Effects and long-term outcomes of endurance versus resistance training as an adjunct to standard medication in patients with stable COPD: a multicenter randomized trial.

BACKGROUND: Comparisons between endurance training (ET) and resistance training (RT) have produced equivocal findings in chronic obstructive pulmonary disease (COPD) patients. The purpose of our study is to investigate the effectiveness and long-term outcomes of adding ET and RT to conventional medical treatment in patients with COPD. A secondary objective is to investigate the clinical improvements resulting from exercise training in patients with different disease severities. METHODS: The study was a multicenter, prospective trial in people with stable COPD. The cohort was randomized to three groups: individualized medical treatment group (MT), MT + endurance training group (MT + ET) and MT + resistance training group (MT + RT). Exercise was performed 3 times weekly over a 12-week period. The endpoints of exercise capacity, health-related quality of life, COPD symptoms, lung function, and anxiety and depression questionnaires were re-evaluated at baseline, at the completion of the intervention and at 6 and 12-month follow-up. According to the COPD assessment tool offered by GOLD guidelines, patients were stratified into GOLD A and B groups and GOLD C and D groups for further subgroup analysis. RESULTS: The intention-to-treat (ITT) population included 366 patients, 328 of them completed the study protocol over 12 months (the PP-population). There were no significant differences in the primary outcome, quality of life, between patients who underwent medical treatment (MT) alone, MT + endurance training (MT + ET), or MT + resistance training (MT + RT) at the completion of the intervention, 6-, or 12-month follow-up. Additionally, no significant differences were observed between MT, MT + RT, or MT + ET groups concerning the primary outcome, exercise capacity (3MWD), after initial 3 months of intervention. However, a small statistically significant difference was noted in favor of MT + ET compared to MT + RT at 12 months (ITT: Δ3MWD in ET vs RT = 5.53 m, 95% confidence interval: 0.87 to 13.84 m, P = 0.03) (PP: Δ3MWD in ET vs RT = 7.67 m, 95% confidence interval: 0.93 to 16.27 m, P = 0.04). For patients in the GOLD C and D groups, improvement in quality of life following ET or RT was significantly superior to medical intervention alone. Furthermore, upon completion of the exercise regimen, RT exhibited a greater improvement in anxiety compared to ET in these patients (ITT: ΔHAD-A at 3-month: RT = -1.63 ± 0.31 vs ET = -0.61 ± 0.33, p < 0.01) (PP: ΔHAD-A at 3-month: RT = -1.80 ± 0.36 vs ET = -0.75 ± 0.37, p < 0.01). CONCLUSIONS: Our study presents evidence of the beneficial effects of ET and RT in combination with standard medical treatment, as well as the long-term effects over time after the intervention. While the statistically significant effect favoring ET over RT in terms of exercise capacity was observed, it should be interpreted cautiously. Patients in severe stages of COPD may derive greater benefits from either ET or RT and should be encouraged accordingly. These findings have implications for exercise prescription in patients with COPD. TRIAL REGISTRATION: ChiCTR-INR-16009892 (17, Nov, 2016).

Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury.

BACKGROUND: Polymorphonuclear neutrophils (PMNs) play an important role in sepsis-related acute lung injury (ALI). Accumulating evidence suggests PMN-derived exosomes as a new subcellular entity acting as a fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-derived exosomes in sepsis-related ALI and the underlying mechanisms remains unclear. METHODS: Tumor necrosis factor-α (TNF-α), a key regulator of innate immunity in sepsis-related ALI, was used to stimulate PMNs from healthy C57BL/6J mice in vitro. Exosomes isolated from the supernatant were injected to C57BL/6J wild-type mice intraperitoneally (i.p.) and then examined for lung inflammation, macrophage (Mϕ) polarization and pyroptosis. In vitro co-culture system was applied where the mouse Raw264.7 macrophages or bone marrow-derived macrophages (BMDMs) were co-cultured with PMN-derived exosomes to further confirm the results of in vivo animal study and explore the potential mechanisms involved. RESULTS: Exosomes released by TNF-α-stimulated PMNs (TNF-Exo) promoted M1 macrophage activation after in vivo i.p. injection or in vitro co-culture. In addition, TNF-Exo primed macrophage for pyroptosis by upregulating NOD-like receptor 3 (NLRP3) inflammasome expression through nuclear factor κB (NF-κB) signaling pathway. Mechanistic studies demonstrated that miR-30d-5p mediated the function of TNF-Exo by targeting suppressor of cytokine signaling (SOCS-1) and sirtuin 1 (SIRT1) in macrophages. Furthermore, intravenous administration of miR-30d-5p inhibitors significantly decreased TNF-Exo or cecal ligation and puncture (CLP)-induced M1 macrophage activation and macrophage death in the lung, as well as the histological lesions. CONCLUSIONS: The present study demonstrated that exosomal miR-30d-5p from PMNs contributed to sepsis-related ALI by inducing M1 macrophage polarization and priming macrophage pyroptosis through activating NF-κB signaling. These findings suggest a novel mechanism of PMN-Mϕ interaction in sepsis-related ALI, which may provide new therapeutic strategies in sepsis patients.

