Remendable Cross-Linked Alginate/Gelatin Hydrogels Incorporating Nanofibers for Wound Repair and Regeneration.

Wound dressings made from natural-derived polymers are highly valued for their biocompatibility, biodegradability, and biofunctionality. However, natural polymer-based hydrogels can come with their own set of limitations, such as low mechanical strength, limited cell affinity, and the potential cytotoxicity of cross-linkers, which delineate the boundaries of their usage and hamper their practical application. To overcome the limitation of natural-derived polymers, this study utilized a mixture of oxidized alginate and gelatin with 5 mg/mL polycaprolactone (PCL):gelatin nanofiber fragments at a ratio of 7:3 (OGN-7) to develop a hydrogel composite wound dressing that can be injected and has the ability to be remended. The in situ formation of the remendable hydrogel is facilitated by dual cross-linking of oxidized alginate chains with gelatin and PCL/gelatin nanofibers through Schiff-base mechanisms, supported by the physical integration of nanofibers, thereby obviating the need for additional cross-linking agents. Furthermore, OGN-7 exhibits increased stiffness (γ = 79.4-316.3%), reduced gelation time (543 ± 5 to 475 ± 5 s), improved remendability of the hydrogel, and excellent biocompatibility. Notably, OGN-7 achieves full fusion within 1 h of incubation and maintains structural integrity under external stress, effectively overcoming the inherent mechanical weaknesses of natural polymer-based dressings and enhancing biofunctionality. The therapeutic efficacy of OGN-7 was validated through a full-thickness in vivo wound healing analysis, which demonstrated that OGN-7 significantly accelerates wound closure compared to alginate-based dressings and control groups. Histological analysis further revealed that re-epithelialization and collagen deposition were markedly enhanced in the regenerating skin of the OGN-7 group, confirming the superior therapeutic performance of OGN-7. In summary, OGN-7 optimized the synergistic effects of natural polymers, which enhances their collective functionality as a wound dressing and expands their utility across diverse biomedical applications.

Association of Cough Severity with Asthma Control and Quality of Life in Patients with Severe Asthma.

PURPOSE: Symptoms are important components in determining asthma control and in the adjustment of treatment levels. However, clinical relevance of cough in severe asthma is not well-understood. This study aimed to evaluate the severity and association of cough with patient-reported outcomes (PROs) in patients with severe asthma. METHODS: This study analyzed cross-sectional data from the Korean Severe Asthma Registry. The severity of coughing and wheezing symptoms was assessed using a Visual Analog Scale (VAS) ranging from 0 to 100 for each symptom. Additionally, PROs included the Asthma Control Test (ACT), the Severe Asthma Questionnaire (SAQ), and the EuroQoL 5-Dimension (EQ-5D) index. Multivariate linear regression analysis was employed to explore the relationship between cough severity and other PRO scores. RESULTS: A total of 498 patients with severe asthma (age: 57.9 ± 13.1 years, females: 60.2%) were analyzed. The cough VAS score was higher than the wheeze score (median 30, [interquartile range 10-50] vs. 20 [0-50]; P < 0.001). Additionally, 22.5% of patients ranked in a higher tertile for cough severity compared to wheezing, while 18.5% ranked higher for wheezing severity than cough. Significant correlations were observed between cough and wheeze VAS scores (r = 0.61, P < 0.05) and between each symptom's VAS score and the SAQ (cough: r = -0.41, P < 0.001; wheeze: r = -0.52, P < 0.001), ACT scores (cough: r = -0.50, P < 0.001; wheeze: r = -0.63, P < 0.001) and EQ-5D index (cough: r = -0.40, P < 0.001; wheeze: r = -0.45, P < 0.001). In univariate regression analysis, the cough VAS score had weaker descriptive power (R2) values than the wheeze VAS score in relation to the PRO measures. Nevertheless, cough severity remained significantly associated with ACT, SAQ scores and EQ-5D index in multivariate analyses adjusted for wheeze severity and other confounders. CONCLUSION: Cough frequently presents as a severe symptom in patients with severe asthma and could have distinct impact on asthma control and quality of life.

