Quotient spaces of boundedly rational types

By identifying types whose low-order beliefs – up to level li – about the state of nature coincide, we obtain quotient type spaces that are typically smaller than the original ones, preserve basic topological properties, and allow standard equilibrium analysis even under bounded reasoning. Our Bayesian Nash (li; l-i)-equilibria capture players’ inability to distinguish types belonging to the same equivalence class. The case with uncertainty about the vector of levels (li; l-i) is also analyzed. Two examples illustrate the constructions.Incomplete-information games, high-order reasoning, type space, quotient space, hierarchies of beliefs, bounded rationality

Determination of liver specific toxicities in rat hepatocytes by high content imaging during 2-week multiple treatment

AbstractDILI is a major safety issue during drug development and one of the leading causes for market withdrawal. Despite many efforts made in the past, the prediction of DILI using in vitro models remains very unreliable. In the present study, the well-established hepatocyte Collagen I-Matrigel™ sandwich culture was used, mimicking chronic drug treatment after multiple incubations for 14days. Ten drugs associated with different types of specific preclinical and clinical liver injury were evaluated at non-cytotoxic concentrations. Mrp2-mediated transport, intracellular accumulation of neutral lipids and phospholipids were selected as functional endpoints by using Cellomics™ Arrayscan® technology and assessed at five timepoints (day 1, 3, 7, 10, 14). Liver specific functional impairments after drug treatment were enhanced over time and could be monitored by HCI already after few days and before cytotoxicity. Phospholipidosis-inducing drugs Chlorpromazine and Amiodarone displayed the same response as in vivo. Cyclosporin A, Chlorpromazine, and Troglitazone inhibited Mrp2-mediated biliary transport, correlating with in vivo findings. Steatosis remained difficult to be reproduced under the current in vitro testing conditions, resulting into false negative and positive responses. The present results suggest that the repeated long-term treatment of rat hepatocytes in the Collagen I-Matrigel™ sandwich configuration might be a suitable tool for safety profiling of the potential to induce phospholipidosis and impair Mrp2-mediated transport processes, but not to predict steatosis

The Hadamard product, its residual, and its dual residual in the dioid of counters: algorithms and implementation in C++

This report presents the algorithms for computing the Hadamard product, its residual, and its dual residual between formal power series in the dioid of counters. The algorithms have been implemented in the C++ toolbox ETVO ((Event|Time)-Variant Operators). After proving the correctness of the algorithms, we present a user guide for the C++ implementation.Comment: 26 pages, 2 figures, technical repor

Vaccination with Flt3L-induced CD8α+ dendritic cells prevents CD4+ T helper cell-mediated experimental autoimmune myocarditis

Experimental autoimmune myocarditis (EAM) represents a CD4(+) T helper (Th) cell-mediated mouse model of inflammatory heart disease. Interferon (IFN)-γ, typically produced by Th1 cells, reduces EAM severity in myosin heavy-chain-(MyHC)-α peptide/Complete Freund adjuvant-immunized mice. Thus, developing a vaccination strategy that promotes differentiation of Th1 cells may be beneficial in EAM. FMS-like tyrosine kinase 3 ligand (Flt3L)-induced splenic CD8α(+) dendritic cells (DC), which produce interleukin (IL)-12p35, were identified to selectively induce biased differentiation towards Th1. Mice vaccinated with MyHC-α-loaded Flt3L-induced splenic CD8α(+) DC were protected from EAM. In contrast, when Flt3L-induced splenic CD8α(+) DC were pre-stimulated and over-activated with LPS and αCD40 antibodies or loaded with unspecific OVA(323-339) peptide instead of MyHC-α peptide, mice developed similar disease scores as non-vaccinated controls. Vaccination efficacy depended on IFN-γ, since CD8α(+)-vaccinated IFN-γR(-/-) mice were not protected. Importantly, splenic CD8α(+) vaccination was independent of regulatory T cells. Taken together, Flt3L-induced dendritic cell-based antigen-specific vaccination limits expansion of auto-reactive Th cells and protects mice from autoimmune heart inflammation

Profibrotic potential of Prominin-1+ epithelial progenitor cells in pulmonary fibrosis

Background In idiopathic pulmonary fibrosis loss of alveolar epithelium induces inflammation of the pulmonary tissue followed by accumulation of pathogenic myofibroblasts leading eventually to respiratory failures. In animal models inflammatory and resident cells have been demonstrated to contribute to pulmonary fibrosis. Regenerative potential of pulmonary and extra-pulmonary stem and progenitor cells raised the hope for successful treatment option against pulmonary fibrosis. Herein, we addressed the contribution of lung microenvironment and prominin-1+ bone marrow-derived epithelial progenitor cells in the mouse model of bleomycin-induced experimental pulmonary fibrosis. Methods Prominin-1+ bone marrow-derived epithelial progenitors were expanded from adult mouse lungs and differentiated in vitro by cytokines and growth factors. Pulmonary fibrosis was induced in C57Bl/6 mice by intratracheal instillation of bleomycin. Prominin-1+ progenitors were administered intratracheally at different time points after bleomycin challenge. Green fluorescence protein-expressing cells were used for cell tracking. Cell phenotypes were characterized by immunohistochemistry, flow cytometry and quantitative reverse transcription-polymerase chain reaction. Results Prominin-1+ cells expanded from healthy lung represent common progenitors of alveolar type II epithelial cells, myofibroblasts, and macrophages. Administration of prominin-1+ cells 2 hours after bleomycin instillation protects from pulmonary fibrosis, and some of progenitors differentiate into alveolar type II epithelial cells. In contrast, prominin-1+ cells administered at day 7 or 14 lose their protective effects and differentiate into myofibroblasts and macrophages. Bleomycin challenge enhances accumulation of bone marrow-derived prominin-1+ cells within inflamed lung. In contrast to prominin-1+ cells from healthy lung, prominin-1+ precursors isolated from inflamed organ lack regenerative properties but acquire myofibroblast and macrophage phenotypes. Conclusion The microenvironment of inflamed lung impairs the regenerative capacity of bone marrow-derived prominin-1+ progenitors and promotes their differentiation into pathogenic phenotypes

Phlebovirus detection in phlebotominae vectors captured in endemic areas

The Toscana Virus (TOSV), is a common human pathogen widespread in the Mediterranean area which causes a mild three-day fever. Sandfly collections from the leishmaniosis endemic area of Lampedusa were analysed for TOSV.peer-reviewe

Vandetanib versus cabozantinib in medullary thyroid carcinoma:A focus on anti‐angiogenic effects in zebrafish model

Medullary thyroid carcinoma (MTC) is a tumor deriving from the thyroid C cells. Vandetanib (VAN) and cabozantinib (CAB) are two tyrosine kinase inhibitors targeting REar-ranged during Transfection (RET) and other kinase receptors and are approved for the treatment of advanced MTC. We aim to compare the in vitro and in vivo anti‐tumor activity of VAN and CAB in MTC. The effects of VAN and CAB on viability, cell cycle, and apoptosis of TT and MZ‐CRC‐1 cells are evaluated in vitro using an MTT assay, DNA flow cytometry with propidium iodide, and An-nexin V‐FITC/propidium iodide staining, respectively. In vivo, the anti‐angiogenic potential of VAN and CAB is evaluated in Tg(fli1a:EGFP)y1 transgenic fluorescent zebrafish embryos by ana-lyzing the effects on the physiological development of the sub‐intestinal vein plexus and the tu-mor‐induced angiogenesis after TT and MZ‐CRC‐1 xenotransplantation. VAN and CAB exert comparable effects on TT and MZ‐CRC‐1 viability inhibition and cell cycle perturbation, and stimulated apoptosis with a prominent effect by VAN in MZ‐CRC‐1 and CAB in TT cells. Regard-ing zebrafish, both drugs inhibit angiogenesis in a dose‐dependent manner, in particular CAB shows a more potent anti‐angiogenic activity than VAN. To conclude, although VAN and CAB show comparable antiproliferative effects in MTC, the anti‐angiogenic activity of CAB appears to be more relevant.</p

Modeling Lung Carcinoids with Zebrafish Tumor Xenograft

Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)(y1) zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening