Molecular Signatures of Quiescent, Mobilized and Leukemia-Initiating Hematopoietic Stem Cells

Hematopoietic stem cells (HSC) are rare, multipotent cells capable of generating all specialized cells of the blood system. Appropriate regulation of HSC quiescence is thought to be crucial to maintain their lifelong function; however, the molecular pathways controlling stem cell quiescence remain poorly characterized. Likewise, the molecular events driving leukemogenesis remain elusive. In this study, we compare the gene expression profiles of steady-state bone marrow HSC to non-self-renewing multipotent progenitors; to HSC treated with mobilizing drugs that expand the HSC pool and induce egress from the marrow; and to leukemic HSC in a mouse model of chronic myelogenous leukemia. By intersecting the resulting lists of differentially regulated genes we identify a subset of molecules that are downregulated in all three circumstances, and thus may be particularly important for the maintenance and function of normal, quiescent HSC. These results identify potential key regulators of HSC and give insights into the clinically important processes of HSC mobilization for transplantation and leukemic development from cancer stem 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. 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Rapid and Efficient Generation of Recombinant Human Pluripotent Stem Cells by Recombinase-mediated Cassette Exchange in the AAVS1 Locus

Even with the revolution of gene-targeting technologies led by CRISPR-Cas9, genetic modification of human pluripotent stem cells (hPSCs) is still time consuming. Comparative studies that use recombinant lines with transgenes integrated into safe harbor loci could benefit from approaches that use site-specific targeted recombinases, like Cre or FLPe, which are more rapid and less prone to off-target effects. Such methods have been described, although they do not significantly outperform gene targeting in most aspects. Using Zinc-finger nucleases, we previously created a master cell line in the AAVS1 locus of hPSCs that contains a GFP-Hygromycin-tk expressing cassette, flanked by heterotypic FRT sequences. Here, we describe the procedures to perform FLPe recombinase-mediated cassette exchange (RMCE) using this line. The master cell line is transfected with a RMCE donor vector, which contains a promoterless Puromycin resistance, and with FLPe recombinase. Application of both a positive (Puromycin) and negative (FIAU) selection program leads to the selection of RMCE without random integrations. RMCE generates fully characterized pluripotent polyclonal transgenic lines in 15 d with 100% efficiency. Despite the recently described limitations of the AAVS1 locus, the ease of the system paves the way for hPSC transgenesis in isogenic settings, is necessary for comparative studies, and enables semi-high-throughput genetic screens for gain/loss of function analysis that would otherwise be highly time consuming

Atmospheric drying as the main driver of dramatic glacier wastage in the southern Indian Ocean

This study was funded by IPEV-1048 GLACIOCLIM-KESAACO and LEFE-INSU KCRuMBLE programs, and the Agence Nationale de la Recherche through contract ANR-14-CE01-0001-01 (ASUMA).The ongoing retreat of glaciers at southern sub-polar latitudes is particularly rapid and widespread. Akin to northern sub-polar latitudes, this retreat is generally assumed to be linked to warming. However, no long-term and well-constrained glacier modeling has ever been performed to confirm this hypothesis. Here, we model the Cook Ice Cap mass balance on the Kerguelen Islands (Southern Indian Ocean, 49°S) since the 1850s. We show that glacier wastage during the 2000s in the Kerguelen was among the most dramatic on Earth. We attribute 77% of the increasingly negative mass balance since the 1960s to atmospheric drying associated with a poleward shift of the mid-latitude storm track. Because precipitation modeling is very challenging for the current generation of climate models over the study area, models incorrectly simulate the climate drivers behind the recent glacier wastage in the Kerguelen. This suggests that future glacier wastage projections should be considered cautiously where changes in atmospheric circulation are expected.Publisher PDFPeer reviewe