Loss-of-function of EBP50 is a new cause of hereditary peripheral neuropathy: EBP50 functions in peripheral nerve system.

Finding causative genetic mutations is important in the diagnosis and treatment of hereditary peripheral neuropathies. This study was conducted to find new genes involved in the pathophysiology of hereditary peripheral neuropathy. We identified a new mutation in the EBP50 gene, which is co-segregated with neuropathic phenotypes, including motor and sensory deficit in a family with Charcot-Marie-Tooth disease. EBP50 is known to be important for the formation of microvilli in epithelial cells, and the discovery of this gene mutation allowed us to study the function of EBP50 in the nervous system. EBP50 was strongly expressed in the nodal and paranodal regions of sciatic nerve fibers, where Schwann cell microvilli contact the axolemma, and at the growth tips of primary Schwann cells. In addition, EBP50 expression was decreased in mouse models of peripheral neuropathy. Knockout mice were used to study EBP50 function in the peripheral nervous system. Interestingly motor function deficit and abnormal histology of nerve fibers were observed in EBP50+/- heterozygous mice at 12 months of age, but not 3 months. in vitro studies using Schwann cells showed that NRG1-induced AKT activation and migration were significantly reduced in cells overexpressing the I325V mutant of EBP50 or cells with knocked-down EBP50 expression. In conclusion, we show for the first time that loss of function due to EBP50 gene deficiency or mutation can cause peripheral neuropathy.

The structure of AcrIC9 revealing the putative inhibitory mechanism of AcrIC9 against the type IC CRISPR-Cas system.

CRISPR-Cas systems are known to be part of the bacterial adaptive immune system that provides resistance against intruders such as viruses, phages and other mobile genetic elements. To combat this bacterial defense mechanism, phages encode inhibitors called Acrs (anti-CRISPR proteins) that can suppress them. AcrIC9 is the most recently identified member of the AcrIC family that inhibits the type IC CRISPR-Cas system. Here, the crystal structure of AcrIC9 from Rhodobacter capsulatus is reported, which comprises a novel fold made of three central antiparallel ß-strands surrounded by three α-helixes, a structure that has not been detected before. It is also shown that AcrIC9 can form a dimer via disulfide bonds generated by the Cys69 residue. Finally, it is revealed that AcrIC9 directly binds to the type IC cascade. Analysis and comparison of its structure with structural homologs indicate that AcrIC9 belongs to DNA-mimic Acrs that directly bind to the cascade complex and hinder the target DNA from binding to the cascade.

Helical filament structure of the DREP3 CIDE domain reveals a unified mechanism of CIDE-domain assembly.

The cell-death-inducing DFF45-like effector (CIDE) domain is a protein-interaction module comprising ∼80 amino acids and was initially identified in several apoptotic nucleases and their regulators. CIDE-domain-containing proteins were subsequently identified among proteins involved in lipid metabolism. Given the involvement of CIDE-domain-containing proteins in cell death and lipid homeostasis, their structure and function have been intensively studied. Here, the head-to-tail helical filament structure of the CIDE domain of DNA fragmentation factor-related protein 3 (DREP3) is presented. The helical filament structure was formed by opposing positively and negatively charged interfaces of the domain and was assembled depending on protein and salt concentrations. Although conserved filament structures are observed in CIDE family members, the structure elucidated in this study and its comparison with previous structures indicated that the size and the number of molecules used in one turn vary. These findings suggest that this charged-surface-based head-to-tail helical filament structure represents a unified mechanism of CIDE-domain assembly and provides insight into the function of various forms of the filament structure of the CIDE domain in higher-order assembly for apoptotic DNA fragmentation and control of lipid-droplet size.

Pleiotropic functions of antioxidant nanoparticles for longevity and medicine.

Nanomedicine is a rapidly emerging interdisciplinary field in which medicine is coupled with nanotechnology tools and techniques for advanced therapy with the aid of molecular knowledge and its associated treatment tools. This field creates a myriad of opportunities for improving the health and life of humans. Unchecked chronic inflammation, oxidative stress, and free-radical damage causes proportionate aging and other related diseases/disorders. Antioxidants act as free radical scavengers, singlet oxygen ((1)O2) quenchers, peroxides and other ROS inactivators, as well as metal ion chelators, quenchers of secondary oxidation products and inhibitors of pro-oxidative enzymes. Nanoparticles possessing antioxidative properties have recently emerged as potent therapeutic agents owing to their potential applications in life sciences for improvement of the quality of life and longevity. Accordingly, the use of antioxidant nanoparticles/nanomaterials is burgeoning in biomedical, pharmaceutical, cosmetic, food and nutrition fields. Due to the smaller size, greater permeability, increased circulation ability and biocompatibility of these nanoparticles to alleviate oxidative stress, they have become indispensable agents for controlling aging and its associated pathologies, including neurodegenerative diseases, cardiovascular diseases, and pulmonary diseases. This review discusses antioxidant nanoparticles, which are nano-dimensioned metals, non-metals, metal oxides, synthetic and natural antioxidants and polymers, and the molecular/biochemical mechanisms underpinning their activities.

Silk fibroin particles as templates for mineralization of calcium-deficient hydroxyapatite.

Silk fibroin particles prepared by phase separation with polyethylene oxide were coated with calcium-deficient hydroxyapatite (CDHA) crystals under various pH conditions. For different pH values, the growth and the morphology of CDHA crystals on the surface of silk fibroin particles were investigated in detail by zeta potential analysis, scanning electron microscopy, transmission electron microscopy, and X-ray diffraction techniques. Negative charges formed by deprotonation of the functional groups on the surface of silk fibroin particles at high pH lead to an increase of binding affinity between the calcium ions of the CDHA crystals and the functional groups of the silk fibroin particles. Consequently, the generation of many CDHA crystals was promoted to deposit on the surface of silk fibroin particles at a high pH value.