The tidyomics ecosystem: enhancing omic data analyses.

The growth of omic data presents evolving challenges in data manipulation, analysis and integration. Addressing these challenges, Bioconductor provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming offers a revolutionary data organization and manipulation standard. Here we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analyzing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas, spanning six data frameworks and ten analysis tools.

Cysteine-rich 61 inhibition attenuates hepatic insulin resistance and improves lipid metabolism in high-fat diet fed mice and HepG2 cells.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with insulin resistance development. Hepatic lipid accumulation and inflammation are considered the main drivers of hepatic insulin resistance in MASLD. Cysteine-rich 61 (Cyr61 also called CCN1), a novel secretory matricellular protein, is implicated in liver inflammation, and its role in MASLD is not clearly understood. Therefore, we investigated the role of Cyr61 in hepatic insulin resistance and lipid metabolism as major factors in MASLD pathogenesis. In high-fat diet (HFD)-fed C57BL/6J mice, Cyr61 was downregulated or upregulated via viral transduction. Measurements of glucose homeostasis, histological assessment of liver tissues, and gene expression and signaling pathways of lipogenesis, fatty acid oxidation, and inflammation were performed using liver samples from these mice. Cyr61 levels in HepG2 cells were reduced using RNAi-mediated gene knockdown. Inflammation and insulin resistance were evaluated using real-time polymerase chain reaction and western blotting. HFD/AAV-shCyr61 mice exhibited enhanced glucose tolerance via the protein kinase B pathway, reduced hepatic inflammation, decreased lipogenesis, and increased fatty acid oxidation. Notably, HFD/AAV-shCyr61 mice showed elevated protein expression of sirtuin 6 and phosphorylated-AMP-activated protein kinase. In vitro experiments demonstrated that inhibition of Cyr61 downregulated pro-inflammatory cytokines such as interleukin-1 beta, IL-6, and tumor necrosis factor-alpha via the nuclear factor kappa B/c-Jun N-terminal kinase pathway, and alleviated insulin resistance. Cyr61 affected hepatic inflammation, lipid metabolism, and insulin resistance. Inhibition of Cyr61 reduced inflammation, recovered insulin resistance, and altered lipid metabolism in vivo and in vitro. Therefore, Cyr61 is a potential therapeutic target in MASLD.

Plasmonic Annular Nanotrenches with 1 nm Nanogaps for Detection of SARS-CoV-2 Using SERS-Based Immunoassay.

This study represents the synthesis of a novel class of nanoparticles denoted as annular Au nanotrenches (AANTs). AANTs are engineered to possess embedded, narrow circular nanogaps with dimensions of approximately 1 nm, facilitating near-field focusing for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via a surface-enhanced Raman scattering (SERS)-based immunoassay. Notably, AANTs exhibited an exceedingly low limit of detection (LOD) of 1 fg/mL for SARS-CoV-2 spike glycoproteins, surpassing the commercially available enzyme-linked immunosorbent assay (ELISA) by 6 orders of magnitude (1 ng/mL from ELISA). To assess the real-world applicability, a study was conducted on 50 clinical samples using an SERS-based immunoassay with AANTs. The results revealed a sensitivity of 96% and a selectivity of 100%, demonstrating the significantly enhanced sensing capabilities of the proposed approach in comparison to ELISA and commercial lateral flow assay kits.

Effects of sleep quality on diurnal variation of brain volume in older adults: A retrospective cross-sectional study.

AIM: Brain volume is influenced by several factors that can change throughout the day. In addition, most of these factors are influenced by sleep quality. This study investigated diurnal variation in brain volume and its relation to overnight sleep quality. METHODS: We enrolled 1,003 healthy Koreans without any psychiatric disorders aged 60 years or older. We assessed sleep quality and average wake time using the Pittsburgh Sleep Quality Index, and divided sleep quality into good, moderate, and poor groups. We estimated the whole and regional brain volumes from three-dimensional T1-weighted brain MRI scans. We divided the interval between average wake-up time and MRI acquisition time (INT) into tertile groups: short (INT1), medium (INT2), and long (INT3). RESULTS: Whole and regional brain volumes showed no significance with respect to INT. However, the `interaction between INT and sleep quality showed significance for whole brain, cerebral gray matter, and cerebrospinal fluid volumes (p < .05). The INT2 group showed significantly lower volumes of whole brain, whole gray matter, cerebral gray matter, cortical gray matter, subcortical gray matter, and cerebrospinal fluid than the INT1 and INT3 groups only in the individuals with good sleep quality. CONCLUSION: Human brain volume changes significantly within a day associated with overnight sleep in the individuals with good sleep quality.

c-MET-positive circulating tumor cells and cell-free DNA as independent prognostic factors in hormone receptor-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Endocrine therapy resistance in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) is a significant clinical challenge that poses several unmet needs in the management of the disease. This study aimed to investigate the prognostic value of c-MET-positive circulating tumor cells (cMET+ CTCs), ESR1/PIK3CA mutations, and cell-free DNA (cfDNA) concentrations in patients with hormone receptor-positive (HR+) metastatic breast cancer (mBC). METHODS: Ninety-seven patients with HR+ mBC were prospectively enrolled during standard treatment at Samsung Medical Center. CTCs were isolated from blood using GenoCTC® and EpCAM or c-MET CTC isolation kits. PIK3CA and ESR1 hotspot mutations were analyzed using droplet digital PCR. CfDNA concentrations were calculated using internal control copies from the ESR1 mutation test. Immunocytochemistry was performed to compare c-MET overexpression between primary and metastatic sites. RESULTS: The proportion of c-MET overexpression was significantly higher in metastatic sites than in primary sites (p = 0.00002). Survival analysis showed that c-MET+ CTC, cfDNA concentration, and ESR1 mutations were significantly associated with poor prognosis (p = 0.0026, 0.0021, and 0.0064, respectively) in HR+/HER2- mBC. By contrast, EpCAM-positive CTC (EpCAM+ CTC) and PIK3CA mutations were not associated with progression-free survival (PFS) in HR+/HER2- mBC. Multivariate analyses revealed that c-MET+ CTCs and cfDNA concentration were independent predictors of PFS in HR+/HER2- mBC. CONCLUSIONS: Monitoring c-MET+ CTC, rather than assessing c-MET expression in the primary BC site, could provide valuable information for predicting disease progression, as c-MET expression can change during treatment. The c-MET+ CTC count and cfDNA concentration could provide complementary information on disease progression in HR+ /HER2- mBC, highlighting the importance of integrated liquid biopsy.

Case of Human Orthohantavirus Infection, Michigan, USA, 2021.

Orthohantaviruses cause hantavirus cardiopulmonary syndrome; most cases occur in the southwest region of the United States. We discuss a clinical case of orthohantavirus infection in a 65-year-old woman in Michigan and the phylogeographic link of partial viral fragments from the patient and rodents captured near the presumed site of infection.

Molecular detection and genomic characterization of Samak Micromys paramyxovirus-1 and -2 in Micromys minutus, Republic of Korea.

BACKGROUND: The discovery of viruses in small mammalian populations, particularly rodents, has expanded the family Paramyxoviridae. The overlap in habitats between rodents and humans increases the risk of zoonotic events, underscoring the importance of active surveillance. Rodent species, such as Apodemus agrarius, are natural hosts for Paramyxoviridae in the Republic of Korea (ROK). However, it is unknown whether Paramyxoviridae is present in Micromys minutus, another common rodent. METHOD: Here, we screened M. minutus collected from the Gangwon Province in the ROK for paramyxoviruses using nested polymerase chain reaction and confirm positive samples by next-generation metagenomic sequencing. Complete paramyxovirus genomes were further characterized by phylogenetic analysis, amino acid similarity, secondary structure, and cophylogeny. RESULT: Overall, 57 of 145 (39.3%) M. minutus kidney samples tested positive for paramyxoviruses. Among them, four whole genome sequences were identified and clustered within the genus Jeilongvirus. One sequence was determined as Samak Micromys paramyxovirus 1 (SMPV-1; 19,911 nucleotides long) and three sequences as Samak Micromys paramyxovirus 2 (SMPV-2; 18,199 nucleotides long). SMPV-1 has a smaller hydrophobic gene and a longer glycoprotein gene than SMPV-2. Cophylogenetic analysis suggests that SMPV-1 evolved through co-divergence, whereas SMPV-2 was inferred to have undergone transfer events. CONCLUSION: These findings highlight the prevalence of paramyxoviruses in the wild and the potential of M. minutus as a natural viral reservoir. The discovery of SMPV-1 and SMPV - 2 also reveals the genetic diversity and evolutionary history of the genus Jeilongvirus in the Paramyxoviridae.

Effects of parental holding on pain response in young children during cystometry: A randomized controlled trial.

