Ethoxyquin mediates lung fibrosis and cellular immunity in BLM-CIA mice by inhibiting HSP90.

BACKGROUND: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are characterized by severe pulmonary fibrosis and immune dysregulation. Heat shock protein 90 (HSP90) is involved in the progression of pulmonary fibrosis and the immune response. OBJECTIVES: This study aimed to explore whether HSP90 regulates the development of RA-ILD and its underlying mechanism. MATERIAL AND METHODS: In vivo, collagen-induced arthritis (CIA)-mice were treated with bleomycin (BLM) to establish an arthritic mouse model of pulmonary fibrosis. In vitro, human lung fibroblast 1 (HLF1) was exposed to transforming growth factor beta 1 (TGF-ß1) to simulate an RA-ILD model. The RA-ILD models were treated with the HSP90 inhibitor ethoxyquin (EQ) to explore the potential mechanism of HSP90 in RA-ILD. Histopathological analysis was performed, and pulmonary fibrosis was evaluated. The differentiation of M1/M2 macrophages and Th1/Th17/Treg cells was assessed. The role of the TGF-ß/Smad2/3 pathway in EQ-mediated RA-ILD progression was also explored. RESULTS: HSP90α and HSP90ß were upregulated in the RA-ILD models. Ethoxyquin mitigated arthritis in BLM-CIA mice, and reduced the expression of alpha-smooth muscle actin (α-SMA), collagen I (Col-1) and fibronectin (FN), as well as hydroxyproline content, thereby relieving pulmonary fibrosis. In addition, EQ increased M1 macrophages and inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-α) levels; conversely, EQ decreased M2 macrophages and vascular endothelial growth factor (VEGF)-A and TGF-ß1 contents. It also decreased Th17 (interleukin (IL)-17) while increasing Th1 (interferon gamma (IFN-γ)) and Treg (Foxp3), and restricted the expression of transforming growth factor beta type receptor I and II (TGF-ßRI and TGF-ßRII) and the phosphorylation of Smad2 and Smad3. CONCLUSIONS: This study revealed that EQ regulated pulmonary fibrosis and cellular immunity by inhibiting HSP90, appearing to act through the TGF-ß/Smad2/3 pathway. These findings suggest that EQ holds potential as a therapeutic agent for treating RA-ILD.

Transcriptomic analysis and validation study of key genes and the HIF­1α/HO­1 pathway associated with ferroptosis in neutrophilic asthma.

Ferroptosis, as a unique form of cell death caused by iron overload and lipid peroxidation, is involved in the pathogenesis of various inflammatory diseases of the airways. Inhibition of ferroptosis has become a novel strategy for reducing airway epithelial cell death and improving airway inflammation. The aim of the present study was to analyze and validate the key genes and signaling pathways associated with ferroptosis by bioinformatic methods combined with experimental analyzes in vitro and in vivo to aid the diagnosis and treatment of neutrophilic asthma. A total of 1,639 differentially expressed genes (DEGs) were identified in the transcriptome dataset. After overlapping with ferroptosis-related genes, 11 differentially expressed ferroptosis-related genes (DE-FRGs) were obtained. A new diagnostic model was constructed by these DE-FRGs from the transcriptome dataset with those from the GSE108417 dataset. The receiver operating characteristic curve analysis indicated that the area under the curve had good diagnostic performance (>0.8). As a result, four key DE-FRGs (CXCL2, HMOX1, IL-6 and SLC7A5) and biological pathway [hypoxia-inducible factor 1 (HIF-1) signaling pathway] associated with ferroptosis in neutrophilic asthma were identified by the bioinformatics analysis combined with experimental validation. The upstream regulatory network of key DE-FRGs and target drugs were predicted and the molecular docking results from screened 37 potential therapeutic drugs revealed that the 13 small-molecule drugs exhibited a higher stable binding to the primary proteins of key DE-FRGs. The results suggested that four key DE-FRGs and the HIF-1α/heme oxygenase 1 pathway associated with ferroptosis have potential as novel markers or targets for the diagnosis or treatment of neutrophilic asthma.

Na(C2H10N2)2[Zn3(PO4)2(H0.5PO4)]2: A Short-Wave Ultraviolet Open-Framework Zincophosphate Exhibiting Substantial Optical Dispersion Ability.

