Genetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome. We identified three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes. We used linkage analysis and whole-exome sequencing to identify the disease-causing gene. A founder mutation was identified in DYRK1B, substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain. The mutation precisely cosegregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Functional characterization of the disease gene revealed that nonmutant protein encoded by DYRK1B inhibits the SHH (sonic hedgehog) and Wnt signaling pathways and consequently enhances adipogenesis. Furthermore, DYRK1B promoted the expression of the key gluconeogenic enzyme glucose-6-phosphatase. The R102C allele showed gain-of-function activities by potentiating these effects. A second mutation, substituting proline for histidine 90, was found to cosegregate with a similar clinical syndrome in an ethnically distinct family. These findings indicate a role for DYRK1B in adipogenesis and glucose homeostasis and associate its altered function with an inherited form of the metabolic syndrome. (Funded by the National Institutes of Health.)

This article presents a new understanding on the deformation mechanics of flexible roll forming and is focused on the occurrence of flange wrinkling. The presentation draws from the experimental and numerical simulation of flexible roll forming to the determination of the wrinkling limits by means of a new theoretical and experimental methodology based on the utilization of rectangular test specimens loaded in axial compression. This research work is performed in mild steel sheets and the results show that the combined evolution of the effective strain with stress triaxiality obtained from finite element modelling of flexible roll forming and from the rectangular test specimens loaded in axial compression can be successfully utilized to predict the occurrence of flange wrinkling in variable cross-sectional profiles produced by flexible roll forming. The proposed methodology can, therefore, be considered an alternative to existing approaches based on simplified analytical and numerical procedures.

Flexible roll forming is an advanced sheet metal forming process for producing variable cross section profiles. Flange wrinkling at the transition zone where the cross section changes is a major defect in the flexible roll forming process. In this paper, the flange wrinkling at the transition zone is studied using finite element analysis. The results showed that the strip deformation at the transition zone can be considered as a combination of two strip deformations observed in the conventional roll forming process and the flanging process. According to finite element analysis results, when the flange wrinkling occurs, compressive longitudinal strain is smaller than the necessary compressive longitudinal strain calculated by mathematical modeling to obtain the intended profile geometry in the compression zone. Therefore, comparison of compressive longitudinal strain obtained from the finite element analysis and the necessary compressive longitudinal strain is a good criterion to predict the flange wrinkling occurrence. A flexible roll forming setup was developed. Longitudinal strain history is obtained from the finite element simulation and is compared with the experimental data from the flexible roll forming setup. Results show a good agreement and confirm the finite element analysis