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In this study, we developed a multi-walled carbon nanotube (MWCNT)-based field-effect transistor (MWCNT-FET) sensor with high sensitivity and selectivity for microcystin-LR (MC-LR). Carboxylated MWCNTs were activated with an MC-LR-targeting aptamer (MCTA). Subsequently the bioactivated MWCNTs were immobilized between interdigitated drain (D) and source (S) electrodes through self-assembly. The top-gated MWCNT-FET sensor was configured by dropping the sample solution onto the D and S electrodes and immersing a Ag/AgCl electrode in the sample solution as a gate (G) electrode. We believe that the FET sensor’s conduction path arises from the interplay between the MCTAs, with the applied gate potential modulating this path. Using standard instruments and a personal computer, the sensor’s response was detected in real-time within a 10 min time frame. This label-free FET sensor demonstrated an impressive detection capability for MC-LR in the concentration range of 0.1–0.5 ng/mL, exhibiting a lower detection limit of 0.11 ng/mL. Additionally, the MWCNT-FET sensor displayed consistent reproducibility, a robust selectivity for MC-LR over its congeners, and minimal matrix interferences. Given these attributes, this easily mass-producible FET sensor is a promising tool for rapid, straightforward, and sensitive MC-LR detection in freshwater environments.

The increasing number of structural collapses, slope failures and other naturaldisasters has lead to a demand for new sensors, sensor integration techniques and dataprocessing strategies for deformation monitoring systems. In order to meet extraordinaryaccuracy requirements for displacement detection in recent deformation monitoringprojects, research has been devoted to integrating Global Positioning System (GPS) as amonitoring sensor. Although GPS has been used for monitoring purposes worldwide,certain environments pose challenges where conventional processing techniques cannotprovide the required accuracy with sufficient update frequency. Described is thedevelopment of a fully automated, continuous, real-time monitoring system that employsGPS sensors and pseudolite technology to meet these requirements in such environments.Ethernet and/or serial port communication techniques are used to transfer data betweenGPS receivers at target points and a central processing computer. The data can beprocessed locally or remotely based upon client needs. A test was conducted that illustrateda 10 mm displacement was remotely detected at a target point using the designed system.This information could then be used to signal an alarm if conditions are deemed to beunsafe.

(1) Background: Astragalus membranaceus (AM) has antioxidant and anti-inflammatory effects, but its specific mechanism of action in the brain is still unclear. In this study, we developed a roasting process to maximize the cognitive improvement impact of AM. We focused on enhancing physiological activity to enhance the brain neuron protection effect and alleviate neuronal damage caused by neurodegenerative diseases. (2) Methods: AM was roasted at 260 °C for 20, 30, or 40 min, and the hot water extracts were tested on HT22 cells for ROS levels, apoptosis, and antioxidant protein expression. The effect on the BDNF-AKT-CREB pathway under stress was also analyzed. (3) Results: Roasted AM decreased ROS production and the expression of apoptosis-related factors while activating the expression of antioxidant proteins in HT22 cells treated with Aβ25–35. In particular, 30 min roasting (R-AM2) significantly reduced ROS production, inhibited cell death, and increased antioxidant protein expression. The Nrf2 pathway was activated Bax, and cleaved caspase-3 levels were reduced. BDNF and p-CREB expression were increased by 20% and 50–70%, respectively. In the MAPK pathway, p-ERK levels were increased by 30%, and p-P38 levels were increased by approximately 20%. (4) Conclusions: These findings suggest that roasted AM upregulates brain-derived neurotrophic factor (BDNF) in HT22 cells, providing neuroprotective effects by activating the AKT/CREB/BDNF pathway and inhibiting neuronal apoptosis. Therefore, roasted AM shows potential as a neuroprotective agent for preventing or treating neurodegenerative diseases, such as Alzheimer’s, linked to BDNF deficiency.

Abstract Introduction Lenvatinib is approved for the treatment of patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, clinical outcomes of lenvatinib therapy in patients with post‐liver transplantation (LT) HCC recurrence remain unclear. We investigated the efficacy and safety of lenvatinib in patients with post‐LT HCC recurrence. Methods This multinational, multicenter, retrospective study included 45 patients with recurrent HCC after LT who received lenvatinib at six institutions in three countries (Korea, Italy, and Hong Kong) from June 2017 to October 2021. Results At the time of lenvatinib initiation, 95.6% (n = 43) of patients had Child–Pugh A status, and 35 (77.8%) and 10 (22.2%) participants were classified as having albumin–bilirubin (ALBI) grades 1 and 2, respectively. The objective response rate was 20.0%. With a median follow‐up duration of 12.9 months (95% confidence interval [CI]: 11.2–14.7), the median progression‐free survival and overall survival (OS) were 7.6 (95% CI: 5.3–9.8) months, and 14.5 (95% CI: 0.8–28.2) months, respectively. Patients with ALBI grade 1 showed significantly better OS (52.3 months, [95% CI: not assessable]) than patients with ALBI grade 2 (11.1 months [95% CI: 0.0–30.4 months], p = 0.003). The most common adverse events were hypertension (n = 25, 55.6%), fatigue (n = 17, 37.8%), and anorexia (n = 14, 31.1%). Conclusion Lenvatinib showed consistent efficacy and toxicity profiles in patients with post‐LT HCC recurrence that were comparable to those reported from previous studies among non‐LT HCC patients. The baseline ALBI grade correlated with better OS in post‐LT lenvatinib‐treated patients.

Background/Aims The eradication success rate of Helicobacter pylori (H. pylori) infection with a first-line standard triple therapy (STT) has been decreasing in Korea. However, treatment outcomes of H. pylori infection in Yeongdong, Gangwon Province have been scarcely reported. This study aimed to investigate the treatment outcomes of H. pylori infection in a single tertiary care hospital with regional characteristics. Materials and Methods From July 2018 to June 2019, a total of 592 patients who underwent STT consisting of a proton pump inhibitor, amoxicillin, and clarithromycin for 7 to 14 days as a first-line H. pylori eradication therapy were included. Demographic data and treatment outcomes were retrospectively reviewed using medical records. Results The median age of 592 patients was 58 years (range 23 to 86) and 329 patients (55.6%) were men. The indication for eradication therapy included chronic atrophic gastritis (57.9%), peptic ulcer disease (19.6%), and gastric neoplasm after endoscopic resection (5.9%). Most patients (92.2%) received a 7-day course of STT. Eradication rate of STT was 64.0% (379/592). Rescue therapy was performed in 146 patients, and the final eradication rate reached 85.6% (507/592). Conclusions Eradication rate of STT in Yeongdong area of Gangwon Province was unsatisfactory, warranting the consideration of a first-line eradication regimen other than STT.

Abstract The optimal timing of endoscopy in patients with acute upper gastrointestinal bleeding (UGIB) remains controversial. In this study, we investigated the clinical outcomes of urgent endoscopy in patients with UGIB compared with elective endoscopy. From January 2016 to December 2018, consecutive patients who visited the emergency department and underwent endoscopy for clinical manifestations of acute UGIB, including variceal bleeding, were eligible. Urgent endoscopy (within 6 h) and elective endoscopy (after 6 h) were defined as the time taken to perform endoscopy after presentation to the emergency department. The primary outcome was mortality rate within 30 days. A total of 572 patients were included in the analysis. Urgent endoscopy was performed in 490 patients (85.7%). The 30-day mortality rate did not differ between the urgent and elective endoscopy groups (5.3% and 6.1%, p = 0.791). There was no difference regarding the recurrent bleeding rate, total amount of transfusion, or length of hospital between the groups. In multivariate analysis, age and the amount of transfusion were associated with mortality. Urgent endoscopy was not associated with a lower 30-day mortality rate compared with elective endoscopy in patients with acute UGIB.

The present paper describes experiments and research outcomes concerning the construction of cement concrete pavements in South Kazakhstan, taking into account significant climate changes. The study has identified potential problems in the construction of cement concrete pavements in the region, where there was no experience of their construction until the mid-2000s. In order to develop an optimal solution, the technical factors that characterize the process of arranging these coatings using sliding molds are analyzed and quantitatively normalized. These factors include the optimal amount of mortar for curing concrete, the optimal joint cutting time, the interval and effective width of expansion joints to prevent the formation of cracks in concrete at an early age. The effectiveness of the use of polyethylene film to prevent the formation of contraction cracks and maintain the required mode of hardening of the cement concrete pavement is shown. The main cause of damage to the expansion joints along the length of the day coverage of coatings in the conditions of South Kazakhstan has been established. Recommendations have been developed for the installation of cement-concrete pavement and expansion joints during the construction of roads in this region. The accumulated data on climatic factors and methods of work with the use of polyethylene film have made it possible to create an optimal method for the construction of cement concrete pavements, which will improve the quality of roads in South Kazakhstan.

