Enhanced Osteogenic Differentiation of Pluripotent Stem Cells via γ-Secretase Inhibition

Bone healing is a complex, well-organized process. Multiple factors regulate this process, including growth factors, hormones, cytokines, mechanical stimulation, and aging. One of the most important signaling pathways that affect bone healing is the Notch signaling pathway. It has a significant role in controlling the differentiation of bone mesenchymal stem cells and forming new bone. Interventions to enhance the healing of critical-sized bone defects are of great importance, and stem cell transplantations are eminent candidates for treating such defects. Understanding how Notch signaling impacts pluripotent stem cell differentiation can significantly enhance osteogenesis and improve the overall healing process upon transplantation. In Rancourt’s lab, mouse embryonic stem cells (ESC) have been successfully differentiated to the osteogenic cell lineage. This study investigates the role of Notch signaling inhibition in the osteogenic differentiation of mouse embryonic and induced pluripotent stem cells (iPS). Our data showed that Notch inhibition greatly enhanced the differentiation of both mouse embryonic and induced pluripotent stem cells.     

Hyper-reduced direct numerical simulation of voids in welded joints via image-based modeling

Defects such as gas pores can be formed and trapped in the fusion zone during laser welding. These defects can significantly affect the mechanical reliability of the welded joint. Current nondestructive inspection technologies are able to detect micro-voids in a mass production context. Finite element analysis can therefore be used to assess the lifetime of an observed component via image-based modeling. Unfortunately, running a simulation per component entails a huge and generally unaffordable computational cost. In addition, voids do not admit a parametric modeling. In this paper, a numerical method is proposed to study the impact of defects on the mechanical response of a welded joint. It is based on model order reduction techniques that decrease the computational cost of each simulation related to an image-based modeling. To tackle the reduction of nonparametric defects, a multiscale construction of the reduced basis is proposed, although no scale separation is assumed when computing the mechanical response of the structure. Some empirical modes are representing the structure behavior and other empirical modes are related to the defect-induced local fluctuations. They are then assembled to simulate a defective joint. Assets and limitations of the proposed method are explored through a simplified two-dimensional (2D) problem. For the sake of reproducibility, this 2D problem is fully parametric. Finally, a realistic three-dimensional (3D) industrial case is presented, where voids geometries have been measured via computed tomography. This 3D problem being nonparametric, fluctuation modes must be computed on the fly, once the computed tomography has been performed.     

Intracellular expression of a single-chain antibody directed against human papillomavirus type 16 E7 oncoprotein achieves targeted antineoplastic effects

Human papillomavirus type 16 (HPV16) E7 is a viral oncoprotein that is believed to play a major role in cervical neoplasia. Anti-HPV16 E7 intracellular single-chain antibodies (scFvs) were constructed to down-regulate HPV16 E7 oncoprotein in HPV DNA-containing cell lines. In these studies, we transfected anti-E7 scFvs into the HPV16-positive human cervical carcinoma cell lines CaSki and SiHa and tested them for their ability to inhibit cell proliferation and alter the level of HPV16 E7 oncoprotein. Our results showed that anti-HPV16 E7 scFvs inhibited cell proliferation by >85% in CaSki cells and by 95% in SiHa cells. E7 oncoprotein was down-regulated by anti-HPV16 E7 scFv, and its expression was inversely related to the amount of scFv transfected. However, there were no effects of transfecting scFvs alone in HPV-negative cell lines. These results imply that anti-HPV16 E7 scFvs only have specific anti-HPV16 E7 effects on cell proliferation and on the synthesis of virally encoded proteins in HPV-positive cell lines. Thus, transfection of HPV16 E7-positive tumors with antigen-specific scFvs may be a viable strategy for cervical cancer gene therapy.