Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization.

OBJECTIVES: Acute lung injury (ALI) is a highly inflammatory condition with the involvement of M1 alveolar macrophages (AMs) polarization, eventually leading to the development of non-cardiogenic edema in alveolar and interstitial regions, accompanied by persistent hypoxemia. Given the significant mortality rate associated with ALI, it is imperative to investigate the underlying mechanisms of this condition so as to identify potential therapeutic targets. The therapeutic effects of the inhibition of bromodomain containing protein 4 (BRD4), an epigenetic reader, has been proven with high efficacy in ameliorating various inflammatory diseases through mediating immune cell activation. However, little is known about the therapeutic potential of BRD4 degradation in acute lung injury. METHODS: This study aimed to assess the protective efficacy of ARV-825, a novel BRD4-targeted proteolysis targeting chimera (PROTAC), against ALI through histopathological examination in lung tissues and biochemical analysis in bronchoalveolar lavage fluid (BALF). Additionally, the underlying mechanism by which BRD4 regulated M1 AMs was elucidated by using CUT & Tag assay. RESULTS: In this study, we found the upregulation of BRD4 in a lipopolysaccharide (LPS)-induced ALI model. Furthermore, we observed that intraperitoneal administration of ARV-825, significantly alleviated LPS-induced pulmonary pathological changes and inflammatory responses. These effects were accompanied by the suppression of M1 AMs. In addition, our findings revealed that the administration of ARV-825 effectively suppressed M1 AMs by inhibiting the expression of IRF7, a crucial transcriptional factor involved in M1 macrophages. CONCLUSION: Our study suggested that targeting BRD4 using ARV-825 is a potential therapeutic approach for ALI.

Human genetic associations of the airway microbiome in chronic obstructive pulmonary disease.

Little is known about the relationships between human genetics and the airway microbiome. Deeply sequenced airway metagenomics, by simultaneously characterizing the microbiome and host genetics, provide a unique opportunity to assess the microbiome-host genetic associations. Here we performed a co-profiling of microbiome and host genetics with the identification of over 5 million single nucleotide polymorphisms (SNPs) through deep metagenomic sequencing in sputum of 99 chronic obstructive pulmonary disease (COPD) and 36 healthy individuals. Host genetic variation was the most significant factor associated with the microbiome except for geography and disease status, with its top 5 principal components accounting for 12.11% of the microbiome variability. Within COPD individuals, 113 SNPs mapped to candidate genes reported as genetically associated with COPD exhibited associations with 29 microbial species and 48 functional modules (P < 1 × 10-5), where Streptococcus salivarius exhibits the strongest association to SNP rs6917641 in TBC1D32 (P = 9.54 × 10-8). Integration of concurrent host transcriptomic data identified correlations between the expression of host genes and their genetically-linked microbiome features, including NUDT1, MAD1L1 and Veillonella parvula, TTLL9 and Stenotrophomonas maltophilia, and LTA4H and Haemophilus influenzae. Mendelian randomization analyses revealed a potential causal link between PARK7 expression and microbial type III secretion system, and a genetically-mediated association between COPD and increased relative abundance of airway Streptococcus intermedius. These results suggest a previously underappreciated role of host genetics in shaping the airway microbiome and provide fresh hypotheses for genetic-based host-microbiome interactions in COPD.

Enhancing regional control in p16-negative oropharyngeal cancer: A propensity score-matched analysis of upfront neck dissection and definitive chemoradiotherapy.

BACKGROUND: The presence of p16 and neck disease is important predictors of prognosis for oropharyngeal squamous cell carcinoma (OPSCC). Patients who are p16-negative and have clinically node-positive (cN+) disease generally have worse oncologic outcomes. This study aimed to investigate whether upfront neck dissection (UFND) could provide potential benefits for patients with cN+ p16-negative OPSCC. METHODS: Through this retrospective study, 76 patients with cN+ p16-negative OPSCC were analyzed, those who received either definite concurrent chemoradiotherapy (CCRT group) or UFND followed by chemoradiotherapy (UFND group). The primary endpoints were regional recurrence-free survival (RRFS), disease-specific survival (DSS), and overall survival (OS). Factors associated with survival were evaluated by univariate and multivariate analysis. Survival between the two groups was compared by propensity score-matched analysis. RESULTS: Matched 23 patients in each group through propensity analysis, the UFND group showed a significantly better 5-year RRFS (94.1% vs 61.0%, p = 0.011) compared to the CCRT group. Univariate analysis revealed that UFND was the sole factor associated with regional control (hazard ratio [HR] = 0.110; 95% CI, 0.014-0.879; p = 0.037). Furthermore, the study found that the CCRT group was associated with a higher dose of radiotherapy and exhibited a significantly higher risk of mortality due to pneumonia. CONCLUSION: The study indicated that UFND followed by CCRT may be a potential treatment option for patients with cN+ p16-negative OPSCC, as it can reduce the risk of regional recurrence. Additionally, the study highlights that definite CCRT is connected to a larger dose of radiotherapy and a higher risk of fatal pneumonia. These findings could be beneficial in informing clinical decision-making and improving treatment outcomes for patients with OPSCC.

A phase 4 multicentre, 2×2 factorial randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety of tobramycin inhalation solution for Pseudomonas aeruginosa eradication in bronchiectasis: ERASE.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.

Profiles of Cough and Associated Risk Factors in Nonhospitalized Individuals With SARS-CoV-2 Omicron Variant Infection: Cross-Sectional Online Survey in China.

BACKGROUND: Cough is a common symptom during and after COVID-19 infection; however, few studies have described the cough profiles of COVID-19. OBJECTIVE: The aim of this study was to investigate the prevalence, severity, and associated risk factors of severe and persistent cough in individuals with COVID-19 during the latest wave of the Omicron variant in China. METHODS: In this nationwide cross-sectional study, we collected information of the characteristics of cough from individuals with infection of the SARS-CoV-2 Omicron variant using an online questionnaire sent between December 31, 2022, and January 11, 2023. RESULTS: There were 11,718 (n=7978, 68.1% female) nonhospitalized responders, with a median age of 37 (IQR 30-47) years who responded at a median of 16 (IQR 12-20) days from infection onset to the time of the survey. Cough was the most common symptom, occurring in 91.7% of participants, followed by fever, fatigue, and nasal congestion (68.8%-87.4%). The median cough visual analog scale (VAS) score was 70 (IQR 50-80) mm. Being female (odds ratio [OR] 1.31, 95% CI 1.20-1.43), having a COVID-19 vaccination history (OR 1.71, 95% CI 1.37-2.12), current smoking (OR 0.48, 95% CI 0.41-0.58), chronic cough (OR 2.04, 95% CI 1.69-2.45), coronary heart disease (OR 1.71, 95% CI 1.17-2.52), asthma (OR 1.22, 95% CI 1.02-1.46), and gastroesophageal reflux disease (GERD) (OR 1.21, 95% CI 1.01-1.45) were independent factors for severe cough (VAS>70, 37.4%). Among all respondents, 35.0% indicated having a productive cough, which was associated with risk factors of being female (OR 1.44, 95% CI 1.31-1.57), having asthma (OR 1.84, 95% CI 1.52-2.22), chronic cough (OR 1.44, 95% CI 1.19-1.74), and GERD (OR 1.22, 95% CI 1.01-1.47). Persistent cough (>3 weeks) occurred in 13.0% of individuals, which was associated with the risk factors of having diabetes (OR 2.24, 95% CI 1.30-3.85), asthma (OR 1.70, 95% CI 1.11-2.62), and chronic cough (OR 1.97, 95% CI 1.32-2.94). CONCLUSIONS: Cough is the most common symptom in nonhospitalized individuals with Omicron SARS-CoV-2 variant infection. Being female, having asthma, chronic cough, GERD, coronary heart disease, diabetes, and a COVID-19 vaccination history emerged as independent factors associated with severe cough, productive cough, and persistent cough.

Strain Effects in Ru-Au Bimetallic Aerogels Boost Electrocatalytic Hydrogen Evolution.

