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Background: Neutrophilic asthma (NA) is a clinically important asthma phenotype, the cellular and molecular basis of which is not completely understood. Airway macrophages are long-lived immune cells that exert important homeostatic and inflammatory functions which are dysregulated in asthma. Unique transcriptomic programmes reflect varied macrophage phenotypes in vitro. We aimed to determine whether airway macrophages are transcriptomically altered in NA., Methods: We performed RNASeq analysis on flow cytometry-isolated sputum macrophages comparing NA (n = 7) and non-neutrophilic asthma (NNA, n = 13). qPCR validation of RNASeq results was performed (NA n = 13, NNA n = 23). Pathway analysis (PANTHER, STRING) of differentially expressed genes (DEGs) was performed. Gene set variation analysis (GSVA) was used to test for enrichment of NA macrophage transcriptomic signatures in whole sputum microarray (cohort 1 - controls n = 16, NA n = 29, NNA n = 37; cohort 2 U-BIOPRED - controls n = 16, NA n = 47, NNA n = 57)., Results: Flow cytometry-sorting significantly enriched sputum macrophages (99.4% post-sort, 44.9% pre-sort, p < .05). RNASeq analysis confirmed macrophage purity and identified DEGs in NA macrophages. Selected DEGs (SLAMF7, DYSF, GPR183, CSF3, PI3, CCR7, all p < .05 NA vs. NNA) were confirmed by qPCR. Pathway analysis of NA macrophage DEGs was consistent with responses to bacteria, contribution to neutrophil recruitment and increased expression of phagocytosis and efferocytosis factors. GSVA demonstrated neutrophilic macrophage gene signatures were significantly enriched in whole sputum microarray in NA vs. NNA and controls in both cohorts., Conclusions: We demonstrate a pathophysiologically relevant sputum macrophage transcriptomic programme in NA. The finding that there is transcriptional activation of inflammatory programmes in cell types other than neutrophils supports the concept of NA as a specific endotype., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Orosomucoid 1-like protein 3 (ORMDL3), a transmembrane protein localized in the endoplasmic reticulum (ER), has been genetically associated with chronic obstructive pulmonary disease (COPD), in addition to childhood-onset asthma. However, the functional role of ORMDL3 in the pathogenesis of COPD is still unknown., Objective: Because cigarette smoke is the major risk factor for COPD, we aimed to investigate the role of ORMDL3 in cigarette smoke-induced human airway smooth muscle cell (HASMC) injury., Methods: The mRNA and protein expression of ORMDL3 was examined in HASMCs from nonsmokers and smokers without or with COPD. Knockdown of ORMDL3 in primary healthy HASMCs was performed using small interfering RNA before exposure to cigarette smoke medium (CSM) for 24 hours. Inflammatory, proliferative/apoptotic, ER stress, and mitochondrial markers were evaluated., Results: Elevation of ORMDL3 mRNA and protein expression was observed in HASMCs of smokers without or with COPD. CSM caused significant upregulation of ORMDL3 expression in healthy nonsmokers. ORMDL3 knockdown regulated CSM-induced inflammation, cell proliferation, and apoptosis. Silencing ORMDL3 led to reduction of CSM-induced ER stress via inhibition of unfolded protein response pathways such as activating transcription factor 6 and protein kinase RNA-like ER kinase. ORMDL3 was also involved in CSM-induced mitochondrial dysfunction via the mitochondrial fission process., Conclusions: We report the induction of ORMDL3 in HASMCs after cigarette smoke exposure. ORMDL3 may mediate cigarette smoke-induced activation of unfolded protein response pathways during airway smooth muscle cell injury., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Exacerbation-prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear., Objectives: To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U-BIOPRED cohort., Methods: We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, <2 exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures., Results: Of 317 patients, 62.4% had FE, of whom 63.6% had PFE, while 37.6% had IE, of whom 61.3% had PIE. Using multivariate analysis, FE was associated with short-acting beta-agonist use, sinusitis and daily oral corticosteroid use, while PFE was associated with eczema, short-acting beta-agonist use and asthma control index. CEA cell adhesion molecule 5 (CEACAM5) was the only differentially expressed transcript in bronchial biopsies between PE and IE. There were no differentially expressed genes in the other four compartments. There were higher expression scores for type 2, T-helper type-17 and type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while there were higher expression scores of type 2, type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE., Conclusion: The FE group and its PFE subgroup are associated with poor asthma control while expressing higher type 1 and type 2 activation pathways compared to IE and PIE, respectively., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: There is a link between exposure to air pollution and the increased prevalence of chronic obstructive pulmonary disease (COPD) and declining pulmonary function, but the association with O 2 desaturation during exercise in COPD patients with emphysema is unclear. Our aims were to estimate the prevalence of O 2 desaturation during exercise in patients with COPD, and determine the association of exposure to air pollution with exercise-induced desaturation (EID), the degree of emphysema, and dynamic hyperinflation (DH)., Methods: We assessed the effects of 10-year prior to the HRCT assessment and 7 days prior to the six-minute walking test exposure to particulate matter with an aerodynamic diameter of < 10 µm (PM 10 ) or of < 2.5 µM (PM 2.5) , nitrogen dioxide (NO 2 ), and ozone (O 3 ) in patients with emphysema in this retrospective cohort study. EID was defined as a nadir standard pulse oximetry (SpO 2 ) level of < 90% or a delta (△)SpO 2 level of ≥ 4%. Ambient air pollutant (PM 2.5 , PM 10 , O 3 , and NO 2 ) data were obtained from Taiwan Environmental Protection Administration (EPA) air-monitoring stations, usually within 10 km to each participant's home address., Results: We recruited 141 subjects with emphysema. 41.1% of patients with emphysema exhibited EID, and patients with EID had more dyspnea, worse lung function, more severe emphysema, more frequent acute exacerbations, managed a shorter walking distance, had DH, and greater long-term exposure to air pollution than those without EID. We observed that levels of 10-year concentrations of PM 10 , PM 2.5 , and NO 2 were significantly associated with EID, PM 10 and PM 2.5 were associated with the severity of emphysema, and associated with DH in patients with emphysema. In contrast, short-term exposure did not have any effect on patients., Conclusion: Long-term exposure to ambient PM 10 , PM 2.5 and NO 2 , but not O 3 , was associated with EID., (© 2022. The Author(s).)

Species of Broussonetia have been essential in the development of papermaking technology. In Japan and Korea, a hybrid between B. monoica and B. papyrifera (= B. × kazinoki) known as kōzo and daknamu is still the major source of raw materials for making traditional paper washi and hanji, respectively. Despite their cultural and practical significance, however, the origin and taxonomy of kōzo and daknamu remain controversial. Additionally, the long-held generic concept of Broussonetia s.l., which included Sect. Allaeanthus and Sect. Broussonetia, was challenged as phylogenetic analyses showed Malaisia is sister to the latter section. To re-examine the taxonomic proposition that recognizes Allaeanthus, Broussonetia, and Malaisia (i.e., Broussonetia alliance), plastome and nuclear ribosomal DNA (nrDNA) sequences of six species of the alliance were assembled. Characterized by the canonical quadripartite structure, genome alignments and contents of the six plastomes (160,121-162,594 bp) are highly conserved, except for the pseudogenization and/or loss of the rpl22 gene. Relationships of the Broussonetia alliance are identical between plastome and nrDNA trees, supporting the maintenance of Malaisia and the resurrection of Allaeanthus. The phylogenomic relationships also indicate that the monoecy in B. monoica is a derived state, possibly resulting from hybridization between the dioecious B. kaempferi (♀) and B. papyrifera (♂). Based on the hypervariable ndhF-rpl32 intergenic spacer selected by sliding window analysis, phylogeographic analysis indicates that B. monoica is the sole maternal parent of B. × kazinoki and that daknamu carries multiple haplotypes, while only one haplotype was detected in kōzo. Because hybridizations between B. monoica and B. papyrifera are unidirectional and have occurred rarely in nature, our data suggest that daknamu might have originated via deliberate hybrid breeding selected for making hanji in Korea. On the contrary, kōzo appears to have a single origin and the possibility of a Korean origin cannot be ruled out., (© 2022. The Author(s) under exclusive licence to The Botanical Society of Japan.)

