Sox2 Is Required for Maintenance and Differentiation of Bronchiolar Clara, Ciliated, and Goblet Cells

The bronchioles of the murine lung are lined by a simple columnar epithelium composed of ciliated, Clara, and goblet cells that together mediate barrier function, mucociliary clearance and innate host defense, vital for pulmonary homeostasis. In the present work, we demonstrate that expression of Sox2 in Clara cells is required for the differentiation of ciliated, Clara, and goblet cells that line the bronchioles of the postnatal lung. The gene was selectively deleted in Clara cells utilizing Scgb1a1-Cre, causing the progressive loss of Sox2 in the bronchioles during perinatal and postnatal development. The rate of bronchiolar cell proliferation was decreased and associated with the formation of an undifferentiated, cuboidal-squamous epithelium lacking the expression of markers of Clara cells (Scgb1a1), ciliated cells (FoxJ1 and α-tubulin), and goblet cells (Spdef and Muc5AC). By adulthood, bronchiolar cell numbers were decreased and Sox2 was absent in extensive regions of the bronchiolar epithelium, at which time residual Sox2 expression was primarily restricted to selective niches of CGRP staining neuroepithelial cells. Allergen-induced goblet cell differentiation and mucus production was absent in the respiratory epithelium lacking Sox2. In vitro, Sox2 activated promoter-luciferase reporter constructs for differentiation markers characteristic of Clara, ciliated, and goblet cells, Scgb1a1, FoxJ1, and Agr2, respectively. Sox2 physically interacted with Smad3 and inhibited TGF-β1/Smad3-mediated transcriptional activity in vitro, a pathway that negatively regulates proliferation. Sox2 is required for proliferation and differentiation of Clara cells that serve as the progenitor cells from which Clara, ciliated, and goblet cells are derived

Comparative transcriptome analysis of embryonic and adult stem cells with extended and limited differentiation capacity

Comparison of the transcriptomes of pluripotent embryonic stem cells, multipotent adult progenitor cells and lineage restricted mesenchymal stem cells identified a unique gene expression profile of multipotent adult progenitor cells

Finding robust solutions for constraint satisfaction problems with discrete and ordered domains by coverings

Constraint programming is a paradigm wherein relations between variables are stated in the form of constraints. Many real life problems come from uncertain and dynamic environments, where the initial constraints and domains may change during its execution. Thus, the solution found for the problem may become invalid. The search forrobustsolutions for constraint satisfaction problems (CSPs) has become an important issue in the ¿eld of constraint programming. In some cases, there exists knowledge about the uncertain and dynamic environment. In other cases, this information is unknown or hard to obtain. In this paper, we consider CSPs with discrete and ordered domains where changes only involve restrictions or expansions of domains or constraints. To this end, we model CSPs as weighted CSPs (WCSPs) by assigning weights to each valid tuple of the problem constraints and domains. The weight of each valid tuple is based on its distance from the borders of the space of valid tuples in the corresponding constraint/domain. This distance is estimated by a new concept introduced in this paper: coverings. Thus, the best solution for the modeled WCSP can be considered as a most robust solution for the original CSP according to these assumptionsThis work has been partially supported by the research projects TIN2010-20976-C02-01 (Min. de Ciencia e Innovacion, Spain) and P19/08 (Min. de Fomento, Spain-FEDER), and the fellowship program FPU.Climent Aunés, LI.; Wallace, RJ.; Salido Gregorio, MA.; Barber Sanchís, F. (2013). Finding robust solutions for constraint satisfaction problems with discrete and ordered domains by coverings. Artificial Intelligence Review. 1-26. https://doi.org/10.1007/s10462-013-9420-0S126Climent L, Salido M, Barber F (2011) Reformulating dynamic linear constraint satisfaction problems as weighted csps for searching robust solutions. In: Ninth symposium of abstraction, reformulation, and approximation (SARA-11), pp 34–41Dechter R, Dechter A (1988) Belief maintenance in dynamic constraint networks. In: Proceedings of the 7th national conference on, artificial intelligence (AAAI-88), pp 37–42Dechter R, Meiri I, Pearl J (1991) Temporal constraint networks. Artif Intell 49(1):61–95Fargier H, Lang J (1993) Uncertainty in constraint satisfaction problems: a probabilistic approach. In: Proceedings of the symbolic and quantitative approaches to reasoning and uncertainty (EC-SQARU-93), pp 97–104Fargier H, Lang J, Schiex T (1996) Mixed constraint satisfaction: a framework for decision problems under incomplete knowledge. In: Proceedings of the 13th national conference on, artificial intelligence, pp 175–180Fowler D, Brown K (2000) Branching constraint satisfaction problems for solutions robust under likely changes. In: Proceedings of the international conference on principles and practice of constraint programming (CP-2000), pp 500–504Goles E, Martínez S (1990) Neural and automata networks: dynamical behavior and applications. Kluwer Academic Publishers, DordrechtHays W (1973) Statistics for the social sciences, vol 410, 2nd edn. Holt, Rinehart and Winston, New YorkHebrard E (2006) Robust solutions for constraint satisfaction and optimisation under uncertainty. PhD thesis, University of New South WalesHerrmann H, Schneider C, Moreira A, Andrade Jr J, Havlin S (2011) Onion-like network topology enhances robustness against malicious attacks. J Stat Mech Theory Exp 2011(1):P01,027Larrosa J, Schiex T (2004) Solving weighted CSP by maintaining arc consistency. Artif Intell 159:1–26Larrosa J, Meseguer P, Schiex T (1999) Maintaining reversible DAC for Max-CSP. J Artif Intell 107(1):149–163Mackworth A (1977) On reading sketch maps. In: Proceedings of IJCAI’77, pp 598–606Sam J (1995) Constraint consistency techniques for continuous domains. These de doctorat, École polytechnique fédérale de LausanneSchiex T, Fargier H, Verfaillie G (1995) Valued constraint satisfaction problems: hard and easy problems. In: Proceedings of the 14th international joint conference on, artificial intelligence (IJCAI-95), pp 631–637Taillard E (1993) Benchmarks for basic scheduling problems. Eur J Oper Res 64(2):278–285Verfaillie G, Jussien N (2005) Constraint solving in uncertain and dynamic environments: a survey. Constraints 10(3):253–281Wallace R, Freuder E (1998) Stable solutions for dynamic constraint satisfaction problems. In: Proceedings of the 4th international conference on principles and practice of constraint programming (CP-98), pp 447–461Wallace RJ, Grimes D (2010) Problem-structure versus solution-based methods for solving dynamic constraint satisfaction problems. In: Proceedings of the 22nd international conference on tools with artificial intelligence (ICTAI-10), IEEEWalsh T (2002) Stochastic constraint programming. In: Proceedings of the 15th European conference on, artificial intelligence (ECAI-02), pp 111–115William F (2006) Topology and its applications. Wiley, New YorkWiner B (1971) Statistical principles in experimental design, 2nd edn. McGraw-Hill, New YorkYorke-Smith N, Gervet C (2009) Certainty closure: reliable constraint reasoning with incomplete or erroneous data. J ACM Trans Comput Log (TOCL) 10(1):

