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Background/Aims There is limited knowledge regarding the management of duodenal subepithelial lesions (SELs) owing to a lack of understanding of their natural course. This study aimed to assess the natural course of asymptomatic duodenal SELs and provide management recommendations. Methods Patients diagnosed with duodenal SELs and followed up for a minimum of 6 months were retrospectively investigated. Results Among the 443,533 patients who underwent esophagogastroduodenoscopy between 2008 and 2020, duodenal SELs were identified in 0.39% (1,713 patients). Among them, 396 duodenal SELs were monitored for a median period of 72.5 months (interquartile range, 37.7–111.3 mo). Of them, 16 SELs (4.0%) showed substantial changes in size or morphology at a median follow-up of 35.1 months (interquartile range, 21.7–51.4 mo). Of these SELs with substantial changes, tissues of two SELs were acquired using endoscopic ultrasound-guided fine needle aspiration biopsy: one was a lipoma and the other was non-diagnostic. Three SELs were surgically or endoscopically removed; two were diagnosed as gastrointestinal stromal tumors, and one was a lipoma. An initial size of 20 mm or larger was associated with substantial changes during follow-up (p = 0.016). Conclusions While the majority of duodenal SELs may not exhibit substantial interval changes, regular follow-up with endoscopy may be necessary for cases with an initial size of 20 mm or larger, considering a possibility of malignancy.

Background/Aims To overcome the technical limitations of classic endoscopic resection for gastric gastrointestinal stromal tumors (GISTs), various methods have been developed. In this study, we examined the role and feasibility of clip-and-cut procedures (clip-and-cut endoscopic full-thickness resection [cc-EFTR]) for gastric GISTs. Methods Medical records of 83 patients diagnosed with GISTs after endoscopic resection between 2005 and 2021 were retrospectively reviewed. Moreover, clinical characteristics and outcomes were analyzed. Results Endoscopic submucosal dissection (ESD) and cc-EFTR were performed in 51 and 32 patients, respectively. The GISTs were detected in the upper third of the stomach for ESD (52.9%) and cc-EFTR (90.6%). Within the cc-EFTR group, a majority of GISTs were located in the deep muscularis propria or serosal layer, accounting for 96.9%, as opposed to those in the ESD group (45.1%). The R0 resection rates were 51.0% and 84.4% in the ESD and cc-EFTR groups, respectively. Seven (8.4%) patients required surgical treatment (six patients underwent ESD and one underwent cc-EFTR,) due to residual tumor (n=5) and post-procedure adverse events (n=2). Patients undergoing R0 or R1 resection did not experience recurrence during a median 14-month follow-up period, except for one patient in the ESD group. Conclusions cc-EFTR displayed a high R0 resection rate; therefore, it is a safe and effective therapeutic option for small gastric GISTs.

Extracellular matrix (ECM) undergoes dynamic inflation that dynamically changes ligand nanospacing but has not been explored. Here we utilize ECM-mimicking photocontrolled supramolecular ligand-tunable Azo+ self-assembly composed of azobenzene derivatives (Azo+) stacked via cation-π interactions and stabilized with RGD ligand-bearing poly(acrylic acid). Near-infrared-upconverted-ultraviolet light induces cis-Azo+-mediated inflation that suppresses cation-π interactions, thereby inflating liganded self-assembly. This inflation increases nanospacing of “closely nanospaced” ligands from 1.8 nm to 2.6 nm and the surface area of liganded self-assembly that facilitate stem cell adhesion, mechanosensing, and differentiation both in vitro and in vivo, including the release of loaded molecules by destabilizing water bridges and hydrogen bonds between the Azo+ molecules and loaded molecules. Conversely, visible light induces trans-Azo+ formation that facilitates cation-π interactions, thereby deflating self-assembly with “closely nanospaced” ligands that inhibits stem cell adhesion, mechanosensing, and differentiation. In stark contrast, when ligand nanospacing increases from 8.7 nm to 12.2 nm via the inflation of self-assembly, the surface area of “distantly nanospaced” ligands increases, thereby suppressing stem cell adhesion, mechanosensing, and differentiation. Long-term in vivo stability of self-assembly via real-time tracking and upconversion are verified. This tuning of ligand nanospacing can unravel dynamic ligand-cell interactions for stem cell-regulated tissue regeneration.

Background: Regular physical activities reduce the growth of breast cancer, but research on the effects of steady exercise on metastasis and its mechanisms is limited. In this study, the effects of steady exercise on breast cancer metastasis and its possible mechanism were demonstrated. Methods: Experimental metastasis was induced after 8 weeks of steady exercise using a mouse model. Furthermore, one of the myokines, irisin, was studied to elucidate the effects of metastasis-regulating protein expression, and colony and sphere formation, which are cancer stem cell properties. Results: Low- and moderate-intensity exercise significantly reduced the number and volume of metastasized tumors. Among myokines, only irisin was significantly increased by steady exercise but decreased by a high-fat diet. In vitro studies, irisin significantly decreased the number of colonies and sphere formation. Irisin also inhibited cell migration and invasion and suppressed the malignancy of breast cancer cells by reducing the expression of vimentin, MMP-2, MMP-9, and HIF-1 and by increasing the expression of TIMP-1 and TIMP-2. Conclusion: Steady exercise modulates myokine secretions and among them, irisin suppresses breast cancer metastasis by decreasing self-renewal properties and invasion regulating protein expressions. Thus, regular exercise may be beneficial in the prevention of breast tumor metastasis.

Wearable and stretchable strain sensors have potential values in the fields of human motion and health monitoring, flexible electronics, and soft robotic skin. The wearable and stretchable strain sensors can be directly attached to human skin, providing visualized detection for human motions and personal healthcare. Conductive polymer composites (CPC) composed of conductive fillers and flexible polymers have the advantages of high stretchability, good flexibility, superior durability, which can be used to prepare flexible strain sensors with large working strain and outstanding sensitivity. This review has put forward a comprehensive summary on the fabrication methods, advanced mechanisms and strain sensing abilities of CPC strain sensors reported in recent years, especially the sensors with superior performance. Finally, the structural design, bionic function, integration technology and further application of CPC strain sensors are prospected.

