Functional Characterization of Gonadotropin-Releasing Hormone and Corazonin Signaling Systems in Pacific Abalone: Toward Reclassification of Invertebrate Neuropeptides.

INTRODUCTION: The proposed evolutionary origins and corresponding nomenclature of bilaterian gonadotropin-releasing hormone (GnRH)-related neuropeptides have changed tremendously with the aid of receptor deorphanization. However, the reclassification of the GnRH and corazonin (CRZ) signaling systems in Lophotrochozoa remains unclear. METHODS: We characterized GnRH and CRZ receptors in the mollusk Pacific abalone, Haliotis discus hannai (Hdh), by phylogenetic and gene expression analyses, bioluminescence-based reporter, Western blotting, substitution of peptide amino acids, in vivo neuropeptide injection, and RNA interference assays. RESULTS: Two Hdh CRZ-like receptors (Hdh-CRZR-A and Hdh-CRZR-B) and three Hdh GnRH-like receptors (Hdh-GnRHR1-A, Hdh-GnRHR1-B, and Hdh-GnRHR2) were identified. In phylogenetic analysis, Hdh-CRZR-A and -B grouped within the CRZ-type receptors, whereas Hdh-GnRHR1-A/-B and Hdh-GnRHR2 clustered within the GnRH/adipokinetic hormone (AKH)/CRZ-related peptide-type receptors. Hdh-CRZR-A/-B and Hdh-GnRHR1-A were activated by Hdh-CRZ (pQNYHFSNGWHA-NH2) and Hdh-GnRH (pQISFSPNWGT-NH2), respectively. Hdh-CRZR-A/-B dually coupled with the Gαq and Gαs signaling pathways, whereas Hdh-GnRHR1-A was linked only with Gαq signaling. Analysis of substituted peptides, [I2S3]Hdh-CRZ and [N2Y3H4]Hdh-GnRH, and in silico docking models revealed that the N-terminal amino acids of the peptides are critical for the selectivity of Hdh-CRZR and Hdh-GnRHR. Two precursor transcripts for Hdh-CRZ and Hdh-GnRH peptides and their receptors were mainly expressed in the neural ganglia, and their levels increased in starved abalones. Injection of Hdh-CRZ peptide into abalones decreased food consumption, whereas Hdh-CRZR knockdown increased food consumption. Moreover, Hdh-CRZ induced germinal vesicle breakdown in mature oocytes. CONCLUSION: Characterization of Hdh-CRZRs and Hdh-GnRHRs and their cognate peptides provides new insight into the evolutionary route of GnRH-related signaling systems in bilaterians.

Associations of personal urinary volatile organic compounds and lung function in children.

BACKGROUND: We investigated the correlation between urine VOC metabolites and airway function in children exposed to anthropogenic volatile organic compounds (VOCs), notable pollutants impacting respiratory health. METHODS: Out of 157 respondents, 141 completed skin prick tests, spirometry, IOS, and provided urine samples following the International Study of Asthma and Allergies in Childhood (ISAAC)-related questions. Allergic sensitization was assessed through skin prick tests, and airway functions were evaluated using spirometry and impulse oscillometry (IOS). Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) was recorded and FEV1/FVC ratio was calculated. Airway mechanics parameters including respiratory resistance at 5 Hz (Rrs5) mean respiratory resistance between 5 Hz and 20 Hz (Rrs5-20), were also recorded. Urine concentrations of metabolites of benzene, ethylbenzene, toluene, xylene, styrene, formaldehyde, carbon-disulfide were analyzed by gas chromatography/tandem mass spectroscopy. RESULTS: The median age at study participation was 7.1 (SD 0.3) years. Muconic acid (benzene metabolites) and o-methyl-hippuric acid (xylene metabolites) above medians were associated with a significant increase in Rrs5 (muconic acid: aß = 0.150, p = .002; o-methyl-hippuric acid: aß = 0.143, p = .023) and a decrease in FEV1/FVC (o-methyl-hippuric acid: aß = 0.054, p = .028) compared to those below median. No associations were observed for Rrs5-20 and FEV1 between the groups categorized as above and below the median (all parameter p values > .05). CONCLUSIONS: Elevated levels of benzene and xylene metabolites were associated with a significant increase in Rrs5 and a decrease in FEV1/FVC, related to increased resistance and restrictive lung conditions compared to individuals with concentrations below the median.

Characterization of myoinhibitory peptide signaling system and its implication in larval metamorphosis and spawning behavior in Pacific abalone.

Myoinhibitory peptides (MIPs) affect various physiological functions, including juvenile hormone signaling, muscle contraction, larval development, and reproduction in invertebrates. Although MIPs are ligands for MIP and/or sex peptide receptors (MIP/SPRs) in diverse arthropods and model organisms belonging to Lophotrochozoa, the MIP signaling system has not yet been fully investigated in mollusks. In this study, we identified the MIP signaling system in the Pacific abalone Haliotis discus hannai (Hdh). Similar to the invertebrate MIPs, a total of eight paracopies of MIPs (named Hdh-MIP1 to Hdh-MIP8), harboring a WX5-7Wamide motif, except for Hdh-MIP2, were found in the Hdh-MIP precursor. Furthermore, we characterized a functional Hdh-MIPR, which responded to the Hdh-MIPs, except for Hdh-MIP2, possibly linked with the PKC/Ca2+ and PKA/cAMP signaling pathways. Hdh-MIPs delayed larval metamorphosis but increased the spawning behavior. These results suggest that the Hdh-MIP signaling system provides insights into the unique function of MIP in invertebrates.

Crustacean cardioactive peptide signaling system in the gastropod mollusk Pacific abalone.

Crustacean cardioactive peptide (CCAP) signaling systems have been characterized in a diverse range of protostomes, representatively in arthropods. The cyclic CX5C-type CCAP regulates various biological activities through CCAP receptors (CCAPRs), which are orthologous to neuropeptide S receptors (NPSRs) in deuterostomes. However, the CCAPRs of the lophotrochozoa remain poorly characterized; therefore, the relationship between the CCAP, NPS, and CX4C-type oxytocin/vasopressin (OT/VP) signaling systems is unclear. In this study, we identified a CCAP precursor and two CCAPR isoforms in the Pacific abalone (Haliotis discus hannai; Hdh). The Hdh-CCAP precursor was found to harbor three CX5C-type and one CX4C-type CCAPs. The Hdh-CCAPRs displayed homology with protostome CCAPRs and deuterostome NPSRs, having characteristics of the rhodopsin-type G protein-coupled receptors. Phylogenetic analysis showed that lophotrochozoan CCAPRs, including Hdh-CCAPRs, form a monophyletic group distinct from arthropod CCAPRs. Reporter assays demonstrated that all examined Hdh-CCAPs and insect CCAP-induced intracellular Ca2+ mobilization and cAMP accumulation in Hdh-CCAPR-expressing HEK293 cells, whereas none of the CCAP peptides inhibited the forskolin-stimulated cAMP signaling pathway even at micromolar concentrations. In silico ligand-receptor docking models showed that the N-terminal FCN motifs of Hdh-CCAPs are deeply inserted inside the binding pocket of Hdh-CCAPR, forming extensive hydrophobic interactions. In mature Pacific abalone, the transcripts for Hdh-CCAP precursor and Hdh-CCAPR were highly expressed in the neural ganglia compared to the peripheral tissues. Collectively, this study characterized the first CCAP signaling system linked to both Ca2+/PKC and cAMP/PKA signal transduction pathways in gastropod mollusks and gives insights into the evolutional origins of deuterostomian NPS and OT/VP signaling systems.

Pneumonia Prevalence Upon Chest Radiography According to Vaccination Status Among Patients Under 50 Years of Age With Coronavirus Disease 2019.

