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Abstract Optimizing process and heat-treatment parameters of laser powder bed fusion for producing Ti-6Al-4V alloys with high strength and ductility is crucial to meet performance demands in various applications. Nevertheless, inherent trade-offs between strength and ductility render traditional trial-and-error methods inefficient. Herein, we present Pareto active learning framework with targeted experimental validation to efficiently explore vast parameter space of 296 candidates, pinpointing optimal parameters to augment both strength and ductility. All Ti-6Al-4V alloys produced with the pinpointed parameters exhibit higher ductility at similar strength levels and greater strength at similar ductility levels compared to those in previous studies. By improving one property without significantly compromising the other, the framework demonstrates efficiency in overcoming the inherent trade-offs. Ultimately, Ti-6Al-4V alloys with ultimate tensile strength and total elongation of 1190 MPa and 16.5%, respectively, are produced. The proposed framework streamlines discovery of optimal processing parameters and promises accelerated development of high-performance alloys.

Various diseases can affect the esophagus. Endoscopic ultrasound (EUS), which provides precise information about the layers of the esophageal wall, is the primary approach used to investigate esophageal diseases. However, CT is one of the most important imaging modalities for diagnosing esophageal diseases as it can elucidate mediastinal involvement, adjacent lymphadenopathy, and distant disease spread. These two modalities complement each other in the diagnosis of esophageal diseases. Although radiologists may be unfamiliar with EUS procedures and their interpretation, understanding them aids in the differential diagnosis of esophageal conditions. This pictorial essay illustrates the EUS and CT findings of various esophageal diseases originating in the esophageal wall.

Repair offers significant time—cost savings and durability by reusing existing parts efficiently. Prior to implementation of repaired parts, it is crucial to clarify mechanical properties and deformation mechanisms to ensure proper performance. In this study, a repair deposition was performed on the groove of wrought stainless steel 316L using the same material powder. The repaired sample exhibited an excellent combination of ductility and strength (T.EL: 58%, YS: 407 MPa, UTS: 673 MPa) compared to the wrought counterpart. With heterogeneity in microstructure, the hetero-deformation-induced strengthening of the repaired sample resulted in a synergy of strength-ductility combinations.

Direct energy deposition (DED) has gained attention in the field of metal repair because of its ability to integrate additively deposited material with preexisting components. Having the beneficial aspects of depositing right material, DED is evaluated the best option for repair deposition. Machining grooves in damaged components is the common first to repair, which is necessary to remove cracked or damaged material and provide suitable geometry for deposition. Preprocessing as grooving is commonly applied to prevent the propagation cracks or tears. However, challenges such as dimensional error and crack induced by residual stress emerge owning to complex interactions between the DED parameters and groove geometry during repair deposition. This study investigates effective deposition strategies for repairing 316L stainless steel grooves with wall-angles of 90° and 135° by exploring the relationship between the repair integrity and parameters such as groove angles, laser energy input, and powder supply, all with reference to the underlying mechanism of metallurgical bonding in angled areas. Based thereon, a modified effective repair strategy is proposed, using enhanced dual laser power to address bonding issues in the angled areas. Samples repaired using this method exhibit a defect-free groove–deposit interface and a continuous columnar-grained microstructure with abrupt changes in grain size between the repaired area and groove. This microstructural heterogeneity results in an exceptional combination of strength and ductility when compared to the base material and samples repaired using a single laser strategy. The findings of this study provide insights into the optimization of DED strategies for achieving robust metallurgical bonding within grooves, thereby advancing technological maturity in the field of metal repair.

High-strength materials are essential for applications in the structural industry. However, their limited formability restricts broader industrial use. This study proposes a novel methodology to achieve an excellent combination of formability and strength. Surface heterostructuring through laser treatment induces local austenitization on the as-rolled martensitic stainless steel. The resultant bendability was significantly improved, enabling its bending to ∼180° folding while maintaining high tensile strength. Consequently, the present surface heterostructuring suggests achieving the superior combination of strength and formability by tailoring the microstructure specifically to forming. This surface heterostructuring will explore the empty area of the formability-strength relationship.

Mg-Gd-Zn based alloys have better creep resistance than other Mg alloys and attract more attention at elevated temperatures. However, the multiple alloying elements and various heat treatment conditions, combined with complex microstructural evolution during creep tests, bring great challenges in understanding and predicting creep behaviors. In this study, we proposed to predict the creep properties and reveal the creep mechanisms of Mg-Gd-Zn based alloys by machine learning. On the one hand, the minimum creep rates were effectively predicted by using a support vector regression model. The complex and nonmonotonic effects of test temperature, test stress, alloying elements, and heat treatment conditions on the creep properties were revealed. On the other hand, the creep stress exponents and creep activation energies were calculated by machine learning to analyze the variation of creep mechanisms, based on which the constitutive equations of Mg-Gd-Zn based alloys were obtained. This study introduces an efficient method to comprehend creep behaviors through machine learning, offering valuable insights for the future design and selection of Mg alloys.

Purpose This study compared the diagnostic performance of quantitative ultrasonography (QUS) with that of conventional ultrasonography (US) in assessing hepatic steatosis among individuals undergoing health screening using magnetic resonance imaging–derived proton density fat fraction (MRI-PDFF) as the reference standard. Methods This single-center prospective study enrolled 427 participants who underwent abdominal MRI and US. Measurements included the attenuation coefficient in tissue attenuation imaging (TAI) and the scatter-distribution coefficient in tissue scatter-distribution imaging (TSI). The correlation between QUS and MRI-PDFF was evaluated. The diagnostic capabilities of QUS, conventional B-mode US, and their combined models for detecting hepatic fat content of ≥5% (MRI-PDFF ≥5%) and ≥10% (MRI-PDFF ≥10%) were compared by analyzing the areas under the receiver operating characteristic curves. Additionally, clinical risk factors influencing the diagnostic performance of QUS were identified using multivariate linear regression analyses. Results TAI and TSI were strongly correlated with MRI-PDFF (r=0.759 and r=0.802, respectively; both P

Background: The effectiveness of COVID-19 vaccines is generally reduced in cancer patients compared to the general population. However, there are only a few studies that compare the relative risk of breakthrough infections and severe COVID-19 outcomes in fully vaccinated cancer patients versus their unvaccinated counterparts. Methods: To assess the effectiveness of COVID-19 vaccines in cancer patients, we employed (1) a self-controlled risk interval (SCRI) design, and (2) a retrospective matched cohort design. A SCRI design was used to compare the risk of breakthrough infection in vaccinated cancer patients during the period immediately following vaccination (“control window”) and the period in which immunity is achieved (“exposure windows”). The retrospective matched cohort design was used to compare the risk of severe COVID-19 outcomes between vaccinated and unvaccinated cancer patients. For both studies, data were extracted from the Korea Disease Control and Prevention Agency-COVID-19-National Health Insurance Service cohort, including demographics, medical history, and vaccination records of all individuals confirmed with COVID-19. We used conditional Poisson regression to calculate the incidence rate ratio (IRR) for breakthrough infection and Cox regression to estimate the hazard ratio (HR) for severe outcomes. Results: Of 14,448 cancer patients diagnosed with COVID-19 between October 2020 and December 2021, a total of 217 and 3996 cancer patients were included in the SCRI and cohort study respectively. While the risk of breakthrough infections, measured by the incidence rate in the control and exposure windows, did not show statistically significant difference in vaccinated cancer patients (IRR=0.88, 95% CI: 0.64–1.22), the risk of severe COVID-19 outcomes was significantly lower in vaccinated cancer patients compared to those unvaccinated (HR=0.27, 95% CI: 0.22–0.34). Conclusion: COVID-19 vaccines significantly reduce the risk of severe outcomes in cancer patients, though their efficacy against breakthrough infections is less evident.

A key pathogenic mechanism of dry age-related macular degeneration (AMD) is lysosomal dysfunction in retinal pigment epithelium (RPE) cells, which results in the accumulation of lipofuscins such as A2E (N-retinylidene-N-retinylethanolamine) that further compromises lysosomal function. This vicious cycle leads to cell death and poor visual acuity. Here, we established an in vitro model of AMD by treating a human RPE cell line (ARPE-19) with A2E and examined whether raising zinc levels confers protective effects against lysosomal dysfunction and cytotoxicity. MTT assay showed that A2E induced apoptosis in ARPE-19 cells. pHrodo™ Red fluorescence staining showed that lysosomal pH increased in A2E-treated ARPE-19 cells. Treatment with a zinc ionophore (clioquinol) reduced A2E accumulation, restored lysosomal pH to the acidic range, and reduced A2E-induced cell death, all of which were reversed by the addition of a zinc chelator (TPEN). Consistent with the in vitro results, subretinal injections of A2E in mouse eyes resulted in the death of RPE cells as well as lysosomal dysfunction, all of which were reversed by co-treatment with clioquinol. Our results suggest that restoring the levels of intracellular zinc, especially in lysosomes, would be helpful in mitigating A2E-induced cytotoxic changes including lysosomal dysfunction in RPE cells in the pathogenesis of AMD.