To improve the sluggish kinetics of the hydrogen evolution reaction (HER), a key component in water-splitting applications, there is an urgent desire to develop efficient, cost-effective, and stable electrocatalysts. Strain engineering is proving an efficient strategy for increasing the catalytic activity of electrocatalysts. This work presents the development of Ru-Au bimetallic aerogels by a simple one-step in situ reduction-gelation approach, which exhibits strain effects and electron transfer to create a remarkable HER activity and stability in an alkaline environment. The surface strain induced by the bimetallic segregated structure shifts the d-band center downward, enhancing catalysis by balancing the processes of water dissociation, OH* adsorption, and H* adsorption. Specifically, the optimized catalyst shows low overpotentials of only 24.1 mV at a current density of 10 mA cm-2 in alkaline electrolytes, surpassing commercial Pt/C. This study can contribute to the understanding of strain engineering in bimetallic electrocatalysts for HER at the atomic scale.

The influence of repeated study and repeated testing on the testing effect and the transfer effect over time.

Many studies have shown that compared to the restudy condition (RS), retrieval practice (RP) enhances the long-retention memory of retrieved items (i.e., the testing effect), and facilitates later memory of non-retrieved but related items (i.e., the transfer effect). However, previous studies have usually used repeated study and repeated testing, which are included in study-testing cycles. Therefore, it is unclear to what extent the factors of repeated study and repeated testing influence testing and transfer effects over time. In this study, participants studied sentences that described various episodes, then tested a half subset of the original sentences under three conditions (RP, RS, control). After retention intervals of 10 min, 1 day and 7 days, they recalled all of the information in the sentences. The results showed that the testing effect was enhanced by repeated study or repeated testing, while the transfer effect occurred only after both repeated study and repeated testing. Furthermore, repeated study or repeated testing slowed down the forgetting of retrieved items, while the forgetting of non-retrieved items occurred after both repeated study and repeated testing. The testing effect increased over time, but the transfer effect remained relatively stable over time. These results clarified different roles of multiple study repetitions and testing opportunities in the testing effect and the transfer effect, and suggest that the repeated retrieval could be combined with repeated study to optimally promote long-term retention of the memory of tested and non-tested items.

A machine learning-based radiomics model for prediction of tumor mutation burden in gastric cancer.

Purpose: To evaluate the potential of machine learning (ML)-based radiomics approach for predicting tumor mutation burden (TMB) in gastric cancer (GC). Methods: The contrast enhanced CT (CECT) images with corresponding clinical information of 256 GC patients were retrospectively collected. Patients were separated into training set (n = 180) and validation set (n = 76). A total of 3,390 radiomics features were extracted from three phases images of CECT. The least absolute shrinkage and selection operator (LASSO) model was used for feature screening. Seven machine learning (ML) algorithms were employed to find the optimal classifier. The predictive ability of radiomics model (RM) was evaluated with receiver operating characteristic. The correlation between RM and TMB values was evaluated using Spearman's correlation coefficient. The explainability of RM was assessed by the Shapley Additive explanations (SHAP) method. Results: Logistic regression algorithm was chosen for model construction. The RM showed good predictive ability of TMB status with AUCs of 0.89 [95% confidence interval (CI): 0.85-0.94] and 0.86 (95% CI: 0.74-0.98) in the training and validation sets. The correlation analysis revealed a good correlation between RM and TMB levels (correlation coefficient: 0.62, p < 0.001). The RM also showed favorable and stable predictive accuracy within the cutoff value range 6-16 mut/Mb in both sets. Conclusion: The ML-based RM offered a promising image biomarker for predicting TMB status in GC patients.

Complete Glucose Electrooxidation Enabled by Coordinatively Unsaturated Copper Sites in Metal-Organic Frameworks.

The electrocatalytic oxidation of glucose plays a vital role in biomass conversion, renewable energy, and biosensors, but significant challenges remain to achieve high selectivity and high activity simultaneously. In this study, we present a novel approach for achieving complete glucose electrooxidation utilizing Cu-based metal-hydroxide-organic framework (Cu-MHOF) featuring coordinatively unsaturated Cu active sites. In contrast to traditional Cu(OH)2 catalysts, the Cu-MHOF exhibits a remarkable 40-fold increase in electrocatalytic activity for glucose oxidation, enabling exclusive oxidation of glucose into formate and carbonate as the final products. The critical role of open metal sites in enhancing the adsorption affinity of glucose and key intermediates was confirmed by control experiments and density functional theory simulations. Subsequently, a miniaturized nonenzymatic glucose sensor was developed showing superior performance with a high sensitivity of 214.7 µA mM-1 cm-2 , a wide detection range from 0.1 µM to 22 mM, and a low detection limit of 0.086 µM. Our work provides a novel molecule-level strategy for designing catalytically active sites and could inspire the development of novel metal-organic framework for next-generation electrochemical devices.

