Mouton, C. | Search bioRxiv

bioRxiv2023

Image-based parametric finite element modelling for studying contact mechanics in human knee joints

PurposeThis study presents a framework for generating patient-specific finite element models, parameterised and optimised for contact mechanics from computed tomography (CT) scans, by avoiding the segmentation step usually employed to transform medical images into 3D models. Two morphological parameters affecting contact mechanics were investigated in the framework development: tibial cartilage thickness and tibial spine height. This study explores the effect of the interplay of these parameters in load sharing between meniscus and articulating cartilage, meniscal posterior and anterior roots strain and menisci kine-matics. MethodsMorphological measurements from four knee CT scans were collected, such as the maximum thickness of the tibial cartilage (ranging from 1.1 to 5.2 mm), the height of the tibial spine (ranging from 3.55 to 10.1 mm), and the width of the tibial plateau in both the coronal (ranging from 27.3 to 36.17 mm) and sagittal (ranging from 31.79 to 53.77 mm) planes. These measurements were taken for the lateral tibial plateau for both left and right knees. Subsequently, three finite element (FE) models were generated, comprising lateral tibial plateaus, lateral femoral condyle and lateral meniscus. The tibial cartilage thickness was kept at a constant value of 1 mm while varying the tibial spine height within the range measured from the CT images. This resulted in three FE models with varying spine heights, categorised as large (height = 7.42 mm), medium (height = 4.25 mm), and small (height = 1.63 mm) tibial spine heights. The menisci in the FE models were generated to be congruent with the tibial plateau. For the first time, this study advances the representations of the knee menisci microstructure in FE modelling, such that we have generated meniscus FE models with three layers of a hyperelastic model in which layer thickness and layer-specific hyperelastic material parameters are derived from our previous experimental work. ResultsThe load sharing between the meniscus and articular cartilage was not sensitive to the varying tibial spine heights. In all three FE models, cartilage carried more than 90% of the applied load. However, the meniscus kinematics and root strains varied considerably with changing tibial spine heights. The small tibial spine height model predicted the highest meniscus movements (8.12 and 9.33 mm in the radial and circumferential directions, respectively) and the highest root strain (21.92 and 22.19 mm/mm in the anterior and posterior roots, respectively). ConclusionOur framework can generate finite element models of patients knees using clinical data (i.e., CT scans) without the need for lengthy image segmentation. This process is not only time-efficient but also independent of imaging operators. The models converge quickly ({inverted question}30 minutes on 2 cores) using an implicit solver with non-linear geometry and have the capability to predict contact mechanics between the articulating surfaces, meniscus kinematics and root strains. The modelling strategy presented here can provide valuable insights into predicting changes in the mechanics of soft tissues in the knee joint. It is particularly useful for investigating injury and surgical mechanisms related to the meniscus.

bioengineering↗

bioRxiv2022

Constitutive Activation and Oncogenicity Are Mediated by Loss of Helical Structure at the Cytosolic Boundary of the Thrombopoietin Receptor

Dimerization of the thrombopoietin receptor (TpoR) is necessary for receptor activation and downstream signaling through activated Janus kinase 2. We have shown previously that different orientations of the transmembrane (TM) helices within a receptor dimer can lead to different signaling outputs. Here we addressed the structural basis of activation for receptor mutations S505N and W515K that induce myeloproliferative neoplasms. We show using in vivo bone marrow reconstitution experiments that ligand-independent activation of TpoR by TM asparagine (Asn) substitutions is proportional to the proximity of the mutation to the intracellular membrane surface. Solid-state NMR experiments on TM peptides indicate a progressive loss of helical structure in the juxtamembrane (JM) R/KWQFP motif with either proximity of Asn substitutions to the cytosolic boundary or mutation of W515 in the motif. Mutational studies in the TpoR cytosolic JM region show that the helical loss by itself can induce activation, but is localized to a maximum of 6 amino acids downstream of W515, the rest of the region until Box 1 requiring helicity for receptor function. The constitutive activation of TpoR mutants S505N and W515K can be inhibited by rotation of TM helices within the TpoR dimer, which also restores helicity around W515. Together these data allow us to develop a general model for activation and to explain the critical role of the JM W515 residue in the regulation of receptor activity. (Total manuscript without References and Figure Legends 6507 words, main text (without methods and materials):)

molecular biology↗

bioRxiv2020

A novel rare c. -39C>T mutation in the PROS1 5'UTR causing PS deficiency by creating a new upstream translation initiation codon and inhibiting the production of the natural protein.

Inherited Protein S deficiency (PSD) (MIM176880) is a rare automosal dominant disorder caused by rare mutations, mainly located in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism. To identify the molecular defect underlying PSD observed in an extended French pedigree with 7 PSD affected members in who no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via a MLPA approach, a whole genome sequencing strategy was adopted. This led to the identification of a never reported C to T substitution at c.-39 from the natural ATG codon of the PROS1 gene that completely segregates with PSD in the whole family. This substitution ACG->ATG creates a new start codon upstream of the main ATG. We experimentally demonstrated that the variant generates a novel overlapping ORF and inhibits the translation of the wild type protein from the main ORF in HeLa cells. This work describes the first example of 5UTR PROS1 mutation causing PSD through the creation of an upstream ORF, a mutation that is not predicted to be deleterious by standard annotation softwares.

genetics↗