BACKGROUND: Coronavirus disease 2019 (COVID-19) vaccination is effective in preventing the disease transmission and progression. However, the relatively mild disease course of the omicron variant and the decrease in antibodies over time after vaccination raise questions about the effectiveness of vaccination, especially in young people. We compared the prevalence of pneumonia and chest X-ray severity score according to vaccination status among patients < 50 years old with COVID-19. METHODS: From January 17 to March 17, 2022, 579 patients with COVID-19, who were < 50 years old and had a known vaccination history in our institution, were all included in this study. All patients underwent initial chest radiography, and follow-up chest radiographs were obtained every two days until discharge. Pneumonia was scored from the radiographs using the Brixia scoring system. The scores of the six lung zones were added for a total score ranging from 0 to 18. Patients were divided into four groups according to 10-year age intervals. Differences between groups were analyzed using the χ² or Fisher's exact tests for categorical variables and the Kruskal-Wallis test or analysis of variance for continuous variables. RESULTS: Among patients aged 12-19 years, the prevalence of pneumonia did not differ depending on vaccination status (non-vaccinated vs. vaccinated, 1/47 [2.1%] vs. 1/18 [5.6%]; P = 0.577). Among patients in their 20s, the prevalence of pneumonia was significantly higher among non-vaccinated patients than among vaccinated patients (8/28, 28.6% vs. 7/138, 5.1%, P < 0.001), similar to patients in their 40s (32/52 [61.5%] vs. 18/138 [13.0%]; P < 0.001). The chest X-ray severity score was also significantly higher in non-vaccinated patients than that in vaccinated patients in their 20s to their 40s (P < 0.001), but not among patients aged 12-19 years (P = 0.678). CONCLUSION: In patients aged 20-49 years, vaccinated patients had a significantly lower prevalence of pneumonia and chest X-ray severity score than non-vaccinated patients.

Stratification of Nontuberculous Mycobacterial Disease Risk in Type 2 Diabetes Based on Metformin Use: a Population-Based Cohort Study in South Korea.

In a 1:4 case-control matched analysis of data from a nationwide population-based cohort in South Korea, we evaluated whether metformin use mitigates the risk of nontuberculous mycobacterial disease in patients with type 2 diabetes. Multivariable analysis revealed no significant association of metformin use with a diminished risk for incident nontuberculous mycobacterial disease in patients with type 2 diabetes.

Neutrophil-Lymphocyte Ratio and Monocyte-Lymphocyte Ratio According to the Radiologic Severity of Mycobacterium avium Complex Pulmonary Disease.

BACKGROUND: To date, no study has investigated whether the neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR) have a clinical value in Mycobacterium avium complex (MAC)-pulmonary disease (PD). METHODS: We aimed to assess whether the baseline NLR and MLR were different according to the severity of MAC-PD based on the radiologic classification by retrospectively analyzing 549 patients treated in a tertiary referral center in South Korea. RESULTS: Both NLR and MLR were significantly higher as 3.33 and 0.43 respectively in the fibrocavitary type, followed by 2.34 and 0.27 in the cavitary nodular bronchiectatic type and significantly lower as 1.88 and 0.23 in the non-cavitary nodular bronchiectatic type. CONCLUSION: The baseline NLR and MLR showed a distinct difference in accordance with the radiologic severity of MAC-PD.

Incidence of cancer after asthma development: 2 independent population-based cohort studies.