Longitudinal reciprocal association between rheumatoid arthritis and chronic obstructive pulmonary disease and mediation of inflammation.

OBJECTIVES: To elucidate the longitudinal reciprocal association between rheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD), and the mediating role of systemic inflammation in the association. METHODS: 403045 participants from UK Biobank were enrolled in this study. A cross-lagged panel model was used to investigate the longitudinal reciprocal association between RA and COPD. Cox-proportional hazard regression and logistic regression models were also conducted to examine the association between baseline RA and COPD during follow-up, and vice versa. Causal mediation analysis was then performed to explore the mediating roles of 160 systemic inflammatory biomarkers in the bidirectional association. RESULTS: At baseline, 4755 (1.2%) and 6989 (1.7%) individuals were diagnosed with RA and COPD, respectively. After adjusting for the covariates, the result of cross-lagged panel model revealed a bidirectional association between RA and COPD (ß = 0.018, P < 0.001 for RA→COPD path; ß = 0.010, P < 0.001 for COPD→RA path). In the non-COPD population, the risk of future COPD was increased in RA patients (Cox: HR = 1.65, 95% CI, 1.50-1.83; logistic: OR = 1.85, 95% CI, 1.66-2.07). In the non-RA population, baseline COPD was associated with a higher risk of RA during follow-up (Cox: HR = 1.67, 95% CI, 1.44-1.92; logistic: OR = 1.70, 95% CI, 1.47-1.97). Five inflammatory factors mediated the RA→COPD path, and C-reactive protein mediated the COPD→RA path (FDR < 0.05). CONCLUSIONS: A significant bidirectional association exists between RA and COPD, and it is partially mediated by systemic inflammation.

Characteristics of the pulmonary microbiota in patients with mild and severe pulmonary infection.

Background: Lung infection is a global health problem associated with high morbidity and mortality and increasing rates of hospitalization. The correlation between pulmonary microecology and infection severity remains unclear. Therefore, the purpose of this study was to investigate the differences in lung microecology and potential biomarkers in patients with mild and severe pulmonary infection. Method: Patients with pulmonary infection or suspected infection were divided into the mild group (140 cases) and the severe group (80 cases) according to pneomonia severity index (PSI) scores. Here, we used metagenomic next-generation sequencing (mNGS) to detect DNA mainly from bronchoalveolar lavage fluid (BALF) collected from patients to analyze changes in the lung microbiome of patients with different disease severity. Result: We used the mNGS to analyze the pulmonary microecological composition in patients with pulmonary infection. The results of alpha diversity and beta diversity analysis showed that the microbial composition between mild and severe groups was similar on the whole. The dominant bacteria were Acinetobacter, Bacillus, Mycobacterium, Staphylococcus, and Prevotella, among others. Linear discriminant analysis effect size (LEfSe) results showed that there were significant differences in virus composition between the mild and severe patients, especially Simplexvirus and Cytomegalovirus, which were prominent in the severe group. The random forest model screened 14 kinds of pulmonary infection-related pathogens including Corynebacterium, Mycobacterium, Streptococcus, Klebsiella, and Acinetobacter. In addition, it was found that Rothia was negatively correlated with Acinetobacter, Mycobacterium, Bacillus, Enterococcus, and Klebsiella in the mild group through co-occurrence network, while no significant correlation was found in the severe group. Conclusion: Here, we describe the composition and diversity of the pulmonary microbiome in patients with pulmonary infection. A significant increase in viral replication was found in the severe group, as well as a significant difference in microbial interactions between patients with mild and severe lung infections, particularly the association between the common pathogenic bacteria and Rothia. This suggests that both pathogen co-viral infection and microbial interactions may influence the course of disease. Of course, more research is needed to further explore the specific mechanisms by which microbial interactions influence disease severity.

Dynamic changes in macrophage subtypes during lung cancer progression and metastasis at single-cell resolution.

Background: Lung cancer remains a major global health challenge. Macrophages (Macs) are one important component of tumor microenvironments (TMEs); however, their prognostic relevance to lung cancer is currently unknown due to the complexity of their phenotypes. Methods: In the present study, reanalysis and atlas reconstruction of downloaded single-cell RNA sequencing (scRNAseq) data were used to systematically compare the component and transcriptional changes in Mac subtypes across different stages of lung cancer. Results: We found that with the progression of lung cancer, the proportion of alveolar macrophages (aMacs) gradually decreased, while the proportions of Macs and monocytes (Monos) gradually increased, suggesting a chemotaxis process followed by a Mono-Mac differentiation process. Meanwhile, through ligand-receptor (LR) screening, we identified 9 Mac-specific interactions that were enriched during the progression and metastasis of lung cancer, which could potential promote M2 polarization or the infiltration of M2 Macs. Moreover, we found that the expression of SPP1 in Macs increased with lung cancer progression, and identified 9 genes that were correlated with the expression of SPP1 in Macs, which might also contribute to the immunosuppression process in lung cancer. Conclusions: Our results revealed detailed changes in Macs at different stages of lung cancer progression and metastasis and provided potential therapeutic targets that could be used in future lung cancer treatments.

Sex-based differences in cardiac resynchronization therapy upgrade and outcome for patients with pacemaker and new-onset heart failure.

BACKGROUND: Patients with chronic right ventricular (RV) pacing are at an increased risk of heart failure. Previous studies have indicated that cardiac resynchronization therapy (CRT) is underused in this setting, and that there may be sex-based differences in both CRT use and clinical outcome. OBJECTIVE: To evaluate sex-based differences in CRT use and clinical outcome for patients with new-onset heart failure post RV pacing. METHODS: Data from the Swedish pacemaker registry was matched with data from the national death and disease registries. Patients with de novo pacemaker implant due to AV block during the period 2005-2020 were included. New-onset heart-failure within two years post-implant was evaluated, primary outcome was all-cause mortality. RESULTS: In all, 30183 patients (37% female) were included. Women were on average 3 years older, but had less comorbidities than men. Median follow-up time was 4.5 [2.0-8.0] years. Women had better age- and comorbidity-adjusted survival (HR 0.78 [0.73-0.84], p < .001). For the 3560 patients (12.4% men and 10.7% women, p < .001) who were diagnosed with new-onset heart failure, 5-year mortality was similar for men and women (50% vs. 48%, p = .29). However, women were less likely to receive CRT-upgrade (3.8% vs. 9.1%, p < .001), and those who did were almost ten years younger than the men. CONCLUSION: Women with pacemaker due to AV block are older but have less comorbidities than men. They are less likely to develop new-onset heart failure, but also less likely to receive a CRT upgrade if they do develop heart failure. Increased awareness of the positive effects of CRT upgrade and potential sex- and age-based discrimination is warranted.

Effects of prior knowledge on brain activation and functional connectivity during memory retrieval.

Previous studies have shown that the ventral medial prefrontal cortex (vmPFC) plays an important role in schema-related memory. However, there is an intensive debate to what extent the activation of subregions of the hippocampus is involved in retrieving schema-related memory. In addition, it is unclear how the functional connectivity (FC) between the vmPFC and the hippocampus, as well as the connectivity of the vmPFC with other regions, are modulated by prior knowledge (PK) during memory retrieval over time. To address these issues, participants learned paragraphs that described features of each unfamiliar word from familiar and unfamiliar categories (i.e., high and low PK conditions) 20 min, 1 day, and 1 week before the test. They then performed a recognition task to judge whether the sentences were old in the scanner. The results showed that the activation of the anterior-medial hippocampus (amHPC) cluster was stronger when the old sentences with high (vs. low) PK were correctly retrieved. The activation of the posterior hippocampus (pHPC) cluster, as well as the vmPFC, was stronger when the new sentences with high (vs. low) PK were correctly rejected (i.e., CR trials), whereas the cluster of anterior-lateral hippocampus (alHPC) showed the opposite. The FC of the vmPFC with the amHPC and perirhinal cortex/inferior temporal gyrus was stronger in the high (vs. low) PK condition, whereas the FC of the vmPFC with the alHPC, thalamus and frontal regions showed the opposite for the CR trials. This study highlighted that different brain networks, which were associated with the vmPFC, subregions of the hippocampus and cognitive control regions, were responsible for retrieving the information with high and low PK.

Age-stratified comparison of prognosis in cardiac resynchronization therapy with or without prophylactic defibrillator for nonischemic cardiomyopathy-a nationwide cohort study.

AIMS: Prior studies have suggested that the benefit from primary preventive defibrillator treatment for patients with nonischemic cardiomyopathyy, treated with cardiac resynchronization therapy, may be age-dependent. We aimed to compare age-stratified mortality rates and mode of death in patients with nonischemic cardiomyopathy who are treated with either primary preventive cardiac resynchronization therapy with defibrillator (CRT-D) or CRT with pacemaker (CRT-P). METHODS AND RESULTS: All patients with nonischemic cardiomyopathy and CRT-P or primary preventive CRT-D who were implanted in Sweden during the period 2005-2020 were included. Propensity scoring was used to create a matched cohort. Primary outcome was all-cause mortality within 5 years. In all, 4027 patients were included: 2334 with CRT-P and 1693 with CRT-D. Crude 5-year mortality was 635 (27%) vs. 246 (15%), P < 0.001. In Cox regression analysis, adjusted for clinically relevant covariables, CRT-D was independently associated with higher 5-year survival [0.72 (0.61-0.85), P < 0.001]. Cardiovascular mortality was similar between groups (62 vs. 64%, P = 0.64), but death from heart failure was more common in the CRT-D group (46 vs. 36%, P = 0.007). In the matched cohort (n = 2414), 5-year mortality was 21% (24 vs. 16%, P < 0.001). In age-stratified analyses, CRT-P was associated with higher mortality in age groups <60 years and 70-79 years, but there was no difference in age groups 60-69 years or 80-89 years. CONCLUSION: In this nationwide registry-based study, patients with CRT-D had better 5-year survival compared to patients with CRT-P. The interaction between age and mortality reduction was not consistent, but patients with CRT-D aged <60 years had the largest absolute mortality reduction.

LERMS: A Low-Latency and Reliable Downlink Packet-Level Encoding Transmission Method in Untrusted 5GA Edge Network.

The increasing demand for end-to-end low-latency and high-reliability transmissions between edge computing nodes and user elements in 5G Advance edge networks has brought new challenges to the transmission of data. In response, this paper proposes LERMS, a packet-level encoding transmission scheme designed for untrusted 5GA edge networks that may encounter malicious transmission situations such as data tampering, discarding, and eavesdropping. LERMS achieves resiliency against such attacks by using 5GA Protocol data unit (PDU) coded Concurrent Multipath Transfer (CMT) based on Lagrangian interpolation and Raptor's two-layer coding, which provides redundancy to eliminate the impact of an attacker's malicious behavior. To mitigate the increased queuing delay resulting from encoding in data blocks, LERMS is queue-aware with variable block length. Its strategy is modeled as a Markov chain and optimized using a matrix method. Numerical results demonstrate that LERMS achieves the optimal trade-off between delay and reliability while providing resiliency against untrusted edge networks.

Distribution of drug-resistant genes in alveolar lavage fluid from patients with psittacosis and traceability analysis of causative organisms.

