New, efficient, and accurate high order derivative and dissipation operators satisfying summation by parts, and applications in three-dimensional multi-block evolutions

We construct new, efficient, and accurate high-order finite differencing operators which satisfy summation by parts. Since these operators are not uniquely defined, we consider several optimization criteria: minimizing the bandwidth, the truncation error on the boundary points, the spectral radius, or a combination of these. We examine in detail a set of operators that are up to tenth order accurate in the interior, and we surprisingly find that a combination of these optimizations can improve the operators' spectral radius and accuracy by orders of magnitude in certain cases. We also construct high-order dissipation operators that are compatible with these new finite difference operators and which are semi-definite with respect to the appropriate summation by parts scalar product. We test the stability and accuracy of these new difference and dissipation operators by evolving a three-dimensional scalar wave equation on a spherical domain consisting of seven blocks, each discretized with a structured grid, and connected through penalty boundary conditions.Comment: 16 pages, 9 figures. The files with the coefficients for the derivative and dissipation operators can be accessed by downloading the source code for the document. The files are located in the "coeffs" subdirector

Generation of donor-specific Tr1 cells to be used after kidney transplantation and definition of the timing of their in vivo infusion in the presence of immunosuppression

Background: Operational tolerance is an alternative to lifelong immunosuppression after transplantation. One strategy to achieve tolerance is by T regulatory cells. Safety and feasibility of a T regulatory type 1 (Tr1)-cell-based therapy to prevent graft versus host disease in patients with hematological malignancies has been already proven. We are now planning to perform a Tr1-cell-based therapy after kidney transplantation. Methods: Upon tailoring the lab-grade protocol to patients on dialysis, aims of the current work were to develop a clinical-grade compatible protocol to generate a donor-specific Tr1-cell-enriched medicinal product (named T10 cells) and to test the Tr1-cell sensitivity to standard immunosuppression in vivo to define the best timing of cell infusion. Results: We developed a medicinal product that was enriched in Tr1 cells, anergic to donor-cell stimulation, able to suppress proliferation upon donor- but not third-party stimulation in vitro, and stable upon cryopreservation. The protocol was reproducible upon up scaling to leukapheresis from patients on dialysis and was effective in yielding the expected number of T10 cells necessary for the planned infusions. The tolerogenic gene signature of circulating Tr1 cells was minimally compromised in kidney transplant recipients under standard immunosuppression and it eventually started to recover 36weeks post-transplantation, providing rationale for selecting the timings of the cell infusions. Conclusions: These data provide solid ground for proceeding with the trial and establish robust rationale for defining the correct timing of cell infusion during concomitant immunosuppressive treatment

On the inviscid and non-resistive limit for the equations of incompressible magnetohydrodynamics

We prove the convergence of the solutions for the incompressible homogeneous magnetohydrodynamics (MHD) system to the solutions to ideal MHD one in the inviscid and non-resistive limit, detailing the explicit convergence rates. For this study we consider a fluid occupying the whole space R3 and we assume that the viscosity effects in this fluid can be described by two different operators: the usual Laplacian operator affected by the inverse of the Reynolds number or by a viscosity operator introduced by S. I. Braginskii in 1965

On the well posedness of the Baumgarte-Shapiro-Shibata-Nakamura formulation of Einstein's field equations

We give a well posed initial value formulation of the Baumgarte-Shapiro-Shibata-Nakamura form of Einstein's equations with gauge conditions given by a Bona-Masso like slicing condition for the lapse and a frozen shift. This is achieved by introducing extra variables and recasting the evolution equations into a first order symmetric hyperbolic system. We also consider the presence of artificial boundaries and derive a set of boundary conditions that guarantee that the resulting initial-boundary value problem is well posed, though not necessarily compatible with the constraints. In the case of dynamical gauge conditions for the lapse and shift we obtain a class of evolution equations which are strongly hyperbolic and so yield well posed initial value formulations

Generation of donor-specific T regulatory type 1 cells from patients on dialysis for cell therapy after kidney transplantation

