or induce myorelaxant effects. We used quantitative receptor autoradiography to investigate the effects of Julibroside C1 on alterations in mouse brain receptors. After acute treatment with Julibroside C1 (0.5mg/kg), [3H]-8-OH-DPAT binding was significantly decreased in the CA1 region of the hippocampus and [3H]-flunitrazepam binding was decreased remarkably in the cingulate cortex region. However, [3H]-muscimol binding did not show a significant change in any brain region. Taken together, our findings suggest that Julibroside C1 shows anxiolytic-like effects, which might be mediated by the 5-HT1A and GABAA–benzodiazepine receptor systems. [Copyright &y& Elsevier]

Abstract: Oxethazaine, an over-the-counter (OTC) antacid, is a precursor of phentermine, which is the most abused anorectic by methamphetamine users in Korea. However, no studies have investigated the abuse potential of oxethazaine. Therefore, we examined and compared the consequences of oxethazaine and phentermine treatment on animal models of conditioned place preference (CPP) and self-administration. Furthermore, oxethazaine and its metabolites in rat plasma were monitored using liquid chromatography–tandem mass spectrometry (LC–MS/MS) after oxethazaine administration, and compared with phentermine itself after phentermine administration to clarify the relationship between phentermine production by oxethazaine ingestion and the possible oxethazaine dependence. Oxethazaine metabolites were also determined by LC–MS/MS in rat hair after oxethazaine administration to investigate the possibility of phentermine detection in hair from oxethazaine abusers. In the behavioral experiment, phentermine (3mg/kg) produced CPP in mice while oxethazaine (5, 10, and 15mg/kg) did not. Moreover, phentermine (0.25mg/kg/infusion) was self-administered by rats at 80% of free-feeding weight, whereas oxethazaine was not. In the analytical study, mephentermine and phentermine, both oxethazaine metabolites, were detected below the limit of quantitation or not detected in both plasma and hair from rats that had ingested oxethazaine (10mg/kg, single dose or for 2weeks). On the other hand, phentermine was detected in plasma and hair samples from rats that had ingested phentermine (10mg/kg, single dose or for 2weeks). Consequently, phentermine induced significant rewarding effects, but oxethazaine did not. Presumably, either oxethazaine does not have any abuse potential or oxethazaine metabolism to phentermine does not result in a pharmacologically active level of psychostimulant in the body. Furthermore, phentermine was not a major metabolite in hair obtained from oxethazaine abusers, which should make it possible to differentiate between chronic oxethazaine and phentermine users. [Copyright &y& Elsevier]

Abstract: The transient receptor potential vanilloid type 1 channel (TRPV1) receptors are expressed in various regions of the brain. Much less is known about whether TRPV1 receptors affect higher brain functions. In the present study, we demonstrated that TRPV1-knockout (TRPV1KO) mice showed antidepressant-like behaviors in a novelty-suppressed feeding test and forced swim test when compared to wild-type (WT) mice. Additionally, TRPV1KO mice exhibited increased aggressiveness and reduced social interactions in a social dominance test and social interaction test. TRPV1KO mice showed reduced short-term memory and normal long-term memory in a novel object recognition test and passive avoidance test versus WT mice. Based on these behavioral data, we investigated changes in specific receptors related to depression, anxiety, and memory in the brains of TRPV1KO and WT mice. Binding of [3H]-8-OH-DPAT was significantly higher in the frontal associated cortex (FrA), nucleus accumbens (NAc), and the cingulate cortex (CC) of TRPV1KO mice than WT mice, while the expression of 5-HT1A receptors was higher in the FrA, NAc, and cortex of TRPV1KO mice than WT mice. [3H]-flunitrazepam binding was also significantly higher in the FrA, striatum (CPU), and the CC of TRPV1KO versus WT mice. In contrast, [3H]-musicmol binding in the FrA, CPU, NAc, CC, and the dentate gyrus (DG) was significantly lower in TRPV1KO mice than WT mice. The expression of GABAAγ2 was higher in the NAc, CPU, and cortex of TRPV1KO versus WT mice, whereas the expression of GABAAα2 was lower in the FrA, CPU, NAc, and cortex in TRPV1KO mice than WT mice. Finally, [3H]-MK-801 binding was decreased in the CPU and CA1 of TRPV1KO versus WT mice. The expression of NR2A was lower in the hippocampus of TRPV1KO versus WT mice. These data suggest that the loss of TRPV1 results in antidepressant-like, anxiolytic, abnormal social and reduced memorial behaviors due to changes in expression of 5-HT1A, GABAA, and NMDA receptors. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’. [Copyright &y& Elsevier]

Abstract: In the present study, we examined whether aqueous extract of Eucommia ulmoides Oliv. Bark (EUE) with graded doses exerted its neuroprotective effects on amyloid beta25–35 (Aβ25–35)-induced learning and memory impairments in mice. Mice received a single intracerebroventricular (i.c.v.) injection of Aβ25–35 6nmol as the critical factor in Alzheimer''s disease (AD), cognition was evaluated using Y-maze, passive avoidance, and Morris water maze tests. EUE significantly improved the Aβ25–35-induced memory deficit in the Y-maze test. Also, EUE increased step-through latency time with Aβ25–35-induced learning and memory deficits in the passive avoidance test. In addition, EUE decreased the escape latencies with Aβ25–35-induced cognitive impairments in the Morris water maze test. In the probe trial session, EUE increased time spent in the target quadrant. In the in vitro study, EUE was found to inhibit acetylcholinesterase (AChE) activity in a dose-dependent manner (IC50 value; 172μg/ml). Ex vivo study, EUE significantly inhibited AChE activity in the hippocampus and frontal cortex. These results demonstrate that EUE possesses potent neuroprotective effects and that its beneficial effects are mediated, in part, by AChE inhibition, and therefore, might be a potential candidate in neurodegenerative diseases such as AD. [Copyright &y& Elsevier]

Abstract: Chlorogenic acid is a major polyphenolic component of many plants and beverages, and is particularly abundant in coffee. We evaluated the neuroprotective effects of chlorogenic acid on learning and memory impairment induced by scopolamine (0.5mg/kg, i.p.), a muscarinic antagonist, using the Y-maze, passive avoidance, and Morris water maze tests. The chlorogenic acid significantly improved the impairment of short-term or working memory induced by scopolamine in the Y-maze test, and significantly reversed cognitive impairments in mice as measured by the passive avoidance test. In addition, chlorogenic acid decreased escape latencies in the Morris water maze test. In a probe trial session, chlorogenic acid increased the latency time in the target quadrant in a dose-dependent manner. Ex vivo, chlorogenic acid inhibited acetylcholinesterase activity in the hippocampus and frontal cortex. Chlorogenic acid also decreased malondialdehyde levels in the hippocampus and frontal cortex. In vitro, chlorogenic acid was found to inhibit acetylcholinesterase activity (IC50 =98.17μg/ml) and free radical scavenging activity (IC50 =3.09μg/ml) in a dose-dependent manner. These results indicate that chlorogenic acid may exert anti-amnesic activity via inhibition of acetylcholinesterase and malondialdehyde in the hippocampus and frontal cortex. [ABSTRACT FROM AUTHOR]

An experimental investigation of the characteristics of the slamming impact loads on the bow of a ship-type Floating Production Storage and Offloading (FPSO) under breaking and irregular wave conditions was conducted. The breaking waves were generated by the focusing wave method and three different heading angles were applied. To examine the repeatability of the slamming loads, the model experiments were repeated 20 times for each heading condition. The slamming impact loads were measured using 15 force sensors attached to the bow of the FPSO unit model, while force panels were used to measure the local impact loads. The locations of the largest slamming impact loads were observed to vary with the heading angle. Two types of slamming impact loads were identified and damping was also observed in the slamming impact load with two peaks. Irregular wave tests conducted under oblique wave conditions were further used to investigate the characteristics of the slamming impact loads, and the velocities of the directional sway and roll motions were found to be significant determinants of the slamming impact load. • In order to investigate the characteristics of bow slamming impact loads under breaking and irregular wave conditions, the experiments were conducted using the FPSO with 15 force sensors. • Breaking waves were generated by the focusing wave method and three different heading angles were applied. Each heading condition was repeated 20 times to verify the repeatability of the slamming impact loads. • Two types of slamming impact loads can be classified in the breaking wave condition: (i) slamming impact load with one peak; (ii) slamming impact load with two peaks, and damping was observed in the case of the slamming impact load with two peaks. • The velocities of the sway and roll motions were found to be significant determinants of the slamming impact load under the oblique wave conditions. [ABSTRACT FROM AUTHOR]