Calcitonin Gene-Related Peptide Negatively Regulates Alarmin-Driven Type 2 Innate Lymphoid Cell Responses.

Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide calcitonin gene-related peptide (CGRP) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production as well as exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.

Development of the multiplex imaging chamber at PAL-XFEL.

Various X-ray techniques are employed to investigate specimens in diverse fields. Generally, scattering and absorption/emission processes occur due to the interaction of X-rays with matter. The output signals from these processes contain structural information and the electronic structure of specimens, respectively. The combination of complementary X-ray techniques improves the understanding of complex systems holistically. In this context, we introduce a multiplex imaging instrument that can collect small-/wide-angle X-ray diffraction and X-ray emission spectra simultaneously to investigate morphological information with nanoscale resolution, crystal arrangement at the atomic scale and the electronic structure of specimens.

Melatonin alleviates myocardial dysfunction through inhibition of endothelial-to-mesenchymal transition via the NF-κB pathway.

Endothelial-to-mesenchymal transition (EndMT) is a complex biological process of cellular transdifferentiation by which endothelial cells (ECs) lose their characteristics and acquire mesenchymal properties, leading to cardiovascular remodeling and complications in the adult cardiovascular diseases environment. Melatonin is involved in numerous physiological and pathological processes, including aging, and has anti-inflammatory and antioxidant activities. This molecule is an effective therapeutic candidate for preventing oxidative stress, regulating endothelial function, and maintaining the EndMT balance to provide cardiovascular protection. Although recent studies have documented improved cardiac function by melatonin, the mechanism of action of melatonin on EndMT remains unclear. The present study investigated the effects of melatonin on induced EndMT by transforming growth factor-ß2/interleukin-1ß in both in vivo and in vitro models. The results revealed that melatonin reduced the migratory ability and reactive oxygen species levels of the cells and ameliorated mitochondrial dysfunction in vitro. Our findings indicate that melatonin prevents endothelial dysfunction and inhibits EndMT by activating related pathways, including nuclear factor kappa B and Smad. We also demonstrated that this molecule plays a crucial role in restoring cardiac function by regulating the EndMT process in the ischemic myocardial condition, both in vessel organoids and myocardial infarction (MI) animal models. In conclusion, melatonin is a promising agent that attenuates EC dysfunction and ameliorates cardiac damage compromising the EndMT process after MI.

Consumption of sugar-sweetened beverages before 2 years of age and attention-deficit/hyperactivity disorder.

INTRODUCTION: This study examined the association between sugar-sweetened beverage consumption before the first 24 months of life and attention-deficit/hyperactivity disorder (ADHD). METHODS: A population administrative cohort study was conducted in Korea (2008-2019) using linked national insurance data and a health screening survey. The cohort included 25,305 children in the exposed group with high sugar-sweetened beverage drinks (≥200 ml) and 339,931 in the reference groups (<200 ml) at 24 months of age. The primary outcome was the development of ADHD based on the International Classification of Disease (ICD) codes. Cox proportional model was used to identify the association between sugar-sweetened beverage consumption during early childhood and the later development of ADHD while controlling for multiple risk factors. RESULTS: Over a mean follow-up period of 9.2 years, the incidence rates of ADHD were 29.6 and 23.8 per 10,000 person-years (PY) in the exposed and reference groups, respectively. Compared with the reference group, children consuming high-sugar drinks were at an increased risk of ADHD (adjusted hazard ratio [aHR] 1.17, 95% confidence interval [CI] 1.08-1.27). These associations remained significant even after applying alternative ADHD definitions or adjusting for confounding variables. CONCLUSION: Children who consume sweetened beverages during early childhood are at increased risk of developing ADHD later in life.

Developing and Validating the Senior Meaning in Life Evaluation (SMiLE) Scale.

The Senior Meaning in Life Evaluation scale encompasses not only older adults' personal motivation and growth but also the meaning for them in society and in their relationships: With this scale, we aimed to present their voices. A three-phase process was followed: The scale's items were developed empirically from interviews of older adults; exploratory factor analysis (EFA) was conducted to test convergent and concurrent validity; and finally, confirmatory factor analysis (CFA) was performed. EFA resulted in 18 items grouped into 4 factors (i.e., proactive on life, overcoming emptiness, acceptance in life, and social contribution), which was supported by the CFA.

A novel paper-based lysis strip for SARS-CoV-2 RNA detection at low resource settings.

Infectious respiratory diseases such as COVID-19 are serious and global concerns from the past to the present. To isolate the spread of infectious diseases even in the absence of a health system, a simple, inexpensive, reliable, sensitive, and selective molecular diagnosis platform for Point of Care Test (POCT) is required. Especially, the nucleic acid extraction step is difficult to perform out of laboratory. Here, we propose a paper-based lysis (PBL) strip for nucleic acid extraction, especially in low-resource settings (LRS). PBL strips are suitable for isolating RNA from viruses with biological interference and inhibitors. We optimized the buffer compositions and membranes of the strip. A simple preparation method using a PBL strip could obtain an eluent for downstream inspection within 20 min. Overall, 104 copies/swaps were detected for 20 min for amplification in combination with Reverse Transcription Loop-Mediated Amplification (RT-LAMP).

Extracurricular activities in medical education: an integrative literature review.

BACKGROUND: The importance of extracurricular activities (EAs) has been emphasized in medical education. These activities could enhance medical students' emotional and physical health and afford them developmental opportunities. Despite the growing amount of research related to this theme, few studies review and synthesize the existing literature. This study aims to provide an understanding of the educational implications of EAs in medical colleges and constructs an integrated conceptual framework concerning their types and learning outcomes by literature review. METHODS: An integrative literature review was conducted following Torraco's method, with the aim to generate a new framework for the given topic. The authors utilized Scopus and PubMed as databases, using search terms "extracurricular," "medical," and "students." Initially, titles and abstracts were screened to include relevant studies, and the researchers verified the eligibility of the articles by following the inclusion and exclusion criteria. Of the 263 articles identified, 64 empirical studies were selected for further review. RESULTS: EAs in undergraduate medical education can be classified into direct extracurricular activities and indirect extracurricular activities, the latter of which is sorted into nine sub-categories. We identified seven main categories regarding the learning outcomes of EAs. In addition to general activities (e.g., pro-social activities, team sports), some distinctive activities such as research have been largely addressed in previous studies. The results of EAs were discussed in relation to academic growth, career development, and psychological experiences. CONCLUSIONS: This review identified the types and learning outcomes of EAs in the context of medical education, thereby suggesting ways to improve the quality of EAs and maximize their educational effects.

Rapid and simple detection of influenza virus via isothermal amplification lateral flow assay.

Respiratory illness caused by influenza virus is a serious public health problem worldwide. As the symptoms of influenza virus infection are similar to those of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, it is essential to distinguish these two viruses. Therefore, to properly respond to a pathogen, a detection method that is capable of rapid and accurate diagnosis in a hospital or at home is required. To satisfy this need, we applied loop-mediated isothermal amplification (LAMP) and an isothermal nucleic acid amplification technique, along with a system to analyze the results without specialized equipment, a lateral flow assay (LFA). Using the platform developed in this study, all processes, from sample preparation to detection, can be performed without special equipment. Unlike existing PCR methods, the nucleic acid amplification can be performed in the field because hot packs do not require electricity. Thus, the designed platform can provide rapid results without the need to transport the samples to a laboratory or hospital. These advantages are not limited to operations in developing countries with poor access to medical systems. In conclusion, the developed technology is a promising tool for infectious disease management that allows for rapid identification of infectious diseases and appropriate treatment of patients.

Regulation of Inflammation-Mediated Endothelial to Mesenchymal Transition with Echinochrome a for Improving Myocardial Dysfunction.

Endothelial-mesenchymal transition (EndMT) is a process by which endothelial cells (ECs) transition into mesenchymal cells (e.g., myofibroblasts and smooth muscle cells) and induce fibrosis of cells/tissues, due to ischemic conditions in the heart. Previously, we reported that echinochrome A (EchA) derived from sea urchin shells can modulate cardiovascular disease by promoting anti-inflammatory and antioxidant activity; however, the mechanism underlying these effects was unclear. We investigated the role of EchA in the EndMT process by treating human umbilical vein ECs (HUVECs) with TGF-ß2 and IL-1ß, and confirmed the regulation of cell migration, inflammatory, oxidative responses and mitochondrial dysfunction. Moreover, we developed an EndMT-induced myocardial infarction (MI) model to investigate the effect of EchA in vivo. After EchA was administered once a day for a total of 3 days, the histological and functional improvement of the myocardium was investigated to confirm the control of the EndMT. We concluded that EchA negatively regulates early or inflammation-related EndMT and reduces the myofibroblast proportion and fibrosis area, meaning that it may be a potential therapy for cardiac regeneration or cardioprotection from scar formation and cardiac fibrosis due to tissue granulation. Our findings encourage the study of marine bioactive compounds for the discovery of new therapeutics for recovering ischemic cardiac injuries.

MR1- and HLA-E-Dependent Antigen Presentation of Mycobacterium tuberculosis.

MR1 and HLA-E are highly conserved nonclassical antigen-presenting molecules. They can present antigens derived from Mycobacterium tuberculosis to a distinct subset of MR1-restricted or HLA-restricted CD8+ T cells. MR1 presents small microbial metabolites, and HLA-E presents peptides and glycopeptides. In this review, we will discuss the current understanding of MR1 and HLA-E antigen presentation in the context of Mycobacterium tuberculosis infection.

Changes in the Equity of the Long-Term Care System in Korea Based on Coulter Index Differences for the Years 2000, 2008, and 2015.

In this study, we examined the adequacy of supply and demand under private expansion of the long-term care (LTC) infrastructure after the introduction of long-term care insurance (LTCI) for the older people in Korea. We used Coulter's coefficient of inequality (Coulter index) to analyze the equity of LTC services by region. In addition, we analyzed the trend of equity changes through equity analysis for three time points: 2000, 2008, and 2015. We found that the level of inequity in LTC service infrastructure in Korea is lower in 2015 compared with 2000, but the differences among regions are high. The adjustment factors in 2015 showed prominent shortages of facilities in urban areas and oversupply in suburban areas. Based on these results, we propose an LTC service infrastructure that meets the demand and improves service access according to regional characteristics.

Slc25a17 acts as a peroxisomal coenzyme A transporter and regulates multiorgan development in zebrafish.

Slc25a17 is known as a peroxisomal solute carrier, but the in vivo role of the protein has not been demonstrated. We found that the zebrafish genome contains two slc25a17 genes that function redundantly, but additively. Notably, peroxisome function in slc25a17 knockdown embryos is severely compromised, resulting in an altered lipid composition. Along the defects found in peroxisome-associated phenotypic presentations, we highlighted that development of the swim bladder is also highly dependent on Slc25a17 function. As Slc25a17 showed substrate specificity towards coenzyme A (CoA), injecting CoA, but not NAD+ , rescued the defective swim bladder induced by slc25a17 knockdown. These results indicated that Slc25a17 acts as a CoA transporter, involved in the maintenance of functional peroxisomes that are essential for the development of multiple organs during zebrafish embryogenesis. Given high homology in protein sequences, the role of zebrafish Slc25a17 may also be applicable to the mammalian system.

Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc-fused interleukin-1 receptor antagonist, in healthy subjects: A first-in-human study.

AIMS: We performed a first-in-human study with HL2351, a novel hybrid Fc-fused interleukin (IL)-1 receptor antagonist, to evaluate its tolerability, pharmacokinetics and pharmacodynamics (PD) after a single subcutaneous (SC) administration in healthy subjects. METHODS: A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted. Eligible subjects randomly received a single SC administration of HL2351 (1, 2, 4, 8 and 12 mg/kg) or placebo in a ratio of 8:2. Subjects in the active-controlled group received a single SC administration of anakinra at 100 mg. Serial blood samples were collected for pharmacokinetics and PD analyses. An ex-vivo activation test was performed to evaluate the PD using peripheral blood mononuclear cells treated with IL-1ß. Anti-HL2351 antibodies were determined at baseline and 29 days postdose. Tolerability was assessed throughout the study. RESULTS: HL2351 was eliminated more slowly than anakinra (terminal half-life: 27.21-45.28 vs 3.97 h). Serum concentrations of HL2351 were increased dose-proportionally. The mean apparent clearance of HL2351 were 0.6, 0.66, 0.75, 0.51, 0.65 L/h at 1, 2, 4, 8 and 12 mg/kg, respectively. The percent inhibition of IL-6 expression varied widely (range: 0-92.1%), showing no clear trend or discernible difference between HL2351, anakinra and placebo. HL2351 was well tolerated after a single SC administration. CONCLUSION: HL2351 was well tolerated and showed linear pharmacokinetic characteristics after a single SC administration at doses up to 12 mg/kg in healthy subjects. HL2351 remained in the body 7-11 times longer than anakinra. HL2351 can be developed as a potential therapeutic alternative to anakinra.

An innovative blood plasma separation method for a paper-based analytical device using chitosan functionalization.

This study describes a microfluidic paper-based analytical device (µPAD) for separating plasma from whole blood and measuring glucose concentration. A two-dimensional µPAD was fabricated by wax printing, using chromatographic paper and was functionalized by the incorporation of chitosan into the plasma separation zone. Red blood cells were isolated from whole blood in the plasma separation zone consisting of a chitosan polymer structure and a wax barrier. The separated plasma, with buffer, was injected into the test zone to cause a color change. The colorimetric results were digitized with a scanner, and the concentration was calculated using a calibration curve. This µPAD, which separated the plasma from whole blood without a separation membrane, will be useful for constructing point-of-care testing devices that detect analytes in small sample volumes.

