The diversity of peripheral blood T cells and myeloid-derived suppressor cells in patients with idiopathic membranous nephropathy.

OBJECTIVE: Membranous nephropathy is a leading cause of adult-onset nephrotic syndrome. Peripheral T cells and myeloid-derived suppressor cells (MDSCs) are closely associated with autoimmune diseases, while their exact roles and interaction in these processes are unclear. Here, we studied the roles of T cells, MDSCs, and their subsets in patients with idiopathic membranous nephropathy (IMN). MATERIALS AND METHODS: 35 IMN patients and 30 healthy controls were included in this retrospective study. Flow cytometry was performed to determine the phenotype of human T cells and MDSCs in peripheral blood mononuclear cells (PBMCs). Anti-PLA2R was measured by ELISA. Values ≥ 20 RU/mL were defined as positive and < 14 RU/mL as negative. RESULTS: A higher ratio of CD4/CD8 T cells with a lower proportion of Tregs, a remarkably lower proportion of G-MDSCs (but not M-MDSCs), lower frequency of PD-L2+G-MDSCs, and higher frequency of PD-L1+M-MDSCs were found in IMN patients compared to healthy controls. The ratio of CD4/CD8 T cells was higher, and the frequencies of PD-1+CD4+ T cells, CTLA-4+CD4+ T cells, PD-1+Tregs, and CTLA-4+Tregs were lower in PBMCs of PLA2R-positive IMN patients compared to PLA2R-negative IMN patients. CONCLUSION: Tregs and G-MDSCs were reduced in the circulation of the IMN patients, which may promote understanding of the crucial functions that are mediated by these cells in the pathogenesis of IMN.

Anthocyanins Inhibit Airway Inflammation by Downregulating the NF-κB Pathway via the miR-138-5p/SIRT1 Axis in Asthmatic Mice.

OBJECTIVE: Asthma, caused by chronic inflammation, is a common disease. Anthocyanins are involved in asthma treatment. This study explored the mechanism of anthocyanins on airway inflammation in asthmatic mice by regulating nuclear factor-κB (NF-κB) via the miR-138-5p/sirtuin-1 (SIRT1) axis. METHODS: The asthmatic mouse model was established by ovalbumin (OVA) induction and treated with anthocyanins or simultaneously injected with the lentivirus miR-138-5p mimic, followed by the measurement of lung inflammatory injury and IL-4, IL-5, IL-13, and IFN-γ levels in bronchoalveolar lavage fluid. Human bronchial epithelial (HBE) cells 16HBE14o-160 were induced by OVA to establish an asthmatic cell model, treated with anthocyanins and manipulated with miR-138-5p mimic and pcDNA3.1-SIRT1. The releases of inflammatory cytokines, the nuclear translocation of p-p65/p65 in the NF-κB pathway, and the levels of miR-138-5p and SIRT1 mRNA were detected. RESULTS: In vivo experiments showed that anthocyanins could reduce the OVA-induced airway hyperresponsiveness and airway inflammation, improve the inflammatory infiltration and mucus in lung tissues, and diminish the miR-138-5p level in asthmatic mice. Infection with the miR-138-5p mimic averted the remission effect of anthocyanins in asthmatic mice. In vitro experiments showed that in HBE cells exposed to OVA, anthocyanins reduced the miR-138-5p level, increased the SIRT1 level, inhibited the release of inflammatory factors, and reduced the nuclear translocation of NF-κB p65. miR-138-5p targeted SIRT1. miR-138-5p overexpression partially reversed the therapeutic effect of anthocyanins, while SIRT1 overexpression antagonized the effect of miR-138-5p overexpression. CONCLUSION: Anthocyanins inhibited the NF-κB pathway by regulating the miR-138-5p/SIRT1 axis, thus inhibiting airway inflammation in asthmatic mice.

IRAK-M Associates with Susceptibility to Adult-Onset Asthma and Promotes Chronic Airway Inflammation.

IL-1R-associated kinase (IRAK)-M regulates lung immunity during asthmatic airway inflammation. However, the regulatory effect of IRAK-M differs when airway inflammation persists. A positive association between IRAK-M polymorphisms with childhood asthma has been reported. In this study, we investigated the role of IRAK-M in the susceptibility to adult-onset asthma and in chronic airway inflammation using an animal model. Through genetic analysis of IRAK-M polymorphisms in a cohort of adult-onset asthma patients of Chinese Han ethnicity, we identified two IRAK-M single nucleotide polymorphisms, rs1624395 and rs1370128, genetically associated with adult-onset asthma. Functionally, the top-associated rs1624395, with an enhanced affinity to the transcription factor c-Jun, was associated with a higher expression of IRAK-M mRNA in blood monocytes. In contrast to the protective effect of IRAK-M in acute asthmatic inflammation, we found a provoking impact of IRAK-M on chronic asthmatic inflammation. Following chronic OVA stimulation, IRAK-M knockout (KO) mice presented with significantly less inflammatory cells, a lower Th2 cytokine level, a higher IFN-γ concentration, and increased percentage of Th1 cells in the lung tissue than wild type mice. Moreover, lung dendritic cells (DC) from OVA-treated IRAK-M KO mice expressed a higher percentage of costimulatory molecules PD-L1 and PD-L2. Mechanistically, in vitro TLR ligation led to a greater IFN-γ production by IRAK-M KO DCs than wild type DCs. These findings demonstrated a distinctive role of IRAK-M in maintaining chronic Th2 airway inflammation via inhibiting the DC-mediated Th1 activation and indicated a complex role for IRAK-M in the initiation and progression of experimental allergic asthma.

Design and Integrated Analysis of a Flexible Support Microstructure with a Honeycomb Sandwich for the Optical Window of a Hypersonic Remote Sensor.

In order to reduce the influence of the optical window on the image quality of a hypersonic visible light optical remote sensor, we propose a method of adding a double-layer semicircular honeycomb core microstructure with flexible support of a high temperature elastic alloy between a window glass and a frame to reduce the influence of complex thermal stress on the surface accuracy of the optical window. An equivalent model of a semicircular honeycomb structure was established, the elastic parameters of the semicircular honeycomb sandwich microstructure were derived by an analytical method, and a numerical verification and finite element simulation were carried out. The results show that the equivalent model is in good agreement with the detailed model. The optical-mechanical-thermal integrated simulation analysis of the optical window assembly with flexible supporting microstructure proves that the semicircular honeycomb sandwich flexible supporting structure has a positive effect on stress attenuation of the window glass and ensures the wave aberration accuracy of the transmitted optical path difference of the optical window (PV < 0.665 λ, RMS < 0.156 λ, λ = 632.8 nm). Combined with the actual optical system, the optical performance of the window assembly under the flexible support structure is verified. The simulation results show that the spatial frequency of the modulation transfer function (MTF) of the optical system after focusing is not less than 0.58 in the range of 0-63 cycle/mm and the relative decline of MTF is not more than 0.01, which meet the imaging requirements of a remote sensor. The study results show that the proposed metal-based double-layer semicircular honeycomb sandwich flexible support microstructure ensures the imaging quality of the optical window under ultra-high temperature conditions.

An improved clear cell renal cell carcinoma stage prediction model based on gene sets.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and accounts for cancer-related deaths. Survival rates are very low when the tumor is discovered in the late-stage. Thus, developing an efficient strategy to stratify patients by the stage of the cancer and inner mechanisms that drive the development and progression of cancers is critical in early prevention and treatment. RESULTS: In this study, we developed new strategies to extract important gene features and trained machine learning-based classifiers to predict stages of ccRCC samples. The novelty of our approach is that (i) We improved the feature preprocessing procedure by binning and coding, and increased the stability of data and robustness of the classification model. (ii) We proposed a joint gene selection algorithm by combining the Fast-Correlation-Based Filter (FCBF) search with the information value, the linear correlation coefficient, and variance inflation factor, and removed irrelevant/redundant features. Then the logistic regression-based feature selection method was used to determine influencing factors. (iii) Classification models were developed using machine learning algorithms. This method is evaluated on RNA expression value of clear cell renal cell carcinoma derived from The Cancer Genome Atlas (TCGA). The results showed that the result on the testing set (accuracy of 81.15% and AUC 0.86) outperformed state-of-the-art models (accuracy of 72.64% and AUC 0.81) and a gene set FJL-set was developed, which contained 23 genes, far less than 64. Furthermore, a gene function analysis was used to explore molecular mechanisms that might affect cancer development. CONCLUSIONS: The results suggested that our model can extract more prognostic information, and is worthy of further investigation and validation in order to understand the progression mechanism.

Lack of ethnic differences in the pharmacokinetics and pharmacodynamics of evolocumab between Caucasian and Asian populations.

AIMS: To evaluate the potential ethnic differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of evolocumab in Caucasian and Asian populations using population PK/PD modelling analysis. METHODS: Data from different ethnic groups in 5 Phase I clinical trials, including two American studies, one Japanese study and two Chinese studies, were chosen for model building and evaluation. A target-mediated drug disposition model together with an indirect response model best captured evolocumab binding and the removal of unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) as well as a reduction in circulating low-density lipoprotein cholesterol (LDL-C). Ethnicity and other related factors (body weight, target expression level etc.) were analysed as potential covariates. RESULTS: The estimated linear clearance and volume of evolocumab were 0.24 l day-1 and 2.75 l, respectively, which was consistent with the previous modelling results from the American trials. The time course of the LDL-C reduction was described by an indirect response model with the elimination rate of LDL-C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with the half-maximal inhibition of LDL-C elimination was 1.28 nmol l-1 . Both the PK and PD characteristics were consistent between the Caucasian and Asian populations. CONCLUSION: The target-mediated drug disposition model successfully described the PK and PD characteristics of evolocumab, and this analysis found no significant differences in the PK/PD relationship for its LDL-C lowering effects between Caucasians and Asians.

GPCR structure and function relationship: identification of a biased apelin receptor mutant.

Biased ligands of G protein-coupled receptors (GPCRs) may have improved therapeutic benefits and safety profiles. However, the molecular mechanism of GPCR biased signaling remains largely unknown. Using apelin receptor (APJ) as a model, we systematically investigated the potential effects of amino acid residues around the orthosteric binding site on biased signaling. We discovered that a single residue mutation I109A (I1093.32) in the transmembrane domain 3 (TM3) located in the deep ligand-binding pocket was sufficient to convert a balanced APJ into a G protein signaling biased receptor. APJ I109A mutant receptor retained full capabilities in ligand binding and G protein activation, but was defective in GRK recruitment, ß-arrestin recruitment, and downstream receptor-mediated ERK activation. Based on molecular dynamics simulations, we proposed a molecular mechanism for biased signaling of I109A mutant receptor. We postulate that due to the extra space created by I109A mutation, the phenyl group of the last residue (Phe-13) of apelin rotates down and initiates a cascade of conformational changes in TM3. Phe-13 formed a new cluster of hydrophobic interactions with the sidechains of residues in TM3, including F1103.33 and M1133.36, which stabilizes the mutant receptor in a conformation favoring biased signaling. Interruption of these stabilizing interactions by double mutation F110A/I109A or M113A/I109A largely restored the ß-arrestin-mediated signaling. Taken together, we describe herein the discovery of a biased APJ mutant receptor and provide detailed molecular insights into APJ signaling selectivity, facilitating the discovery of novel therapeutics targeting APJ.

Computer-Aided Diagnosis (CAD) of Pulmonary Nodule of Thoracic CT Image Using Transfer Learning.

Computer-aided diagnosis (CAD) has already been widely used in medical image processing. We recently make another trial to implement convolutional neural network (CNN) on the classification of pulmonary nodules of thoracic CT images. The biggest challenge in medical image classification with the help of CNN is the difficulty of acquiring enough samples, and overfitting is a common problem when there are not enough images for training. Transfer learning has been verified as reasonable in dealing with such problems with an acceptable loss value. We use the classic LeNet-5 model to classify pulmonary nodules of thoracic CT images, including benign and malignant pulmonary nodules, and different malignancies of the malignant nodules. The CT images are obtained from Lung Image Database Consortium and Image Database Resource Initiative (LIDC-IDRI) where both pulmonary nodule scanning and nodule annotations are available. These images are labeled and stored in a medical images knowledge base (KB), which is designed and implemented in our previous work. We implement the 10-folder cross validation (CV) to testify the robustness of the classification model we trained. The result demonstrates that the transfer learning of the LeNet-5 is good for classifying pulmonary nodules of thoracic CT images, and the average values of Top-1 accuracy are 97.041% and 96.685% respectively. We believe that our work is beneficial and has potential for practical diagnosis of lung nodules.

Acute-Phase Plasma PCSK9 Levels and Recurrent Cardiovascular Events in a Chinese Acute Myocardial Infarction Cohort.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising target for lowering plasma low-density lipoprotein cholesterol and preventing cardiovascular (CV) disease. Whether plasma PCSK9 measured during the acute phase predicts recurrent CV events in patients with acute myocardial infarction (AMI) remains unresolved. METHODS AND RESULTS: Plasma PCSK9 levels were measured in 1,646 patients with AMI from the China PEACE-Prospective AMI Study at the acute phase. Additionally, 248 patients were resampled and measured at 1 month post-AMI. Associations of acute-phase PCSK9 tertiles with clinical characteristics and recurrent CV events within 1 year were assessed. Female gender (OR 1.94, 95% CI 1.24-3.03), premature coronary heart disease (CHD; OR 2.12, 95% CI 1.37-3.26), higher high-sensitivity C-reactive protein (OR 1.67, 95% CI 1.44-1.95), and higher triglycerides (OR 1.46, 95% CI 1.03-2.09) were associated with higher baseline PCSK9. Plasma PCSK9 levels in the highest tertile (versus lowest) did not have an increased risk of 1-year recurrent CV events in the AMI cohort (HR 0.78, 95% CI 0.52-1.16) or any subgroup. There was also no association between percentage changes in PCSK9 over the first month and 1-year recurrent events, although there was a trend of differences between patients in the upper versus lower tertiles. CONCLUSION: Plasma PCSK9 levels measured during the acute phase were associated with high-sensitivity C-reactive protein, triglycerides, premature CHD, and gender in patients with AMI but did not predict recurrent CV events within 1 year. Dynamic changes in PCSK9 suggested a trend yet no significance value in predicting recurrent CV events.

Critical Role of IRAK-M in Regulating Antigen-Induced Airway Inflammation.

Asthma is an airway epithelium disorder involving allergic lung inflammation. IL-1 receptor-associated kinase M (IRAK-M) is a negative regulator of Toll-like receptor (TLR) signaling on airway epithelial cells and macrophages, and it is known to limit the overproduction of cytokines during the inflammatory process. However, the direct role of IRAK-M in asthma pathogenesis is unclear. In the present study, we found a significant elevation of IRAK-M expression in mouse lungs after ovalbumin (OVA) exposure. Compared with wild-type mice, IRAK-M knockout (KO) mice responded to OVA challenge with significantly worse infiltration of airway inflammatory cells, greater airway responsiveness, higher proinflammatory cytokine levels in lung homogenates, and more prominent T-helper cell type 2 (Th2) and Th17 deviation. OVA exposure also induced higher activities of dendritic cells (DCs) and macrophages from IRAK-M KO mouse lungs. Furthermore, adoptive transfer of either IRAK-M KO bone-marrow-derived DCs or macrophages into wild-type mice aggravated OVA-induced airway inflammation. In vitro experiments showed that IRAK-M KO naive CD4+ T cells were more prone to differentiate into Th17 cells, but not regulatory T cells. Consistently, activation of IκBζ was significantly increased in the absence of IRAK-M, facilitating Th17 polarization. These findings suggest that IRAK-M plays a crucial role in the regulation of allergic airway inflammation by modifying the function of airway epithelia, DCs, and macrophages, and the differentiation of naive CD4+ T cells. Modulation of IRAK-M may provide a novel target for the control of asthma.

Clinical Analysis of 77 Patients with Allergic Bronchopulmonary Aspergillosis in Peking Union Medical College Hospital.

Objective To summarize the clinical features of allergic bronchopulmonary aspergillosis(ABPA)to facilitate its early diagnosis and treatment. Methods We retrospectively analyzed the clinical data of 77 patients who had been admitted to Peking Union Medical College Hospital from January 1996 to July 2015 with ABPA. Results The average age of these 77 patients(38 men and 39 women)was(41.8±18.3)years. The co-morbidities included bronchial asthma(n=74,96%)and pulmonary cystic fibrosis(n=3,4%). The main symptoms and signs of ABPA were chronic cough(100%),sputum production(97%),wheeze(86%),sputum plugs(25%),blood-stained sputum(18%),hemoptysis(9%),chest pain(9%),fever(47%),weight loss(30%),and night sweat(12%). Laboratory tests revealed elevated levels of blood eosinophils absolute count(87%),anti-aspergillus antigen-specific IgE(89%)and specific IgG(57%)as well as a positive result of Aspergillus antigen skin test(88%). Pulmonary function testing showed that the incidences of obstructive ventilation and diffusion dysfunction were 66% and 65%,respectively;in addition,bronchodilatation test showed positive result in 60% of the patients. The most common CT findings were central bronchiectasis(81%),patchy infiltrations(79%),pleural thickening(49%),mediastinal adenopathy(35%),nodular opacities(25%),mucoid impaction(21%),and fleeting infiltrations(35%). In addition,44 cases(58%)were misdiagnosed as tuberculosis,pneumonia,lung abscess,and/or lung cancer autoimmune diseases. Conclusions ABPA can be easily misdiagnosed. ABPA should be carefully considered in patients with asthma or pulmonary cystic fibrosis who also suffer from wheeze,sputum plugs,elevated eosinophils central bronchiectasis,and fleeting infiltrations.

Efficacy and Safety of Tiotropium in the Treatment of Severe Persistent Asthma:Meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of tiotropium in treatment of severe persistent asthma. METHODS: Reports of randomized controlled trials (RCTs) describing tiotropium for treatment of severe persistent asthma published from January 1946 to February 2015 were searched in Cochrane Library, ClinicalTrials.gov, PubMed, Ovid Medline, CNKI, and CSJD. The data of the included RCTs were extracted and the data quality was evaluated. Meta-analyses were performed with Revman 5.3 software. RESULTS: Five RCTs including 1433 patients were analyzed. Meta-analysis of the data showed that compared with the placebo group, tiotropium treatment significantly improved the patients' peak forced expiratory volume in one second (FEV1) [weighted mean difference (WMD): 0.13 L, 95% confidence interval (CI): 0.10-0.16 L, P<0.00001], trough FEV1 (WMD: 0.09 L, 95%CI: 0.06-0.12 L, P<0.00001), peak forced vital capacity (FVC) (WMD: 0.10 L, 95%CI: 0.06-0.14 L, P<0.00001), trough FVC (WMD: 0.12 L, 95%CI: 0.08-0.17 L, P<0.00001), morning peak expiratory flow (PEF) (WMD: 9.21 L/min, 95%CI: 4.2-14.23 L/min, P=0.0003), evening PEF (WMD: 22.06 L/min, 95%CI 13.05-31.08 L/min, P<0.00001). The scores of asthma control questionnaire (ACQ) (WMD: 0.01, 95% CI: -0.07-0.09, P=0.86) or asthma quality of life questionnaire (AQLQ)(WMD: 0.06, 95% CI:-0.18-0.06, P=0.33) were not affected by tiotropium. No significant difference with adverse events between tiotropium group and placebo group were reported in these included studies (P>0.05). CONCLUSIONS: Tiotropium for severe persistent asthma treatment can improve FEV1, FVC, and PEF but may not improve the quality of life of the patients. Tiotropium is well tolerated and can be an add-on therapy for severe persistent asthma.

[Clinical Analysis of 35 Inpatients with Diffuse Panbronchiolitis in Peking Union Medical College Hospital].

OBJECTIVE: To summarize the clinical features of diffuse panbronchiolitis (DPB). METHOD: We retrospectively analyzed the clinical data of 35 patients who had been admitted to Peking Union Medical College Hospital from December 1996 to July 2014 due to DPB,which was confirmed basing on the diagnostic criteria proposed in 1998 by a working group of the Ministry of Health and Welfare of Japan or histopathological examination. RESULTS: The average age of these 35 patients (20 men and 15 women,with a sex ratio of 1.33 to 1) was (42.2<15.6) years,mainly distributed in the 40-49 age group. The average clinical history was (8.4<8.5) years. The main symptoms and signs of DPB included chronic cough (n=35,100%),copious purulent sputum production (n=31,88.6%),exertional dyspnoea (n=24,68.6%),end-inspiratory crackles (n=28,80.0%). Also,26 patients (74.3%) had a history of sinusitis. Cold agglutination test in 15 out of 15 patients were negative. Pseudomonas aeruginosa and Haemophilus influenza were isolated from 22 patients (73.3%,22/30),and 26 patients (83.9%,26/31) had hypoxemia. The mean values of forced expiratory volume in the first second/forced vital capacity,residua volume/total lung volume,maximum forced expiratory volume of 50% lung volume,and maximum forced expiratory volume of 25% lung volume were 60.5%,53.8%,25.9%,and 31.2%,respectively. The most common CT findings from this cohort of patients were bronchiectasis and bronchiolitis,with nodular shadows distributed in a centrilobular pattern. Finally,29 patients were misdiagnosed as other conditions such as pulmonary infection and bronchiectasis. CONCLUSIONS: DPB in Chinese populations have different presentations compared to that Japanese populations:for instance,the serum cold agglutination test always shows negative results,which is often inconsistent with the pathogens in sputum. DPB usually is misdiagnosed. Clinicians should take DPB into consideration when patients had pulmonary infection and sinusitis.

Flurbiprofen improves dysfunction of T-lymphocyte subsets and natural killer cells in cancer patients receiving post-operative morphine analgesia.

OBJECTIVE: Acute pain can lead to immune dysfunction, which can be partly ameliorated by successful pain management. Opioids, which are widely used for analgesia, can result in the deterioration of immune function. This study aimed to investigate the influence of morphine with or without flurbiprofen as post-operative analgesics on the immune systems of patients undergoing gastric cancer surgery. METHODS: 60 patients undergoing gastric cancer surgery were equally randomized into two groups. They received post-operative patient-controlled intravenous (IV) analgesia using morphine either with or without flurbiprofen. Visual analogue scale (VAS) scores, Bruggemann comfort scale (BCS) scores, morphine consumption, time of first flatus, incidence of nausea/vomiting, and T-lymphocyte subsets (CD3⁺, CD4⁺, and CD8⁺) and natural killer cells (CD3⁻CD16⁺CD56⁺) were evaluated. RESULTS: No significant difference was observed in the VAS scores, BCS scores, and nausea/vomiting incidence between groups. Less morphine was consumed and the time of first flatus was earlier in patients receiving morphine with flurbiprofen than morphine alone. The expression of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and CD3⁻CD16⁺CD56⁺ decreased at 2 hours after incision and, except for CD3⁻CD16⁺CD56⁺, returned to baseline at 120 hours after surgery. Moreover, the expression of CD3⁻CD16⁺CD56⁺ at 2 hours after incision and the expression of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and CD3⁻CD16⁺CD56⁺ at 24 hours after surgery were higher in patients receiving morphine with flurbiprofen than morphine alone. CONCLUSION: The combination of morphine and flurbiprofen ameliorates the immune depression in Tlymphocyte subsets and natural killer cells and provides a similar analgesic efficacy to morphine alone in patients undergoing gastric cancer surgery.

Myeloid­derived suppressor cell accumulation induces Treg expansion and modulates lung malignancy progression.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T cell immunity in tumor-bearing hosts. The present study aimed to examine roles of T and MDSC subsets in lung malignancy. The study analyzed 102 cases with lung malignancy and 34 healthy individuals. Flow cytometry was performed for identification of T cell and MDSC subsets and their phenotypic characteristics in peripheral blood. The lung malignancy cases exhibited lower frequencies of granulocyte-like MDSCs (G-MDSCs) expressing PD-L2 and PD-L1 than healthy controls (P=0.013 and P<0.001, respectively). Additionally, there was a higher frequency of monocyte-like MDSCs (M-MDSCs) expressing PD-L1 in the peripheral blood of patients with lung malignancy than healthy controls (P<0.001). The frequencies of G-MDSCs and M-MDSCs were positively correlated with proportions of PD-1+ and CTLA-4+ regulatory T cells (Tregs). In vitro co-culture assay demonstrated M-MDSCs of lung malignancy enhanced naive T cell apoptosis and promoted Treg subset differentiation compared with M-MDSCs of healthy controls. The findings suggested accumulation of MDSC subsets in lung malignancy and MDSCs expressing PD-L2 and PD-L1 induced Treg expansion by binding to PD-1 on the surface of Tregs.

Interaction energy flow paths analysis of PMSG-based wind power integrated systems during LVRT and its parameter adjustment strategy.

To solve the problem of oscillation instability in permanent magnetic synchronous generator (PMSG)-based wind power connected systems during low-voltage ride through (LVRT) process, a parameter adjustment strategy based on interaction energy path optimization is proposed in this paper. Firstly, a modular state-space model of PMSG under fault transient conditions is constructed, and the system is divided into five subsystems. Then, the dynamic energy function of subsystems reflecting the oscillation stability of the system is derived. Based on that, the dynamic energy flow path is described considering the introduction of LVRT control. On this basis, the interaction energy between LVRT control links and subsystems is analyzed, and the coupling mechanism of voltage support and damping characteristics in the LVRT process is explained. Further, aiming at the optimal change rate of the total interaction energy in the LVRT process, the adjustment strategy of LVRT control parameters is constructed to meet voltage and damping requirements. Finally, a PMSG-connected system model is built on the MATLAB/Simulink platform to verify the effectiveness of the adjustment strategy. The results show that the proposed method can effectively improve the damping level under the fault transient condition, as well as supporting system voltage.

The clinical association of programmed death-1/PD-L1 axis, myeloid derived suppressor cells subsets and regulatory T cells in peripheral blood of stable COPD patients.

Background: Myeloid-derived suppressor cells (MDSCs) have crucial immunosuppressive role in T cell dysfunction in various disease processes. However, the role of MDSCs and their impact on Tregs in COPD have not been fully understood. The aim of the present study is to investigate the immunomodulatory role of MDSCs and their potential impact on the expansion and function of Tregs in COPD patients. Methods: Peripheral blood samples were collected to analyze circulating MDSCs, Tregs, PD-1/PD-L1 expression to assess the immunomodulatory role of MDSC and their potential impact on the expansion and function of Treg in COPD. A total of 54 COPD patients and 24 healthy individuals were enrolled in our study. Flow cytometric analyses were performed to identify granulocytic MDSCs (G-MDSCs), monocytic MDSCs (M-MDSCs), Tregs, and the expression of PD-1/PD-L1(L2) on MDSCs and Tregs in peripheral blood. Results: Our results revealed a significantly higher percentage of G-MDSCs and M-MDSCs (p < 0.001) in COPD patients compared to the healthy controls. Additionally, a significantly higher proportion of peripheral blood Tregs was observed in COPD patients. Furthermore, an increased expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on Tregs (p < 0.01) was detected in COPD patients. The expression of PD-1 on CD4+ Tcells and Tregs, but not CD8+Tcells, was found to be increased in patients with COPD compared to controls. Furthermore, an elevated expression of PD-L1 on M-MDSCs (p < 0.01) was also observed in COPD patients. A positive correlation was observed between the accumulation of M-MDSCs and Tregs in COPD patients. Additionally, the percentage of circulating M-MDSCs is positively associated with the level of PD-1 (r = 0.51, p < 0.0001) and CTLA-4 (r = 0.42, p = 0.0014) on Tregs in COPD. Conclusion: The recruitment of MDSCs, accumulation of Tregs, and up-regulation of CTLA-4 on Treg in COPD, accompanied by an increased level of PD-1/PD-L1, suggest PD-1/PD-L1 axis may be potentially involved in MDSCs-induced the expansion and activation of Treg at least partially in COPD.

Recombinant strains for the enhanced production of bioengineered rapalogs.

The rapK gene required for biosynthesis of the DHCHC starter acid that initiates rapamycin biosynthesis was deleted from strain BIOT-3410, a derivative of Streptomyces rapamycinicus which had been subjected to classical strain and process development and capable of robust rapamycin production at titres up to 250mg/L. The resulting strain BIOT-4010 could no longer produce rapamycin, but when supplied exogenously with DHCHC produced rapamycin at titres equivalent to its parent strain. This strain enabled mutasynthetic access to new rapalogs that could not readily be isolated from lower titre strains when fed DHCHC analogs. Mutasynthesis of some rapalogs resulted predominantly in compounds lacking late post polyketide synthase biosynthetic modifications. To enhance the relative production of fully elaborated rapalogs, genes encoding late-acting biosynthetic pathway enzymes which failed to act efficiently on the novel compounds were expressed ectopically to give strain BIOT-4110. Strains BIOT-4010 and BIOT-4110 represent valuable tools for natural product lead optimization using biosynthetic medicinal chemistry and for the production of rapalogs for pre-clinical and early stage clinical trials.

Class I histone deacetylase inhibitor valproic acid reverses cognitive deficits in a mouse model of septic encephalopathy.

Accumulating evidence suggests that histone deacetylase inhibitor exert neuroprotective effects in animal models of neurological diseases. We investigated for the first time whether class I histone deacetylase inhibitor valproic acid (VPA) can reverse cognitive deficits in a mouse model of sepsis-associated encephalopathy (SAE). Moreover, the possible mechanisms of protection were also explored. A mouse model of SAE was induced in adult male mice by cecal ligation and puncture (CLP). Mice received an administration of saline or VPA (100 mg/kg) once daily for 14 consecutive days starting either immediately or 2 weeks after operation. Furthermore, the TrkB antagonist K252a was used in another group of experiment to investigate whether brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway is involved in the protection of VPA. Our data suggested that CLP resulted in significant cognitive impairments accompanied by increased expressions in interleukin-1ß and caspase-3, and decreased expressions in BDNF, phospho-TrkB (pTrkB), postsynaptic density 95, and synapses, which were reversed by VPA. However, TrkB antagonist K252a abolished the beneficial effects of VPA with regard to cognition and decreased pTrkB expression and synapses in the hippocampus. Taken together, the findings of the present study suggested chronic treatment with VPA reverses cognitive deficits through mechanisms probably via a reduction in inflammation and apoptosis in the brain, as well as the activation of the BDNF-TrkB signaling pathway in a mouse model of SAE.