BACKGROUND: Evidence regarding the risk of cancer development after asthma diagnosis is controversial and inconclusive. OBJECTIVE: This study sought to determine whether asthma is associated with an increased risk for incident cancer. METHODS: Two independent, population-based, longitudinal cohorts were examined, and estimated hazard ratios were determined using Cox regression. One group consisted of an unmatched cohort of 475,197 participants and a propensity score-matched cohort of 75,307 participants from the National Health Insurance Service-National Sample Cohort (NHIS-NSC; claims-based data from 2003 to 2015). The other group consisted of 5,440 participants from the Ansan-Ansung cohort (interview-based data from 2001 to 2014). RESULTS: The NHIS-NSC matched cohort had 572,740 person-years of follow-up, 6,885 people with new asthma diagnoses, and 68,422 people without asthma diagnoses. Adults with asthma had a 75% greater risk of incident cancer overall. The excess risk for incident cancer was greatest during the first 2 years after asthma diagnosis, and this risk remained elevated throughout follow-up. Patients with nonatopic asthma had a greater risk of overall cancer than those with atopic asthma. A high cumulative dose of inhaled corticosteroids among asthma patients was associated with a 56% reduced risk of lung cancer, but had no effect on the risk of overall cancer. The results from the NHIS-NSC unmatched cohort and the Ansan-Ansung cohort were similar to the primary results from the NHIS-NSC matched cohort. CONCLUSIONS: Asthma development was associated with an increased risk of subsequent cancer in 2 different Korean cohorts. Our findings provide an improved understanding of the pathogenesis of asthma and its relationship with carcinogenesis and suggest that clinicians should be aware of the higher risk of incident cancer among patients with asthma.

Effects of Radix Polygalae on Cognitive Decline and Depression in Estradiol Depletion Mouse Model of Menopause.

Postmenopausal syndrome refers to symptoms caused by the gradual decrease in female hormones after mid-40 years. As a target organ of estrogen, decrease in estrogen causes various changes in brain function such as a decrease in choline acetyltransferase and brain-derived neurotrophic factor; thus, postmenopausal women experience cognitive decline and more depressive symptoms than age-matched men. Radix Polygalae has been used for memory boosting and as a mood stabilizer and its components have shown neuroprotective, antidepressant, and stress relief properties. In a mouse model of estrogen depletion induced by 4-vinylcyclohexene diepoxide, Radix Polygalae was orally administered for 3 weeks. In these animals, cognitive and depression-related behaviors and molecular changes related to these behaviors were measured in the prefrontal cortex and hippocampus. Radix Polygalae improved working memory and contextual memory and despair-related behaviors in 4-vinylcyclohexene diepoxide-treated mice without increasing serum estradiol levels in this model. In relation to these behaviors, choline acetyltransferase and brain-derived neurotrophic factor in the prefrontal cortex and hippocampus and bcl-2-associated athanogene expression increased in the hippocampus. These results implicate the possible benefit of Radix Polygalae in use as a supplement of estrogen to prevent conditions such as postmenopausal depression and cognitive decline.

Association of phthalate exposure and airway dysfunction with mediation by serum periostin.

BACKGROUND: Phthalates can cause respiratory and immunological disorders. However, little is known about the role of serum periostin and YKL-40 levels in mediating the effects of phthalates. We investigated the mediating role of these biomarkers in the relationship between phthalates and airway dysfunction. METHODS: A total of 487 children (aged 10-12 years old) were examined. Four high-molecular-weight phthalate (HMWP) [Σ4 HMWP] metabolites and 3 low-molecular-weight phthalate (LMWP) [Σ3 LMWP] metabolites in urine samples were measured. Serum periostin and YKL-40 levels were measured. Airway function was measured using impulse oscillometry. A mediation model was used to quantify the mediating effects of periostin and YKL-40 on airway dysfunction. RESULTS: After adjustment for height, gender, BMI z-score, aeroallergen sensitization, secondary smoking, and vitamin D level, the level of urinary Σ3 LMWP metabolites was significantly associated with respiratory system resistance at 5 Hz (Rrs5; adjusted ß: 0.020, 95% CI: 0.005-0.034; p = .010). The levels of urinary Σ4 HMWP and Σ3 LMWP metabolites were significantly associated with periostin level, but not with YKL-40 level. In addition, the periostin level was associated with Rrs5 (adjusted ß: 0.048, 95% CI: 0.015-0.081; p = .005) and Rrs20-5 (adjusted ß: 0.040, 95% CI: 0.011-0.069; p = .007). Serum periostin level had a significant effect in mediating the relationship between Σ3 LMWP and Rrs5 (13.9%, 95% CI: 10.7-77.0; p < .001). CONCLUSION: Exposure to LMWPs was significantly associated with airway dysfunction, and this effect was partially attributable to increased serum periostin level.