Objectives The incidence of treatment failures following standard triple therapy (STT) for Helicobacter pylori eradication (HPE) has reached an unacceptable level. Sequential therapy (SQ) has emerged as a promising approach to counteract the escalation of antibiotic resistance. In this study, we used a chronological cohort dataset to conduct a comparative analysis of the eradication rates, compliance, and adverse events associated with the 7-day STT and SQ. Methods A total of 789 patients underwent HPE treatment at Asan Medical Center between July 2013 and August 2017. Among them, 378 received a 7-day STT and 411 received a 10-day SQ. Baseline clinical data and treatment parameters were compared between the two treatment groups. Results SQ demonstrated an eradication rate of 84.7% (348/411), which was superior to that of the 7-day STT (74.1%; p

Aramid copolymers have garnered significant interest due to their potential applications in extreme environments such as the aerospace, defense, and automotive industries. Recent developments in aramid copolymers have moved beyond their traditional use in high-strength, high-temperature resistant fibers. There is now a demand for new polymers that can easily be processed into thin films for applications such as electrical insulation films and membranes, utilizing the inherent properties of aramid copolymers. In this work, we demonstrate two novel aramid copolymers that are capable of polymerizing in polar organic solvents with a high degree of polymerization, achieved by incorporating flexible bis(4-aminophenoxy) benzene moieties into the chain backbone. The synthesized MBAB-aramid and PBAB-aramid have enabled the fabrication of exceptionally thin, clear films, with an average molecular weight exceeding 150 kDa and a thickness ranging from 3 to 10 μm. The dynamic mechanical analysis (DMA) and thermogravimetric analysis (TGA) reveal that the thin films of MBAB-aramid and PBAB-aramid exhibited glass transition temperatures of 270.1 °C and 292.7 °C, respectively, and thermal decomposition temperatures of 449.6 °C and 465.5 °C, respectively. The mechanical tensile analysis of the 5 μm thick films confirmed that the tensile strengths, with elongation at break, are 107.1 MPa (50.7%) for MBAB-aramid and 113.5 MPa (58.4%) for PBAB-aramid, respectively. The thermal and mechanical properties consistently differ between the two polymers, which is attributed to variations in the linearity of the polymer structures and the resulting differences in the density of intermolecular hydrogen bonding and pi-pi interactions. The resulting high-strength, ultra-thin aramid materials offer numerous potential applications in thin films, membranes, and functional coatings across various industries.

Purpose: This study examines the pull and push aspects of Koreans' sustainable consumption behaviors and their impact on their well-being since Koreans have recently shifted their consumption values toward healthier food, such as plant-based meat products. Methodology: To analyze the interrelationships, the study uses two different models: the Theory of Planned Behaviour (TPB) and the Pull-Push Model (PPM). PLS-SEM was used to analyze the primary data collected from 159 vegans and vegetarians in Korea who responded to an online survey. Findings: The findings indicate that pull factors have considerable beneficial impacts on the consumption behavior of consumers about plant-based meat products, whereas push factors do not have significant negative effects, except meat attachment. A consumer's personal life and the product itself significantly influence the consumer's level of well-being. By analyzing both pull and push factors, this study significantly contributes to the expanding research on consumers' environmentally responsible consumption practices. The study's findings could assist government officials and politicians in developing regulations that encourage people to consume more food that is produced sustainably. Promoting a company's wares can be accomplished by utilizing crucial aspects of businesses. Implications: This study attempts to fill a gap in the literature by focusing on the push and pull factors of plant-based meat products on consumers' sustainable consumption behaviors, explored through the lens of Planned Behaviour (TPB) and the Pull-Push Model (PPM).

Colorectal cancer (CRC) is a type of cancer that develops in the colon or rectum and is the second leading cause of cancer-related death worldwide. Several epidemiology studies have identified a significant sexual dimorphism in CRC, with women exhibiting a lower incidence rate and delayed onset compared to men. This study aims to investigate the sexual dimorphism in the inflammatory response in colitis-associated CRC and its relationship with estrogen and estrogen receptors. An azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model was used to induce colitis-associated CRC. Five-week-old male and female mice were randomly assigned into either the control group or the AOM/DSS CRC group, with 10 mice in each group. Colitis-associated CRC was induced by injecting AOM (10 mg/kg) and administering two-cycles of DSS treatment in the drinking water. The results revealed a significant decrease in colon length exclusively in the female group, indicating more severe colonic inflammation (P

Background/Aims: Although gastric neuroendocrine tumors (NETs) are uncommon neoplasms, their prevalence is increasing. The clinical importance of the World Health Organization (WHO) classification of gastric NETs, compared with NETs in other organs, has been underestimated. This study aimed to systematically evaluate the clinical and pathologic characteristics of gastric NETs based on the 2019 WHO classification and to assess the survival outcomes of patients from a single-center with a long-term follow-up. Methods: The medical records of 427 patients with gastric NETs who underwent endoscopic or surgical resection between January 2000 and March 2020 were retrospectively reviewed. All specimens were reclassified according to the 2019 WHO classification. The clinicopathologic characteristics, treatment, and oncologic outcomes of 139 gastric NETs were analyzed. Results: The patients’ median age was 53.0 years (interquartile range [IQR], 46.0 to 63.0 years). The median follow-up period was 36.0 months (IQR, 15.0 to 63.0 months). Of the patients, 92, 44, and 3 had grades 1, 2, and 3 NETs, respectively. The mean tumor size significantly increased as the tumor grade increased (p=0.025). Patients with grades 2 and 3 gastric NETs more frequently had lymphovascular invasion (29.8% vs 10.9%, p=0.005) and deeper tissue invasion (8.5% vs 0%, p=0.012) than those with grade 1 tumors. The overall disease-specific survival rate was 100%. Two patients with grades 2-3 gastric NETs experienced extragastric recurrence. Conclusions: Although gastric NETs have an excellent prognosis, grade 2 or grade 3 gastric NETs are associated with a larger size, deeper invasion, and extragastric recurrence, which require active treatment.

The spread of COVID-19 has significantly increased research on antiviral drugs and measures such as case isolation and contact tracing. This study compared the effects of lopinavir/ritonavir and remdesivir on COVID-19 patients with a control group receiving no antiviral drugs. Patients confirmed to have a SARS-CoV-2 infection via real-time RT-PCR were divided into three groups: lopinavir/ritonavir, remdesivir, and control. We assessed the efficacy of these drugs in reducing viral load and viral shedding duration using real-time RT-PCR and Vero E6 cell cultures. Lopinavir/ritonavir led to no detectable infectious SARS-CoV-2, with a median viral clearance time of one day, whereas one remdesivir-treated case remained culture-positive until day 12. Lopinavir/ritonavir significantly reduced viral load compared to remdesivir and control groups (p = 0.0117 and p = 0.0478). No infectious virus was detected in the lopinavir/ritonavir group, and the non-infectious SARS-CoV-2 proportion remained constant at 90%, higher than in the remdesivir and control groups (p = 0.0097). There was a significant difference in culture positivity among the groups (p = 0.0234), particularly between the lopinavir/ritonavir and remdesivir groups (p = 0.0267). These findings suggest that lopinavir/ritonavir reduces viral load and shortens the viral shedding duration compared to remdesivir, despite not being an effective treatment option.

Abstract We present an in-depth single-cell atlas of in vitro multiculture systems on human primary airway epithelium derived from normal and diseased lungs of 27 individual donors. Our large-scale single-cell profiling identified new cell states and differentiation trajectories of rare airway epithelial cell types in human distal lungs. By integrating single-cell datasets of human lung tissues, we discovered immune-primed subsets enriched in lungs and organoids derived from patients with chronic respiratory disease. To demonstrate the full potential of our platform, we further illustrate transcriptomic responses to various respiratory virus infections in vitro airway models. Our work constitutes a single-cell roadmap for the cellular and molecular characteristics of human primary lung cells in vitro and their relevance to human tissues in vivo.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD can result in various complications. Owing to the lack of effective pharmacological therapies, lifestyle modifications are the cornerstone treatment for NAFLD. However, there has been no recommendation for a specific dietary therapy. Because no significant effects have been observed in previous studies. Intermittent calorie restriction (ICR) consists of alternating phases of extreme energy restriction and regular energy intake. Recent studies have demonstrated a significantly higher reduction in liver fat content in the ICR group than in the standard of care (SOC) or continuous calorie restriction groups in patients with NAFLD. However, critical weaknesses limit the broader application of ICR in clinical practice; those are a lack of appropriate assessment tools, different cutoffs of body mass index (BMI) used to define obesity, and different food portions. Thus, we report a protocol for a prospective, randomized controlled trial. The trial will evaluate the effect of 12-week ICR on improving liver fat content in NAFLD patients (Nonalcoholic Fatty Liver Disease-Intermittent Calorie Restriction [FLICR]). Methods We will include adult (19–75 years) NAFLD patients. NAFLD will be diagnosed by histologic assessment or magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 8%. A total of 72 patients will be classified according to BMI (obese group: BMI ≥ 25 kg/m2 [n = 36] and non-obese group: BMI

Spotted fever group rickettsiae are tick-borne obligate intracellular bacteria that infect microvascular endothelial cells. Humans and mammalian infection results in endothelial cell barrier dysfunction and increased vascular permeability. We previously demonstrated that treatment of Rickettsia parkeri-infected cells with the calcium channel blocker benidipine significantly delayed vascular barrier permeability. Thus, we hypothesized that benidipine, known to be safe and effective for other clinical processes, could reduce rickettsia-induced vascular permeability in vivo in an animal model of spotted fever rickettsiosis. Based on liver, lung and brain vascular FITC-dextran extravasation studies, benidipine did not reliably impact vascular permeability. However, it precipitated a deleterious effect on responses to control sublethal R. parkeri infection. Animals treated with benidipine alone had no clinical signs or changes in histopathology and splenic immune cell distributions. Benidipine-treated infected animals had marked increases in tissue and blood bacterial loads, more extensive inflammatory histopathologic injury, and changes in splenic architecture and immune cell distributions potentially reflecting diminished Ca2+ signaling, reduced innate immune cell activation, and loss of rickettsial propagation control. Impaired T cell activation by R. parkeri antigen in the presence of benidipine was confirmed in vitro with the use of NKT cell hybridomas. The unexpected findings stand in stark contrast to recent discussions of the benefits of calcium channel blockers for viral infections and chronic infectious or inflammatory diseases. A role for calcium channel blockers in exacerbation of human rickettsiosis and acute inflammatory infections should be evaluated by a retrospective review of patient's outcomes and medications.

Goji berry (Lycium barbarum L.), a deciduous solanaceous shrub, were subjected to extraction using five solvents (water, 50% and 70% ethanol, and 50% and 70% methanol) and dried using two methods: freeze drying (FD) and spray drying (SD). To investigate the chemical properties of these various goji berry powders, an examination was conducted on the content of volatile compounds, betaine, antioxidant effect, total phenolic content (TPC), and total flavonoid compounds (TFC) (p

Abstract This multicenter (four institutions), randomized, investigator-masked, parallel-group clinical trial evaluated and compared the efficacy and safety of preservative-free and preserved brimonidine tartrate 0.15% in open-angle glaucoma and ocular hypertension. Sixty eyes of 60 patients with intraocular pressure (IOP) ≥ 15 mmHg diagnosed with open-angle glaucoma or ocular hypertension were randomized to preserved (n = 31) and preservative-free (n = 29) brimonidine groups. The enrolled eyes received brimonidine monotherapy three times daily. Main outcome measures were corneal/conjunctival staining score, ocular surface disease index, patient satisfaction score, drug tolerance, and drug adherence rate 12 weeks post first administration. Secondary outcome measurements included visual acuity, IOP, drug tolerance, tear-film break-up time, hemodynamic changes including blood pressure and heart rates, and ocular adverse events. After 12 weeks, both preserved and preservative-free groups showed similar IOP reduction, corneal and conjunctival staining scores, drug tolerance, and adherence rates. The preservative-free group showed significantly better tear-film break-up time and higher patient satisfaction regarding drug use and management. Systolic and diastolic blood pressure reductions during the 12 weeks were significantly lower in the preserved group than in the preservative-free group. Preservative-free brimonidine tartrate showed comparable efficacy and safety, better corneal tear film stability, and patient satisfaction than preserved brimonidine.

The torsion of the uterus is a rare gynecological emergency. It occurs mainly in the gravid uterus and extremely rarely in the non-gravid uterus. In this article, we report a case of a torsion of non-gravid uterus accompanied by a huge intramural leiomyoma with focus on CT and MR imaging findings.

Excessive sugar consumption provides energy but has little nutritional value, contributing to the prevalence of obesity. Hence, “sugar-free” products using artificial or natural sweeteners, including sugar alcohols, have become popular. Accordingly, safety concerns and curiosity have arisen. Therefore, this study used a double-blind, crossover design to compare the effects of commercial sugar-free and sugar jellies (control) on the glycemic response in 16 adults without diabetes. Blood samples were collected to measure blood glucose, insulin, glucagon, ghrelin, C-peptide, glycated hemoglobin, and glycated albumin levels, and an oral glucose tolerance test was performed. Questionnaires on satiety and intestinal health were also administered. Sugar-free jellies resulted in significantly lower glucose and insulin levels and a reduced area under the curve while showing higher glucagon levels than the controls. Moreover, the sugar-free jelly initially resulted in the greater secretion of ghrelin; however, after 2 h, the control jelly resulted in higher ghrelin. No significant differences were observed in gut quotient, C-peptide, glycated hemoglobin, and glycated albumin levels. In conclusion, substituting sugar jelly with sugar-free jelly may induce lower blood glucose and insulin levels and higher glucagon levels, indicating a better ability to control glucose metabolism. Appetite was not stimulated by sugar-free jelly consumption.

The apprenticeship-based training method (ABTM) is highly effective for gastrointestinal (GI) endoscopic training. However, the conventional ABTM has significant issues. Although many supplementary training methods (TMs) have been developed and utilized, they cannot entirely replace the ABTM, which remains the major TM strategy. Currently, new TM construction is crucial and necessary due to financial constraints, difficulty of obtaining sufficient training time due to patient safety-related regulations, and catastrophic damage caused by disasters such as the coronavirus disease 2019 pandemic. The simulator-based TM (SBTM) is widely accepted as an alternative to the ABTM, owing to the SBTM’s advantages. Since the 1960s, many GI endoscopy training simulators have been developed and numerous studies have been published on their effectiveness. While previous studies have focused on the simulator’s validity, this review focused on the accessibility of simulators that were introduced by the end of 2021. Although the current SBTM is effective in GI endoscopic education, extensive improvements are needed to replace the ABTM. Incorporating simulator-incorporated TMs into an improved ABTM is an attempt to overcome the incompleteness of the current SBTM. Until a new simulator is developed to replace the ABTM, it is desirable to operate a simulator-integrated and well-coordinated TM that is suitable for each country and institution.

Peroral endoscopic myotomy (POEM) can be safely performed for achalasia. During POEM, gas is insufflated via the endoscope inside the submucosal tunnel. Gas-related complications often cannot be avoided because of the lack of serosa in the esophagus and the inability of the adventitia to function as a resistant barrier to gas. However, tension pneumothorax causing respiratory failure is a rare complication of POEM. Herein, we describe a 32-year-old female who developed tension pneumothorax after POEM. She showed respiratory compromise after POEM, and emergency chest radiography revealed pneumothorax with mediastinal shift. Tension pneumothorax was managed by chest tube drainage with the application of negative-suction pressure via the tube, after which her vital signs stabilized. On post-procedural day 4, the tube was removed. Our case suggests the importance of considering tension pneumothorax if respiratory compromise occurs despite oxygen administration after POEM even in the absence of immediate complications during the procedure, and performing chest radiography promptly.

Abstract Ingroup favoritism and fairness are two potentially competing motives guiding intergroup behaviors in human. Here, we investigate if and how limited resources can modulate the way these two motives affect individuals’ decisions in intergroup situation. In the present study, participants (N = 58) were asked to accept or reject three types of resource allocation proposals generated by a computer: the ingroup advantageous condition, outgroup advantageous condition, and neutral condition. In general, participants were more willing to accept the proposals in the ingroup advantageous condition than the outgroup advantageous or the neutral conditions, and also in the moderate inequality than the extreme inequality condition. This may indicate that people sought a careful balance between ingroup favoritism and fairness, although we also found marked individual differences in their preferences for ingroup favoritism or fairness. Importantly, as predicted, participants were more likely to show ingroup favoritism only when limited resources affect the well-being of ingroup members. The present study provides novel insights into the situational and personality factors affecting human intergroup behaviors, shedding light on motives underlying intergroup conflicts prevalent in human societies.

To supply stable and high-quality power according to the advancement of industrial growth, electric power companies have performed maintenance of power facilities using various methods. In the case of domestic power distribution facilities, there are limitations in performing diagnostic management on all facilities owing to the large number of facilities; therefore, old facilities are managed using the health index assessment method. The health index assessment comprises only facility operation data and external environmental data and is managed only for four types of distribution facilities including overhead/underground transformers and switchgears. In the case of high voltage overhead lines, there are a large number of wires such as transformers and switchgears connected to the lines, and the ripple effect of power outages is large. However, in Korea, there is no overhead line health index standard. In overseas cases, a health index for overhead lines was developed, but only the material characteristics and surrounding environment of the overhead lines were considered and economic feasibility was not considered. Therefore, in this paper, we developed a health index evaluation methodology for ultra-high voltage overhead lines that considers economic feasibility. In this paper, unlike the existing health index evaluation method that uses only operational data and external environmental data to determine facility performance evaluation and aging replacement standards, we developed an economic health index evaluation methodology that additionally considers failure probability and risk costs. Using the health index assessment methodology developed in this paper, it is possible to expect a reduction in facility operating costs and investment costs from the perspective of the electric power companies through the replacement of old extra-high voltage overhead cables. In addition, from the perspective of consumers, it is expected to increase power reliability and reduce the ripple effect of failure by preferentially replacing equipment with a high probability of failure.

Background/Aims Coronavirus disease 2019 (COVID-19) is associated with acute respiratory syndrome. The mechanisms underlying the different degrees of pneumonia severity in patients with COVID-19 remain elusive. This study provides evidence that COVID-19 is associated with eosinophil-mediated inflammation. Methods We performed a retrospective case series of three patients with laboratory and radiologically confirmed COVID-19 pneumonia admitted to Chosun University Hospital. Demographic and clinical data on inflammatory cell lung infiltration and cytokine levels in patients with COVID-19 were collected. Results Cytological analysis of sputum, tracheal aspirates, and bronchoalveolar lavage fluid (BALF) samples from all three patients revealed massive infiltration of polymorphonuclear cells (PMNs), such as eosinophils and neutrophils. All sputum and BALF specimens contained high levels of eosinophil cationic proteins. The infiltration of PMNs into the lungs, together with elevated levels of natural killer T (NKT) cells in BALF and peripheral blood samples from patients with severe pneumonia in the acute phase was confirmed by flow cytometry. Conclusions These results suggest that the lungs of COVID-19 patients can exhibit eosinophil-mediated inflammation, together with an elevated NKT cell response, which is associated with COVID-19 pneumonia.