Background. Tregulatory type 1 (Tr1) cell-mediated induction of tolerance in preclinicalmodels of transplantation is remarkably effective. The clinical application of such a therapy in patients on dialysis undergoing kidney transplantation should take into account the possible alterations of the immune systemobserved in these patients. Herein, we aimed at testing the ability to generate donor-specific Tr1 cell-enriched lymphocytes from patients on dialysis on the waiting list for kidney transplantation. Methods. The Tr1 cell-enriched lymphocytes were generated by coculturing interleukin-10-producing dendritic cells obtained from healthy donors with peripheral bloodmononuclear cells (PBMCs) of patients on dialysis, following the same protocol used in a previous cell therapy clinical trial to prevent graft-versus-host disease. Alternatively, purified CD4+ Tcells were used instead of total PBMCs. The ability to generate clinical-grade Tr1 cell-enriched products was defined by testing the reduced response to restimulation withmature dendritic cells generated fromthe original donor (i.e., anergy assay). Results. The Tr1 cell-enrichedmedicinal products generated from PBMCs of patients on dialysis showed a low anergic phenotype, incompatible with their eventual clinical application. This was irrespective of HLA matching with the donor or the intrinsically reduced ability to proliferate in response to alloantigens. On the contrary, the use of purified CD4+ T cells isolated from patients on dialysis led to the generation of a highly anergic donor-specific medicinal product containing an average of 10% Tr1 cells. Conclusions. The Tr1 cell-enriched medicinal products can be efficiently generated from patients on dialysis by carefully tailoring the protocol on the patients' immunological characteristics

Stability of general-relativistic accretion disks

Self-gravitating relativistic disks around black holes can form as transient structures in a number of astrophysical scenarios such as binary neutron star and black hole-neutron star coalescences, as well as the core-collapse of massive stars. We explore the stability of such disks against runaway and non-axisymmetric instabilities using three-dimensional hydrodynamics simulations in full general relativity using the THOR code. We model the disk matter using the ideal fluid approximation with a $\Gamma$-law equation of state with $\Gamma=4/3$. We explore three disk models around non-rotating black holes with disk-to-black hole mass ratios of 0.24, 0.17 and 0.11. Due to metric blending in our initial data, all of our initial models contain an initial axisymmetric perturbation which induces radial disk oscillations. Despite these oscillations, our models do not develop the runaway instability during the first several orbital periods. Instead, all of the models develop unstable non-axisymmetric modes on a dynamical timescale. We observe two distinct types of instabilities: the Papaloizou-Pringle and the so-called intermediate type instabilities. The development of the non-axisymmetric mode with azimuthal number m = 1 is accompanied by an outspiraling motion of the black hole, which significantly amplifies the growth rate of the m = 1 mode in some cases. Overall, our simulations show that the properties of the unstable non-axisymmetric modes in our disk models are qualitatively similar to those in Newtonian theory.Comment: 30 pages, 21 figure

Role of videocapillaroscopy in early detection of transition from primary to secondary Raynaud's fenomenon in systemic sclerosis

Patients initially diagnosed as having primary Raynaud's phenomenon (PRP) may shift to secondary (SRP) during the follow-up. Nailfold videocapillaroscopy (NVC) is a tool that allows to distinguish between PRP and SRP through the identification of the "early" scleroderma-pattern of microangiopathy. The aim of this study was to evaluate the transition from PRP to SRP in an Italian cohort of patients during their follow-up. 129 patients with PRP were identified and followed-up for 2721 months. The diagnosis of PRP was achieved as suggested by LeRoy. The NVC diagnosis of scleroderma-pattern was based on the presence of specific "early" capillary abnormalities (i.e. giant capillaries, microhaemorrhages, and/or slight reduction of capillary density). Based on the identification of the "early" scleroderma-pattern by NVC, 14% of patients changed from PRP to SRP during the follow-up. Interestingly, 4.6% of these patients showed at baseline a fully normal NVC pattern (transition from normal to scleroderma NVC pattern in 3427 months), and 10% showed slight and not-specific nailfold capillary abnormalities (i.e. dystrophic capillaries and/or enlarged capillaries) at baseline (transition to scleroderma NVC pattern in 2515 months). Following a careful NVC analysis, we showed the progression from PRP to SRP in 14% of the analyzed patients. We suggest the capillaroscopic analysis twice a year in presence of PRP, in order to early detect the transition to SRP in patients showing at the beginning a normal pattern or not-specific nailfold capillary abnormalities, as assessed by NVC