Background: Chlamydia psittaci is a small bacterium often found in birds, including poultry, and domesticated mammals, which causes psittacosis (or parrot fever) in humans. Different strains of C. psittaci respond variably to antibiotics, suggesting a possible risk of antibiotic resistance. In general, different genotypes of C. psittaci have relatively stable hosts and different pathogenicity. Methods: Macrogenomic sequencing was performed using nucleic acids extracted from psittacosis patients' alveolar lavage fluid samples and analyzed for genetic variability and antibiotic resistance genes. Nucleic acid amplification sequences specific to the core coding region of the C. psittaci ompA gene were used, and a phylogenetic tree was constructed with C. psittaci genotypic sequences from other sources, including Chinese published sources. The C. psittaci found in each patient were genotyped by comparing ompA gene sequences. In addition, to better illustrate the relationship between genotype and host of C. psittaci, 60 bird fecal samples were collected from bird-selling stores for screening and C. psittaci typing. Results: Macrogenomic sequence alignment revealed the presence of resistance genes in varying abundance in samples from all three patients, including C. psittaci resistance gene sequences from two patients that matched those previously published on NCBI. Based on ompA genotyping, two patients were infected with C. psittaci genotype A and one patient was infected with genotype B. All five C. psittaci-positive samples obtained from bird-selling stores were genotype A. Both genotypes are reported to be infectious to humans. The host origin of the samples and the previously reported main sources of each genotype suggested that all but one of the C. psittaci genotype A in this study were derived from parrots, while genotype B was probably derived from chickens. Conclusion: The presence of bacterial resistance genes in psittacosis patients may affect the efficacy of clinical antibiotic therapy. Focusing on the developmental progression of bacterial resistance genes and differences in the therapeutic efficacy may facilitate effective treatment of clinical bacterial infections. Pathogenicity genotypes (e.g., genotype A and genotype B) are not limited to one animal host, suggesting that monitoring the development and changes of C. psittaci may help prevent transmission to humans.

Single-cell multi-omics sequencing reveals the immunological disturbance underlying STAT3-V637M Hyper-IgE syndrome.

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by, among others, the excessive production of IgE and repetitive bacterial/fungal infections. Mutations in STAT3, a transcription factor that orchestrates immune responses, may cause HIES, but the underlying mechanisms are not fully understood. Here, we used multi-omic approaches to comprehensively decipher the immune disturbance in a male HIES patient harboring STAT3-V637M. In his peripheral blood mononuclear cell (PBMC) we found significant clonal expansion of CD8 T cells (with increased CD8 subunits expression, potentially enhancing responsiveness to MHC I molecules), but not in his CD4 T cells and B cells. Although his B cells exhibited a higher potential in producing immunoglobulin, elevated SPIC binding might bias the products toward IgE isotype. Immune checkpoint inhibitors, including CTLA4, LAG3, were overexpressed in his PBMC-CD4 T cells, accompanied by reduced CD28 and IL6ST (gp130) expression. In his CD4 T cells, integrative analyses predicted upstream transcription factors (including ETV6, KLF13, and RORA) for LAG3, IL6ST, and CD28, respectively. The down-regulation of phagocytosis and nitric oxide synthesis-related genes in his PBMC-monocytes seem to be the culprit of his disseminated bacterial/fungal infection. Counterintuitively, in his PBMC we predicted increased STAT3 binding in both naïve and mature CD4 compartments, although this was not observed in most of his PBMC. In his bronchoalveolar lavage fluid (BALF), we found two macrophage subtypes with anti-bacterial properties, which were identified by CXCL8/S100A8/S100A9, or SOD2, respectively. Together, we described how the immune cell landscape was disturbed in STAT3-V637M HIES, providing a resource for further studies.

NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1.

Resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) remains one of the major challenges in lung adenocarcinoma (LUAD) therapy. Here, we find an increased frequency of the L12_16 amino acid deletion mutation in the signal peptide region of NOTCH4 (NOTCH4ΔL12_16) in EGFR-TKI-sensitive patients. Functionally, exogenous induction of NOTCH4ΔL12_16 in EGFR-TKI -resistant LUAD cells sensitizes them to EGFR-TKIs. This process is mainly mediated by the reduction of the intracellular domain of NOTCH4 (NICD4) caused by the NOTCH4ΔL12_16 mutation, which results in a lower localization of NOTCH4 in the plasma membrane. Mechanistically, NICD4 transcriptionally upregulates the expression of HES1 by competitively binding to the gene promoter relative to p-STAT3. Because p-STAT3 can downregulate the expression of HES1 in EGFR-TKI-resistant LUAD cells, the reduction of NICD4 induced by NOTCH4ΔL12_16 mutation leads to a decrease in HES1. Moreover, inhibition of the NOTCH4-HES1 pathway using inhibitors and siRNAs abolishes the resistance of EGFR-TKI. Overall, we report that the NOTCH4ΔL12_16 mutation sensitizes LUAD patients to EGFR-TKIs through transcriptional down-regulation of HES1 and that targeted blockade of this signaling cohort could reverse EGFR-TKI -resistance in LUAD, providing a potential approach to overcome resistance to EGFR-TKI -therapy.