31 research outputs found
Topology Optimization in Mechanical Engineering: Implementation and practical aspects
No full textOne of the most applied optimization methods in mechanical engineering is topology optimization (TO). The benefits of its integration in the product development process are several, such as reducing material usage in manufacturing, shortening the design cycle, and enhancing product quality. However, the implementation of TO is characterized by the following bottlenecks: the geometrical complexity of its optimized designs, the long optimization times, the sensitivity of its results to the given parameters, and the need for numerous inputs during its workflow. All these issues make TO a complex and time-demanding procedure dependent on designers’ starting guesses and choices during its implementation. It is clear that there is a need for a more automatic and effective optimization procedure.
In this thesis, the author uses TO for the weight reduction of structures in mechanical engineering. First, he explores the workflow of the TO and identifies interesting practical aspects in its implementation. The most popular TO-methods, such as SIMP and BESO, are described, categorized, and compared. In addition, the three following TO-practices are developed with respect to the size of the available design space for optimization: TO with limited design space, TO with maximum possible design space, and combined size/shape/topology optimization. The author states that the designer’s choices (inputs) affect the TO-results and categorizes them into five clusters of parameters: design constraints, supports and connections, loads, geometric restrictions due to manufacturing constraints, and software constraints. The sensitivity of the TO-results to the variations of these parameters is explored.
Furthermore, different multi-objective, multi-level, and multi-scale optimization workflows are used in the pursuit of the lightest design solutions. To identify the software constraints, a literature review is conducted among the most applied TO-software platforms. As a result, an online library of 70 commercial and open source TO software is developed in the form of a table. This table encompasses the name, company, optimization types, and methods that software uses, as well as its available objective functions and constraints in TO. Moreover, relative research works and representative literature for each software are included. Different 3D models are designed, optimized, and used as case studies to support the theory and tie the academic text to real-world applications of TO. Finally, the educational perspective of TO is checked. The author developed an educational framework of a topology optimization-based learning (TOBL) combining the CDIO-approach and TO. The implementation of the developed TOBL-framework in any study program in CAD-engineering can educate modern CAD-designers to conceive, design, implement, and operate optimized products.
The current research work is addressed to practitioners, researchers, teachers, and other engineers looking for new lightweight design concepts. Hence, the aim of this thesis is to provide them, through valuable insights, with a better understanding of TO, as well as to advise them with guidelines and recommendations to avoid common pitfalls
Lck is required for stromal cell–derived factor 1α (CXCL12)–induced lymphoid cell chemotaxis
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Reduced Cbl phosphorylation and degradation of the ζ-chain of the T-cell receptor/CD3 complex in T cells with low Lck levels
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Selective Activation of cAMP-dependent Protein Kinase Type I Inhibits Rat Natural Killer Cell Cytotoxicity
No full textT Cell-Signaling Network Analysis Reveals Distinct Differences between CD28 and CD2 Costimulation Responses in Various Subsets and in the MAPK Pathway between Resting and Activated Regulatory T Cells
No full textAbstract
To uncover signaling system differences between T cell stimuli and T cell subsets, phosphorylation status of 18 signaling proteins at six different time points following TCR triggering and CD28/CD2 costimulation was examined in human T cell subsets by phospho-epitope–specific flow cytometry of fluorescent cell barcoded samples, thereby providing a high-resolution signaling map. Compared with effector/memory T cells, naive T cells displayed stronger activation of proximal signaling molecules after TCR triggering alone. Conversely, distal phosphorylation events, like pErk and pS6-ribosomal protein, were stronger in effector/memory subsets. CD28 costimulation specifically induced signaling necessary for proper NF-κB activation, whereas CD2 signaled more strongly to S6-ribosomal protein. Analysis of resting regulatory T cells (rTregs; CD4+CD45RA+FOXP3+) and activated regulatory T cells (actTregs; CD4+CD45RA−FOXP3++) revealed that, although rTregs had low basal, but inducible, Erk activity, actTregs displayed high basal Erk phosphorylation and little or no Akt activation. Interestingly, the use of Mek inhibitors to block Erk activation inhibited activation-dependent FOXP3 upregulation in rTregs, their transition to actTregs, and the resulting increase in suppressive capacity. In summary, our systems approach unraveled distinct differences in signaling elicited by CD28 and CD2 costimulation and between rTregs and actTregs. Blocking rTreg transition to highly suppressive actTregs by Mek inhibitors might have future therapeutic applications.</jats:p
Docking of PRAK/MK5 to the atypical MAPKs ERK3 and ERK4 defines a novel MAPK interaction motif
No full textERK3 and ERK4 are atypical MAPKs in which the canonical TXY motif within the activation loop of the classical MAPKs is replaced by SEG. Both ERK3 and ERK4 bind, translocate, and activate the MAPK-activated protein kinase (MK) 5. The classical MAPKs ERK1/2 and p38 interact with downstream MKs (RSK1-3 and MK2-3, respectively) through conserved clusters of acidic amino acids, which constitute the common docking (CD) domain. In contrast to the classical MAPKs, the interaction between ERK3/4 and MK5 is strictly dependent on phosphorylation of the SEG motif of these kinases. Here we report that the conserved CD domain is dispensable for the interaction of ERK3 and ERK4 with MK5. Using peptide overlay assays, we have defined a novel MK5 interaction motif (FRIEDE) within both ERK4 and ERK3 that is essential for binding to the C-terminal region of MK5. This motif is located within the L16 extension lying C-terminal to the CD domain in ERK3 and ERK4 and a single isoleucine to lysine substitution in FRIEDE totally abrogates binding, activation, and translocation of MK5 by both ERK3 and ERK4. These findings are the first to demonstrate binding of a physiological substrate via this region of the L16 loop in a MAPK. Furthermore, the link between activation loop phosphorylation and accessibility of the FRIEDE interaction motif suggests a switch mechanism for these atypical MAPKs in which the phosphorylation status of the activation loop regulates the ability of both ERK3 and ERK4 to bind to a downstream effector