INTRODUCTION: Cystometry is essential for evaluating bladder function. However, children may react negatively to the physical pain of urethral catheterization or anxiety and fear of an unfamiliar environment. These pain responses during the cystometry procedure may interfere with the cystometry procedure and make it difficult to interpret the cystometry result. In this regard, the International Children's Continence Society has advised performing cystometry while holding infants as an effective nonpharmacological pain management method, but there is insufficient evidence to support this. PURPOSE: This study aimed to analyze the effect of parental holding on reducing pain in children during cystometry. METHODS: This was an experimental study in a randomized controlled pre-post test design. A total of 64 participants aged 6-18 months were recruited. During cystometry, the participants in the experimental group were placed on the parent's laps and held in the parents' arms. The participants in the control group were laid down on the examination table. During the procedure, both groups of parents were allowed to touch their children in all ways except holding them and to use the pacifier if they wished. The behavioral (face, leg, activity, cry, consolability scale) and physiological (oxygen saturation and heart rate) pain responses were measured at three-time points (immediately, 3, and 10 min after urethral catheter insertion). RESULTS: Comparing the two groups, in the experimental group, the behavioral pain response at 3 min after urethral catheter insertion (t = -2.165, p = 0.034) and 10 min after (t = -3.155, p = 0.002) was decreased compared with that immediately after urethral catheter insertion. In addition, oxygen saturation increased more (t = 2.021, p = 0.048), and the heart rate decreased more (t = -2.033, p = 0.047) at 10 min than at 3 min after urethral catheter insertion in the experimental group. CONCLUSIONS: This study revealed that parental holding could reduce pain responses during cystometry in children. Further research is required to confirm the applicability and usefulness of parental holding during cystometry.

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.

Heterogeneity in the health effects of PM2.5 sources across the major metropolitan cities, South Korea: Significance of region-specific management.

Ambient PM2.5, well-known for its adverse impacts on human health, is a very heterogeneous pollutant. Its chemical composition and attributable sources vary by region, influenced by meteorological and geographical conditions as well as emission sources. However, administrative policies are currently focused on mass concentrations. However, not all PM2.5 sources provide equally toxic particles. Thus, those sources that should be the focus of controls has not been the priority. In the present study, we conducted source apportionment utilizing positive matrix factorization (PMF) and investigated the association of PM2.5 source contributions with emergency department visits (EDVs) in major megacities in South Korea. Overall, an interquartile range (IQR) increment in source contribution increased the number of emergency room visits. Industry and coal combustion sources, marked by heavy metals, were principally associated with the adverse health impacts. However, the sources showing significant associations with EDVs differed across the study area. In addition, we found that region-specific relationships between PM2.5 sources and morbidity were plausible, considering the existence of relevant sources such as industrial complexes and coal-fired power plants. The analysis of source contributions according to wind conditions also supported the source-morbidity relationships. These findings suggest that administrative policies for PM2.5 control should be established and implemented considering region-specific characteristics of the links between PM2.5 sources and health impacts to maximize the control's public health effects. Furthermore, the results of the present study indicate that PMF was an effective method for linking acute exposure to PM2.5 source types with health outcomes to prioritize its sources.

Pectoralis Muscle Area as a Predictor of Mortality in Patients Hospitalized with Bronchiectasis Exacerbation.

INTRODUCTION: Data on factors related to mortality in patients with bronchiectasis exacerbation are insufficient. Computed tomography (CT) can measure the pectoralis muscle area (PMA) and is a useful tool to diagnose sarcopenia. This study aimed to evaluate whether PMA can predict mortality in patients with bronchiectasis exacerbation. METHODS: Patients hospitalized due to bronchiectasis exacerbation at a single center were retrospectively divided into survivors and non-survivors based on 1-year mortality. Thereafter, a comparison of the clinical and radiologic characteristics was conducted between the two groups. RESULTS: A total of 66 (14%) patients died at 1 year. In the multivariate analysis, age, BMI <18.4 kg/m2, sex-specific PMA quartile, ≥3 exacerbations in the previous year, serum albumin <3.5 g/dL, cystic bronchiectasis, tuberculosis-destroyed lung, and diabetes mellitus were independent predictors for the 1-year mortality in patients hospitalized with bronchiectasis exacerbation. A lower PMA was associated with a lower overall survival rate in the survival analysis according to sex-specific quartiles of PMA. PMA had the highest area under the curve during assessment of prognostic performance in predicting the 1-year mortality. The lowest sex-specific PMA quartile group exhibited higher disease severity than the highest quartile group. CONCLUSIONS: CT-derived PMA was an independent predictor of 1-year mortality in patients hospitalized with bronchiectasis exacerbation. Patients with lower PMA exhibited higher disease severity. These findings suggest that PMA might be a useful marker for providing additional information regarding prognosis of patients with bronchiectasis exacerbation.

Toxicology and safety study of L-tryptophan and its impurities for use in broiler feed.

L-tryptophan has been utilized as a feed additive in animal nutrition to improve growth performance, as well as a dietary supplement to alleviate various emotional symptoms in humans. Despite its benefits, concerns regarding its safety arose following the outbreak of eosinophilia-myalgia syndrome (EMS) among individuals who consumed L-tryptophan. The causative material of EMS was determined to be not L-tryptophan itself, but rather L-tryptophan impurities resulting from a specific manufacturing process. To investigate the effect of L-tryptophan and its impurities on humans who consume meat products derived from animals that were fed L-tryptophan and its impurities, an animal study involving broiler chickens was conducted. The animals in test groups were fed diet containing 0.065%-0.073% of L-tryptophan for 27 days. This study aimed to observe the occurrence of toxicological or EMS-related symptoms and analyze the residues of L-tryptophan impurities in meat products. The results indicated that there was no evidence of adverse effects associated with the test substance in the investigated parameters. Furthermore, most of the consumed EMS-causing L-tryptophan impurities did not remain in the meat of broiler chickens. Thus, this study demonstrated the safety of L-tryptophan and some of its impurities as a feed additive.

Toxicology and safety study of L-tryptophan and its impurities for use in swine.

L-tryptophan, an essential amino acid for physiological processes, metabolism, development, and growth of organisms, is widely utilized in animal nutrition and human health as a feed additive and nutritional supplement, respectively. Despite its known benefits, safety concerns have arisen due to an eosinophilia-myalgia syndrome (EMS) outbreak linked to L-tryptophan consumed by humans. Extensive research has established that the EMS outbreak was caused by an L-tryptophan product that contained certain impurities. Therefore, safety validations are imperative to endorse the use of L-tryptophan as a supplement or a feed additive. This study was conducted in tertiary hybrid [(Landrace × Yorkshire) × Duroc] pigs to assess general toxicity and potential risks for EMS-related symptoms associated with L-tryptophan used as a feed additive. Our investigation elucidated the relationship between L-tryptophan and EMS in swine. No mortalities or clinical signs were observed in any animals during the administration period, and the test substance did not induce toxic effects. Hematological analysis and histopathological examination revealed no changes in EMS-related parameters, such as eosinophil counts, lung lesions, skin lesions, or muscle atrophy. Furthermore, no test substance-related changes occurred in other general toxicological parameters. Through analyzing the tissues and organs of swine, most of the L-tryptophan impurities that may cause EMS were not retained. Based on these findings, we concluded that incorporating L-tryptophan and its impurities into the diet does not induce EMS in swine. Consequently, L-tryptophan may be used as a feed additive throughout all growth stages of swine without safety concerns.

The Analysis of in vitro Fertilization Outcomes after Fertility-Preserving Therapy for Endometrial Hyperplasia or Carcinoma.

OBJECTIVES: This study aimed to evaluate the clinical efficacy of fertility-preserving therapy through in vitro fertilization (IVF) procedures in women who were pathologically diagnosed with endometrial hyperplasia or carcinoma. DESIGN: A retrospective cohort study on fertility-preserving therapy was conducted. Participants/Materials, Setting: A total of 82 women were enrolled who had simple endometrial hyperplasia (SH), complex hyperplasia (CH), complex atypical hyperplasia (CAH), and endometrioid endometrial carcinoma stage IA (EC IA) and underwent IVF at Gangnam CHA fertility center between January 2008 and December 2020. METHODS: The primary endpoints were oncologic outcomes and subsequent reproductive outcomes of patients who underwent fertility-preserving treatments analyzed by χ2 test or Fisher's exact test. RESULTS: Of the 82 patients, 33 had a cumulative clinical pregnancy (40.2%), and 25 had a cumulative live birth (30.5%) through IVF procedures following pathologic confirmation of complete remission or non-progressive status. The cumulative clinical pregnancy rates and live birth rates for SH were 50.0% and 30.0%, for CH were 37.8% and 28.9%, for CAH were 25.0% and 25.0%, and for EC were 38.5% and 38.5%, respectively. There were no significant differences in cumulative clinical pregnancy rates or live birth rates when comparing the four groups. There was a difference in endometrial thickness between medroxyprogesterone acetate (MPA) treatment group and intrauterine device (IUD) group (p = 0.036); however, there were no significant differences in clinical pregnancy rates among MPA, IUD, and MPA+IUD groups. LIMITATIONS: Because of the retrospective nature of the study, many factors relevant to the treatment decision were not strictly controlled. CONCLUSIONS: All endometrial hyperplasia and carcinoma groups had competent cumulative live birth rates by IVF procedures. There may be differences in endometrial thickness depending on the treatment methods, but this does not affect clinical pregnancy rates. Therefore, the fertility-preserving treatment for endometrial hyperplasia and carcinoma is a safe and feasible method that results in good IVF outcomes.