The exploration of short-wave ultraviolet (SUV; λ < 280 nm) transparent phosphates with substantial birefringence is crucial for the advancement of SUV laser industry. Despite their SUV transparency and potential for constructing materials with large birefringence, open-framework (OF) phosphates have rarely been explored for their birefringent properties. Herein, through a systematic exploration in this field, a new ethylenediamine-based OF zincophosphate, Na(C2H10N2)2[Zn3(PO4)2(H0.5PO4)]2 (NEZPO), has been developed. NEZPO exhibits remarkable SUV transparency and significant birefringence (Δn = 0.060 at 546 nm), highlighting the potential for the development of benign SUV crystals within the OF phosphates family.

Mycobacterium vaccae attenuates airway inflammation by inhibiting autophagy and activating PI3K/Akt signaling pathway in OVA-induced allergic airway inflammation mouse model.

PURPOSE: The etiology of asthma remains elusive, with no known cure. Based on accumulating evidence, autophagy, a self-degradation process that maintains cellular metabolism and homeostasis, participates in the development of asthma. Mycobacterium vaccae vaccine (M. vaccae), an immunomodulatory agent, has previously been shown to effectively alleviate airway inflammation and airway remodeling. However, its therapeutic effect on asthma via the regulation of autophagy remains unknown. Therefore, this study aimed to investigate the impact of M. vaccae in attenuating asthma airway inflammation via autophagy-mediated pathways. METHODS: Balb/c mice were used to generate an ovalbumin (OVA)-immunized allergic airway model and were subsequently administered either M. vaccae or M. vaccae + rapamycin (an autophagy activator) prior to each challenge. Next, airway inflammation, mucus secretion, and airway remodeling in mouse lung tissue were assessed via histological analyses. Lastly, the expression level of autophagy proteins LC3B, Beclin1, p62, and autolysosome was determined both in vivo and in vitro, along with the expression level of p-PI3K, PI3K, p-Akt, and Akt in mouse lung tissue. RESULTS: The findings indicated that aerosol inhalation of M. vaccae in an asthma mouse model has the potential to decrease eosinophil counts, alleviate airway inflammation, mucus secretion, and airway remodeling through the inhibition of autophagy. Likewise, M. vaccae could reduce the levels of OVA-specific lgE, IL-5, IL-13, and TNF-α in asthma mouse models by inhibiting autophagy. Furthermore, this study revealed that M. vaccae also suppressed autophagy in IL-13-stimulated BEAS-2B cells. Moreover, M. vaccae may activate the PI3K/Akt signaling pathway in the lung tissue of asthmatic mice. CONCLUSION: In summary, the present study suggests that M. vaccae may contribute to alleviating airway inflammation and remodeling in allergic asthma by potentially modulating autophagy and the PI3K/Akt signaling pathway. These discoveries offer a promising avenue for the development of therapeutic interventions targeting allergic airway inflammation.

Exploring Ribosomal Genes as Potential Biomarkers of the Immune Microenvironment in Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is the most common pathogen causing acute lower respiratory tract infection in infants and children. Due to limited knowledge of the pathological and molecular mechanisms of immunodeficiency underlying RSV disease, there is currently a lack of an approved and effective RSV vaccine to combat RSV infections. This study aimed to identify genes associated with immune dysfunction using bioinformatics methods to gain insights into the role of dysregulated immune genes in RSV disease progression, and to predict potential therapeutic drugs by targeting dysregulated immune-related genes. 423 immune-related differential genes (DEIRGs) were filtered from the blood samples of 87 healthy individuals and 170 RSV patients. According to CIBERSORT analysis, the blood of RSV patients showed increased infiltration of various immune cells. Subsequently, ten immune-related hub genes were screened via Protein-Protein Interaction Networks. Six signature immune-related genes (RPS2, RPS5, RPS13, RPS14, RPS18, and RPS4X) as candidate characteristic genes for the diagnostic model were identified by Lasso regression. The AUC value of the ROC curve of the six signature genes was 0.884. This result, intriguingly, suggested that all six immune-related genes with a good internal validation effect were ribosome family genes. Finally, through molecular docking analyses targeting these differential immune genes, ADO and fluperlapine were found to have high stable binding to major proteins of important immune-related genes in nine drug-protein interactions. Overall, the present study screened immune-related genes that are dysregulated in the development of RSV disease to investigate the pathogenesis of RSV infection from the standpoint of immune disorders. Unexpectedly, bioinformatics analysis revealed that ribosome family genes may be involved in the immune dysregulation of RSV disease, and these genes as targets formed the basis for potential drug modification candidates in RSV disease.

RNA-Seq and miRNA-Seq data from Epstein-Barr virus-infected tree shrews reveal a ceRNA network contributing to immune microenvironment regulation.

