Exposure to Air Pollution Exacerbates Inflammation in Rats with Preexisting COPD.

Particulate matter with an aerodynamic diameter equal or less than 2.5 micrometers (PM2.5) is associated with the development of chronic obstructive pulmonary disease (COPD). The mechanisms by which PM2.5 accelerates disease progression in COPD are poorly understood. In this study, we aimed to investigate the effect of PM2.5 on lung injury in rats with hallmark features of COPD. Cardinal features of human COPD were induced in a rat model by repeated cigarette smoke inhalation and bacterial infection for 8 weeks. Then, from week 9 to week 16, some of these rats with COPD were subjected to real-time concentrated atmospheric PM2.5. Lung function, pathology, inflammatory cytokines, oxidative stress, and mucus and collagen production were measured. As expected, the COPD rats had developed emphysema, inflammation, and deterioration in lung function. PM2.5 exposure resulted in greater lung function decline and histopathological changes, as reflected by increased Mucin (MUC) 5ac, MUC5b, Collagen I, Collagen III, and the profibrotic cytokine α-smooth muscle-actin (SMA), transforming growth factor- (TGF-) β1 in lung tissues. PM2.5 also aggravated inflammation, increasing neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF) and cytokines including Interleukin- (IL-) 1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-4. The likely mechanism is through oxidative stress as antioxidants levels were decreased, whereas oxidants were increased, indicating a detrimental shift in the oxidant-antioxidant balance. Altogether, these results suggest that PM2.5 exposure could promote the development of COPD by impairing lung function and exacerbating pulmonary injury, and the potential mechanisms are related to inflammatory response and oxidative stress

The p21-Dependent Radiosensitization of Human Breast Cancer Cells by MLN4924, an Investigational Inhibitor of NEDD8 Activating Enzyme

Radiotherapy is a treatment choice for local control of breast cancer. However, intrinsic radioresistance of cancer cells limits therapeutic efficacy. We have recently validated that SCF (SKP1, Cullins, and F-box protein) E3 ubiquitin ligase is an attractive radiosensitizing target. Here we tested our hypothesis that MLN4924, a newly discovered investigational small molecule inhibitor of NAE (NEDD8 Activating Enzyme) that inactivates SCF E3 ligase, could act as a novel radiosensitizing agent in breast cancer cells. Indeed, we found that MLN4924 effectively inhibited cullin neddylation, and sensitized breast cancer cells to radiation with a sensitivity enhancement ratio (SER) of 1.75 for SK-BR-3 cells and 1.32 for MCF7 cells, respectively. Mechanistically, MLN4924 significantly enhanced radiation-induced G2/M arrest in SK-BR-3 cells, but not in MCF7 cells at early time point, and enhanced radiation-induced apoptosis in both lines at later time point. However, blockage of apoptosis by Z-VAD failed to abrogate MLN4924 radiosensitization, suggesting that apoptosis was not causally related. We further showed that MLN4924 failed to enhance radiation-induced DNA damage response, but did cause minor delay in DNA damage repair. Among a number of tested SCF E3 substrates known to regulate growth arrest, apoptosis and DNA damage response, p21 was the only one showing an enhanced accumulation in MLN4924-radiation combination group, as compared to the single treatment groups. Importantly, p21 knockdown via siRNA partialy inhibited MLN4924-induced G2/M arrest and radiosensitization, indicating a causal role played by p21. Our study suggested that MLN4924 could be further developed as a novel class of radiosensitizer for the treatment of breast cancer

Evidence for a vector charmonium-like state in e+e−→Ds+Ds2∗(2573)−+c.c.e^+e^- \to D^+_sD^*_{s2}(2573)^-+c.c.

We report the measurement of $e^+e^- \to D^+_sD^*_{s2}(2573)^-+c.c.$ via initial-state radiation using a data sample of an integrated luminosity of 921.9 fb$^{-1}$ collected with the Belle detector at the $\Upsilon(4S)$ and nearby. We find evidence for an enhancement with a 3.4$\sigma$ significance in the invariant mass of $D^+_sD^*_{s2}(2573)^- +c.c.$ The measured mass and width are $(4619.8^{+8.9}_{-8.0}({\rm stat.})\pm2.3({\rm syst.}))~{\rm MeV}/c^{2}$ and $(47.0^{+31.3}_{-14.8}({\rm stat.})\pm4.6({\rm syst.}))~{\rm MeV}$, respectively. The mass, width, and quantum numbers of this enhancement are consistent with the charmonium-like state at 4626 MeV/$c^2$ recently reported by Belle in $e^+e^-\to D^+_sD_{s1}(2536)^-+c.c.$ The product of the $e^+e^-\to D^+_sD^*_{s2}(2573)^-+c.c.$ cross section and the branching fraction of $D^*_{s2}(2573)^-\to{\bar D}^0K^-$ is measured from $D^+_sD^*_{s2}(2573)^-$ threshold to 5.6 GeV.Comment: 9 pages, 4 figure

Methylglyoxal Mediates Adipocyte Proliferation by Increasing Phosphorylation of Akt1

Methylglyoxal (MG) is a highly reactive metabolite physiologically presented in all biological systems. The effects of MG on diabetes and hypertension have been long recognized. In the present study, we investigated the potential role of MG in obesity, one of the most important factors to cause metabolic syndrome. An increased MG accumulation was observed in the adipose tissue of obese Zucker rats. Cell proliferation assay showed that 5–20 µM of MG stimulated the proliferation of 3T3-L1 cells. Further study suggested that accumulated-MG stimulated the phosphorylation of Akt1 and its targets including p21 and p27. The activated Akt1 then increased the activity of CDK2 and accelerated the cell cycle progression of 3T3-L1 cells. The effects of MG were efficiently reversed by advanced glycation end product (AGE) breaker alagebrium and Akt inhibitor SH-6. In summary, our study revealed a previously unrecognized effect of MG in stimulating adipogenesis by up-regulation of Akt signaling pathway and this mechanism might offer a new approach to explain the development of obesity

Climate Variability and Hemorrhagic Fever with Renal Syndrome Transmission in Northeastern China

Background: The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by climatic variables. However, few studies have examined the quantitative relationship between climate variation and HFRS transmission. ---------- Objective: We examined the potential impact of climate variability on HFRS transmission and developed climate-based forecasting models for HFRS in northeastern China. ---------- Methods: We obtained data on monthly counts of reported HFRS cases in Elunchun and Molidawahaner counties for 1997–2007 from the Inner Mongolia Center for Disease Control and Prevention and climate data from the Chinese Bureau of Meteorology. Cross-correlations assessed crude associations between climate variables, including rainfall, land surface temperature (LST), relative humidity (RH), and the multivariate El Niño Southern Oscillation (ENSO) index (MEI) and monthly HFRS cases over a range of lags. We used time-series Poisson regression models to examine the independent contribution of climatic variables to HFRS transmission. ----------- Results: Cross-correlation analyses showed that rainfall, LST, RH, and MEI were significantly associated with monthly HFRS cases with lags of 3–5 months in both study areas. The results of Poisson regression indicated that after controlling for the autocorrelation, seasonality, and long-term trend, rainfall, LST, RH, and MEI with lags of 3–5 months were associated with HFRS in both study areas. The final model had good accuracy in forecasting the occurrence of HFRS. ---------- Conclusions: Climate variability plays a significant role in HFRS transmission in northeastern China. The model developed in this study has implications for HFRS control and prevention

Multifunctional Adaptive NS1 Mutations Are Selected upon Human Influenza Virus Evolution in the Mouse

The role of the NS1 protein in modulating influenza A virulence and host range was assessed by adapting A/Hong Kong/1/1968 (H3N2) (HK-wt) to increased virulence in the mouse. Sequencing the NS genome segment of mouse-adapted variants revealed 11 mutations in the NS1 gene and 4 in the overlapping NEP gene. Using the HK-wt virus and reverse genetics to incorporate mutant NS gene segments, we demonstrated that all NS1 mutations were adaptive and enhanced virus replication (up to 100 fold) in mouse cells and/or lungs. All but one NS1 mutant was associated with increased virulence measured by survival and weight loss in the mouse. Ten of twelve NS1 mutants significantly enhanced IFN-β antagonism to reduce the level of IFN β production relative to HK-wt in infected mouse lungs at 1 day post infection, where 9 mutants induced viral yields in the lung that were equivalent to or significantly greater than HK-wt (up to 16 fold increase). Eight of 12 NS1 mutants had reduced or lost the ability to bind the 30 kDa cleavage and polyadenylation specificity factor (CPSF30) thus demonstrating a lack of correlation with reduced IFN β production. Mutant NS1 genes resulted in increased viral mRNA transcription (10 of 12 mutants), and protein production (6 of 12 mutants) in mouse cells. Increased transcription activity was demonstrated in the influenza mini-genome assay for 7 of 11 NS1 mutants. Although we have shown gain-of-function properties for all mutant NS genes, the contribution of the NEP mutations to phenotypic changes remains to be assessed. This study demonstrates that NS1 is a multifunctional virulence factor subject to adaptive evolution

PDlim2 Selectively Interacts with the PDZ Binding Motif of Highly Pathogenic Avian H5N1 Influenza A Virus NS1

The multi-functional NS1 protein of influenza A virus is a viral virulence determining factor. The last four residues at the C-terminus of NS1 constitute a type I PDZ domain binding motif (PBM). Avian influenza viruses currently in circulation carry an NS1 PBM with consensus sequence ESEV, whereas human influenza viruses bear an NS1 PBM with consensus sequence RSKV or RSEV. The PBM sequence of the influenza A virus NS1 is reported to contribute to high viral pathogenicity in animal studies. Here, we report the identification of PDlim2 as a novel binding target of the highly pathogenic avian influenza virus H5N1 strain with an NS1 PBM of ESEV (A/Chicken/Henan/12/2004/H5N1, HN12-NS1) by yeast two-hybrid screening. The interaction was confirmed by in vitro GST pull-down assays, as well as by in vivo mammalian two-hybrid assays and bimolecular fluorescence complementation assays. The binding was also confirmed to be mediated by the interaction of the PDlim2 PDZ domain with the NS1 PBM motif. Interestingly, our assays showed that PDlim2 bound specifically with HN12-NS1, but exhibited no binding to NS1 from a human influenza H1N1 virus bearing an RSEV PBM (A/Puerto Rico/8/34/H1N1, PR8-NS1). A crystal structure of the PDlim2 PDZ domain fused with the C-terminal hexapeptide from HN12-NS1, together with GST pull-down assays on PDlim2 mutants, reveals that residues Arg16 and Lys31 of PDlim2 are critical for the binding between PDlim2 and HN12-NS1. The identification of a selective binding target of HN12-NS1 (ESEV), but not PR8-NS1 (RSEV), enables us to propose a structural mechanism for the interaction between NS1 PBM and PDlim2 or other PDZ-containing proteins

A comparison of hepatitis B viral markers of patients in different clinical stages of chronic infection

Hepatitis B viral markers may be useful for predicting outcomes such as liver-related deaths or development of hepatocellular carcinoma. We determined the frequency of these markers in different clinical stages of chronic hepatitis B infection. We compared baseline hepatitis B viral markers in 317 patients who were enrolled in a prospective study and identified the frequency of these tests in immune-tolerant (IT) patients, in inactive carriers , and in patients with either hepatitis B e antigen ( HBeAg)- positive or HBeAg-negative chronic hepatitis or cirrhosis. IT patients were youngest (median age 27 years) and HBeAg- negative patients with cirrhosis were oldest (median age 58 years) (p = 0.03 to < 0.0001). The male to female ratio was similar both in IT patients and in inactive carriers, but there was a male preponderance both in patients with chronic hepatitis and in patients with cirrhosis (p < 0.0001). The A1896 precore mutants were most prevalent in inactive carriers (36.4%) and HBeAg- negative patients with chronic hepatitis (38.8%; p < 0.0001), and the T 1762/A1764 basal core promoter mutants were most often detected in HBeAg- negative patients with cirrhosis (65.1%; p = 0.02). Genotype A was detected only in 5.3% of IT patients, and genotype B was least often detected in both HBeAg-Positive patients with chronic hepatitis and cirrhosis (p = 0.03). The hepatitis B viral DNA levels were lowest in inactive carriers (2.69 log(10) IU/mL) and highest in IT patients (6. 80 log(10) IU/mL; p = 0.02 to < 0.0001). At follow-up, HBeAg-positive and HBeAg-negative patients with cirrhosis accounted for 57 of 64 (89.1%) liver-related deaths (p < 0. 0001). Differences in baseline hepatitis B viral markers were detected in patients in various clinical stages of hepatitis B virus infection. HBeAg-positive and HBeAg- negative patients with cirrhosis accounted for the majority of the liver-related fatalities

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques