Pneumococcal Pneumolysin Induces DNA Damage and Cell Cycle Arrest

Streptococcus pneumoniae produces pneumolysin toxin as a key virulence factor against host cells. Pneumolysin is a cholesterol-dependent cytolysin (CDC) toxin that forms lytic pores in host membranes and mediates pneumococcal disease pathogenesis by modulating inflammatory responses. Here, we show that pneumolysin, which is released during bacterial lysis, induces DNA double strand breaks (DSBs), as indicated by ataxia telangiectasia mutated (ATM)-mediated H2AX phosphorylation (γH2AX). Pneumolysin-induced γH2AX foci recruit mediator of DNA damage checkpoint 1 (MDC1) and p53 binding protein 1 (53BP1), to sites of DSBs. Importantly, results show that toxin-induced DNA damage precedes cell cycle arrest and causes apoptosis when DNA-dependent protein kinase (DNA-PK)-mediated non-homologous end joining is inhibited. Further, we observe that cells that were undergoing DNA replication harbored DSBs in greater frequency during pneumolysin treatment. This observation raises the possibility that DSBs might be arising as a result of replication fork breakdown. Additionally, neutralizing the oligomerization domain of pneumolysin with monoclonal antibody suppresses DNA damage and also cell cycle arrest, indicating that pneumolysin oligomerization is important for causing DNA damage. Taken together, this study reveals a previously unidentified ability of pneumolysin to induce cytotoxicity via DNA damage, with implications in the pathophysiology of S. pneumoniae infection

A study of student participation and nonparticipation in prelecture electronic surveys

Student nonparticipation in electronic surveys represents a challenge to educators as it may impact significantly on the implementation or evaluation of the associated teaching activities. We here study the student evaluation of a pedagogical project consisting of prelecture online polling followed by linked revision lectures. This investigation involves studying the responses from 43 undergraduate students following a course in accounting at a British university. With regard to the students’ views on the use of prelecture polling, our study shows that there are no statistically significant differences between those who did not participate in the online polling and those who did. Both groups of students were generally positive about the use of (1) polling results in structuring the revision lecture, (2) online survey in helping them prepare for the examination and (3) online polling as a teaching platform in other courses. Our findings therefore suggest that prelecture electronic surveys can help engage students with follow-up lectures, including those who did not participate in the prelecture survey

Regeneration of Alveolar Type I and II Cells from Scgb1a1-Expressing Cells following Severe Pulmonary Damage Induced by Bleomycin and Influenza

The lung comprises an extensive surface of epithelia constantly exposed to environmental insults. Maintaining the integrity of the alveolar epithelia is critical for lung function and gaseous exchange. However, following severe pulmonary damage, what progenitor cells give rise to alveolar type I and II cells during the regeneration of alveolar epithelia has not been fully determined. In this study, we have investigated this issue by using transgenic mice in which Scgb1a1-expressing cells and their progeny can be genetically labeled with EGFP. We show that following severe alveolar damage induced either by bleomycin or by infection with influenza virus, the majority of the newly generated alveolar type II cells in the damaged parenchyma were labeled with EGFP. A large proportion of EGFP-expressing type I cells were also observed among the type II cells. These findings strongly suggest that Scgb1a1-expressing cells, most likely Clara cells, are a major cell type that gives rise to alveolar type I and II cells during the regeneration of alveolar epithelia in response to severe pulmonary damage in mice..Singapore. National Research FoundationSingapore–MIT Alliance for Research and Technology (Infectious Disease-IRG research programme

Bench to Bed Evidences for Pharmacokinetic and Pharmacodynamic Interactions Involving Oseltamivir and Chinese Medicine

Oseltamivir (OA), an ethyl ester prodrug of oseltamivir carboxylate (OC), is clinically used as a potent and selective inhibitor of neuraminidase. Chinese medicines have been advocated to combine with conventional drug for avian influenza. The current study aims to investigate the potential pharmacokinetic and pharmacodynamic interactions of a Chinese medicine formula, namely, Yin Qiao San and Sang Ju Yin (CMF1), commonly used for anti-influenza in combination with OA in both rat and human, and to reveal the underlined mechanisms. It was found that although Cmax, AUC and urinary recovery of OC, as well as metabolic ratio (AUCOC/AUCOA), were significantly decreased in a dose-dependent manner following combination use of CMF1 and OA in rat studies (P<0.01), such coadministration in 14 healthy volunteers only resulted in a trend of minor decrease in the related parameters. Further mechanistic studies found that although CMF1 could reduce absorption and metabolism of OA, it appears to enhance viral inhibition of OA (P<0.01). In summary, although there was potential interaction between OA and CMF1 found in rat studies, its clinical impact was expected to be minimal. The coadministration of OA and CMF1 at the clinical recommended dosages is, therefore, considered to be safe

Risk of adenocarcinomas of the oesophagus and gastric cardia in patients hospitalized for asthma

In the first cohort study of the question we followed 92 986 (42 663 men and 50 323 women) adult patients hospitalized for asthma in Sweden from 1965 to 1994 for an average of 8.5 years to evaluate their risk of oesophageal and gastric cardia adenocarcinoma. Standardized incidence ratio (SIR) adjusted for gender, age and calendar year was used to estimate relative risk, using the Swedish nationwide cancer incidence rates as reference. Asthmatic patients overall had a moderately elevated risk for oesophageal adenocarcinoma (SIR = 1.5, 95% confidence interval CI, 0.9–2.5) and gastric cardia cancer (SIR = 1.4, 95% CI, 1.0–1.9). However, the excess risks were largely confined to asthmatic patients who also had a discharge record of gastro-oesophageal reflux (SIR = 7.5, 95% CI, 1.6–22.0 and SIR = 7.1, 95% CI, 3.1–14.0, respectively). No significant excess risk for oesophageal squamous-cell carcinoma or distal stomach cancer was observed. In conclusion, asthma is associated with a moderately elevated risk of developing oesophageal or gastric cardia adenocarcinoma. Special clinical vigilance vis-à-vis gastro-esophageal cancers seems unwarranted in asthmatic patients, but may be appropriate in those with clinically manifest gastro-oesophageal reflux.   http://www.bjcancer.com © 2001 Cancer Research Campaig

Evidence for long-term Gamma-ray and X-ray variability from the unidentified TeV source HESS J0632+057

HESS J0632+057 is one of only two unidentified very-high-energy gamma-ray sources which appear to be point-like within experimental resolution. It is possibly associated with the massive Be star MWC 148 and has been suggested to resemble known TeV binary systems like LS I +61 303 or LS 5039. HESS J0632+057 was observed by VERITAS for 31 hours in 2006, 2008 and 2009. During these observations, no significant signal in gamma rays with energies above 1 TeV was detected from the direction of HESS J0632+057. A flux upper limit corresponding to 1.1% of the flux of the Crab Nebula has been derived from the VERITAS data. The non-detection by VERITAS excludes with a probability of 99.993% that HESS J0632+057 is a steady gamma-ray emitter. Contemporaneous X-ray observations with Swift XRT reveal a factor of 1.8+-0.4 higher flux in the 1-10 keV range than earlier X-ray observations of HESS J0632+057. The variability in the gamma-ray and X-ray fluxes supports interpretation of the ob ject as a gamma-ray emitting binary.Comment: 8 pages, 3 figures, Accepted for publication in The Astrophysical Journa

A connection between star formation activity and cosmic rays in the starburst galaxy M 82

Although Galactic cosmic rays (protons and nuclei) are widely believed to be dominantly accelerated by the winds and supernovae of massive stars, definitive evidence of this origin remains elusive nearly a century after their discovery [1]. The active regions of starburst galaxies have exceptionally high rates of star formation, and their large size, more than 50 times the diameter of similar Galactic regions, uniquely enables reliable calorimetric measurements of their potentially high cosmic-ray density [2]. The cosmic rays produced in the formation, life, and death of their massive stars are expected to eventually produce diffuse gamma-ray emission via their interactions with interstellar gas and radiation. M 82, the prototype small starburst galaxy, is predicted to be the brightest starburst galaxy in gamma rays [3, 4]. Here we report the detection of >700 GeV gamma rays from M 82. From these data we determine a cosmic-ray density of 250 eV cm-3 in the starburst core of M 82, or about 500 times the average Galactic density. This result strongly supports that cosmic-ray acceleration is tied to star formation activity, and that supernovae and massive-star winds are the dominant accelerators.Comment: 18 pages, 4 figures; published in Nature; Version is prior to Nature's in-house style editing (differences are minimal

Detection of Extended VHE Gamma Ray Emission from G106.3+2.7 with VERITAS

We report the detection of very-high-energy (VHE) gamma-ray emission from supernova remnant (SNR) G106.3+2.7. Observations performed in 2008 with the VERITAS atmospheric Cherenkov gamma-ray telescope resolve extended emission overlapping the elongated radio SNR. The 7.3 sigma (pre-trials) detection has a full angular extent of roughly 0.6deg by 0.4deg. Most notably, the centroid of the VHE emission is centered near the peak of the coincident 12CO (J = 1-0) emission, 0.4deg away from the pulsar PSR J2229+6114, situated at the northern end of the SNR. Evidently the current-epoch particles from the pulsar wind nebula are not participating in the gamma-ray production. The VHE energy spectrum measured with VERITAS is well characterized by a power law dN/dE = N_0(E/3 TeV)^{-G} with a differential index of G = 2.29 +/- 0.33stat +/- 0.30sys and a flux of N_0 = (1.15 +/- 0.27stat +/- 0.35sys)x 10^{-13} cm^{-2} s^{-1} TeV^{-1}. The integral flux above 1 TeV corresponds to ~5 percent of the steady Crab Nebula emission above the same energy. We describe the observations and analysis of the object and briefly discuss the implications of the detection in a multiwavelength context.Comment: 5 pages, 2 figure

Therapeutic Effect of Repurposed Temsirolimus in Lung Adenocarcinoma Model

Lung cancer is one of the major cause of cancer-related deaths worldwide. The poor prognosis and resistance to both radiation and chemotherapy urged the development of potential targets for lung cancer treatment. In this study, using a network-based cellular signature bioinformatics approach, we repurposed a clinically approved mTOR inhibitor for renal cell carcinomans, temsirolimus, as the potential therapeutic candidate for lung adenocarcinoma. The PI3K-AKT-mTOR pathway is known as one of the most frequently dysregulated pathway in cancers, including non-small-cell lung cancer. By using a well-documented lung adenocarcinoma mouse model of human pathophysiology, we examined the effect of temsirolimus on the growth of lung adenocarcinoma in vitro and in vivo. In addition, temsirolimus combined with reduced doses of cisplatin and gemcitabine significantly inhibited the lung tumor growth in the lung adenocarcinoma mouse model compared with the temsirolimus alone or the conventional cisplatin–gemcitabine combination. Functional imaging techniques and microscopic analyses were used to reveal the response mechanisms. Extensive immunohistochemical analyses were used to demonstrate the apparent effects of combined treatments on tumor architecture, vasculature, apoptosis, and the mTOR-pathway. The present findings urge the further exploration of temsirolimus in combination with chemotherapy for treating lung adenocarcinoma