Low threshold soliton and a noise-like pulse conversion in an all-polarization-maintaining figure-eight cavity.

We experimentally report a low threshold soliton and a noise-like mode-locked fiber laser using an all-polarization-maintaining figure-eight cavity. We built a bidirectional pump structure without a phase shifter at the beginning of the experiment. The resonator has a high mode-locking threshold of 620 mW. Afterwards, we used a phase shifter in the resonator, and the laser can self-start in a conventional soliton (CS) mode-locked state when pump1 reaches the threshold of only 70 mW. The CS pulse with a duration of 863.8 fs can be observed at 1560 nm. When the two pump powers increase to 350 mW and 50 mW, the conventional soliton can convert to noise-like pulses. The central wavelength and pulse duration of noise-like mode-locked pulse are 1560.4 nm and 417.9 fs, respectively. The laser can realize conversion between ultrafast pulses and high-energy pulses, and have a low threshold that can be used for nonlinear frequency conversion, supercontinuum generation, sensing, etc.

S1PR3 deficiency alleviates radiation-induced pulmonary fibrosis through the regulation of epithelial-mesenchymal transition by targeting miR-495-3p.

Radiation-induced pulmonary fibrosis (RIPF) is a life-threatening complication of thoracic radiotherapy, which contributes to continued deterioration in pulmonary function. Sphingosine-1 phosphate receptor 3 (S1PR3) has been identified as a crucial molecule in fibrosis. Accumulating evidence indicated that the inhibition of the S1PRs ameliorates fibrogenesis. Thus, this study aims to explore whether S1PR3 participates in RIPF and elucidates the molecular mechanisms underlying S1PR3-modulated epithelial-mesenchymal transition (EMT) in transforming growth factor-ß1-induced pulmonary epithelia. A recombinant adeno-associated viral-mediated S1PR3 (AAV-S1PR3) gene therapy analyzed the effect of S1PR3 gene deficiency on the altered histology structure and molecular mechanisms in the lung of mice with whole-lung irradiation. Compared with the AAV-negative control mice, AAV-mediated S1PR3 knockdown in the lung of mice attenuated pulmonary fibrosis induced by the radiation, as indicated by the alleviation of collagen accumulation, lessened histopathological alterations, and the suppression of inflammatory cells infiltration. S1PR3 deficiency reversed the RIPF concomitantly with abrogated EMT-related protein (α-smooth muscle actin). Consistently, S1PR3-deficient pulmonary epithelia inhibited the EMT process changes and fibrosis formation. Furthermore, S1PR3 was designated as one of the target genes for microRNA-495-3p (miR-495-3p). The inhibition of miR-495-3p promoted the expression of S1PR3 in pulmonary epithelia, whereas the overexpression of miR-495-3p inhibited the S1PR3/SMAD2/3 pathway and suppressed the EMT process. Collectively, miR-495-3p might be a negative regulator of the EMT process in fibrosis formation by inhibiting the targeted S1PR3 gene. These results established a link between the S1PR3 gene, the EMT process, and the fibrosis, suggesting the pharmacological blockage of S1PR3 as a potential therapeutic strategy for RIPF.

Nanoparticle reinforced bacterial outer-membrane vesicles effectively prevent fatal infection of carbapenem-resistant Klebsiella pneumoniae.