Epstein-Barr virus (EBV) infection in humans is ubiquitous and associated with various diseases. Remodeling of the immune microenvironment is the primary cause of EBV infection and pathogenesis; however, the underlying mechanism has not been fully elucidated. In this study, we used whole-transcriptome RNA-Seq to detect mRNAs, long non-coding RNAs (lncRNA), and microRNA (miRNA) profiles in the control group, 3 days, and 28 days after EBV infection, based on the tree shrew model that we reported previously. First, we estimated the proportion of 22 cell types in each sample using CIBERSORT software and identified 18 high-confidence DElncRNAs related to immune microenvironment regulation after EBV infection. Functional enrichment analysis of these differentially expressed lncRNAs primarily focused on the autophagy, endocytosis, and ferroptosis signalling pathways. Moreover, EBV infection affects miRNA expression patterns, and many miRNAs are silenced. Finally, three competing endogenous RNA regulatory networks were built using lncRNAs that significantly correlated with immune cell types, miRNAs that responded to EBV infection, and potentially targeted the mRNA of the miRNAs. Among them, MRPL42-AS-5 might act as an hsa-miR-296-5p "sponge" and compete with target mRNAs, thus increasing mRNA expression level, which could induce immune cell infiltration through the cellular senescence signalling pathway against EBV infection. Overall, we conducted a complete transcriptomic analysis of EBV infection in vivo for the first time and provided a novel perspective for further investigation of EBV-host interactions.

Insight into the role of mitochondrion-related gene anchor signature in mitochondrial dysfunction of neutrophilic asthma.

OBJECTIVE: At present, targeting molecular-pharmacological therapy is still difficult in neutrophilic asthma. The investigation aims to identify and validate mitochondrion-related gene signatures for diagnosis and specific targeting therapeutics in neutrophilic asthma. METHODS: Bronchial biopsy samples of neutrophilic asthma and healthy people were identified from the GSE143303 dataset and then matched with human mitochondrial gene data to obtain mitochondria-related differential genes (MitoDEGs). Signature mitochondria-related diagnostic markers were jointly screened by support vector machine (SVM) analysis, least absolute shrinkage, and selection operator (LASSO) regression. The expression of marker MitoDEGs was evaluated by validation datasets GSE147878 and GSE43696. The diagnostic value was evaluated by receiver operating characteristic (ROC) curve analysis. Meanwhile, the infiltrating immune cells were analyzed by the CIBERSORT. Finally, oxidative stress level and mitochondrial functional morphology for asthmatic mice and BEAS-2B cells were evaluated. The expression of signature MitoDEGs was verified by qPCR. RESULTS: 67 MitoDEGs were identified. Five signature MitoDEGs (SOD2, MTHFD2, PPTC7, NME6, and SLC25A18) were further screened out. The area under the curve (AUC) of signature MitoDEGs presented a good diagnostic performance (more than 0.9). There were significant differences in the expression of signature MitoDEGs between neutrophilic asthma and non-neutrophilic asthma. In addition, the basic features of mitochondrial dysfunction were demonstrated by in vitro and in vivo experiments. The expression of signature MitoDEGs in the neutrophilic asthma mice presented a significant difference from the control group. CONCLUSIONS: These MitoDEGs signatures in neutrophilic asthma may hold potential as anchor diagnostic and therapeutic targets in neutrophilic asthma.

Mycobacterium vaccae alleviates allergic airway inflammation and airway hyper-responsiveness in asthmatic mice by altering intestinal microbiota.

Host immunity can influence the composition of the gut microbiota and consequently affect disease progression. Previously, we reported that a Mycobacterium vaccae vaccine could ameliorate allergic inflammation in asthmatic mice by regulating inflammatory immune processes. Here, we investigated the anti-inflammatory effects of M. vaccae on allergic asthma via gut microbiota modulation. An ovalbumin (OVA)-induced asthmatic murine model was established and treated with M. vaccae. Gut microbiota profiles were determined in 18 BALB/c mice using 16S rDNA gene sequencing and metabolomic profiling was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. Mycobacterium vaccae alleviated airway hyper-reactivity and inflammatory infiltration in mice with OVA-induced allergic asthma. The microbiota of asthmatic mice is disrupted and that this can be reversed with M. vaccae. Additionally, a total of 24 differential metabolites were screened, and the abundance of PI(14:1(9Z)/18:0), a glycerophospholipid, was found to be correlated with macrophage numbers (r = 0.52, p = 0.039). These metabolites may affect chemokine (such as macrophage chemoattractant protein-1) concentrations in the serum, and ultimately affect pulmonary macrophage recruitment. Our data demonstrated that M. vaccae might alleviate airway inflammation and hyper-responsiveness in asthmatic mice by reversing imbalances in gut microbiota. These novel mechanistic insights are expected to pave the way for novel asthma therapeutic strategies.