Background/Aims We aimed to investigate the silent atherosclerotic burden of cervicocephalic vessels in cirrhotic patients compared with the general population, as well as the relevant risk factors including coronary parameters. Methods This study included 993 stroke-free patients with liver cirrhosis (LC) who underwent magnetic resonance angiography (MRA) of the head and neck as a pre-liver transplant assessment and 6,099 health checkup participants who underwent MRA examination. The two cohorts were matched for cerebrovascular risk factors, and the prevalence of atherosclerosis in major intracranial and extracranial arteries was compared in 755 matched pairs. Moreover, traditional, hepatic, and coronary variables related to cerebral atherosclerosis were assessed in cirrhotic patients. Results Overall, intracranial atherosclerosis was significantly less prevalent in the LC group than in the matched control group (2.3% vs. 5.4%, P=0.002), whereas the prevalence of extracranial atherosclerosis was similar (4.4% vs. 5.8%, P=0.242). These results were maintained in multivariate analyses of the pooled samples, with corresponding adjusted odds ratios [ORs] of LC of 0.56 and 0.77 (95% confidence intervals [CIs], 0.36–0.88 and 0.55–1.09). In the LC group, lower platelet count was inversely correlated with intracranial atherosclerosis (adjusted OR, 0.31; 95% CI, 0.13–0.76). Coronary artery calcium (CAC) score ≥100 was the only predictive factor for both intracranial and extracranial atherosclerosis (adjusted ORs, 4.06 and 5.43, respectively). Conclusions LC confers protection against intracranial atherosclerosis, and thrombocytopenia may be involved in this protective effect. High CAC score could serve as a potential surrogate for cervicocerebral vascular screening in asymptomatic cirrhotic patients.

Abstract We aimed to investigate the dynamic changes of gene expression profiles and immune microenvironment linked to resistance to cetuximab-based treatments in patients with metastatic colorectal cancer (mCRC). A total of 106 patients with RAS-wild type mCRC who were treated with cetuximab-based treatments were included as the study population. RNA-sequencing and multiplexed immunohistochemistry were performed using paired or unpaired pre-treatment and post-treatment tumor tissues. Differentially expressed gene analysis of paired pre-treatment and post-treatment tumor tissues that develop acquired resistance (AR) identified the AR signature. Gene ontology analysis of the AR signature indicated enrichment of immune-related pathway genes. Among the immune subsets whose abundance was estimated by CIBERSORT, M2 macrophages showed the most prominent positive correlation with the expression of the AR signature. Among the post-treatment samples, progressive disease (PD) tumors showed a significantly higher abundance of M2 macrophages compared to non-PD tumors. These findings were validated by multiplexed immunohistochemistry analysis: the density of CD68+CD206+ M2 macrophages significantly increased at the time of PD following cetuximab-based treatment, whereas it did not consistently change in the tumor pairs of non-PD. In conclusion, a dynamic increase of M2 macrophages is associated with disease progression during cetuximab-based treatment of mCRCs. Targeting M2 macrophages is a promising immunotherapeutic strategy in this clinical context.

Local lymph node assay (LLNA) is a predictive in vivo method to provide estimates of relative potency and to contribute to risk assessment/risk management regarding skin sensitizing potency of chemicals and formulations as a stand-alone alternative test. In addition, LLNA is relatively rapid and cost-effective compared to the Buehler method (Guinea pig test), and confers important animal welfare benefits. CBA/J and BALB/c strains are widely commercially available and have been evaluated by formal LLNA validation studies. However, the LLNA method using BrdU with ELISA, unlike other LLNA methods (OECD TG 429, 442 A, 442B), has not been previously validated. Therefore, in this study a validation method was performed to evaluate if the LLNA:BrdU-ELISA method could also be used to identify sensitizers among chemicals listed in OECD TG 429 using CBA/J and BALB/c strains. Here, we newly found that the LLNA:BrdU-ELISA validation method correctly identified 12 of 13 sensitizers in the BALB/c, 11 of 13 sensitizers in the CBA/J, and 3 of 5 non-sensitizers were identified in the two strains. Collectively, we found that the results of LLNA:BrdU-ELISA method provide a similar level of performance for accuracy and sensitivity in two mouse strains BALB/c and CBA/J.

Abstract Background Ingested foreign objects frequently require emergency removal. This study aimed to investigate the clinical outcomes of endoscopic removal of foreign bodies from the upper gastrointestinal tract and the risk factors for adverse events. Methods Adults (> 18 years) who underwent endoscopic management of ingested foreign bodies at two centers, one inland and one on the coast, between January 2008 and December 2017 were eligible. Clinical characteristics and procedure-related outcomes were retrospectively reviewed. Patients were divided into two groups, based on whether the foreign bodies were sharp or blunt in shape. Results A total of 853 patients aged 19–96 years were analyzed. Ingestion of fish bones was more common in the coastal area, whereas ingestion of food boluses was more common in the inland area. The duration of impaction ranged from 1 h to over 1 month and was significantly longer in patients who ingested blunt than sharp foreign bodies (15 vs. 5 h, p

ABSTRACT: The proteolysis trends and meat quality of the chicken pectoralis major (PM) and iliotibialis (IL) muscles stored at 4°C for 7 d were investigated. After 7 d of storage, the purge loss was higher (P < 0.05) in PM than in IL muscle. The difference in the composition of muscle fibers between PM (100% fast type) and IL (88.85% fast and 11.15% slow types) resulted in differences in proteolysis. Fructose-bisphosphate aldolase, troponin I, myosin heavy chain, and malate dehydrogenase exhibited the same tendencies, but pyruvate kinase, creatine kinase, L-lactate dehydrogenase, and triosephosphate isomerase exhibited different tendencies in the 2 muscles. The activity of cathepsin B was higher in PM than in IL during storage (P < 0.05). These results indicate that the proteolysis trend and changes in meat quality during cold storage are dependent on the different muscle fiber characteristics.

Melanin is a brown or black pigment that protects skin from ultraviolet radiation and reactive oxygen species (ROS). However, overproduction of melanin is associated with lentigines, melasma, freckles and skin cancer. Licorice has shown antioxidant, anti-tumor, anti-platelet, anti-inflammatory and immunomodulatory activities and is used as a natural treatment for skin whitening. We aimed to confirm the potential of Wongam, a new cultivar of licorice developed by the Rural Development Administration (RDA), as a whitening agent in cosmetics. In addition, we verified the effect of heat treatment on the bioactivity of licorice by comparing antioxidant and anti-melanogenic activities of licorice extract before and after heating (130 °C). The heat-treated licorice extract (WH-130) showed higher radical-scavenging activities in the ABTS+ (2,2′-azino-bis-(3-ethylbenzothiazolin-6-sulfonic acid) diammonium salt) and DPPH (2,2-diphenyl-1-picrylhydrazyl) assays. In addition, WH-130 inhibited melanogenesis more effectively due to downregulation of tyrosinase in B16F10 melanoma cells than non-heated licorice extract. Moreover, heat treatment increased total phenolic content. In particular, isoliquiritigenin, an antioxidant and anti-melanogenic compound of licorice, was produced by heat treatment. In conclusion, WH-130, with increased levels of bioactive phenolics such as isoliquiritigenin, has potential for development into a novel skin whitening material with applications in cosmetics.

PurposeImmune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab (N/I) are important treatment options for advanced renal cell carcinoma (RCC). The tumor microenvironment (TME) in these ICI-treated patients is largely unknown.MethodsTwenty-four patients treated with N/I between July 2015 and June 2020 were analyzed. Multiplexed immunohistochemistry (mIHC) was conducted to define the TME, including various T cell subsets, B cells, macrophages, and dendritic cells.ResultsThe median age of the study patients was 61 years (range, 39–80) and 75.0% of these cases were men. The objective response rate with N/I was 50.0%. The densities of the CD8+ cytotoxic T cells (P=0.005), specifically CD137+ CD8+ T cells (P=0.017), Foxp3- CD4+ helper T cells (P=0.003), Foxp3+ CD4+ regulatory T cells (P=0.045), CD68+ CD206- M1 macrophages (P=0.008), and CD68+ CD206+ M2 macrophages (P=0.021) were significantly higher in the treatment responders. At a median follow-up duration of 24.7 months, the median progression-free survival (PFS) was 11.6 months. The high densities (≥median) of Foxp3- CD4+ helper T cells (P=0.016) and CD68+ CD206- M1 macrophages (P=0.008) were significantly associated with better PFS, and the density of CD137+ CD8+ cytotoxic T cells (P=0.079) was marginally associated with better PFS. After multivariate analysis, the higher density of Foxp3- CD4+ helper T cells was independently associated with better PFS (hazard ratio 0.19; P=0.016).ConclusionThe properties and clinical implications of the TME properties in RCC indicate that Foxp3- CD4+ helper T cells, M1 macrophages, and CD137+ CD8+ T cells are potential predictive biomarkers and treatment targets.

Aurantii Fructus Immaturus (AFI), extensively used in traditional herbal medicine, is known to have diverse physiological effects against various diseases, including obesity, diabetes, and cardiovascular disease. However, the effects of AFI on the immune system, especially natural killer (NK) cells, remain largely unknown. We aimed to investigate the effect of AFI on NK cell activity in vitro and in vivo and to elucidate the underlying mechanisms. Further, we verified the anticancer efficacy of AFI in a mouse lung metastasis model, underscoring the therapeutic potential of AFI in cancer therapy. Our results revealed that AFI significantly enhanced the cytolytic activity of NK cells in a dose-dependent manner, accompanied by an increase in the expression of NK cell-activating receptors, especially NKp30 and NKp46. AFI treatment also increased the expression of cytolytic granules, including granzyme B and perforin. Furthermore, the expression of CD107a, a degranulation marker, was increased upon treatment with AFI. A signaling study using western blot analysis demonstrated that the phosphorylation of extracellular signal-regulated kinase (ERK) was involved in increasing the NK cell activity following AFI treatment. In the in vivo study performed in mice, oral administration of AFI markedly enhanced the cytotoxic activity of spleen mononuclear cells against YAC-1 cells, which was accompanied by NKp46 upregulation. In addition, we confirmed that cancer metastasis was inhibited in a mouse cancer metastasis model, established using the mouse melanoma B16F10 cell line, by the administration of AFI in vivo. Collectively, these results indicate that AFI enhances NK cell-mediated cytotoxicity in vitro and in vivo via activation of the ERK signaling pathway and suggest that AFI could be a potential supplement for cancer immunotherapy.

Owing to the difficulties associated with conducting millimeter‐wave (mmWave) field measurements, especially in high‐speed train (HST) environments, most propagation channels for mmWave HST have been studied using methods based on simulation rather than measurement. In this study, considering a linear cell layout in which base stations are installed along a railway, measurements were performed at 28 GHz with a speed up to 170 km/h in two prevalent HST scenarios: viaduct and tunnel scenarios. By observing the channel impulse responses, we could identify single‐ and double‐bounced multipath components (MPCs) caused by railway static structures such as overhead line equipment. These MPCs affect the delay spread and Doppler characteristics significantly. Moreover, we observed distinct path loss behaviors for the two scenarios, although both are considered line‐of‐sight (LoS) scenarios. In the tunnel scenario, the path loss exponent (PLE) is 1.3 owing to the waveguide effect, which indicates that the path loss is almost constant with respect to distance. However, the LoS PLE in the viaduct scenario is 2.46, which is slightly higher than the free‐space loss.

Abstract To evaluate the relationship between muscle fiber characteristics and the quality of frozen/thawed pork meat, four different muscles, M. longissimus thoracis et lumborum (LTL), M. psoas major (PM), M. semimembranosus (SM), and M. semitendinosus (ST), were analyzed from twenty carcasses. Meat color values (lightness, redness, yellowness, chroma, and hue) changed due to freezing/thawing in LTL, which showed larger IIAX, IIX, and IIXB fibers than found in SM (P

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing. [ABSTRACT FROM AUTHOR]

Abstract Background Risk stratification before endoscopy is crucial for proper management of patients suspected as having upper gastrointestinal bleeding (UGIB). There is no consensus regarding the role of nasogastric lavage for risk stratification. In this study, we investigated the usefulness of nasogastric lavage to identify patients with UGIB requiring endoscopic examination. Methods From January 2017 to December 2018, patients who visited the emergency department with a clinical suspicion of UGIB and who underwent nasogastric lavage before endoscopy were eligible. Patients with esophagogastric variceal bleeding were excluded. The added predictive ability of nasogastric lavage to the Glasgow–Blatchford score (GBS) was estimated using category-free net reclassification improvement and integrated discrimination improvement. Results Data for 487 patients with nonvariceal UGIB were analyzed. The nasogastric aspirate was bloody in 67 patients (13.8 %), coffee-ground in 227 patients (46.6 %), and clear in 193 patients (39.6 %). The gross appearance of the nasogastric aspirate was associated with the presence of UGIB. Model comparisons showed that addition of nasogastric lavage findings to the GBS improved the performance of the model to predict the presence of UGIB. Subgroup analysis showed that nasogastric lavage improved the performance of the prediction model in patients with the GBS ≤ 11, whereas no additive value was found when the GBS was greater than 11. Conclusions Nasogastric lavage is useful for predicting the presence of UGIB in a subgroup of patients, while its clinical utility is limited in high-risk patients with a GBS of 12 or more.

Background: Cabozantinib, a multiple kinase inhibitor, was recently approved for patients with previously treated unresectable hepatocellular carcinoma (uHCC). We investigated the real-world safety and efficacy profiles of cabozantinib. Methods: This multicenter retrospective study included 110 patients with uHCC who received cabozantinib after progression on other systemic treatments between October 2019 and May 2021. Results: The median age was 58 (range, 20–77) years, and 98 (89.1%) were male. Prior to cabozantinib, all patients were treated with other systemic therapies: sorafenib ( n = 104, 94.5%) and regorafenib ( n = 91, 82.7%) were the most commonly used agents. Immune checkpoint inhibitors were previously used in 93 patients (84.5%). Cabozantinib was used beyond the third-line of therapy in most patients ( n = 90, 81.8%). With a median follow-up duration of 11.9 months [95% confidence interval (CI), 10.8–17.2], the median progression-free survival (PFS) was 3.7 months (95% CI, 3.1–4.9), and the median overall survival (OS) was 7.5 months (95% CI, 5.5–9.5). The disease control rate and overall response rate (ORR) were 66.3% and 3.6%, respectively. In the Child–Pugh A cohort ( n = 88), the ORR was 4.5%, and the median PFS and OS were 4.3 months (95% CI, 3.6–5.8) and 9.0 months (95% CI, 7.5–11.7), respectively. Conclusion: Cabozantinib showed consistent efficacy outcomes with a prior phase III trial, although in this study, it was used as later-line therapy for patients who were refractory to multiple systemic treatments, including immune checkpoint inhibitors.

Measuring the diffraction loss for high frequencies, long distances, and large diffraction angles is difficult because of the high path loss. Securing a well‐controlled environment to avoid reflected waves also makes long‐range diffraction measurements challenging. Thus, the prediction of diffraction loss at millimeter‐wave frequency bands relies on theoretical models, such as the knife‐edge diffraction (KED) and geometrical theory of diffraction (GTD) models; however, these models produce different diffraction losses even under the same environment. Our observations revealed that the KED model underestimated the diffraction loss in a large Fresnel‐Kirchhoff diffraction parameter environment. We collected power‐delay profiles when millimeter waves propagated over a building rooftop at millimeter‐wave frequency bands and calculated the diffraction losses from the measurements while eliminating the multipath effects. Comparisons between the measurements and the KED and GTD diffraction‐loss models are shown. Based on the measurements, an approximation model is also proposed that provides a simple method for calculating the diffraction loss using geometrical parameters.

A review of the 2nd generation of intact stability by the International Maritime Organization is performed. The main issues with the new stability criteria are reviewed. In particular, the physical background and related mathematical formulations of the pure loss of stability and parametric roll are summarized. Based on a literature review, benchmark calculation results for 17 different types of ships are discussed, and the final results are in excellent agreement with our physical expectations. Some relatively serious design problems are found in the application of the new stability criteria to sample ships built in Korea, and possible technical solutions are proposed, which have to be improved in the coming years.

l-threonine, l-tryptophan and l-valine play a fundamental role in animal and human nutrition as essential amino acids required for normal growth. In addition, each amino acid is codified as a generally recognized as safe (GRAS) amino acid for the use in animal feed additives and presents no exposure risk from animal to humans consuming tissues or products from the target animal. Taking into account the important role of mutagenicity and genotoxicity in the risk of the three amino acid additives (l-threonine, l-tryptophan, and l-valine) fermentation products and other unknown impurities and derivatives from Corynebacterium glutamicum (C. glutamicum), the safety evaluation of these amino acid additives is not performed. Therefore, the purpose of this study is to evaluate toxicological effects, including Ames test, an in vitro mammalian chromosomal aberration test and an acute oral animal toxicity of the three amino acid additives in accordance with the Organisation for Economic Co-operation and Development (OECD) guidelines and the principles of Good Laboratory Practice (GLP). As a result, these amino acid additives were classified as non-mutagenic and non-clastogenic, and did not induce any toxicity in acute oral toxicity test. Collectively, these results suggest that the three amino acid additives are safe with no adverse effects, and able to be applied as an ingredient or other biological uses.

The usage of cladocerans as non-model organisms in ecotoxicological and risk assessment studies has intensified in recent years due to their ecological importance in aquatic ecosystems. The molecular assessment such as gene expression analysis has been introduced in ecotoxicological and risk assessment to link the expression of specific genes to a biological process in the cladocerans. The validity and accuracy of gene expression analysis depends on the quantity, quality and integrity of extracted ribonucleic acid (RNA) of the sample. However, the standard methods of RNA extraction from the cladocerans are still lacking. This study evaluates the extraction of RNA from tropical freshwater cladocerans Moina micrura using two methods: the phenol-chloroform extraction method (QIAzol) and a column-based kit (Qiagen Micro Kit). Glycogen was introduced in both approaches to enhance the recovery of extracted RNA and the extracted RNA was characterised using spectrophotometric analysis (NanoDrop), capillary electrophoresis (Bioanalyzer). Then, the extracted RNA was analysed with reverse transcription polymerase chain reaction (RT-PCR) to validate the RNA extraction method towards downstream gene expression analysis. The results indicate that the column-based kit is most suitable for the extraction of RNA from M. micrura, with the quantity (RNA concentration = 26.90 ± 6.89 ng/μl), quality (A260:230 = 1.95 ± 0.15, A280:230 = 1.85 ± 0.09) and integrity (RNA integrity number, RIN = 7.20 ± 0.16). The RT-PCR analysis shows that the method successfully amplified both alpha tubulin and actin gene at 33–35 cycles (i.e. Ct = 32.64 to 33.48). The results demonstrate that the addition of glycogen is only suitable for the phenol-chloroform extraction method. RNA extraction with high and comprehensive quality control assessment will increase the accuracy and reliability of downstream gene expression, thus providing more ecotoxicological data at the molecular biological level on other freshwater zooplankton species.

The microrchidia (MORC)-family CW-type zinc finger 2 (MORC2) gene is related to DNA repair, adipogenesis and epigenetic silencing via the human silencing hub (HUSH) complex. MORC2 missense mutation is known to cause peripheral neuropathy of Charcot-Marie-Tooth disease type 2 Z (CMT2Z). However, there have been reports of peripheral and central neuropathy in patients, and the disease has been co-categorized with developmental delay, impaired growth, dysmorphic facies and axonal neuropathy (DIGFAN). The etiology of MORC2 mutation-mediated neuropathy remains uncertain. Here, we established and analyzed Morc2a p.S87L mutant mice. Morc2a p.S87L mice displayed the clinical symptoms expected in human CMT2Z patients, such as axonal neuropathy and skeletal muscle weakness. Notably, we observed severe central neuropathy with cerebella ataxia, cognition disorder and motor neuron degeneration in the spinal cord, and this seemed to be evidence of DIGFAN. Morc2a p.S87L mice exhibited an accumulation of DNA damage in neuronal cells, followed by p53/cytochrome c/caspase 9/caspase 3-mediated apoptosis. This study presents a new mouse model of CMT2Z and DIGFAN with a Morc2a p.S87L mutation. We suggest that neuronal apoptosis is a possible target for therapeutic approach in MORC2 missense mutation. This article has an associated First Person interview with the first author of the paper.

Background Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.Methods To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed “ABL503”) uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.Results Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys.Conclusion The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.