Abstract Background Viruses have notable effects on agroecosystems, wherein they can adversely affect plant health and cause problems (e.g., increased biosecurity risks and economic losses). However, our knowledge of their diversity and interactions with specific host plants in ecosystems remains limited. To enhance our understanding of the roles that viruses play in agroecosystems, comprehensive analyses of the viromes of a wide range of plants are essential. High-throughput sequencing (HTS) techniques are useful for conducting impartial and unbiased investigations of plant viromes, ultimately forming a basis for generating further biological and ecological insights. This study was conducted to thoroughly characterize the viral community dynamics in individual plants. Results An HTS-based virome analysis in conjunction with proximity sampling and a tripartite network analysis were performed to investigate the viral diversity in chunkung (Cnidium officinale) plants. We identified 61 distinct chunkung plant-associated viruses (27 DNA and 34 RNA viruses) from 21 known genera and 6 unclassified genera in 14 known viral families. Notably, 12 persistent viruses (7 DNA and 5 RNA viruses) were exclusive to dwarfed chunkung plants. The detection of viruses from the families Partitiviridae, Picobirnaviridae, and Spinareoviridae only in the dwarfed plants suggested that they may contribute to the observed dwarfism. The co-infection of chunkung by multiple viruses is indicative of a dynamic and interactive viral ecosystem with significant sequence variability and evidence of recombination. Conclusions We revealed the viral community involved in chunkung. Our findings suggest that chunkung serves as a significant reservoir for a variety of plant viruses. Moreover, the co-infection rate of individual plants was unexpectedly high. Future research will need to elucidate the mechanisms enabling several dozen viruses to co-exist in chunkung. Nevertheless, the important insights into the chunkung virome generated in this study may be relevant to developing effective plant viral disease management and control strategies.

This study aims to suggest variability mechanisms for software product line development and to explain the results of case study. Software product line engineering is an extension of software engineering and many organizations constantly engage in reengineering and refactoring to adopt the software product line engineering. Software product line engineering has two engineering processes: domain engineering process and application engineering process. Feature Identification and feature model are key success factor to construct variability model. Feature model describes the variable parts to be extended or replaced and common part to be reuse by themselves. Feature model gives the directions to the following architecture design and component implementation. However, feature model is not the design strategy and variability mechanism for product line implementation. Therefore, these are the obstacles for organizations that are unfamiliar with feature model and variability mechanism to adopt software product line engineering. Several variability mechanisms for software intensive software are suggested but these are not applicable for embedded software since it has different development process and structure. In this paper, variability elements in architecture design and component design of embedded software are identified as state variable, state transition information, and algorithm. Variability management mechanisms are defined for these elements. To provide the detail strategy and to evaluate the suggested variability management methods, process and results of real case study are described.

Septo-optic dysplasia (SOD) is a rare congenital anomaly that is clinically defined by developmental delay and characteristic brain magnetic resonance imaging findings, including optic nerve hypoplasia, pituitary hormone abnormalities, and midline brain defects. The occurrence of SOD is generally sporadic; however, it can be inherited rarely. Although an association with HESX1, SOX2, and SOX3 mutations has been identified, the detailed etiology is multifactorial and unclear. Here, we present the case of a 7-year-old girl who was clinically diagnosed with SOD and 15q13.3 duplication. Patients with duplication at chromosome 15q13.3 were reported to be diagnosed with autism spectrum disorder, epilepsy, and schizophrenia in previous studies. The relationship between SOD and the microduplication of 15q13.3 has not yet been explored. In this study, we suggest that there may be an association between chromosome 15q13.3 microduplication and SOD.

Background: The importance of enhancing education to promote nursing students’ patient safety competency is increasing. Hence, implementing diverse educational programs and assessing their outcomes is essential. Objectives: To examine the effects of flipped learning and gamification on nursing students’ patient safety education. Design: A mixed-method design employing a quasi-experimental design with a pre-post control group design and qualitative thematic analysis. Methods: The study was conducted at a South Korean university in W City from September to December 2022. It included 55 s-year nursing students. The experimental group (n = 28) participated in a 30-h patient safety education course using flipped learning and gamification, whereas the control group (n = 27) received only written patient safety education materials. Learning motivation, collective efficacy, patient safety competency, and game evaluations were measured. Data were analyzed using the χ2 test, Fisher's exact test, t-test, repeated-measures multivariate analysis of covariance, repeated measure analysis of covariance, and generalized estimating equations. Self-reflection journals on game participation experiences were analyzed using qualitative thematic analysis. Results: Learning motivation scores did not differ significantly between groups for time, or interactions between groups and time, but collective efficacy and patient safety competency scores showed significant differences in the interactions between groups and time. The experimental group showed a high satisfaction score in game evaluation. Qualitative analyses were used to extract four themes—three positives: “fun and immersion differentiated from existing classes,” “improved the learning outcomes and learning motivation,” and “realized the value of collaboration and communication,” and one negative: “feeling down due to unfamiliarity.” Conclusions: This program creates positive learning experiences and enhances nursing students’ collective efficacy and patient-safety competencies. It is expected to be utilized in various future nursing courses.

Abstract Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with β‐glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin‐induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. β‐Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with β‐glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of β‐glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury‐mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury‐mediated disorders.

A ruptured brain arteriovenous malformation (bAVM) presenting with a hematoma may have unseen parts of the shunts in diagnostic angiography in the acute phase, which may lead to innate incomplete evaluation for the whole angioarchitecture of the bAVM. Even though it is generally accepted that the nidus of a ruptured bAVM may be underestimated in angiography during the acute phase due to hematoma compression, documentation of the underestimated parts has not been described in the literature. The authors report 2 cases of ruptured bAVMs in which the obscured segments were cast with liquid embolic material, which suggests a potential presence of obscured segments in bAVMs.

Bladder cancer is the most common urological malignancy worldwide, and its high recurrence rate leads to poor survival outcomes. The effect of anticancer drug treatment varies significantly depending on individual patients and the extent of drug resistance. In this study, we developed a validation system based on an organ-on-a-chip integrated with artificial intelligence technologies to predict resistance to anticancer drugs in bladder cancer. As a proof-of-concept, we utilized the gemcitabine-resistant bladder cancer cell line T24 with four distinct levels of drug resistance (parental, early, intermediate, and late). These cells were co-cultured with endothelial cells in a 3D microfluidic chip. A dataset comprising 2,674 cell images from the chips was analyzed using a convolutional neural network (CNN) to distinguish the extent of drug resistance among the four cell groups. The CNN achieved 95.2% accuracy upon employing data augmentation and a step decay learning rate with an initial value of 0.001. The average diagnostic sensitivity and specificity were 90.5% and 96.8%, respectively, and all area under the curve (AUC) values were over 0.988. Our proposed method demonstrated excellent performance in accurately identifying the extent of drug resistance, which can assist in the prediction of drug responses and in determining the appropriate treatment for bladder cancer patients.

Two new neolignans, myrifralignans F–G (14 and 18), four new diarylnonanoid derivatives, myrifragranones A–D (21–24), and 18 known compounds were isolated and structurally elucidated from nutmeg (Myristica fragrans Houtt.) seeds. The absolute configurations of these secondary metabolites were determined using the electronic circular dichroism technique. The inhibitory potential of these isolated compounds on soluble epoxide hydrolase (sEH) was investigated for the first time. Among them, malabaricones B and C (19 and 20) and four new compounds 21–24 displayed inhibitory activities against sEH, with IC50 values ranging from 14.24 to 46.35 µM. Additionally, the binding mechanism, key binding interactions, stability, and dynamic behaviour of the active compounds with the sEH enzyme were analysed using in silico molecular docking and dynamics simulations. Our findings suggest that nutmeg could become a promising natural source for discovering and developing new sEH inhibitors.

Abstract The efficient extraction of lipid species in plasma was developed for quick sample preparation and accurate lipid analysis, using spin column with superabsorbent polymer beads (SAP), as the improvement of previous SAP method reported before. The modified SAP (mSAP) method is composed of simple steps, including sample loading, swelling, solvent addition, centrifugation, and drying of the resulting lipid solution. The mSAP method offers several advantages over the conventional and the previous SAP methods for lipid analysis in plasma sample. The mSAP method was approximately 10 times faster than the modified Folch protocol (Matyash method), methyl-tert-butyl ether based extraction method. The mSAP method offered an excellent recovery rate for most all major classes in the lipid standard mixture, outperforming the Matyash method. The limit of detection (LOD) of 1,2-diheptadecanoyl-sn-glycero-3-phophocholine (PC 17:0/17:0) spiking in plasma by the mSAP method is about seven times lower than those of the conventional methods. The relative standard deviation (RSD) values for inter- and intra-day variability of the mSAP method over a 5-day period were significantly lower than those of the previous SAP and Matyash methods. The mSAP method has been shown to be more time-saving, sensitive, reproducible and reliable, as evidence by its faster processing time, lower LOD, lower RSD values and high recovery rate for different lipid classes. Overall, these findings suggest that this method may be a promising approach for the application of total lipid analysis in lipidomic research in future.

Background/Aim This study aimed to determine the diagnostic performance of 2022 Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) imaging criteria compared with the 2018 KLCA-NCC for hepatocellular carcinoma (HCC) in high-risk patients using magnetic resonance imaging (MRI). Methods This retrospective study included 415 treatment-naïve patients (152 patients who underwent extracellular contrast agent [ECA]-MRI and 263 who underwent hepatobiliary agent [HBA]-MRI; 535 lesions, including 412 HCCs) with a high risk of HCC who underwent contrast-enhanced MRI. Two readers evaluated all lesions according to the 2018 and 2022 KLCA-NCC imaging diagnostic criteria, and the per-lesion diagnostic performances were compared. Results In “definite” HCC category of both 2018 and 2022 KLCA-NCC, HBA-MRI showed a significantly higher sensitivity for the diagnosis of HCC than ECA-MRI (77.0% vs. 64.3%, P=0.006) without a significant difference in specificity (94.7% vs. 95.7%, P=0.801). On ECAMRI, “definite” or “probable” HCC categories of the 2022 KLCA-NCC had significantly higher sensitivity than those of the 2018 KLCA-NCC (85.3% vs. 78.3%, P=0.002) with identical specificity (93.6%). On HBA-MRI, the sensitivity and specificity of “definite” or “probable” HCC categories of both 2018 and 2022 KLCA-NCC were not significantly different (83.3% vs. 83.6%, P>0.999 and 92.1% vs. 90.8%, P>0.999, respectively). Conclusions In “definite” HCC category of both 2018 and 2022 KLCA-NCC, HBA-MRI provides better sensitivity than ECA-MRI without compromising specificity. On ECA-MRI, “definite” or “probable” HCC categories of the 2022 KLCA-NCC may improve sensitivity in the diagnosis of HCC compared with the 2018 KLCA-NCC.

Objective In this study, we investigated the effects of Rubus coreanus-derived lactic acid bacteria (LAB) fermented feed (RC-LAB fermented feed) and three types of LAB (Lactobacillus plantarum, Lactobacillus acidophilus, Bifidobacterium animalis) on the expression of transcription factors and cytokines in Th1, Th2, Th17, and Treg cells in the intestinal lymph nodes and spleens of rats. In addition, the effect on intestinal microbiota composition and body weight was investigated. Methods Five-week-old male rats were assigned to five treatments and eight replicates. The expression of transcription factors and cytokines of Th1, Th2, Th17, and Treg cells in the intestinal lymph nodes and spleens was analyzed using real-time reverse transcriptase polymerase chain reaction assays. Intestinal tract microbiota compositions were analyzed by next-generation sequencing and quantitative polymerase chain reaction assays. Results RC-LAB fermented feed and three types of LAB increased the expression of transcription factors and cytokines in Th1, Treg cells and Galectin-9, but decreased in Th2 and Th17 cells. In addition, the intestinal microbiota composition changed, the body weight and Firmicutes to Bacteroidetes (F/B) ratio decreased, and the relative abundance of LAB increased. Conclusion LAB fermented feed and three types of LAB showed an immune modulation effect by inducing T cell polarization and increased LAB in the intestinal microbiota.

Recently, there has been development toward metal additive manufacturing (MAM) because of its benefits like fabrication of complex geometries, waste minimization, freedom of design, and low-cost customization. Despite these advantages, the influence of the processing parameters on the properties of MAM products is neither well understood nor easily predictable. In this study, explainable machine learning (xML) models were applied to predict and understand the geometry and types of defects in MAM-processed Fe-Ni alloys. Gaussian process regression (GPR) was used to predict the as-printed height and porosity using data from Fe-Ni alloys produced via laser metal deposition (LMD) processing. Defect types (gas porosity, keyhole, and lack of fusion) were classified using a support vector machine (SVM) by comparing the measured and predicted porosities based on GPR. The Shapley additive explanation (SHAP) approach for xML was utilized to analyze feature importance based on both GPR and SVM data. This study provides insight into the use of the xML model in MAM to link processing with results.

Systemic delivery of oncolytic viruses has been widely regarded as an impractical option for antitumor treatment. Here, we selected two target genes as leading components, and significant therapeutic effects were obtained by simultaneously reducing the expression of transforming growth factor β 1 (TGF-β1) and heat shock protein 27 (HSP27) in various cancer cell types. Downregulation of HSP27 reduced the cellular levels of tumor progression-related proteins, and the simultaneous downregulation of HSP27 and TGF-β1 increased tumor cell death beyond that observed with TGF-β1 downregulation alone. To increase the potential for systemic administration, we generated modified mesenchymal stem cells (MSCs) to act as oncolytic adenovirus factories and carriers and assessed bioavailability in tumors after MSC injection. The MSCs were modified to express 78-kDa glucose-regulated protein (GRP78) and adenovirus early-region 1B 55 kDa (E1B55K). The tightly controlled inducible system permitted selective timing of viral release from carrier MSCs within the tumor. This approach significantly improved viral production, tumor targeting, timely viral release at the tumor site, and antitumor efficacy of the oncolytic adenovirus. These combined results demonstrate that engineered MSCs can significantly enhance the antitumor effects of oncolytic viruses without adverse safety issues, which may greatly extend the clinical applicability of oncolytic adenoviruses.

Abstract Backgrounds The aims of this study were to construct spore-displayed p40, a Lacticaseibacillus rhamnosus GG-derived soluble protein, using spore surface display technology and to evaluate transcriptional responses in human intestinal epithelial cells. Results p40 was displayed on the surface of Bacillus subtilis spores using spore coat protein CotG as an anchor protein. Effects of spore-displayed p40 (CotG-p40) on gene expression of intestinal epithelial cell line HT-29 were evaluated by transcriptome analysis using RNA-sequencing. As a result of differentially expressed gene (DEG) analysis, 81 genes were up-regulated and 82 genes were down-regulated in CotG-p40 stimulated cells than in unstimulated cells. Gene ontology enrichment analysis showed that CotG-p40 affected biological processes such as developmental process, metabolic process, cell surface receptor linked signaling pathway, and retinoic acid metabolic process. Gene-gene network analysis suggested that 10 DEGs (EREG, FOXF1, GLI2, PTGS2, SPP1, MMP19, TNFRSF1B, PTGER4, CLDN18, and ALDH1A3) activated by CotG-p40 were associated with probiotic action. Conclusions This study demonstrates the regulatory effects of CotG-p40 on proliferation and homeostasis of HT-29 cells. This study provided comprehensive insights into the transcriptional response of human intestinal epithelial cells stimulated by CotG-p40.

Abstract Background Acute aortic regurgitation (AR) is uncommon condition and usually results in an emergent situation because the left ventricle does not adapt quickly due to a sudden increase in end-diastolic volume caused by the regurgitant flow. Thoracic endovascular aortic repair (TEVAR) is a procedure that places a stent-graft on the lesion of thoracic aorta through a minimally invasive approach. Case presentation Here we report that a catheter-induced aortic valve injury associated with TEVAR can cause delayed AR, exemplified by the case of a patient who developed acute AR 42 months after TEVAR. For this, aortic valve replacement was performed and the patient was discharged without complications. Conclusion Our results demonstrate that when a catheter-related procedure is performed around the aortic valve, slight injury of the valve can cause aortic insufficiency even 3 years after surgery. Consequently, when performing a catheter-related procedure around the aortic valve, special attention is always required.

Abstract Prior experiences of successful and failed treatments are known to influence the efficacy of a newly applied treatment. However, whether that carry-over effect applies to non-pharmacological treatments is unknown. This study investigated how a failed treatment history with placebo analgesic cream affected the therapeutic outcomes of cold-pack treatment. The neural correlates underlying those effects were also explored using functional magnetic resonance imaging. The effect of the placebo analgesic cream was induced using placebo conditioning with small (44.5 °C to 43.7 °C, negative experience) and large (44.5 °C to 40.0 °C, positive experience) thermal stimuli changes. After the placebo conditioning, brain responses and self-reported evaluations of the effect of subsequent treatment with a cold-pack were contrasted between the two groups. The negative experience group reported less pain and lower anxiety scores in the cold-pack condition than the positive experience group and exhibited significantly greater activation in the right inferior parietal lobule (IPL), which is known to be involved in pain relief. These findings suggest that an unsatisfying experience with an initial pain-relief treatment could increase the expectations for the complementary treatment outcome and improve the analgesic effect of the subsequent treatment. The IPL could be associated with this expectation-induced pain relief process.

Purpose This study investigated the utility of second-line contrast-enhanced ultrasonography (CEUS) using Sonazoid in Liver Imaging Reporting and Data System category 3 (LR-3) and 4 (LR-4) observations on gadoxetate-enhanced magnetic resonance imaging (MRI). Methods This retrospective study included LR-3 or LR-4 observations on gadoxetate-enhanced MRI subsequently evaluated with CEUS from 2013 to 2017. The presence of MRI features, CEUS-arterial phase hyperenhancement (CEUS-APHE), and Kupffer phase defect (KPD) was evaluated. Multivariable logistic regression analysis was performed to identify significant imaging features associated with the diagnosis of hepatocellular carcinoma (HCC). The optimal diagnostic criteria were investigated using the McNemar test. Results In total, 104 patients with 104 observations (63 HCCs) were included. The presence of both CEUS-APHE and KPD on CEUS enabled the additional detection of 42.3% (11/26) of LR-3 HCCs and 78.4% (29/37) of LR-4 HCCs. Transitional phase (TP) hypointensity (adjusted odds ratio [OR], 10.59; P

Abstract Obesity is a major health problem worldwide and is associated with chronic kidney disease (CKD). Body mass index (BMI) is a common method of diagnosing obesity, but there are concerns about its accuracy and ability to measure body composition. This study evaluated the risk of CKD development in a middle-aged population in association with various body composition metrics. From a prospective cohort of 10,030 middle-aged adults, we enrolled 6727 for whom baseline and follow-up data were available. We collected data pertaining to participants' BMI, manually measured waist–hip ratio (WHR), and various measurements of bioelectrical impedance analysis (BIA), including total body fat content, muscle content, and calculated WHR, and classified the participants into quintiles accordingly. CKD was defined as an estimated glomerular filtration rate (eGFR)

In this study, Rubus coreanus (R. coreanus) byproducts with high polyphenol content were fermented with R. coreanus-derived lactic acid bacteria (Lactobacillus plantarum GBL 16 and 17). Then the effect of R. coreanus-derived lactic acid bacteria fermented feed (RC-LAB fermented feed) with probiotics (Bacillus subtills, Aspergillus oryzae, Yeast) as a feed additive for pigs on the composition of intestinal microbes and the regulation of intestinal immune homeostasis was investigated. Seventy-two finishing Berkshire pigs were randomly allotted to four different treatment groups and 18 replicates. RC-LAB fermented feed with probiotics increased the genera Lactobacillus, Streptococcus, Mitsuokella, Prevotella, Bacteroides spp., Roseburia spp., and Faecalibacterium prausnitzii, which are beneficial bacteria of the digestive tract of pigs. Also, RC-LAB fermented feed with probiotics decreased the genera Clostridium, Terrisporobacter, Romboutsia, Kandleria, Megasphaera and Escherichia, which are harmful bacteria. In particular, the relative abundance of the genera Lactobacillus and Streptococcus increased by an average of 8.51% and 4.68% in the treatment groups and the classes Clostridia and genera Escherichia decreased by an average of 27.05% and 2.85% in the treatment groups. In mesenteric lymph nodes (MLN) and spleens, the mRNA expression of transcription factors and cytokines in Th1 and Treg cells increased and the mRNA expression of Th2 and Th17 transcription factors and cytokines decreased, indicating a regulatory effect on intestinal immune homeostasis. RC-LAB fermented feed regulates gut immune homeostasis by influencing the composition of beneficial and detrimental microorganisms in the gut and regulating the balance of Th1/Th2 and Th17/Treg cells.

