The Effect of Axial Compression and Distraction on Cervical Facet Cartilage Apposition During Shear and Bending Motions

During cervical spine trauma, complex intervertebral motions can cause a reduction in facet joint cartilage apposition area (CAA), leading to cervical facet dislocation (CFD). Intervertebral compression and distraction likely alter the magnitude and location of CAA, and may influence the risk of facet fracture. The aim of this study was to investigate facet joint CAA resulting from intervertebral distraction (2.5 mm) or compression (50, 300 N) superimposed on shear and bending motions. Intervertebral and facet joint kinematics were applied to multi rigid-body kinematic models of twelve C6/C7 motion segments (70 ± 13 year, nine male) with specimen-specific cartilage profiles. CAA was qualitatively and quantitatively compared between distraction and compression conditions for each motion; linear mixed-effects models (a = 0.05) were applied. Distraction significantly decreased CAA throughout all motions, compared to the compressed conditions (p<0.001), and shifted the apposition region towards the facet tip. These observations were consistent bilaterally for both asymmetric and symmetric motions. The results indicate that axial neck loads, which are altered by muscle activation and head loading, influences facet apposition. Investigating CAA in longer cervical spine segments subjected to quasistatic or dynamic loading may provide insight into dislocation and fracture mechanisms.Ryan D. Quarrington, Darcy W. Thompson-Bagsshaw and Claire F. Jone

Src homology 2 domain containing protein 5 (SH2D5) binds the breakpoint cluster region protein, BCR, and regulates levels of Rac1-GTP

SH2D5 is a mammalian-specific, uncharacterized adaptor-like protein that contains an N-terminal phosphotyrosine binding (PTB) domain and a C-terminal Src Homology 2 (SH2) domain. We show that SH2D5 is highly enriched in adult mouse brain, particularly in purkinjie cells in the cerebellum and the cornu ammonis of the hippocampus. Despite harboring two potential phosphotyrosine (pTyr) recognition domains, SH2D5 binds minimally to pTyr ligands, consistent with the absence of a conserved pTyr-binding arginine residue in the SH2 domain. Immunoprecipitation coupled to mass spectrometry (IP-MS) from cultured cells revealed a prominent association of SH2D5 with Breakpoint Cluster Region protein (BCR), a RacGAP that is also highly expressed in brain. This interaction occurred between the PTB domain of SH2D5 and an NxxF motif located within the N-terminal region of BCR. siRNA-mediated depletion of SH2D5 in a neuroblastoma cell line, B35, induced a cell rounding phenotype correlated with low levels of activated Rac1-GTP, suggesting that SH2D5 affects Rac1-GTP levels. Taken together, our data provide the first characterization of the SH2D5 signaling protein

The Structural Response of the Human Head to a Vertex Impact.

OnlinePublIn experimental models of cervical spine trauma caused by near-vertex head-first impact, a surrogate headform may be substituted for the cadaveric head. To inform headform design and to verify that such substitution is valid, the force-deformation response of the human head with boundary conditions relevant to cervical spine head-first impact models is required. There are currently no biomechanics data that characterize the force-deformation response of the isolated head supported at the occiput and compressed at the vertex by a flat impactor. The effect of impact velocity (1, 2 or 3 m/s) on the response of human heads (N = 22) subjected to vertex impacts, while supported by a rigid occipital mount, was investigated. 1 and 2 m/s impacts elicited force-deformation responses with two linear regions, while 3 m/s impacts resulted in a single linear region and skull base ring fractures. Peak force and stiffness increased from 1 to 2 and 3 m/s. Deformation at peak force and absorbed energy increased from 1 to 2 m/s, but decreased from 2 to 3 m/s. The data reported herein enhances the limited knowledge on the human head's response to a vertex impact, which may allow for validation of surrogate head models in this loading scenario.Darcy W. Thompson, Bagshaw, Ryan D. Quarrington, Andrew M. Dwyer, Nigel R. Jones, Claire F. Jone

Protein interaction network of the mammalian hippo pathway reveals mechanisms of kinase-phosphatase interactions

10.1126/scisignal.2004712Science Signaling6302rs15

Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions

Rho GTPases are central regulators of the cytoskeleton and, in humans, are controlled by 145 multidomain guanine nucleotide exchange factors (RhoGEFs) and GTPase-activating proteins (RhoGAPs). How Rho signalling patterns are established in dynamic cell spaces to control cellular morphogenesis is unclear. Through a family-wide characterization of substrate specificities, interactomes and localization, we reveal at the systems level how RhoGEFs and RhoGAPs contextualize and spatiotemporally control Rho signalling. These proteins are widely autoinhibited to allow local regulation, form complexes to jointly coordinate their networks and provide positional information for signalling. RhoGAPs are more promiscuous than RhoGEFs to confine Rho activity gradients. Our resource enabled us to uncover a multi-RhoGEF complex downstream of G-protein-coupled receptors controlling CDC42-RHOA crosstalk. Moreover, we show that integrin adhesions spatially segregate GEFs and GAPs to shape RAC1 activity zones in response to mechanical cues. This mechanism controls the protrusion and contraction dynamics fundamental to cell motility. Our systems analysis of Rho regulators is key to revealing emergent organization principles of Rho signalling