Parametric Optimization Of Magneto-Rheological Fluid Damper Using Particle Swarm Optimization

This paper presents a parametric modeling of a magneto-rheological (MR) damper using a Particle Swarm Optimization (PSO) method. The objective of this paper is to optimize the parameter values of the MR fluid damper behavior using the Bouc-Wen model. The parametric identification was imposed beforehand in replicating the behavior of the MR fluid damper. The algebraic function from a number of hysteresis models was steered by comparing selected models: Bingham, Bouc-Wen and BoucWen by Kwok. A simulation method was operated in investigating these models by employing MATLAB reliant from the model intricacy. The experimental data was presented in terms of the time histories of the displacement, the velocity and the force parameters, measured for both constant and variable current settings and at a selected frequency applied to the damper. The model parameters were determined using a set of experimental measurements corresponding to different current constant values. It has been shown that the MR damper model’s response via the proposed approach is in good agreement with the MR damper test rig counterpar

Collateral Damage of Nonhematopoietic Tissue by Hematopoiesis-Specific T Cells Results in Graft-versus-Host Disease During an Ongoing Profound Graft-versus-Leukemia Reaction

AbstractAfter allogeneic stem cell transplantation (allo-SCT), donor T cells may recognize minor histocompatibility antigens (MiHA) specifically expressed on cells of the recipient. It has been hypothesized that T cells recognizing hematopoiesis-restricted MiHA mediate specific graft-versus-leukemia (GVL) activity without inducing graft-versus-host disease (GVHD), whereas T cells recognizing ubiquitously expressed MiHA induce both GVL and GVHD reactivity. It also has been hypothesized that alloreactive CD4 T cells are capable of mediating specific GVL reactivity due to the hematopoiesis-restricted expression of HLA class II. However, clinical observations suggest that an overt GVL response, associated with expansion of T cells specific for hematopoiesis-restricted antigens, is often associated with GVHD reactivity. Therefore, we developed in vitro models to investigate whether alloreactive T cells recognizing hematopoiesis-restricted antigens induce collateral damage to surrounding nonhematopoietic tissues. We found that collateral damage to MiHA-negative fibroblasts was induced by misdirection of cytotoxic granules released from MiHA-specific T cells activated by MiHA-positive hematopoietic cells, resulting in granzyme-B–mediated activation of apoptosis in the surrounding fibroblasts. We demonstrated that direct contact between the activated T cell and the fibroblast is a prerequisite for this collateral damage to occur. Our data suggest that hematopoiesis-restricted T cells actively participate in an overt GVL response and may contribute to GVHD via induction of collateral damage to nonhematopoietic targets

Double Umbilical Cord Blood Transplantation in High-Risk Hematological Patients: A Phase II Study Focusing on the Mechanism of Graft Predominance

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Class I major histocompatibility complexes loaded by a periodate trigger

Class I major histocompatibility complexes (MHCs) present peptide ligands on the cell surface for recognition by appropriate cytotoxic T cells. The unstable nature of unliganded MHC necessitates the production of recombinant class I complexes through in vitro refolding reactions in the presence of an added excess of peptides. This strategy is not amenable to high-throughput production of vast collections of class I complexes. To address this issue, we recently designed photocaged MHC ligands that can be cleaved by a UV light trigger in the MHC bound state under conditions that do not affect the integrity of the MHC structure. The results obtained with photocaged MHC ligands demonstrate that conditional MHC ligands can form a generally applicable concept for the creation of defined peptide−MHCs. However, the use of UV exposure to mediate ligand exchange is unsuited for a number of applications, due to the lack of UV penetration through cell culture systems and due to the transfer of heat upon UV irradiation, which can induce evaporation. To overcome these limitations, here, we provide proof-of-concept for the generation of defined peptide−MHCs by chemical trigger-induced ligand exchange. The crystal structure of the MHC with the novel chemosensitive ligand showcases that the ligand occupies the expected binding site, in a conformation where the hydroxyl groups should be reactive to periodate. We proceed to validate this technology by producing peptide−MHCs that can be used for T cell detection. The methodology that we describe here should allow loading of MHCs with defined peptides in cell culture devices, thereby permitting antigen-specific T cell expansion and purification for cell therapy. In addition, this technology will be useful to develop miniaturized assay systems for performing high-throughput screens for natural and unnatural MHC ligands

High-Throughput Identification of Potential Minor Histocompatibility Antigens by MHC Tetramer-Based Screening: Feasibility and Limitations

T-cell recognition of minor histocompatibility antigens (MiHA) plays an important role in the graft-versus-tumor (GVT) effect of allogeneic stem cell transplantation (allo-SCT). However, the number of MiHA identified to date remains limited, making clinical application of MiHA reactive T-cell infusion difficult. This study represents the first attempt of genome-wide prediction of MiHA, coupled to the isolation of T-cell populations that react with these antigens. In this unbiased high-throughput MiHA screen, both the possibilities and pitfalls of this approach were investigated. First, 973 polymorphic peptides expressed by hematopoietic stem cells were predicted and screened for HLA-A2 binding. Subsequently a set of 333 high affinity HLA-A2 ligands was identified and post transplantation samples from allo-SCT patients were screened for T-cell reactivity by a combination of pMHC-tetramer-based enrichment and multi-color flow cytometry. Using this approach, 71 peptide-reactive T-cell populations were generated. The isolation of a T-cell line specifically recognizing target cells expressing the MAP4K1IMA antigen demonstrates that identification of MiHA through this approach is in principle feasible. However, with the exception of the known MiHA HMHA1, none of the other T-cell populations that were generated demonstrated recognition of endogenously MiHA expressing target cells, even though recognition of peptide-loaded targets was often apparent

Kant's conception of proper science

Kant is well known for his restrictive conception of proper science. In the present paper I will try to explain why Kant adopted this conception. I will identify three core conditions which Kant thinks a proper science must satisfy: systematicity, objective grounding, and apodictic certainty. These conditions conform to conditions codified in the Classical Model of Science. Kant's infamous claim that any proper natural science must be mathematical should be understood on the basis of these conditions. In order to substantiate this reading, I will show that only in this way it can be explained why Kant thought (1) that mathematics has a particular foundational function with respect to the natural sciences and (2) as such secures their scientific status. © 2009 The Author(s)

M-CSF Signals through the MAPK/ERK Pathway via Sp1 to Induce VEGF Production and Induces Angiogenesis In Vivo

BACKGROUND: M-CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors. VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation. Previously, we reported that in vitro M-CSF induces the expression of biologically-active VEGF from human monocytes. METHODOLOGY AND RESULTS: In this study, we demonstrate the molecular mechanism of M-CSF-induced VEGF production. Using a construct containing the VEGF promoter linked to a luciferase reporter, we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M-CSF stimulation. Further analysis revealed that M-CSF induced VEGF through the MAPK/ERK signaling pathway via the transcription factor, Sp1. Thus, inhibition of either ERK or Sp1 suppressed M-CSF-induced VEGF at the mRNA and protein level. M-CSF also induced the nuclear localization of Sp1, which was blocked by ERK inhibition. Finally, mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M-CSF-treated human monocytes. To evaluate the biological significance of M-CSF induced VEGF production, we used an in vivo angiogenesis model to illustrate the ability of M-CSF to recruit mononuclear phagocytes, increase VEGF levels, and enhance angiogenesis. Importantly, the addition of a neutralizing VEGF antibody abolished M-CSF-induced blood vessel formation. CONCLUSION: These data delineate an ERK- and Sp1-dependent mechanism of M-CSF induced VEGF production and demonstrate for the first time the ability of M-CSF to induce angiogenesis via VEGF in vivo

The European Hematology Association Roadmap for European Hematology Research: a consensus document

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients

The European Hematology Association Roadmap for European Hematology Research. A Consensus Document

Abstract The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at Euro 23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. Received December 15, 2015. Accepted January 27, 2016. Copyright © 2016, Ferrata Storti Foundatio