The domain interface method: a general-purpose non-intrusive technique for non-conforming domain decomposition problems

A domain decomposition technique is proposed which is capable of properly connecting arbitrary non-conforming interfaces. The strategy essentially consists in considering a fictitious zero-width interface between the non-matching meshes which is discretized using a Delaunay triangulation. Continuity is satisfied across domains through normal and tangential stresses provided by the discretized interface and inserted in the formulation in the form of Lagrange multipliers. The final structure of the global system of equations resembles the dual assembly of substructures where the Lagrange multipliers are employed to nullify the gap between domains. A new approach to handle floating subdomains is outlined which can be implemented without significantly altering the structure of standard industrial finite element codes. The effectiveness of the developed algorithm is demonstrated through a patch test example and a number of tests that highlight the accuracy of the methodology and independence of the results with respect to the framework parameters. Considering its high degree of flexibility and non-intrusive character, the proposed domain decomposition framework is regarded as an attractive alternative to other established techniques such as the mortar approach

Model Order Reduction in Computational multiscale fracture mechanics

Nowadays, the model order reduction techniques have become an intensive research eld because of the increasing interest in the computational modeling of complex phenomena in multi-physic problems, and its conse- quent increment in high-computing demanding processes; it is well known that the availability of high-performance computing capacity is, in most of cases limited, therefore, the model order reduction becomes a novelty tool to overcome this paradigm, that represents an immediately challenge in our research community. In computational multiscale modeling for instance, in order to study the interaction between components, a di erent numerical model has to be solved in each scale, this feature increases radically the computational cost. We present a reduced model based on a multi-scale framework for numerical modeling of the structural failure of heterogeneous quasi-brittle materials using the Strong Discontinuity Approach (CSD). The model is assessed by application to cementitious materials. The Proper Orthogonal Decomposition (POD) and the Reduced Order Integration Cubature are the pro- posed techniques to develop the reduced model, these two techniques work together to reduce both, the complexity and computational time of the high-delity model, in our case the FE2 standard mode

Effect of strain and magnetic field on the critical current and electric resistance of the joints between HTS coated conductors

Engineering of devices and systems such as magnets, fault current limiters or cables, based on High Temperature Superconducting wires requires a deep characterization of the possible degradation of their properties by handling at room temperature as well as during the service life thus establishing the limits for building up functional devices and systems. In the present work we report our study regarding the mechanical behavior of spliced joints between commercial HTS coated conductors based on YBCO at room temperature and service temperature, 77 K. Tensile tests under axial stress and the evolution of the critical current and the electric resistance of the joints have been measured. The complete strain contour for the tape and the joints has been obtained by using Digital Image Correlation. Also, tensile tests under external magnetic field have been performed and the effect of the applied field on the critical current and the electric resistance of the joints has been studied. Additionally, fatigue tests under constant cyclic stress and loading-unloading ramps have been carried out in order to evaluate the electromechanical behavior of the joints and the effect of maximum applied stress on the critical current. Finally, a preliminary numerical study by means of the Finite Element Method (FEM) of the electromechanical behavior of the joints between commercial HTS is presented

Effect of strain and magnetic field on the critical current and electric resistance of the joints between HTS coated conductors

Engineering of devices and systems such as magnets, fault current limiters or cables, based on High Temperature Superconducting wires requires a deep characterization of the possible degradation of their properties by handling at room temperature as well as during the service life thus establishing the limits for building up functional devices and systems. In the present work we report our study regarding the mechanical behavior of spliced joints between commercial HTS coated conductors based on YBCO at room temperature and service temperature, 77 K. Tensile tests under axial stress and the evolution of the critical current and the electric resistance of the joints have been measured. The complete strain contour for the tape and the joint has been obtained by using Digital Image Correlation. Also, tensile tests under external magnetic field have been performed and the effect of the applied field on the critical current and the electric resistance of the joints has been studied. Finally, a preliminary numerical study by means of Finite Element Method (FEM) of the mechanical behavior of the joints between commercial HTS is presented

A population pharmacokinetic model to predict the individual starting dose of tacrolimus in adult renal transplant recipients

Aims: The aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clinical tool for selecting the best starting dose for each patient. Methods: Data on tacrolimus exposure were collected for the first 3 months following renal transplantation. A population pharmacokinetic analysis was conducted using nonlinear mixed-effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. Results: A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two-compartment model. The mean absorption rate was 3.6 h-1 , clearance was 23.0 l h-1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose: [Formula: see text] Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added value of the starting dose model. Conclusions: For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation

Pre-transplant donor-specific T-cell alloreactivity is strongly associated with early acute cellular rejection in kidney transplant recipients not receiving T-cell depleting induction therapy

Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rap- idly recognize alloantigens and activate the effector immune response, which leads to allo- graft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by denovo activated na ï ve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell re- sponses were evaluated using the IFN- γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90), to assess the main clinical variables associated with cel- lular sensitization and its predominant time-frame impact on allograft outcome, and was fur- ther validated in an independent new set of kidney transplant recipients (n = 67). We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year inci- dence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular re- jection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosup- pression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensiti- zation before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction therapy

The timing of immunomodulation induced by mesenchymal stromal cells determines the outcome of the graft in experimental renal allotransplantation

