Lethal perinatal hypophosphatasia caused by a novel compound heterozygous mutation: a case report.

BACKGROUND: Hypophosphatasia (HPP) is a rare hereditary disorder characterized by defective bone and tooth mineralization and deficiency of tissue non-specific alkaline phosphatase (TNAP) activity. The clinical presentation of HPP is highly variable, and the prognosis for the infantile form is poor. CASE PRESENTATION: This study reports a male infant diagnosed with lethal perinatal HPP. His gene analysis showed two heterozygous missense variants c.406C > T (p.R136C) and c.461C > T (p.A154V). The two mutations originated separately from his parents, consistent with autosomal recessive perinatal HPP, and the c.461C > T (p.A154V) was the novel mutation. Three-level structure model provide an explanation of the two mutated alleles correlating with the lethal phenotype of our patient. Results of SIFT, PolyPhen_2, and REVEL showed two mutations were pathogenic. CONCLUSIONS: We demonstrated a case of perinatal lethal HPP caused by two heterozygous mutations, and one of which was novel. This finding will prove relevant for genetic counseling and perinatal gene testing for affected families.

A Novel Cytocompatibility Strengthening Strategy of Ultrafine-Grained Pure Titanium.

Ultrafine-grained pure (UFG) titanium processed by equal channel angular pressing possesses mechanical properties comparable to those of Ti-6Al-4V and features more favorable friction resistance, biocompatibility, and corrosion resistance than does commercially pure (CP) titanium. Nevertheless, UFG titanium is still a bio-inert material with a lack of bone-inducing ability. Here, TiO2-hydroxyapatite (TiO2-HA) coatings were fabricated on CP titanium and UFG titanium through combining micro-arc oxidation and hydrothermal treatment together to improve their cytocompatibility. The results indicate that, compared with conventional coatings that use CP titanium as the substrate, such coatings formed on the UFG titanium possess additional hydrophilicity and in vitro cytocompatibility. The fantastic hierarchical structure of the UFG TiO2-HA coating (UG-MH coating), including microscale and nanoscale pores and short column-shaped and sheet-shaped HA grains with varying geometric shapes, excellent hydrophilicity, and high polar force, enhances the mutual effects between the osteoblasts and titanium implant since it provides an adequate microenvironment for the ingrowth of osteoblasts, inducing osteoblast adhesion, proliferation, and differentiation. The UG-MH coating has a synergistic effect due to its fantastic hydrophilic hierarchical structure and high polar force on the up-regulated expression of cytoskeletal actin proteins as well as osteocalcin, protein kinase C (PKC), nuclear factor of activated T-cells (NFAT), and Wnt5, enabling osteoblasts to differentiate via the Wnt calcium-dependent signaling pathway. This study highlights the idea that the modified UFG titanium will be more suitable than CP titanium in dental and orthopedic applications.

Transplantation of neural scaffolds consisting of dermal fibroblast-reprogrammed neurons and 3D silk fibrous materials promotes the repair of spinal cord injury.

Transplantation of tissue-engineered neural scaffolds bears great potential for reconstructing neural circuits after spinal cord injury (SCI). In this study, a 3D porous silk fibrous scaffold (3D-SF) with biomimetic interconnected micro- to nanofibrous structure and good biocompatibility is fabricated. Then, a small-molecule combination CFLSSVY (CHIR99021, Forskolin, LDN193189, SB431542, SP600125, VPA, and Y27632) that efficiently reprograms rat dermal fibroblasts into neurons is screened, and these chemically induced neurons (CiNs) are shown to readily communicate on the 3D-SF and form neural scaffolds. After transplantation of these silk-based neural scaffolds into the stumps of transected spinal cords in rats, the damaged tissue is repaired significantly, as indicated by the reduced cavity areas, decreased GFAP expression, and improved axonal regeneration and myelination in the injury site. Moreover, the hindlimb movement and motor-nerve conductivity are greatly improved as indicated by the elevated BBB score, the alternate movement of two hindlimbs during the 45° inclined grid test, and the shortened latency and enhanced amplitude in cMEP detection. Together, these results demonstrate that transplantation of neural scaffolds consisting of 3D-SF and dermal fibroblast-reprogrammed neurons leads to significant nerve regeneration and functional recovery, providing a promising therapeutic strategy for SCI.

The effects of electrospun TSF nanofiber diameter and alignment on neuronal differentiation of human embryonic stem cells.

Although transplantation of human embryonic stem cells (hESCs)-derived neural precursors (NPs) has been demonstrated with some success for nervous repair in small animal model, control of the survival, and directional differentiation of these cells is still challenging. Meanwhile, the notion that using suitable scaffolding materials to control the growth and differentiation of grafted hESC-derived NPs raises the hope for better clinical nervous repair. In this study, we cultured hESC-derived NPs on Tussah silk fibroin (TSF)-scaffold of different diameter (i.e., 400 and 800 nm) and orientation (i.e., random and aligned) to analyze the effect of fiber diameter and alignment on the cell viability, neuronal differentiation, and neurite outgrowth of hESC-derived NPs. The results show that TSF-scaffold supports the survival, migration, and differentiation of hESC-derived NPs. Aligned TSF-scaffold significantly promotes the neuronal differentiation and neurite outgrowth of hESC-derived neurons compared with random TSF-scaffold. Moreover, on aligned 400 nm fibers cell viability, neuronal differentiation and neurite outgrowth are greater than that on aligned 800 nm fibers. Together, these results demonstrate that aligned 400 nm TSF-scaffold is more suitable for the development of hESC-derived NPs, which shed light on optimization of the therapeutic potential of hESCs to be employed for neural regeneration.