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Glutathione (GSH), an abundant nonprotein thiol antioxidant, participates in several biological processes and determines the functionality of stem cells. A detailed understanding of the molecular network mediating GSH dynamics is still lacking. Here, we show that activating transcription factor-2 (ATF2), a cAMP-response element binding protein (CREB), plays a crucial role in maintaining the level and activity of GSH in human mesenchymal stem cells (MSCs) by crosstalking with nuclear factor erythroid-2 like-2 (NRF2), a well-known master regulator of cellular redox homeostasis. Priming with ascorbic acid 2-glucoside (AA2G), a stable vitamin C derivative, increased the expression and activity of ATF2 in MSCs derived from human embryonic stem cells and umbilical cord. Subsequently, activated ATF2 crosstalked with the CREB1-NRF2 pathway to preserve the GSH dynamics of MSCs through the induction of genes involved in GSH synthesis (GCLC and GCLM) and redox cycling (GSR and PRDX1). Accordingly, shRNA-mediated silencing of ATF2 significantly impaired the self-renewal, migratory, proangiogenic, and anti-inflammatory capacities of MSCs, and these defects were rescued by supplementation of the cells with GSH. In addition, silencing ATF2 attenuated the ability of MSCs to alleviate airway inflammatory responses in an ovalbumin-induced mouse model of allergic asthma. Consistently, activation of ATF2 by overexpression or the AA2G-based priming procedure enhanced the core functions of MSCs, improving the in vivo therapeutic efficacy of MSCs for treating asthma. Collectively, our findings suggest that ATF2 is a novel modulator of GSH dynamics that determines the core functionality and therapeutic potency of MSCs used to treat allergic asthma.

Aberrant activation of embryogenesis-related molecular programs in urothelial bladder cancer (BC) is associated with stemness features related to oncogenic dedifferentiation and tumor metastasis. Recently, we reported that overexpression of transcription factor CP2-like protein-1 (TFCP2L1) and its phosphorylation at Thr177 by cyclin-dependent kinase-1 (CDK1) play key roles in regulating bladder carcinogenesis. However, the clinical relevance and therapeutic potential of this novel CDK1-TFCP2L1 molecular network remain elusive. Here, we demonstrated that inhibitor of DNA binding-2 (ID2) functions as a crucial mediator by acting as a direct repressive target of TFCP2L1 to modulate the stemness features and survival of BC cells. Low ID2 and high CDK1 expression were significantly associated with unfavorable clinical characteristics. TFCP2L1 downregulated ID2 by directly binding to its promoter region. Consistent with these findings, ectopic expression of ID2 or treatment with apigenin, a chemical activator of ID2, triggered apoptosis and impaired the proliferation, suppressed the stemness features, and reduced the invasive capacity of BC cells. Combination treatment with the specific CDK1 inhibitor RO-3306 and apigenin significantly suppressed tumor growth in an orthotopic BC xenograft animal model. This study demonstrates the biological role and clinical utility of ID2 as a direct target of the CDK1-TFCP2L1 pathway for modulating the stemness features of BC cells.

This study aimed to investigate the risk of all-cause mortality and incidence of CVD according to metabolic health and body mass index (BMI) in Korean adults. This study was retrospectively designed using the National Health Insurance Service-National Health Screening Cohort data. Participants were divided into six groups according to two category of metabolic syndrome and three categories of BMI. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the composite outcome (all-cause mortality and incidence of CVDs) were estimated using multivariable Cox proportional hazards regression models. 151,706 participants aged ≥ 40 years were enrolled; median follow-up period was 9.7 years in the study. Compared to metabolically healthy normal weight, the fully adjusted HRs (95% CIs) of metabolically healthy overweight, metabolically healthy obese, metabolically unhealthy normal weight, metabolically unhealthy overweight, and metabolically unhealthy obese for composite outcome were 1.07 (1.03–1.12), 1.12 (1.07–1.17), 1.33 (1.25–1.41), 1.28 (1.22–1.34), and 1.31 (1.26–1.37), respectively, in men, and 1.10 (1.05–1.16), 1.22 (1.16–1.29), 1.34 (1.26–1.43), 1.27 (1.19–1.34), and, 1.40 (1.34–1.47), respectively, in women. High BMI and metabolic unhealthiness were associated with an increased risk on the composite of all-cause mortality and incidence of CVD in both sexes.

KRAS-mutant non-small cell lung cancer (NSCLC) is a major lung cancer subtype that leads to many cancer-related deaths worldwide. Although numerous studies on KRAS-mutant type NSCLC have been conducted, new oncogenic or tumor suppressive genes need to be detected because a large proportion of NSCLC patients does not respond to currently used therapeutics. Here, we show the tumor-promoting function of a cell cycle-related protein, PIERCE1, in KRAS-mutant NSCLC. Mechanistically, PIERCE1 depletion inhibits cell growth and AKT phosphorylation (pAKT) at S473, which is particularly observed in KRAS-mutant lung cancers. Analyses of AKT-related genes using microarray, immunoblotting, and real-time quantitative PCR indicated that PIERCE1 negatively regulates the gene expression of the AKT suppressor, TRIB3, through the CHOP pathway, which is a key regulatory pathway for TRIB3 expression. Similarly, in vivo analyses of PIERCE1 depletion in the KRAS mutation-related lung cancer mouse models revealed the suppressive effect of PIERCE1 knockout in urethane- and KRASG12D-induced lung tumorigenesis with decreased pAKT levels observed in the tumors. Tissue microarrays of human lung cancers indicated the expression of PIERCE1 in 83% of lung cancers and its correlation with pAKT expression. Thus, we illustrate how PIERCE1 depletion may serve as a therapeutic strategy against KRAS-mutant NSCLC and propose the clinical benefit of PIERCE1.

The aim of this study is to explore the wear performance of AISI 316L stainless steel fabricated via selective laser melting along different directions with respect to the building direction and via post annealing. The wear behavior of the alloy under high-speed sliding was investigated with high sliding velocities of up to 1 m/s. It was shown that the wear behavior of the alloy was completely different from that in quasi-static wear environments. The high-speed wear resistance was significantly affected by the building direction. After the annealing heat treatment of the alloy at 800 °C for 4 h, the high-speed wear resistance significantly decreased. Therefore, special care must be taken in using SLM 316L alloys when subjected to wear environments with high sliding velocities.

The added resistance of a ship in waves can be related to ship-generated unsteady waves. In the present study, the unsteady wave-pattern analysis is applied to calculate the added resistance in waves for two modified Wigley models using a Cartesian-grid method. In the present numerical method, a first-order fractional-step method is applied to the velocity-pressure coupling in the fluid domain, and one of volume-of-fluid (VOF) methods is adopted to capture the fluid interface. A ship is embedded in a Cartesian grid, and the volume fraction of the ship inside the grid is calculated by identifying whether each grid is occupied by liquid, gas, and solid body. The sensitivity to the location of measuring position of unsteady waves as well as the number of solution grids is examined. The added resistance computed by direct pressure integration and wave pattern analysis is compared with experimental data. In addition, nonlinear characteristics of the added resistance in waves are investigated by detailed analyses of unsteady flow field and resulting wave pattern.

Trehalose is a non-reducing disaccharide found in various organisms, including bacteria, fungi, invertebrates, and plants. It plays essential roles in diverse biological processes such as stress resistance, metabolism, and development in plants. Despite the important role of trehalose, it is challenging to increase trehalose levels because of its negative effects on plant growth and development. In this study, we tested several combinations of different promoters and trehalose biosynthetic genes to efficiently accumulate trehalose in potato plants. Transgenic potato plants expressing TPSP (trehalose-6-phosphate synthase/phosphatase) fusion gene under the control of Rd29A promoter increased trehalose content in response to high salt stress and did not show significant growth retardation. Although constitutive overexpression of plastid-targeted MTSH (maltooligosyltrehalose synthase/trehalohydrolase) fusion gene driven by CaMV 35S promoter remarkably accumulated trehalose, the transgenic potato plants showed a severely stunted phenotype. By contrast, stress-inducible expression of plastid-targeted MTSH under the control of Rd29A promoter led to trehalose accumulation without growth defects in response to high salt stress. Besides, tuber-specific expression of plastid-targeted MTSH driven by GBSS (granule-bound starch synthase) promoter specifically increased trehalose level in potato tubers without stunting growth. Consequently, we suggest that heterologous expression of TPSP and MTSH fusion genes driven by stress-inducible or tuber-specific promoters can be an effective strategy for accumulating trehalose in potato plants as well as minimizing its adverse effects on potato growth.

