Numerical solution of perfect plastic problems with contact: part II - numerical realization

This contribution is a continuation of our contribution denoted as PART I, where the discretized contact problem for elasto-perfectly plastic bodies was studied and suitable numerical methods were introduced. In particular, frictionless contact boundary conditions and Hencky’s material model with the von Mises criterion are considered. Here we describe some implementation details and present several numerical examples

Numerical solution of perfect plastic problems with contact: part I - theory and numerical methods

The contribution deals with a static case of discretized elasto-perfectly plastic problems obeying Hencky’s law in combination with frictionless contact boundary conditions. The main interest is focused on the analysis of the formulation in terms of displacements, limit load analysis and related numerical methods. This covers the study of: i) the dependence of the solution set on the loading parameter ζ, ii) relation between ζ and the parameter α representing the work of external forces, iii) loading process controlled by ζ and by α, iv) numerical methods for solving problems with prescribed value of ζ and α

An improved return-mapping scheme for nonsmooth yield surfaces: PART I - the Haigh-Westergaard coordinates

The paper is devoted to the numerical solution of elastoplastic constitutive initial value problems. An improved form of the implicit return-mapping scheme for nonsmooth yield surfaces is proposed that systematically builds on a subdifferential formulation of the flow rule. The main advantage of this approach is that the treatment of singular points, such as apices or edges at which the flow direction is multivalued involves only a uniquely defined set of non-linear equations, similarly to smooth yield surfaces. This paper (PART I) is focused on isotropic models containing: $a)$ yield surfaces with one or two apices (singular points) laying on the hydrostatic axis; $b)$ plastic pseudo-potentials that are independent of the Lode angle; $c)$ nonlinear isotropic hardening (optionally). It is shown that for some models the improved integration scheme also enables to a priori decide about a type of the return and investigate existence, uniqueness and semismoothness of discretized constitutive operators in implicit form. Further, the semismooth Newton method is introduced to solve incremental boundary-value problems. The paper also contains numerical examples related to slope stability with available Matlab implementation.Comment: 25 pages, 10 figure

Parameter identification of chaboche material model using indantation test data and inverse approach

In this paper genetic algorithm and sensitivity analysis are used to identify 6 parameters of Chaboche kinematic hardening model using repeated Finite element (FE) simulations of indentation test. Five of them are material constants of Chaboche kinematic hardening model itself. The last one represents the stiffness of the foundation and the indenter. To obtain experimental data indentation test under cyclic loading on universal tensile testing machine was performed. Because for sensitivity analysis to obtain all possible combinations of parameters and its values large number of simulation have to be performed supercomputer Anselm hosted by IT4Innovation has been used. Advantage of using supercomputer is that every simulation could use multiple cores which will reduce computational time. Moreover, since each simulation is independent, computational time could be further reduced by performing multiple simulations at the same time. It is clear from the comparison of both methods that the genetic algorithm is very good choice for the parameter estimation

Differential Expression of MicroRNAs in CD34+ Cells of 5q- Syndrome

<p>Abstract</p> <p>Background</p> <p>Myelodysplastic syndrome with isolated chromosome 5q deletion (5q- syndrome) is a clonal stem cell disorder characterized by ineffective hematopoiesis. MicroRNAs (miRNAs) are important regulators of hematopoiesis and their aberrant expression was detected in some clonal hematopoietic disorders. We thus analyzed miRNA expressions in bone marrow CD34+ cells of 5q- syndrome patients. Further, we studied gene expressions of <it>miR-143</it>, <it>miR-145</it>, <it>miR-378 </it>and <it>miR-146a </it>mapped within the 5q deletion.</p> <p>Results</p> <p>Using microarrays we identified 21 differently expressed miRNAs in 5q- patients compared to controls. Especially, <it>miR-34a </it>was markedly overexpressed in 5q- patients, suggesting its role in an increased apoptosis of bone marrow progenitors. Out of four miRNAs at del(5q), only <it>miR-378 </it>and <it>miR-146a </it>showed reduced gene expression in the patients. An integrative analysis of mRNA profiles and predicted putative targets defined potential downstream targets of the deregulated miRNAs. The list of targets included several genes that play an important role in the regulation of hematopoiesis (e.g. <it>KLF4</it>, <it>LEF1</it>, <it>SPI1</it>).</p> <p>Conclusions</p> <p>The study demonstrates global overexpression of miRNAs is associated with 5q- phenotype. Identification of hematopoiesis-relevant target genes indicates that the deregulated miRNAs may be involved in the pathogenesis of 5q- syndrome by a modulation of these targets. The expression data on miRNAs at del(5q) suggest the presence of mechanisms for compensation of a gene dosage.</p

BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations

A transition from fetal hemoglobin (HbF) to adult hemoglobin (HbA) normally occurs within a few months after birth. Increased production of HbF after this period of infancy ameliorates clinical symptoms of the major disorders of adult ß-hemoglobin: ß-thalassemia and sickle cell disease. The transcription factor BCL11A silences HbF and has been an attractive therapeutic target for increasing HbF levels; however, it is not clear to what extent BCL11A inhibits HbF production or mediates other developmental functions in humans. Here, we identified and characterized 3 patients with rare microdeletions of 2p15-p16.1 who presented with an autism spectrum disorder and developmental delay. Moreover, these patients all exhibited substantial persistence of HbF but otherwise retained apparently normal hematologic and immunologic function. Of the genes within 2p15-p16.1, only BCL11A was commonly deleted in all of the patients. Evaluation of gene expression data sets from developing and adult human brains revealed that BCL11A expression patterns are similar to other genes associated with neurodevelopmental disorders. Additionally, common SNPs within the second intron of BCL11A are strongly associated with schizophrenia. Together, the study of these rare patients and orthogonal genetic data demonstrates that BCL11A plays a central role in silencing HbF in humans and implicates BCL11A as an important factor for neurodevelopment

Labile plasma iron levels predict survival in patients with lower-risk Myelodysplastic syndromes

Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion dependent patient groups. Hepcidin levels significantly decreased over time in transfusion independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion dependent patient groups. Detectable labile plasma iron levels in transfusion dependent patients without ringed sideroblasts were associated with decreased survival. IN CONCLUSION: toxic iron species occurred in all transfusion dependent patients and in transfusion independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion dependent patients. This trial was registered at www.clinicaltrials.gov as #NCT00600860

Toxic iron species in lower-risk myelodysplastic syndrome patients : course of disease and effects on outcome

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Prognostic impact of a suboptimal number of analyzed metaphases in normal karyotype lower-risk MDS

Conventional karyotype is one of the most relevant prognostic factors in MDS. However, about 50% of patients with MDS have a normal karyotype. Usually, 20-25 normal metaphases (nMP) are considered to be optimal to exclude small abnormal clones which might be associated with poor prognosis. This study evaluated the impact of examining a suboptimal number of metaphases in patients recruited to the EUMDS Registry with low and intermediate-1 risk according to IPSS. Only 179/1049 (17%) of patients with a normal karyotype had a suboptimal number of nMP, defined as less than 20 metaphases analyzed. The outcome (overall survival and progression-free survival) of patients with suboptimal nMP was not inferior to those with higher numbers of analyzed MP both in univariate and multivariate analyses. For patients with an abnormal karyotype, 224/649 (35%) had a suboptimal number of MP assessed, but this did not impact on outcome. For patients with a normal karyotype and suboptimal numbers of analyzable metaphases standard evaluation might be acceptable for general practice, but we recommend additional FISH-analyses or molecular techniques, especially in candidates for intensive interventions

Time-dependent changes in mortality and transformation risk in MDS

In myelodysplastic syndromes (MDSs), the evolution of risk for disease progression or death has not been systematically investigated despite being crucial for correct interpretation of prognostic risk scores. In a multicenter retrospective study, we described changes in risk over time, the consequences for basal prognostic scores, and their potential clinical implications. Major MDS prognostic risk scoring systems and their constituent individual predictors were analyzed in 7212 primary untreated MDS patients from the International Working Group for Prognosis in MDS database. Changes in risk of mortality and of leukemic transformation over time from diagnosis were described. Hazards regarding mortality and acute myeloid leukemia transformation diminished over time from diagnosis in higher-risk MDS patients, whereas they remained stable in lower-risk patients. After approximately 3.5 years, hazards in the separate risk groups became similar and were essentially equivalent after 5 years. This fact led to loss of prognostic power of different scoring systems considered, which was more pronounced for survival. Inclusion of age resulted in increased initial prognostic power for survival and less attenuation in hazards. If needed for practicability in clinical management, the differing development of risks suggested a reasonable division into lower- and higher-risk MDS based on the IPSS-R at a cutoff of 3.5 points. Our data regarding time-dependent performance of prognostic scores reflect the disparate change of risks in MDS subpopulations. Lower-risk patients at diagnosis remain lower risk whereas initially high-risk patients demonstrate decreasing risk over time. This change of risk should be considered in clinical decision making