A missense mutation in Kcnc3 causes hippocampal learning deficits in mice.

Although a wide variety of genetic tools has been developed to study learning and memory, the molecular basis of memory encoding remains incompletely understood. Here, we undertook an unbiased approach to identify novel genes critical for memory encoding. From a large-scale, in vivo mutagenesis screen using contextual fear conditioning, we isolated in mice a mutant, named Clueless, with spatial learning deficits. A causative missense mutation (G434V) was found in the voltage-gated potassium channel, subfamily C member 3 (Kcnc3) gene in a region that encodes a transmembrane voltage sensor. Generation of a Kcnc3G434V CRISPR mutant mouse confirmed this mutation as the cause of the learning defects. While G434V had no effect on transcription, translation, or trafficking of the channel, electrophysiological analysis of the G434V mutant channel revealed a complete loss of voltage-gated conductance, a broadening of the action potential, and decreased neuronal firing. Together, our findings have revealed a role for Kcnc3 in learning and memory.

Maximizing Photoelectrochemical Performance in Metal-Oxide Hybrid Composites via Amorphous Exsolution-A New Exsolution Mechanism for Heterogeneous Catalysis.

Exsolution generates metal nanoparticles anchored within crystalline oxide supports, ensuring efficient exposure, uniform dispersion, and strong nanoparticle-perovskite interactions. Increased doping level in the perovskite is essential for further enhancing performance in renewable energy applications; however, this is constrained by limited surface exsolution, structural instability, and sluggish charge transfer. Here, hybrid composites are fabricated by vacuum-annealing a solution containing SrTiO3 photoanode and Co cocatalyst precursors for photoelectrochemical water-splitting. In situ transmission electron microscopy identifies uniform, high-density Co particles exsolving from amorphous SrTiO3 films, followed by film-crystallization at elevated temperatures. This unique process extracts entire Co dopants with complete structural stability, even at Co doping levels exceeding 30%, and upon air exposure, the Co particles embedded in the film oxidize to CoO, forming a Schottky junction at the interface. These conditions maximize photoelectrochemical activity and stability, surpassing those achieved by Co post-deposition and Co exsolution from crystalline oxides. Theoretical calculations demonstrate in the amorphous state, dopant─O bonds become weaker while Ti─O bonds remain strong, promoting selective exsolution. As expected from the calculations, nearly all of the 30% Fe dopants exsolve from SrTiO3 in an H2 environment, despite the strong Fe─O bond's low exsolution tendency. These analyses unravel the mechanisms driving the amorphous exsolution.

Mechanism for Site-Selective Hydroboration of C70 Fullerene with Borane by DFT-D3 Study.

We studied the hydroboration of the C70 fullerene using both B3LYP-D3(BJ)/6-311G(d,p) and M06-2X-D3/6-311G(d,p) levels of theory, incorporating the empirical dispersion interaction, and Fukui index calculations. Potential energy surfaces (PESs) and Gibbs free energy surfaces (GFESs) were calculated for the pathways from four BH3 adducts (located at the AB, CC, D, and E sites) on the C70 to eight products formed by the 1,2-addition of BH3 across the four [6,6]-ring fused bonds (AB, CC, DE, and EE) and across the two [5,6]-ring fused bonds (AA and DD). These pathways are two-step consecutive reactions. We denoted the positions on the fullerene cage as A through E, from the pole to the equator, based on the D5h symmetry of the C70 fullerene. In the first step reaction, the product ratios for the four adduct intermediates should be as the primary intermediate BH3(D), the secondary intermediate BH3(AB), the tertiary intermediate BH3(CC), and the minor intermediate BH3(E), based on the Fukui indices. In addition, in the second step reaction, transition states (TSs) from four adduct intermediates to eight product isomers, namely, BH2(A)H (B) to BH2(E)H (E), were obtained using the QST2 method. The calculated reaction coordinates showed exothermic reactions for all bonds except the EE bond. We also confirmed the transition states by frequency calculations and intrinsic reaction coordinate (IRC) analyses. The PESs and GFESs suggest spontaneous processes for the four isomers, of which the primary products are BH2(A)H (B) and its isomer BH2(B)H (A), the secondary product is BH2(C)H (C), and the tertiary product is BH2(D)H (D), all formed through adduct intermediates. Therefore, through the hydroboration reaction of C70, we could predict and design the site selectivity of C70 by controlling the energy barrier of the transition state in the second step of the reaction. This implies that we could selectively synthesize mainly BH2(B)H (A) isomers across the AB-[6,6]-ring fused bond and also design BH2(D)H(D) isomers across the DD-[5,6]-ring fused bond. Also, the calculations of formation rate constants can well simulate the experimental ratio of two C70H2 isomers by the hydrolysis of BH2(A)H(B), BH2(B)H(A), and BH2(C)H(C) products at room temperature.

Analysis of PM2.5 inorganic and organic constituents to resolve contributing sources in Seoul, South Korea and Beijing, China and their possible associations with cytokine IL-8.

China and South Korea are the most polluted countries in East Asia due to significant urbanization and extensive industrial activities. As neighboring countries, collaborative management plans to maximize public health in both countries can be helpful in reducing transboundary air pollution. To support such planning, PM2.5 inorganic and organic species were determined in simultaneously collected PM2.5 integrated filters. The resulting data were used as inputs to positive matrix factorization, which identified nine sources at the ambient air monitoring sites in both sites. Secondary nitrate, secondary sulfate/oil combustion, soil, mobile, incinerator, biomass burning, and secondary organic carbon (SOC) were found to be sources at both sampling sites. Industry I and II were only identified in Seoul, whereas combustion and road dust sources were only identified in Beijing. A subset of samples was selected for exposure assessment. The expression levels of IL-8 were significantly higher in Beijing (167.7 pg/mL) than in Seoul (72.7 pg/mL). The associations between the PM2.5 chemical constituents and its contributing sources with PM2.5-induced inflammatory cytokine (interleukin-8, IL-8) levels in human bronchial epithelial cells were investigated. For Seoul, the soil followed by the secondary nitrate and the biomass burning showed increase with IL-8 production. However, for the Beijing, the secondary nitrate exhibited the highest association with IL-8 production and SOC and biomass burning showed modest increase with IL-8. As one of the highest contributing sources in both cities, secondary nitrate showed an association with IL-8 production. The soil source having the strongest association with IL-8 production was found only for Seoul, whereas SOC showed a modest association only for Beijing. This study can provide the scientific basis for identifying the sources to be prioritized for control to provide effective mitigation of particulate air pollution in each city and thereby improve public health.

Del-1 Plays a Protective Role against COPD Development by Inhibiting Inflammation and Apoptosis.

Neutrophilic inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD). Developmental endothelial locus-1 (Del-1) has been reported to limit excessive neutrophilic inflammation by inhibiting neutrophil adhesion to the vascular endothelial cells. However, the effects of Del-1 in COPD are not known. We investigated the role of Del-1 in the pathogenesis of COPD. Del-1 protein expression was decreased in the lungs of COPD patients, especially in epithelial cells and alveolar macrophages. In contrast to human lung tissue, Del-1 expression was upregulated in lung tissue from mice treated with cigarette smoke extracts (CSE). Overexpression of Del-1 significantly suppressed IL-8 release and apoptosis in CSE-treated epithelial cells. In contrast, knockdown of Del-1 enhanced IL-8 release and apoptosis. In macrophages, overexpression of Del-1 significantly suppressed inflammatory cytokine release, and knockdown of Del-1 enhanced it. This anti-inflammatory effect was mediated by inhibiting the phosphorylation and acetylation of NF-κB p65. Nuclear factor erythroid 2-related factor 2 (Nrf2) activators, such as quercetin, resveratrol, and sulforaphane, increased Del-1 in both cell types. These results suggest that Del-1, mediated by Nrf2, plays a protective role against the pathogenesis of COPD, at least in part through anti-inflammatory and anti-apoptotic effects.

Skin-Deep Aspect of Thermopower in Bi2Q3, PbQ, and BiCuQO (Q = Se, Te): Hidden One-Dimensional Character of Their Band Edges Leading to High Thermopower.

ConspectusThermoelectric (TE) materials have received much attention because of their ability to convert heat energy to electrical energy. At a given temperature T, the efficiency of a TE material for this energy conversion is measured by the figure of merit zT, which is related to the thermopower (or Seebeck coefficient) S, the thermal conductivity κ, and the electrical conductivity σ of the TE material as zT = (S2σT)/κ. Bi2Q3 and PbQ (Q = Se, Te) are efficient TE materials with high zT, although they are not ecofriendly and their stability is poor at high temperature. In principle, a TE material can have a high zT if it has a low thermal conductivity and a high electrical conductivity, but the latter condition is hardly met in a real material because the parameters S, σ and κ have a conflicting dependence on material properties. The difficulty in searching for TE materials of high zT is even more exasperated because the relationship between the thermopower S and the carrier density n (hereafter, the S-vs-n relationship) for the well-known hole-doped samples of BiCuSeO showed that the hole carriers responsible for their thermopower are associated largely with the electronic states lying within ∼0.5 eV of its valence band maximum (VBM). Thus, the states governing the TE properties lie in the "skin-deep" region from the VBM. For electron-doped TE systems, the electron carriers responsible for their thermopower should also be associated with the electronic states lying within ∼0.5 eV of the conduction band minimum (CBM). This makes it difficult to predict TE materials of high zT. One faces a similar skin-deep phenomenon in searching for superconductors of high transition temperature because the transition from a normal metallic to a superconducting state involves the normal metallic states in the vicinity of the Fermi level EF. Other skin-deep phenomena in metallic compounds include the formation of charge density wave (CDW), which involves the electronic states in the vicinity of their Fermi levels. For magnetic materials of transition-metal ions, the preferred orientation of their spin moments is a skin-deep phenomenon because it is governed by the interaction between the highest-occupied and the lowest unoccupied d-states of these ions. In the present work we probe the issues concerning how to find the possible range of thermopower expected for a given TE material and hence how to recognize what experimental values of thermopower are expected or unusual. For these purposes, we analyze the accumulated S and n data on the three well-studied TE materials, Bi2Q3, PbQ, and BiCuQO (Q = Se, Te), as representative examples, in terms of the ideal theoretical S-vs-n relationships, which we determine for their defect-free Bi2Q3, PbQ, and BiCuQO structures using density functional theory (DFT) calculations under the rigid band approximation. We find that the general trends in the experimental S-vs-n relationships are reasonably well explained by the calculated S-vs-n relationships, and the carrier densities covering these relationships are associated with the states lying within ∼0.5 eV from their band edges confirming the skin-deep nature of their thermoelectric properties. Despite the fact that these TE materials are not one-dimensional (1D) in structure, they mostly possess sharp density-of-state peaks around their band edges because their band dispersions have a hidden 1D character so their thermopower is generally high in magnitude.

Older Age is Associated With Positional Obstructive Sleep Apnea.

OBJECTIVES: Untreated obstructive sleep apnea (OSA) is associated with cognitive dysfunction; however studies report low adherence rates to standard continuous positive airway pressure (CPAP) treatment in the elderly. Positional OSA (p-OSA) is a subset that can be cured by positional therapy of avoiding supine sleep. However, there is no well-established criteria to identify patients who could benefit from positional therapy as an alternative or adjunct to CPAP. This study investigates if older age is related to p-OSA using different diagnostic criteria. DESIGN: Cross-sectional study. PARTICIPANTS: Participants aged 18 years old or more who underwent polysomnography for clinical reasons at University of Iowa Hospitals and Clinics over a 1-year period from July 2011 to June 2012 were enrolled retrospectively. MEASUREMENT: P-OSA was defined as a high supine-position dependency of obstructive breathing events with potential resolution of OSA in nonsupine positions [high apnea-hypopnea index on supine positions (s-AHI)/ AHI on nonsupine positions (ns0AHI) combined with ns-AHI < 5/hour]. Different cutoff points (2, 3, 5, 10, 15, 20) were applied to determine a meaningful ratio of supine-position dependency of obstructions [s-AHI/ns-AHI]. We compared the proportion of patients with p-OSA between the older age group (≥65 years old) and the propensity score (PS)-matched (upto 1:4) younger age group (<65 years old) using logistic regression analyses. RESULTS: In total, 346 participants were included. The older age group had a higher s-AHI/ns-AHI ratio than the younger age group (mean 31.6 [SD 66.2] versus 9.3 [SD 17.4], median 7.3 [interquartile range [IQR], 3.0-29.6) versus 4.1 (IQR, 1.9-8.7). After PS-matching, the older age group (n = 44) had higher proportion of those with a high s-AHI/ns-AHI ratio and ns-AHI< 5/hour compared with the younger age group (n = 164). (s-AHI/ns-AHI≥10: 54.6% versus 31.7%, OR 2.44 (95% CI, 1.22-4.90); s-AHI/ns-AHI≥15: 47.7% versus 26.2%, OR 2.24 (95% CI, 1.14-4.37); s-AHI/ns-AHI≥20: 40.9% versus 19.5%, OR 2.52 (95% CI, 1.22-5.20)) CONCLUSION: Older patients with OSA are more likely to have severe position dependent OSA, that is potentially more treatable with positional therapy. Thus, clinicians treating older, cognitively impaired geriatric patients unable to tolerate CPAP therapy should consider positional therapy as an adjunct or alternative.

Machine Learning-Based Proteomics Reveals Ferroptosis in COPD Patient-Derived Airway Epithelial Cells Upon Smoking Exposure.

BACKGROUND: Proteomics and genomics studies have contributed to understanding the pathogenesis of chronic obstructive pulmonary disease (COPD), but previous studies have limitations. Here, using a machine learning (ML) algorithm, we attempted to identify pathways in cultured bronchial epithelial cells of COPD patients that were significantly affected when the cells were exposed to a cigarette smoke extract (CSE). METHODS: Small airway epithelial cells were collected from patients with COPD and those without COPD who underwent bronchoscopy. After expansion through primary cell culture, the cells were treated with or without CSEs, and the proteomics of the cells were analyzed by mass spectrometry. ML-based feature selection was used to determine the most distinctive patterns in the proteomes of COPD and non-COPD cells after exposure to smoke extract. Publicly available single-cell RNA sequencing data from patients with COPD (GSE136831) were used to analyze and validate our findings. RESULTS: Five patients with COPD and five without COPD were enrolled, and 7,953 proteins were detected. Ferroptosis was enriched in both COPD and non-COPD epithelial cells after their exposure to smoke extract. However, the ML-based analysis identified ferroptosis as the most dramatically different response between COPD and non-COPD epithelial cells, adjusted P value = 4.172 × 10-6, showing that epithelial cells from COPD patients are particularly vulnerable to the effects of smoke. Single-cell RNA sequencing data showed that in cells from COPD patients, ferroptosis is enriched in basal, goblet, and club cells in COPD but not in other cell types. CONCLUSION: Our ML-based feature selection from proteomic data reveals ferroptosis to be the most distinctive feature of cultured COPD epithelial cells compared to non-COPD epithelial cells upon exposure to smoke extract.

A unique population of neutrophils generated by air pollutant-induced lung damage exacerbates airway inflammation.

BACKGROUND: Diesel exhaust particles (DEPs) are the main component of traffic-related air pollution and have been implicated in the pathogenesis and exacerbation of asthma. However, the mechanism by which DEP exposure aggravates asthma symptoms remains unclear. OBJECTIVE: This study aimed to identify a key cellular player of air pollutant-induced asthma exacerbation and development. METHODS: We examined the distribution of innate immune cells in the murine models of asthma induced by house dust mite and DEP. Changes in immune cell profiles caused by DEP exposure were confirmed by flow cytometry and RNA-Seq analysis. The roles of sialic acid-binding, Ig-like lectin F (SiglecF)-positive neutrophils were further evaluated by adoptive transfer experiment and in vitro functional studies. RESULTS: DEP exposure induced a unique population of lung granulocytes that coexpressed Ly6G and SiglecF. These cells differed phenotypically, morphologically, functionally, and transcriptionally from other SiglecF-expressing cells in the lungs. Our findings with murine models suggest that intratracheal challenge with DEPs induces the local release of adenosine triphosphate, which is a damage-associated molecular pattern signal. Adenosine triphosphate promotes the expression of SiglecF on neutrophils, and these SiglecF+ neutrophils worsen type 2 and 3 airway inflammation by producing high levels of cysteinyl leukotrienes and neutrophil extracellular traps. We also found Siglec8- (which corresponds to murine SiglecF) expressing neutrophils, and we found it in patients with asthma-chronic obstructive pulmonary disease overlap. CONCLUSION: The SiglecF+ neutrophil is a novel and critical player in airway inflammation and targeting this population could reverse or ameliorate asthma.

Ghost-Template-Faceted Synthesis of Tunable Amorphous Hollow Silica Nanostructures and Their Ordered Mesoscale Assembly.

Despite the enormous applications of and fundamental scientific interest in amorphous hollow-silica nanostructures (h-SiNSs), their synthesis in crystal-like nonspherical polygonal architectures is challenging. Herein, we present a facile one-shot synthetic procedure for various unconventional h-SiNSs with controllable surface curvatures (concave, convex, or angular), symmetries (spherical, polygonal, or Janus), and interior architectures (open or closed walls) by the addition of a metal salt and implementing kinetic handles of silica precursor (silanes/ammonia) concentrations and reverse-micellar volume. During the silica growth, we identified the key role of transiently in situ crystallized metal coordination complexes as a nanopolyhedral "ghost template", which provides facet-selective interactions with amino-silica monomers and guides the differential silica growth that produces different h-SiNSs. Additionally, crystal-like well-defined polygonal h-SiNSs with flat surfaces, assembled as highly ordered close-packed octahedral mesoscale materials (ca. 3 µm) where h-SiNSs with different nanoarchitectures act as building units (ca. 150 nm) to construct customizable cavities and nanospaces, differ from conventionally assembled materials.

Orbital Order Melting at Reduced Dimensions.

The orbital degree of freedom, strongly coupled with the lattice and spin, is an important factor when designing correlated functions. Whether the long-range orbital order is stable at reduced dimensions and, if not, what the critical thickness is remains a tantalizing question. Here, we report the melting of orbital ordering, observed by controlling the dimensionality of the canonical eg1 orbital system LaMnO3. Epitaxial films are synthesized with vertically aligned orbital ordering planes on an orthorhombic substrate, so that reducing film thickness changes the two-dimensional planes into quasi-one-dimensional nanostrips. The orbital order appears to be suppressed below the critical thickness of about six unit cells by changing the characteristic phonon modes and making the Mn d orbital more isotropic. Density functional calculations reveal that the electronic energy instability induced by bandwidth narrowing via the dimensional crossover and the interfacial effect causes the absence of orbital order in the ultrathin thickness.

Expression-based species deconvolution and realignment removes misalignment error in multispecies single-cell data.

BACKGROUND: Although single-cell RNA sequencing of xenograft samples has been widely used, no comprehensive bioinformatics pipeline is available for human and mouse mixed single-cell analyses. Considering the numerous homologous genes across the human and mouse genomes, misalignment errors should be evaluated, and a new algorithm is required. We assessed the extents and effects of misalignment errors and exonic multi-mapping events when using human and mouse combined reference data and developed a new bioinformatics pipeline with expression-based species deconvolution to minimize errors. We also evaluated false-positive signals presumed to originate from ambient RNA of the other species and address the importance to computationally remove them. RESULT: Error when using combined reference account for an average of 0.78% of total reads, but such reads were concentrated to few genes that were greatly affected. Human and mouse mixed single-cell data, analyzed using our pipeline, clustered well with unmixed data and showed higher k-nearest-neighbor batch effect test and Local Inverse Simpson's Index scores than those derived from Cell Ranger (10 × Genomics). We also applied our pipeline to multispecies multisample single-cell library containing breast cancer xenograft tissue and successfully identified all samples using genomic array and expression. Moreover, diverse cell types in the tumor microenvironment were well captured. CONCLUSION: We present our bioinformatics pipeline for mixed human and mouse single-cell data, which can also be applied to pooled libraries to obtain cost-effective single-cell data. We also address misalignment, multi-mapping error, and ambient RNA as a major consideration points when analyzing multispecies single-cell data.

Impact of smoking on the development of idiopathic pulmonary fibrosis: results from a nationwide population-based cohort study.

BACKGROUND: Smoking has been considered an important risk factor for idiopathic pulmonary fibrosis (IPF) incidence. However, there are no population-based large-scale studies demonstrating the effects of smoking on the development of IPF. We aimed to evaluate the effect of smoking on IPF development using a nationwide population-based cohort. METHODS: Using the Korean National Health Information Database, we enrolled individuals who had participated in the health check-up service between 2009 and 2012. Participants having a prior diagnosis of IPF were excluded. The history of smoking status and quantity was collected by a questionnaire. We identified all cases of incident IPF through 2016 on the basis of ICD-10 codes for IPF and medical claims. Cox proportional hazards models were used to calculate the adjusted HR (aHR) of the development of IPF. RESULTS: A total of 25 113 individuals (0.11%) with incident IPF were identified out of 23 242 836 participants registered in the database. The risk of IPF was significantly higher in current and former smokers than in never smokers, with an aHR of 1.66 (95% CI 1.61 to 1.72) and 1.42 (95% CI 1.37 to 1.48), respectively. Current smokers had a higher risk of IPF than former smokers (aHR 1.17, 95% CI 1.13 to 1.21). The risk of IPF development increased as the smoking intensity and duration increased. CONCLUSION: Smoking significantly increased the risk of IPF development. Current smokers had a higher risk of IPF than former smokers. A dose-response relationship was observed between smoking and the development of IPF.

Orchardgrass ACTIVATOR OF HSP90 ATPASE possesses autonomous chaperone properties and activates Hsp90 transcription to enhance thermotolerance.

High temperature stress is an environmental factor that negatively affects the growth and development of crops. Hsp90 (90 kDa heat shock protein) is a major molecular chaperone in eukaryotic cells, contributing to the maintenance of cell homeostasis through interaction with co-chaperones. Aha1 (activator of Hsp90 ATPase) is well known as a co-chaperone that activates ATPase activity of Hsp90 in mammals. However, biochemical and physiological evidence relating to Aha has not yet been identified in plants. In this study, we investigated the heat-tolerance function of orchardgrass (Dactylis glomerata L.) Aha (DgAha). Recombinant DgAha interacted with cytosolic DgHsp90s and efficiently protected substrates from thermal denaturation. Furthermore, heterologous expression of DgAha in yeast (Saccharomyces cerevisiae) cells and Arabidopsis (Arabidopsis thaliana) plants conferred thermotolerance in vivo. Enhanced expression of DgAha in Arabidopsis stimulates the transcription of Hsp90 under heat stress. Our data demonstrate that plant Aha plays a positive role in heat stress tolerance via chaperone properties and/or activation of Hsp90 to protect substrate proteins in plants from thermal injury.

Deep Learning Prediction of Survival in Patients with Chronic Obstructive Pulmonary Disease Using Chest Radiographs.

Background Preexisting indexes for predicting the prognosis of chronic obstructive pulmonary disease (COPD) do not use radiologic information and are impractical because they involve complex history assessments or exercise tests. Purpose To develop and to validate a deep learning-based survival prediction model in patients with COPD (DLSP) using chest radiographs, in addition to other clinical factors. Materials and Methods In this retrospective study, data from patients with COPD who underwent postbronchodilator spirometry and chest radiography from 2011-2015 were collected and split into training (n = 3475), validation (n = 435), and internal test (n = 315) data sets. The algorithm for predicting survival from chest radiographs was trained (hereafter, DLSPCXR), and then age, body mass index, and forced expiratory volume in 1 second (FEV1) were integrated within the model (hereafter, DLSPinteg). For external test, three independent cohorts were collected (n = 394, 416, and 337). The discrimination performance of DLSPCXR was evaluated by using time-dependent area under the receiver operating characteristic curves (TD AUCs) at 5-year survival. Goodness of fit was assessed by using the Hosmer-Lemeshow test. Using one external test data set, DLSPinteg was compared with four COPD-specific clinical indexes: BODE, ADO, COPD Assessment Test (CAT), and St George's Respiratory Questionnaire (SGRQ). Results DLSPCXR had a higher performance at predicting 5-year survival than FEV1 in two of the three external test cohorts (TD AUC: 0.73 vs 0.63 [P = .004]; 0.67 vs 0.60 [P = .01]; 0.76 vs 0.77 [P = .91]). DLSPCXR demonstrated good calibration in all cohorts. The DLSPinteg model showed no differences in TD AUC compared with BODE (0.87 vs 0.80; P = .34), ADO (0.86 vs 0.89; P = .51), and SGRQ (0.86 vs 0.70; P = .09), and showed higher TD AUC than CAT (0.93 vs 0.55; P < .001). Conclusion A deep learning model using chest radiographs was capable of predicting survival in patients with chronic obstructive pulmonary disease. © RSNA, 2022 Online supplemental material is available for this article.

Treatment patterns and cost of exacerbations in patients with chronic obstructive pulmonary disease using multiple inhaler triple therapy in South Korea.

BACKGROUND: Multiple inhaler triple therapy (MITT), comprising inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), has been used as an escalation treatment for patients with chronic obstructive pulmonary disease (COPD). However, real-world use of MITT has not been investigated in Asia, including South Korea. This study reports baseline characteristics of patients with COPD initiated on MITT in South Korea, and their treatment patterns. Healthcare resource utilization (HRU) and costs associated with COPD exacerbations following MITT initiation were also assessed. METHODS: This was a retrospective cohort study using the South Korea National Health Insurance database (2014-2018). Included patients were ≥ 40 years, had a COPD diagnosis, were newly initiated on MITT and had ≥ 12 months' data both before (baseline) and after index date (the first day with overlapping supply of all MITT components). Treatment immediately before initiation and immediately following discontinuation of MITT were identified, and proportion of days covered (PDC) by MITT was calculated. HRU and costs (per person per year [PPPY]) associated with exacerbations were identified following MITT initiation; costs were calculated using the average 2020 exchange rate (0.0008 USD/KRW). RESULTS: Among 37,400 patients, the mean age was 69 (SD 10) years and 73% were males; 56% had ≥ 1 COPD exacerbation during the baseline period, with a mean of 2 (SD 5) events/year. ICS/LABA was the most frequent regimen prescribed immediately before initiation (37%) and immediately following discontinuation (41% of 34,264 patients) of MITT. At 3, 6, and 12 months from treatment initiation, mean PDC was 81%, 63% and 49%, respectively; median treatment duration was 102 days. The mean (95% confidence interval [CI]) number of total visits for severe COPD exacerbations was 0.77 PPPY (0.75-0.78); mean PPPY total healthcare costs were 2093 USD. CONCLUSIONS: Patients with COPD in South Korea experienced frequent exacerbations prior to MITT, and PDC by MITT was low. Patients may benefit from early optimization of COPD therapy, and greater emphasis on adherence to inhaled COPD therapy. Severe exacerbations were found to incur substantial costs; treatment alternatives that can reduce the rate of severe exacerbations are likely to minimize healthcare costs.

Effect of chlorhexidine Mouthrinse on prevention of microbial contamination during EBUS-TBNA: a randomized controlled trial.

BACKGROUND: Although endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure, fatal infectious complications have been reported. However, adequate preventive strategies have not been determined. We aimed to investigate the effect of chlorhexidine mouthrinse on the prevention of microbial contamination during EBUS-TBNA. METHODS: In this single-center, assessor-blinded, parallel-group randomized controlled trial, we randomly assigned adult participants undergoing EBUS-TBNA using a convex probe to gargle for 1 minute with 100 mL of 0.12% chlorhexidine gluconate before EBUS-TBNA or to receive usual care (no chlorhexidine mouthrinse). Aspiration needle wash samples were collected immediately after completion of EBUS-TBNA by instilling sterile saline into the used needle. The primary outcome was colony forming unit (CFU) counts per mL of needle wash samples in aerobic cultures. Secondary outcomes were CFU counts per mL of needle wash samples in anaerobic cultures, fever within 24 hours after EBUS-TBNA, and infectious complications within 4 weeks after EBUS-TBNA. RESULTS: From January 2021 to June 2021, 106 patients received either chlorhexidine mouthrinse (n = 51) or usual care (n = 55). The median CFU counts of needle wash samples in aerobic cultures were not significantly different in the two groups (10 CFU/mL vs 20 CFU/mL; P = 0.70). There were no significant differences between the groups regarding secondary outcomes, including median CFU counts in anaerobic cultures (P = 0.41) and fever within 24 hours after EBUS-TBNA (11.8% vs 5.6%, P = 0.31). There were no infectious complications within 4 weeks in both groups. CONCLUSIONS: Chlorhexidine mouthrinse did not reduce CFU counts in needle wash samples of EBUS-TBNA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04718922 . Registered on 22/01/2021.

Spin-Peierls Distortion of TiPO4 Causing a Transition from a Magnetic to a Nonmagnetic Insulating State and Its Effect on the Thermoelectric Properties: Density Functional Theory Analysis.