Infection resulting from carbapenem-resistant Klebsiella pneumoniae (CRKP) is an intractable clinical problem. Outer membrane vesicles (OMVs) from CRKP are believed to be potential vaccine candidates. However, their immune response remains elusive due to low structural stability and poor size homogeneity. In this study, hollow OMVs were reinforced internally by size-controlled BSA nanoparticles to obtain uniform and stable vaccines through hydrophobic interaction. The result showed that the BSA-OMV nanoparticles (BN-OMVs) were homogenous with a size around 100 nm and exhibited a core-shell structure. Remarkably, subcutaneous BN-OMVs vaccination mediated significantly higher CRKP specific antibody titers. The survival rate of the mice infected with a lethal dose of CRKP was increased significantly after BN-OMV immunization. The adoptive transfer experiment demonstrated that the protective effect of BN-OMVs was dependent on humoral and cellular immunity. This study demonstrated that the structure optimization improved the immune efficacy of OMVs for vaccine development against CRKP.

Self-organized structures of bound states in a 2 µm dispersion-managed mode-locked fiber laser.

We report on the experimental generation of various self-organized structures of bound states in a near zero-dispersion mode-locked fiber laser. When the pump power is fixed at 492 mW, appropriately adjusting polarization controllers, the switching of the cavity feedback results in the evolution from the single pulse to the dispersion-managed soliton (i.e., stretched-pulse) pair. With the increase of pump power, bound states composed of more than two pulses can also be observed. Our results of the self-organized structures might enlarge the data-carrying capacity of current fiber-optical communication systems and benefit the investigation of nonlinear dynamics of bound states in fiber lasers at 2 µm.

Fine Particulate Constituents and Lung Dysfunction: A Time-Series Panel Study.

The evidence is quite limited regarding the constituents of fine particulate matter (PM2.5) responsible for lung dysfunction. We designed a time-series panel study in 28 patients to examine the effects of 10 major constituents of PM2.5 on lung function with repeated daily measurements from December 2012 to May 2013 in Shanghai, China. We applied a linear mixed-effect model combined with a distributed lag model to estimate the cumulative effects of PM2.5 constituents on morning/evening forced expiratory volume in 1-s (FEV1) and peak expiratory flow (PEF) over a week. The cumulative decreases in morning FEV1, evening FEV1, morning PEF and evening PEF associated with an interquartile range (35.8 µg/m3) increase in PM2.5 concentrations were 33.49 [95% confidence interval(CI):2.45,54.53] mL, 16.80 (95%CI:3.75,29.86) mL, 4.48 (95%CI:2.30,6.66) L/min, and 1.31 (95%CI:-0.85,3.47) L/min, respectively. These results were not substantially changed after adjusting for gases in two-pollutant models. The associations of elemental carbon (EC) and nitrates with morning/evening FEV1, and the associations of EC and sulfates with morning PEF were robust after controlling for PM2.5. This study demonstrated that short-term exposure to PM2.5 was associated with reduced pulmonary function. Some constituents (EC, sulfate and nitrate) may be responsible for the detrimental effects.

Nuclear SPHK2/S1P induces oxidative stress and NLRP3 inflammasome activation via promoting p53 acetylation in lipopolysaccharide-induced acute lung injury.

A bulk of evidence identified that macrophages, including resident alveolar macrophages and recruited macrophages from the blood, played an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). However, the molecular mechanisms of macrophages-induced acute lung injury (ALI) by facilitating oxidative stress and inflammatory responses remain unclear. Herein, we noticed that the levels of mitochondrial reactive oxygen species (mtROS), SPHK2 and activated NLRP3 inflammasome were higher in peripheral blood mononuclear cells (PBMCs) of ARDS patients than that in healthy volunteers. Similar observations were recapitulated in LPS-treated RAW264.7 and THP-1 cells. After exposure to LPS, the SPHK2 enzymatic activity, NLRP3 inflammasome activation and mtROS were significantly upregulated in macrophages. Moreover, knockdown SPHK2 via shRNA or inhibition SPHK2 could prominently decrease LPS-induced M1 macrophage polarization, oxidative stress and NLRP3 inflammasome activation. Further study indicated that upregulated SPHK2 could increase nuclear sphingosine-1-phosphate (S1P) levels and then restrict the enzyme activity of HDACs to facilitate p53 acetylation. Acetylation of p53 reinforced its binding to the specific region of the NLRP3 promoter and drove expression of NLRP3. In the in vivo experiments, it was also observed that treating with Opaganib (ABC294640), a specific SPHK2 inhibitor, could observably alleviate LPS-induced ALI, evidencing by lowered infiltration of inflammatory cells, increased M2 macrophages polarization and reduced oxidative damage in lung tissues. Besides, SPHK2 inhibition can also decrease the accumulation of acetylated p53 protein and the activation of NLRP3 inflammasome. Taken together, our results demonstrated for the first time that nuclear S1P can regulate the acetylation levels of non-histone protein through affecting HDACs enzyme activities, linking them to oxidative stress and inflammation in response to environmental signals. These data provide a theoretical basis that SPHK2 may be an effective therapeutic target of ARDS.

Evaluation of antibacterial effect of a cationic porphyrin derivative on Pseudomonas aeruginosa in photodynamic therapy.

BACKGROUND: Pseudomonas aeruginosa is a gram-negative bacterium without spores, and it is one of the pathogens that easily cause secondary infectious diseases when human immune function is low. The purpose of this study is to explore the inhibitory effect of photodynamic antibacterial chemotherapy-induced by cationic porphyrin derivative on clinical P. aeruginosa and its mechanism. METHODS: The uptake of photosensitizer by P. aeruginosa and L929 cells was measured by an ultraviolet spectrophotometer. Effect of laser energy density on the bacterial activity of P. aeruginosa and post antibiotic effect were measured by bacterial suspension and tenfold dilution method. Flow cytometry and scanning electron microscopy were used to observe the activity and morphological changes of P. aeruginosa after PACT treatment. RESULTS: The uptake of Tetra-ATPP-Lys-by P. aeruginosa and L929 was shown as concentration-dependent and time-dependent. However the uptake of L929 cell had a clear difference with P. aeruginosa at the same time and concentration intervals(P < 0.05).The increasing laser energy density had a high inactivation effect of on P. aeruginosa at the same Tetra-ATPP-Lys-concentration(P < 0.05). Post-antibiotic effect of Tetra-ATPP-Lys -PACT was dose-dependent(P < 0.05). Bacterial viability which evaluated by the flow cytometry method demonstrated that the proportion of viable bacteria is decreased with the photosensitizer dose-dependent. The morphology and microstructure of P. aeruginosa after Tetra-ATPP-Lys -PACT was demonstrated by a scanning electron microscope(SEM). After PACT, the morphology of P. aeruginosa was rod-shaped, the outer membrane surface was rough, and the bacteria were dry flat, sunken, shrunk and deformed. CONCLUSIONS: Cationic porphyrin photosensitizer had a great damage effect on P. aeruginosa under the PACT, which can effectively destroy the microstructure of bacteria and lead to bacterial inactivation and death.

Non-drug efflux function of ABCC5 promotes enzalutamide resistance in castration-resistant prostate cancer via upregulation of P65/AR-V7.

Drug resistance is responsible for castration-resistant prostate cancer (CRPC)-associated mortality. While ATP binding cassette subfamily C member 5 (ABCC5) has been reported to regulate multiple drug resistance, its drug-efflux function may not be the main reason underlying resistance to enzalutamide, an androgen receptor inhibitor. Here, we aimed to determine whether the non-drug efflux function of ABCC5 affects enzalutamide resistance. The ABCC5 expression data in patients with prostate cancer (PCa) were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus, and their correlation with disease prognosis was analyzed. Immunohistochemical staining was performed on a cohort of 80 patient samples. Proliferation of enzalutamide-resistant 22RV1 and C4-2B cells was investigated using CCK-8, EdU, and colony formation assays. The effect of ABCC5 silencing on enzalutamide resensitization was evaluated in vitro and in vivo. Functional assays indicated that ABCC5 depletion resensitized enzalutamide-resistant cells to inhibit cell growth and impeded xenograft tumor proliferation. Mechanistically, luciferase and ChIP assays confirmed that P65 regulated AR expression and activity by binding to its promoter, while ABCC5-mediated resistance effected by AR-V7 (one of the widely studied AR splicing variants that meditate AR antagonist resistance) upregulation could be reversed by P65 knockdown. Furthermore, activation of the NF-κB pathway reversed the effects of ABCC5 knockdown by extra AR-V7 expression. Thus, ABCC5 might be a novel target for enzalutamide-resistant CRPC treatment.

Inhaled Pro-Efferocytic Nanozymes Promote Resolution of Acute Lung Injury.

Acute lung injury (ALI) is a significant contributor to the morbidity and mortality of sepsis. Characterized by uncontrolled inflammation and excessive inflammatory cells infiltration in lung, ALI has been exacerbated by impaired efferocytosis (clearance of apoptotic cells by macrophages). Through specific receptor recognition and activation of downstream signaling, efferocytic macrophages promote resolution of inflammation by efficiently engulfing dying cells, avoiding the consequent release of cellular inflammatory contents. Here, inspired by the intrinsic recovery mechanism of efferocytosis, an apoptotic cell membrane (ACM) coated antioxidant nanozyme (AOzyme) is engineered, thus obtaining an inhalable pro-efferocytic nanozyme (AOzyme@ACM). Notably, AOzyme@ACM can efficiently increase apoptotic cell removal by combing enhanced macrophages recognition of "eat me" signals through apoptotic body mimicking and scavenge of intracellular excessive reactive oxygen species (ROS), a significant barrier for efferocytosis. AOzyme@ACM can significantly inhibit inflammatory response, promote pro-resolving (M2) phenotype transition of macrophage, and alleviate ALI in endotoxemia mice compared with AOzyme group. By addressing the critical factor in the pathogenesis of sepsis-related ALI through restoring efferocytosis activity, the ACM-based antioxidant nanozyme in this study is envisioned to provide a promising strategy to treat this complex and challenging disease.

Self-Albumin Camouflage of Carrier Protein Prevents Nontarget Antibody Production for Enhanced LDL-C Immunotherapy.

Elevated low-density lipoprotein cholesterol (LDL-C) increases the risk of atherosclerotic cardiovascular disease. Peptide-based PCSK9 vaccines have shown a promising prospect of reducing LDL-C. In peptide vaccine (pVax) design, the peptide antigens need to conjugate with carrier protein (CP). However, CP incorporation can induce undesirable anti-CP antibodies, which sterically mask peptide epitopes from being recognized by specific B cells and impair subsequent therapeutically antibody production. This epitopic suppression has posed a barrier in clinical translation of conjugate vaccines all along. A model CP (keyhole limpet hemocyanin, KLH) is herein camouflaged with serum albumin (SA) into hybrid nanocarriers (SA@N), with PCSK9 peptide being anchored onto the surface to form nanovaccine (SA@NVax). Such camouflage of KLH via high "self" SA coverage is able to inhibit KLH from extracellular immune recognition and prevent detectable anti-KLH antibody production. Furthermore, the nanovaccine around 70 nm stabilized by intermolecular disulfide network is ideal for internalization and biodegradation by antigen presenting cells as well as better retention in draining lymph nodes and spleen. As expected, the SA@NVax efficiently primes higher anti-PCSK9 IgG antibody titer than PCSK9 pVax.

The Combination of Hemogram Indexes to Predict Exacerbation in Stable Chronic Obstructive Pulmonary Disease.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary and systemic inflammatory processes, and exacerbation of COPD represents a critical moment in the progression of COPD. Several biomarkers of inflammation have been proposed to have a predictive function in acute exacerbation. However, their use is still limited in routine clinical practice. The purpose of our study is to explore the prognostic efficacy of novel inflammatory hemogram indexes in the exacerbation among stable COPD patients. Method: A total of 275 stable COPD patients from the Shanghai COPD Investigation Comorbidity Program were analyzed in our study. Blood examinations, especially ratio indexes like platelet-lymphocyte ratio (PLR), platelet × neutrophil/lymphocyte ratio [systemic immune-inflammation index (SII)], and monocyte × neutrophil/lymphocyte ratio [systemic inflammation response index (SIRI)], lung function test, CT scans, and questionnaires were performed at baseline and routine follow-ups. Clinical characteristics and information of exacerbations were collected every 6 months. The relationship between hemogram indexes and diverse degrees of exacerbation was assessed by logistic regression. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the ability of hemogram indexes to predict exacerbation of COPD. Furthermore, the discrimination and accuracy of combined indexes were measured by ROC and calibration curve. Result: There was a significant positive correlation between PLR levels and total exacerbation of COPD patients in a stable stage in a year. Also, the predictive ability of PLR exceeded any other ratio indexes, with an AUC of 0.66. SII and SIRI ranked second only to PLR, with an AUC of 0.64. When combining PLR with other indexes (sex, COPD year, and St. George's Respiratory Questionnaire scores), they were considered as the most suitable panel of index to predict total exacerbation. Based on the result of the ROC curve and calibration curve, the combination shows optimal discrimination and accuracy to predict exacerbation events in COPD patients. Conclusion: The hemogram indexes PLR, SII, and SIRI were associated with COPD exacerbation. Moreover, the prediction capacity of exacerbation was significantly elevated after combining inflammatory hemogram index PLR with other indexes, which will make it a promisingly simple and effective marker to predict exacerbation in patients with stable COPD.

Serum Exosomal MicroRNAs Predict Acute Respiratory Distress Syndrome Events in Patients with Severe Community-Acquired Pneumonia.

BACKGROUND: Severe community-acquired pneumonia (SCAP) requiring intensive care unit (ICU) treatment commonly causes acute respiratory distress syndrome (ARDS) with high mortality. This study was aimed at evaluating whether microRNAs (miRNAs) in circulating exosomes have the predictive values for patients at risk of developing ARDS due to SCAP. METHODS: ARDS/ALI-relevant miRNAs were obtained by literature search. Exosomes in serum were isolated by ultracentrifugation method and identified by Transmission Electron Microscopy. Then the miR profiling in the exosomes using real-time PCR was analyzed in SCAP patients with or without ARDS. Moreover, multivariate Cox proportional regression analysis was performed to estimate the odds ratio of miRNA for the occurrence of ARDS and prognosis. The receiver operating characteristics (ROC) curves were calculated to discriminate ARDS cases. Finally, the Kaplan-Meier curve using log-rank method was performed to test the equality for survival distributions with different miRNA classifiers. RESULTS: A total of 53 SCAP patients were finally recruited. Ten miRNAs were picked out. Further, a subset of exosomal miRNAs, including the miR-146a, miR-27a, miR-126, and miR-155 in ARDS group exhibited significantly elevated levels than those in non-ARDS group. The combined expression of miR-126, miR-27a, miR-146a, and miR-155 predicted ARDS with an area under the curve of 0.909 (95 % CI 0.815 -1). Only miR-126 was selected to have potential to predict the 28-day mortality (OR=1.002, P=0.024) with its median value classifier. CONCLUSIONS: The altered levels of circulating exosomal microRNAs may be useful biologic confirmation of ARDS in patients with SCAP.

Melatonin Alleviates Radiation-Induced Lung Injury via Regulation of miR-30e/NLRP3 Axis.

Melatonin is a well-known anti-inflammatory and antioxidant molecule, which plays a crucial role in various physiological functions. In this study, mice received a single dose of 15 Gy radiation delivered to the lungs and daily intraperitoneal administration of melatonin. After 7 days, mice were processed to harvest either bronchoalveolar lavage fluid for cytokine assays or lungs for flow cytometry and histopathological studies. Herein, we showed that melatonin markedly alleviated the oxidative stress and injury, especially suppressing the infiltration of macrophages (CD11b+CD11c-) and neutrophils (CD11b+Ly6G+) to the irradiated lungs. Moreover, in the irradiated RAW 264.7 cells, melatonin blocked the NLRP3 inflammasome activation accompanied with the inhibition of the IL-1ß release and caspase-1 activity. However, melatonin restored the downregulated miR-30e levels. Quantitative PCR analysis of miR-30e and NLRP3 indicated the negative correlation between them. Notably, immunofluorescence staining showed that overexpression of miR-30e dramatically diminished the increased NLRP3 expression. Luciferase reporter assay confirmed that NLRP3 was a target gene of miR-30e. Western blotting revealed that transfection with miR-30e mimics markedly reduced the expressions of NLRP3 and cleaved caspase-1, whereas this phenomenon was reversed by the miR-30e inhibitor. Consistent with this, the beneficial effect of melatonin under irradiated exposure was blunted in cells transfected with anti-miR-30e. Collectively, our results demonstrate that the NLRP3 inflammasome contributed to the pathogenesis of radiation-induced lung injury. Meanwhile, melatonin exerted its protective effect through negatively regulating the NLRP3 inflammasome in macrophages. The melatonin-mediated miR-30e/NLRP3 signaling may provide novel therapeutic targets for radiation-induced injury.

PCSK9 Hapten Multicopy Displayed onto Carrier Protein Nanoparticle: An Antiatherosclerosis Vaccine.

In recent years, various vaccination strategies have shed new light on the treatment of atherosclerosis. Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a hot target in the development of antiatherosclerosis vaccine. However, the efficacy of conventional PCSK9 is largely limited by poor immunogenicity and low hapten density. Therefore, we hypothesized whether a nanostructure synthesized by self-assembled carrier protein accompanied by multicopy hapten display could improve the efficacy of vaccine. In this study, bovine serum albumin (BSA) was self-assembled into sub-100 nm nanoparticles via an intermolecular disulfide network as the inner core. Then, sequences of PCSK9 were conjugated onto the surface of nanoparticles by "click" chemistry to consequently form an orderly structured of nanovaccine with repetitive hapten display. Compared with conventional PCSK9 peptide vaccine, our immunization study demonstrated that the PCSK9 multicopy display nanovaccine (PMCDN) was able to induce higher titers of PCSK9 antibody and more efficient lymph node drainage and improve endocytosis by antigen presenting cells.

Comprehensive physical and psychological training of modern pentathlon athletes / Treinamento físico e psicológico abrangente de atletas modernos do pentatlo / Entrenamiento físico y psicológico integral de los atletas del pentatlón moderno

ABSTRACT Introduction: The modern pentathlon requires athletes to participate in 5 individual sports (fencing, swimming, equestrian, running, and shooting combined) in one day. All of these belong to different categories, resulting in high demand for physical and mental control by the athlete. The importance of psychological factors in everyday physical activity has increased attention. Objective: This paper explores the role of comprehensive psychological training in modern pentathlon. Methods: Forty-seven modern pentathletes were selected by random sampling method. A questionnaire survey method was used to analyze the volunteers. Interviews on the psychological status of the athletes before the competition were also conducted. Finally, a statistical method was used to determine the participants' interview and questionnaire results. Results: The athletes in all five sports experienced high stress before the competitions. The second highest stress was during preparation, before the games. The incidence of anxiety, indifference, and disproportionate confidence before the competition was lower. Conclusion: The psychological state of modern pentathletes before competition is directly related to their competitive state and level. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O pentatlo moderno exige que os atletas participem de 5 esportes individuais (esgrima, natação, hipismo, corrida e tiro combinados) em um dia. Todos esses itens são pertencentes a diferentes categorias, resultando numa alta demanda de controle físico e mental pelo atleta. A importância dos fatores psicológicos na atividade física cotidiana tem aumentado a atenção. Objetivo: Este artigo explora o papel da formação psicológica abrangente no pentatlo moderno. Métodos: Foram selecionados 47 pentatletas modernos por método de amostragem aleatória. Utilizou-se um método de pesquisa de questionário para analisar os voluntários. Também foram realizadas entrevistas sobre o estado psicológico dos atletas antes da competição. Por fim, utilizou-se o método estatístico para trabalhar os resultados das entrevistas e questionários sobre os participantes. Resultados: Os atletas dos cinco esportes experimentaram um estresse elevado antes das competições. O segundo maior momento de tensão foi durante a preparação, antes dos jogos. A incidência de ansiedade, indiferença e confiança desproporcional antes da competição é menor. Conclusão: O estado psicológico dos pentatletas modernos antes da competição está diretamente relacionado ao estado competitivo e nível desses atletas. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: El pentatlón moderno requiere que los atletas participen en 5 deportes individuales (esgrima, natación, hípica, carrera y tiro combinados) en un día. Todos estos elementos pertenecen a diferentes categorías, lo que supone una gran exigencia de control físico y mental por parte del atleta. La importancia de los factores psicológicos en la actividad física diaria ha aumentado la atención. Objetivo: Este trabajo explora el papel del entrenamiento psicológico integral en el pentatlón moderno. Métodos: Se seleccionaron 47 pentatletas modernos por el método de muestreo aleatorio. Para analizar a los voluntarios se utilizó un método de encuesta por cuestionario. También se realizaron entrevistas sobre el estado psicológico de los atletas antes de la competición. Por último, se utilizó el método estadístico para elaborar los resultados de las entrevistas y los cuestionarios sobre los participantes. Resultados: Los atletas de los cinco deportes experimentaron un gran estrés antes de las competiciones. El segundo momento de mayor estrés fue durante la preparación, antes de los partidos. La incidencia de la ansiedad, la indiferencia y la confianza desproporcionada antes de la competición es menor. Conclusión: El estado psicológico de los pentatletas modernos antes de la competición está directamente relacionado con el estado y el nivel competitivo de estos atletas. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Multiplex picoliter-droplet digital PCR for quantitative assessment of EGFR mutations in circulating cell-free DNA derived from advanced non-small cell lung cancer patients.

To explore the possible diagnostic value of liquid biopsy, two multiplex panels using picoliter-droplet digital polymerase chain reaction (ddPCR) were established to quantitatively assess the epidermal growth factor receptor (EGFR) mutations in cell­free DNA (cfDNA) extracted from the plasma of advanced non­small cell lung cancer (NSCLC) patients. Plasma samples derived from 22 patients with stage IIIB/IV NSCLC harboring EGFR mutations in matched tumor tissues confirmed by amplification refractory mutation system (ARMS) analysis were subjected to two multiplex ddPCR panels to assess the abundance of tyrosine kinase inhibitor (TKI) ­sensitive (19DEL, L858R) and TKI­resistant (T790 M) mutations. Fluctuations in EGFR mutant abundance were monitored by either of the multiplex ddPCR panels for three patients undergoing EGFR­TKI treatment, with serial plasma sample collections over 2 months. The multiplex ddPCR panels applied to plasma cfDNA from advanced NSCLC patients achieved a total concordance rate of 80% with the EGFR mutation profiles obtained by ARMS from matched biopsy tumor specimens (90% for 19DEL, 95% for L858R, 95% for T790M, respectively) and revealed additional mutant alleles in two subjects. The respective sensitivity and specificity were 90.9 and 88.9% for 19DEL, 87.5 and 100% for L858R, 100 and 93.8% for T790M. The fluctuations of EGFR mutant abundance in serial plasma cfDNA were in accordance with the changes in tumor size as assessed by imaging scans. The authors demonstrated the utility of multiplex ddPCR panels with ultra­sensitivity for quantitative analysis of EGFR mutations in plasma cfDNA and obtained promising usefulness in EGFR­TKI decision­making for advanced NSCLC patients.

Synthesis, characterization and in vitro photodynamic antimicrobial activity of basic amino acid-porphyrin conjugates.

Photodynamic antimicrobial chemotherapy (PACT), as a novel and effective modality for the treatment of infection with the advantage of circumventing multidrug resistance, receives great attention in recent years. The photosensitizer is the crucial element in PACT, and cationic porphyrins have been demonstrated to usually be more efficient than neutral and negatively charged analogues towards bacteria in PACT. In this work, three native basic amino acids, l-lysine, l-histidine and l-arginine, were conjugated with amino porphyrins as cationic auxiliary groups, and 13 target compounds were synthesized. This paper reports their syntheses, structural characterizations, oil-water partition coefficients, singlet oxygen generation yields, photo-stability, as well as their photo inactivation efficacies against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli and Pseudomonas aeruginosa in vitro. The preliminary structure-activity relationship was discussed. Compound 4i, with porphyrin bearing four lysine moieties, displays the highest photo inactivation efficacy against the tested bacterial strains at 3.91 µM with a low light dose (6 J/cm(2)), and it is stable in serum and lower cytotoxicity to A929 cells. These basic amino acid-porphyrin conjugates are potential photosensitizers for PACT.

Study of cross-shaped ultrasonic array sensor applied to partial discharge location in transformer oil.

A conformal combined sensor is designed and it is used in Partial Discharge (PD) location experiments in transformer oil. The sensor includes a cross-shaped ultrasonic phased array of 13 elements and an ultra-high-frequency (UHF) electromagnetic rectangle array of 2 × 2 elements. Virtual expansion with high order cumulants, the ultrasonic array can achieve the effect of array with 61 elements. This greatly improves the aperture and direction sharpness of original array and reduces the cost of follow-up hardware. With the cross-shaped ultrasonic array, the results of PD location experiments are precise and the maximum error of the direction of arrival (DOA) is less than 5°.