LIRAGLUTIDE ALLEVIATES ACUTE LUNG INJURY AND MORTALITY IN PNEUMONIA-INDUCED SEPSIS THROUGH REGULATING SURFACTANT PROTEIN EXPRESSION AND SECRETION.

ABSTRACT: Glucagon-like peptide 1 (GLP-1) analogs are used to treat type 2 diabetes, and they can regulate insulin secretion, energy homeostasis, inflammation, and immune cell function. This study sought to determine whether the GLP-1 analog liraglutide exerts a beneficial action in an acute lung injury model of pneumonia-induced sepsis. Methods: Wild-type FVB/NJ mice (n = 114) were infected by intratracheal injection with Pseudomonas aeruginosa Xen5 (4 × 10 4 CFU/mouse) or an equal volume (50 µL) of saline (control) with or without a subcutaneous injection of liraglutide (2 mg/kg, 30 min after infection). Mice were killed 24 h after infection. Lung tissues and BALF were analyzed. In separate experiments, the dynamic growth of bacteria and animal mortality was monitored using in vivo imaging system within 48 h after infection. In addition, primary lung alveolar type II cells isolated from mice were used to study the mechanism of liraglutide action. Result: Liraglutide improved survival ( P < 0.05), decreased bacterial loads in vivo , and reduced lung injury scores ( P < 0.01) in septic mice. Liraglutide-treated mice showed decreased levels of inflammatory cells ( P < 0.01) and proinflammatory cytokines (TNF-α and IL-6) ( P < 0.01) in the lung compared with septic controls. Liraglutide significantly increased pulmonary surfactant proteins (SP-A and SP-B) expression/secretion ( P < 0.01) and phospholipid secretion ( P < 0.01) in vivo . Primary alveolar type II cells pretreated with liraglutide improved SP-A and SP-B expression after LPS exposure ( P < 0.01). Conclusion: Liraglutide attenuates mortality and lung inflammation/injury in pneumonia-induced sepsis. The increased surfactant expression/secretion and anti-inflammatory effects of liraglutide represent potential mechanisms by GLP-1 agonists potentiate host defense and maintain alveolar respiratory function in acute lung injury.

Natural compound chaetocin induced DNA damage and apoptosis through reactive oxygen species-dependent pathways in A549 lung cancer cells and in vitro evaluations.

There is an urgent need for potential pharmaceutics for lung cancer treatment due to the increased number of lung cancer deaths and the resistance of cancer cells to present therapeutics. The present work aims to discover the anticancer potential of the natural compound chaetocin as a therapeutic for lung cancer treatment. Results showed the significance of chaetocin-induced cell growth inhibition by the expression of G2 /M phase arrest and reactive oxygen species (ROS) dependent apoptosis in A549 lung cancer cells. Results concluded that chaetocin could produce ROS and nuclear damage against A549 lung cancer cells. Interestingly, chaetocin exhibits a significant level of CD47 that down-regulates the expression of CD47 at mRNA levels. PBMC biocompatibility study revealed that chaetocin is non-toxic to normal cells. Overall, experimental results suggested that chaetocin induces A549 cell apoptosis, by causing ROS and nuclear damage activation pathways. In the future, chaetocin might be an effective bio-safe anticancer agent for lung cancer treatments.

MILD TRAUMATIC BRAIN INJURY ATTENUATES PNEUMONIA-INDUCED LUNG INJURY BY MODULATIONS OF ALVEOLAR MACROPHAGE BACTERICIDAL ACTIVITY AND M1 POLARIZATION.