Characterization of Codeine Treatment Responders Among Patients with Refractory or Unexplained Chronic Cough: A Prospective Real-World Cohort Study.

PURPOSE: Codeine is a narcotic antitussive often considered for managing patients with refractory or unexplained chronic cough. This study aimed to evaluate the proportion and characteristics of patients who responded to codeine treatment in real-world practice. METHODS: Data from the Korean Chronic Cough Registry, a multicenter prospective cohort study, were analyzed. Physicians assessed the response to codeine based on the timing and degree of improvement after treatment initiation. Follow-up assessments included the Leicester Cough Questionnaire and cough severity visual analog scale at six months. In a subset of subjects, objective cough frequency was evaluated following the initiation of codeine treatment. RESULTS: Of 305 patients, 124 (40.7%) responded to treatments based on anatomic diagnostic protocols, while 181 (59.3%) remained unexplained or refractory to etiological treatments. Fifty-one subjects (16.7%) were classified as codeine treatment responders (those showing a rapid and clear response), 57 (18.7%) as partial responders, and 62 (20.3%) as non-responders. Codeine responders showed rapid improvement in objective cough frequency and severity scores within a week of the treatment. At 6 months, responders showed significantly improved scores in cough scores, compared to non-responders. Several baseline parameters were associated with a more favorable treatment response, including older age, non-productive cough, and the absence of heartburn. CONCLUSIONS: Approximately 60% of chronic cough patients in specialist clinics may require antitussive drugs. While codeine benefits some, only a limited proportion (about 20%) of patients may experience rapid and significant improvement. This underscores the urgent need for new antitussive drugs to address these unmet clinical needs.

Cytosolic microRNA-inducible nuclear translocation of Cas9 protein for disease-specific genome modification.

MicroRNA-dependent mRNA decay plays an important role in gene silencing by facilitating posttranscriptional and translational repression. Inspired by this intrinsic nature of microRNA-mediated mRNA cleavage, here, we describe a microRNA-targeting mRNA as a switch platform called mRNA bridge mimetics to regulate the translocation of proteins. We applied the mRNA bridge mimetics platform to Cas9 protein to confer it the ability to translocate into the nucleus via cleavage of the nuclear export signal. This system performed programmed gene editing in vitro and in vivo. Combinatorial treatment with cisplatin and miR-21-EZH2 axis-targeting CRISPR Self Check-In improved sensitivity to chemotherapeutic drugs in vivo. Using the endogenous microRNA-mediated mRNA decay mechanism, our platform is able to remodel a cell's natural biology to allow the entry of precise drugs into the nucleus, devoid of non-specific translocation. The mRNA bridge mimetics strategy is promising for applications in which the reaction must be controlled via intracellular stimuli and modulates Cas9 proteins to ensure safe genome modification in diseased conditions.

Increased Risk of Incident Chronic Obstructive Pulmonary Disease and Related Hospitalizations in Tuberculosis Survivors: A Population-Based Matched Cohort Study.

BACKGROUND: Tuberculosis (TB) survivors have an increased risk of developing chronic obstructive pulmonary disease (COPD). This study assessed the risk of COPD development and COPD-related hospitalization in TB survivors compared to controls. METHODS: We conducted a population-based cohort study of TB survivors and 1:1 age- and sex-matched controls using data from the Korean National Health Insurance Service database collected from 2010 to 2017. We compared the risk of COPD development and COPD-related hospitalization between TB survivors and controls. RESULTS: Of the subjects, 9.6% developed COPD, and 2.8% experienced COPD-related hospitalization. TB survivors had significantly higher COPD incidence rates (36.7/1,000 vs. 18.8/1,000 person-years, P < 0.001) and COPD-related hospitalization (10.7/1,000 vs. 4.3/1,000 person-years, P < 0.001) than controls. Multivariable Cox regression analyses revealed higher risks of COPD development (adjusted hazard ratio [aHR], 1.63; 95% confidence interval [CI], 1.54-1.73) and COPD-related hospitalization (aHR, 2.03; 95% CI, 1.81-2.27) in TB survivors. Among those who developed COPD, the hospitalization rate was higher in individuals with post-TB COPD compared to those with non-TB COPD (10.7/1,000 vs. 4.9/1,000 person-years, P < 0.001), showing an increased risk of COPD-related hospitalization (aHR, 1.84; 95% CI, 1.17-2.92). CONCLUSION: TB survivors had higher risks of incident COPD and COPD-related hospitalization compared to controls. These results suggest that previous TB is an important COPD etiology associated with COPD-related hospitalization.

Baseline Cohort Profile of the Korean Chronic Cough Registry: A Multicenter, Prospective, Observational Study.

PURPOSE: The Korean Chronic Cough Registry study was initiated to characterize patients with chronic cough (CC) and investigate their outcomes in real-world clinical practice. This report aims to describe the baseline cohort profile and study protocols. METHODS: This multicenter, prospective observational cohort study included newly referred CC patients and those already being treated for refractory or unexplained chronic cough (RUCC). Cough status was assessed using a visual analog scale, the Leicester Cough Questionnaire (LCQ), and the Cough Hypersensitivity Questionnaire (CHQ). RESULTS: A total of 610 patients (66.9% women; median age 59.0 years) were recruited from 18 centers, with 176 being RUCC patients (28.9%). The median age at CC onset was 50.1 years, and 94.4% had adult-onset CC (≥ 19 years). The median cough duration was 4 years. Compared to newly referred CC patients, RUCC patients had a longer cough duration (6.0 years vs. 3.0 years) but had fewer symptoms and signs suggesting asthma, rhinosinusitis, or gastroesophageal acid reflux disease. Subjects with RUCC had lower LCQ scores (10.3 ± 3.3 vs. 11.6 ± 3.6; P < 0.001) and higher CHQ scores (9.1 ± 3.9 vs. 8.4 ± 4.1; P = 0.024). There were no marked differences in the characteristics of cough between refractory chronic cough and unexplained chronic cough. CONCLUSIONS: Chronic cough typically develops in adulthood, lasting for years. Cough severity and quality of life impairment indicate the presence of unmet clinical needs and insufficient cough control in real-world clinical practice. Longitudinal follow-up is warranted to investigate the natural history and treatment outcomes.

Association between non-cystic fibrosis bronchiectasis and the risk of incident dementia: A nationwide cohort study.

BACKGROUND: Chronic lung diseases, such as chronic obstructive pulmonary disease or asthma, are associated with an increased risk of dementia. However, few data are available regarding the risk of dementia in individuals with bronchiectasis. OBJECTIVES: To explore the association between bronchiectasis and the risk of incident dementia using a longitudinal population-based cohort. METHODS: A total of 4,068,560 adults older than 50 years without previous dementia were enrolled from the Korean National Health Insurance Service database in 2009. They were followed up until the date of the diagnosis of dementia or December 31, 2020. The study exposure was the diagnosis of bronchiectasis, and the primary outcome was incident dementia comprising Alzheimer's disease and vascular dementia. RESULTS: During the median follow-up duration of 9.3 years, the incidence of all-cause dementia was 1.6-fold higher in individuals with bronchiectasis than in those without bronchiectasis (15.0 vs. 9.3/1000 person-years, p < .001). In the multivariable Cox regression analysis, the risk of all dementia was significantly higher in individuals with bronchiectasis than in those without bronchiectasis (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 1.04-1.14). In a subgroup analysis by dementia type, individuals with bronchiectasis had an increased risk of Alzheimer's disease compared to those without bronchiectasis (aHR 1.07, 95% CI 1.01-1.12); the risk of vascular dementia did not significantly differ between the two groups (aHR 1.05, 95% CI 0.90-1.21). CONCLUSION: Bronchiectasis was associated with an increased risk of dementia, especially Alzheimer's disease.

Association between exercise and risk of cardiovascular diseases in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: Although cardiovascular comorbidities negatively impact survival in patients with bronchiectasis, there is limited evidence to recommend exercise in this population. We aimed to evaluate whether exercise habit changes are related to reduced cardiovascular disease risk and explore an optimal exercise amount. METHODS: This study identified 165,842 patients with newly diagnosed bronchiectasis during 2010-2016 who underwent two health examinations and were followed up until December 2020. The exposure was the change in weekly habits of moderate- or vigorous-intensity physical activity between the two examinations, classified into non-exercisers and exercisers (further classified into new exercisers, exercise dropouts, and exercise maintainers). The amount of exercise was measured using metabolic equivalents of task (MET). The outcome was the incidence of myocardial infarction (MI) or stroke. RESULTS: During a mean of 6.2 ± 2.1 follow-up years, 4,233 (2.6%) and 3,745 (2.3%) of patients with bronchiectasis had MI or stroke, respectively. Compared to non-exercisers, exercisers had a significantly lower risk of MI or stroke by 9-28% (p < 0.001 for both). Among exercisers, exercise maintainers showed the lowest risk of MI (adjusted hazard ratio [aHR], 0.72; 95% confidence interval [CI], 0.64-0.81) and stroke (aHR, 0.72; 95% CI, 0.64-0.82) compared to non-exercisers. Regarding exercise amount, a significant risk reduction was observed only in patients with bronchiectasis who exercised for ≥ 500 MET-min/wk. CONCLUSION: Exercise was associated with a reduced risk of cardiovascular diseases in patients with bronchiectasis. In particular, the risk was lowest in exercise maintainers, and cardiovascular risk reduction was significant when exercising more than 500 MET-min/wk.

Exosomal miRNA-19a and miRNA-614 Induced by Air Pollutants Promote Proinflammatory M1 Macrophage Polarization via Regulation of RORα Expression in Human Respiratory Mucosal Microenvironment.

Air pollution exposure leads to various inflammatory diseases in the human respiratory system. Chronic rhinosinusitis is an inflammatory disease caused by viruses, bacteria, or air pollutants. However, the underlying molecular mechanisms through which air particulate matter (PM) causes inflammation and disease remain unclear. In this article, we report that the induction of exosomal microRNAs (miRNAs) from human nasal epithelial cells upon airborne PM exposure promotes proinflammatory M1 macrophage polarization via downregulated RORα expression. Exposure of human nasal epithelial cells to PM results in inflammation-related miRNA expression, and more miRNA is secreted through exosomes delivered to macrophages. Among these, miRNA-19a and miRNA-614 directly bind to the 3'-untranslated region of RORα mRNA and downregulate RORα expression, which leads to inflammation due to inflammatory cytokine upregulation and induces macrophages to a proinflammatory M1-like state. Finally, we showed enhanced expression of miRNA-19a and miRNA-614 but reduced RORα expression in a chronic rhinosinusitis patient tissue compared with the normal. Altogether, our results suggest that PM-induced exosomal miRNAs might play a crucial role in the proinflammatory mucosal microenvironment and macrophage polarization through the regulation of RORα expression.

Chronic Obstructive Pulmonary Disease is Associated with a More Symptomatic Burden and Severe Presentation of COVID-19: A Korean National COVID-19 Cohort Study.

