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Sickle cell disease is characterized by chronic anemia and vaso-occlusive crises, which eventually lead to multi-organ damage and premature death. Hematopoietic stem cell transplantation is the only curative treatment but it is limited by toxicity and poor availability of HLA-compatible donors. A gene therapy approach based on the autologous transplantation of lentiviral-corrected hematopoietic stem and progenitor cells was shown to be efficacious in one patient. However, alterations of the bone marrow environment and properties of the red blood cells hamper the harvesting and immunoselection of patients' stem cells from bone marrow. The use of Filgrastim to mobilize large numbers of hematopoietic stem and progenitor cells into the circulation has been associated with severe adverse events in sickle cell patients. Thus, broader application of the gene therapy approach requires the development of alternative mobilization methods. We set up a phase I/II clinical trial whose primary objective was to assess the safety of a single injection of Plerixafor in sickle cell patients undergoing red blood cell exchange to decrease the hemoglobin S level to below 30%. The secondary objective was to measure the efficiency of mobilization and isolation of hematopoietic stem and progenitor cells. No adverse events were observed. Large numbers of CD34(+) cells were mobilized extremely quickly. Importantly, the mobilized cells contained high numbers of hematopoietic stem cells, expressed high levels of stemness genes, and engrafted very efficiently in immunodeficient mice. Thus, Plerixafor can be safely used to mobilize hematopoietic stem cells in sickle cell patients; this finding opens up new avenues for treatment approaches based on gene addition and genome editing. Clinicaltrials.gov identifier: NCT02212535.

Summary The spatial organization of chromosomes influences many nuclear processes including gene expression. The cohesin complex shapes the 3D genome by looping together CTCF sites along chromosomes. We show here that chromatin loop size can be increased and that the duration with which cohesin embraces DNA determines the degree to which loops are enlarged. Cohesin’s DNA release factor WAPL restricts this loop extension and also prevents looping between incorrectly oriented CTCF sites. We reveal that the SCC2/SCC4 complex promotes the extension of chromatin loops and the formation of topologically associated domains (TADs). Our data support the model that cohesin structures chromosomes through the processive enlargement of loops and that TADs reflect polyclonal collections of loops in the making. Finally, we find that whereas cohesin promotes chromosomal looping, it rather limits nuclear compartmentalization. We conclude that the balanced activity of SCC2/SCC4 and WAPL enables cohesin to correctly structure chromosomes., Graphical Abstract, Highlights • Hi-C analysis demonstrates that chromatin loop size can be increased genome-wide • The duration with which cohesin embraces DNA determines the length of chromatin loops • Haploid genetics reveals that the SCC2/SCC4 complex promotes loop extension • Cohesin limits the compartmentalization of chromatin within the nucleus, Cohesin's dynamic association with DNA determines the length of chromatin loops and allows this complex to correctly structure chromosomes.

This paper empirically investigates the determinants of willingness to pay (WTP) for the environment, employing micro data from the European Value Survey (EVS) over 2008-2010 in 27 European countries. Using ordered logit, logit and partially constrained generalized ordered logit models, we explore a wide set of individual and country level determinants. Our particular focus is on whether WTP is influenced by the Environmental Fiscal Reforms (EFR), carried out only in some countries of our sample. Our results show that WTP for the environment is lower in countries where an Environmental Fiscal Reform has been introduced. Moreover, analyses conducted on the role of information highlight that being presumably aware of the environmental fiscal reform does not affect positively the marginal willingness to pay for the environment.

Using micro data from the European Value Survey (EVS) over 2008-2010, the paper investigates the individual and country variables that might affect the WTP for the environment of the 27 European Union (EU) Member States and in particular on the correlation of individual preferences to the existence/inexistence of the Environmental Tax Reform (ETR). Analyses, carried out by means of ordered logit OLS, logit and partial generalized ordered logit, provide useful insights to policy makers in fostering the tool of ETR, strongly promoted by the EU. Among others, our results show that WTP for the environment is higher in countries where an ETR has not been implemented. Moreover, further analyses conducted on the role of information highlight that being presumably aware of the ETR has a null/negative impact on the WTP for the environment.

Synthesizing the complex phenomenon of “environment” into a single indicator could leads to a loss of information, which inhibit his use as a reference for the resolution of several issues such as, for example, the allocation of resources. On the other hand it allows to represent the overall environmental performance of cities and to highlight relationships between different sectors. We consider “process oriented” variables instead of aggregated and “outcome oriented” ones, generally used to measure environmental sustainability strictu sensu. In this sense we refers specifically to the concept of “environmental virtuosity”, that allows to rank statistical units (i.e. Italian main municipalities), considering their policy efforts for improving urban environmental quality. Generally an indicator of environmental quality should combine partial information to summarize the main subject. This paper proposes to measure urban environmental virtuosity by multivariate analysis, following OECD (2008) procedure. This methodology will try to overcome the main methodological issues in building up indicators, consisting in the choice of weights and in the common practice of simply adding sub-indicators.