To model dynamic expression patterns in somitogenesis we developed a Java-application for simulating gene regulatory networks in many cells in parallel and visualising the results using the Java3D API, thus simulating the collective behaviour of many thousand cells. According to the 'clock-and-wave-front' model mesodermal segmentation of vertebrate embryos is regulated by a 'segmentation clock', which oscillates with a period of about 2h in mice, and a 'wave front' moving back with the growing caudal end of the presomitic mesoderm. The clock is realised through cycling expression of genes such as Hes1 and Hes7, whose gene products repress the transcription of their encoding genes in a negative feedback loop. By coupling the decay of the Hes1 mRNA to a gradient with the same features and mechanism of formation as the mesodermal Fgf8 gradient we can simulate typical features of the dynamic expression pattern of Hes1 in the presomitic mesoderm. Furthermore, our program is able to synchronise Hes1 oscillations in thousands of cells through simulated Delta-Notch signalling interactions.

The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice.

Background: It is commonly accepted that embryonic segmentation of vertebrates is regulated by a segmentation clock, which is induced by the cycling genes Hes1 and Hes7. Their products form dimers that bind to the regulatory regions and thereby repress the transcription of their own encoding genes. An increase of the half-life of Hes7 protein causes irregular somite formation. This was shown in recent experiments by Hirata et al. In the same work, numerical simulations from a delay differential equations model, originally invented by Lewis, gave additional support. For a longer half-life of the Hes7 protein, these simulations exhibited strongly damped oscillations with, after few periods, severely attenuated the amplitudes. In these simulations, the Hill coefficient, a crucial model parameter, was set to 2 indicating that Hes7 has only one binding site in its promoter. On the other hand, Bessho et al. established three regulatory elements in the promoter region.

Introduction Periprosthetic fractures of the femur are an increasing problem in today's trauma and orthopaedic surgery. Owing to the hip stem, implant anchorage is very difficult in the proximal femur. This study compares two plate systems regarding their biomechanical properties and the handling in periprosthetic fracture fixation of the proximal femur. Materials and methods Using eight pairs of fresh, frozen human proximal femora the Locking Compression Plate/Locking Attachment Plate construct (LCP/LAP) (group I, DePuy Synthes) was compared to the new LOQTEQ® periprosthetic distal lateral femur plate (group II, AAP Implantate AG). After implantation of press fit femoral hip stems a Vancouver B1 fracture model was used. Biomechanical testing was performed by cyclic axial loading with a constant increment of 0.1 N/cycle starting from 750 N axial loading. Every 250 cycles an a.p. x-ray was done to evaluate failure. Results The Group II showed significant higher axial stiffness (+42%) compared with Group I. In addition, Group II withstood significantly more load-cycles until failure (20%). The mode of catastrophic failure was plate breakage in Group II, whereas, in Group I, all plates showed an early bending followed by plate breakage. Discussion and conclusion Both plate systems enable screw placement around hip stems. The hinge plate showed superior biomechanical results compared with the locking compression plate/locking attachment plate construct. Furthermore, the hinge plate offers variable hinges and variable angel locking making bicortical screw placement around hip stems more comfortable and safe. The translational potential of this article The results of this study can be directly transferred to patient care. With the innovative hinge plate, the surgeon has a biomechanically superior implant, which also offers improved options for screw placement compared to a standard locking plate.

During pancreas development, Neurog3 positive endocrine progenitors are specified by Delta/Notch (D/N) mediated lateral inhibition in the growing ducts. During neurogenesis, genes that determine the transition from the proneural state to neuronal or glial lineages are oscillating before their expression is sustained. Although the basic gene regulatory network is very similar, cycling gene expression in pancreatic development was not investigated yet, and previous simulations of lateral inhibition in pancreas development excluded by design the possibility of oscillations. To explore this possibility, we developed a dynamic model of a growing duct that results in an oscillatory phase before the determination of endocrine progenitors by lateral inhibition. The basic network (D/N + Hes1 + Neurog3) shows scattered, stable Neurog3 expression after displaying transient expression. Furthermore, we included the Hes1 negative feedback as previously discussed in neurogenesis and show the consequences for Neurog3 expression in pancreatic duct development. Interestingly, a weakened HES1 action on the Hes1 promoter allows the coexistence of stable patterning and oscillations. In conclusion, cycling gene expression and lateral inhibition are not mutually exclusive. In this way, we argue for a unified mode of D/N mediated lateral inhibition in neurogenic and pancreatic progenitor specification.