Universal health coverage saves more lives among severely ill COVID-19 patients: A difference-in-differences analysis of individual patient data in South Korea.

BACKGROUND: Universal health coverage (UHC) ensures affordability of a variety of essential health services for the general population. Although UHC could mitigate the harmful effects of coronavirus disease 2019 (COVID-19) on patients and their socioeconomic position, the debate on UHC's scope and ability to improve health outcomes is ongoing. This study aimed to identify the impact of UHC policy withdrawal on the health outcomes of South Korea's severely ill COVID-19 patients. METHODS: We used a propensity score matching (PSM) and difference-in-differences combined model. This study's subjects were 44,552 hospitalized COVID-19 patients contributing towards health insurance claims data, COVID-19 notifications and vaccination data extracted from the National Health Information Database and the Korea Disease Control and Prevention Agency from 1 December 2020 to 30 April 2022. After PSM, 2460 patients were included. This study's exposures were severity of illness and UHC policy change. The primary outcome was the case fatality rate (CFR) for COVID-19, which was defined as death within 30 days of a COVID-19 diagnosis. There were four secondary outcomes, including time interval between diagnosis and hospitalization (days), length of stay (days), total medical expenses (USD) and the time interval between diagnosis and death (days). RESULTS: After the UHC policy's withdrawal, the severely ill patients' CFR increased to 284 per 1000 patients [95% confidence interval (CI) 229.1-338.4], hospitalization days decreased to 9.61 days (95% CI -11.20 to -8.03) and total medical expenses decreased to 5702.73 USD (95% CI -7128.41 to -4202.01) compared with those who were not severely ill. CONCLUSIONS: During the pandemic, UHC may have saved the lives of severely ill COVID-19 patients; therefore, expanding services and financial coverage could be a crucial strategy during public health crises.

Novel Amidine Derivative K1586 Sensitizes Colorectal Cancer Cells to Ionizing Radiation by Inducing Chk1 Instability.

Checkpoint kinase 1 (Chk1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair, and DNA replication. Small-molecule Chk1 inhibitors sensitize cancer cells to genotoxic agents and have shown preclinical activity as single agents in cancers characterized by high levels of replication stress. However, the underlying genetic determinants of Chk1-inhibitor sensitivity remain unclear. Although treatment options for advanced colorectal cancer are limited, radiotherapy is effective. Here, we report that exposure to a novel amidine derivative, K1586, leads to an initial reduction in the proliferative potential of colorectal cancer cells. Cell cycle analysis revealed that the length of the G2/M phase increased with K1586 exposure as a result of Chk1 instability. Exposure to K1586 enhanced the degradation of Chk1 in a time- and dose-dependent manner, increasing replication stress and sensitizing colorectal cancer cells to radiation. Taken together, the results suggest that a novel amidine derivative may have potential as a radiotherapy-sensitization agent that targets Chk1.

Influence of Sr-Site Deficiency, Ca/Ba/La Doping on the Exsolution of Ni from SrTiO3.

Cermet catalysts formed via exsolution of metal nanoparticles from perovskites promise to perform better in electro- and thermochemical applications than those synthesized by conventional wet-chemical approaches. However, a shortage of robust material design principles still stands in the way of widespread commercial adoption of exsolution. Working with Ni-doped SrTiO3 solid solutions, we investigated how the introduction of Sr deficiency as well as Ca, Ba, and La doping on the Sr site changed the size and surface density of exsolved Ni nanoparticles. We carried out exsolution on 11 different compositions under fixed conditions. We elucidated the effect of A-site defect size/valence on nanoparticle density and size as well as the effect of composition on nanoparticle immersion and ceramic microstructure. Based on our experimental results, we developed a model that quantitatively predicted a composition's exsolution properties using density functional theory calculations. The model and calculations provide insights into the exsolution mechanism and can be used to find new compositions with high exsolution nanoparticle density.

Concomitant induction of SLIT3 and microRNA-218-2 in macrophages by toll-like receptor 4 activation limits osteoclast commitment.

BACKGROUND: Toll-like receptor 4 (TLR4) conducts a highly regulated inflammatory process by limiting the extent of inflammation to avoid toxicity and tissue damage, even in bone tissues. Thus, it is plausible that strategies for the maintenance of normal bone-immunity to prevent undesirable bone damage by TLR4 activation can exist, but direct evidence is still lacking. METHODS: Osteoclast precursors (OCPs) obtained from WT or Slit3-deficient mice were differentiated into osteoclast (OC) with macrophage colony-stimulating factor (M-CSF), RANK ligand (RANKL) and lipopolysaccharide (LPS) by determining the number of TRAP-positive multinuclear cells (TRAP+ MNCs). To determine the alteration of OCPs population, fluorescence-activated cell sorting (FACS) was conducted in bone marrow cells in mice after LPS injection. The severity of bone loss in LPS injected WT or Slit3-deficient mice was evaluated by micro-CT analysis. RESULT: We demonstrate that TLR4 activation by LPS inhibits OC commitment by inducing the concomitant expression of miR-218-2-3p and its host gene, Slit3, in mouse OCPs. TLR4 activation by LPS induced SLIT3 and its receptor ROBO1 in BMMs, and this SLIT3-ROBO1 axis hinders RANKL-induced OC differentiation by switching the protein levels of C/EBP-ß isoforms. A deficiency of SLIT3 resulted in increased RANKL-induced OC differentiation, and the elevated expression of OC marker genes including Pu.1, Nfatc1, and Ctsk. Notably, Slit3-deficient mice showed expanded OCP populations in the bone marrow. We also found that miR-218-2 was concomitantly induced with SLIT3 expression after LPS treatment, and that this miRNA directly suppressed Tnfrsf11a (RANK) expression at both gene and protein levels, linking it to a decrease in OC differentiation. An endogenous miR-218-2 block rescued the expression of RANK and subsequent OC formation in LPS-stimulated OCPs. Aligned with these results, SLIT3-deficient mice displayed increased OC formation and reduced bone density after LPS challenge. CONCLUSION: Our findings suggest that the TLR4-dependent concomitant induction of Slit3 and miR-218-2 targets RANK in OCPs to restrain OC commitment, thereby avoiding an uncoordinated loss of bone through inflammatory processes. These observations provide a mechanistic explanation for the role of TLR4 in controlling the commitment phase of OC differentiation. Video Abstract.

Textural and Volumetric Changes of the Temporal Lobes in Semantic Variant Primary Progressive Aphasia and Alzheimer's Disease.

BACKGROUND: Texture analysis may capture subtle changes in the gray matter more sensitively than volumetric analysis. We aimed to investigate the patterns of neurodegeneration in semantic variant primary progressive aphasia (svPPA) and Alzheimer's disease (AD) by comparing the temporal gray matter texture and volume between cognitively normal controls and older adults with svPPA and AD. METHODS: We enrolled all participants from three university hospitals in Korea. We obtained T1-weighted magnetic resonance images and compared the gray matter texture and volume of regions of interest (ROIs) between the groups using analysis of variance with Bonferroni posthoc comparisons. We also developed models for classifying svPPA, AD and control groups using logistic regression analyses, and validated the models using receiver operator characteristics analysis. RESULTS: Compared to the AD group, the svPPA group showed lower volumes in five ROIs (bilateral temporal poles, and the left inferior, middle, and superior temporal cortices) and higher texture in these five ROIs and two additional ROIs (right inferior temporal and left entorhinal cortices). The performances of both texture- and volume-based models were good and comparable in classifying svPPA from normal cognition (mean area under the curve [AUC] = 0.914 for texture; mean AUC = 0.894 for volume). However, only the texture-based model achieved a good level of performance in classifying svPPA and AD (mean AUC = 0.775 for texture; mean AUC = 0.658 for volume). CONCLUSION: Texture may be a useful neuroimaging marker for early detection of svPPA in older adults and its differentiation from AD.

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.