Portable and Rapid Dual-Biomarker Detection Using Solution-Gated Graphene Field Transistors in the Accurate Diagnosis of Prostate Cancer.

Prostate-specific antigen (PSA) is the common serum-relevant biomarker for early prostate cancer (PCa) detection in clinical diagnosis. However, it is difficult to accurately diagnose PCa in the early stage due to the low specificity of PSA. Herein, a new solution-gated graphene field transistor (SGGT) biosensor with dual-gate for dual-biomarker detection is designed. The sensing mechanism is that the designed aptamers immobilized on the surface of the gate electrodes can capture PSA and sarcosine (SAR) biomolecules and induce the capacitance changes of the electric double layers of SGGT. The limit of detections of PSA and SAR biomarkers can reach 0.01 fg mL-1 , which is three-to-four orders of magnitude lower than previously reported assays. The detection time of PSA and SAR is ≈4.5 and ≈13 min, which is significantly faster than the detection time (1-2 h) of conventional methods. The clinical serum samples testing demonstrates that the biosensor can distinguish the PCa patients from the control group and the diagnosis accuracy can reach 100%. The SGGT biosensor can be integrated into the portable platform and the diagnostic results can directly display on the smartphone/Pad. Therefore, the integrated portable platform of the biosensor can distinguish cancer types through the dual-biomarker detection.

Methylprednisolone or dexamethasone? How should we choose to respond to COVID-19?: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Methylprednisolone (MP) and dexamethasone (DXM) are commonly prescribed hormone drugs for treating coronavirus pandemic disease 2019 (COVID-19) patients, but conflicting results from previous studies and meta-analyses on their efficacy and safety necessitate further investigation. Therefore, in this study, we conducted a systematic review and meta-analysis of randomized controlled trials to enhance the level of evidence and compare the efficacy and safety of MP and DXM in COVID-19 patients. METHODS: We conducted a comprehensive search of PubMed, Web of Science, Embase, and Cochrane Library databases to retrieve randomized clinical trials. Our primary outcome measure was all-cause mortality, with secondary outcomes including admission to the intensive care unit, length of hospital stay, mechanical ventilation, and adverse events. RESULTS: This study analyzed six randomized controlled trials involving 1403 patients (MP group: 704; DXM group: 699). The results of the analysis showed no significant differences in mortality rates, admission to intensive care units, hospitalization time, mechanical ventilation, or adverse events between the MP and DXM groups (P > .05). However, a significant difference was observed in the incidence of hyperglycemia between these 2 groups (RR = 1.78, 95% CI [1.09, 2.89], P = .02, I2 = 78%). CONCLUSION: The results of this meta-analysis showed that there was no difference in mortality, ICU admission rate, hospital stay, mechanical ventilation, or adverse events between MP and DXM in the treatment of COVID-19. The incidence of hyperglycemia with methylprednisolone was higher than that with dexamethasone.

Incidence, process of care, and outcomes of out-of-hospital cardiac arrest in China: a prospective study of the BASIC-OHCA registry.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is an important global public health issue, but its epidemiology and outcomes in low-income and middle-income countries remain largely unknown. We aim to comprehensively describe the incidence, process of care, and outcomes of OHCA in China. METHODS: In the prospective, multicentre, population-based Baseline Investigation of Out-of-hospital Cardiac Arrest (BASIC-OHCA) registry study, participating sites were selected from both urban and rural areas in all seven geographical regions across China. All patients with OHCA assessed by emergency medical service (EMS) staff were consecutively enrolled from Aug 1, 2019, to Dec 31, 2020. Patients with suspected cardiac arrest assessed by bystanders whose return of spontaneous circulation was achieved without the need for defibrillation or EMS personnel cardiopulmonary resuscitation were excluded. Patients with all key variables missing were excluded, including resuscitation attempt, age, sex, witnessed status, cause, all process of care indicators, and all outcome measures. In this analysis, we included data for EMS agencies serving 25 monitoring sites (20 urban and five rural) that included the entire serving population, data for the whole of 2020, and at least 50 OHCA patients in 2020. Data were collected and reported using the Utstein template. We calculated the crude incidence of EMS-assessed OHCA in 2020. We also report data on baseline characteristics (including sex, cause, location of OHCA, and presence of shockable rhythm), process of care (including EMS response time, cardiopulmonary resuscitation, defibrillation, and advanced life support), and outcomes of non-traumatic OHCA between Aug 1, 2019, and Dec 31, 2020, including survival and survival with favourable neurological outcomes at discharge or 30 days, and at 6 and 12 months. FINDINGS: Of 115·1 million people served by the 25 participating sites, 132 262 EMS-assessed patients with OHCA were enrolled, and resuscitation was attempted for 42 054 (31·8%) patients between Aug 1, 2019, and Dec 31, 2020. The crude incidence of EMS-assessed OHCA was 95·7 per 100 000 population (95% CI 95·6-95·8) in 2020. Among 38 227 individuals with non-traumatic OHCA, 25 958 (67·9%) were male, 30 282 (79·2%) had a cardiac arrest at home, 32 523 (85·1%) had a presumed cardiac cause, and 2297 (6·0%) presented with an initial shockable rhythm. 4049 (11·5%) of 35 090 patients with an unwitnessed or bystander-witnessed OHCA received dispatcher-assisted cardiopulmonary resuscitation and 7121 (20·3%) received bystander cardiopulmonary resuscitation; only 14 (<0·1%) patients were assessed by bystanders with an automated external defibrillator. The median EMS response time was 12 min (IQR 9-16). At hospital discharge or 30 days, 441 (1·2%) of 38 227 survived, 304 (0·8%) survived up to 6 months, and 269 (0·7%) up to 12 months. At hospital discharge or 30 days, 309 (0·8%) survived with favourable neurological outcomes, 257 (0·7%) had favourable neurological outcomes at 6 months, and 236 (0·6%) at 12 months. INTERPRETATION: Our findings revealed a high burden of EMS-assessed OHCA with a low proportion of resuscitation attempts. The suboptimal implementation of chain of survival and unsatisfactory prognosis call for national efforts to improve the care and outcomes of patients with OHCA in China. FUNDING: The National Science & Technology Fundamental Resources Investigation Program of China, the State Key Program of the National Natural Science Foundation of China, Taishan Pandeng Scholar Program of Shandong Province, the Key Research & Development Program of Shandong Province, the Interdisciplinary Young Researcher Groups Program of Shandong University, the Clinical Research Center of Shandong University, the ECCM Program of Clinical Research Center of Shandong University, and the Natural Science Foundation of Shandong Province.

The impact of non-optimum temperatures, heatwaves and cold spells on out-of-hospital cardiac arrest onset in a changing climate in China: a multi-center, time-stratified, case-crossover study.

Background: Out-of-hospital cardiac arrest (OHCA) is a time-critical and fatal medical emergency that has been linked to non-optimal temperatures. However, the future burden of OHCA due to non-optimal temperatures, heatwaves, and cold spells under climate change has not been well evaluated. Methods: We conducted a time-stratified case-crossover study in 15 Northern Chinese cities throughout 2020 to estimate the exposure-response relationships of non-optimal temperatures, heatwaves, and cold spells with hourly OHCA onset in hot and cold seasons. We obtained future daily average temperatures by using 20 general circulation models under two greenhouse gas emission scenarios: one with certain emission control and the other with relaxed control. Lastly, we projected the change of OHCA burden under these two climate scenarios. Findings: We analyzed a total of 29,671 OHCA patients and found that high temperatures and heatwaves as well as low temperatures and cold spells were all significantly associated with an increased risk of OHCA onset. Under the scenario of uncontrolled emissions, the attributable fraction (AF) of OHCA due to high temperatures and heatwaves would increase by 4.94% and 6.99% from the 2010s to 2090s, respectively. The AF due to low temperatures would decrease by 1.27% by the 2090s and the effects of cold spells were projected to be marginal after the 2050s. Under a medium emission control scenario, the upward trend of heat-related OHCA burden would become flat, and the decline in cold-related OHCA burden would also slow down. Interpretation: Our study provides evidence of significant morbidity risk and burden of OHCA associated with global warming across Northern China. Our findings indicate that the increase in OHCA burden attributable to heat could not be offset by the decrements attributable to cold, emphasizing the importance of mitigation policies for limiting global warming and reducing the associated risks of OHCA onset. Funding: National Science & Technology Fundamental Resources Investigation Project (2018FY100600, 2018FY100602), National Key R&D Program of China (2020YFC1512700, 2020YFC1512705, 2020YFC1512703), Key R&D Program of Shandong Province (2021ZLGX02, 2021SFGC0503), Natural Science Foundation of Shandong Province (ZR2021MH231), Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), the Interdisciplinary Young Researcher Groups Program of Shandong University (2020QNQT004), ECCM Program of Clinical Research Center of Shandong University (2021SDUCRCA001, 2021SDUCRCA002), foundation from Clinical Research Center of Shandong University (2020SDUCRCB003), National Natural Science Foundation of China (82272240).

Fine and coarse particulate air pollution and out-of-hospital cardiac arrest onset: a nationwide case-crossover study in China.

Out-of-hospital cardiac arrest (OHCA) is a global public health concern. Nationwide studies on the effects of short-term exposure to particulate matter (PM) on OHCA risk are rare in regions with high PM levels, and evidence for coarse PM (PM2.5-10) is limited and inconsistent. To evaluate the associations between fine PM (PM2.5) and PM2.5-10 and OHCA onset, a time-stratified case-crossover study was conducted on 77,261 patients with cardiac OHCA in 26 cities across China in 2020. Daily PM2.5 and PM2.5-10 concentrations were assessed with high-resolution and full-coverage PM estimations. Conditional logistic regression models were applied in analyses. Each interquartile range of PM increase in 3-day moving average was associated with an increased risk of cardiac OHCA onset of 2.37% (95% CI, 1.20-3.56%) for PM2.5 and 2.12% (95% CI, 0.70-3.56%) for PM2.5-10. Stratified analyses showed higher susceptibility in patients over 75 years for PM2.5 exposure and with diabetes for PM2.5-10. This first nationwide study in region with high PM levels and great PM variability found not only PM2.5 but also PM2.5-10 were associated with a higher risk of OHCA onset, which could add powerful epidemiological evidence to this field and provide new evidence for the formulation of air quality guidelines.

Identification of cuproptosis-related asthma diagnostic genes by WGCNA analysis and machine learning.

OBJECTIVE: Cuproptosis is the latest novel form of cell death. However, the relationship between asthma and cuproptosis is not fully understood. METHODS: In this study, we screened differentially expressed cuproptosis-related genes from the Gene Expression Omnibus (GEO) database and performed immune infiltration analysis. Subsequently, patients with asthma were typed and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG). Weighted gene co-expression network analysis (WGCNA) was performed to calculate the module-trait correlations, and the hub genes of the intersection were taken to construct machine learning (XGB, SVM, RF, GLM). Finally, we used TGF-ß to establish a BEAS-2B asthma model to observe the expression levels of hub genes. RESULTS: Six cuproptosis-related genes were obtained. Immune-infiltration analysis shows that cuproptosis-related genes are associated with a variety of biological functions. We classified asthma patients into two subtypes based on the expression of cuproptosis-related genes and found significant Gene Ontology (GO) and immune function differences between the different subtypes. WGCNA selected 2 significant modules associated with disease features and typing. Finally, we identified TRIM25, DYSF, NCF4, ABTB1, CXCR1 as asthma biomarkers by taking the intersection of the hub genes of the 2 modules and constructing a 5-genes signature, which nomograph, decision curve analysis (DCA) and calibration curves, receiver operating characteristic curve (ROC) showed high efficiency in diagnosing the probability of survival of asthma patients. Finally, in vitro experiments have shown that DYSF and CXCR1 expression is up expressed in asthma. CONCLUSIONS: Our study provides further directions for studying the molecular mechanism of asthma.

Efforts to Improve Survival Outcomes of Out-of-Hospital Cardiac Arrest in China: BASIC-OHCA.

BACKGROUND: Establishing registries to collect demographic characteristics, processes of care, and outcomes of patients with out-of-hospital cardiac arrest (OHCA) can better understand epidemiological trends, measure care quality, and identify opportunities for improvement. This study aimed to describe the design, implementation, and scientific significance of a nationwide registry-the BASIC-OHCA (Baseline Investigation of Out-of-Hospital Cardiac Arrest)-in China. METHODS: BASIC-OHCA was designed as a prospective, multicenter, observational, population-based study. The BASIC-OHCA registry was developed based on Utstein templates. BASIC-OHCA includes all OHCA patients confirmed by emergency medical services (EMS) personnel regardless of age, sex, or cause. Patients declared dead at the scene by EMS personnel for any reasons are also included. To fully characterize an OHCA event, BASIC-OHCA collects data from 3 sources-EMS, the receiving hospital, and patient follow-up-and links them to form a single record. Once data entry is completed and quality is checked, individual identifiers are stripped from the record. RESULTS: Currently, 32 EMS agencies in 7 geographic regions contribute data to BASIC-OHCA. They are distributed in the urban and rural areas, covering ≈9% of the population of mainland China. Data collection started on August 1, 2019. By July 31, 2020, a total of 92 913 EMS-assessed OHCA patients were enrolled. Among 28969 (31.18%) EMS-treated OHCAs, the mean age was 65.79±17.36 years, and 68.35% were males. The majority of OHCAs (76.85%) occurred at home or residence. A shockable initial rhythm was reported in 5.43% of patients. Any return of spontaneous circulation, survival to hospital discharge, and favorable neurological outcome at hospital discharge were 5.98%, 1.15%, and 0.83%, respectively. CONCLUSIONS: BASIC-OHCA is the first nationwide registry on OHCA in China. It can be used as a public health surveillance system and as a platform to produce evidence-based practices to help identify opportunities for improvement. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03926325.