The immunomodulatory characteristics of mesenchymal stromal cells (MSCs) may lead to multifaceted strategies in rejection of organ transplantation. This study was designed to investigate, first, the effect of the donortype MSCs from Wistar rats on the immune system of immunocompetent Lewis rats and, second, the rejection responses in a renal transplantation model of Wistar to Lewis. In the first experimental model, MSCs from the bone marrow induced a systemic immune response in the immunocompetent Lewis rats, characterized by two different phases. In the initial phase (days 1-3 after MSCs infusion), the main findings were a decrease in the percentage of the main peripheral blood (PB) lymphocyte subpopulations [T cells, B cells, and natural killer (NK) cells], an increase in the FOXP3 MFI in Tregs, and an elevated concentration of circulating proinflammatory cytokines (IL-1 beta and TNF-alpha). In the late phase (days 4-6), the percentage of T cells, B cells, and NK cells returned to baseline levels; the concentration of circulating IL-1b and TNF-a decreased; and the level of anti-inflammatory cytokines (IL-10 and IL-4) increased with respect to the initial phase. In the allogeneic kidney transplantation model, rats were randomized into four groups: nontreated, cyclosporine oral administration, and two groups of rats treated with two different schedules of MSC infusion: 4 days (MSCs-4) and 7 days (MSCs-7) before kidney transplantation and in both a further infusion at the day of transplantation. Both MSC treatments decreased the percentage of T, B, and NK cells in PB. Creatinine levels, survival, and histological parameters were better in MSCs-7 than in MSCs-4. We can conclude that MSCs, by themselves, produce changes in the immune system; they do not need a pathological condition to produce immunomodulatory responses. In the renal allograft model, the optimal time schedule for MSC infusion before grafting was 7 days to prevent acute rejection

Role of the human concentrative nucleoside transporter (hCNT1) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug.

We attempt to identify the plasma membrane transporter involved in the uptake of 5'-deoxy-5-fluorouridine (5'-DFUR), an intermediate metabolite of capecitabine. This novel oral fluoropyrimidine is used in cancer treatments and is a direct precursor of the cytostatic agent 5'-fluorouracil. We also examine the role of the transporter in 5'-DFUR cytotoxicity. The human concentrative nucleoside transporter (hCNT1) was cloned from human fetal liver and expressed in Xenopus laevis oocytes. The two-electrode voltage-clamp technique was used to demonstrate that 5'-DFUR, but not capecitabine or 5'-FU, is an hCNT1 substrate. Then, hCNT1 was heterologously expressed in the mammalian cell line Chinese hamster ovary-K1. Functional expression was demonstrated by monitoring transport of radiolabeled substrates and by using a monospecific polyclonal antibody generated against the transporter. hCNT1-expressing cells were more sensitive to 5'-DFUR than vector-transfected or wild-type cells. The sensitivity of the three cell types to other agents such as cisplatin or 5'-FU was identical. In conclusion, this study shows that 1) the pharmacological profile of a nucleoside transporter can be determined by an electrophysiological approach; 2) the hCNT1 transporter is involved in 5'-DFUR uptake; and 3) hCNT1 expression may increase cell sensitivity to 5'-DFUR treatment. This study also reports for the first time the generation of an antibody against hCNT1, which may be useful in the elucidation of the relationship between hCNT1 expression and tumor response to capecitabine treatmen

Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats

Diabetic nephropathy is the main cause of end-stage renal disease requiring dialysis in developed countries. In this study, we demonstrated the therapeutic effect of hepatocyte growth factor (HGF) on advanced rather than early diabetic nephropathy using a rat model of streptozotocin-induced diabetes. Early diabetic nephropathy (16 weeks after induction of diabetes) was characterized by albuminuria, hyperfiltration, and glomerular hypertrophy, whereas advanced diabetic nephropathy showed prominent transforming growth factor (TGF)-beta1 upregulation, mesangial expansion, and glomerulosclerosis. An SP1017-formulated human HGF (hHGF) plasmid was administered by intramuscular injection combined with electroporation over a 30-day follow-up in rats with early and advanced diabetic nephropathy. hHGF gene therapy upregulated endogenous rat HGF in the diabetic kidney (rat HGF by RT-PCR was threefold higher than in diabetic rats without therapy). hHGF gene therapy did not improve functional or morphologic abnormalities in early diabetic nephropathy. hHGF gene therapy reduced albuminuria and induced strong regression of mesangial expansion and glomerulosclerosis in advanced diabetic nephropathy. These findings were associated with suppression of renal TGF-beta1 and mesangial connective tissue growth factor (CTGF) upregulation, inhibition of renal tissue inhibitor of metalloproteinase (TIMP)-1 expression, and reduction of renal interstitial myofibroblasts. In conclusion, our results suggest that hHGF gene therapy may be considered as an innovative therapeutic strategy to treat advanced diabetic nephropathy

Data on genotypic distribution and linkage disequilibrium of several ANRIL polymorphisms in hemodialysis patients

A long non-coding RNA called ANRIL located on chromosome 9p21.3 has been identified as a novel genetic factor associated with cardiovascular disease. Investigation of several single nucleotide polymorphisms (SNPs) of Noncoding Antisense RNA in the INK4 Locus (ANRIL) gene are of particular interest. This article reports data related to the research article entitled: "Association of ANRIL gene polymorphisms with major adverse cardiovascular events in hemodialysis patients" (Arbiol-Roca et al. [1]). Data presented show the genotypic distribution of four selected ANRIL SNPs: rs10757278, rs4977574, rs10757274 and rs6475606 in a cohort constituted by 284 hemodialysis patients. This article analyzes the Hardy-Weinberg disequilibrium of each studied SNP, and the linkage disequilibrium between them