A general comparetive study in long rod penetration using corrective smoothed particle method

Corrective smoothed particle method (CSPM) has been used to study the dynamic behavior of targets with different materials; AL, ALN and AL-ALN FGM in long rod penetration of an AL projectile. A mixed strength model with sigmoid formulation has been used to describe both yielding and fracture phenomena in the FGM. The strength model includes the JC dynamic yield relation and JHB fracture model with a continuum damage description approach. An efficient renormalization in continuity density approach is used to improve the SPH approximation of boundary physical variables. This study shows that the CSPM method in combination with the proper strength model describing the FGM dynamic behavior, can predict the mixed plastic and brittle response of different materials in long rod penetration problems

Role of splenectomy in human liver transplantation under modern-day immunosuppression

Between January 1987 and October 1991, 1466 patients underwent consecutive Orthotopic Liver Transplantation (OLTx) at the University of Pittsburgh. Forty of these patient's had concomitant splenectomy with OLTx. These patients were compared to 147 randomly selected OLTx patients without splenectomy within the same time period. One-year patient and graft survival (PS and GS) were lower in splenectomized (Splx) patients compared to nonsplenectomized (non-Splx) patients (59% vs 86% PS, 55% vs 80% GS, respectively). One-month and one-year patient mortality in the Splx group was higher than in the non-splx patients (20% vs 3.4% P < 0.001 for one month; 40% vs 14.3%, P = 0.003 for one year, respectively). One-month and one-year sepsis-related mortality was also high in Splx patients (17.5% vs 2.7%, P = 0.0022, for one month, and 30% vs 11.5%, P = 0.0043, for one year, respectively). We conclude that concomitant splenectomy with OLTx has a significantly higher patient mortality mainly due to its septic complications and, at present, unless there is a specific indication for a splenectomy, the routine addition of this procedure to liver allograft surgery would not be recommended

NN-EVP: A physics informed neural network-based elasto-viscoplastic framework for predictions of grain size-aware flow response under large deformations

We propose a physics informed, neural network-based elasto-viscoplasticity (NN-EVP) constitutive modeling framework for predicting the flow response in metals as a function of underlying grain size. The developed NN-EVP algorithm is based on input convex neural networks as a means to strictly enforce thermodynamic consistency, while allowing high expressivity towards model discovery from limited data. It utilizes state-of-the-art machine learning tools within PyTorch's high-performance library providing a flexible tool for data-driven, automated constitutive modeling. To test the performance of the framework, we generate synthetic stress-strain curves using a power law-based model with phenomenological hardening at small strains and test the trained model for strain amplitudes beyond the training data. Next, experimentally measured flow responses obtained from uniaxial deformations are used to train the framework under large plastic deformations. Ultimately, the Hall-Petch relationship corresponding to grain size strengthening is discovered by training flow response as a function of grain size, also leading to efficient extrapolation. The present work demonstrates a successful integration of neural networks into elasto-viscoplastic constitutive laws, providing a robust automated framework for constitutive model discovery that can efficiently generalize, while also providing insights into predictions of flow response and grain size-property relationships in metals and metallic alloys under large plastic deformations

Cloning and Expression of Human Membrane-Bound and Soluble Engineered T Cell Receptors for Immunotherapy

We report here the design and construction of several gene vectors for expression in mammalian cells of membrane-bound and soluble human T cell receptors (TR). We designed a vector (TR-ALPHA-IRES-TR-BETA pEF4) that encodes high-level expression of the full-length TR on the surface of T cells. Furthermore, we engineered TR that does not require the presence of endogenous CD3 molecules for surface expression and thus expression is not limited to T cells. We also constructed a vector encoding a single-chain TR (scTR) as a fusion protein of V-ALPHA-V-BETA-C-BETA with CD3Z. Since it is encoded and expressed as a single molecule, this scTR is well suited for gene therapy. Lastly, we successfully used a mammalian expression vector for generation of soluble human TR. The approaches we used here for manipulation of a human tumor-specific TR can be useful for other investigators interested in TR-based immunotherapy

Effects of manipulating the immune system on dystrophin gene transfer and dystrophic phenotype in striated muscles of Duchenne muscular dystrophy model, mdx mouse

Duchenne muscular dystrophy (DMD) is a fatal genetic disorder caused by mutations in the gene coding for dystrophin protein, which give rise to a dysfunctional protein in skeletal muscle. Dystrophic muscle progressively degenerates. In addition, necrotic muscle fibers undergo high levels of inflammation that in turn promote the pathology that is associated with this devastating disease. Therefore, treatments that 1) restore expression a functional dystrophin protein in dystrophic muscles, and 2) lower the ongoing inflammation in the necrotic muscle tissue, are both important in ameliorating DMD phenotype. Transfer of a functional dystrophin gene using a viral vector can help restore the missing dystrophin protein in dystrophic muscles. The host immune system, however, is a major barrier to successful vector-mediated dystrophin protein expression in a dystrophic host, as anti-dystrophin immune response leads to rejection of the protein. Here I show that temporal elimination of the host immune system by irradiation in the mdx mouse, a murine model of DMD, prior to vector-mediated dystrophin gene delivery, leads to a delayed and diminished host anti-dystrophin immune response. These findings are important for a better evaluation of anti-dystrophin immunity in a dystrophic host. In the case of lowering inflammation in dystrophic muscles, I investigated the effects of rapamycin, a potent immunosuppressant, on both dystrophic phenotype and dystrophin gene transfer in mdx mice. Treatment of adult mdx muscles with rapamycin lead to significantly lower levels of muscle fiber necrosis and reduced effector T cell infiltration in dystrophic muscles. These events correlated with a difference in activation of the mammalian target of rapamycin (mTOR) in the diaphragm muscle, but not the TA muscle, suggesting a differential regulation of mTOR activation in the two tissues. Rapamycin treatment, however, did not allow for a higher level of vector-mediated dystrophin protein expression in treated muscles. In general, these findings shed more light on the effects of manipulating the immune system in a dystrophic host in terms of both reducing the inflammation that is associated with DMD and reducing anti-dystrophin responses following gene therapy, suggesting that regulation of the immune system is essential in ameliorating DMD

Immunosuppression for liver transplantation in HCV-infected patients: Mechanism-based principles

We retrospectively analyzed 42 hepatitis C virus (HCV)-infected patients who underwent cadaveric liver transplantation under two strategies of immunosuppression: (1) daily tacrolimus (TAC) throughout and an initial cycle of high-dose prednisone (PRED) with subsequent gradual steroid weaning, or (2) intraoperative antithymocyte globulin (ATG) and daily TAC that was later space weaned. After 36 ± 4 months, patient and graft survival in the first group was 18/19 (94.7%) with no examples of clinically serious HCV recurrence. In the second group, the three-year patient survival was 12/23 (52%), and graft survival was 9/23 (39%); accelerated recurrent hepatitis was the principal cause of the poor results. The data were interpreted in the context of a recently proposed immunologic paradigm that is equally applicable to transplantation and viral immunity. In the framework of this paradigm, the disparate hepatitis outcomes reflected different equilibria reached under the two immunosuppression regimens between the relative kinetics of viral distribution (systemically and in the liver) and the slowly recovering HCV-specific T-cell response. As a corollary, the aims of treatment of the HCV-infected liver recipients should be to predict, monitor, and equilibrate beneficial balances between virus distribution and the absence of an immunopathologic antiviral T-cell response. In this view, favorable equilibria were accomplished in the nonweaned group of patients but not in the weaned group. In conclusion, since the anti-HCV response is unleashed when immunosuppression is weaned, treatment protocols that minimize disease recurrence in HCV-infected allograft recipients must balance the desire to reduce immunosuppression or induce allotolerance with the need to prevent antiviral immunopathology. Copyright © 2005 by the American Association for the Study of Liver Diseases

Disease gravity and urgency of need as guidelines for liver allocation

One thousand one hundred and twenty-eight candidates for liver transplantation were stratified into five urgency-of-need categories by the United Network for Organ Sharing (UNOS) criteria. Most patients of low-risk UNOS 1 status remained alive after 1 yr without transplantation; the mortality while waiting was 3% after a median of 229.5 days. In contrast, only 3% of those entered at the highest risk UNOS 5 category survived without transplantation; 28% died while waiting, the deaths occurring at a median of 5.5 days. The UNOS categories in between showed the expected gradations, in which at each higher level fewer patients remained as candidates throughout the 1-yr duration of study while progressively more died at earlier and earlier times while waiting for an organ. In a separate study of posttransplantation survival during the same time period, the best postoperative results were in the lowest-risk UNOS 1 and 2 patients (88% combined), and the worst results were those in UNOS 5 (71%). However, a relative risk cross-analysis showed that a negative benefit of transplantation may have been the result in terms of 1-yr survival for the low-risk elective patients, but that a gain in life extension was achieved in the potentially lethal UNOS categories 3, 4 and 5 (greatest for UNOS 3). These findings and conclusions are discussed in terms of total care of patients with liver disease, and in the context of organ allocation policies of the United States and Europe

Effect of rapamycin on immunity induced by vector-mediated dystrophin expression in mdx skeletal muscle

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Therapeutic gene replacement of a dystrophin cDNA into dystrophic muscle can provide functional dystrophin protein to the tissue. However, vector-mediated gene transfer is limited by anti-vector and anti-transgene host immunity that causes rejection of the therapeutic protein. We hypothesized that rapamycin (RAPA) would diminish immunity due to vector-delivered recombinant dystrophin in the adult mdx mouse model for DMD. To test this hypothesis, we injected limb muscle of mdx mice with RAPA-containing, poly-lactic-co-glycolic acid (PLGA) microparticles prior to dystrophin gene transfer and analyzed treated tissue after 6 weeks. RAPA decreased host immunity against vector-mediated dystrophin protein, as demonstrated by decreased cellular infiltrates and decreased anti-dystrophin antibody production. The interpretation of the effect of RAPA on recombinant dystrophin expression was complex because of an effect of PLGA microparticles.National Institutes of Health (U.S.) (F31-NS056780-01A2)National Center for Research Resources (U.S.) (KL2 RR024154)United States. Army Medical Research and Materiel Command (grant W81XWH-05-1-0334