Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer

X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mutations in Bruton tyrosine kinase (Btk) and characterized by an arrest in early B-cell development, near absence of serum immunoglobulin, and recurrent bacteria infections. Using Btk- and Tec-deficient mice (BtkTec-/-) as a model for XLA, we determined if Btk gene therapy could correct this disorder. Bone marrow (BM) from 5-fluorouracil (5FU)-treated BtkTec-/- mice was transduced with a retroviral vector expressing human Btk and transplanted into BtkTec-/- recipients. Mice engrafted with transduced hematopoietic cells exhibited rescue of both primary and peripheral B-lineage development, revocery of peritoneal B1 B cells, and correction of serum immunoglobulin M (IgM) and IgG3 levels. Gene transfer also restored T-independent type II immune responses, and B-cell antigen receptor (BCR) proliferative responses. B-cell progenitors derived from Btk-transduced stem cells exhibited higher levels of Btk expression than non-B cells; and marking studies demonstrated a selective advantage for Btk-transduced B-lineage cells. BM derived from primary recipients also rescued Btk-dependent function in secondary hosts that had received a transplant. Together, these data demonstrate that gene transfer into hematopoietic stem cells can reconstitute Btk-dependent B-cell development and function in vivo, and strongly support the feasibility of pursuing Btk gene transfer for XLA

Copula Models of the Joint Distribution of Exchange Rates

Abstract: The paper aims at investigating the joint distribution of currency rates using HAC, HKC and Vine copulas in several time periods. Models were constructed using Archimedean copulas including Gumbel-Hougaard, Joe BB1 and Frank copulas, and their parameters were estimated by maximum likelihood. The best models were built using hierarchical Archimedean copulas and the worst were obtained with vine copulas. In comparison with the HAC, the main advantage of hierarchical Kendall copulas is the possibility to use a two-parameter copula Joe BB1. The best models were obtained with Frank copula, while Gumbel-Hougaard copula has shown a decent result only in the third period. Additionally, in this paper was made an attempt to get the forecast of exchange rates using Kendall’s and Marshall-Olkin’s algorithms. The most accurate forecast was obtained with Gumbel-Hougaard copula for euro and franc