This study examined the effects of heat treatment on the microstructure and wear properties of Al–Zn–Mg–Cu/in-situ Al–9Si–SiCp/pure Al composites. Pure Al powder was used to increase densification but it resulted in heterogeneous precipitation as well as differences in hardness among the grains. Heat treatment was conducted to solve this problem. The heat treatment process consisted of three stages: solution treatment, quenching, and aging treatment. After the solution treatment, the main dissolved phases were η′(Mg4Zn7), η(MgZn2), and Al2Cu phase. An aging treatment was conducted over the temperature range, 100–240 °C, for various times. The GP zone and η′(Mg4Zn7) phase precipitated at a low aging temperature of 100–160 °C, whereas the η(MgZn2) phase precipitated at a high aging temperature of 200–240 °C. The hardness of the sample aged at 100–160 °C was higher than that aged at 200–240 °C. The wear test was conducted under various linear speeds with a load of 100 N. The aged composite showed a lower wear rate than that of the as-sintered composite under all conditions. As the linear speed was increased to 1.0 m/s, the predominant wear behavior changed from abrasive to adhesive wear in all composites.

In this paper, we present the results of our numerical seakeeping analyses of a 6750-TEU containership, which were subjected to the benchmark test of the 2nd ITTC–ISSC Joint Workshop held in 2014. We performed the seakeeping analyses using three different methods based on a 3D Rankine panel method, including 1) a rigid-body solver, 2) a flexible-body solver using a beam model, and 3) a flexible-body solver using the eigenvectors of a 3D Finite Element Model (FEM). The flexible-body solvers adopt a fully coupled approach between the fluid and structure. We consider the nonlinear Froude–Krylov and restoring forces using a weakly nonlinear approach. In addition, we calculate the slamming loads on the bow flare and stern using a 2D generalized Wagner model. We compare the numerical and experimental results in terms of the linear response, the time series of the nonlinear response, and the longitudinal distribution of the sagging and hogging moments. The flexible-body solvers show good agreement with the experimental model with respect to both the linear and nonlinear results, including the high-frequency oscillations due to springing and whipping vibrations. The rigid-body solver gives similar results except for the springing and whipping.

The aim of this study was to investigate the transition of wear behavior for pure aluminum and extruded aluminum alloy 2024-T4 (AA2024-T4). The wear test was carried using a ball-on-disc wear testing machine at various vertical loads and linear speeds. The transition of wear behaviors was analyzed based on the microstructure, wear tracks, wear cross-section, and wear debris. The critical wear rates for each material are occurred at lower linear speed for each vertical load. The transition of wear behavior was observed in which abrasion wears with the generation of an oxide layer, fracture of oxide layer, adhesion wear, severe adhesion wear, and the generation of seizure occurred in sequence. In case of the pure aluminum, the change of wear debris occurred in the order of blocky, flake, and needle-like debris. Cutting chip, flake-like, and coarse flake-like debris was occurred in sequence for the extruded AA2024-T4. The transition in the wear behavior of extruded AA2024-T4 occurred slower than in pure aluminum.

Design rules for very large seagoing vessels are undergoing changes owing to the hydroelasticity of the ship. The hydroelasticity of the ship is in the form of wave-induced vibrations such as springing and whipping, which are known to aggravate fatigue and extreme loads. The present study deals with a method for the estimation of extreme loads. The method consists of a preliminary analysis of linear responses of motions and loads, and a sequential analysis of the nonlinear extreme load. First, a full-time series of the linear response is obtained using response amplitude operators and wave spectra. Next, the candidate waves of extreme event are extracted from the full-time series based on the linear response. The linear response may be a motion or a load depending on the target value of the sequential analysis. Finally, the sequential analysis is conducted using a fully coupled model of the three-dimensional Rankine panel method, three-dimensional finite-element method, and two-dimensional generalized Wagner model with the candidate waves. The method is validated for a nonlinear hogging moment in a short-term sea state and applied for a long-term prediction of an extreme hogging moment on an ultra-large containership. The extreme values of linear and nonlinear loads are compared in terms of the most probable value and probabilistic distribution.

The motion responses of ships carrying liquid cargo are affected not only by external wave excitation, but also by internal sloshing-induced forces and moments. Sloshing flow is coupled with the ship motion. This means the added resistance in waves may change when sloshing occurs inside the tank of the ship. In this study, the motion responses and added resistance of a ship, coupled with the sloshing-induced internal forces and moments are considered by using the linear potential theory. The three-dimensional Rankine panel method, in which the physical quantities are represented by using B-spline basis function, is applied. The sloshing flow of inner tanks is also simulated by using the Rankine panel method and linearized boundary value problem. To study the added resistance, a near-field method, which integrates the second-order pressure on a body surface, is applied. The model ship is a blunt modified Wigley model with two inner tanks. Numerical results obtained without inner tanks are compared with the experimental data, and then the effect of filling ratio of inner tanks on ship motion and added resistance are observed. The components that induce added resistance are examined, and the effects of surge motion on sloshing flow and added resistance are briefly considered. This study shows that the sloshing flow inside the inner tanks may significantly influence not only the motion responses, but also added resistance, especially, when the incident wave frequency approaches the resonance frequency of the sloshing flow.

We investigated the effect of Mg on the nitridation behavior of Al particles during thermal treatment for a range of Mg contents and temperatures. The addition of Mg stimulates the initiation of nitridation because it diffuses and forms an Al-Mg alloy with a lower melting point than that of pure Al. In the initial stages of the nitridation, nitrides without a perfect crystallographic structure are formed on the surface of Al particles and then AlN with a superlattice structure is formed within the reaction product. Since the Al-Mg powder bed is rapidly densified during heat treatment compared to its pure Al counterpart, the pathways in it for nitrogen diffusion are limited in comparison and further nitridation is much suppressed, resulting in much lower total nitridation compared to a pure Al powder bed. This behavior is observed regardless of the Mg content or the nitridation temperature (up to 900 °C), demonstrated in experiment for Al powder beds containing

This study examined the adhesive bond strength and thermal performance of the anodized aluminum 6061 in phosphoric acid electrolyte to improve the adhesive bond strength and thermal performance for use in metal core printed circuit boards (MCPCB). The electrolyte temperature and applied voltage were altered to generate varied pore structures. The thickness, porosity and pore diameter of the anodized layer were measured. The pore morphologies were affected most by temperature, which was the driving force for ion transportation. The mechanism of adhesive bond was penetration of the epoxy into the pores. The optimal anodization conditions for maximum adhesive bond strength, 27 MPa, were 293 K and 100V. The maximum thermal conductivity of the epoxy-treated anodized layer was 1.6 W/m·K at 273 K. Compared with the epoxy-treated Al layer used for conventional MCPCBs, the epoxy-treated anodized layer showed advanced thermal performance due to a low difference of thermal resistance and high heat dissipation.