Insufficient data are available on comprehensive evaluation of demographics, symptoms or signs, laboratory findings, and disease course in patients with coronavirus disease 2019 (COVID-19) and chronic obstructive pulmonary disease (COPD). We aimed to evaluate whether COPD patients are more prone to severe COVID-19 compared with those without COPD. We also investigate the clinical characteristics and disease course of COVID-19 in patients with COPD versus those without COPD. Patients were selected from a Korean nationwide cohort of 5,628 patients with confirmed COVID-19 and who had completed treatment or quarantine by April 30, 2020; 3,673 patients aged 40 years or older were included in this study. COPD was diagnosed using patient reports of physician-diagnosed COPD. During the study period, all patients with COVID-19 in Korea were hospitalized following the national health policy. Of the study participants, 38 (1.0%) had COPD. Regarding initial symptoms, COPD patients with COVID-19 showed greater sputum production (50.0% vs. 29.8%, p < 0.01) and dyspnea (36.8% vs. 14.9%, p < 0.01) than those without COPD. In addition, patients with COPD were more likely to receive oxygen therapy or non-invasive ventilation (29.0% vs. 13.7%, p = 0.01) and had a higher mortality (21.1% vs. 6.4%, p < 0.01) than those without COPD. After adjusting for age, sex, body mass index, and comorbidities, COPD patients showed increased risk of severe COVID-19 compared with those without COPD. Our nationwide study showed that COVID-19 patients with COPD have higher symptomatic burden and more severe disease course than those without COPD.

Phenotype of Asthma-COPD Overlap in COPD and Severe Asthma Cohorts.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are airway diseases with similar clinical manifestations, despite differences in pathophysiology. Asthma-COPD overlap (ACO) is a condition characterized by overlapping clinical features of both diseases. There have been few reports regarding the prevalence of ACO in COPD and severe asthma cohorts. ACO is heterogeneous; patients can be classified on the basis of phenotype differences. This study was performed to analyze the prevalence of ACO in COPD and severe asthma cohorts. In addition, this study compared baseline characteristics among ACO patients according to phenotype. METHODS: Patients with COPD were prospectively enrolled into the Korean COPD subgroup study (KOCOSS) cohort. Patients with severe asthma were prospectively enrolled into the Korean Severe Asthma Registry (KoSAR). ACO was defined in accordance with the updated Spanish criteria. In the COPD cohort, ACO was defined as bronchodilator response (BDR) ≥ 15% and ≥ 400 mL from baseline or blood eosinophil count (BEC) ≥ 300 cells/µL. In the severe asthma cohort, ACO was defined as age ≥ 35 years, smoking ≥ 10 pack-years, and post-bronchodilator forced expiratory volume in 1 s/forced vital capacity < 0.7. Patients with ACO were divided into four groups according to smoking history (threshold: 20 pack-years) and BEC (threshold: 300 cells/µL). RESULTS: The prevalence of ACO significantly differed between the COPD and severe asthma cohorts (19.8% [365/1,839] vs. 12.5% [104/832], respectively; P < 0.001). The percentage of patients in each group was as follows: group A (light smoker with high BEC) - 9.1%; group B (light smoker with low BEC) - 3.7%; group C (moderate to heavy smoker with high BEC) - 73.8%; and group D (moderate to heavy smoker with low BEC) - 13.4%. Moderate to heavy smoker with high BEC group was oldest, and showed weak BDR response. Age, sex, BDR, comorbidities, and medications significantly differed among the four groups. CONCLUSION: The prevalence of ACO differed between COPD and severe asthma cohorts. ACO patients can be classified into four phenotype groups, such that each phenotype exhibits distinct characteristics.

Urine-Derived Stem Cell-Secreted Klotho Plays a Crucial Role in the HK-2 Fibrosis Model by Inhibiting the TGF-ß Signaling Pathway.

Renal fibrosis is an irreversible and progressive process that causes severe dysfunction in chronic kidney disease (CKD). The progression of CKD stages is highly associated with a gradual reduction in serum Klotho levels. We focused on Klotho protein as a key therapeutic factor against CKD. Urine-derived stem cells (UDSCs) have been identified as a novel stem cell source for kidney regeneration and CKD treatment because of their kidney tissue-specific origin. However, the relationship between UDSCs and Klotho in the kidneys is not yet known. In this study, we discovered that UDSCs were stem cells that expressed Klotho protein more strongly than other mesenchymal stem cells (MSCs). UDSCs also suppressed fibrosis by inhibiting transforming growth factor (TGF)-ß in HK-2 human renal proximal tubule cells in an in vitro model. Klotho siRNA silencing reduced the TGF-inhibiting ability of UDSCs. Here, we suggest an alternative cell source that can overcome the limitations of MSCs through the synergetic effect of the origin specificity of UDSCs and the anti-fibrotic effect of Klotho.