ABSTRACT Scrub typhus is a mite-borne disease caused by the obligately intracellular bacterium Orientia tsutsugamushi. We previously demonstrated that ScaA, an autotransporter membrane protein of O. tsutsugamushi, is commonly shared in various genotypes and involved in adherence to host cells. Here, we identified a mixed-lineage leukemia 5 (MLL5) mammalian trithorax group protein as a host receptor that interacts with ScaA. MLL5, identified by yeast two-hybrid screening, is an alternative splicing variant of MLL5 (vMLL5) which contains 13 exons with additional intron sequences encoding a tentative transmembrane domain. Indeed, vMLL5 is expressed on the plasma membrane as well as in intracellular compartments in eukaryotic cells and colocalized with adherent O. tsutsugamushi. In addition, ScaA-expressing Escherichia coli showed significantly increased adherence to vMLL5-overexpressing cells compared with vector control cells. We mapped the C-terminal region of the passenger domain of ScaA as a ligand for vMLL5 and determined that the Su(var)3-9, Enhancer of zeste, Trithorax (SET) domain of MLL5 is an essential and sufficient motif for ScaA binding. We observed significant and specific inhibition of bacterial adhesion to host cells in competitive inhibition assays using the C-terminal fragment of ScaA or the SET domain of vMLL5. Moreover, immunization with the C-terminal fragment of ScaA provided neutralizing activity and protective immunity against lethal challenge with O. tsutsugamushi as efficiently as vaccination with the whole passenger domain of ScaA. These results indicate that vMLL5 is a novel cellular receptor for ScaA-mediated adhesion of O. tsutsugamushi and facilitates bacterial adhesion to host cells, thereby enhancing bacterial infection. IMPORTANCE O. tsutsugamushi is a mite-borne pathogen that causes scrub typhus. As an obligately intracellular pathogen, its adhesion to and invasion of host cells are critical steps for bacterial growth. However, the molecular basis of the bacterial ligand and host receptor interaction is poorly defined. Here, we identified a splicing variant of MLL5 (vMLL5) as a cellular adhesion receptor of ScaA, an outer membrane autotransporter protein of O. tsutsugamushi. We mapped the interacting domains in the bacterial ligand and host receptor and confirmed their functional interaction. In addition, immunization with the C-terminal region of ScaA, which involves an interaction with the SET domain of vMLL5, not only induces enhanced neutralizing antibodies but also provides protective immunity against lethal challenge with O. tsutsugamushi.

Background and objectivesTo compare the long-term clinical outcomes of dual antiplatelet therapy (DAPT) with clopidogrel and DAPT with ticagrelor or prasugrel in patients with acute myocardial infarction (AMI) who underwent coronary intervention.MethodsBetween November 2011 and December 2015, a total of 13,104 patients with AMI were enrolled in the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) registry. Among them, 4,696 patients who received DAPT for more than 24 months were categorized into two groups: the clopidogrel group (n = 4,053) and ticagrelor or prasugrel group (n = 643). Propensity score matching (PSM) was used to reduce the bias due to confounding variables. Following PSM, the impacts of P2Y12 inhibitors on the clinical outcomes in both groups were compared during a 36-month clinical follow-up period.ResultsThere were no significant differences in clinical outcomes in terms of cardiac death (7.1% vs. 9.7%, p = 0.101), stroke (1.4% vs. 1.0%, p = 0.436), major bleeding (0.5% vs. 0.8%, p = 0.478), major adverse cardiac events (MACE) (21.6% vs. 20.5%, p = 0.626), and net adverse cardiac event (NACE) (22.1% vs. 21.3%, p = 0.731) between the groups. The ticagrelor or prasugrel group had a lower incidence of recurrent percutaneous coronary intervention (PCI) (12.2% vs. 7.6%, p = 0.006) than the clopidogrel group. However, no differences were observed in the cumulative incidences of 3-year NACE between the ticagrelor or prasugrel and clopidogrel groups.ConclusionsCumulative incidences of long-term NACE did not differ between the two groups. Therefore, the type and duration of DAPT should be customized for each patient with AMI.

IntroductionDespite of massive endeavors to characterize inflammation in COVID-19 patients, the core network of inflammatory mediators responsible for severe pneumonia stillremain remains elusive. MethodsHere, we performed quantitative and kinetic analysis of 191 inflammatory factors in 955 plasma samples from 80 normal controls (sample n = 80) and 347 confirmed COVID-19 pneumonia patients (sample n = 875), including 8 deceased patients. ResultsDifferential expression analysis showed that 76% of plasmaproteins (145 factors) were upregulated in severe COVID-19 patients comparedwith moderate patients, confirming overt inflammatory responses in severe COVID-19 pneumonia patients. Global correlation analysis of the plasma factorsrevealed two core inflammatory modules, core I and II, comprising mainly myeloid cell and lymphoid cell compartments, respectively, with enhanced impact in a severity-dependent manner. We observed elevated IFNA1 and suppressed IL12p40, presenting a robust inverse correlation in severe patients, which was strongly associated with persistent hyperinflammation in 8.3% of moderate pneumonia patients and 59.4% of severe patients. DiscussionAberrant persistence of pulmonary and systemic inflammation might be associated with long COVID-19 sequelae. Our comprehensive analysis of inflammatory mediators in plasmarevealed the complexity of pneumonic inflammation in COVID-19 patients anddefined critical modules responsible for severe pneumonic progression.

A left gastric artery (LGA) pseudoaneurysm is known to occur as a complication of abdominal surgery, trauma, or pancreatitis. However, an LGA pseudoaneurysm presenting with gastrointestinal bleeding is rare. A 77-year-old man complained of dizziness and three episodes of melena in the last 24 hours. He did not have a history of surgery, trauma, or pancreatitis. He underwent primary coronary intervention for unstable angina and started dual antiplatelet therapy 1 month prior. Esophagogastroduodenoscopy (EGD) revealed a 3-cm ulcer in the lesser curvature of the gastric high body with a pulsating subepithelial tumor-like lesion in the ulcer. Hemostasis was achieved endoscopically. Three days after the endoscopic hemostasis, hematemesis and hypovolemic shock occurred. Emergent angiography of the superior mesenteric artery revealed an LGA pseudoaneurysm with extravasation. Coil embolization was successfully performed. Three days after the angiographic embolization, EGD revealed improvement of the gastric ulcer, which was covered with exudate, and disappearance of the subepithelial tumor-like lesion. At the 2-month follow-up, EGD showed that the ulcer was in the healing stage.

An esophageal perforation is one of the most fatal clinical events, with a mortality rate of up to 21%. This may arise postoperatively or post-endoscopically. In the past, surgical treatment, such as an esophagectomy, was performed these cases. However, the procedure was challenging and had a high risk of postoperative complications. Recently, advancements in endoscopic techniques have been made, and endoscopic procedures became a common treatment modality for patients with esophageal perforation, even in those with underlying diseases. Among the endoscopic procedures, endoscopic vacuum-assisted closure (E-VAC) has been known to be safe and effective. We present the case of a 64-year-old female with advanced liver cirrhosis and an overtube-induced esophageal perforation during esophageal variceal ligation. She was successfully treated with E-VAC.

