Optimal Control for a Pitcher's Motion Modeled as Constrained Mechanical System

In this contribution, a recently developed optimal control method for constrained mechanical systems is applied to determine optimal motions and muscle force evolutions for a pitcher's arm. The method is based on a discrete constrained version of the Lagrange-d'Alembert principle leading to structure preserving time-stepping equations. A reduction technique is used to derive the nonlinear equality constraints for the minimization of a given objective function. Different multi-body models for the pitcher's arm are investigated and compared with respect to the motion itself, the control effort, the pitch velocity, and the pitch duration time. In particular, the use of a muscle model allows for an identification of limits on the maximal forces that ensure more realistic optimal pitch motions

Dendritic cell-specific deletion of β-catenin results in fewer regulatory T-cells without exacerbating autoimmune collagen-induced arthritis

Dendritic cells (DCs) are professional antigen presenting cells that have the dual ability to stimulate immunity and maintain tolerance. However, the signalling pathways mediating tolerogenic DC function in vivo remain largely unknown. The β-catenin pathway has been suggested to promote a regulatory DC phenotype. The aim of this study was to unravel the role of β-catenin signalling to control DC function in the autoimmune collagen-induced arthritis model (CIA). Deletion of β-catenin specifically in DCs was achieved by crossing conditional knockout mice with a CD11c-Cre transgen

Ablation of β-catenin did not influence the maturation and activation of BMDCs.

<p>BMDCs were cultured in the presence of GM-CSF for 10 days, and either left unstimulated (spontaneous maturation), treated with LPS (1 ng/ml), or (chicken) CII (50 μg/ml) or LPS and CII (50 μg/ml; 1 ng/ml respectively) (A, B) or with <i>Mycobacterium tuberculosis</i> (MTB, 25 μg/ml) (C, D). Twenty-four hours after stimulation, BMDCs were collected and analysed by flow cytometry for their maturation status. The levels of β-catenin, co-stimulatory molecules (CD40, CD80, CD86), the co-inhibitory molecule PD-L2 were measured in CD11c⁺ BMDCs derived from control and β-cat^DEL mice. Levels of cytokines associated with tolerance (IL-10) and T cell skewing (IL-23, IL12p70 and IL-6) were determined by ELISA of the supernatants of control and β-cat^DEL BMDCs, left unstimulated or pulsed with CII and LPS (E) Or of the supernatants from BMDCs, left unstimulated or stimulated with MTB (F). All culture conditions were performed in triplicates. Data are representative of two to three independent experiments (<i>n</i> = 6–9 mice/group). Data on (B and D) were analysed by one-way ANOVA followed by a Bonferroni post-test and data on (E and F) was analysed by Mann-Whitney <i>U</i> test. Data are presented as mean ± SEM. <i>*p< 0</i>.<i>05; **p<0</i>.<i>01; ***p<0</i>.<i>001</i>. N.d. Not detectable.</p

β-catenin deletion in DCs did not affect the cytokine production by CD4⁺ T cells in the steady state or during CIA.

<p>Representative FACS plots illustrating the pro-inflammatory cytokines IFNγ, IL-4, IL-17A and anti-inflammatory IL-10 produced by CD4⁺ T cells isolated from spleens of steady-state (left panel, n = 8 mice per group) and CIA (right panel, n = 10 mice per group) mice, on day 35 after the first immunization. Cells were stimulated for 4 hours with phorbolmyristate acetate (PMA) (0.05 μg/ml) and ionomycin (0.5 μg/ml) in the presence of GolgiStop. The frequencies of the different cytokine-secreting Th cells were similar in the β-cat^DEL and control groups in both conditions. Data are presented as mean ± SEM.</p

Ablation of β-catenin in DCs downregulates Tregs during CIA but not under steady state condition.

<p>Representative FACS plots of Tregs (CD4⁺CD62L^-CD25^highFoxP3⁺) isolated from splenocytes from control and β-cat^DEL mice in the steady state and subjected to CIA (35 days after the first immunization) (A). Bar diagrams depicting the frequency of Tregs, expressed as the percentage of effector T cells (CD4⁺CD62L^-), in control and β-cat^DEL groups in the steady state (n = 6 mice per group, left) and in mice subjected to CIA (n = 10 mice per group, right) (B). While in the steady state no differences in the percentage of Tregs were found between the two groups (control = 13.41% ± 4.624 versus β-cat^DEL = 13.31% ± 2.188, <i>p = 0</i>.<i>9372)</i>, in the CIA mice we observed a reduction of 20% in the β-cat^DEL compared to the control group (control = 12.93% ± 0.5691 versus β-cat^DEL = 10.21% ± 0.9003, <i>p = 0</i>.<i>0435)</i>. Data are presented as mean + SEM. Asterisks indicate a significant difference compared with the control (Mann-Whitney <i>U</i> test). <i>*p< 0</i>.<i>05</i>.</p

Serum levels of CII-specific antibodies in CIA mice.

<p>Enzyme-linked immunosorbent assay (ELISA) of chicken and mouse CII-specific IgG1, IgG2c, or total IgG in the serum of β-cat^DEL mice and control littermates at days 14 and 35 after initial immunization (n = 10 mice per group). Data are presented as mean + SEM.</p