A pilot study to investigate the utility of NAT2 genotype-guided isoniazid monotherapy regimens in NAT2 slow acetylators.

Isoniazid is a therapeutic agent for the treatment of latent tuberculosis infection. Genetic variants in the N-acetyltransferase 2 (NAT2) are associated with the safety and pharmacokinetics of isoniazid. The study aimed to evaluate the safety and pharmacokinetics of a NAT2 genotype-guided regimen of isoniazid monotherapy. A randomized, open-label, parallel-group and multiple-dosing study was performed in healthy subjects. The subjects received isoniazid for 29 days. The NAT2 slow acetylators (NAT2*5/*5, -*5/*6, -*5/*7, -*6/*6, -*6/*7, -*7/*7) randomly received standard dose (300 mg, standard-treatment group) or reduced dose (200 mg, PGx-treatment group) of isoniazid. Also, all the NAT2 rapid acetylators (NAT2*4/*4) received isoniazid 300 mg (reference group). The safety and pharmacokinetics were evaluated during the study. The PGx-treatment group showed a more stable serum liver enzyme profile and a lower incidence of adverse drug reactions (ADRs) than the standard-treatment group. The emergence rates of ADRs were 12.5, 60 and 33.3% in the reference, standard-treatment and PGx-treatment groups, respectively. The PGx-treatment group showed higher plasma isoniazid concentrations than the reference group, although the PGx-treatment group received a reduced dose of isoniazid. Our results showed that a NAT2 genotype-guided regimen may reduce ADRs during isoniazid monotherapy without concern over insufficient drug exposure.

Interstitial lung disease increases susceptibility to and severity of COVID-19.

BACKGROUND: There are limited data regarding the relationship between interstitial lung disease (ILD) and the natural course of COVID-19. In this study, we investigate whether patients with ILD are more susceptible to COVID-19 than those without ILD and evaluate the impact of ILD on disease severity in patients with COVID-19. METHODS: A nationwide cohort of patients with COVID-19 (n=8070) and a 1:15 age-, sex- and residential area-matched cohort (n=121 050) were constructed between 1 January 2020 and 30 May 2020 in Korea. We performed a nested case-control study to compare the proportions of patients with ILD between the COVID-19 cohort and the matched cohort. Using the COVID-19 cohort, we also evaluated the risk of severe COVID-19 in patients with ILD versus those without ILD. RESULTS: The proportion of patients with ILD was significantly higher in the COVID-19 cohort than in the matched cohort (0.8% versus 0.4%; p<0.001). The odds of having ILD was significantly higher in the COVID-19 cohort than in the matched cohort (adjusted OR 2.02, 95% CI 1.54-2.61). Among patients in the COVID-19 cohort, patients with ILD were more likely to have severe COVID-19 than patients without ILD (47.8% versus 12.6%), including mortality (13.4% versus 2.8%) (all p<0.001). The risk of severe COVID-19 was significantly higher in patients with ILD than in those without ILD (adjusted OR 2.23, 95% CI 1.24-4.01). CONCLUSION: The risks of COVID-19 and severe presentation were significantly higher in patients with ILD than in those without ILD.

Characteristics of Specialist-Diagnosed Asthma-COPD Overlap in Severe Asthma: Observations from the Korean Severe Asthma Registry (KoSAR).