Rationale: Asthma phenotyping requires novel biomarker discovery., Objectives: To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs)., Methods: An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED., Results: In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation., Conclusions: The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA., Competing Interests: Conflict of interest: M. Sparreman Mikus has nothing to disclose. Conflict of interest: J. Kolmert reports personal fees from Gesynta Pharma AB. Conflict of interest: L.I. Andersson has nothing to disclose. Conflict of interest: J. Östling has nothing to disclose. Conflict of interest: R.G. Knowles has nothing to disclose. Conflict of interest: C. Gómez has nothing to disclose. Conflict of interest: M. Ericsson has nothing to disclose. Conflict of interest: J-O. Thörngren has nothing to disclose. Conflict of interest: P. Emami Khoonsari has nothing to disclose. Conflict of interest: B. Dahlén reports personal fees from AstraZeneca, Teva, Sanofi and grants from Novartis and GlaxoSmithKline outside the submitted work. Conflict of interest: M. Kupczyk has nothing to disclose. Conflict of interest: B. De Meulder report grants from the Innovative Medicines Initiative during the conduct of the study. Conflict of interest: C. Auffray report grants from the Innovative Medicines Initiative during the conduct of the study. Conflict of interest: P.S. Bakke reports personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim and Chiesi outside the submitted work. Conflict of interest: B. Beghe reports personal fees from AstraZeneca, Boehringer Ingelheim, Menarini and GlaxoSmithKline outside the submitted work. Conflict of interest: E.H. Bel reports grants and personal fees from GlaxoSmithKline, AstraZeneca, Novartis, TEVA, Sanofi/Regeneron, Chiesi, and Sterna outside the submitted work. Conflict of interest: M. Caruso has nothing to disclose. Conflict of interest: P. Chanez has nothing to disclose. Conflict of interest: B. Chawes has nothing to disclose. Conflict of interest: S.J. Fowler has nothing to disclose. Conflict of interest: M. Gaga reports grants and personal fees from Novartis, Menarini, Merck Sharp & Dohme, BMS, Galapagos, and AstraZeneca outside the submitted work. Conflict of interest: T. Geiser has nothing to disclose. Conflict of interest: M. Gjomarkaj has nothing to disclose. Conflict of interest: I. Horváth reports grants from EFPIA during the conduct of the study, and personal fees from AstraZeneca, GlaxoSmithKline, Novartis, Boehringer-Ingelheim, Sandoz, Teva and Chiesi outside the submitted work. Conflict of interest: P.H. Howarth has nothing to disclose. Conflict of interest: S.L. Johnston reports personal fees from Virtus Respiratory Research, Myelo Therapeutics GmbH, Concert Pharmaceuticals, Bayer, Synairgen, Novartis, Boehringer Ingelheim, Chiesi, Gerson Lehrman Group, resTORbio, Bioforce, Materia Medical Holdings, PrepBio Pharma, Pulmotect, Virion Health, Lallemand Pharma and AstraZeneca outside the submitted work. In addition, Sebastian L. Johnston also has three patents (Anti-virus therapy for respiratory diseases, UK patent application No. GB 0405634.7, Interferon-Beta for Anti-Virus Therapy for Respiratory Diseases, International Patent Application No. PCT/ GB05/50031 and Interferon Lambda therapy for the treatment of respiratory disease, UK patent application No.6779645.9). Conflict of interest: G. Joos reports grants and personal fees from AstraZeneca, Bayer, Chiesi, Eureca vzw, GlaxoSmithKline and Teva outside the submitted work. Conflict of interest: N. Krug has nothing to disclose. Conflict of interest: P. Montuschi has nothing to disclose. Conflict of interest: J. Musial has nothing to disclose. Conflict of interest: E. Niżankowska-Mogilnicka has nothing to disclose. Conflict of interest: H.K. Olsson reports other support from AstraZeneca outside the submitted work. Conflict of interest: A. Papi reports grants, personal fees, non-financial support and others from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Chiesi, Teva, Mundipharma, Zambon, Novartis, Menarini, Sanofi/Regeneron, Roche, Fondazione Salvatore Maugeri, Chiesi and Edmond pharma outside the submitted work. Conflict of interest: K.F. Rabe reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Sanofi Aventis, MERCK SHARP & DOHME, Novartis, Orion Cooperation, Berlin Chemie, Roche, Chiesi and grants for research from the Ministry of Education and Science, Germany. Conflict of interest: T. Sandström has nothing to disclose. Conflict of interest: D.E. Shaw reports personal fees and non-financial support from GlaxoSmithKline, Novartis and AstraZeneca outside the submitted work. Conflict of interest: N.M. Siafakas has nothing to disclose. Conflict of interest: M. Uhlen has nothing to disclose. Conflict of interest: J.H. Riley is an employee and shareholder in GlaxoSmithKline. Conflict of interest: S. Bates is an employee and shareholder in GlaxoSmithKline. Conflict of interest: R.J.M. Middelveld reports grants from the Swedish Strategic Research Foundation, AstraZeneca, the Swedish Heart Lung Foundation and the Swedish Asthma and Allergy Association outside the submitted work. Conflict of interest: C.E. Wheelock has nothing to disclose. Conflict of interest: K.F. Chung reports grants and personal fees from GlaxoSmithKline, AstraZeneca, Novartis, Merck, Boehringer Ingelheim, Roche and Shionogi outside the submitted work. Conflict of interest: I.M. Adcock has nothing to disclose. Conflict of interest: P.J. Sterk reports grants to Amsterdam UMC from the public private Innovative Medicines Initiative (IMI) covered by the European Union (EU) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) during the conduct of the study. Conflict of interest: R. Djukanovic reports receiving fees for lectures at symposia organised by Novartis, GlaxoSmithKline, AstraZeneca and Teva, consultation fees from Teva and Novartis; he is a co-founder and current consultant and has shares in Synairgen. Conflict of interest: P. Nilsson has nothing to disclose. Conflict of interest: S-E. Dahlén reports personal fees from AstraZeneca, Cayman Chemicals, GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva outside the submitted work. Conflict of interest: A. James has nothing to disclose., (Copyright ©The authors 2022.)

Rationale: Mast cells (MCs) play a role in inflammation and both innate and adaptive immunity, but their involvement in severe asthma (SA) remains undefined. Objectives: We investigated the phenotypic characteristics of the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) asthma cohort by applying published MC activation signatures to the sputum cell transcriptome. Methods: Eighty-four participants with SA, 20 with mild/moderate asthma (MMA), and 16 healthy participants without asthma were studied. We calculated enrichment scores (ESs) for nine MC activation signatures by asthma severity, sputum granulocyte status, and three previously defined sputum molecular phenotypes or transcriptome-associated clusters (TACs) 1, 2, and 3 using gene set variation analysis. Measurements and Main Results: MC signatures except unstimulated, repeated FcεR1-stimulated and IFN-γ-stimulated signatures were enriched in SA. A FcεR1-IgE-stimulated and a single-cell signature from asthmatic bronchial biopsies were highly enriched in eosinophilic asthma and in the TAC1 molecular phenotype. Subjects with a high ES for these signatures had elevated sputum amounts of similar genes and pathways. IL-33- and LPS-stimulated MC signatures had greater ES in neutrophilic and mixed granulocytic asthma and in the TAC2 molecular phenotype. These subjects exhibited neutrophil, NF-κB (nuclear factor-κB), and IL-1β/TNF-α (tumor necrosis factor-α) pathway activation. The IFN-γ-stimulated signature had the greatest ES in TAC2 and TAC3 that was associated with responses to viral infection. Similar results were obtained in an independent ADEPT (Airway Disease Endotyping for Personalized Therapeutics) asthma cohort. Conclusions: Gene signatures of MC activation allow the detection of SA phenotypes and indicate that MCs can be induced to take on distinct transcriptional phenotypes associated with specific clinical phenotypes. IL-33-stimulated MC signature was associated with severe neutrophilic asthma, whereas IgE-activated MC was associated with an eosinophilic phenotype.

The significance of this work is that ambient PM 2.5 is a direct transmission mode for influenza virus infection to the human alveolar epithelium. The concentration of PM 2.5 was 11.7 ± 5.5 μg/m 3 in Taipei during 24 December 2019-13 January 2020. Approximately 79% of inhaled PM 2.5 is able to reach the upper-to-lower airway, and 47% of PM 2.5 is able to reach the alveolar epithelium for influenza virus infection. Influenza A and B viruses were detected in PM 2.5 on 9 days, and the influenza A/H5 virus was detected on 15 days during the study period. FL and Pyr were negatively correlated with the influenza A virus. D(ah)P and Acp were positively correlated with the influenza B and A/H5 viruses, respectively. Cd, V, and Zn were positively correlated with the influenza A, B, and A/H5 viruses, respectively. Next, influenza A, B, and A/H5 viral plasmids interacted with carbon black, H 2 O 2 , DEPs, and UD. We observed that H 2 O 2 significantly decreased levels of complementary DNA of the three influenza viruses. DEPs and UD significantly decreased influenza A and A/H5 viral levels. In conclusion, chemicals in PM 2.5 may play vital roles in terms of viable influenza virus in the atmosphere., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Bronchiectasis is characterized by systemic inflammation and multiple comorbidities. This study aimed to investigate the clinical outcomes based on the bronchiectasis etiology comorbidity index (BACI) score in patients hospitalized for severe bronchiectasis exacerbations. We included non-cystic fibrosis patients hospitalized for severe bronchiectasis exacerbations between January 2008 and December 2016 from the Chang Gung Research Database (CGRD) cohort. The main outcome was the 1-year mortality rate after severe exacerbations. We used the Cox regression model to assess the risk factors of 1-year mortality. Of 1,235 patients who were hospitalized for severe bronchiectasis exacerbations, 641 were in the BACI < 6 group and 594 in the BACI ≥ 6 group. The BACI ≥ 6 group had more previous exacerbations and a lower FEV 1 . Pseudomonas aeruginosa (19.1%) was the most common bacterium, followed by Klebsiella pneumoniae (7.5%). Overall, 11.8% of patients had respiratory failure and the hospital mortality was 3.0%. After discharge, compared to the BACI < 6 group, the BACI ≥ 6 group had a significantly higher cumulative incidence of respiratory failure and mortality in a 1-year follow-up. The risk factors for 1-year mortality in a multivariate analysis include age [hazard ratio (HR) 4.38, p = 0.01], being male (HR 4.38, p = 0.01), and systemic corticosteroid usage (HR 6.35, p = 0.001), while airway clearance therapy (ACT) (HR 0.50, p = 0.010) was associated with a lower mortality risk. An increased risk of respiratory failure and mortality in a 1-year follow-up after severe exacerbations was observed in bronchiectasis patients with multimorbidities, particularly older age patients, male patients, and patients with a history of systemic corticosteroid use. ACT could effectively improve the risk for 1-year mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Chung, Lin, Lo, Huang, Huang, Lai, Gan, Ko, Lin, Chung and Wang.)

Background: The AtyPical Asthma in China (APAC) cohort is a multi-center prospective, observational cohort set-up to investigate the clinical, pathophysiological features, prognosis, and mechanisms of cough variant asthma (CVA)., Objectives: To present the characteristics of newly physician-diagnosed adults with CVA ( n = 328) compared to mild-moderate classic asthma (CA, n = 206)., Methods and Main Results: CVA subjects showed a higher proportion of female (67.1 vs. 55.3%, P = 0.0084), abnormal laryngopharyngeal sensations (71 vs. 51%, p < 0.0001) than CA, but presented with near normal spirometry and higher methacholine PD20-FEV1 values [4.2 (1, 8.6) vs. 0.8 (0.4, 4.7), P < 0.0001]. Lower fractional exhaled nitric oxide (FENO) levels [38.5 (19.8, 72.5) vs. 53. (28.5, 92.2), P = 0.0019], blood eosinophil counts [0.2 (0.1, 0.4) vs. 0.3 (0.2, 0.5), P = 0.0014], and sputum eosinophils [2.3 (0.3, 8.0) vs. 12.2 (2, 34.5), p < 0.0001] were found in CVA. Despite lower total serum IgE levels in CVA, there was similar proportion of atopy in both groups. The prevalence of cough in CA was 86.4%, while CVA reported more severe cough on Visual Analog Scale, Cough Evaluation Test, and Leicester Cough Questionnaire, similar anxiety and depression scores but better asthma control scores as reflected by Asthma Control Test compared to CA. No correlation was found between cough assessment outcomes and sputum eosinophil count, blood eosinophil count, FENO, spirometry variables, or PD20-FEV1., Conclusion: Cough variant asthma is distinctive from classic asthma in regard to clinical features, lung function, and airway inflammation. Quality of life is badly impaired as well in spite of better asthma control scores., Competing Interests: The authors declare that this study received funding from AstraZeneca. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lai, Zhan, Wu, Zhang, Lin, Li, Yi, Jiang, Dai, Li, Lin, Yuan, Jiang, Qiu, Zhao, Chen, Qiu, Li, Chen, Luo, Xie, Guo, Jiang, Yang, Shi, Sun, Chen, Chung, Shen and Zhong.)

The early-diverging eudicot family Berberidaceae is composed of a morphologically diverse assemblage of disjunctly distributed genera long praised for their great horticultural and medicinal values. However, despite century-long studies, generic delimitation of Berberidaceae remains controversial and its tribal classification has never been formally proposed under a rigorous phylogenetic context. Currently, the number of accepted genera in Berberidaceae ranges consecutively from 13 to 19, depending on whether to define Berberis , Jeffersonia , and Podophyllum broadly, or to segregate these three genera further and recognize Alloberberis , Mahonia , and Moranothamnus , Plagiorhegma , and Dysosma , Diphylleia , and Sinopodophyllum , respectively. To resolve Berberidaceae's taxonomic disputes, we newly assembled 23 plastomes and, together with 85 plastomes from the GenBank, completed the generic sampling of the family. With 4 problematic and 14 redundant plastome sequences excluded, robust phylogenomic relationships were reconstructed based on 93 plastomes representing all 19 genera of Berberidaceae and three outgroups. Maximum likelihood phylogenomic relationships corroborated with divergence time estimation support the recognition of three subfamilies Berberidoideae, Nandinoideae, and Podophylloideae, with tribes Berberideae and Ranzanieae, Leonticeae and Nandineae, and Podophylleae, Achlydeae, Bongardieae tr. nov. , Epimedieae, and Jeffersonieae tr. nov . in the former three subfamilies, respectively. By applying specifically stated criteria, our phylogenomic data also support the classification of 19 genera, recognizing Alloberberis , Mahonia , and Moranothamnus , Plagiorhegma , and Diphylleia , Dysosma , and Sinopodophyllum that are morphologically and evolutionarily distinct from Berberis , Jeffersonia , and Podophyllum , respectively. Comparison of plastome structures across Berberidaceae confirms inverted repeat expansion in the tribe Berberideae and reveals substantial length variation in accD gene caused by repeated sequences in Berberidoideae. Comparison of plastome tree with previous studies and nuclear ribosomal DNA (nrDNA) phylogeny also reveals considerable conflicts at different phylogenetic levels, suggesting that incomplete lineage sorting and/or hybridization had occurred throughout the evolutionary history of Berberidaceae and that Alloberberis and Moranothamnus could have resulted from reciprocal hybridization between Berberis and Mahonia in ancient times prior to the radiations of the latter two genera., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hsieh, Yu, Huang and Chung.)

Air pollution has been linked to emphysema in chronic obstruction pulmonary disease (COPD). However, the underlying mechanisms in the development of emphysema due to air pollution remain unclear. The objective of this study was to investigate the role of components of the Hippo signaling pathway for E-cadherin-mediated contact inhibition of proliferation in the lungs after air pollution exposure. E-Cadherin-mediated contact inhibition of proliferation via the Hippo signaling pathway was investigated in Sprague-Dawley (SD) rats whole-body exposed to air pollution, and in alveolar epithelial A549 cells exposed to diesel exhaust particles (DEPs), E-cadherin-knockdown, and high-mobility group box 1 (HMGB1) treatment. Underlying epithelial differentiation, apoptosis, and senescence were also examined, and the interaction network among these proteins was examined. COPD lung sections were used to confirm the observations in rats. Expressions of HMGB1 and E-cadherin were negatively regulated in the lungs and A549 cells by air pollution, and this was confirmed by knockdown of E-cadherin and by treating A549 cells with HMGB1. Depletion of phosphorylated (p)-Yap occurred after exposure to air pollution and E-cadherin-knockdown, which resulted in decreases of SPC and T1α. Exposure to air pollution and E-cadherin-knockdown respectively downregulated p-Sirt1 and increased p53 levels in the lungs and in A549 cells. Moreover, the protein interaction network suggested that E-cadherin is a key activator in regulating Sirt1 and p53, as well as alveolar epithelial cell differentiation by SPC and T1α. Consistently, downregulation of E-cadherin, p-Yap, SPC, and T1α was observed in COPD alveolar regions with particulate matter (PM) deposition. In conclusion, our results indicated that E-cadherin-mediated cell-cell contact directly regulates the Hippo signaling pathway to control differentiation, cell proliferation, and senescence due to air pollution. Exposure to air pollution may initiate emphysema in COPD patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Epidemiological studies identified the relationship between air pollution and pulmonary tuberculosis. Effects of lung-deposited dose of particulate matter (PM) on culture-positive pulmonary tuberculosis remain unclear. This study investigates the association between lung-deposited dose of PM and pulmonary tuberculosis pleurisy. A case-control study of subjects undergoing pleural effusion drainage of pulmonary tuberculosis (case) and chronic heart failure (control) was conducted. Metals and biomarkers were quantified in the pleural effusion. The air pollution exposure was measured and PM deposition in the head, tracheobronchial, alveolar region, and total lung region was estimated by Multiple-path Particle Dosimetry (MPPD) Model. We performed multiple logistic regression to examine the associations of these factors with the risk of tuberculosis. We observed that 1-μg/m 3 increase in PM 10 was associated with 1.226-fold increased crude odds ratio (OR) of tuberculosis (95% confidence interval (CI): 1.023-1.469, p<0.05), 1-μg/m 3 increase in PM 2.5-10 was associated with 1.482-fold increased crude OR of tuberculosis (95% CI: 1.048-2.097, p < 0.05), 1-ppb increase in NO 2 was associated with 1.218-fold increased crude OR of tuberculosis (95% CI: 1.025-1.447, p < 0.05), and 1-ppb increase in O 3 was associated with 0.735-fold decreased crude OR of tuberculosis (95% CI: 0.542 0.995). We observed 1-μg/m 3 increase in PM deposition in head and nasal region was associated with 1.699-fold increased crude OR of tuberculosis (95% CI: 1.065-2.711, p < 0.05), 1-μg/m 3 increase in PM deposition in tracheobronchial region was associated with 1.592-fold increased crude OR of tuberculosis (95% CI: 1.095-2.313, p < 0.05), 1-μg/m 3 increase in PM deposition in alveolar region was associated with 3.981-fold increased crude OR of tuberculosis (95% CI: 1.280-12.386, p < 0.05), and 1-μg/m 3 increase in PM deposition in total lung was associated with 1.511-fold increased crude OR of tuberculosis (95% CI: 1.050-2.173, p < 0.05). The results indicate that particle deposition in alveolar region could cause higher risk of pulmonary tuberculosis pleurisy than deposition in other lung regions., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Depressed people are prone to sleep disturbance, which may in return perpetuate the depression. Both depression and sleep disturbance influence proinflammatory cytokines interleukin (IL) 6 and 1β. Thus interventions for depression should consider the effect on sleep disturbance, and vice versa. Integrative Body-Mind-Spirit (IBMS) and Qigong interventions have been applied in a wide range of health and mental health conditions, including depression and sleep disturbance. This study aimed to evaluate the effect of these two mind-body therapies for persons with both depressive symptoms and sleep disturbance. A three-arm randomized controlled trial was conducted among 281 participants, who were randomly assigned to either IBMS, Qigong or wait list control group. Participants in IBMS and Qigong groups received eight weekly sessions of intervention. Outcome measures were plasma concentrations of IL-6 and IL-1β, and a questionnaire containing Pittsburgh Sleep Quality Index, Center for Epidemiologic Studies Depression Scale, Somatic Symptom Inventory, Perceived Stress Scale and Body-Mind-Spirit Holistic Well-being Scale. Outcomes were assessed at baseline (T0), immediate post-intervention (T1) and at three-months post-intervention (T2). Besides intervention efficacy analysis, path analysis was performed to explore the relations among perceived stress, depression, sleep disturbance, and IL-6 and IL-1β values. The study found both IBMS and Qigong reduced depression, sleep disturbance, painful and painless somatic symptoms, IL-6 and IL-1β levels, and increased holistic well-being. The effect sizes of IBMS and Qigong, mostly in the medium magnitude range, were approximatively equivalent. Path analysis models revealed a predictive role of perceived stress in depression and sleep disturbance, a bidirectional relationship between depression and sleep disturbance, and significant influence of depression and sleep disturbance on IL-6 and IL-1β. Compared with control, the findings support the efficacy of IBMS and Qigong interventions in relieving depression and sleep disturbance, and in reducing IL-6 and IL-1β levels., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The papilionoid legume genus Ormosia (Fabaceae) comprises about 150 species of trees and exhibits a striking disjunct geographical distribution between the New World- and Asian and Australasian wet tropics and subtropics. Modern classifications of Ormosia are not grounded on a well-substantiated phylogenetic hypothesis and have been limited to just portions of the geographical range of the genus. The lack of an evolutionarily-based foundation for systematic studies has hindered taxonomic work on the genus and prevented the testing of biogeographical hypotheses related to the origin of the Old World/New World disjunction and the individual dispersal histories within both areas. Here, we present the most comprehensively sampled molecular phylogeny of Ormosia to date, based on analysis of both nuclear (ITS) and plastid (matK and trnL-F) DNA sequences from 82 species of the genus. Phylogenetically-based divergence times and ancestral range estimations are employed to test hypotheses related to the biogeographical history of the genus. We find strong support for the monophyly of Ormosia and the grouping of all sampled Asian species of the genus into two comparably sized clades, one of which is sister to another large clade containing all sampled New World species. Within the New World clade, additional resolution supports the grouping of most species into three mutually exclusive subordinate clades. The remaining New World species form a fourth well-supported clade in the analyses of plastid sequences, but that result is contradicted by the analysis of ITS. With few exceptions the supported clades have not been previously recognized as taxonomic groups. The biogeographical analysis suggests that Ormosia originated in continental Asia and dispersed to the New World in the Oligocene or early Miocene via long-distance trans-oceanic dispersal. We reject the hypothesis that the inter-hemispheric disjunction in Ormosia resulted from fragmentation of a more continuous "Boreotropical" distribution since the dispersal post-dates Eocene climatic maxima. Both of the Old World clades appear to have originated in mainland Asia and subsequently dispersed into the Malay Archipelago and beyond, at least two lineages dispersing across Wallace's Line as far as the Solomon Islands and northeastern Australia. In the New World, the major clades all originated in Amazonia. Dispersal from Amazonia into peripheral areas in Central America, the Caribbean, and Extra-Amazonian Brazil occurred multiple times over varying time scales, the earliest beginning in the late Miocene. In a few cases, these dispersals were followed by local diversification, but not by reverse migration back to Amazonia. Within each of the two main areas of distribution, multiple modest bouts of oceanic dispersal were required to achieve the modern distributions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases., Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma., Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort., Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, T H 2, and T H 17/T H 22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P < .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P < .05) and particularly in neutrophilic and mixed granulocytic sputum (P < .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with T H 22/IL-22 pathways., Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Interstitial lung abnormalities (ILAs), which refer to mild or subtle nongravity-dependent interstitial changes, may be neglected by some clinicians due to many reasons, such as lack of diagnostic criteria for ILAs and absence of available treatments and surveillance strategies. However, without intervention, some ILAs may progress to interstitial lung disease (ILD). This review summarizes our current knowledge of this condition and ways of diagnosing it together with current management. We hope that this will lead to better recognition of ILAs., Areas Covered: We reviewed the literature on PubMed between 2008 and 2020 focusing on prevalence, etiology, symptoms, diagnostic biomarkers, clinical associations, and management of ILAs., Expert Opinion: Timely diagnosis with close monitoring of ILAs and appropriate intervention should be recognized as the management approach to ILAs. Research into ILAs should continue to improve its management.

Objective: To evaluate the efficacy and credibility of a smartphone-delivered multicomponent lifestyle medicine (LM) intervention, Lifestyle Hub, as a primary modality for managing depressive symptoms in an adult Chinese population., Method: Participants with at least a moderate level of depressive symptoms (n = 79), as indicated by a Patient Health Questionnaire-9 score of ≥10, were randomly assigned to an LM intervention group (LMG; n = 39; eight weekly sessions) or a waitlist control group (WLG; n = 40)., Results: The intention-to-treat analysis revealed significant improvements in depressive symptoms (d = 0.66), generalized anxiety symptoms (d = 0.93), insomnia symptoms (d = 0.20), functional impairment (d = 0.22), and health-related quality of life (HRQoL; d = 0.11) from Week 0 (baseline) to Week 9 (immediate post-intervention assessment) in the LMG relative to the WLG. Moreover, significantly more health-promoting behaviors (overall health behaviors, health responsibility, physical activity level, nutrition, spiritual growth, and stress management) (d = 0.40-0.89) and higher levels of total activity (d = 0.55) and walking activity (d = 0.55) were found at Week 9 in the LMG relative to the WLG. However, no significant differences were observed in interpersonal relationships, vigorous and moderate exercise levels, sedentary behavior levels, or food frequency questionnaire measures at Week 9 between the LMG and the WLG. From Week 9 to Week 13 (1-month follow-up assessment), a significant within-group reduction in HRQoL (d = 0.50) and an increase in alcohol intake (d = 0.41) were observed in the LMG., Conclusions: The smartphone-delivered multicomponent LM intervention Lifestyle Hub may serve as a primary modality for managing depressive symptoms. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background and Objectives: We studied whether the extent of exertional oxygen desaturation and emphysema could cause greater mortality in COPD and asthma independent of airflow obstruction. Materials and Methods: We performed a 5-year longitudinal observational study in COPD and asthma patients who matched for airflow obstruction severity. All subjects performed a 6-min walk test (6MWT) and high-resolution computed tomography (HRCT) and followed spirometry and oxygen saturation (SpO 2 ) during the 6MWT every 3-6 months. Overall survival was recorded. Cumulative survival curves were performed according to the Kaplan-Meier method and compared with the log-rank test. Results: The COPD group had higher emphysema scores, higher Δinspiratory capacities (ICs) and lower SpO 2 during the 6MWT, which showed a greater yearly decline in FEV 1 (40.6 mL) and forced vital capacity (FVC) (28 mL) than the asthma group (FEV 1 , 9.6 mL; FVC, 1.2 mL; p < 0.05). The emphysema-predominant COPD group had an accelerated annual decline in lung function and worse survival. The nadir SpO 2 ≤ 80% and a higher emphysema score were the strong risk factors for mortality in COPD patients. Conclusions: The greater structural changes with a higher emphysema score and greater desaturation during the 6MWT in COPD may contribute to worse yearly decline in FEV 1 and higher five-year mortality than in asthma patients with a similar airflow obstruction. The lowest SpO 2 ≤ 80% during the 6MWT and emphysema-predominant COPD were the strong independent factors for mortality in chronic obstructive airway disease patients.

Objectives: This pilot study aimed to examine the efficacy of integrated cognitive behavioral therapy (CBT) and acupressure in treating insomnia and its daytime impairments in a Chinese adult population., Methods: 40 eligible participants with insomnia were randomly assigned to either the integrated CBT and acupressure (CBTAcup) group (n = 14), the CBT group (n = 13), or the waitlist control (WL) group (n = 13). Participants in the CBTAcup group attended a 2-hour integrated CBT and self-administered acupressure group treatment once per week for six consecutive weeks, while participants in the CBT group attended six weekly 2-hour CBT for insomnia. Sleep, mood, daytime impairments, quality of life, and treatment credibility and adherence were assessed at baseline, immediate post-treatment (Week 7), and 4-week post-treatment (Week 11)., Results: Linear mixed-effects models showed that both the CBTAcup and CBT groups had significantly lower insomnia severity (d = -1.74 and d = -2.61), dysfunctional beliefs related to sleep (d = -2.17 and -2.76), and mental fatigue (d = -1.43 and -1.60) compared with the WL group at Week 7. The CBTAcup group provided additional benefits in reducing total fatigue (d = -1.43) and physical fatigue (d = -1.45). Treatment credibility was found to be improved in the CBTAcup group from baseline to Week 7., Conclusions: Integrated CBT and acupressure demonstrated comparable efficacy to pure CBT in treating insomnia symptoms, with additional advantages to improve fatigue symptoms and acceptability in the Chinese population. Further methodologically rigorous studies on a larger scale and longer follow-up are warranted to confirm these findings., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Accumulating evidence has suggested bidirectionality between sleep problems and depression, but the underlying mechanism is unclear. We assessed the role of sleep in inhibitory control ability with emotional stimuli, which has been shown to be suboptimal among individuals with depression and proposed to perpetuate depressive symptoms., Methods: Emerging adults (aged 18-25 years, 64.6% female) were screened for depressive and other mental disorders by structured clinical interview and questionnaire. Individuals with depressive disorders were assigned to have a polysomnography-monitored daytime sleep opportunity (Sleep-Dep, n = 20), whereas nondepressed individuals were randomized to either have daytime sleep (Sleep-Ctrl, n = 27) or stay awake (Wake-Ctrl, n = 18). Participants completed the Affective Go/No-Go Task two times, separated by experimental conditions., Results: A factorial model with a between-subject factor (Sleep-Dep/Sleep-Ctrl/Wake-Ctrl) and a within-subject factor (test 1/test 2) was used to assess if the groups differed in inhibitory control across test sessions, as inferred by changes in d-prime and false alarm rates (FA). Results from mixed factorial models showed a significant interaction effect between time and group on FA in the block with neutral faces as the target and happy faces as the nontarget (F(2,61) = 5.15, pfdr = .045). Although Sleep-Dep had decreased FA after sleep (t(19) = 2.94, pfdr = .050), Sleep-Ctrl and Wake-Ctrl had no significant between-session changes (p values > .05). Postsleep improvement in FA in Sleep-Dep correlated with longer stage 2 sleep (r(20) = 0.788, pfdr < .001) and stage 2 fast spindle number at O1 (r(18) = 0.692, pfdr = .015)., Conclusions: Sleep gain, particularly stage 2 sleep and related physiology, potentially enhances inhibitory control ability responding to emotional information among individuals with depressive disorders., (Copyright © 2021 by the American Psychosomatic Society.)

Given the growing evidence that a range of lifestyle factors are involved in the etiology of depression, a 'lifestyle medicine' approach can be potentially safe and cost-effective to prevent or treat depression. To examine the effects and acceptability of a group-based, integrative lifestyle medicine intervention as a standalone treatment for managing depressive symptoms, a pilot randomized controlled trial (RCT) was conducted in a Chinese adult population in 2018. Participants (n = 31) with PHQ-9 score above the cut-off of ≥ 10, which was indicative of moderate to severe depression, were recruited from the general community in Hong Kong and randomly assigned to lifestyle medicine group (LM group) or care-as-usual group (CAU group) in a ratio of 1:1. Participants in the LM group received 2-hour group sessions once per week for six consecutive weeks, which covered diet, exercise, mindfulness, psychoeducation, and sleep management. Linear mixed-effects model analyses showed that the LM group had a significant reduction in PHQ-9 scores compared to the CAU group at immediate posttreatment and 12-week posttreatment follow-up (d = 0.69 and 0.73, respectively). Moreover, there were significantly greater improvements in anxiety, stress, and insomnia symptoms (measured by DASS-21 and ISI) at all time points in the LM group (d = 0.42-1.16). The results suggests that our 6-week group-based, integrative lifestyle intervention program is effective in lowering depressive, anxiety, stress, and insomnia symptoms in the Chinese population. Further studies in clinical populations with a larger sample size and longer follow-up are warranted., Competing Interests: None.

Competing Interests: I have received honoraria for participating on Advisory Board meetings of GlaxoSmithKline, AstraZeneca, Roche, Novartis, Merck, Nocion, and Shionogi regarding treatments for asthma, chronic obstructive pulmonary disease, and chronic cough, and have also been renumerated for speaking engagements.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were shown to have potential for immunoregulation and tissue repair. The objective of this study was to investigate the effects of hUC-MSCs on emphysema in chronic obstructive pulmonary disease (COPD). The C57BL/6JNarl mice were exposed to cigarette smoke (CS) for 4 months followed by administration of hUC-MSCs at 3 × 10 6 (low dose), 1 × 10 7 (medium dose), and 3 × 10 7 cells/kg body weight (high dose). The hUC-MSCs caused significant decreases in emphysema severity by measuring the mean linear intercept (MLI) and destructive index (DI). A decrease in neutrophils (%) and an increase in lymphocytes (%) in bronchoalveolar lavage fluid (BALF) were observed in emphysematous mice after hUC-MSC treatment. Lung levels of interleukin (IL)-1β, C-X-C motif chemokine ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and matrix metalloproteinase (MMP)-12 significantly decreased after hUC-MSC administration. Significant reductions in tumor necrosis factor (TNF)-α, IL-1β, and IL-17A in serum occurred after hUC-MSC administration. Notably, the cell viability of lung fibroblasts improved with hUC-MSCs after being treated with CS extract (CSE). Furthermore, the hUC-MSCs-conditioned medium (hUC-MSCs-CM) restored the contractile force, and increased messenger RNA expressions of elastin and fibronectin by lung fibroblasts. In conclusion, hUC-MSCs reduced inflammatory responses and emphysema severity in CS-induced emphysematous mice., Competing Interests: WL, C-HC, and Y-CW are employed by Meridigen Biotech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Chen, Lin, Chen, Wen, Hsiao, Chou, Chung and Chuang.)

The development of emphysema has been linked to air pollution; however, the association of air pollution with the extent of lobar emphysema remains unclear. This study examined the association of particulate matter <2.5 μm in aerodynamic diameters (PM 2.5 ) (≤2.5 μm), nitrogen dioxide (NO 2 ), and ozone (O 3 ) level of exposure with the presence of emphysema in 86 patients with chronic obstructive pulmonary disease (COPD). Exposure to the air pollution estimated using the land-use regression model was associated with lung function, BODE (a body mass index, degree of obstruction, dyspnea severity, and exercise capacity index) quartiles, and emphysema measured as low-attenuation areas on high-resolution CT (HR-CT) lung scans. Using paraseptal emphysema as the reference group, we observed that a 1 ppb increase in O 3 was associated with a 1.798-fold increased crude odds ratio of panlobular emphysema ( p < 0.05). We observed that PM 2.5 was associated with BODE quartiles, modified Medical Research Council (mMRC) dyspnea score, and exercise capacity (all p < 0.05). We found that PM 2.5 , NO 2 , and O 3 were associated with an increased degree of upper lobe emphysema and lower lobe emphysema (all p < 0.05). Furthermore, we observed that an increase in PM 2.5 , NO 2 , and O 3 was associated with greater increases in upper lobe emphysema than in lower lobe emphysema. In conclusion, exposure to O 3 can be associated with a higher risk of panlobular emphysema than paraseptal emphysema in patients with COPD. Emphysema severity in lung lobes, especially the upper lobes, may be linked to air pollution exposure in COPD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tung, Ho, Lu, Chen, Lee, Chen, Wu, Chung, Kuo, Thao, Dung, Thuy, Wu, Kou, Lee and Chuang.)

The novelty of this study is that it identified the associations between PM 2.5 deposition in the lung and the degree of emphysema in different lung lobes of COPD patients, especially in the right middle lobe and both upper lobes https://bit.ly/3k21ri0., Competing Interests: Conflict of interest: N.T. Nguyen has nothing to disclose. Conflict of interest: S-C. Ho has nothing to disclose. Conflict of interest: Y-H. Lu has nothing to disclose. Conflict of interest: T-T. Chen has nothing to disclose. Conflict of interest: K-Y. Lee has nothing to disclose. Conflict of interest: K-Y. Chen has nothing to disclose. Conflict of interest: C-D. Wu has nothing to disclose. Conflict of interest: K.F. Chung has nothing to disclose. Conflict of interest: H-P. Kuo has nothing to disclose. Conflict of interest: H.N.X. Thao has nothing to disclose. Conflict of interest: H.B. Dung has nothing to disclose. Conflict of interest: T.P.C. Tran has nothing to disclose. Conflict of interest: S-M Wu has nothing to disclose. Conflict of interest: H-Y. Kou has nothing to disclose. Conflict of interest: Y-L. Lee has nothing to disclose. Conflict of interest: H-C. Chuang has nothing to disclose., (Copyright ©The authors 2021.)

In response to the worsening situation of the COVID pandemic, this follow-up study aimed to assess the impact of the "third wave" of the outbreak on sleep and mood disturbances among Hong Kong citizens. A total of 339 respondents included in our last study during the second wave (4-11 August 2020) joined this survey (response rate = 51.1%). The questionnaire collected data on sleep conditions, mood, stress, and risk perception. The sleep quality and mood status were assessed using the Insomnia Severity Index (ISI), General Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9. The weighted prevalence of insomnia, anxiety, and depression was 33.6%, 15.3%, and 22.0%, respectively. Compared with the last survey, five out of six sleep parameters significantly worsened despite the lack of difference in the ISI score. The GAD-7 score was significantly lower. Old-aged adults were less likely to maintain good sleep quality compared with middle-aged adults (adjusted OR = 4.03, 95% CI: 1.04-15.73). Respondents without psychiatric disorder were more likely to be anxiety-free across the two time points (adjusted OR = 7.12, 95% CI: 1.33-38.03). One-third of Hong Kong people reported poor sleeping quality in the third wave of the COVID-19 outbreak. Policy-makers need to propose a contingent plan to allocate mental health resources to vulnerable subpopulations.

Despite substantial evidence of marked exposure to and ill-health effects from diesel exhaust (DE) emissions among occupational population (e.g., miners, truck drivers, and taxi drivers), it is less understood to what extent non-occupational population was exposed to DE among various combustion sources, largely due to the lack of biomarkers that would indicate specific exposure to DE. We evaluated whether urinary amino-polycyclic aromatic hydrocarbons (APAHs), such as major metabolites of DE-specific nitrated PAHs, can be used as DE exposure biomarkers in residential settings. We measured five urinary APAHs in 177 urine samples from 98 UK residents, 89 (91%) of them were London residents, and estimated their residential proximity to various traffic indicators (e.g., the road type, road length, traffic flow, and traffic volume). Participants living within 100 m of major roads exhibited increased levels of all five APAHs, among which 2-amino-fluorene (2-AFLU) reached statistical significance ( p < 0.05). We estimated that a 10 m increase in the length of nearby major roads (<100 m) was associated with a 4.4% (95% CI of 1.1 to 7.6%) increase in 2-AFLU levels. Levels of 2-AFLU were significantly associated with the traffic flow of nearby buses and heavy-duty vehicles but not motorbikes, taxis, or coaches. We did not observe a significant association between distance to major roads or the sum of the major road length within 100 m with the other four biomarker concentrations. These results suggest the use of urinary 2-AFLU as a biomarker of DE exposure in urban residents.

Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways. Objectives: To measure whether AR and its ligands are associated with human asthma outcomes. Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (Fe NO ) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey). Measurements and Main Results: In SARP ( n  = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV 1 /FVC ratio ( R 2  = 0.135, P  = 0.0002) and the total Asthma Quality of Life Questionnaire score ( R 2  = 0.056, P  = 0.016) and was negatively associated with Fe NO ( R 2  = 0.178, P  = 9.8 × 10 -6 ) and NOS2 (nitric oxide synthase gene) expression ( R 2  = 0.281, P  = 1.2 × 10 -10 ). In SARP ( n  = 1,659), the Cleveland Clinic Health System ( n  = 32,527), and the NHANES ( n  = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV 1 in both women and men. Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower Fe NO in human asthma. The role of androgens should be considered in asthma management.

Patients with chronic obstructive asthma (COA) develop airflow obstruction caused by subepithelial fibrosis. Although a disintegrin and metalloproteinase 17 (ADAM17) has been implicated in lung inflammation and tissue fibrosis, its role in airway fibrosis in COA has not been explored. Here, we found marked overexpression of ADAM17, phosphorylated ADAM17, and connective tissue growth factor (CTGF) in human airway fibroblasts from COA patients, compared with those of normal subjects. Similarly, levels of ADAM17, CTGF, α-smooth muscle actin (α-SMA), and collagen were increased in endobronchial biopsies from COA patients, but not in controls. In an ovalbumin-challenge asthma model, airway fibrosis was inhibited in ADAM17 f/f /Cre + mice compared to control mice. TGF-β- and thrombin-induced fibrotic protein expression was reduced by ADAM17 small interfering (si)RNA, TAPI-0 (an ADAM17 inhibitor), and EGFR siRNA. In addition, exogenous HB-EGF reversed fibrotic response in ADAM17 knockdown human lung fibroblasts. ADAM17 causes subepithelial fibrosis through regulation of enhanced extracellular matrix production and fibroblast differentiation and is the common pathway for airway fibrosis mediated by TGF-β and thrombin through an aberrant ADAM17/EGFR signalling pathway., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Acupuncture is an alternative treatment for improving sleep, and it may attenuate oxidative stress, which is a possible pathophysiological factor in insomnia. The aim of this study was to examine the efficacy and safety of a semi-individualized acupuncture in improving sleep and explore its effect on oxidative stress parameters in adults with insomnia disorder., Methods: In this randomized sham-controlled trial, 140 participants were randomly assigned to either a 4-week semi-individualized traditional acupuncture (TA) or noninvasive sham acupuncture (SA). The primary outcome measure was the sleep-diary-derived sleep efficiency. Other outcomes included sleep diary and actigraphy, Insomnia Severity Index, anxiety and depressive symptoms, and quality of life. Blood samples were taken to measure oxidative stress parameters (malondialdehyde, glutathione peroxidase, paraoxonase, and arylesterase)., Results: Although no significant difference was found in the primary outcome measure, both sleep-diary-derived and actigraphy-derived total sleep time (TST) were significantly increased in the TA group at 1-week posttreatment (mean difference in sleep diary = 22.0 min, p = 0.01, actigraphy = 18.8 min, p = 0.02). At 5-week posttreatment follow-up, a significantly higher proportion of participants in the TA group showed sleep-diary-derived sleep efficiency (SE) ≥ 85% than in the SA group (55.6% versus 36.4%, p = 0.03)., Conclusion: TA and SA did not significantly differ in improving subjective sleep efficiency in individuals with insomnia disorder. However, the TA group showed a short-term effect on improving TST as measured by both sleep diary and actigraphy at 1-week posttreatment, but there were no differences in the oxidative stress parameters., Clinical Trial Registration: Registry: ClinicalTrials.gov; Title: Acupuncture in the Modulation of Peripheral Oxidative Stress Insomnia; Identifier NCT03447587; URL: https://clinicaltrials.gov/ct2/show/NCT03447587., Competing Interests: The Authors declare that there were no conflicts of interest and no financial assistance was received in support of the study., (© 2021 Yeung et al.)

Fine particulate matter (PM 2.5 ) is an important component of air pollution and can induce lung inflammation and oxidative stress. We hypothesized that PM 2.5 could play a role in the induction of pulmonary fibrosis. We examined whether multiple intranasal instillation of PM 2.5 can induce pulmonary fibrosis in the mouse, and also investigated the underlying pro-fibrotic signaling pathways. C57/BL6 mice were intranasally instilled with 50 μl of PM 2.5 suspension (7.8 μg/g body weight) or PBS three times a week over 3 weeks, 6 weeks or 9 weeks. To observe the recovery of pulmonary fibrosis after the termination of PM 2.5 exposure, 9 week-PM 2.5 instilled mice were also studied at 3 weeks after termination of instillation. There were significant decreases in total lung capacity (TLC) and compliance (Cchord) in the 9-week PM 2.5 -instilled mice, while there were increased histological fibrosis scores with enhanced type I collagen and hydroxyproline deposition, increased mitochondrial ROS levels and NOX activity, decreased total SOD and GSH levels, accompanied by decreased mitochondrial number and aberrant mitochondrial morphology (swelling, vacuolization, cristal disruption, reduced matrix density) in PM 2.5 -instilled mice. Multiple PM 2.5 instillation resulted in increased expression of TGFβ1, increases of N-Cadherin and Vimentin and a decrease of E-Cadherin. It also led to decreases in OPA1 and MFN2, and increases in Parkin, SQSTM1/p62, the ratio of light china (LC) 3B II to LC3B I, PI3k/Akt phosphorylation, and NLRP3 expression. Intranasal instillation of PM 2.5 for 9 weeks induced lung inflammation and pulmonary fibrosis, which was linked with aberrant epithelial-mesenchymal transition, oxidative stress, mitochondrial damage and mitophagy, as well as activation of TGFβ1-PI3K/Akt, TGFβ1- NOX and TGFβ1-NLRP3 pathways., (© 2021 Wiley Periodicals LLC.)

