Helicobacter hepaticus infection in BALB/c mice abolishes subunit-vaccine-induced protection against M. tuberculosis

AbstractBCG, the only licensed vaccine against tuberculosis (TB), provides geographically variable protection, an effect ascribed to exposure to environmental mycobacteria (EM). Here we show that altering the intestinal microbiota of mice by early-life infection with the commensal bacterium Helicobacter hepaticus (Hh) increases their susceptibility to challenge with Mycobacterium tuberculosis (Mtb). Furthermore Hh-infected mice immunised parenterally with the recombinant subunit vaccine, human adenovirus type 5 expressing the immunodominant antigen 85A of Mtb (Ad85A), display a reduced lung immune response and protection against Mtb challenge is also reduced. Expression of interleukin 10 (IL10) messenger RNA is increased in the colon of Hh infected mice. Treatment of Hh-infected Ad85A-immunised mice with anti-IL10 receptor antibody, following challenge with Mtb, restores the protective effect of the vaccine. These data show for the first time that alteration of the intestinal microbiota by addition of a single commensal organism can profoundly influence protection induced by a TB subunit vaccine via an IL10-dependent mechanism, a result with implications for the deployment of such vaccines in the field

The Earth as an extrasolar transiting planet: Earth's atmospheric composition and thickness revealed by Lunar eclipse observations

An important goal within the quest for detecting an Earth-like extrasolar planet, will be to identify atmospheric gaseous bio-signatures. Observations of the light transmitted through the Earth's atmosphere, as for an extrasolar planet, will be the first step for future comparisons. We have completed observations of the Earth during a Lunar eclipse, a unique situation similar to that of a transiting planet. We aim at showing what species could be detected in its atmosphere at optical wavelengths, where a lot of photons are available in the masked stellar light. We present observations of the 2008 August 16 Moon eclipse performed with the SOPHIE spectrograph at the Observatoire de Haute-Provence. Locating the spectrograph fibers in the penumbra of the eclipse, the Moon irradiance is then a mix of direct, unabsorbed Sun light and solar light that has passed through the Earth's limb. This mixture essentially reproduces what is recorded during the transit of an extrasolar planet. We report here the clear detection of several Earth atmospheric compounds in the transmission spectra, such as ozone, molecular oxygen, and neutral sodium as well as molecular nitrogen and oxygen through the Rayleigh signature. Moreover, we present a method that allows us to derive the thickness of the atmosphere versus the wavelength for penumbra eclipse observations. We quantitatively evaluate the altitude at which the atmosphere becomes transparent for important species like molecular oxygen and ozone, two species thought to be tightly linked to the presence of life. The molecular detections presented here are an encouraging first attempt, necessary to better prepare for the future of extremely-large telescopes and transiting Earth-like planets. Instruments like SOPHIE will be mandatory when characterizing the atmospheres of transiting Earth-like planets from the ground and searching for bio-marker signatures.Comment: 15 pages, 14 figures, 2 tables. Accepted for publication in Astronomy and Astrophysic

GERMLINE GAIN-OF-FUNCTION MUTATIONS of ALK DISRUPT CENTRAL NERVOUS SYSTEM DEVELOPMENT

International audienceNeuroblastoma (NB) is a frequent embryonal tumour of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK, MIM 105590) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harbouring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes

Comparative whole genome sequence analysis of the carcinogenic bacterial model pathogen Helicobacter felis

The gram-negative bacterium Helicobacter felis naturally colonizes the gastric mucosa of dogs and cats. Due to its ability to persistently infect laboratory mice, H. felis has been used extensively to experimentally model gastric disorders induced in humans by H. pylori. We determined the 1.67 Mb genome sequence of H. felis using combined Solexa and 454 pyrosequencing, annotated the genome, and compared it with multiple previously published Helicobacter genomes. About 1,063 (63.6%) of the 1,671 genes identified in the H. felis genome have orthologues in H. pylori, its closest relative among the fully sequenced Helicobacter species. Many H. pylori virulence factors are shared by H. felis: these include the gamma-glutamyl transpeptidase GGT, the immunomodulator NapA, and the secreted enzymes collagenase and HtrA. Helicobacter felis lacks a Cag pathogenicity island and the vacuolating cytotoxin VacA but possesses a complete comB system conferring natural competence. Remarkable features of the H. felis genome include its paucity of transcriptional regulators and an extraordinary abundance of chemotaxis sensors and restriction/modification systems. Helicobacter felis possesses an episomally replicating 6.7-kb plasmid and harbors three chromosomal regions with deviating GC content. These putative horizontally acquired regions show homology and synteny with the recently isolated H. pylori plasmid pHPPC4 and homology to Campylobacter bacteriophage genes (transposases, structural, and lytic genes), respectively. In summary, the H. felis genome harbors a variety of putative mobile elements that are unique among Helicobacter species and may contribute to this pathogen's carcinogenic properties.Publisher PDFPeer reviewe