Density functional theory calculations were carried out to probe the nature of the electronic structure change in TiPO4 before and after its spin-Peierls distortion at 74.5 K, which is characterized by the dimerization in the chains of Ti3+ (d1) ions present in TiPO4. These calculations suggest strongly that the electronic state of TiPO4 is magnetic insulating before the distortion, but becomes nonmagnetic insulating after the distortion. Consistent with this suggestion, the phonon dispersion relations calculated for TiPO4 show that the undistorted TiPO4 is stable, while the distorted TiPO4 is not, if each Ti3+ ion has a spin moment, and that the opposite is true if each Ti3+ ion has no spin moment. These observations suggest that the driving force for the spin-Peierls distortion is the formation of direct metal-metal bonds leading to the dimerized chains of Ti3+ ions. The abrupt change in the electronic structures from a magnetic insulating state to a nonmagnetic insulating state explains why the spin-Peierls distortion of TiPO4 exhibits a first-order character. Although the two electronic states of TiPO4 before and after the distortion have a band gap, the substantial spin-Peierls distortion is found to enhance the thermoelectric properties of TiPO4.

Chromosome conformation elucidates regulatory relationships in developing human brain.

Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner. However, the 3D organization of chromosomes during human brain development and its role in regulating gene networks dysregulated in neurodevelopmental disorders, such as autism or schizophrenia, are unknown. Here we generate high-resolution 3D maps of chromatin contacts during human corticogenesis, permitting large-scale annotation of previously uncharacterized regulatory relationships relevant to the evolution of human cognition and disease. Our analyses identify hundreds of genes that physically interact with enhancers gained on the human lineage, many of which are under purifying selection and associated with human cognitive function. We integrate chromatin contacts with non-coding variants identified in schizophrenia genome-wide association studies (GWAS), highlighting multiple candidate schizophrenia risk genes and pathways, including transcription factors involved in neurogenesis, and cholinergic signalling molecules, several of which are supported by independent expression quantitative trait loci and gene expression analyses. Genome editing in human neural progenitors suggests that one of these distal schizophrenia GWAS loci regulates FOXG1 expression, supporting its potential role as a schizophrenia risk gene. This work provides a framework for understanding the effect of non-coding regulatory elements on human brain development and the evolution of cognition, and highlights novel mechanisms underlying neuropsychiatric disorders.

Association between Comorbidities and Preserved Ratio Impaired Spirometry: Using the Korean National Health and Nutrition Examination Survey IV-VI.

BACKGROUND: Preserved ratio impaired spirometry (PRISm) patients have more frequent respiratory symptoms and an increased risk of mortality. However, studies on comorbidities in these patients are lacking. OBJECTIVES: We investigated the association between PRISm and comorbidities using the Korea National Health and Nutrition Examination Survey (KNHANES). METHOD: This cross-sectional study included participants aged ≥50 years from the KNHANES (2007-2015). Participants who did not undergo spirometry or performed inadequately were excluded. We classified participants into 3 groups according to spirometry: PRISm (forced expiratory volume in one second [FEV1] /forced vital capacity [FVC] ≥ 0.7 and FEV1 <80%), chronic obstructive pulmonary disease (COPD) (FEV1/ FVC <0.7), and normal. Multivariate logistic regression analyses were used to evaluate the risk of comorbidities in the PRISm group compared to that in the normal group. RESULT: The study included 17,515 participants: 12,777 (73.0%), 1,563 (8.9%), and 3,175 (18.1%) in normal, PRISm, and COPD groups, respectively. After adjustment for known risk factors of each disease, hypertension (adjusted odds ratio [95% confidence interval]; 1.31 [1.14-1.50]), diabetes (1.51 [1.29-1.78]), hypercholesterolemia (1.20 [1.04-1.37]), obesity (1.31 [1.15-1.48]), ischemic heart disease (1.58 [1.13-2.22]), chronic renal disease (2.31 [1.09-4.88]), and thyroid disease (1.41 [1.09-1.83]) risks were significantly higher in the PRISm group than in the normal group. The average number of comorbidities was 2.45 in the PRISm group, which was higher than that in the normal (2.1) and COPD (2.03) groups (p < 0.05). CONCLUSION: The number of comorbidities was significantly higher in the PRISm group than in others. Hypertension, diabetes, obesity, ischemic heart disease, chronic renal disease, and thyroid disease were associated with PRISm after adjustment for risk factors.