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This paper explores the adaptation of pseudo-rigid-body models (PRBMs) for simulating large geometric nonlinear deflections in passive exoskeletons, expanding upon their traditional application in small compliant systems. Utilizing the AnyBody modeling system, this study employs force-dependent kinematics to reverse the conventional simulation process, enabling the calculation of forces from the deformation of PRBMs. A novel approach, termed “Constraint Force”, is introduced to facilitate this computation. The approach is thoroughly validated through comparative analysis with laboratory trials involving a beam under bending loads. To demonstrate the functionality, the final segment of this study conducts a biomechanical simulation incorporating motion capture data from a lifting test, employing a novel passive exoskeleton equipped with flexible spring elements. The approach is meticulously described to enable easy adaptation, with an example code for practical application. The findings present a user-friendly and visually appealing simulation solution capable of effectively modeling complex mechanical load cases. However, the validation process highlights significant systematic errors in the direction and amplitude of the calculated forces (20% and 35%, respectively, in the worst loading case) compared to the laboratory results. These discrepancies emphasize the inherent accuracy challenges of the “Constraint Force” approach, pointing to areas for ongoing research and enhancement of PRBM methods.

The mesodiencephalic dopaminergic (mdDA) neurons, including the nigrostriatal subset that preferentially degenerates in Parkinson’s Disease (PD), strongly depend on an accurately balanced Wingless-type MMTV integration site family member 1 (WNT1)/beta-catenin signaling pathway during their development. Loss of this pathway abolishes the generation of these neurons, whereas excessive WNT1/b-catenin signaling prevents their correct differentiation. The identity of the cells responding to this pathway in the developing mammalian ventral midbrain (VM) as well as the precise progression of WNT/b-catenin action in these cells are still unknown. We show that strong WNT/b-catenin signaling inhibits the differentiation of WNT/b-catenin-responding mdDA progenitors into PITX3+ and TH+ mdDA neurons by repressing the Pitx3 gene in mice. This effect is mediated by RSPO2, a WNT/b-catenin agonist, and lymphoid enhancer binding factor 1 (LEF1), an essential nuclear effector of the WNT/b-catenin pathway, via conserved LEF1/T-cell factor binding sites in the Pitx3 promoter. LEF1 expression is restricted to a caudolateral mdDA progenitor subset that preferentially responds to WNT/b-catenin signaling and gives rise to a fraction of all mdDA neurons. Our data indicate that an attenuation of WNT/b-catenin signaling in mdDA progenitors is essential for their correct differentiation into specific mdDA neuron subsets. This is an important consideration for stem cell-based regenerative therapies and in vitro models of neuropsychiatric diseases.

The protracted and age-dependent degeneration of dopamine (DA)-producing neurons of the Substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in the mammalian midbrain is a hallmark of human Parkinson's Disease (PD) and of certain genetic mouse models of PD, such as mice heterozygous for the homeodomain transcription factor Engrailed 1 (En1+/− mice). Neurotoxin-based animal models of PD, in contrast, are characterized by the fast and partly reversible degeneration of the SNc and VTA DA neurons. The secreted protein WNT1 was previously shown to be strongly induced in the neurotoxin-injured adult ventral midbrain (VM), and to protect the SNc and VTA DA neurons from cell death in this context. We demonstrate here that the sustained and ectopic expression of Wnt1 in the SNc and VTA DA neurons of En1+/Wnt1 mice also protected these genetically affected En1 heterozygote (En1+/−) neurons from their premature degeneration in the adult mouse VM. We identified a developmental gene cascade that is up-regulated in the adult En1+/Wnt1 VM, including the direct WNT1/β-catenin signaling targets Lef1, Lmx1a, Fgf20 and Dkk3, as well as the indirect targets Pitx3 (activated by LMX1A) and Bdnf (activated by PITX3). We also show that the secreted neurotrophin BDNF and the secreted WNT modulator DKK3, but not the secreted growth factor FGF20, increased the survival of En1 mutant dopaminergic neurons in vitro. The WNT1-mediated signaling pathway and its downstream targets BDNF and DKK3 might thus provide a useful means to treat certain genetic and environmental (neurotoxic) forms of human PD.

An das landwirtschaftliche Wegenetz werden durch die kontinuierliche Größenentwicklung von Landmaschinen neue Anforderungen gestellt. Die Maschinen werden breiter und länger und besitzen mehr Achsen und komplexere Lenksysteme als in der Vergangenheit. Beim landwirtschaftlichen Wegebau hat dies insbesondere Auswirkungen auf die Planung der Kurven. In der Untersuchung wurden die Schleppkurven aktueller Landmaschinen aufgenommen und es wurde geprüft, ob sie mithilfe einer Software simuliert werden können. Dabei zeigt sich, dass die verwendete Simulationssoftware für die Bestimmung von Schleppkurven für Landmaschinen mit komplexen Lenksystemen hinreichend genau ist.