BACKGROUND: While the clinical characteristics and outcomes of asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) have been frequently compared with those of COPD or asthma, the prevalence and features of ACO in patients with severe asthma are unclear. OBJECTIVES: Evaluation of the prevalence and clinical features of ACO using the Korean severe asthma registry. METHODS: At the time of registration, ACO was determined in patients with severe asthma by attending specialists. Patients were classified into ACO and non-ACO groups, and the demographic and clinical characteristics of these two groups were compared. RESULTS: Of 482 patients with severe asthma, 23.7% had ACO. Patients in the ACO group were more likely to be male (P < .001), older (P < .001), and ex- or current smokers (P < .001) compared with those in the non-ACO group. Patients in the ACO group had lower mean forced expiratory volume in 1 second (P < .001) and blood eosinophil percentage (P = .006), but higher blood neutrophil percentage (P = .027) than those in the non-ACO group. The ACO group used more inhaled long-acting muscarinic antagonist (P < .001), methylxanthine (P = .001), or sustained systemic corticosteroid (P = .002). In addition, unscheduled emergency department visits due to exacerbation were more frequent in the ACO group (P = .006). CONCLUSION: Among patients with severe asthma, those with ACO were older, predominantly male, and were more likely to have a smoking history than those with asthma only. Patients with ACO used more systemic corticosteroid and had more frequent exacerbations related to emergency department visits than those with severe asthma only.

Maturation of human intestinal organoids in vitro facilitates colonization by commensal lactobacilli by reinforcing the mucus layer.

Lactobacilli, which are probiotic commensal bacteria that mainly reside in the human small intestine, have attracted attention for their ability to exert health-promoting effects and beneficially modulate host immunity. However, host epithelial-commensal bacterial interactions are still largely unexplored because of limited access to human small intestinal tissues. Recently, we described an in vitro maturation technique for generating adult-like, mature human intestinal organoids (hIOs) from human pluripotent stem cells (hPSCs) that closely resemble the in vivo tissue structure and cellular diversity. Here, we established an in vitro human model to study the response to colonization by commensal bacteria using luminal microinjection into mature hIOs, allowing for the direct examination of epithelial-bacterial interactions. Lactobacillus reuteri and Lactobacillus plantarum were more likely to survive and colonize when microinjected into the lumen of mature hIOs than when injected into immature hIOs, as determined by scanning electron microscopy, colony formation assay, immunofluorescence, and real-time imaging with L plantarum expressing red fluorescent protein. The improved mature hIO-based host epithelium system resulted from enhanced intestinal epithelial integrity via upregulation of mucus secretion and tight junction proteins. Our study indicates that mature hIOs are a physiologically relevant in vitro model system for studying commensal microorganisms.

Brittle intermetallic compound makes ultrastrong low-density steel with large ductility.

Although steel has been the workhorse of the automotive industry since the 1920s, the share by weight of steel and iron in an average light vehicle is now gradually decreasing, from 68.1 per cent in 1995 to 60.1 per cent in 2011 (refs 1, 2). This has been driven by the low strength-to-weight ratio (specific strength) of iron and steel, and the desire to improve such mechanical properties with other materials. Recently, high-aluminium low-density steels have been actively studied as a means of increasing the specific strength of an alloy by reducing its density. But with increasing aluminium content a problem is encountered: brittle intermetallic compounds can form in the resulting alloys, leading to poor ductility. Here we show that an FeAl-type brittle but hard intermetallic compound (B2) can be effectively used as a strengthening second phase in high-aluminium low-density steel, while alleviating its harmful effect on ductility by controlling its morphology and dispersion. The specific tensile strength and ductility of the developed steel improve on those of the lightest and strongest metallic materials known, titanium alloys. We found that alloying of nickel catalyses the precipitation of nanometre-sized B2 particles in the face-centred cubic matrix of high-aluminium low-density steel during heat treatment of cold-rolled sheet steel. Our results demonstrate how intermetallic compounds can be harnessed in the alloy design of lightweight steels for structural applications and others.

Diagnosis of Pneumonia by Cough Sounds Analyzed with Statistical Features and AI.

Pneumonia is a serious disease often accompanied by complications, sometimes leading to death. Unfortunately, diagnosis of pneumonia is frequently delayed until physical and radiologic examinations are performed. Diagnosing pneumonia with cough sounds would be advantageous as a non-invasive test that could be performed outside a hospital. We aimed to develop an artificial intelligence (AI)-based pneumonia diagnostic algorithm. We collected cough sounds from thirty adult patients with pneumonia or the other causative diseases of cough. To quantify the cough sounds, loudness and energy ratio were used to represent the level and its spectral variations. These two features were used for constructing the diagnostic algorithm. To estimate the performance of developed algorithm, we assessed the diagnostic accuracy by comparing with the diagnosis by pulmonologists based on cough sound alone. The algorithm showed 90.0% sensitivity, 78.6% specificity and 84.9% overall accuracy for the 70 cases of cough sound in pneumonia group and 56 cases in non-pneumonia group. For same cases, pulmonologists correctly diagnosed the cough sounds with 56.4% accuracy. These findings showed that the proposed AI algorithm has value as an effective assistant technology to diagnose adult pneumonia patients with significant reliability.

A case report of allergic bronchopulmonary mycosis caused by Alternaria alternata in colonization of Aspergillus.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease caused by a complex hypersensitivity reaction to colonization of the airways with various fungi. ABPA caused by Alternaria alternata, other than Aspergillus spp., is named Allergic bronchopulmonary mycosis (ABPM). OBJECTIVE: To describe the first case of ABPM caused by Alternaria alternata in East Asia. METHODS: Case report. RESULTS: A 58-year-old female visited our hospital due to an abnormal chest x-ray, following chest computed tomography (CT) revealed consolidation in the left lower lobe. On laboratory finding, eosinophil count and total IgE level were high. The skin prick test and specific IgE for Alternaria alternata were positive. After diagnosis of ABPM, the patient was treated with prednisolone without antifungal agents, and her chest image was much improved. CONCLUSIONS: Aspergillus is most common etiology of allergic pulmonary disease, however, Alternaria should be considered even though positive culture of Aspergillus spp.

Characterization of cell signaling, morphology, and differentiation potential of human mesenchymal stem cells based on cell adhesion mechanism.

It is essential to characterize the cellular properties of mesenchymal stem cell populations to maintain quality specifications and control in regenerative medicine. Biofunctional materials have been designed as artificial matrices for the stimulation of cell adhesion and specific cellular functions. We have developed recombinant maltose-binding protein (MBP)-fused proteins as artificial adhesion matrices to control human mesenchymal stem cell (hMSC) fate by using an integrin-independent heparin sulfate proteoglycans-mediated cell adhesion. In this study, we characterize cell adhesion-dependent cellular behaviors of human adipose-derived stem cells (hASCs) and human bone marrow stem cells (hBMSCs). We used an MBP-fused basic fibroblast growth factor (MF)-coated surface and fibronectin (FN)-coated surface to restrict and support, respectively, integrin-mediated adhesion. The cells adhered to MF exhibited restricted actin cytoskeleton organization and focal adhesion kinase phosphorylation. The hASCs and hBMSCs exhibited different cytoplasmic projection morphologies on MF. Both hASCs and hBMSCs differentiated more dominantly into osteogenic cells on FN than on MF. In contrast, hASCs differentiated more dominantly into adipogenic cells on MF than on FN, whereas hBMSCs differentiated predominantly into adipogenic cells on FN. The results indicate that hASCs exhibit a competitive differentiation potential (osteogenesis vs. adipogenesis) that depends on the cell adhesion matrix, whereas hBMSCs exhibit both adipogenesis and osteogenesis in integrin-mediated adhesion and thus hBMSCs have noncompetitive differentiation potential. We suggest that comparing differentiation behaviors of hMSCs with the diversity of cell adhesion is an important way to characterize hMSCs for regenerative medicine.