Enolase of Streptococcus suis serotype 2 promotes biomolecular condensation of ribosomal protein SA for HBMECs apoptosis.

BACKGROUND: Ribosomal protein SA (RPSA) of human brain microvascular endothelial cells (HBMECs) can transfer from the cytosol to the cell surface and act as a receptor for some pathogens, including Streptococcus suis serotype 2 (SS2), a zoonotic pathogen causing meningitis in pigs and humans. We previously reported that SS2 virulence factor enolase (ENO) binds to RPSA on the cell surface of HBMECs and induces apoptosis. However, the mechanism that activates RPSA translocation to the cell surface and induces ENO-mediated HBMEC apoptosis is unclear. RESULTS: Here, we show that RPSA localization and condensation on the host cell surface depend on its internally disordered region (IDR). ENO binds to the IDR of RPSA and promotes its interaction with RPSA and vimentin (VIM), which is significantly suppressed after 1,6-Hexanediol (1,6-Hex, a widely used tool to disrupt phase separation) treatment, indicating that ENO incorporation and thus the concentration of RPSA/VIM complexes via co-condensation. Furthermore, increasing intracellular calcium ions (Ca2+) in response to SS2 infection further facilitates the liquid-like condensation of RPSA and aggravates ENO-induced HBMEC cell apoptosis. CONCLUSIONS: Together, our study provides a previously underappreciated molecular mechanism illuminating that ENO-induced RPSA condensation activates the migration of RPSA to the bacterial cell surface and stimulates SS2-infected HBMEC death and, potentially, disease progression. This study offers a fresh avenue for investigation into the mechanism by which other harmful bacteria infect hosts via cell surfaces' RPSA.

High-dimensional analysis reveals an immune atlas and novel neutrophil clusters in the lungs of model animals with Actinobacillus pleuropneumoniae-induced pneumonia.

Due to the increase in bacterial resistance, improving the anti-infectious immunity of the host is rapidly becoming a new strategy for the prevention and treatment of bacterial pneumonia. However, the specific lung immune responses and key immune cell subsets involved in bacterial infection are obscure. Actinobacillus pleuropneumoniae (APP) can cause porcine pleuropneumonia, a highly contagious respiratory disease that has caused severe economic losses in the swine industry. Here, using high-dimensional mass cytometry, the major immune cell repertoire in the lungs of mice with APP infection was profiled. Various phenotypically distinct neutrophil subsets and Ly-6C+ inflammatory monocytes/macrophages accumulated post-infection. Moreover, a linear differentiation trajectory from inactivated to activated to apoptotic neutrophils corresponded with the stages of uninfected, onset, and recovery of APP infection. CD14+ neutrophils, which mainly increased in number during the recovery stage of infection, were revealed to have a stronger ability to produce cytokines, especially IL-10 and IL-21, than their CD14- counterparts. Importantly, MHC-II+ neutrophils with antigen-presenting cell features were identified, and their numbers increased in the lung after APP infection. Similar results were further confirmed in the lungs of piglets infected with APP and Klebsiella pneumoniae infection by using a single-cell RNA-seq technique. Additionally, a correlation analysis between cluster composition and the infection process yielded a dynamic and temporally associated immune landscape where key immune clusters, including previously unrecognized ones, marked various stages of infection. Thus, these results reveal the characteristics of key neutrophil clusters and provide a detailed understanding of the immune response to bacterial pneumonia.

Lipopolysaccharide increases exosomes secretion from endothelial progenitor cells by toll-like receptor 4 dependent mechanism.

BACKGROUND INFORMATION: Endothelial progenitor cells (EPCs) can exert angiogenic effects by a paracrine mechanism, where exosomes work as an important mediator. Recent studies reported functional expression of toll-like receptor (TLR) 4 on human EPCs and dose-dependent effects of lipopolysaccharide (LPS) on EPC angiogenic properties. To study the effects of TLR4/LPS signaling on EPC-derived exosomes (Exo) and clarify the mechanism, we investigated the role of LPS on exosomes secretion from human EPCs and tested their anti-oxidation/senescence functions. We employed the inhibitors of the plasma membrane Ca2+ -ATPase (PMCA), endoplasmic reticulum Ca2+ -ATPase (ERCA), PLC-IP3 pathway and store-operated calcium entry to assess the effects of LPS on EPC intracellular calcium signalings which critical for exosome secretion. RESULTS: LPS induced the release of Exo in a TLR4-dependent manner in vitro, which effect can be partly abrogated by an membrane-permeable IP 3 R antagonist, 2-aminoethyl diphenylborinate (2-APB), but not PLC inhibitor, U-73122. The LPS can significantly delay the fallback of [Ca2+ ]i after isolating the cellular PMCA activity, and disturb PMCA 1/4 expression. The distribution of elevated intracellular calcium seemed coincident with the development of the multivesicular bodies (MVBs). furthermore, the anti-oxidation/senescence properties of LPS-induced Exo were validated by the senescence-associated ß-galactosidase activity assay and reactive oxygen species (ROS) related H2 DCF-DA assay. CONCLUSIONS: The mechanism of PMCA downregulation and IP3 R-dependent ER Ca2+ release may contribute to the pro-exosomal effects of LPS on EPCs. SIGNIFICANCE: This study provides new insights into the potential role of LPS/TLR4 pathway in regulating EPC-derived exosomes, which may help to develop some feasible approach to manipulate the Exo secretion and promote the clinical application of EPCs therapy in future.

Eosinophils in patients with lone atrial fibrillation.

BACKGROUND: Inflammation has been evidenced as a critical contributable mechanism for the atrial fibrillation (AF) onset and development. As the consistent inflammatory and oxidative marker, the effects of white blood cell (WBC) and its differential on lone atrial fibrillation (LAF) were investigated in the study. METHODS: A total of 126 patients with paroxysmal LAF who scheduled for rhythm control drug therapy and 120 age- and gender-matched subjects in sinus rhythm were included sequentially. Peripheral blood sample and clinic data were collected during the first evaluation. Recurrence of AF was evaluated by outpatient clinics and telephone visits for the following 12 months. RESULTS: Peripheral eosinophil count, neutrophil count, and left atrial diameter (LAD) were significantly higher in LAF than control. Within a follow-up of 12 months, 56 patients (44.4%) had developed AF recurrence. Patients with AF recurrence had higher eosinophil count and LAD. Univariable analyses showed a statistically significant relationship between eosinophil count (P = 0.042), LAD (P = 0.030), and AF recurrence. Multivariate logistic regression analysis showed that LAD (OR: 1.090 per 1 mm increase; 95% CI: 1.007-1.180; P = 0.032) and eosinophil (OR: 1.643 per 1 × 108 /L increase; 95% CI: 1.047-2.578; P = 0.031) were independent predictors of AF recurrence during antiarrhythmic drug therapy. CONCLUSION: Our results support the association of the WBC response and its components with the LAF. Especially, the peripheral eosinophil and LAD may play important roles in mediating inflammation and atrial remodeling in AF.

Safety and efficacy of autologous thymosin ß4 pre-treated endothelial progenitor cell transplantation in patients with acute ST segment elevation myocardial infarction: A pilot study.

BACKGROUND: Experimental studies and clinical trials suggest that endothelial progenitor cell (EPC) transplantation can repair "broken" heart. However, transplantation of autologous EPCs has numerous limitations, including the limited supply of expanded EPCs, the impaired function and activity of the transplanted cells and so on. Therefore, we investigated the feasibility, safety and initial clinical outcome of autologous thymosin ß4 (Tß4) pre-treated EPC transplantation in patients with acute ST segment elevation myocardial infarction (STEMI). METHODS: Ten patients with STEMI were included; they were randomized to 2 groups: EPC transplantation group (control group; n = 5) and Tß4-pre-treated EPC transplantation group (experimental group; n = 5). EPCs were pre-treated with Tß4 24 hours before transplantation in experimental group. Cardiac function was evaluated using echocardiography and emission computed tomography, as well as the 6-min walking test before and 6 months after the intervention. RESULTS: After 6 months of follow-up, the average 6-min walking distance was increased by 38.2 m (from 263 ± 42 m to 302 ± 34 m) in the control group and 75.7 m (from 264 ± 42 m to 340 ± 44 m) in the experimental group; the average difference of the 6-min walking distance was 37.5 m (95% confidence interval [CI], 28.7-56.3 m; P < 0.01). In addition, the cardiac function in the experimental group was more significantly improved than that of the control group. There were no severe complications related to the procedure in either group during the follow-up. DISCUSSION: Our pilot study suggested that Tß4-optimized EPC transplantation appeared to be feasible and safe, and might have beneficial effects on exercise capacity and left ventricular function in patients with STEMI.