Identidication of novel biomarkers in non-small cell lung cancer using machine learning.

Lung cancer is one of the leading causes of cancer-related deaths worldwide, and non-small cell lung cancer (NSCLC) accounts for a large proportion of lung cancer cases, with few diagnostic and therapeutic targets currently available for NSCLC. This study aimed to identify specific biomarkers for NSCLC. We obtained three gene-expression profiles from the Gene Expression Omnibus database (GSE18842, GSE21933, and GSE32863) and screened for differentially expressed genes (DEGs) between NSCLC and normal lung tissue. Enrichment analyses were performed using Gene Ontology, Disease Ontology, and the Kyoto Encyclopedia of Genes and Genomes. Machine learning methods were used to identify the optimal diagnostic biomarkers for NSCLC using least absolute shrinkage and selection operator logistic regression, and support vector machine recursive feature elimination. CIBERSORT was used to assess immune cell infiltration in NSCLC and the correlation between biomarkers and immune cells. Finally, using western blot, small interfering RNA, Cholecystokinin-8, and transwell assays, the biological functions of biomarkers with high predictive value were validated. A total of 371 DEGs (165 up-regulated genes and 206 down-regulated genes) were identified, and enrichment analysis revealed that these DEGs might be linked to the development and progression of NSCLC. ABCA8, ADAMTS8, ASPA, CEP55, FHL1, PYCR1, RAMP3, and TPX2 genes were identified as novel diagnostic biomarkers for NSCLC. Monocytes were the most visible activated immune cells in NSCLC. The knockdown of the TPX2 gene, a biomarker with a high predictive value, inhibited A549 cell proliferation and migration. This study identified eight potential diagnostic biomarkers for NSCLC. Further, the TPX2 gene may be a therapeutic target for NSCLC.

Mycobacterium Vaccae Regulate γδT17 and γδTreg Cells in Mice Asthmatic Lung.

Background Dysregulation of the balance between different T cell populations is believed to be an important basis for asthma.Objective To observe the changes in γδT subtypes in transgenic asthmatic mice after aerosol inhalation of Mycobacterium vaccae, and to further investigate the mechanism of M. vaccae in asthmatic mice and its relationship with γδT cells.Methods TCR-ß-/- mice were exposed to atomized normal saline or M. vaccae for 5 days and the γδT cells from the lung tissues were isolated. Changes in γδT17 and γδTreg populations were detected. Asthma was induced in BALB/c mice using ovalbumin, which was then transplanted with control or M. vaccae-primed γδT cells. First we analyzed the content of γδT cells that secrete IL-17 (IL-17 γδT cells) and Foxp3+ γδT cells in lung tissues and then measured the content of IL-17 in the bronchoalveolar lavage fluid (BALF) by ELISA.Results Exposure to M. vaccae increased and decreased the relative proportions of Foxp3+ γδT cells and IL-17+ γδT cells, respectively, thereby decreasing airway reactivity and inflammation levels in asthmatic mice, and significantly decreasing IL-17 levels in BALF. Furthermore, mice treated with these primed T cells showed a decrease in IL-17+ γδT cells, and a concomitant increase in Foxp3+ γδT cells in their lung tissues. Furthermore, adoptive transfer of M. vaccae-primed γδT cells decreased GATA3 and NICD and increased T-bet in lung.Conclusions The M. vaccae-primed γδT cells alleviated the symptoms of asthma by reversing Th2 polarization in the lungs and inhibiting the Notch/GATA3 pathway.