Teneligliptin versus sitagliptin in Korean patients with type 2 diabetes inadequately controlled with metformin and glimepiride: A randomized, double-blind, non-inferiority trial.

AIM: To assess the efficacy and safety of add-on therapy with the dipeptidyl peptidase-4 inhibitor teneligliptin compared with sitagliptin in patients with type 2 diabetes (T2DM) inadequately controlled with metformin and glimepiride. MATERIALS AND METHODS: This was a phase 3, randomized, double-blind, non-inferiority study of adult Korean subjects with T2DM (n = 201), with HbA1c ranging from 7.0% to 11.0%, on stable doses of metformin plus glimepiride. Subjects were randomized in a 1:1 fashion to receive either oral teneligliptin 20 mg or sitagliptin 100 mg for 24 weeks. The primary endpoint was change from baseline in HbA1c. RESULTS: At baseline, mean age was 60.56 ± 9.41 years, body mass index was 25.23 ± 2.85 kg/m2 and HbA1c was 8.11% ± 0.79%. At 24 weeks, both groups achieved significant reductions from baseline in HbA1c (teneligliptin, -1.03% ± 0.10% [P < 0.0001]; sitagliptin, -1.02% ± 0.10% [P < 0.0001]). The inter-group difference was -0.01% (95% confidence interval [CI]: -0.28, 0.26; P = 0.9497); the upper limit of the 95% CI was within the preset limit for non-inferiority (0.4%). There were no significant differences between groups in the proportion of patients achieving HbA1c targets, or changes from baseline in fasting plasma glucose, body weight or lipid levels at 24 weeks. Rates of adverse events (teneligliptin, n = 63 [61.76%]; sitagliptin, n = 61 [62.24%]; P = 0.9442) and hypoglycaemia (teneligliptin, n = 32 [31.37%]; sitagliptin, n = 28 [28.57%]; P = 0.6656) were similar. CONCLUSION: Teneligliptin was non-inferior to sitagliptin in the context of triple therapy for T2DM and is an important option in this setting.

Pulmonary Colonization Resistance to Pathogens via Noncanonical Wnt and Interleukin-17A by Intranasal pep27 Mutant Immunization.

Background: Previous studies have focused on colonization resistance of the gut microbiota against antibiotic resistant strains. However, less research has been performed on respiratory colonization resistance. Methods: Because respiratory colonization is the first step of respiratory infections, intervention to prevent colonization would represent a new approach for preventive and therapeutic measures. The Th17 response plays an important role in clearance of respiratory pathogens. Thus, harnessing the Th17 immune response in the mucosal site would be an effective method to design a respiratory mucosal vaccine. Results: In this study, we show that intranasal Δpep27 immunization induces noncanonical Wnt and subsequent interleukin (IL)-17 secretion, and it inhibits Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae colonization. Moreover, IL-17A neutralization or nuclear factor of activated T-cell inhibition augmented bacterial colonization, indicating that noncanonical Wnt signaling is involved in pulmonary colonization resistance. Conclusions: Therefore, Δpep27 immunization can provide nonspecific respiratory colonization resistance via noncanonical Wnt signaling and IL-17A-related pathways.

Catalase inhibition induces pexophagy through ROS accumulation.

Peroxisomes are dynamic and multifunctional organelles involved in various cellular metabolic processes, and their numbers are tightly regulated by pexophagy, a selective degradation of peroxisomes through autophagy to maintain peroxisome homeostasis in cells. Catalase, a major peroxisome protein, plays a critical role in removing peroxisome-generated reactive oxygen species (ROS) produced by peroxisome enzymes, but the contribution of catalase to pexophagy has not been reported. Here, we investigated the role of catalase in peroxisome degradation during nutrient deprivation. Both short interfering RNA-mediated silencing of catalase and pharmacological inhibition by 3-aminotriazole (3AT) decreased the number of peroxisomes and resulted in the downregulation of peroxisomal proteins, such as PMP70 and PEX14 under serum starvation. In addition, treatment with 3AT induced NBR1-dependent autophagy and PEX5 ubiquitination in the absence of serum, which was accompanied by accumulation of ROS. Co-treatment with antioxidant agent N-acetyl-l-cysteine (NAC) prevented ROS accumulation and pexophagy by modulating peroxisome protein levels and the association of NBR1, a pexophagy receptor with peroxisomes. Taken together, these findings demonstrate that catalase plays an important role in pexophagy during nutrient deprivation.

Protective roles of fenofibrate against cisplatin-induced ototoxicity by the rescue of peroxisomal and mitochondrial dysfunction.

Cisplatin is an alkylating agent that interferes with DNA replication and kills proliferating carcinogenic cells. Several studies have been conducted to attenuate the side effects of cisplatin; one such side effect in cancer patients undergoing cisplatin chemotherapy is ototoxicity. However, owing to a lack of understanding of the precise mechanism underlying cisplatin-induced side effects, management of cisplatin-induced ototoxicity remains unsolved. We investigated the protective effects of fenofibrate, a PPAR-α activator, on cisplatin-induced ototoxicity. Fenofibrate prevented cisplatin-induced loss of hair cells and improved cell viability; moreover, fenofibrate significantly attenuated the threshold of auditory brainstem responses (ABR) in cisplatin-injected mice. Fenofibrate significantly increased PPAR-α, PPAR-γ, and PGC-1α expression, which consequently resulted in increased number and functional enzyme levels of peroxisomes and mitochondria, and markedly decreased phospho-p53 (S15), activated caspase-3, cleaved-PARP, and NF-κB p65 nuclear translocation, which reduced NADPH oxidase isoform (NOX3 and NOX4) expression, thereby decreasing reactive oxygen species (ROS) production in cisplatin-treated tissues ex vivo. Taken together, these results indicate that fenofibrate rescues cisplatin-induced ototoxicity by maintaining peroxisome and mitochondria number and function, reducing inflammation, and decreasing ROS levels. Our findings suggest that fenofibrate administration might serve as an effective therapeutic agent against cisplatin-induced ototoxicity.

Sex consideration in diet-biomarker-related indices: a systematic review.

OBJECTIVE: An index of biomarkers derived from dietary factors (diet-biomarker-related index) identifies foods and nutrients that encompass physiological potentials and provides scientific evidence for dietary patterns that increase the risk of disease associated with specific biomarkers. Although men and women have different dietary patterns and physiological characteristics, sex is not often considered when investigators develop a diet-biomarker-related index. We aimed to review whether epidemiological studies developed diet-biomarker-related indices in a sex-specific way. DESIGN: We systematically searched for epidemiological studies that developed diet-biomarker-related indices, including (i) biomarker prediction indices that include dietary factors as explanatory variables and (ii) dietary patterns to explain biomarker variations, in the PubMed and EMBASE databases. We qualitatively reviewed the sex consideration in index development. RESULTS: We identified seventy-nine studies that developed a diet-biomarker-related index. We found that fifty-four studies included both men and women. Of these fifty-four studies, twenty-nine (53·7 %) did not consider sex, eleven (20·3 %) included sex in the development model, seven (13·0 %) considered sex but did not include sex in the development model, and seven (13·0 %) derived a diet-biomarker-related index for men and women separately. A list of selected dietary factors that explained levels of biomarkers generally differed by sex in the studies that developed a diet-biomarker-related index in a sex-specific way. CONCLUSIONS: Most studies that included both men and women did not develop the diet-biomarker-related index in a sex-specific way. Further research is needed to identify whether a sex-specific diet-biomarker-related index is more predictive of the disease of interest than an index without sex consideration.

Kidney Transplantation in Patients with Atypical Hemolytic Uremic Syndrome due to Complement Factor H Deficiency: Impact of Liver Transplantation.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease that is often associated with genetic defects. Mutations of complement factor H (CFH) are the most common genetic defects that cause aHUS and often result in end-stage renal disease. Since CFH is mainly produced in the liver, liver transplantation (LT) has been performed in patients with defective CFH. METHODS: The clinical courses of four kidney allograft recipients who lost their native kidney functions due to aHUS associated with a CFH mutation were reviewed. RESULTS: Subject A underwent kidney transplantation (KT) twice, aHUS recurred and the allograft kidney failed within a few years. Subject B received a KT and soon experienced a recurrence of aHUS coinciding with infection. Her allograft kidney function has worsened, and she remains on plasma infusion therapy. Subject C underwent LT followed by KT. She is doing well without plasma infusion therapy after combined LT-KT for 3 years. Subject D received KT following LT and is now recurrence-free from aHUS. CONCLUSION: In patients with aHUS associated with a CFH mutation, KT without LT was complicated with a recurrence of aHUS, which might lead to allograft loss. Conversely, LT was successful in preventing the recurrence of aHUS and thus might be another option for a recurrence-free life for aHUS patients associated with CFH mutation.