Well-posedness of the fully coupled quasi-static thermo-poro-elastic equations with nonlinear convective transport

This paper is concerned with the analysis of the quasi-static thermo-poroelastic model. This model is nonlinear and includes thermal effects compared to the classical quasi-static poroelastic model (also known as Biot's model). It consists of a momentum balance equation, a mass balance equation, and an energy balance equation, fully coupled and nonlinear due to a convective transport term in the energy balance equation. The aim of this article is to investigate, in the context of mixed formulations, the existence and uniqueness of a weak solution to this model problem. The primary variables in these formulations are the fluid pressure, temperature and elastic displacement as well as the Darcy flux, heat flux and total stress. The well-posedness of a linearized formulation is addressed first through the use of a Galerkin method and suitable a priori estimates. This is used next to study the well-posedness of an iterative solution procedure for the full nonlinear problem. A convergence proof for this algorithm is then inferred by a contraction of successive difference functions of the iterates using suitable norms.Comment: 22 page

Hematopoietic stem cell targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice.

Infantile malignant osteopetrosis (IMO) is a fatal disease caused by lack of functional osteoclasts, and the only available treatment is hematopoietic stem cell (HSC) transplantation. In the majority of patients, the TCIRG1 gene, coding for a subunit of a proton pump essential for bone resorption, is mutated. Oc/oc mice have a deletion in the homologue gene (tcirg 1) and die at 3 to 4 weeks, but can be rescued by neonatal transplantation of HSCs. Here, HSC-targeted gene therapy of osteopetrosis in the oc/oc mouse model was developed. oc/oc fetal liver cells depleted of Ter119-expressing erythroid cells were transduced with a retroviral vector expressing tcirgl and GFP, and subsequently transplanted intraperitoneally to irradiated neonatal oc/oc mice. Eight of 15 mice survived past the normal life span of oc/oc mice. In vitro osteoclastogenesis revealed formation of GFPpositive osteoclasts and bone resorption, albeit at a lower level than from wild-type cells. The skeletal phenotype was analyzed by X-ray and histopathology and showed partial correction at 8 weeks and almost normalization after 18 weeks. In summary, osteopetrosis in oc/oc mice can be reversed by neonatal transplantation of gene-modified HSCs leading to long-term survival. This represents a significant step toward the development of gene therapy for osteopetrosis