The configurational design of heterostructures has received considerable attention to achieve a superior combination of strength and ductility. Although heterostructuring for enhanced tensile properties has been widely analyzed, studies on the effect of heterogeneity on sheet formability are still insufficient. Sheet metal formability is one of the most crucial factors for determining hetero-materials’ industrial utilization. To broaden the industrial applicability of heterostructured layered materials, investigating the effects of heterogeneity in the layered structure on formability is necessary. This study investigated the stretch formability of aluminum-steel-aluminum clad sheets using the Erichsen cupping test. The three-layered clad sheets showed additional hardening with a slight increase in ductility owing to hetero-deformation-induced hardening because the strain-hardening exponent has a linear relationship with stretchability or necking resistance. After necking, damage evolution owing to severe internal stress concentration led to delamination at the interface. Interestingly, delamination serves as a block to full cracking through the thickness during forming. This study contributes to the industrial applicability of heterogeneous structuring by elucidating the characteristics of heterogeneity and formability.

Abstract A ureterocele is a rare congenital anomaly with cystic dilation of the terminal segment of the ureter entirely within the bladder (orthotopic) or associated with ectopic ureter (ectopic). Its aetiology has not been fully clarified; however, it may involve genetic or acquired factors. Urothelial carcinoma (UC) is the most common type of canine urinary tract neoplasm, among which over 90% of cases are invasive. The non‐papillary (flat) non‐infiltrating form accounts for a very small percentage of canine UCs and is considered carcinoma in situ (CIS). The neoplastic cells of CIS remain within the ureteral mucosa and do not breach the basement membrane. UCs originating from the canine ureter are extremely rare, and no report of a ureteral UC concurrently occurring with a ureterocele has been reported. A 7‐year‐old castrated male Maltese dog weighing 3.5 kg was referred with a 2‐week history of lethargy, anorexia, pollakiuria and intermittent panting. The dog underwent open surgery for removal of bladder calculi 2 years prior, and at the time of the surgery, no other urinary system abnormalities were identified. Ultrasonographic and computed tomographic scans revealed a severely enlarged right kidney and ureter with a ureterocele on the ipsilateral side. A diagnosis of an orthotopic ureterocele causing hydronephrosis and hydroureter was established. Complete nephroureterectomy and ureterocelectomy using the marsupialisation technique were performed. The postoperative histological examination of the excised tissues showed a multifocal carcinoma in situ (non‐papillary non‐infiltrating UC) in the proximal ureter and a fluid‐filled kidney with a thin rim of fibrotic renal tissue. No neoplastic changes were observed in the ureterocele tissue. Postoperatively, the dog recovered rapidly without complications except temporary urinary incontinence, and no evidence of tumour recurrence was detected by ultrasonography performed 6 months after surgery. This case report describes the first case of a dog with an orthotopic ureterocele and ureteral UC, which occurred concurrently at the ipsilateral side of the ureter. The condition was successfully managed with a nephroureterectomy and partial ureterocelectomy.

Abstract The use of minipigs (Sus scrofa) as a platform for toxicological and pharmacological research is well established. In the present study, we investigated the effect of formaldehyde (FA) exposure on helper T cell-mediated splenic immune responses in Yucatan minipigs. The minipigs were exposed to different inhaled concentrations of FA (0, 2.16, 4.62, or 10.48 mg/m3) for a period of 2 weeks. Immune responses elicited by exposure to FA were determined by assessing physiological parameters, mRNA expression, and cytokine production. Additionally, the distribution of helper T cells and regulatory T (Treg) cells and expression of NFAT families, which are well-known T cell receptor signalling proteins associated with regulatory T cell development, were evaluated. Exposure to FA suppressed the expression of genes associated with Th1 and Th2 cells in minipigs in a concentration-dependent manner. The subsequent production of cytokines also declined post-FA exposure. Furthermore, exposure to FA induced the differentiation of CD4+ Foxp3+ Treg cells with divergent expression levels of NFAT1 and NFAT2. These results indicated that exposure to FA increased the Treg cell population via the NFAT-mediated T cell receptor signalling pathway, leading to suppression of effector T cell activity with a decline in T cell-related cytokine production.

Background Success of T cell immunotherapy hinges on the tumor microenvironment (TME), and abnormal tumor vasculature is a hallmark of most solid tumors and associated with immune evasion. The efficacy of T cell engaging bispecific antibody (BsAb) treatment relies on the successful trafficking and cytolytic activity of T cells in solid tumors. Normalization of tumor vasculature using vascular endothelial growth factor (VEGF) blockades could improve efficacy of BsAb-based T cell immunotherapy.Methods Anti-human VEGF (bevacizumab, BVZ) or anti-mouse VEGFR2 antibody (DC101) was used as VEGF blockade, and ex vivo armed T cells (EATs) carrying anti-GD2, anti-HER2, or anti-glypican3 (GPC3) IgG-(L)-scFv platformed BsAb were used. BsAb-driven intratumoral T cell infiltration and in vivo antitumor response were evaluated using cancer cell line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) carried out in BALB-Rag2-/-IL-2R-γc-KO (BRG) mice. VEGF expression on human cancer cell lines was analyzed by flow cytometry, and VEGF levels in mouse serum were measured using VEGF Quantikine ELISA Kit. Tumor infiltrating lymphocytes (TILs) were evaluated using flow cytometry and by bioluminescence; both TILs and tumor vasculature were studied using immunohistochemistry.Results VEGF expression on cancer cell lines increased with seeding density in vitro. BVZ significantly reduced serum VEGF levels in mice. BVZ or DC101 increased high endothelial venules (HEVs) in the TME and substantially enhanced (2.1–8.1 fold) BsAb-driven T cell infiltration into neuroblastoma and osteosarcoma xenografts, which was preferential for CD8(+) TILs versus CD4(+) TILs, leading to superior antitumor effects in multiple CDX and PDX tumor models without added toxicities.Conclusions VEGF blockade using specific antibodies against VEGF or VEGFR2 increased HEVs in the TME and cytotoxic CD8(+) TILs, significantly improving the therapeutic efficacy of EAT strategies in preclinical models, supporting the clinical investigation of VEGF blockades to further enhance BsAb-based T cell immunotherapies.

Purpose The aim of this study was to evaluate the association of contrast-enhanced ultrasound (CEUS) features using Sonazoid for liver nodules with Liver Imaging Reporting and Data System (LI-RADS) categories and to identify the usefulness of Kupffer-phase images. Methods This retrospective study was conducted in 203 patients at high risk of hepatocellular carcinoma (HCC) who underwent CEUS with Sonazoid from 2013 to 2016. Nodule enhancement in the arterial, portal venous, late, and Kupffer phases; CEUS LI-RADS major features; and Kupffer-phase defects were evaluated. According to the computed tomography/magnetic resonance imaging (CT/MRI) LI-RADS v2018, all nodules were assigned an LR category (n=4/33/99/67 for LR-M/3/4/5) and comparisons across LR categories were made. We defined modified CEUS LI-RADS as using Kupffer-phase defects as an alternative to late and mild washout in CEUS LI-RADS and compared the diagnostic performance for HCC. Results On CEUS of 203 nodules, 89.6% of CT/MRI LR-5 and 85.9% of LR-4 nodules showed hyperenhancement in the arterial phase, while 57.6% of LR-3 nodules showed hyperenhancement. Among the CT/MRI LR-5 nodules that showed arterial phase hyperenhancement or isoenhancement, 59.7% showed hypoenhancing changes from the portal venous phase, 23.9% from the late phase, and 13.4% additionally in the Kupffer phase. The modified CEUS LI-RADS showed higher sensitivity than CEUS LI-RADS (83.2% vs. 74.2%, P=0.008) without compromising specificity (63.6% vs. 69.7%, P=0.500). Conclusion The Kupffer phase best shows hypoenhancing changes in LR-5 lesions and is expected to improve the sensitivity for HCC in high-risk patients.

Purpose The balloon-stent technique (BST) has certain strengths as an assisted technique for the treatment of complex aneurysms. After Atlas release, the BST can be executed without an exchange maneuver of the balloon to the stent-delivery catheter. The purpose of this article is to share our experience with the BST using the Scepter-Atlas combination. Materials and Methods Device inspection led us to a simple method to avoid failure in loading Atlas to the Scepter. From March 2018 to December 2019, 57 unruptured distal internal carotid artery (dICA) aneurysms were treated with coil embolization; among which, 25 aneurysms in 23 patients were treated with BST. Clinical and angiographic data were retrospectively collected and reviewed. Results The technical success rate of the Scepter-Atlas combination increased from 50% to 100% after careful inspection. BST angiographic results were comparable to the stent-assisted coil (SAC) group treated during the immediately post-embolization same period (modified Raymond-Roy classification [MRRC] 1 & 2 84% in BST, 96.3% in SAC) and during short-term follow-up (MRRC 1 & 2 95.8% in BST, 88.4% in SAC). A small number of patients showed periprocedural complications, but none had clinical consequences. Conclusion BST using the Scepter-Atlas combination can provide an effective and safe method for the treatment of dICA aneurysms. Scepters can be used as delivery catheters for Atlas.