Relationship between impaired mucociliary clearance and airway inflammation in chronic airway diseases

Chronic airway diseases including cystic fibrosis (CF), asthma and chronic obstructive pulmonary disease (COPD) are characterized by reduced mucociliary clearance (MCC) that leads to mucus-obstructed and chronically inflamed airways and structural changes of the lung. Mice with airway-specific overexpression of the β-subunit of the epithelial sodium channel (Scnn1b) exhibit airway surface dehydration, mucus hyperconcentration and impaired MCC and share pathogenic key features of CF and other muco-obstructive lung diseases. Therefore, the Scnn1b-transgenic (Tg) mouse is a useful model to study pathophysiological mechanisms of chronic airway diseases in vivo. In this study, we investigated the role of MCC as an important innate defense mechanism in the pathogenesis of allergic airway disease and also aimed to understand the role of T and B cells as key cells of the adaptive immunity in chronic airway diseases. We analyzed allergen clearance mechanisms in juvenile wild-type (WT) and Scnn1b-Tg mice and validated the role of impaired MCC on allergen-induced type 2 airway inflammation in a house dust mite allergen (HDM) exposure model. Further, we determined effects of impaired MCC and allergen-induced type 2 airway inflammation in adult mice. Finally, we investigated if pharmacological improvement of MCC could prevent allergen-induced type 2 airway inflammation. To investigate the role of T and B cells in the pathogenesis of chronic airway diseases in vivo, we crossed Scnn1b-Tg mice with recombination activating gene 1 (RAG1) deficient mice (Rag1-/-) that lack mature T and B cells and compared inflammatory cell counts in bronchoalveolar lavage (BAL), transcript levels of T helper (Th)1, Th2 and Th17 cytokines, airway mucus obstruction and structural lung damage in juvenile Scnn1b-Tg mice with Scnn1b-Tg/Rag1-/- mice, and their WT and Rag1-/- littermates. We found that reduced allergen clearance from the airways aggravated eosinophilic airway inflammation, secretion of type 2 signature cytokines, and airway hyperresponsiveness (AHR) in juvenile Scnn1b-Tg mice. Interestingly, the induction of allergen-induced type 2 airway inflammation in adult WT and Scnn1b-Tg mice was abrogated demonstrating an age-dependent susceptibility caused by a type 2 biased immunity during the neonatal/juvenile age. Pharmacological improvement of airway surface hydration reduced allergen-induced airway inflammation and AHR in Scnn1b-Tg mice. Lack of Rag1 had no effect on elevated levels of neutrophils and eosinophils in BAL from juvenile Scnn1b-Tg mice. We identified elevated transcript levels of the cytokine Interleukin (IL)-17A in juvenile Scnn1b-Tg mice that was reduced in Scnn1b-Tg/Rag1-/- mice. Flow cytometry revealed γδ T, CD4+ T cells and type 3 innate lymphoid Abstract XIV cells (ILC3s) as major sources of IL-17A in lungs of Scnn1b-Tg mice. Increased IL-17A-production did not affect mucus plugging but might be associated with structural lung damage in juvenile Scnn1b-Tg mice. In summary, our data support that impaired clearance of inhaled allergens plays an important role in the pathogenesis of type 2 airway inflammation and suggest that therapeutic improvement of MCC may be an effective strategy to prevent disease-aggravating inflammatory responses in patients with allergic asthma and other chronic airway diseases associated with mucociliary dysfunction including CF and COPD. Further, results from our study provide first insights into T and B cell-dependent mechanisms that might contribute to pathophysiological features of CF lung disease

A detailed description of two controlled experiments concerning the usefulness of assertions as a means for programming

Assertions or more generally "Programming by contract" have gained widespread acceptance in the computer science community as a means for correct program development. However, the literature lacks an empirically evaluation of the benefits a programmer gains by using assertions in his software development. This paper reports about two controlled experiments to close this gap. Both experiments compared "Programming by contract" to the traditional programming style without assertions. The evaluation suggests that assertions tend to decrease the programming effort and that assertions lead to more reliable programs compared to those programs written without using them

Fluid mechanics moderate the effect of implementation intentions on a health prospective memory task in older adults

The aim of the present study was to test if a cognitive strategy improves older adults' prospective memory performance in a naturalistic health task. Moreover, it was tested if a possible strategy effect is moderated by individual differences. Therefore, a group of older adults was asked to perform a task taken from the medication adherence literature (i.e., blood pressure monitoring). Half of them were asked to form implementation intentions. Additionally, crystallized pragmatics and fluid mechanics, conscientiousness, self-efficacy, and lifestyle factors were assessed as possible moderators. Results showed a strong positive strategy effect on prospective memory. Moreover, the effect was qualified by a significant interaction and only emerged for participants with low levels in fluid mechanics. No other moderator showed an effect. In conclusion, an enhancing effect of implementation intentions on prospective memory seems to be dependent on individual differences in cognitive capacity and less related to key motivational or personality variables

Borexino : geo-neutrino measurement at Gran Sasso, Italy

Geo-neutrinos, electron anti-neutrinos produced in beta-decays of naturally occurring radioactive isotopes in the Earth, are a unique direct probe of our planet's interior. After a brief introduction of the geo-neutrinos' properties and of the main aims of their study, we discuss the features of a detector which has recently provided breakthrough achievements in the field, Borexino, a massive, calorimetric liquid scintillator detector installed at the underground Gran Sasso Laboratory. With its unprecedented radiopurity levels achieved in the core of the detection medium, it is the only experiment in operation able to study in real time solar neutrino interactions in the challenging sub-MeV energy region. Its superior technical properties allowed Borexino also to provide a clean detection of terrestrial neutrinos. Therefore, the description of the characteristics of the detected geo-neutrino signal and of the corresponding geological implications are the main core of the discussion contained in this work

Potential of Core-Collapse Supernova Neutrino Detection at JUNO

JUNO is an underground neutrino observatory under construction in Jiangmen, China. It uses 20kton liquid scintillator as target, which enables it to detect supernova burst neutrinos of a large statistics for the next galactic core-collapse supernova (CCSN) and also pre-supernova neutrinos from the nearby CCSN progenitors. All flavors of supernova burst neutrinos can be detected by JUNO via several interaction channels, including inverse beta decay, elastic scattering on electron and proton, interactions on C12 nuclei, etc. This retains the possibility for JUNO to reconstruct the energy spectra of supernova burst neutrinos of all flavors. The real time monitoring systems based on FPGA and DAQ are under development in JUNO, which allow prompt alert and trigger-less data acquisition of CCSN events. The alert performances of both monitoring systems have been thoroughly studied using simulations. Moreover, once a CCSN is tagged, the system can give fast characterizations, such as directionality and light curve

Detection of the Diffuse Supernova Neutrino Background with JUNO

As an underground multi-purpose neutrino detector with 20 kton liquid scintillator, Jiangmen Underground Neutrino Observatory (JUNO) is competitive with and complementary to the water-Cherenkov detectors on the search for the diffuse supernova neutrino background (DSNB). Typical supernova models predict 2-4 events per year within the optimal observation window in the JUNO detector. The dominant background is from the neutral-current (NC) interaction of atmospheric neutrinos with 12C nuclei, which surpasses the DSNB by more than one order of magnitude. We evaluated the systematic uncertainty of NC background from the spread of a variety of data-driven models and further developed a method to determine NC background within 15\% with {\it{in}} {\it{situ}} measurements after ten years of running. Besides, the NC-like backgrounds can be effectively suppressed by the intrinsic pulse-shape discrimination (PSD) capabilities of liquid scintillators. In this talk, I will present in detail the improvements on NC background uncertainty evaluation, PSD discriminator development, and finally, the potential of DSNB sensitivity in JUNO

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival