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Abstract Notum is a direct target of Wnt/β-catenin signaling and plays a crucial role as a Wnt inhibitor within a negative feedback loop. In the tooth, Notum is known to be expressed in odontoblasts, and severe dentin defects and irregular tooth roots have been reported in Notum-deficient mice. However, the precise expression pattern of Notum in early tooth development, and the role of Notum in crown and root patterns remain elusive. In the present study, we identified a novel Notum expression in primary enamel knot (EK), secondary EKs, and dental papilla during tooth development. Notum-deficient mice exhibited enlarged secondary EKs, resulting in broader cusp tips, altered cusp patterns, and reduced concavity in crown outline. These alterations in crown outline led to a reduction in cervical tongue length, thereby inducing root fusion in Notum-deficient mice. Overall, these results suggest that the secondary EK size, regulated by the Wnt/Notum negative feedback loop, has a significant impact on the patterns of crown and root during tooth morphogenesis.

Introduction: Synthetic hydroxyapatite (HAp) scaffolds have shown promising therapeutic outcomes in both animals and patients. In this study, we aim to evaluate the chemical and physical phenotype, biocompatibility, and bone repair effects of hydrothermally treated coral with natural coral and synthetic HAp.Methods: The phase composition, surface pattern, 3D structures, and porosity of the scaffolds were characterized, and cell viability, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) after seeding onto the scaffold were determined. The scaffolds were implanted into rats to assess their bone repair effects using micro-CT analysis, mechanical testing, and histological staining.Results: The results showed that the phase composition, porous structure, and porosity of hydrothermally treated coral were comparable to pure HAp scaffold. While only the natural coral happens to be dominantly calcium carbonate. Higher cell proliferation and osteogenic differentiation potential were observed in the hydrothermally treated coral scaffold compared to natural coral and pure HAp. Histological results also showed increased new bone formation in the hydrothermally treated coral group.Discussion: Overall, our study suggests that hydrothermal modification enhances the cytocompatibility and therapeutic capacity of coral without altering its physical properties, showing superior effectiveness in bone repair to synthetic HAp.

To reduce the environmental impact of concrete, recycled aggregates are of significant interest. Recycled concrete aggregate (RCA) presents a significant resource opportunity, although its performance as an aggregate in concrete is variable. This study presents a meta-analysis of the published literature to refine the understanding of how the moisture content of RCA, as well as other parameters, affects the compressive strength of concrete. Seven machine learning models were used to predict the compressive strength of concrete with RCA, including linear regression, support vector regression (SVR), and k-nearest neighbors (KNN) as single models, and decision tree, random forest, XGBoost, and LightGBM as ensemble models. The results of this study demonstrate that ensemble models, particularly the LightGBM model, exhibited superior prediction accuracy compared to single models. The LightGBM model yielded the highest prediction accuracy with R2 = 0.94, RMSE = 4.16 MPa, MAE = 3.03 MPa, and Delta RMSE = 1.4 MPa, making it the selected final model. The study, employing feature importance with LightGBM as the final model, identified age, water/cement ratio, and fine RCA aggregate content as key factors influencing compressive strength in concrete with RCA. In an interaction plot analysis using the final model, lowering the water–cement ratio consistently improved compressive strength, especially between 0.3 and 0.4, while increasing the fine RCA ratio decreased compressive strength, particularly in the range of 0.4 to 0.6. Additionally, it was found that maintaining moisture conditions of RCA typically between 0.0 and 0.8 was crucial for maximizing strength, whereas extreme moisture conditions, like fully saturated surface dry (SSD) state, negatively impacted strength.

Macroalgae is regarded as a promising third-generation marine biomass that can be utilized as a sustainable feedstock for bio-industry due to the high sugar level and absence of lignin. Alginate, composed of 1,4-linked D-mannuronate (M) and L-guluronate (G), is one of the major carbohydrates in brown macroalgae. It is difficult to be assimilated by most industrial microorganisms. Therefore, developing engineered microorganisms that can utilize alginate as a feedstock in order to produce natural products from marine biomass is critical. In this study, we isolated, characterized, and sequenced Vibrio sp. SP1 which rapidly grows using alginate as a sole carbon source. We further engineered this strain by introducing genes encoding enzymes under the control of synthetic expression cassettes to produce lycopene and β-carotene which are attractive phytochemicals owing to the antioxidant property. We confirmed that the engineered Vibrio sp. SP1 could successfully produce 2.13 ± 0.37 mg L−1 of lycopene, 2.98 ± 0.43 mg L−1 of β -carotene, respectively, from 10 g L−1 of alginate as a sole carbon source. Furthermore, our engineered strain could directly convert 60 g L−1 of brown macroalgae Sargassum fusiforme into 1.23 ± 0.21 mg L−1 of lycopene without any pretreatment which had been vitally required for the previous productions. As the first demonstrated strain to produce high-value product from Sargassum, Vibrio sp. SP1 is evaluated to be a desirable platform for the brown macroalgae-based biorefinery.

Abstract Currently, a reliable serum biomarker for hepatocellular carcinoma (HCC) has not been established, particularly for early‐stage HCC (single tumor 0.8. In our validation study, serum exo‐miR‐4661‐5p could diagnose HCC in all stages (AUROC = 0.917), even in early stage (AUROC = 0.923), with a greater accuracy than other candidate serum exo‐miRs and serum AFP. The panel composed of exo‐miR‐4661‐5p and exo‐miR‐4746‐5p was identified as the most accurate biomarker for early‐stage HCC (AUROC = 0.947, 95% confidence interval = 0.889‐0.980, sensitivity = 81.8%, and specificity = 91.7%). In conclusion, exo‐miR‐4661‐5p–based serum panel is a promising diagnostic marker for early‐stage HCC.

We examined whether recombinant human bone morphogenetic protein-2 (rhBMP-2) when applied to collagen membranes, would reinforce them during guided bone regeneration. Four critical cranial bone defects were created and treated in 30 New Zealand white rabbits, including a control group, critical defect only; group 1, collagen membrane only; group 2, biphasic calcium phosphate (BCP) only; group 3, collagen membrane + BCP; group 4, collagen membrane with rhBMP-2 (1.0 mg/mL); group 5, collagen membrane with rhBMP-2 (0.5 mg/mL); group 6, collagen membrane with rhBMP-2 (1.0 mg/mL) + BCP; and group 7, collagen membrane with rhBMP-2 (0.5 mg/mL) + BCP. After a 2-, 4-, or 8-week healing period, the animals were sacrificed. The combination of collagen membranes with rhBMP-2 and BCP yielded significantly higher bone formation rates compared to the other groups (control group and groups 1–5 < groups 6 and 7; p < 0.05). A 2-week healing period yielded significantly lower bone formation than that at 4 and 8 weeks (2 < 4 = 8 weeks; p < 0.05). This study proposes a novel GBR concept in which rhBMP-2 is applied to collagen membranes outside instead of inside the grafted area, thereby inducing quantitatively and qualitatively enhanced bone regeneration in critical bone defects.

Background/AimsBarcelona Clinic Liver Cancer (BCLC) C stage demonstrates considerable heterogeneity because it includes patients with either symptomatic tumors (performance status [PS], 1–2) or with an invasive tumoral pattern reflected by the presence of vascular invasion (VI) or extrahepatic spread (EHS). This study aimed to derive a more relevant staging system by modification of the BCLC system considering the prognostic implication of PS.Methods : A total of 7,501 subjects who were registered in the Korean multicenter hepatocellular carcinoma (HCC) registry database from 2008 to 2013 were analyzed. The relative goodness-of-fit between staging systems was compared using the Akaike information criterion (AIC) and integrated area under the curve (IAUC). Three modified BCLC (m-BCLC) systems (#1, #2, and #3) were devised by reducing the role of PS.Results : As a result, the BCLC C stage, which includes patients with PS 1–2 without VI/EHS, was reassigned to stage 0, A, or B according to their tumor burden in the m-BCLC #2 model. This model was identified as the most explanatory and desirable model for HCC staging by demonstrating the smallest AIC (AIC=70,088.01) and the largest IAUC (IAUC=0.722), while the original BCLC showed the largest AIC (AIC=70,697.17) and the smallest IAUC (IAUC=0.705). The m-BCLC #2 stage C was further subclassified into C1, C2, C3, and C4 according to the Child-Pugh score, PS, presence of EHS, and tumor extent. The C1 to C4 subgroups showed significantly different overall survival distribution between groups (p

Background/AimsLittle evidence is available about the effect of change in nonalcoholic fatty liver disease (NAFLD) status on risk of diabetes mellitus (DM) development. In this study, we tried to analyze the DM risk according to change in NAFLD status over time.Methods : Among a total of 10,141 individuals for whom routine healthcare assessment was performed, 2,726 subjects were selected according to the inclusion/exclusion criteria. NAFLD status change was determined by using serial abdominal ultrasonography and fatty liver index (FLI) during the follow-up period.Results : Subjects were categorized according to change in NAFLD status as follows: 670 subjects in the persistent NAFLD group, 155 subjects in the resolved NAFLD group, 498 subjects in the incident NAFLD group, and 1,403 subjects in the no NAFLD group. Multivariate Cox regression analysis revealed that incident NAFLD (hazard ratio [HR], 1.94; 95% confidence interval [CI], 1.08 to 3.50; p=0.026) and persistent NAFLD (HR, 3.59; 95% CI, 2.05 to 6.27; p

With the development of maritime technology and equipment, most ships are equipped with an automatic identification system (AIS) to store navigation information. Over time, the size of the data increases, rendering its storage and processing difficult. Hence, it is necessary to transform the AIS data into trajectories, and then simplify the AIS trajectories to remove unnecessary information that is not related to route shape. Moreover, topographic information must be considered because otherwise, the simplified trajectory can intersect obstacles. In this study, we propose an AIS trajectory simplification algorithm considering topographic information. The proposed algorithm simplifies the trajectories without the intersection of the trajectory and obstacle using the improved Douglas–Peucker algorithm. Polygon map random (PMR) quadtree was used to consider topographic information on the coast, and the intersection between topographic information and simplified trajectories was efficiently computed using the PMR quadtree. To verify the effectiveness of the proposed algorithm, experiments were conducted on real-world trajectories in the Korean sea. The proposed algorithm yielded simplified trajectories with no intersections of the trajectory and obstacle. In addition, the computational efficiency of the proposed algorithm with the PMR quadtree was superior to that without the PMR quadtree.

In the event of a maritime accident, surveying the maximum area efficiently in the least amount of time is crucial for rescuing survivors. Increasingly, unmanned aerial vehicles (UAVs) are being used in search and rescue operations. This study proposes a method to generate a search path that covers all generated nodes in the shortest amount of time with multiple heterogeneous UAVs. The proposed model, which is a mixed-integer linear programming (MILP) model based on a hexagonal grid-based decomposition method, was verified through a simulation analysis based on the performance of an actual UAV. This study presents both the optimization technique’s calculation time as a function of the search area size and the various UAV routes derived as the search area grows. The results of this study can have wide-ranging applications for emergency search and rescue operations.

Coronary artery disease and peripheral arterial disease are strong predictors of risk for a future ischemic event. Despite the utilization of effective secondary prevention strategies, the prevalence of ischemic recurrences remains high, underscoring the need for effective secondary prevention antithrombotic treatment regimens. To date, most of the tested approaches have been with the use of antiplatelet therapies, used either individually or in combination. However, most recent findings support the potential role of oral anticoagulant therapy in addition to antiplatelet therapy to reduce the risk of ischemic recurrences. This approach has been tested in both acute and stable settings of patients with cardiovascular disease manifestations. The present manuscript provides an overview on the rationale and clinical trial updates on the role of oral anticoagulant therapy, in particular rivaroxaban used at the so-called vascular protection dose, in adjunct to antiplatelet therapy (i.e. aspirin), a strategy known as dual pathway inhibition, for secondary prevention of ischemic recurrences in patients with stable atherosclerotic disease manifestations.

The rapid increase in international trade volume has caused frequent fluctuation of the vessels’ arrival time in container terminals. In order to solve this problem, this study proposes a methodology for rescheduling berth and quay cranes caused by updated information on the arrival time of vessels. A mixed-integer linear programming model was formulated for the berth allocation and crane assignment problem, and we solved the problem using a rolling-horizon approach. Numerical experiments were conducted under three scenarios with empirical data from a container terminal located in Busan, Korea. The experiments revealed that the proposed model reduces penalty costs and overall delayed departure time compared to the results of the terminal planner.

Background/AimsTo determine the efficacies of entecavir (ETV) in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients and in those with prior lamivudine (LAM) use who did not develop resistance.MethodsWe retrospectively enrolled 337 patients with CHB who were treated with ETV (0.5 mg daily) for at least 30 months. The study included 270 (80.1%) NA-naïve patients and 67 (19.9%) LAM-use patients. Ten of the LAM-use patients were refractory to LAM therapy without developing resistance.ResultsGenotypic resistance to ETV developed more frequently in the LAM-use group (13.1%) than in the NA-naïve group (2.6%) at 60 months (P=0.009). In subgroup analysis, after excluding the 10 patients who were refractory to LAM therapy, the cumulative probability of ETV resistance did not differ significantly between the two groups (P=0.149). Prior LAM refractoriness and a higher hepatitis B virus DNA level at month 12 were independent predictive factors for the development of ETV resistance.ConclusionsETV resistance developed more frequently in LAM-use patients with CHB. However, prior LAM use without refractoriness did not affect the development of ETV resistance. The serum hepatitis B virus DNA level at month 12 was a major predictor for the development of ETV resistance.

Background/AimsTransferrin and alpha-1 antitrypsin are reportedly associated with liver fibrosis. We evaluated the usefulness of serum transferrin and alpha-1 antitrypsin as new liver fibrosis markers in patients with chronic hepatitis B.MethodsThe study included 293 patients with chronic hepatitis B who underwent a liver biopsy between October 2005 and June 2009, and who had no history of hepatocellular carcinoma. Serum markers and liver fibrosis stages were compared.ResultsUnivariate analysis revealed that age (P

Background/AimsRelapse has been reported after stopping nucleos(t)ide (NUC) therapy in the majority of chronic HBeAg negative hepatitis patients. However, the ideal treatment duration of HBeAg negative chronic hepatitis B (CHB) is not well known. We investigated the frequency of relapse in HBeAg negative CHB patients receiving NUC therapy.MethodsThe NUC therapy was discontinued at least 3 times undetectable level of HBV DNA leave 6 months space in 45 patients. Clinical relapse was defined as HBV DNA >2,000 IU/mL and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times of upper limit of normal range. Virological relapse was defined as HBV DNA >2,000 IU/mL.ResultsClinical relapse developed in 16 (35.6%) and 24 (53.3%) patients after stopping therapy at 6 months and 12 months off therapy, respectively. Virological relapse developed 22 (48.9%) and 33 (73.3%) patients at 6 months and 12 months off therapy. The factors such as age, gender, cirrhosis, baseline AST, ALT, HBV DNA levels, treatment duration, and consolidation duration were analyzed to investigate the predictive factors associated with 1 year sustained response. Of these factors, cirrhosis (86.1% in CHB, 22.2% in LC) was significantly associated with 1 year virological relapse rate. Baseline HBV DNA and total treatment duration tended to be associated with virological relapse.ConclusionsVirological relapse developed in the majority (73.3%) of HBeAg negative CHB patients and clinical relapse developed in the half (53.3%) of patients at 1 year off therapy. Cirrhosis may be associated with the low rate of virological relapse.

Background/AimsCarnitine and vitamin complex (Godex®) is widely used in patients with chronic liver disease who show elevated liver enzyme in South Korea. The purpose of this study is to identify the efficacy and safety of carnitine from entecavir combination therapy in Alanine aminotransferase (ALT) elevated Chronic Hepatitis B (CHB) patients.Methods130 treatment-naïve patients with CHB were enrolled from 13 sites. The patients were randomly selected to the entecavir and the complex of entecavir and carnitine. The primary endpoint of the study is ALT normalization level after 12 months.ResultsAmong the 130 patients, 119 patients completed the study treatment. The ALT normalization at 3 months was 58.9% for the monotherapy and 95.2% for the combination therapy (P

CD8+ T cells are key factors mediating hepatitis B virus (HBV) clearance. However, these cells are killed through HBV-induced apoptosis during the antigen-presenting period in HBV-induced chronic liver disease (CLD) patients. Interferon-inducible protein 6 (IFI6) delays type I interferon-induced apoptosis in cells. We hypothesized that single nucleotide polymorphisms (SNPs) in the IFI6 could affect the chronicity of CLD. The present study included a discovery stage, in which 195 CLD patients, including chronic hepatitis B (HEP) and cirrhosis patients and 107 spontaneous recovery (SR) controls, were analyzed. The genotype distributions of rs2808426 (C > T) and rs10902662 (C > T) were significantly different between the SR and HEP groups (odds ratio [OR], 6.60; 95% confidence interval [CI], 1.64 to 26.52, p = 0.008 for both SNPs) and between the SR and CLD groups (OR, 4.38; 95% CI, 1.25 to 15.26; p = 0.021 and OR, 4.12; 95% CI, 1.18 to 14.44; p = 0.027, respectively). The distribution of diplotypes that contained these SNPs was significantly different between the SR and HEP groups (OR, 6.58; 95% CI, 1.63 to 25.59; p = 0.008 and OR, 0.15; 95% CI, 0.04 to 0.61; p = 0.008, respectively) and between the SR and CLD groups (OR, 4.38; 95% CI, 1.25 to 15.26; p = 0.021 and OR, 4.12; 95% CI, 1.18 to 14.44; p = 0.027, respectively). We were unable to replicate the association shown by secondary enrolled samples. A large-scale validation study should be performed to confirm the association between IFI6 and HBV clearance.

Background/AimsApolipoprotein E (ApoE) plays an important role in regulating lipid and lipoprotein metabolism, and ApoE genotypes are known to affect plasma lipoprotein concentrations. We investigated whether ApoE genotype determines the disease outcome in hepatitis B virus (HBV)-infected individuals, and verified the association between ApoE genotype and the occurrence of hepatocellular carcinoma (HCC) in patients with chronic liver diseases of various etiologies.MethodsThis hospital-based, case-controlled study enrolled 156 subjects (47 healthy controls, 50 HBV-related liver cirrhosis patients, and 59 HCC patients). ApoE genotypes were determined using PCR-based ApoE genotyping kits. The biological significance of ApoE genotype was verified by measuring serum ApoE levels using an ELISA kits.ResultsThe ε3 allele was the most common allele, with allele frequencies among the entire cohort of 5.8%, 84.3%, and 9.9% for the ε2, ε3, and ε4 alleles, respectively. Significantly more of those patients carrying the ε3/3 genotype had developed liver cirrhosis compared to the control subjects. Being an ApoE4 carrier was associated with a lower probability of developing liver cirrhosis. The allele frequencies and genotype distribution of ApoE did not differ significantly between the liver cirrhosis and HCC patients. The serum level of ApoE was significantly higher in patients with liver cirrhosis than in the healthy controls, but did not differ significantly with the ApoE genotype.ConclusionsThe ApoE ε3/3 genotype frequency was higher in patients with HBV-associated liver cirrhosis than in the controls.