Galaxy Zoo: Passive Red Spirals

We study the spectroscopic properties and environments of red spiral galaxies found by the Galaxy Zoo project. By carefully selecting face-on, disk dominated spirals we construct a sample of truly passive disks (not dust reddened, nor dominated by old stellar populations in a bulge). As such, our red spirals represent an interesting set of possible transition objects between normal blue spirals and red early types. We use SDSS data to investigate the physical processes which could have turned these objects red without disturbing their morphology. Red spirals prefer intermediate density regimes, however there are no obvious correlations between red spiral properties and environment - environment alone is not sufficient to determine if a spiral will become red. Red spirals are a small fraction of spirals at low masses, but are a significant fraction at large stellar masses - massive galaxies are red independent of morphology. We confirm that red spirals have older stellar popns and less recent star formation than the main spiral population. While the presence of spiral arms suggests that major star formation cannot have ceased long ago, we show that these are not recent post-starbursts, so star formation must have ceased gradually. Intriguingly, red spirals are ~4 times more likely than normal spirals to host optically identified Seyfert or LINER, with most of the difference coming from LINERs. We find a curiously large bar fraction in the red spirals suggesting that the cessation of star formation and bar instabilities are strongly correlated. We conclude by discussing the possible origins. We suggest they may represent the very oldest spiral galaxies which have already used up their reserves of gas - probably aided by strangulation, and perhaps bar instabilities moving material around in the disk.Comment: MNRAS in press, 20 pages, 15 figures (v3

Eosinophils suppress Th1 responses and restrict bacterially induced gastrointestinal inflammation.

Eosinophils are predominantly known for their contribution to allergy. Here, we have examined the function and regulation of gastrointestinal eosinophils in the steady-state and during infection with or We find that eosinophils are recruited to sites of infection, directly encounter live bacteria, and activate a signature transcriptional program; this applies also to human gastrointestinal eosinophils in humanized mice. The genetic or anti-IL-5-mediated depletion of eosinophils results in improved control of the infection, increased inflammation, and more pronounced Th1 responses. Eosinophils control Th1 responses via the IFN-γ-dependent up-regulation of PD-L1. Furthermore, we find that the conditional loss of IFN-γR in eosinophils phenocopies the effects of eosinophil depletion. Eosinophils further possess bactericidal properties that require their degranulation and the deployment of extracellular traps. Our results highlight two novel functions of this elusive cell type and link it to gastrointestinal homeostasis and anti-bacterial defense

Submicroscopic Deletions at 13q32.1 Cause Congenital Microcoria.

International audienceCongenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR

Parenthood in survivors of Hodgkin lymphoma: an EORTC-GELA general population case-control study.

Contains fulltext : 108966.pdf (publisher's version ) (Open Access)PURPOSE: We investigated the impact of Hodgkin lymphoma (HL) on parenthood, including factors influencing parenthood probability, by comparing long-term HL survivors with matched general population controls. PATIENTS AND METHODS: A Life Situation Questionnaire was sent to 3,604 survivors treated from 1964 to 2004 in successive clinical trials. Responders were matched with controls (1:3 or 4) for sex, country, education, and year of birth (10-year groups). Controls were given an artificial date of start of treatment equal to that of their matched case. The main end point was presence of biologic children after treatment, which was evaluated by using conditional logistic regression analysis. Logistic regression analysis was used to analyze factors influencing spontaneous post-treatment parenthood. RESULTS: In all, 1,654 French and Dutch survivors were matched with 6,414 controls. Median follow-up was 14 years (range, 5 to 44 years). After treatment, the odds ratio (OR) for having children was 0.77 (95% CI, 0.68 to 0.87; P < .001) for survivors compared with controls. Of 898 survivors who were childless before treatment, 46.7% achieved post-treatment parenthood compared with 49.3% of 3,196 childless controls (OR, 0.87; P = .08). Among 756 survivors with children before treatment, 12.4% became parents after HL treatment compared with 22.2% of 3,218 controls with children before treatment (OR, 0.49; P < .001). Treatment with alkylating agents, second-line therapy, and age older than 35 years at treatment appeared to reduce the chances of spontaneous post-treatment parenthood. CONCLUSION: Survivors of HL had slightly but significantly fewer children after treatment than matched general population controls. The difference concerned only survivors who had children before treatment and appears to have more personal than biologic reasons. The chance of successful post-treatment parenthood was 76%

The SOPHIE search for northern extrasolar planets XIV. A temperate (Teq ~ 300 K) super-earth around the nearby star Gliese 411

Periodic radial velocity variations in the nearby M-dwarf star Gl 411 are reported, based on measurements with the SOPHIE spectrograph. Current data do not allow us to distinguish between a 12.95-day period and its one-day alias at 1.08 days, but favour the former slightly. The velocity variation has an amplitude of 1.6 m s−1, making this the lowest-amplitude signal detected with SOPHIE up to now. We have performed a detailed analysis of the significance of the signal and its origin, including extensive simulations with both uncorrelated and correlated noise, representing the signal induced by stellar activity. The signal is significantly detected, and the results from all tests point to its planetary origin. Additionally, the presence of an additional acceleration in the velocity time series is suggested by the current data. On the other hand, a previously reported signal with a period of 9.9 days, detected in HIRES velocities of this star, is not recovered in the SOPHIE data. An independent analysis of the HIRES dataset also fails to unveil the 9.9-day signal. If the 12.95-day period is the real one, the amplitude of the signal detected with SOPHIE implies the presence of a planet, called Gl 411 b, with a minimum mass of around three Earth masses, orbiting its star at a distance of 0.079 AU. The planet receives about 3.5 times the insolation received by Earth, which implies an equilibrium temperature between 256 and 350 K, and makes it too hot to be in the habitable zone. At a distance of only 2.5 pc, Gl 411 b, is the third closest low-mass planet detected to date. Its proximity to Earth will permit probing its atmosphere with a combination of high-contrast imaging and high-dispersion spectroscopy in the next decade

Training family physicians and residents in family medicine in shared decision making to improve clinical decisions regarding the use of antibiotics for acute respiratory infections: protocol for a clustered randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>To explore ways to reduce the overuse of antibiotics for acute respiratory infections (ARIs), we conducted a pilot clustered randomized controlled trial (RCT) to evaluate DECISION+, a training program in shared decision making (SDM) for family physicians (FPs). This pilot project demonstrated the feasibility of conducting a large clustered RCT and showed that DECISION+ reduced the proportion of patients who decided to use antibiotics immediately after consulting their physician. Consequently, the objective of this study is to evaluate, in patients consulting for ARIs, if exposure of physicians to a modified version of DECISION+, DECISION+2, would reduce the proportion of patients who decide to use antibiotics immediately after consulting their physician.</p> <p>Methods/design</p> <p>The study is a multi-center, two-arm, parallel clustered RCT. The 12 family practice teaching units (FPTUs) in the network of the Department of Family Medicine and Emergency Medicine of Université Laval will be randomized to a DECISION+2 intervention group (experimental group) or to a no-intervention control group. These FPTUs will recruit patients consulting family physicians and residents in family medicine enrolled in the study. There will be two data collection periods: pre-intervention (baseline) including 175 patients with ARIs in each study arm, and post-intervention including 175 patients with ARIs in each study arm (total n = 700). The primary outcome will be the proportion of patients reporting a decision to use antibiotics immediately after consulting their physician. Secondary outcome measures include: 1) physicians and patients' decisional conflict; 2) the agreement between the parties' decisional conflict scores; and 3) perception of patients and physicians that SDM occurred. Also in patients, at 2 weeks follow-up, adherence to the decision, consultation for the same reason, decisional regret, and quality of life will be assessed. Finally, in both patients and physicians, intention to engage in SDM in future clinical encounters will be assessed. Intention-to-treat analyses will be applied and account for the nested design of the trial will be taken into consideration.</p> <p>Discussion</p> <p>DECISION+2 has the potential to reduce antibiotics use for ARIs by priming physicians and patients to share decisional process and empowering patients to make informed, value-based decisions.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="NCT01116076">NCT01116076</a></p