Conventional liquefied natural gas (LNG) vessels with membrane cargo containment systems have tank filling restrictions from 0.10 to 0.70 H (with H the internal tank height). The main reason for such restrictions is high sloshing loads around these filling depths. The new designs of prismatic LNG cargo tanks are proposed by increasing the lower chamfer length. Numerical sloshing analysis was used to optimize tank shape out of the several candidates. To validate the effectiveness of the modified tank, 1/50 scaled model tests were conducted. In these tests, 24 different irregular seaways were tested for both the conventional and the optimized tank and their statistical pressures were compared. Modified tank design was quite effective in reducing sloshing loads for a 0.30 H filling depth, and it did not significantly increase sloshing loads at other filling conditions. This study demonstrated the possibility of all filling operations for an LNG cargo containment system.

An Euler equation solver based on a Cartesian-grid and non-uniform staggered grid system is applied to simulate and analyze the ship motion and added resistance in waves. Water, air, and solid phases are distinguished using a volume fraction function for each phase and in each cell. To capture the water interface, the tangent of hyperbola for interface capturing scheme is used with a weighted line interface calculation method. The volume fraction of a solid body embedded in a Cartesian-grid system is calculated using a level-set algorithm, and the body boundary condition is imposed using a volume-weighted formula. Numerical simulations for a Wigley III hull and an S175 containership in regular waves are carried out to validate the newly developed code and to compare the effects of numerical methods for calculating the added resistance. All the results are compared with experimental data, and a calculation for the KRISO’s very large crude carrier 2 is also performed. From the grid convergence test for incident wave generation and the added resistance calculation, the sensitivity of the grid spacing is investigated, and the minimum requirements for the number of gird points are suggested to reliably calculate the added resistance in waves.

This paper presents a panel generation framework for seakeeping analysis of multiple bodies and offshore structures. The configurations of multiple bodies and offshore structures are different from those of a single ship. In particular, the topological structure of the free surfaces becomes complicated due to the multiple floating bodies, resulting in multiple classifications for the free surfaces based on their genus. The multi-body configuration consists of two floating bodies placed in two configurations, i.e., side by side and tandem, which would generate two holes in the free surface. For the offshore structure case, multiple holes are generated in the free-surface domain due to the legs of the offshore structure. In this work, strategies for generating body and free-surface panels are provided, and the results are analyzed. A software prototype that implements the proposed methods is developed to provide efficient panel generation for multiple bodies and offshore structures. Examples demonstrate that the proposed framework can be successfully used for seakeeping analysis of multiple bodies and offshore structures.

This study developed a sensor to monitor the corrosion of reinforced concrete structures. Concrete pile specimens with embedded sensors were used to obtain data on corrosion and cathodic protection for bridge columns in a real marine environment. Corrosion potential, cathodic protection current density, concrete resistivity, and the degree of depolarization potential were measured with the embedded sensors in concrete pile specimens. The cathodic protection (CP) state was accurately monitored by sensors installed in underwater, tidal, splash, and atmospheric zones. The protection potential measurements confirmed that the CP by Zn-mesh sacrificial anode was fairly effective in the marine pile environment. The protection current densities in the tidal, splash zones were 2–3 times higher than those in underwater and atmospheric zones. The concrete resistivity in the tidal and splash zones was decreased through the installation of both mortar-embedded Zn-mesh (sacrificial anode) and outside an FRP jacket (cover). Considering the CP, the cathodic prevention was more effective than cathodic protection.

This paper considers a comparative study on model-scale sloshing tests. There are two primary scopes of this study: the comparison of sloshing pressure measured in 1/50-scale model tests at Seoul National University (SNU) with (1) the data measured at the other facility for the same model, and (2) the data measured on a smaller scale model. For the comparative study, model tanks are excited with the same irregular motions with Froude scale, and sloshing pressure signals are measured at the same locations. The statistical quantities of 1/50-scale model tests are compared with those of other facility and 1/70-scale model tests. In this study, it is found that peak pressure measured at SNU are slightly lower than those of other facility, and this difference may be due to different sensor types and sensing diameters.

Therefore, 3,895 candidate genes related to anthocyanin biosynthesis in Chinese cabbage were identified using a 300K Brassica rapa microarray analysis. Gene expression during six stages of leaf developmental stages were examined in FC (green leaf) and FA(red leaf) Chinese cabbage cultivars. The 317 transcription factor genes found to be associated with anthocyanin were classified into 11 functional groups. The ratio of expression levels of each transcription factor between the two cultivars was examined during the six leaf developmental stages. A total of 14 genes were found to be expressed in all developmental stages commonly. Among these genes, 10 unknown and hypothetical genes were differentially revealed to be expressed between the two cultivars at each developmental stage, as determined by microarray analysis, and were verified by RT-PCR validation. These genes most likely play regulatory roles in either anthocyanin production or metabolism during flavonoid biosynthesis. While these genes require further validation and characterization, our results illustrate the potential usefulness of this multi-layered screening method using Chinese cabbage (Brassica rapa) microarrays.

The total economic value for a transportation service consists of use, option, and non-use value. The use benefit is based on a traveler’s willingness to pay for usual consumption of the service. The optional value, on the other hand, is related to the possible use of the service for trips not yet anticipated or currently accommodated by other travel modes. The non-use value, however, is derived from the intrinsic merit of the service, even though a trip-maker never actually or potentially depends on the mode. A closed-ended contingent valuation method is considered for the quantification of the option and non-use values. A survey of single- and double-bounded dichotomous choices is conducted with a case study of South Korean bus operations. A logistic regression model and a survival analysis for the single- and double-bounded approaches, respectively, are applied. The estimation result is examined according to the statistical property required and the behavioral validity expected. In particular, three issues from the output are discussed. First, the results help to show the preferable framework between single- and double-bounded surveys for addressing an individual’s option and non-use values. Second, the differences in the absolute values of option and non-use values are compared. Thirdly, the relationship between trip-makers’ willingness to pay and the level of service of their primary travel modes are investigated. In conclusion, the summary of research and the possibilities for future studies are given.

Fanconi anemia is a rare recessive disorder characterized by genome instability, congenital malformations, progressive bone marrow failure and predisposition to hematologic malignancies and solid tumors. At the cellular level, hypersensitivity to DNA interstrand crosslinks is the defining feature in Fanconi anemia. Mutations in thirteen distinct Fanconi anemia genes have been shown to interfere with the DNA-replication-dependent repair of lesions involving crosslinked DNA at stalled replication forks. Depletion of SLX4, which interacts with multiple nucleases and has been recently identified as a Holliday junction resolvase, results in increased sensitivity of the cells to DNA crosslinking agents. Here we report the identification of biallelic SLX4 mutations in two individuals with typical clinical features of Fanconi anemia and show that the cellular defects in these individuals' cells are complemented by wildtype SLX4, demonstrating that biallelic mutations in SLX4 (renamed here as FANCP) cause a new subtype of Fanconi anemia, Fanconi anemia-P.

The violent sloshing flow inside a rectangular tank is computed by the CIP (Constrained Interpolation Profile)[1] based Cartesian grid method. Two kinds of CIP scheme, the original CIP scheme and the RCIP scheme, have been applied to the flow solver. 2-D and 3-D computations using the two CIP schemes are carried out and their performances are discussed by comparing the results of the impact pressures on the wall and the free surface profiles to the experimental measurements.

To better understand the functional characterization of anthocyanin gene expression in black rice, we performed a detailed computational examination. The experiment was performed using the newly designed 135K Oryza sativa microarray to assess gene expression at three time points after the heading stage in Ds insertion lines. Transcription factors related to anthocyanin pigmentation biosynthesis were clustered. A total of 8,517 genes exhibited greater than 2.5-fold up- or downregulation in each comparison between three rice groups and three seed developmental stages. The resultant 82 transcription factor genes found to be associated with anthocyanin were classified into 12 groups. In addition, 12 unknown and hypothetical genes were identified from comparisons between the white cultivar and two black Ds insertion mutants tested. We identified 12 unknown and hypothetical genes involved in anthocyanin biosynthesis. These genes likely play either a regulatory role in the anthocyanin production process or are related to anthocyanin metabolism during flavonoid biosynthesis. While these genes require further characterization and validation, the results here underline the potential use of the newly designed microarray.

The pH variation induced electrochemical reactions for Zn, Mg, MgO and the mixture MgMgO (25 wt.% Mg and 75 wt.% MgO) fabricated by high-energy mechanical ball milling in 3.5 wt.% NaCl have been investigated using the potentiodynamic method and electrochemical impedance spectroscopy to control the rate of magnesium dissolution as cathodic protection. It is known that pH variation is a good measurement of dissolution for cathodic protection materials. The pH of Zn was modestly increased because of the formation of ZnO. Mg showed a relatively high pH value when forming as Mg(OH)2. Highly activated MgMgO showed the highest pH value, located between Mg and MgO, of equilibrium potentials and impedance. This indicates that the electrochemical reaction in 3.5 wt.% NaCl has been changed by mechanical ball milling. This implies that the dissolution rate can be controlled by high-energy mechanical ball milling.

This paper studies the springing response of a flexible floating barge under an oblique wave. A time domain Rankine panel method was used to represent fluid motion surrounding a flexible seagoing vessel, and a finite element method was used for structural response. For accurate prediction of the structural response under an oblique wave, special attention was given to the structural model, such as the effect of warping distortion and bending-torsion coupling. The Vlasov assumption was followed for a deformable beam element to take into account the effect of warping distortion so that the cross section of the beam deforms out of its original plane without changing its cross-section contour. The coupled equation for both the fluid and structural domain was solved by using the implicit iterative method. A fixed point iteration with a relaxation scheme was employed in this study with the aid of the Aitken δ2 process seeking acceleration of solution convergence. Accuracy of a developed computer program was verified through the comparison with experimental work done by Remy et al. (Experimental and numerical study of the wave response of a flexible barge, Hydroelasticity in Marine Technology, Wuxi, 2006) resulting in good correspondence between the two results.

Recently the demand for sloshing analyses is rising because of the construction of large LNG carriers and LNG platforms. This study considers the experimental and numerical observations of strongly nonlinear sloshing flows in ship cargo and their coupling effects with ship motion. Violent sloshing flows in experiments are observed, and two different numerical methods, the finite-difference method and smoothed-particle-hydrodynamics (SPH) method, are applied for the simulation of violent sloshing flows. Several physical issues are introduced in the analysis of sloshing flows, and the corresponding numerical models are described. This study demonstrates that physics-based numerical schemes are essential in the prediction of violent sloshing flows and sloshing-induced impact pressure. To study the sloshing effects on ship-motion, a ship-motion program based on an impulsive response function (IRF) is coupled with the developed numerical models for sloshing analysis. The results show that the nonlinearity of sloshing-induced forces and moments plays a critical role in the coupling effects.

Drug resistance to BCR-ABL1 tyrosine kinase inhibitor (TKI) and disease progression to blast crisis (BC) are major clinical problems in chronic myeloid leukemia (CML); however, underlying mechanisms governing this process remain to be elucidated. Here, we report Cordon-bleu protein-like 1 (Cobll1) as a distinct molecular marker associated with drug resistance as well as progression to BC. In detail, Cobll1 increases IKKγ stability, leading to NF-κB activation and reduction of nilotinib-dependent apoptosis, suggesting Cobll1-mediated NF-κB could be involved in drug resistance. Recently, NF-κB signalling has been highlighted as a core mechanism for chronic phase (CP)-BC progression, stem cell survival and tyrosine kinase inhibitor resistance. We also demonstrated that high expression of Cobll1 confers drug resistance to tyrosine kinase inhibitors in CML cell line as well as patient samples. The analysis of large sets of primary CML samples (n=90) shows that Cobll1 expression is dramatically increased in BC but not in CP, which is correlated with a poor survival rate (P=0.002). Moreover, our studies show that Cobll1 is highly expressed in CD34+ primitive stem cell populations, and the zebrafish paralog Cobll1b is important for normal hematopoiesis during embryonic development. Based on these results, we propose that Cobll1 is a novel biomarker and potential therapeutic target for CML-BC.