Background: Although estimates of suboptimal adherence to oral corticosteroids in asthma range from 30% to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high., Research Questions: What is the prevalence of suboptimal adherence detected by self-reporting and direct measures? Is suboptimal adherence associated with disease activity?, Study Design and Methods: Data were included from individuals with severe asthma taking part in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study and prescribed daily oral corticosteroids. Participants completed the Medication Adherence Report Scale, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid chromatography-mass spectrometry., Results: Data from 166 participants were included in this study: mean (SD) age, 54.2 (± 11.9) years; FEV 1 , 65.1% (± 20.5%) predicted; female, 58%; 37% completing the Medication Adherence Report Scale reported suboptimal adherence; and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 49 of the 142 (35%) of participants in whom both methods were performed; adherence detection did not match between methods in 53%. Self-reported high adherers had better asthma control and quality of life, whereas directly measured high adherers had lower blood eosinophil levels., Interpretation: Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods, suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: Despite substantial evidence on the contribution of the diversity of the gut microbiome to the pathogenesis of asthma and allergic diseases, little is known about their relationship with asthma severity and/or clinical phenotypes. We analyzed the difference in composition of the gut microbiome between subjects with asthma and healthy subjects and explored its role in the development of asthma., Methods: Fecal samples from 15 subjects with severe asthma (SA), 14 with non-severe asthma (NSA), and 15 healthy subjects were assessed by 16S ribosomal RNA gene sequencing methods to identify the gut bacterial composition., Results: Compared with those in the NSA group, patients in the SA group had a higher dose of inhaled corticosteroids, and there were more atopic subjects (60% vs. 35.7%, respectively). No significant differences were found at the phylum level either in operational taxonomic unit numbers or in diversity scores among the SA, NSA, and healthy groups. However, at the family level, the relative abundance of Acidaminococcaceae in the SA group was remarkedly lower than that in the group with healthy subjects (P<0.05). Furthermore, Veillonellaceae and Prevotellaceae were significantly more common in samples from the SA group than in those from the NSA group (P<0.05). In the SA group, positive correlations were observed between the relative abundance of Veillonellaceae and mid-expiratory flow 25% (MEF25%) predicted (r=0.538, P=0.047), as well as between the relative abundance of Acidaminococcaceae and body mass index (r=0642, P=0.010). Principal component analysis suggested that the relative abundances of Acidaminococcaceae and Prevotellaceae were associated with severe asthma. Moreover, we found that class Betaproteobacteria , order Burkholderiales , and family Alcaligenaceae were significantly different among the groups defined by serum immunoglobulin E (IgE) levels., Conclusions: Our findings suggest that altered gut microbiome compositions are involved in the severity of asthma and that there are specific bacteria related to different asthma phenotypes in terms of serum IgE levels., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form. (Available at https://dx.doi.org/10.21037/jtd-20-2189). Prof. Kian Fan Chung serves as an unpaid associate editor-in-chief of Journal of Thoracic Disease. The authors have no other conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Purpose: Although genome-wide association studies (GWASs) represent the most powerful approach for identifying genes that influence asthma, to date, no studies have established genetic susceptibility to asthma in the Korean population. This study aimed to identify genetic variants associated with adult Korean asthmatics and compare them with the significant single nucleotide polymorphisms (SNPs) of UK asthmatics from the UK Biobank., Methods: Patients were defined as having asthma if they were diagnosed by a doctor or taking medications for asthma. Controls were defined as individuals without asthma or chronic obstructive pulmonary disease. We performed quality control, genotype imputation, GWAS, and PrediXcan analyses. In the GWAS, a P value of < 5 × 10 -8 was considered significant. We compared significant SNPs between Korean and UK patients with asthma., Results: A total of 1,386 asthmatic patients and 5,205 controls were analyzed. The SNP rs1770, located near the human leukocyte antigen (HLA)-DQB1, was the most significant SNP ( P = 4.5 × 10 -10 ). In comparison with 24 SNPs in a GWAS of UK asthmatics, six SNPs were significant with the same odds ratio (OR) direction, including signals related to type 2 inflammation ( e.g. , IL1RL1, TSLP, and GATA3) and mucus plugging ( e.g. , MUC5AC). HLA-DQA1 showed an opposite OR direction. The HLA-DQB1 gene demonstrated significantly imputed mRNA expression in the lung tissue and whole blood., Conclusions: The SNP rs1770 of HLA-DQB1 was the most significant in Korean asthmatics. Similarities and discrepancies were found in the genetic variants between Korean and UK asthmatics. GWAS of Korean asthmatics should be replicated and compared with those of GWAS of other ethnicities., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2021 The Korean Academy of Asthma, Allergy and Clinical Immunology · The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Type 1 CD4 + T helper (Th1) cells mediate resistance to Mycobacterium tuberculosis (Mtb), and Th2 immunity generates specific immunoglobulin E upon allergen exposure. We investigated the impact of active tuberculosis (TB), atopic status, and anti-TB treatment on the balance between Th1 and Th2 (type 2 CD4 + T helper) immunity. CD4 + /interferon (IFN)-γ + Th1 cells (%Th1) and CD4 + /interleukin-4 + Th2 cells (%Th2) in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) were measured by flow cytometry. The BAL %Th1 was higher in TB patients at baseline, compared to that in non-TB subjects, and was further increased in TB patients after stimulation with phorbol myristate acetate and ionomycin. The stimulated BAL %Th1 was inversely correlated with the severity score of chest radiography in TB patients. Heat-killed Mtb triggered more IFN-γ and nitrite production, as determined by enzyme-linked immunosorbent assay and the Griess reaction, respectively, from the alveolar macrophages of TB patients than that of non-TB subjects. Non-atopic TB participants had a higher %Th1 in PBMCs, compared to atopic individuals, and their %Th1 decreased after 3-month anti-TB treatment. Th1 response is provoked by active TB infection, is associated with less severe radiographic changes, is reduced in atopic patients with active TB infection, and is attenuated after anti-TB treatment.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is often misdiagnosed as severe asthma due to their similar clinical presentations. We compared the pulmonary radiologic features of EGPA to those of severe asthma by high-resolution computed tomography (HRCT) in order to early diagnose EGPA., Methods: We retrospectively reviewed clinical records and HRCT findings of 96 patients with EGPA and 82 patients with severe asthma who were seen at our hospital from 2011 to 2017. We used a semi-quantitative grading system to evaluate radiological findings. A radiological only and a clinical-radiological model were used to differentiate EGPA from severe asthma., Results: Bronchial wall thickening, air trapping, tree-in-bud opacities, bronchial mucus plugging, bronchiectasis, diffuse ground-glass opacities (GGOs), consolidation, and increased small vascular markings were more common in EGPA patients than in severe asthmatics (P<0.05). The gradings of GGO (grade 2 vs. grade 1) and tree-in-bud opacities (grade 2 vs. grade 0) were higher in EGPA patients than in severe asthmatics. The total image score of EGPA patients was significantly higher than that of severe asthmatics (P<0.05). In the radiological only and the clinical-radiological model, the area under the receiver operating characteristic (ROC) curves (AUCs) for the identification of EGPA and severe asthma were 0.904 [95% confidence interval (CI): 0.860 to 0.948] and 0.974 (95% CI: 0.955 to 0.993), respectively., Conclusions: Lung HRCT scan is useful in differentiating EGPA from severe asthma. In patients with difficult-to-treat asthma, an HRCT scan of the thorax should be performed should there be features that raise the suspicion of EGPA., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-2243). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein; however, the role of pulmonary ITIH4 after exposure to air pollution remains unclear. In this study, we investigated the role of ITIH4 in the lungs in response to air pollution. ITIH4 expression in bronchoalveolar lavage fluid (BAL) of 47 healthy human subjects and of Sprague-Dawley rats whole-body exposed to air pollution was determined, and the underlying antiapoptotic and matrix-stabilizing pathways in alveolar epithelial A549 cells induced by diesel exhaust particles (DEPs) as well as ITIH4-knockdown were investigated. We found that an interquartile range (IQR) increase in PM 2.5 was associated with a decrease of 2.673 ng/mL in ITIH4, an increase of 1.104 pg/mL of 8-isoprostane, and an increase of 6.918 pg/mL of interleukin (IL)-6 in human BAL. In rats, increases in 8-isoprostane, IL-6, and p53 and a decrease in sirtuin-1 (Sirt1) in the lungs and decreases in ITIH4 in the BAL, lungs, and serum were observed after PM 2.5 and gaseous exposure. ITIH4 levels in lung lysates were correlated with levels in BAL samples (r = 0.377, p < 0.01), whereas ITIH4 levels in BAL were correlated with IL-6 levels (r = -0.420, p < 0.01). ITIH4 expression was significantly reduced in alveolar epithelial A549 cells by DEP in a dose-dependent manner. A decrease in Sirt1 and increases in phosphorylated extracellular signal-regulated kinase (p-ERK) and caspase-3 were observed after DEP exposure and ITIH4-knockdown. In conclusion, air pollution decreased ITIH4 expression in the lungs, which was associated with alveolar epithelial cell senescence and apoptosis. ITIH4 could be a vital protein in regulating alveolar cell destruction and its inhibition after exposure to air pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Shaping global water and carbon cycles, plants lift water from roots to leaves through xylem conduits. The importance of xylem water conduction makes it crucial to understand how natural selection deploys conduit diameters within and across plants. Wider conduits transport more water but are likely more vulnerable to conduction-blocking gas embolisms and cost more for a plant to build, a tension necessarily shaping xylem conduit diameters along plant stems. We build on this expectation to present the Widened Pipe Model (WPM) of plant hydraulic evolution, testing it against a global dataset. The WPM predicts that xylem conduits should be narrowest at the stem tips, widening quickly before plateauing toward the stem base. This universal profile emerges from Pareto modeling of a trade-off between just two competing vectors of natural selection: one favoring rapid widening of conduits tip to base, minimizing hydraulic resistance, and another favoring slow widening of conduits, minimizing carbon cost and embolism risk. Our data spanning terrestrial plant orders, life forms, habitats, and sizes conform closely to WPM predictions. The WPM highlights carbon economy as a powerful vector of natural selection shaping plant function. It further implies that factors that cause resistance in plant conductive systems, such as conduit pit membrane resistance, should scale in exact harmony with tip-to-base conduit widening. Furthermore, the WPM implies that alterations in the environments of individual plants should lead to changes in plant height, for example, shedding terminal branches and resprouting at lower height under drier climates, thus achieving narrower and potentially more embolism-resistant conduits., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Given that the perinatal period is a time of increased risk for pregnant women to manifest mental health problems, the identification of antenatal hypomanic symptoms is particularly important. However, data on antenatal hypomanic symptoms is lacking. The present study was aimed at filling this research gap by investigating the prevalence of hypomanic symptoms, including the "active-elated" and "irritable/risk-taking" sides of hypomanic symptoms at the first trimester, and examining their associations with anxiety and depressive symptoms at the following time points: the first trimester, the second trimester, and up to 6-week postpartum. A prospective longitudinal design with a quantitative approach was adopted. A consecutive sample of 229 pregnant Chinese women in Hong Kong was assessed. Hypomanic symptoms were assessed with the Hypomania Checklist-32 (HCL-32). Of the sample, 43.6% had elevated levels of hypomanic symptoms in the first trimester. Multiple regression analysis showed that after adjusting for potential confounding factors, irritable/risk-taking symptoms were independently associated with higher anxiety symptoms in the first and second trimesters and in the 6-week postpartum period. Primary healthcare practitioners should be made aware of antenatal hypomanic symptoms in pregnant women to facilitate early identification and intervention for anxiety and depression to improve the well-being of both mothers and infants.