Branch-and-lift algorithm for deterministic global optimization in nonlinear optimal control

This paper presents a branch-and-lift algorithm for solving optimal control problems with smooth nonlinear dynamics and potentially nonconvex objective and constraint functionals to guaranteed global optimality. This algorithm features a direct sequential method and builds upon a generic, spatial branch-and-bound algorithm. A new operation, called lifting, is introduced, which refines the control parameterization via a Gram-Schmidt orthogonalization process, while simultaneously eliminating control subregions that are either infeasible or that provably cannot contain any global optima. Conditions are given under which the image of the control parameterization error in the state space contracts exponentially as the parameterization order is increased, thereby making the lifting operation efficient. A computational technique based on ellipsoidal calculus is also developed that satisfies these conditions. The practical applicability of branch-and-lift is illustrated in a numerical example. © 2013 Springer Science+Business Media New York

The SEURAT-1 Approach towards Animal Free Human Safety Assessment

SEURAT-1 is a European public-private research consortium that is working towards animal-free testing of chemical compounds and the highest level of consumer protection. A research strategy was formulated based on the guiding principle to adopt a toxicological mode-of-action framework to describe how any substance may adversely affect human health. The proof of the initiative will be in demonstrating the applicability of the concepts on which SEURAT-1 is built on three levels: (i) Theoretical prototypes for adverse outcome pathways are formulated based on knowledge already available in the scientific literature on investigating the toxicological modes-of-action leading to adverse outcomes (addressing mainly liver toxicity); (ii) adverse outcome pathway descriptions are used as a guide for the formulation of case studies to further elucidate the theoretical model and to develop integrated testing strategies for the prediction of certain toxicological effects (i.e., those related to the adverse outcome pathway descriptions); (iii) further case studies target the application of knowledge gained within SEURAT-1 in the context of safety assessment. The ultimate goal would be to perform ab initio predictions based on a complete understanding of toxicological mechanisms. In the near-term, it is more realistic that data from innovative testing methods will support read-across arguments. Both scenarios are addressed with case studies for improved safety assessment. A conceptual framework for a rational integrated assessment strategy emerged from designing the case studies and is discussed in the context of international developments focusing on alternative approaches for evaluating chemicals using the new 21st century tools for toxicity testing

Plasticity and cardiovascular applications of multipotent adult progenitor cells

Cardiovascular disease is the leading cause of death worldwide, which has encouraged the search for new therapies that enable the treatment of patients in palliative and curative ways. In the past decade, the potential benefit of transplantation of cells that are able to substitute for the injured tissue has been studied with several cell populations, such as stem cells. Some of these cell populations, such as myoblasts and bone marrow cells, are already being used in clinical trials. The laboratory of CM Verfaillie has studied primitive progenitors, termed multipotent adult progenitor cells, which can be isolated from adult bone marrow. These cells can differentiate in vitro at the single-cell level into functional cells that belong to the three germ layers and contribute to most, if not all, somatic cell types after blastocyst injection. This remarkably broad differentiation potential makes this particular cell population a candidate for transplantation in tissues in need of regeneration. Here, we focus on the regenerative capacity of multipotent adult progenitor cells in several ischemic mouse models, such as acute and chronic myocardial infarction and limb ischemia