Many people have difficulty empathizing with others who have dissimilar characteristics, such as physical disabilities. We hypothesized that people with no disabilities imitating the movements of individuals with disabilities could improve the empathic capacity toward their difficulties. To evaluate this hypothesis, we used functional magnetic resonance imaging to measure the neural activity patterns of 26 healthy participants while they felt the difficulties of individuals with hemiplegia by adopting their perspective. The participants initially either imitated or observed hemiplegic hand movements shown in video clips. Subsequently, the videos were rewatched and their difficulties were rated. Analysis of the subjective rating scores indicated that after imitating the hemiplegic movements, the participants felt into the difficulties of hemiplegia better than if they simply observed them. The cross-validation approach of multivoxel pattern analyses demonstrated that the information regarding the effect of imitation on empathizing with the difficulties was represented in specific activation patterns of brain regions involved in the mirror neuron system and cognitive empathy by comparing to other conditions that did not contain the information. The cross-classification approach detected distinct activation patterns in the brain regions involved in affective and cognitive empathy, commonly while imitating the hemiplegic movements and subsequently feeling them. This indicated that the common representation related to these two types of empathy existed between imitating and feeling the hemiplegic movements. Furthermore, representational similarity analysis revealed that activity patterns in the anterior cingulate cortex linked to affective empathy tuned to the subjective assessment of hemiplegic movements. Our findings indicate that imitating the movements of individuals with hemiplegia triggered the affective empathic response and improved the cognitive empathic response toward them. The affective empathic response also linked the subjective assessment to the difficulties of hemiplegia, which was especially modulated by the experience of imitation. Imitating the movements of individuals with disabilities likely encourages empathic capacity from both affective and cognitive aspects, resulting in people with no disabilities precisely feeling what they are feeling.

Perovskite halide nanocrystals have been actively investigated for use in white-luminescence photonic devices. Herein, a remote phosphor-layered composite consisting of all-halide red and green nanocrystals embedded in an ultraviolet (UV)-cured matrix is proposed as a facile way to create competitive white luminescence. Alternating stacks of cast halide layers with controlled concentration and thickness yielded true white luminescence characteristics when the halide layers were combined with a bottom blue chip. Specifically, the adjusted prismatic pattern for the red halide layer was found to effectively strengthen the emission of white luminescence. In particular, a phosphor-stacked structure of green and red layers with a 9-μm-pitch prismatic pattern resulted in an enhanced luminous efficacy of ∼54.4 lm W−1, which is higher than those of a non-prismatic layer or a larger pitch pattern. Encapsulating both sides of the halide layers with polydimethylsiloxane (PDMS) maintained very effectively the luminescence of the halide layers over the exposure of 300 h.

In this study, the alloying of Ti, Al and Dy powders by high energy ball milling, and the spark plasma sintering (SPS) characteristics of as milled powders have been investigated based on the observation of microstructure. Pure Ti, 6wt% Al and 4wt% Dy powders were mixed and milled with zirconia balls at 600 ~ 1000 rpm for 3h in an Ar gas. The initial sizes of Ti, Al and Dy powders were approximately 20, 40, and 200 μm, respectively. With increasing the milling speed from 600 to 1000 rpm, the size of mixing powders reduced from 120 to 15 μm. On the other hand, from XRD results of powders milled at higher speeds than 700rpm, the peaks of Ti3Al and AlDy phases were identified, indicating the successful alloying. Therefore, the powders milled at 800 rpm have been employed for the SPS under the applied pressure of 50 MPa at 1373K for 15 min. In the SPSed sample, the Al3Dy and two ternary Ti-Al-Dy phases were newly detected, while the peak of AlDy phase disappeared. The SPSed Ti-6Al-4Dy alloy revealed high relative density and micro-hardness of approximately 99% and 950Hv, respectively.

Abstract Tertiary lymphoid structures (TLSs) provide specialized niches for immune cells, resulting in improved prognoses for patients undergoing cancer immunotherapy. Shaping TLS‐like niches may improve anti‐cancer immunity and overcome the current limitations of immune cell‐based immunotherapy. Here, it is shown that stromal vascular fraction (SVF) from adipose tissues can enhance dendritic cell (DC)‐mediated T cell immunity by inducing ectopic T lymphocyte clusters. SVF cells expanded ex vivo have phenotypes and functions similar to those of fibroblastic reticular cells in a secondary lymphoid organ, and their properties can be modulated using three‐dimensional spheroid culture and coculture with DCs spiked with antigen‐loaded iron oxide–zinc oxide core‐shell nanoparticles. Thereby, the combination of SVF spheroids and mature DCs significantly augments T cell recruitment and retention at the injection site. This strategy elicits enhanced antigen‐specific immune response and anti‐tumoral immunity in mice, illustrating the potential for a novel immunotherapeutic design using SVF as a structural scaffold for TLS.

The current COVID-19 pandemic has highlighted the power, speed, and simplicity of point-of-care (POC) diagnostics. POC diagnostics are available for a wide range of targets, including both drugs of abuse as well as performance-enhancing drugs. For pharmacological monitoring, minimally invasive fluids such as urine and saliva are commonly sampled. However, false positives or negatives caused by interfering agents excreted in these matrices may confound results. For example, false positives have, in most cases, prevented the use of POC diagnostics for pharmacological agent detection; the consequence is that centralized labs are instead tasked to perform these screenings, resulting in significant delays between sampling and testing. Thus, a rapid, simple, and inexpensive methodology for sample purification is required for the POC to reach a field-deployable tool for the pharmacological human health and performance assessments. Buffer exchange is a simple, rapid approach to remove interfering agents, but has traditionally been difficult to perform on small pharmacological molecules. Therefore, in this communication, we use salbutamol, a performance-enhancing drug, as a case example to demonstrate the efficacy of ion-exchange chromatography as a technique to perform buffer exchange for charged pharmacological agents. This manuscript demonstrates the efficacy of this technique leveraging a commercial spin column to remove interfering agents found in simulant urines, such as proteins, creatinine, and urea, while retaining salbutamol. The utility and efficacy of the method was then confirmed in actual saliva samples. The eluent was then collected and run on the lateral flow assays (LFAs), improving the reported limit of detection by over 5× (new lower limit of detection of 10 ppb compared to reported 60 ppb by the manufacturer) while simultaneously removing noise due to background interfering agents.

Non-charge-storage-based nonvolatile memory characteristics associated with oxygen ion exchange are demonstrated in a thin-film transistor (TFT) composed of an indium-zinc oxide (IZO) channel and an oxygen-deficient HfO2–x gate oxide. A nonvolatile increase in drain current and a reduced threshold voltage are obtained upon application of positive gate voltage, with the opposite characteristics upon application of negative voltage. The device shows nonvolatile retention properties and suitable endurance properties after repeated operations. Modulation of channel conductance occurs as a results of oxygen ion exchange between the HfO2–x gate oxide and the IZO channel, which consequently alters the oxygen vacancy concentration in the IZO channel; these vacancies act as n-type dopants. For comparison, a device with a thin SiO2 layer inserted between the HfO2–x gate oxide and the IZO channel to prevent oxygen ion exchange shows only the increased threshold voltage upon application of a positive gate voltage as a result of electron charging. These results verify the conductance modulation mechanism associated with oxygen ion exchange at the interface of the HfO2–x gate oxide and the IZO channel. In addition, the nonvolatile memory characteristics of the device are indicative of its potential for non-charge-storage-based nonvolatile memory application.

BackgroundDespite the use of vaccines and therapeutics against the coronavirus disease 2019 (COVID-19) pandemic, this severe disease has been a critical burden on public health, whereas the pathogenic mechanism remains elusive. Recently, accumulating evidence underscores the potential role of the aberrant B-cell response and humoral immunity in disease progression, especially in high-risk groups.MethodsUsing single-cell RNA (scRNA) sequencing analysis, we investigated transcriptional features of B-cell population in peripheral blood from COVID-19 patients and compared them, according to clinical severity and disease course, against a public B-cell dataset.ResultsWe confirmed that acute B cells differentiate into plasma cells, particularly in severe patients, potentially through enhanced extrafollicular (EF) differentiation. In severe groups, the elevated plasma B-cell response displayed increased B-cell receptor (BCR) diversity, as well as higher levels of anti–severe acute respiratory syndrome coronavirus 2 (anti–SARS-CoV-2) spike antibodies in plasma, than those in moderate cases, suggesting more robust and heterogeneous plasma cell response in severe COVID-19 patients. Trajectory analysis identified a differentiation pathway for the EF B-cell response from active naïve to atypical memory B cells (AM2), in addition to the emergence of an aberrant plasma cell subset (PC2), which was associated with COVID-19 progression and severity. The AM2 and PC2 subsets surged in the acute phase of the severe disease and presented multiple inflammatory features, including higher cytokine expression and humoral effector function, respectively. These features differ from other B-cell subsets, suggesting a pathogenic potential for disease progression.ConclusionThe acute surge of AM2 and PC2 subsets with lower somatic hypermutation and higher inflammatory features may be driven by the EF B-cell response during the acute phase of severe COVID-19 and may represent one of the critical drivers in disease severity.

Diffusion-weighted imaging (DWI) with an apparent diffusion coefficient (ADC) value is a relatively new magnetic resonance imaging (MRI) sequence that provides functional information on the lesion by measuring the microscopic movement of water molecules. While numerous studies have evaluated the promising role of DWI in musculoskeletal radiology, most have focused on tumorous diseases related to cellularity. This review article aims to summarize DWI-acquisition techniques, considering pitfalls such as T2 shine-through and T2 black-out, and their usefulness in interpreting musculoskeletal diseases with imaging. DWI is based on the Brownian motion of water molecules within the tissue, achieved by applying diffusion-sensitizing gradients. Regardless of the cellularity of the lesion, several pitfalls must be considered when interpreting DWI with ADC values in musculoskeletal radiology. This review discusses the application of DWI in musculoskeletal diseases, including tumor and tumor mimickers, as well as non-tumorous diseases, with a focus on lesions demonstrating T2 shine-through and T2 black-out effects. Understanding these pitfalls of DWI can provide clinically useful information, increase diagnostic accuracy, and improve patient management when added to conventional MRI in musculoskeletal diseases.

Middle-aged women belong to a risk group for metabolic dysregulation and menopausal symptoms, mainly due to a dramatic hormonal shift. Supplementation with functional compounds or a single nutrient has been dominantly explored as a nutritional approach for improving aging-related health parameters. However, a meal-based approach might be another strategy for promoting the overall health of the target population. This pilot study aimed to develop a meal-based intervention for middle-aged women and to evaluate its potential health benefits. Considering the nutrient intake status of Korean middle-aged women, diets enriched with four major nutrients (isoflavone, omega-3, fiber, and calcium) were designed and provided to forty-nine women aged 50 to 65 with mild levels of menopausal symptoms for 8 weeks. In the post-intervention phase, they showed reduced body weight and body fat, and improved biochemical metabolic parameters with decreased levels of cholesterol, low-density lipoprotein-cholesterol, ApoB, and fasting insulin. Moreover, bone resorption markers and menopause symptoms were lower in the post-intervention phase. In conclusion, the meal-based intervention might be a prominent strategy for overall health promotion in relatively healthy middle-aged women and further investigation is needed to test its efficacy with a randomized controlled study.

Patients with galactosemia accumulate galactose in their bodies, requiring a lifelong galactose-restricted diet. Therefore, accurate information on the galactose content in commercial agro-food resources is essential. The HPLC method generally used for sugar analysis has low separation and detection sensitivity. Here, we sought to establish an accurate analytical method for determining the galactose content in commercial agro-food resources. To that aim, we employed gas chromatography with flame-ionization detection to detect trimethylsilyl-oxime (TMSO) sugar derivatives (concentration: ≤0.1 mg/100 g). The galactose content in 107 Korean agro-food resources reflecting intake patterns was then analyzed. The galactose content in steamed barley rice was 5.6 mg/100 g, which was higher than that in steamed non-glutinous and glutinous rice. Moist-type and dry-type sweet potatoes, blanched zucchini, and steamed Kabocha squash had high galactose content (36.0, 12.8, 23.1, and 61.6 mg/100 g, respectively). Therefore, these foods are detrimental to patients with galactosemia. Among fruits, avocado, blueberry, kiwi, golden kiwifruit, and sweet persimmon had galactose contents of ≥10 mg/100 g. Dried persimmon had 132.1 mg/100 g and should therefore be avoided. Mushrooms, meat, and aquatic products showed low galactose content (≤10 mg/100 g), making them safe. These findings will help patients to manage their dietary galactose intake.

Anaplasma phagocytophilum, a tick-borne obligately intracellular bacterium of neutrophils, causes human granulocytic anaplasmosis. Ankyrin A (AnkA), an effector protein with multiple ankyrin repeats (AR) is injected via type IV-secretion into the host neutrophil to gain access to the nucleus where it modifies the epigenome to promote microbial fitness and propagation. AR proteins transported into the host cell nucleus must use at least one of two known eukaryotic pathways, the classical importin β-dependent pathway, and/or the RanGDP- and AR (ankyrin-repeat)-dependent importin β-independent (RaDAR) pathway. Truncation of the first four AnkA N-terminal ARs (AR1-4), but not other regions, prevents AnkA nuclear accumulation. To investigate the mechanism of nuclear import, we created point mutations of AnkA N-terminal ARs, predicted to interfere with RaDAR protein import, and used importazole, a specific inhibitor of the importin α/β, RanGTP-dependent pathway. Nuclear colocalization analysis shows that nuclear localization of AnkA is unaffected by single AR1-4 mutations but is significantly reduced by single mutations in consecutive ARs suggesting RaDAR protein nuclear import. However, AnkA nuclear localization was also decreased with importazole, and with GTPγS. Furthermore, A. phagocytophilum growth in HL-60 cells was completely suppressed with importazole, indicating that A. phagocytophilum propagation requires a β-importin-dependent pathway. A typical classical NLS overlapping AR4 was subsequently identified suggesting the primacy of the importin-α/β system in AnkA nuclear localization. Whether the mutational studies of putative key residues support RaDAR NLS function or simply reflect structural changes that diminish engagement of an AR-NLS-importin pathway needs to be resolved through careful structure-function studies.

Serologic and molecular surveillance of serum collected from 152 suspected scrub typhus patients in Myanmar revealed Orientia tsutsugamushi of genotypic heterogeneity. In addition, potential co-infection with severe fever with thrombocytopenia syndrome virus was observed in 5 (3.3%) patients. Both scrub typhus and severe fever with thrombocytopenia syndrome are endemic in Myanmar.

Food insecurity refers to the uncertain availability of or limited access to nutritious food. Poor diets prevalent among food insecure populations may incite an inflammatory state and subsequently negatively affect skeletal muscle metabolism. To examine the inflammatory mechanistic potential of the association between food insecurity and the risk of low muscle strength, we analyzed cross-sectional data from 8624 adults aged ≥20 years from the Korean National Health and Nutrition Examination Survey 2014–2015. Household food security status was assessed using an 18-item food security survey module. The inflammatory potential of diets was estimated by the dietary inflammation index (DII). Low muscle strength was ascertained using hand grip strength. In the multivariable-adjusted model, greater food insecurity was significantly associated with a higher DII score and risk of low muscle strength. The multivariable-adjusted mean difference (95% confidence interval) on the DII, comparing the “moderate-to-severe” food insecurity group with the “food secure” group, was 0.43 (0.06–0.80) (P-trend:

The construct validity of group factor models of personality, which are typically derived from factor analysis of questionnaire items, relies on the ability of each factor to predict meaningful and differentiated real-world outcomes. In a sample of 481 participants, we used the Big Five Aspect Scales (BFAS) personality questionnaire, two laboratory-measured reaction time (RT) tasks, and a short-form test of cognitive ability (ICAR-16) to test the hypothesis that the Intellect and Openness aspects of Big Five Openness to Experience differentially correlate with reaction time moments. We found that higher scores on the Intellect aspect significantly correlate with faster and less variable response times, while no such association is observed for the Openness aspect. Further, we found that this advantage lies solely in the decisional, but not perceptual, stage of information processing; no other Big Five aspect showed a similar pattern of results. In sum, these findings represent the largest and most comprehensive study to date on personality factors and reaction time, and the first to demonstrate a mechanistic validation of BFAS Intellect through a differential pattern of associations with RT and Big Five personality aspects.

Bacterial central nervous system (CNS) infections are serious and carry significant morbidity and mortality. They encompass many syndromes, the most common being meningitis, which may occur spontaneously or as a consequence of neurosurgical procedures. Many classes of antimicrobials are in clinical use for therapy of CNS infections, some with established roles and indications, others with experimental reporting based on case studies or small series. This review delves into the specifics of the commonly utilized antibacterial agents, updating their therapeutic use in CNS infections from the pharmacokinetic and pharmacodynamic perspectives, with a focus on the optimization of dosing and route of administration that have been described to achieve good clinical outcomes. We also provide a concise synopsis regarding the most focused, clinically relevant information as pertains to each class and subclass of antimicrobial therapeutics. CNS infection morbidity and mortality remain high, and aggressive management is critical in ensuring favorable patient outcomes while averting toxicity and upholding patient safety.

The use of vaccines is the most effective and reliable method for the prevention of viral infections. However, research on evaluation of effective therapeutic agents for use in treatment after infection is necessary. Zanamivir was administered through inhalation for treatment of pandemic influenza A/H1N1 in 2009. However, the emergence of drug-resistant strains can occur rapidly. Alloferon, an immunomodulatory drug developed as an NK cell activator, exerts antiviral effects against various viruses, particularly influenza viruses. Therefore, alloferon and zanamivir were administered in combination in an effort to improve the antiviral effect of zanamivir by reducing H1N1 resistance. First, we confirmed that administration of combined treatment would result in effective inhibition of viral proliferation in MDCK and A549 cells infected with H1N1. Production of IL-6 and MIP-1α in these cells and the activity of p38 MAPK and c-Jun that are increased by H1N1 were inhibited by combined treatment. Mice were then infected intranasally with H1N1, and examination of the antiviral efficacy of the alloferon/zanamivir combination was performed. The results showed that combined treatment after infection with H1N1 prevented weight loss, increased the survival rate, and improved lung fibrosis. Combined treatment also resulted in reduced infiltration of neutrophils and macrophages into the lungs. Combined treatment effectively inhibited the activity of p38 MAPK and c-Jun in lung tissue, which was increased by infection with H1N1. Therefore, the combination of alloferon/zanamivir effectively prevents the development of H1N1-mediated inflammation in the lungs by inhibiting the production of inflammatory mediators and migration of inflammatory cells into lung tissue.

Our previous big data analyses reported a strong association between CHI3L1 expression and lung tumor development. In this present study, we investigated whether a CHI3L1-inhibiting natural compound, ebractenoid F, inhibits lung cancer cell growth and migration and induces apoptosis. Ebractenoid F concentration-dependently (0, 17, 35, 70 µM) and significantly inhibited the proliferation and migration of A549 and H460 lung cancer cells and induced apoptosis. In the mechanism study, we found that ebractenoid F bound to CHI3L1 and suppressed CHI3L1-associated AKT signaling. Combined treatment with an AKT inhibitor, LY294002, and ebractenoid F synergistically decreased the expression of CHI3L1. Moreover, the combination treatment further inhibited the growth and migration of lung cancer cells and further induced apoptosis, as well as the expression levels of apoptosis-related proteins. Thus, our data demonstrate that ebractenoid F may serve as a potential anti-lung cancer compound targeting CHI3L1-associated AKT signaling.

Summary: Despite the worldwide effect of the coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased T helper (Th)2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation are associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of Fcγ receptor (FcγR) signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients.