Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids.

Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.

Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma.

Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting ß-catenin/TGF-ß1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy.

Comparative single-cell RNA sequencing analysis of immune response to inactivated vaccine and natural SARS-CoV-2 infection.

Uncovering the immune response to an inactivated SARS-CoV-2 vaccine (In-Vac) and natural infection is crucial for comprehending COVID-19 immunology. Here we conducted an integrated analysis of single-cell RNA sequencing (scRNA-seq) data from serial peripheral blood mononuclear cell (PBMC) samples derived from 12 individuals receiving In-Vac compared with those from COVID-19 patients. Our study reveals that In-Vac induces subtle immunological changes in PBMC, including cell proportions and transcriptomes, compared with profound changes for natural infection. In-Vac modestly upregulates IFN-α but downregulates NF-κB pathways, while natural infection triggers hyperactive IFN-α and NF-κB pathways. Both In-Vac and natural infection alter T/B cell receptor repertoires, but COVID-19 has more significant change in preferential VJ gene, indicating a vigorous immune response. Our study reveals distinct patterns of cellular communications, including a selective activation of IL-15RA/IL-15 receptor pathway after In-Vac boost, suggesting its potential role in enhancing In-Vac-induced immunity. Collectively, our study illuminates multifaceted immune responses to In-Vac and natural infection, providing insights for optimizing SARS-CoV-2 vaccine efficacy.

Novel Electrospun Sn-Based Composite Cathodes Exhibiting Extended Cycle Life for Hybrid Magnesium-Lithium Batteries.

In this study, we present a strategic approach for the structural design and composite modification of one-dimensional Sn-based nanocomposites to enhance the overall electrochemical performance of hybrid magnesium-lithium batteries (MLIBs), which are emerging as promising successors to lithium-ion batteries. By using electrospinning technology, we successfully synthesized NST-SnO2, NST-SnO2-NiO, Sn-CNF, and Ni3Sn2-CNF composite cathodes, as well as analyzed the synthesis mechanism of the four Sn-based cathodes. The 100-cycle testing at a current density of 500 mA·g-1 revealed that NST-SnO2 maintained a discharge specific capacity of 129.8 mA h·g-1 with a retention rate of 90.76%, while NST-SnO2-NiO achieved a higher capacity of 147.4 mA h·g-1 and an 88.05% retention rate. Notably, Sn-CNF and Ni3Sn2-CNF exhibited initial discharge capacities of 66.7 and 79.6 mA h·g-1, respectively, coupled with exceptional cycle stability, evidenced by retention rates of 104.19 and 102.38%. The remarkable cycling stability observed in these novel cathodes is attributed to their robust structural integrity, thus demonstrating the potential for an extended cycle life in MLIBs. This work provides significant advancement in the development of high-performance electrode materials for next-generation hybrid magnesium-lithium energy storage systems.

Quantitative imaging for predicting hematoma expansion in intracerebral hemorrhage: A multimodel comparison.

BACKGROUND: Several studies report that radiomics provides additional information for predicting hematoma expansion in intracerebral hemorrhage (ICH). However, the comparison of diagnostic performance of radiomics for predicting revised hematoma expansion (RHE) remains unclear. METHODS: The cohort comprised 312 consecutive patients with ICH. A total of 1106 radiomics features from seven categories were extracted using Python software. Support vector machines achieved the best performance in both the training and validation datasets. Clinical factors models were constructed to predict RHE. Receiver operating characteristic curve analysis was used to assess the abilities of non-contrast computed tomography (NCCT) signs, radiomics features, and combined models to predict RHE. RESULTS: We finally selected the top 21 features for predicting RHE. After univariate analysis, 4 clinical factors and 5 NCCT signs were selected for inclusion in the prediction models. In the training and validation dataset, radiomics features had a higher predictive value for RHE (AUC = 0.83) than a single NCCT sign and expansion-prone hematoma. The combined prediction model including radiomics features, clinical factors, and NCCT signs achieved higher predictive performances for RHE (AUC = 0.88) than other combined models. CONCLUSIONS: NCCT radiomics features have a good degree of discrimination for predicting RHE in ICH patients. Combined prediction models that include quantitative imaging significantly improve the prediction of RHE, which may assist in the risk stratification of ICH patients for anti-expansion treatments.

m6Am methyltransferase PCIF1 negatively regulates ciliation by inhibiting BICD2 expression.

N6, 2'-O-dimethyladenosine (m6Am) is a widespread RNA modification catalyzed by the methyltransferase PCIF1 (phosphorylated CTD interacting factor 1). Despite its prevalence, the biological functions of m6Am in RNA remain largely elusive. Here, we report a critical role of PCIF1-dependent m6Am RNA modification in ciliogenesis in RPE-1 cells. Our findings demonstrate that PCIF1 acts as a negative regulator of ciliation through its m6Am methyltransferase activity. A quantitative proteomic analysis identifies BICD2 as a downstream target of PCIF1, with PCIF1 depletion resulting in a significant increase in BICD2 levels. BICD2 depletion leads to a significant reduction in ciliation. Crucially, the ciliary phenotype in PCIF1-depleted cells is reversed upon BICD2 knockdown. Further investigations reveal that PCIF1 regulates BICD2 protein levels through its m6Am catalytic activity, which reduces the stability and translation efficiency of BICD2 mRNA. Single-base resolution LC-MS analysis identifies the m6Am site on BICD2 mRNA modified by PCIF1. These findings establish the essential involvement of PCIF1-dependent m6Am modification in ciliogenesis.

Comparison of volume-controlled ventilation, pressure-controlled ventilation and pressure-controlled ventilation-volume guaranteed in infants and young children in the prone position: A prospective randomized study.

STUDY OBJECTIVE: To explore if the pressure-controlled ventilation (PCV) and pressure-controlled ventilation-volume guaranteed (PCV-VG) modes are superior to volume-controlled ventilation (VCV) in optimizing intraoperative respiratory mechanics in infants and young children in the prone position. DESIGN: A single-center prospective randomized study. SETTING: Children's Hospital, Zhejiang University School of Medicine. PATIENTS: Pediatric patients aged 1 month to 3 years undergoing elective spinal cord detethering surgery. INTERVENTIONS: Patients were randomly allocated to the VCV group, PCV group and PCV-VG group. The target tidal volume (VT) was 8 mL/kg and the respiratory rate (RR) was adjusted to maintain a constant end tidal CO2. MEASUREMENTS: The primary outcome was intraoperative peak airway pressure (Ppeak). Secondary outcomes included other respiratory and ventilation variables, gas exchange values, serum lung injury biomarkers concentration, hemodynamic parameters and postoperative respiratory complications. MAIN RESULTS: A total of 120 patients were included in the final analysis (40 in each group). The VCV group showed higher Ppeak at T2 (10 min after prone positioning) and T3 (30 min after prone positioning) than the PCV and PCV-VG groups (T2: P = 0.015 and P = 0.002, respectively; T3: P = 0.007 and P = 0.009, respectively). The prone-related decrease in dynamic compliance was prevented by PCV and PCV-VG ventilation modalities at T2 and T3 than by VCV (T2: P = 0.008 and P = 0.015, respectively; T3: P = 0.015 and P = 0.014, respectively). Additionally, there were no significant differences in other secondary outcomes among the three groups. CONCLUSION: In infants and young children undergoing spinal cord detethering surgery in the prone position, PCV-VG may be a better ventilation mode due to its ability to mitigate the increase in Ppeak and decrease in Cdyn while maintaining consistent VT.

Microstructure changes and miRNA-mRNA network in a developmental dysplasia of the hip rat model.

MicroRNAs (miRNAs) interact with mRNAs in various pathophysiological processes. In developmental dysplasia of the hip (DDH), the miRNA-mRNA pairs affecting acetabular cartilage (AC) development remain unknown. We investigated dynamic microstructure changes and mRNA and miRNA expression profiles in the AC proliferative zone in a DDH rat model. Abnormal chondrocyte proliferation was observed, and several differentially expressed mRNAs and miRNAs were identified. Downregulated mRNAs and target genes of upregulated miRNAs were primarily enriched in bone and cartilage development. Six hub genes were identified using the predicted miRNA-mRNA interaction network and gene expression pattern analysis. The expression levels of these hub genes and paired miRNAs aligned with our predictions, and most of the pairs were significantly negatively correlated. Excessive chondrocyte proliferation in the AC proliferative zone can delay AC ossification, which might be crucial to DDH development. Specific miRNA-mRNA interaction pairs may serve as diagnostic biomarkers and therapeutic targets.

Efficacy of Da Vinci Robot-assisted Thoracoscopic Surgery in Children With Congenital Cystic Adenomatiod Malformation.

BACKGROUND: Surgical intervention is advisable for both asymptomatic and symptomatic CCAM children. This study aims to compare and analyze the efficacy of thoracoscopic and Da Vinci robot-assisted procedures in the management of CCAM among pediatric patients. METHODS: The clinical data of 188 pediatric patients diagnosed with CCAM and admitted to the Children's Hospital, Zhejiang University School of Medicine, from April 2019 to April 2023 were retrospectively analyzed. The Clavien-Dindo classification was employed for the systematic categorization of postoperative complications. RESULTS: The demographic and clinical characteristics of the patients were comparable between the two groups. Postoperative outcomes, such as the chest tube indwelling rate (92.6% vs 36.2%, p < 0.001∗), chest tube duration (2.0 (2.0-3.0) days vs 1.0 (1.0-2.0) days, p < 0.001∗), and length of postoperative hospital stay (6.0 (5.0-7.0) days vs 5.0 (5.0-6.0) days, p < 0.001∗), favored RATS over VATS. Additionally, there was no significant difference in complications between the two group, but the p-value is in a critical state. Ⅲa complications (mainly composed of postoperative thoracentesis procedures) manifesting as a higher rate in the RATS, nearly double that observed in the VATS. CONCLUSIONS: Robot-assisted thoracoscopic lung resection is demonstrated to be safe and feasible, with notable advantages in short-term postoperative clinical outcomes. Nevertheless, the practicality and long-term benefits of this technique necessitate further refinement and dedicated study. LEVEL OF EVIDENCE: LEVEL III.

Fucosyltransferase 8 regulates adult neurogenesis and cognition of mice by modulating the Itga6-PI3K/Akt signaling pathway.

Fucosyltransferase 8 (Fut8) and core fucosylation play critical roles in regulating various biological processes, including immune response, signal transduction, proteasomal degradation, and energy metabolism. However, the function and underlying mechanism of Fut8 and core fucosylation in regulating adult neurogenesis remains unknown. We have shown that Fut8 and core fucosylation display dynamic features during the differentiation of adult neural stem/progenitor cells (aNSPCs) and postnatal brain development. Fut8 depletion reduces the proliferation of aNSPCs and inhibits neuronal differentiation of aNSPCs in vitro and in vivo, respectively. Additionally, Fut8 deficiency impairs learning and memory in mice. Mechanistically, Fut8 directly interacts with integrin α6 (Itga6), an upstream regulator of the PI3k-Akt signaling pathway, and catalyzes core fucosylation of Itga6. Deletion of Fut8 enhances the ubiquitination of Itga6 by promoting the binding of ubiquitin ligase Trim21 to Itga6. Low levels of Itga6 inhibit the activity of the PI3K/Akt signaling pathway. Moreover, the Akt agonist SC79 can rescue neurogenic and behavioral deficits caused by Fut8 deficiency. In summary, our study uncovers an essential function of Fut8 and core fucosylation in regulating adult neurogenesis and sheds light on the underlying mechanisms.

Construction of a gene model related to the prognosis of patients with gastric cancer receiving immunotherapy and exploration of COX7A1 gene function.

BACKGROUND: GC is a highly heterogeneous tumor with different responses to immunotherapy, and the positive response depends on the unique interaction between the tumor and the tumor microenvironment (TME). However, the currently available methods for prognostic prediction are not satisfactory. Therefore, this study aims to construct a novel model that integrates relevant gene sets to predict the clinical efficacy of immunotherapy and the prognosis of GC patients based on machine learning. METHODS: Seven GC datasets were collected from the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) database and literature sources. Based on the immunotherapy cohort, we first obtained a list of immunotherapy related genes through differential expression analysis. Then, Cox regression analysis was applied to divide these genes with prognostic significancy into protective and risky types. Then, the Single Sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to score the two categories of gene sets separately, and the scores differences between the two gene sets were used as the basis for constructing the prognostic model. Subsequently, Weighted Correlation Network Analysis (WGCNA) and Cytoscape were applied to further screen the gene sets of the constructed model, and finally COX7A1 was selected for the exploration and prediction of the relationship between the clinical efficacy of immunotherapy for GC. The correlation between COX7A1 and immune cell infiltration, drug sensitivity scoring, and immunohistochemical staining were performed to initially understand the potential role of COX7A1 in the development and progression of GC. Finally, the differential expression of COX7A1 was verified in those GC patients receiving immunotherapy. RESULTS: First, 47 protective genes and 408 risky genes were obtained, and the ssGSEA algorithm was applied for model construction, showing good prognostic discrimination ability. In addition, the patients with high model scores showed higher TMB and MSI levels, and lower tumor heterogeneity scores. Then, it is found that the COX7A1 expressions in GC tissues were significantly lower than those in their corresponding paracancerous tissues. Meanwhile, the patients with high COX7A1 expression showed higher probability of cancer invasion, worse clinical efficacy of immunotherapy, worse overall survival (OS) and worse disease-free survival (DFS). CONCLUSIONS: The ssGSEA score we constructed can serve as a biomarker for GC patients and provide important guidance for individualized treatment. In addition, the COX7A1 gene can accurately distinguish the prognosis of GC patients and predict the clinical efficacy of immunotherapy for GC patients.

Multifaceted role of SARS-CoV-2 structural proteins in lung injury.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus to cause acute respiratory distress syndrome (ARDS) and contains four structural proteins: spike, envelope, membrane, and nucleocapsid. An increasing number of studies have demonstrated that all four structural proteins of SARS-CoV-2 are capable of causing lung injury, even without the presence of intact virus. Therefore, the topic of SARS-CoV-2 structural protein-evoked lung injury warrants more attention. In the current article, we first synopsize the structural features of SARS-CoV-2 structural proteins. Second, we discuss the mechanisms for structural protein-induced inflammatory responses in vitro. Finally, we list the findings that indicate structural proteins themselves are toxic and sufficient to induce lung injury in vivo. Recognizing mechanisms of lung injury triggered by SARS-CoV-2 structural proteins may facilitate the development of targeted modalities in treating COVID-19.

Severe pediatric COVID-19: a review from the clinical and immunopathophysiological perspectives.

BACKGROUND: Coronavirus disease 2019 (COVID-19) tends to have mild presentations in children. However, severe and critical cases do arise in the pediatric population with debilitating systemic impacts and can be fatal at times, meriting further attention from clinicians. Meanwhile, the intricate interactions between the pathogen virulence factors and host defense mechanisms are believed to play indispensable roles in severe COVID-19 pathophysiology but remain incompletely understood. DATA SOURCES: A comprehensive literature review was conducted for pertinent publications by reviewers independently using the PubMed, Embase, and Wanfang databases. Searched keywords included "COVID-19 in children", "severe pediatric COVID-19", and "critical illness in children with COVID-19". RESULTS: Risks of developing severe COVID-19 in children escalate with increasing numbers of co-morbidities and an unvaccinated status. Acute respiratory distress stress and necrotizing pneumonia are prominent pulmonary manifestations, while various forms of cardiovascular and neurological involvement may also be seen. Multiple immunological processes are implicated in the host response to COVID-19 including the type I interferon and inflammasome pathways, whose dysregulation in severe and critical diseases translates into adverse clinical manifestations. Multisystem inflammatory syndrome in children (MIS-C), a potentially life-threatening immune-mediated condition chronologically associated with COVID-19 exposure, denotes another scientific and clinical conundrum that exemplifies the complexity of pediatric immunity. Despite the considerable dissimilarities between the pediatric and adult immune systems, clinical trials dedicated to children are lacking and current management recommendations are largely adapted from adult guidelines. CONCLUSIONS: Severe pediatric COVID-19 can affect multiple organ systems. The dysregulated immune pathways in severe COVID-19 shape the disease course, epitomize the vast functional diversity of the pediatric immune system and highlight the immunophenotypical differences between children and adults. Consequently, further research may be warranted to adequately address them in pediatric-specific clinical practice guidelines.

A Patient Similarity Network (CHDmap) to Predict Outcomes After Congenital Heart Surgery: Development and Validation Study.

Background: Although evidence-based medicine proposes personalized care that considers the best evidence, it still fails to address personal treatment in many real clinical scenarios where the complexity of the situation makes none of the available evidence applicable. "Medicine-based evidence" (MBE), in which big data and machine learning techniques are embraced to derive treatment responses from appropriately matched patients in real-world clinical practice, was proposed. However, many challenges remain in translating this conceptual framework into practice. Objective: This study aimed to technically translate the MBE conceptual framework into practice and evaluate its performance in providing general decision support services for outcomes after congenital heart disease (CHD) surgery. Methods: Data from 4774 CHD surgeries were collected. A total of 66 indicators and all diagnoses were extracted from each echocardiographic report using natural language processing technology. Combined with some basic clinical and surgical information, the distances between each patient were measured by a series of calculation formulas. Inspired by structure-mapping theory, the fusion of distances between different dimensions can be modulated by clinical experts. In addition to supporting direct analogical reasoning, a machine learning model can be constructed based on similar patients to provide personalized prediction. A user-operable patient similarity network (PSN) of CHD called CHDmap was proposed and developed to provide general decision support services based on the MBE approach. Results: Using 256 CHD cases, CHDmap was evaluated on 2 different types of postoperative prognostic prediction tasks: a binary classification task to predict postoperative complications and a multiple classification task to predict mechanical ventilation duration. A simple poll of the k-most similar patients provided by the PSN can achieve better prediction results than the average performance of 3 clinicians. Constructing logistic regression models for prediction using similar patients obtained from the PSN can further improve the performance of the 2 tasks (best area under the receiver operating characteristic curve=0.810 and 0.926, respectively). With the support of CHDmap, clinicians substantially improved their predictive capabilities. Conclusions: Without individual optimization, CHDmap demonstrates competitive performance compared to clinical experts. In addition, CHDmap has the advantage of enabling clinicians to use their superior cognitive abilities in conjunction with it to make decisions that are sometimes even superior to those made using artificial intelligence models. The MBE approach can be embraced in clinical practice, and its full potential can be realized.

Continuous age- and sex-specific reference ranges of liver enzymes in Chinese children and application in pediatric non-alcoholic fatty liver disease.

BACKGROUND: Alanine aminotransferase (ALT) is widely used to screen patients with hepatic diseases. However, the current reference ranges (< 50 U/L) were developed by laboratories and have not been validated in populations with a large number of healthy individuals. METHODS: This study collected venous blood and anthropometric data from a total of 13,287 healthy children aged 3 months to 18 years who underwent routine physical examinations in the Department of Pediatric Healthcare. We applied the least mean square algorithm to establish age- and sex-related reference percentiles of serum levels of transaminases. For validation, we recruited 4276 children and adolescents with obesity/overweight who underwent evaluation and metabolic tests in the hospital. Using receiver operating characteristic curves, we determined age- and sex-specific upper limit percentiles of liver enzymes for fatty liver diseases. RESULTS: This study revealed a significant correlation between serum transaminase levels and age and sex (P < 0.01). These transaminase levels exhibited age- and sex-specific patterns. Among individuals in the non-alcoholic fatty liver disease (NAFLD) cohort, elevated ALT levels displayed a positive association with clinical markers of disease severity, including homeostatic model assessment of insulin resistance, waist-hip ratio, and serum uric acid levels (P < 0.01). According to the receiver operating characteristic curves, ALT levels at the 92.58th percentile for boys and the 92.07th percentile for girls yielded the highest accuracy and specificity. CONCLUSIONS: This study provides age- and sex-specific reference ranges for ALT, aspartate aminotransferase, and γ-glutamyltransferase in Chinese children and adolescents, making it the largest population study to date. Furthermore, the study establishes a precise upper limit for ALT levels, facilitating their use in NAFLD screening. Video Abstract.