Background/Aims This study was conducted to clarify the sustained virological response (SVR) prediction ability of baseline and treatment-related factors in patients with chronic hepatitis C virus (HCV) infection. Methods This retrospective study collected data at four tertiary referral hospitals between June 2004 and July 2012. Out of 476 patients, 330 treatment-naïve patients with chronic HCV infection were recruited. Pegylated interferon α-2a/- 2b plus ribavirin was administered for either 24 or 48 weeks depending on the HCV genotype. The baseline and treatment-related predictive factors of SVR were evaluated by analyzing data measured before treatment (i.e., baseline) and during treatment. Results SVR rates for genotypes 1 and 2 were 63% (97/154) and 79.5% (140/176), respectively (p = 0.001). Multivariate analysis for baseline factors revealed that young age (p = 0.009), genotype 2 (p = 0.001), HCV RNA level of < 800,000 IU/mL (p < 0.001), and a baseline platelet count of > 150 × 103 /µL (p < 0.001) were significant SVR predictors, regardless of the genotype. In particular, predictive accuracy for achievement of SVR was 87.3% for a baseline platelet count of > 150 × 103 /µL. In multivariate analysis for treatment-related factors, SVR was associated with achievement of a rapid virological response (RVR; p < 0.001), treatment adherence of ≥ 80/80/80 (p < 0.001). Conclusions Young age, genotype 2, low HCV RNA level, RVR, and treatment adherence were significantly associated with SVR. In addition, platelet count was an independent predictive factor for SVR. Therefore, platelet count could be used to develop individualized treatment regimens and to optimize treatment outcomes in patients with chronic HCV infection.

Assuming omnidirectional antenna reception, the ITU‐R recently developed a new propagation model on building entry loss (BEL) for 5G millimeter‐wave frequency sharing and compatibility studies, which is a simplified outdoor‐to‐indoor path loss model. Considering the utilization of high‐gain narrow‐beamwidth beamforming, the omnidirectional‐based ITU‐R BEL model may not be appropriate to predict propagation characteristics for directional beamforming scenarios. This paper studies the effects of beamwidth on the ITU‐R BEL model. This study is based on field measurements collected with four different beamwidth antennas: omnidirectional, 10° horn, 30° horn, and 60° horn. The measurement campaigns were conducted at two types of building sites: traditional and thermally efficient buildings. These sites, as well as the measurement scenarios, were carefully chosen to comply with the ITU‐R BEL measurement guidelines and the ITU‐R building types. We observed the importance of accurate beam alignment from the BEL variation range. We were able to quantify the beamwidth dependency by fitting to a model that is inversely proportional to the beamwidth.

Abstract Background Rubus coreanus fruit (RF) has been used as a traditional medicine formulation to treat various diseases including diarrhea, asthma, and cancer in East Asia (Korea, China, and Japan). RF, which is native to Korea, has a larger fruit size than that of exotic species. In this study, we aimed to compare the anti-inflammatory activities of immature and mature RF extracted with different solvents. Methods Mature and immature RF (MRF and IRF) were extracted with 30% ethanol, 70% ethanol and water at room temperature. The antioxidant activity was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) assays. Anti-inflammatory activity was determined by measuring nitric oxide (NO) production, expression of inflammatory proteins (inducible NO synthase [iNOS], cyclooxygenase [COX]-2, nuclear factor [NF]-κB, and inhibitor of NF-κB [IκB]), and inflammatory cytokines using polymerase chain reaction in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Results The IRF 30% ethanol extract showed higher radical scavenging activity in DPPH and ABTS assays (half-maximal inhibitory concentration [IC50] 16.0 ± 0.5 and 15.9 ± 0.4) than MRF did. In addition, the IRF 30% ethanol extract (200 μg/mL) significantly reduced the production of the inflammatory mediator NO by approximately 80% and inhibited iNOS, COX-2, phosphorylated (p)-IκB, and p-NF-κB activation compared with MRF. Moreover, IRF extract decreased the inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 compared with the MRF extract. Conclusions This study revealed that IRF showed more beneficial effects than MRF did in LPS-stimulated RAW 264.7 macrophages, suggesting that IRF may be a useful anti-inflammatory agent.

A modified interlaminar (MIL) approach has been proposed for improved accessibility to the target epidural space. However, even with fluoroscopic guidance, uncertainty about the distance between the needle tip and the epidural space can remain. Using the contralateral oblique (CLO) view, determination of the epidural space can be easier with clearer identification of the interlaminar opening. We inserted the needle at the midpoint of the interlaminar opening on the fluoroscopic anteroposterior (AP) view and made the needle oriented toward the pedicle of the target side. Then, CLO view was created by rotating the intensifier approximately 45 degrees to the contralateral side of the target. Through the CLO view, the ventral interlaminar line (VILL) was confirmed and the needle was able to enter the epidural space more easily. The medical records of 29 patients who were conducted MIL approach using CLO view were retrospectively analyzed to evaluate the effectiveness and safety of this procedure. The accessibility to the ventral epidural space was 93.1%. There was no procedure-related complication. Using CLO view, uncertainty can be reduced during the MIL approach, which in turn shortens procedure time and improves safety.