Oral abrocitinib in the treatment of granuloma annulare: a case report.

Aim: To evaluate the therapeutic efficacy and safety of JAK inhibitor abrocitinib in patients with localized granuloma annulare (GA) and to review the available cases documented in English.Methods: We presented a patient who had a persistent, localized granuloma anulare (GA) for one year and did not respond to traditional therapies. This patient was treated with oral abrocitinib at a dosage of 150 mg daily.Results: After 6 weeks of treatment with abrocitinib, the patient exhibited notable symptom improvement with no new lesions. No adverse events or recurrences were reported during the 5-month follow-up period.Conclusions: Abrocitinib may be a promising and safe treatment option for patients with localized GA who do not respond to traditional therapies.

Abrocitinib as a Novel Treatment for Multiple Skin Disorders: 3 Case Reports and a Scoping Review.

Janus kinase (JAK) inhibitors are increasingly being used in dermatology due to their broad potential in managing both local and systemic inflammation. More recently, abrocitinib, an oral JAK 1 inhibitor, has shown promising clinical efficacy in the treatment of various skin disorders beyond moderate to severe atopic dermatitis (AD). We firstly presented three cases, each with diagnosis of pyoderma gangrenosum (PG), livedoid vasculopathy (LV), or hidradenitis suppurativa (HS), and conducted a comprehensive scoping review of the available literature on the use of abrocitinib in the treatment of diverse skin disorders. We summarized a total of 16 skin disorders, including our cases. The results indicated that abrocitinib, whether used as monotherapy or in combination with other treatments, was effective and well-tolerated in these disorders. These findings expanded the range of diseases for which abrocitinib may serve as an alternative therapeutic choice.

Brain Immune Cell Infiltration and Serum Metabolomic Characteristics Reveal that Lauric Acid Promotes Immune Cell Infiltration in Brain and Streptococcus suis Meningitis in Mice.

Although naturally Streptococcus suis serotype 2 (SS2) causes meningitis resulting in death or sequela of neurological symptoms in pigs and humans, severely threatening public health in the world, it has been difficult to build up and confirm experimental meningitis mouse models with obvious neurological syndrome for about two decades, which strongly hampers the in-depth study on the control measures and mechanisms of SS2-induced meningitis. In this study, a typical meningitis mouse model of SS2 was successfully established, as confirmed by the behavioral indicators of balance beam test, suspension test, and gait analysis. With bacteria gathering in the brain, distinguishable unique features including meningeal thickening, vacuolization of the Nissl body, brain barrier damage, glial cell activation, and more infiltration of T cells, macrophages, and DCs are observed in SS2 meningitis mice with typical neurological signs. Some meningitis mice were also accompanied by identical nephritis, ophthalmia, and cochlearitis. Investigation of the metabolic features demonstrated the downregulated cholic acid and upregulated 2-hydroxyvaleric acid, tetrahydrocortisone, nicotinic acid, and lauric acid in blood serum of mice and piglets with meningitis. And feeding trials show that lauric acid can promote meningitis by promoting the infiltration of immune cells into brain. These findings demonstrated that infection of ICR (improved castle road) mice with SS2 was able to induce typical meningitis accompanied by immune cell infiltration and lauric acid upregulation. These data provide a basis for the deep study of SS2 meningitis.

Angioimmunoblastic T-cell lymphoma involving the nasopharynx: An easily misdiagnosed disease with atypical histopathological features.

OBJECTIVES: To explore the clinicopathologic features, treatment, and survival outcomes of angioimmunoblastic T-cell lymphoma (AITL) involving the nasopharynx. METHODS: We retrospectively analyzed 73 cases of AITL. Among them, 64 cases with complete pre-treatment 18F-FDG positron emission tomography/computed tomography (PET/CT) images were integrated into the analysis of clinical characteristics and PET/CT findings of AITL involving the nasopharynx; 14 cases with both biopsies from lymph node and nasopharynx were included in the comparison of pathological characteristics of AITL in the two areas. Forty-six of the 73 patients who received first-line systemic treatment at our institute were included in the treatment efficacy and survival analyses. RESULTS: Nasopharyngeal involvement was seen in 44/64 (68.8%) patients. Histologically, lymph node and nasopharyngeal biopsies in 14 patients both showed small to medium-sized tumor cells, complex inflammatory infiltration, and Reed-Sternberg-like cells or B immunoblasts. However, tumor cells with clear cytoplasm, significant high endothelial venule (HEV) hyperplasia, and perivascular infiltration were observed in 5/14, 3/14, and 2/14 nasopharyngeal biopsies, respectively, but in all fourteen lymph node biopsies (P < 0.05). Immunophenotypic profiles and gene rearrangements were highly concordant. Treatment efficacy and survival were similar between patients with nasopharyngeal involvement and those without (P > 0.05), indicating nasopharyngeal involvement is not a prognostic factor for AITL patients. CONCLUSIONS: Nasopharyngeal involvement is common in AITL but can be easily misdiagnosed because of its atypical pathologic pattern, especially when a lymph node biopsy is unavailable. However, the patient's clinical presentation, PET/CT manifestations, the typical immunophenotype, and gene rearrangements help the diagnosis.

Adh Promotes Actinobacillus pleuropneumoniae Survival in Porcine Alveolar Macrophages by Inhibiting CHAC2-Mediated Respiratory Burst and Inflammatory Cytokine Expression.

Actinobacillus pleuropneumoniae (A. pleuropneumoniae) causes porcine pleuropneumonia that seriously endangers pig's health. Adh, located in the head region of trimeric autotransporter adhesion of A. pleuropneumoniae, affects bacterial adhesion and pathogenicity. However, how Adh mediates A. pleuropneumoniae immune invasion is still unclear. Here, we established the A. pleuropneumoniae strain L20 or L20 ΔAdh-infected porcine alveolar macrophages (PAM) model, and applied protein overexpression, RNA interference, qRT-PCR, Western blot and immunoflourescence techniques to dissect the effects of Adh on PAM during A. pleuropneumoniae infection. We found that Adh could increase the A. pleuropneumoniae adhesion and intracellular survival in PAM. Gene chip analysis of piglet lungs further showed that Adh significantly induced cation transport regulatory-like protein 2 (CHAC2) expression, whose overexpression suppressed the phagocytic capacity of PAM. Furthermore, CHAC2 overexpression dramatically increased glutathione (GSH) expression, decreased reactive oxygen species (ROS), and promoted A. pleuropneumoniae survival in PAM, while the knockdown of CHAC2 reversed these phenomena. Meanwhile, CHAC2 silence activated the NOD1/NF-κB pathway, resulting in an increase in IL-1ß, IL-6, and TNF-α expression, whereas this effect was weakened by CHAC2 overexpression and addition of NOD1/NF-κB inhibitor ML130. Moreover, Adh enhanced the secretion of LPS of A. pleuropneumoniae, which regulated the expression of CHAC2 via TLR4. In conclusion, through a LPS-TLR4-CHAC2 pathway, Adh inhibits respiratory burst and inflammatory cytokines expression to promote A. pleuropneumoniae survival in PAM. This finding may provide a novel target for the prevention and treatment of A. pleuropneumoniae.

Development and application of an indirect ELISA and nested PCR for the epidemiological analysis of Klebsiella pneumoniae among pigs in China.

Introduction: Klebsiella pneumoniae (K. pneumoniae) is an important opportunistic and zoonotic pathogen which is associated with many diseases in humans and animals. However, the pathogenicity of K. pneumoniae has been neglected and the prevalence of K. pneumoniae is poorly studied due to the lack of rapid and sensitive diagnosis techniques. Methods: In this study, we infected mice and pigs with K. pneumoniae strain from a human patient. An indirect ELISA was established using the KHE protein as the coating protein for the detection of K. pneumoniae specific antibody in clinical samples. A nested PCR method to detect nuclei acids of K. pneumoniae was also developed. Results: We showed that infection with K. pneumoniae strain from a human patient led to mild lung injury of pigs. For the ELISA, the optimal coating concentration of KHE protein was 10 µg/mL. The optimal dilutions of serum samples and secondary antibody were 1:100 and 1:2500, respectively. The analytical sensitivity was 1:800, with no cross-reaction between the coated antigen and porcine serum positive for antibodies against other bacteria. The intra-assay and inter-assay reproducibility coefficients of variation are less than 10%. Detection of 920 clinical porcine serum samples revealed a high K. pneumoniae infection rate by established indirect ELISA (27.28%) and nested PCR (19.13%). Moreover, correlation analysis demonstrated infection rate is positively correlated with gross population, Gross Domestic Product (GDP), and domestic tourists. Discussion: In conclusion, K. pneumoniae is highly prevalent among pigs in China. Our study highlights the role of K. pneumoniae in pig health, which provides a reference for the prevention and control of diseases associated with K. pneumoniae.

Endothelial progenitor cells: current development of their paracrine factors in cardiovascular therapy.

Endothelial progenitor cells were initially considered to radically alter the concepts of adult tissue angiogenesis for their contribution of incorporation into new blood vessels. Nevertheless, controversy arises over their mechanism of action due to rare cell population and decreased number and impaired activity under pathological changes. Recent studies show that endothelial progenitor cells also function in a paracrine manner by secreting multiple cytokines and growth factors, but the beneficial paracrine signals remain partially unidentified. In this review, we provide an overview of varieties and signal pathways of factors secreted by endothelial progenitor cells and further present the prospect of new ways to encourage cardiovascular protection such as neovascularization, reendothelialization of larger vessels, and myocardial remodeling based on the paracrine factors.

MicroRNAs as potential novel therapeutic targets and tools for regulating paracrine function of endothelial progenitor cells.

Endothelial progenitor cells (EPCs) play a protective role in the cardiovascular system by enhancing the maintenance of endothelium homeostasis and the process of new vessel formation. Recent studies show that EPCs may induce vascular regeneration and neovascularization mainly through paracrine signaling, that is, through the secretion of growth factors and pro-angiogenic cytokines. However, multiple factors might function synergistically and therefore make it difficult to manipulate EPC paracrine effects. MicroRNAs, a family of small, non-coding RNAs, are characterized by post-transcriptionally regulating multiple functionally related genes, which renders them potentially powerful therapeutic targets or tools. In this paper we propose the hypothesis that microRNAs can be utilized as a novel therapeutic strategy for regulating EPC paracrine secretion.

TLR4-SIRT3 Mechanism Modulates Mitochondrial and Redox Homeostasis and Promotes EPCs Recruitment and Survival.

The low survival rate of endothelial progenitor cells (EPCs) in vivo which are susceptible to adverse microenvironments including inflammation and oxidative stress has become one primary challenge of EPCs transplantation for regenerative therapy. Recent studies reported functional expression of toll-like receptor (TLR) 4 on EPCs and dose-dependent effects of lipopolysaccharide (LPS) on cellular oxidative stress and angiogenic properties. However, the involved mechanism has not yet been elucidated well, and the influence of TLR4 signaling on EPCs survival and function in vivo is unknown. In the present study, we observed the effects of LPS and TLR4/SIRT3 on EPCs mitochondrial permeability and intracellular mitochondrial superoxide. We employed the monocrotaline-induced pulmonary arteriolar injury model to observe the effects of TLR4/SIRT3 on the recruitment and survival of transplanted EPCs. We found the destructive effects of 10 µg/mL LPS on mitochondrial homeostasis, and cellular viability was mediated by TLR4/SIRT3 signals at least partially, and the TLR4 mediates the early-stage recruitment of transplanted EPCs in pulmonary arteriolar inflammation injury; however, SIRT3 has more contribution to the survival of incorporated EPCs and ameliorated arteriolar remodeling in lung vascular tissue. The study provides insights for the critical role of TLR4/SIRT3 in LPS-induced oxidative stress and mitochondrial disorder in EPCs in vitro and in vivo. The TLR4/SIRT3 signaling is important for EPCs resistance against inflammation and oxidative stress and may represent a new manipulating target for developing efficient cell therapy strategy.

A Novel Monopolar Cross-Scale Nanopositioning Stage Based on Dual Piezoelectric Stick-Slip Driving Principle.

The precise characterization and measurement of new nanomaterials and nano devices require in situ SEM nanorobotic instrumentation systems, which put forward further technical requirements on nanopositioning techniques of compact structure, cross-scale, nanometer accuracy, high vacuum and non-magnetic environment compatibility, etc. In this work, a novel cross-scale nanopositioning stage was proposed, which combined the advantages of piezoelectric stick-slip positioner and piezoelectric scanner techniques and adopted the idea of macro/micro positioning. A new structure design of a single flexible hinge shared by a small and large PZT was proposed to effectively reduce the size of the positioning stage and achieve millimeter stroke and nanometer motion positioning accuracy. Then, the cross-scale motion generation mechanism of the dual piezoelectric stick-slip drive was studied, the system-level dynamics model of the proposed positioning stages was constructed, and the mechanism design was optimized. Further, a prototype was manufactured and a series of experiments were carried out to test the performance of the stage. The results show that the proposed positioning stage has a maximum motion range of 20 mm and minimum step length of 70 nm under the small piezoceramic ceramic macro-motion stepping mode, and a maximum scanning range of 4.9 µm and motion resolution of 16 nm under the large piezoceramic ceramic micro-motion scanning mode. Moreover, the proposed stage has a compact structure size of 30 × 17 × 8 mm3, with a maximum motion speed of 10 mm/s and maximum load of 2 kg. The experimental results confirm the feasibility of the proposed stage, and nanometer positioning resolution, high accuracy, high speed, and a large travel range were achieved, which demonstrates that the proposed stage has significant performance and potential for many in situ SEM nanorobotic instrument systems.

Automated Denudation of Oocytes.

Denudation is a technique for removal of the cumulus cell mass from oocytes in clinical intracytoplasmic sperm injection (ICSI). Manual oocyte denudation requires long training hours and stringent skills, but still suffers from low yield rate and denudation efficiency due to human fatigue and skill variations across operators. To address these limitations, this paper reports a robotic system for automated oocyte denudation. In this system, several key techniques are proposed, including a vision-based contact detection method for measuring the relative z position between the micropipette tip and the dish substrate, recognition of oocytes and the surrounding cumulus cells, automated calibration algorithm for eliminating the misalignment angle, and automated control of the flow rate based on the model of oocyte dynamics during micropipette aspiration and deposition. Experiments on mouse oocytes demonstrated that the robotic denudation system achieved a high yield rate of 97.0 ± 2.8% and denudation efficiency of 95.0 ± 0.8%. Additionally, oocytes denuded by the robotic system showed comparable fertilization rate and developmental competence compared with manual denudation. Our robotic denudation system represents one step towards the automation and standardization of ICSI procedures.

Magnetic Resonance Imaging Data Features to Evaluate the Efficacy of Compound Skin Graft for Diabetic Foot.

This study aimed to analyze the role of magnetic resonance imaging (MRI) data characteristics based on the deep learning algorithm in evaluating the treatment of diabetic foot (DF) with composite skin graft. In this study, 78 patients with DF were randomly rolled into the experimental group (composite skin graft) and control group (autologous skin graft) with 39 patients in each group. MRI scans were performed before and after treatment to compare the changes of experimental observation indicators such as healing time, recurrence rate, and scar score. The results showed that T1-weighted imaging (T1WI) of the scanning sequence was considerably increased in the experimental group after treatment. The signal intensity of fat-suppressed T2-weighted imaging (T2WI) and fat-suppressed T1WI enhancement sequences was considerably decreased (P < 0.05). In addition, compared with the control group, the recurrence rate, healing time, and scar score in the experimental group were considerably decreased (P < 0.05). The accuracy, specificity, and sensitivity of MRI imaging information in evaluating the therapeutic effect of DF patients were 85.2%, 89.75%, and 86.47%, respectively. According to the specificity and sensitivity, the subject operating characteristic curve was drawn, and the area under the curve was determined to be 0.838. In summary, MRI image data characteristics based on the deep learning algorithm can provide auxiliary reference information for the efficacy evaluation of compound skin transplantation for DF.

IL-5 enhances the resistance of Actinobacillus pleuropneumoniae infection in mice through maintaining appropriate levels of lung M2, PMN-II and highly effective neutrophil extracellular traps.

Interleukin 5 (IL-5) regulates the maturation, activation, proliferation and function of immune cells, and plays an important role in the inflammatory response induced by an allergy. However, its anti-pathogen effect is poorly understood currently, especially on pneumonia. Here, this study was designed to elucidate the immunological role of IL-5 in the infection of mice with Actinobacillus pleuropneumoniae (APP). We established an acute lung infection model of APP in IL-5 knockout mice (IL-5-/-) and wild-type mice (WT) through nasal infusion or intraperitoneal injection, compared the survival rate, clinical symptoms, lung bacterial load, proportion of various immune cells, immune molecular expression, and neutrophil germicidal ability through flow cytometry, RT-qPCR, ELISA and immunofluorescence. Compared to WT mice, the IL-5-/- mice had a lower survival rate, more severe clinical symptoms, significantly increased bacterial load, and inflammatory cell infiltration in the lung after APP infection. In an uninfected state, IL-5 deficiency decreased the number of M1 interstitial macrophages and CD14- monocytes, while after infection, IL-5 deficiency significantly reduced the M2 alveolar macrophages, and increased PMN-II cells in the lung. Furthermore, the expression of IL-10, IL-4, IL-33, TNF-α, iNOS in the lung was lower in IL-5-/- mice under an uninfected condition, and the secretion of IL-18 was significantly increased after infection. In addition, IL-5 deficiency decreased bactericidal ability by inhibiting the formation of neutrophil extracellular traps (NETs). Collectively, these results provide evidence that IL-5 can enhance the resistance of APP infection, and its anti-infection mechanism, implying new targets and ideas for APP or similar respiratory agents' prevention and treatment.

Predicting the Prognosis of Patients in the Coronary Care Unit: A Novel Multi-Category Machine Learning Model Using XGBoost.

Background: Early prediction and classification of prognosis is essential for patients in the coronary care unit (CCU). We applied a machine learning (ML) model using the eXtreme Gradient Boosting (XGBoost) algorithm to prognosticate CCU patients and compared XGBoost with traditional classification models. Methods: CCU patients' data were extracted from the MIMIC-III v1.4 clinical database, and divided into four groups based on the time to death: <30 days, 30 days-1 year, 1-5 years, and ≥5 years. Four classification models, including XGBoost, naïve Bayes (NB), logistic regression (LR), and support vector machine (SVM) were constructed using the Python software. These four models were tested and compared for accuracy, F1 score, Matthews correlation coefficient (MCC), and area under the curve (AUC) of the receiver operating characteristic curves. Subsequently, Local Interpretable Model-Agnostic Explanations method was performed to improve XGBoost model interpretability. We also constructed sub-models of each model based on the different categories of death time and compared the differences by decision curve analysis. The optimal model was further analyzed using a clinical impact curve. At last, feature ablation curves of the XGBoost model were conducted to obtain the simplified model. Results: Overall, 5360 CCU patients were included. Compared to NB, LR, and SVM, the XGBoost model showed better accuracy (0.663, 0.605, 0.632, and 0.622), micro-AUCs (0.873, 0.811, 0.841, and 0.818), and MCC (0.337, 0.317, 0.250, and 0.182). In subgroup analysis, the XGBoost model had a better predictive performance in acute myocardial infarction subgroup. The decision curve and clinical impact curve analyses verified the clinical utility of the XGBoost model for different categories of patients. Finally, we obtained a simplified model with thirty features. Conclusions: For CCU physicians, the ML technique by XGBoost is a potential predictive tool in patients with different conditions, and it may contribute to improvements in prognosis.

[Effects of proton pump inhibitors on in-stent restenosis in patients receiving clopidogrel: a retrospective analysis].

OBJECTIVE: To determine the effect of proton pump inhibitor (PPI) on in-stent restenosis (ISR) in patients receiving clopidogrel therapy. METHODS: Total 439 patients underwent percutaneous coronary intervention (PCI) were enrolled in the study,including 250 post-PCI patients discharged on clopidogrel alone and 189 patients discharged on clopidogrel with PPI. The in-stent restenosis (ISR) ratio of the patients in these two groups were observed. RESULTS: During a mean follow-up period of (13 ± 5.9) months, the post-PCI patients discharged on concomitant clopidogrel-PPI therapy had higher risk of ISR than those discharged on clopidogrel alone (19.6% Compared with 8%, P<0.001). CONCLUSION: Concomitant use of clopidogrel and PPI after hospital discharge would increase the risk of ISR for post-PCI patients.