Evaluation of Quality Properties of Brown Tigernut (Cyperus esculentus L.) Tubers from Six Major Growing Regions of China: A New Source of Vegetable Oil and Starch.

Tigernut has been recognized as a promising resource for edible oil and starch. However, the research on the quality characteristics of tigernut from different regions is lagging behind, which limits the application of tigernut in food industry. Tigernut tubers were obtained from six major growing regions in China, and the physicochemical properties of their main components, oil and starch, were characterized. Tigernut tubers from Baoshan contained the most oil (30.12%), which contained the most ß-carotene (130.4 µg/100 g oil) due to high average annual temperature. Gas chromatography analysis and fingerprint analysis results indicated that tigernut oil (TNO) consists of seven fatty acids, of which oleic acid is the major component. Changchun TNO contained the least total tocopherols (6.04 mg/100 g oil) due to low average annual temperature. Tigernut tubers from Chifeng (CF) contained the most starch (34.85%) due to the large diurnal temperature range. Xingtai starch contained the most amylose (28.4%). Shijiazhuang starch showed the highest crystallinity (19.5%). Anyang starch had the highest pasting temperature (76.0°C). CF starch demonstrated superior freeze-thaw stability (syneresis: 50%) due to low mean annual precipitation. The results could be further applied to support tigernut industries and relevant researchers that looks for geographical origin discrimination and improvements on tigernut quality, with unique physicochemical and technological properties.

Inhalation of panaxadiol alleviates lung inflammation via inhibiting TNFA/TNFAR and IL7/IL7R signaling between macrophages and epithelial cells.

Background: Lung inflammation occurs in many lung diseases, but has limited effective therapeutics. Ginseng and its derivatives have anti-inflammatory effects, but their unstable physicochemical and metabolic properties hinder their application in the treatment. Panaxadiol (PD) is a stable saponin among ginsenosides. Inhalation administration may solve these issues, and the specific mechanism of action needs to be studied. Methods: A mouse model of lung inflammation induced by lipopolysaccharide (LPS), an in vitro macrophage inflammation model, and a coculture model of epithelial cells and macrophages were used to study the effects and mechanisms of inhalation delivery of PD. Pathology and molecular assessments were used to evaluate efficacy. Transcriptome sequencing was used to screen the mechanism and target. Finally, the efficacy and mechanism were verified in a human BALF cell model. Results: Inhaled PD reduced LPS-induced lung inflammation in mice in a dose-dependent manner, including inflammatory cell infiltration, lung tissue pathology, and inflammatory factor expression. Meanwhile, the dose of inhalation was much lower than that of intragastric administration under the same therapeutic effect, which may be related to its higher bioavailability and superior pharmacokinetic parameters. Using transcriptome analysis and verification by a coculture model of macrophage and epithelial cells, we found that PD may act by inhibiting TNFA/TNFAR and IL7/IL7R signaling to reduce macrophage inflammatory factor-induced epithelial apoptosis and promote proliferation. Conclusion: PD inhalation alleviates lung inflammation and pathology by inhibiting TNFA/TNFAR and IL7/IL7R signaling between macrophages and epithelial cells. PD may be a novel drug for the clinical treatment of lung inflammation.

Function and mechanism of TREM2 in bacterial infection.

Triggering receptor expressed on myeloid cells 2 (TREM2), which is a lipid sensing and phagocytosis receptor, plays a key role in immunity and inflammation in response to pathogens. Here, we review the function and signaling of TREM2 in microbial binding, engulfment and removal, and describe TREM2-mediated inhibition of inflammation by negatively regulating the Toll-like receptor (TLR) response. We further illustrate the role of TREM2 in restoring organ homeostasis in sepsis and soluble TREM2 (sTREM2) as a diagnostic marker for sepsis-associated encephalopathy (SAE). Finally, we discuss the prospect of TREM2 as an interesting therapeutic target for sepsis.