Cuproptosis-related lncRNA predict prognosis and immune response of lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) accounts for 50% of lung cancers, with high mortality and poor prognosis. Long non-coding RNA (lncRNA) plays a vital role in the progression of tumors. Cuproptosis is a newly discovered form of cell death that is highly investigated. Therefore, in the present study, we aimed to investigate the role of cuproptosis-related lncRNA signature in clinical prognosis prediction and immunotherapy and the relationship with drug sensitivity. MATERIAL AND METHODS: Genomic and clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and cuproptosis-related genes were obtained from cuproptosis-related studies. The prognostic signature was constructed by co-expression analysis and Cox regression analysis. Patients were divided into high and low risk groups, and then, a further series of model validations were carried out to assess the prognostic value of the signature. Subsequently, lncRNAs were analyzed for gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes Enrichment (KEGG), immune-related functions, and tumor mutation burden (TMB). Finally, we used tumor immune dysfunction and exclusion (TIDE) algorithms on immune escape and immunotherapy of cuproptosis-related lncRNAs, thereby identifying its sensitivity toward potential drugs for LUAD. RESULTS: A total of 16 cuproptosis-related lncRNAs were obtained, and a prognostic signature was developed. We found that high-risk patients had worse overall survival (OS) and progression-free survival (PFS) and higher mortality. Independent prognostic analyses, ROC, C-index, and nomogram showed that the cuproptosis-related lncRNAs can accurately predict the prognosis of patients. The nomogram and heatmap showed a distinct distribution of the high- and low-risk cuproptosis-related lncRNAs. Enrichment analysis showed that the biological functions of lncRNAs are associated with tumor development. We also found that immune-related functions, such as antiviral activity, were suppressed in high-risk patients who had mutations in oncogenes. OS was poorer in patients with high TMB. TIDE algorithms showed that high-risk patients have a greater potential for immune escape and less effective immunotherapy. CONCLUSION: To conclude, the 16 cuproptosis-related lncRNAs can accurately predict the prognosis of patients with LUAD and may provide new insights into clinical applications and immunotherapy.

Bayesian tensor logistic regression with applications to neuroimaging data analysis of Alzheimer's disease.

Alzheimer's disease (AD) can be diagnosed by utilizing traditional logistic regression models to fit magnetic resonance imaging (MRI) data of brain, which is regarded as a vector of covariates. But its parameter estimation is inefficient and computationally extensive due to ultrahigh dimensionality and complicated structure of MRI data. To overcome this deficiency, this paper proposes a tensor logistic regression model (TLRM) for AD's MRI data by regarding MRI tensor as covariates. Under this framework, a tensor candecomp/parafac (CP) decomposition tool is employed to reduce ultrahigh dimensional tensor to a high dimensional level, a novel Bayesian adaptive Lasso method is developed to simultaneously select important components of tensor and estimate model parameters by incorporating the Po´lya-Gamma method leading a closed-form likelihood and avoiding the usage of the Metropolis-Hastings algorithm, and Gibbs sampler technique in Markov chain Monte Carlo (MCMC). A tensor's product technique is utilized to optimize the calculation program and speed up the calculation of MCMC. Bayes factor together with the path sampling approach is presented to select tensor rank in CP decomposition. Effectiveness of the proposed method is illustrated on simulation studies and an MRI data analysis.

Aerosol Inhalation of Heat-Killed Clostridium butyricum CGMCC0313-1 Alleviates Allergic Airway Inflammation in Mice.

Epidemiological studies have shown that exposure to beneficial microorganisms can reduce the risk of asthma, but the clinical use of live probiotics is controversial due to the risk of infection. As heat-killed probiotics can also exhibit immunomodulatory activity, this study is aimed at investigating whether heat-killed Clostridium butyricum (HKCB) CGMCC0313-1 could reduce allergic airway inflammation in an ovalbumin-induced mouse model. Mice received aerosol inhalation of HKCB, oral administration of HKCB, or oral administration of live Clostridium butyricum (CB) during sensitization. Bronchoalveolar lavage fluid cell number, histology, and levels of the cytokines interferon-gamma and IL-4, the autophagy-related proteins LC3B, Beclin1, and p62, and members of the nuclear factor kappa B (NF-κB)/NLRP3 inflammasome signaling pathway were examined. Our results demonstrated that aerosol inhalation of HKCB, oral HKCB administration, and oral live CB administration alleviated allergic airway inflammation and mucus secretion in allergic mice. Aerosol inhalation of HKCB was the most effective method; it restored the Th1/Th2 balance, ameliorated autophagy, and inhibited the NF-κB/NLRP3 inflammasome signaling pathway in the lungs of allergic mice. Thus, aerosol inhalation of HKCB could be a promising strategy for the prevention or treatment of asthma.