ABSTRACT: Traumatic brain injury is one of the main causes of death and disability worldwide, and results in multisystem complications. However, the mechanism of mild traumatic brain injury (MTBI) on lung injury remains unclear. In this study, we used a murine model of MTBI and pneumonia ( Pseudomonas aeruginosa ;) to explore the relationship between these conditions and the underlying mechanism. Methods: Mice (n = 104) were divided into control, MTBI, pneumonia, and MTBI + pneumonia groups. MTBI was induced by the weight-drop method. Pneumonia was induced by intratracheal injection with P. aeruginosa Xen5 strain. Animals were killed 24 h after bacterial challenging. Histological, cellular, and molecular indices of brain and lung injury were assessed using various methods. Results: Mice in both the MTBI and pneumonia groups had more Fluoro-Jade C-positive neurons than did the controls ( P < 0.01), but mice in the MTBI + pneumonia group had fewer Fluoro-Jade C-positive cells than did the pneumonia group ( P < 0.01). The MTBI + pneumonia mice showed decreased bacterial load ( P < 0.05), reduced lung injury score and pulmonary permeability ( P < 0.01), less inflammatory cells, and lower levels of proinflammatory cytokines (TNF-α and IL-1ß; P < 0.01) when compared with the pneumonia group. Molecular analysis indicated lower levels of phosphorylated nuclear factor-κB in the lung of MTBI + pneumonia mice compared with the pneumonia group ( P < 0.01). Furthermore, alveolar macrophages from MTBI mice exhibited enhanced bactericidal capacity compared with those from controls ( P < 0.01). Moreover, MTBI + pneumonia mice exhibited less CD86-positive M1 macrophages compared with the pneumonia group ( P < 0.01). Conclusions: MTBI attenuates pneumonia-induced acute lung injury through the modulation of alveolar macrophage bactericidal capacity and M1 polarization in bacterial pneumonia model.

Low-Cost Metamaterial Antennas: Forward-Looking Imaging Experiment and Analysis.

A phase error correction method is proposed to compensate for the phase error in super-resolution correlated imaging based on metamaterial antennas. The varying carrier frequencies of a metamaterial antenna can generate the random radiation field for super-resolution correlation imaging, but the variation of the signal carrier frequency leads to large phase errors in the imaging results. In this proposed method, the sampling matrix in the super-resolution correlated imaging algorithm is used to compensate for the phase errors. Each element of the matrix is multiplied by a compensation phase corresponding to the phase error, and the error is subtly removed from the algorithm. In the experiment, the antenna pattern at each frequency of the metamaterial antenna is measured and recorded. In addition, an external field experiment is also carried out, and the collected data are imaged with the improved algorithm. Experimental results show that this technology can effectively solve the effect of phase errors on imaging results caused by signal carrier frequency changes.

Establishment of a no-notice drill mode evaluation system for public health emergencies.

OBJECTIVE: At present, there are some no-notice drill mode evaluation systems for public health emergencies in Chinese hospitals, which are the subjects of assessment in this study. However, there is a lack of CDC. This study builds a set of no-notice drill mode evaluation systems for public health emergencies that involve the CDC. METHODS: The indexes for these systems were based on the performance of two no-notice drills for public health emergencies in Guangdong Province. Twenty experts were invited to screen the indicators during two rounds of the Delphi method to determine the weight of first- and second-level indexes through the analytic hierarchy process, and the weight of the third-level index was calculated using the percentage method. RESULTS: After two rounds of expert consultation, we obtained four first-level indicators, twenty-six second-level indicators and eighty-six third-level indicators. According to the weight calculated by analytic hierarchy process, the weights of the first-level indicators are emergency preparation (0.2775), verification and consultation regarding an epidemic situation (0.165), field investigation and control (0.3925) and summary report (0.165). Sensitivity analysis shows that the stability of the index is good. CONCLUSION: The no-notice drill mode evaluation system for public health emergencies constructed in this study can be applied to public health departments such as the CDC. Through promotion, it can provide a scientific basis for epidemiological investigation assessment.

The epidemic of Q fever in 2018 to 2019 in Zhuhai city of China determined by metagenomic next-generation sequencing.

Q fever is a worldwide zoonosis caused by Coxiella burnetii (Cb). From January 2018 to November 2019, plasma samples from 2,382 patients with acute fever of unknown cause at a hospital in Zhuhai city of China were tested using metagenomic next-generation sequencing (mNGS). Of those tested, 138 patients (5.8%) were diagnosed with Q fever based on the presence of Cb genomic DNA detected by mNGS. Among these, 78 cases (56.5%) presented from Nov 2018 to Mar 2019, suggesting an outbreak of Q fever. 55 cases with detailed clinical information that occurred during the outbreak period were used for further analysis. The vast majority of plasma samples from those Cb-mNGS-positive patients were positive in a Cb-specific quantitative polymerase chain reaction (n = 38) and/or indirect immunofluorescence assay (n = 26). Mobile phone tracing data was used to define the area of infection during the outbreak. This suggested the probable infection source was Cb-infected goats and cattle at the only official authorized slaughterhouse in Zhuhai city. Phylogenic analysis based on genomic sequences indicated Cb strains identified in the patients, goat and cattle were formed a single branch, most closely related to the genomic group of Cb dominated by strains isolated from goats. Our study demonstrates Q fever was epidemic in 2018-2019 in Zhuhai city, and this is the first confirmed epidemic of Q fever in a contemporary city in China.

LassoNet: Neural Networks with Feature Sparsity.

Much work has been done recently to make neural networks more interpretable, and one approach is to arrange for the network to use only a subset of the available features. In linear models, Lasso (or ℓ 1-regularized) regression assigns zero weights to the most irrelevant or redundant features, and is widely used in data science. However the Lasso only applies to linear models. Here we introduce LassoNet, a neural network framework with global feature selection. Our approach achieves feature sparsity by allowing a feature to participate in a hidden unit only if its linear representative is active. Unlike other approaches to feature selection for neural nets, our method uses a modified objective function with constraints, and so integrates feature selection with the parameter learning directly. As a result, it delivers an entire regularization path of solutions with a range of feature sparsity. In experiments with real and simulated data, LassoNet significantly outperforms state-of-the-art methods for feature selection and regression. The LassoNet method uses projected proximal gradient descent, and generalizes directly to deep networks. It can be implemented by adding just a few lines of code to a standard neural network.

Chronic bilateral asynchronous achilles tendon rupture treated using modified whole flexor hallucis longus transfer reconstruction: A case report.

INTRODUCTION: Achilles tendon rupture is common, but bilateral ruptures are very rare. Treatment of chronic Achilles tendon rupture is very challenging due tendon retraction and atrophied. We report a case of bilateral asynchronous Achilles tendon rupture patient who was treated with modified minimally invasive whole flexor hallucis longus (FHL) tendon transfer to repair the defects. PATIENT CONCERNS: A 52-year-old male farmer presented to our hospital complaining of bilateral heel pain that had disrupted his walking for 6 months. The patient had been misdiagnosed and under-treated for 1 year. Physical examination showed that his plantar flexors were tender and weak, with marked hypotrophy of the calf muscles. Bilateral ankle radiographs of both X-ray and computed topography (CT) revealed no bone injure. DIAGNOSIS: Magnetic resonance imaging (MRI) indicated a bilateral Achilles tendon rupture. The diagnosis was further confirmed by postoperative histological examination, which revealed Achilles tendonitis accompanied by regional calcification and chondrometaplasia. INTERVENTIONS: Surgical reconstruction of the ruptured Achilles tendons was done through a modified minimally invasive whole FHL tendon transfer followed by physiotherapy. OUTCOMES: The patient was immobilized in a cast for the next 6 weeks, gradual weight bearing gradually was then encouraged for another 6 weeks, and full weight-bearing started 3 months after surgery. By 6-month postoperation, the patient could walk and jog normally returned to his pre-injury working condition. CONCLUSION: Surgical intervention is among the primary treatment of chronic Achilles tendon rupture. However, one of the challenges in its treatment is providing suitable graft for tendon reconstruction. Our case presents a successful reconstruction procedure using less-invasive whole FHL transfer technique. This surgical technique provides satisfactory clinical and functional outcome and can be considered for future therapy.

Food Poisoning Caused by Deoxynivalenol at a School in Zhuhai, Guangdong, China, in 2019.

Deoxynivalenol (DON) or "vomitoxin" is a mycotoxin produced by Fusarium species. Few food poisoning cases caused by DON have been reported since the 1990s in China. However, on May 16, 2019, the Zhuhai Center for Disease Control and Prevention received a case report from primary school "S" that many students began vomiting after eating breakfast. To discern the cause and control the outbreak effectively, an epidemiological investigation was carried out. This retrospective cohort study defined both suspected and probable cases of food poisoning using ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry to detect 16 mycotoxins simultaneously. A total of 101 cases (14 suspected and 87 probable) were identified, with an overall attack rate of 8.1%. All cases were in grades 1-3. The main symptoms of probable cases were vomiting (100%) and nausea (63%). The average incubation time was 25 min after eating. Comparison of students who ate breakfast provided by the school with those who did not revealed the relative risk was 6.0 (95% confidence intervals [CI] = 2.2-16) among students in grades 1-3. The concentration of DON in the leftover raw breakfast noodles ranged from 6856 to 11,982 µg/kg and 878.3 to 1074.2 µg/kg in leftover cooked noodles. DON exposure was 1.3-1.6 µg/kg body weight for grades 1-2 and 1.7-2.1 µg/kg body weight for grade 3. The attack rate of grade 3 was 4.3 times higher than that for grades 1-2 (95% CI = 3.0-6.3). The food poisoning outbreak on May 16, 2019 in primary school "S" in China, was determined to be caused by DON-contaminated commercial raw noodles.

Regulatory Roles of Human Surfactant Protein B Variants on Genetic Susceptibility to Pseudomonas Aeruginosa Pneumonia-Induced Sepsis.

Surfactant protein B (SP-B) is essential for life and plays critical roles in host defense and lowering alveolar surface tension. A single-nucleotide polymorphism (SNP rs1130866) of human SP-B (hSP-B) alters the N-linked glycosylation, thus presumably affecting SP-B function. This study has investigated the regulatory roles of hSP-B genetic variants on lung injury in pneumonia-induced sepsis. METHODS: Wild-type (WT) FVB/NJ and humanized transgenic SP-B-T and SP-B-C mice (expressing either hSP-B C or T allele without mouse SP-B gene) were infected intratracheally with 50 µL (4 × 10 colony-forming units [CFUs]/mouse) Pseudomonas aeruginosa Xen5 or saline, and then killed 24 or 48 h after infection. Bacterial dynamic growths were monitored from 0 to 48 h postinfection by in vivo imaging. Histopathological, cellular, and molecular changes of lung tissues and bronchoalveolar lavage fluid (BALF) were analyzed. Surface tension of surfactants was determined with constrained drop surfactometry. RESULTS: SP-B-C mice showed higher bioluminescence and CFUs, increased inflammation and mortality, the higher score of lung injury, and reduced numbers of lamellar bodies in type II cells compared with SP-B-T or WT (P < 0.05). Minimum surface tension increased dramatically in infected mice (P < 0.01) with the order of SP-B-C > SP-B-T > WT. Levels of multiple cytokines in the lung of infected SP-B-C were higher than those of SP-B-T and WT (P < 0.01). Furthermore, compared with SP-B-T or WT, SP-B-C exhibited lower SP-B, higher NF-κB and NLRP3 inflammasome activation, and higher activated caspase-3. CONCLUSIONS: hSP-B variants differentially regulate susceptibility through modulating the surface activity of surfactant, cell death, and inflammatory signaling in sepsis.

Expression and function of miR-155 in rat synovial fibroblast model of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint synovial inflammation and is a challenge for researchers and clinicians. MicroRNAs (miRNAs/miRs) represent a group of small non-coding RNA molecules that post-transcriptionally regulate mRNA expression and are involved in various diseases, including cancer, autoimmune and metabolic diseases, as well as neurological disorders. In the present study, various experiments were performed to investigate the effects and underlying mechanism of miR-155 in RA using rat synoviocytes induced by lipopolysaccharide (LPS) to model rheumatoid arthritis. It was revealed that synovial fibroblasts exhibited significantly higher miR-155 mRNA levels than the control group. Compared with the RA group, the viability of synovial fibroblasts was significantly decreased in the miR-155 mimics + RA group, but markedly increased in the miR-155 inhibitor + RA group. Compared with that in the RA + NC mimic or RA + NC inhibitor groups, the apoptosis of synovial fibroblasts increased significantly in the miR-155 mimics + RA group, but was significantly decreased in the miR-155 inhibitor + RA group. The miR-155 mimics + RA group exhibited higher expression levels of ß-catenin, matrix metalloproteinase 7 and cyclin D1 compared with the miR-155 inhibitor + RA group, and the glycogen synthase kinase protein levels was lower compared with the miR-155 inhibitor + RA group. In brief, it was inferred that the Wnt signaling pathway is involved in the miR-155-associated inhibition of RA synovial fibroblast viability and induction of cell apoptosis. Inhibition of miR-155 may be an effective treatment for RA through regulation of the Wnt signaling pathway to reduce cell apoptosis and enhance cell viability.

Human Menstrual Blood-Derived Stem Cells Inhibit the Proliferation of HeLa Cells via TGF-ß1-Mediated JNK/P21 Signaling Pathways.

Human menstrual blood-derived stem cells (hMBSCs) are a novel type of mesenchymal stem cells (MSCs) that have a high proliferative rate, multilineage differentiation potential, low immunogenicity, and low oncogenicity, making them suitable candidates for regenerative medicine. The therapeutic efficacy of hMBSCs has been demonstrated in some diseases; however, their effects on cervical cancer remain unclear. In the present study, we investigated whether hMBSCs have anticancer properties on cervical cancer cells in vivo and in vitro, which has not yet been reported. In vitro, transwell coculturing experiments revealed that hMBSCs suppress the proliferation and invasion of HeLa cervical cancer cells by inducing G0/G1 cell cycle arrest. In vivo, we established a xenografted BALB/c nude mouse model by subcutaneously coinjecting HeLa cells with hMBSCs for 21 days. We found that hMBSCs significantly decrease the average volume and average weight of xenografted tumors. ELISA, TGF-ß1 antibody, and recombinant human TGF-ß1 (rhTGF-ß1) were used to analyze whether TGF-ß1 contributed to cell cycle arrest. We found that hMBSC-secreted TGF-ß1 and rhTGF-ß1 induced cell cycle arrest and increased the expression of phospho-JNK and phospho-P21 in HeLa cells, which was mostly reversed by TGF-ß1 antibody. These results indicate that hMBSCs have antitumor properties on cervical cancer in vitro and in vivo, mediated by the TGF-ß1/JNK/p21 signaling pathway. In conclusion, this study suggests that hMBSC-based therapy is promising for the treatment of cervical cancer.

Ripasudil Attenuates Lipopolysaccharide (LPS)-Mediated Apoptosis and Inflammation in Pulmonary Microvascular Endothelial Cells via ROCK2/eNOS Signaling.

BACKGROUND Microvascular endothelial inflammation and apoptosis are responsible for septic acute lung injury (ALI). Ripasudil is a novel Rho/Rho kinase (ROCK) inhibitor which shows therapeutic effects on several vascular diseases. The aim of this study was to investigate the protective effects and correlated molecular mechanisms of ripasudil on lipopolysaccharide- induced inflammation and apoptosis of pulmonary microvascular endothelial cells (PMVECs). MATERIAL AND METHODS Cultured PMVECs were exposed to lipopolysaccharide (LPS). Ripasudil at various concentrations was used to treat the cells. Several cells were also co-administrated with the endothelial nitric oxide synthase (eNOS) inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Cell viability was assessed by MTT assay. Terminal dUTP transferase nick-end labeling (TUNEL) assay was used to detect the apoptosis. The colorimetric method was used to measure the activity of eNOS and ROCK2. Protein phosphorylation and expression were assessed by Western blotting. RESULTS Ripasudil attenuated the LPS-induced inflammation and apoptosis in PMVECs, which was reversed by L-NAME. Ripasudil suppressed ROCK2 activity and further increased the eNOS activity. Ripasudil treatment increased the phosphorylation of eNOS, increased the expression level of Bcl2, and decreased the expression level of active caspase3 in LPS-treated PMVECs. Moreover, the ripasudil treatment also inhibited the nuclear translocation of NF-κB and further suppressed the levels of interleukin (IL) 6 and tumor necrosis factor (TNF) α. The co-treatment with L-NAME, however, impaired the anti-apoptotic and anti-inflammatory effects of ripasudil on PMVECs without affecting ROCK2. CONCLUSIONS The novel ROCK2 inhibitor ripasudil suppressed LPS-induced apoptosis and inflammation in PMVECs by regulating the ROCK2/eNOS signaling pathway.

Characterizing Listener Engagement with Popular Songs Using Large-Scale Music Discovery Data.

Music discovery in everyday situations has been facilitated in recent years by audio content recognition services such as Shazam. The widespread use of such services has produced a wealth of user data, specifying where and when a global audience takes action to learn more about music playing around them. Here, we analyze a large collection of Shazam queries of popular songs to study the relationship between the timing of queries and corresponding musical content. Our results reveal that the distribution of queries varies over the course of a song, and that salient musical events drive an increase in queries during a song. Furthermore, we find that the distribution of queries at the time of a song's release differs from the distribution following a song's peak and subsequent decline in popularity, possibly reflecting an evolution of user intent over the "life cycle" of a song. Finally, we derive insights into the data size needed to achieve consistent query distributions for individual songs. The combined findings of this study suggest that music discovery behavior, and other facets of the human experience of music, can be studied quantitatively using large-scale industrial data.

Clitocine potentiates TRAIL-mediated apoptosis in human colon cancer cells by promoting Mcl-1 degradation.

Among anti-cancer candidate drugs, TRAIL might be the most specific agent against cancer cells due to its low toxicity to normal cells. Unfortunately, cancer cells usually develop drug resistance to TRAIL, which is a major obstacle for its clinical application. One promising strategy is co-administrating with sensitizer to overcome cancer cells resistance to TRAIL. Clitocine, a natural amino nucleoside purified from wild mushroom, is recently demonstrated that can induce apoptosis in multidrug-resistant human cancer cells by targeting Mcl-1. In the present study,we found that pretreatment with clitocine dramatically enhances TRAIL lethality in its resistant human colon cancer cells by inducing apoptosis. More importantly, combination of clitocine and TRAIL also effectively inhibits xenograft growth and induces tumor cells apoptosis in athymic mice. The disruption of the binding between Mcl-1 and Bak as well as mitochondrial translocation of Bax mediated by clitocine are identified as the key underlying mechanisms, which leading to mitochondrial membrane permeabilization. Enforced exogenous Mcl-1 can effectively attenuate clitocine/TRAIL-induced apoptosis by suppressing the activation of intrinsic apoptotic pathway. Furthermore, clitocine regulates Mcl-1 expression at the posttranslational level as no obvious change is observed on mRNA level and proteasome inhibitor MG132 almost blocks the Mcl-1 suppression by clitocine. In fact, more ubiquitinated Mcl-1 was detected under clitocine treatment. Our findings indicate that clitocine is potentially an effective adjuvant agent in TRAIL-based cancer therapy.

Independent Prognostic Factors for Acute Organophosphorus Pesticide Poisoning.

BACKGROUND: Acute organophosphorus pesticide poisoning (AOPP) is becoming a significant problem and a potential cause of human mortality because of the abuse of organophosphate compounds. This study aims to determine the independent prognostic factors of AOPP by using multivariate logistic regression analysis. METHODS: The clinical data for 71 subjects with AOPP admitted to our hospital were retrospectively analyzed. This information included the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, admission blood cholinesterase levels, 6-h post-admission blood cholinesterase levels, cholinesterase activity, blood pH, and other factors. Univariate analysis and multivariate logistic regression analyses were conducted to identify all prognostic factors and independent prognostic factors, respectively. A receiver operating characteristic curve was plotted to analyze the testing power of independent prognostic factors. RESULTS: Twelve of 71 subjects died. Admission blood lactate levels, 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, blood pH, and APACHE II scores were identified as prognostic factors for AOPP according to the univariate analysis, whereas only 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, and blood pH were independent prognostic factors identified by multivariate logistic regression analysis. The receiver operating characteristic analysis suggested that post-admission 6-h lactate clearance rates were of moderate diagnostic value. CONCLUSIONS: High 6-h post-admission blood lactate levels, low blood pH, and low post-admission 6-h lactate clearance rates were independent prognostic factors identified by multivariate logistic regression analysis.