Site-Specific Fracture Healing: Comparison between Diaphysis and Metaphysis in the Mouse Long Bone

The process of fracture healing varies depending upon internal and external factors, such as the fracture site, mode of injury, and mechanical environment. This review focuses on site-specific fracture healing, particularly diaphyseal and metaphyseal healing in mouse long bones. Diaphyseal fractures heal by forming the periosteal and medullary callus, whereas metaphyseal fractures heal by forming the medullary callus. Bone healing in ovariectomized mice is accompanied by a decrease in the medullary callus formation both in the diaphysis and metaphysis. Administration of estrogen after fracture significantly recovers the decrease in diaphyseal healing but fails to recover the metaphyseal healing. Thus, the two bones show different osteogenic potentials after fracture in ovariectomized mice. This difference may be attributed to the heterogeneity of the skeletal stem cells (SSCs)/osteoblast progenitors of the two bones. The Hox genes that specify the patterning of the mammalian skeleton during embryogenesis are upregulated during the diaphyseal healing. Hox genes positively regulate the differentiation of osteoblasts from SSCs in vitro. During bone grafting, the SSCs in the donor’s bone express Hox with adaptability in the heterologous bone. These novel functions of the Hox genes are discussed herein with reference to the site-specificity of fracture healing.     

Natural Killer T Cells Are Involved in Atherosclerotic Plaque Instability in Apolipoprotein-E Knockout Mice

The infiltration and activation of macrophages as well as lymphocytes within atherosclerotic lesion contribute to the pathogenesis of plaque rupture. We have demonstrated that invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens, play a crucial role in atherogenesis. However, it remained unclear whether iNKT cells are also involved in plaque instability. Apolipoprotein E (apoE) knockout mice were fed a standard diet (SD) or a high-fat diet (HFD) for 8 weeks. Moreover, the SD- and the HFD-fed mice were divided into two groups according to the intraperitoneal injection of α-galactosylceramide (αGC) that specifically activates iNKT cells or phosphate-buffered saline alone (PBS). ApoE/Jα18 double knockout mice, which lack iNKT cells, were also fed an SD or HFD. Plaque instability was assessed at the brachiocephalic artery by the histological analysis. In the HFD group, αGC significantly enhanced iNKT cell infiltration and exacerbated atherosclerotic plaque instability, whereas the depletion of iNKT cells attenuated plaque instability compared to PBS-treated mice. Real-time PCR analyses in the aortic tissues showed that αGC administration significantly increased expressional levels of inflammatory genes such as IFN-γ and MMP-2, while the depletion of iNKT cells attenuated these expression levels compared to those in the PBS-treated mice. Our findings suggested that iNKT cells are involved in the exacerbation of plaque instability via the activation of inflammatory cells and upregulation of MMP-2 in the vascular tissues.     

Self-expandable hydrogel biliary stent design utilizing the swelling property of poly(vinyl alcohol) hydrogel

We have developed a novel self-expandable biliary stent comprising poly(vinyl alcohol) (PVA). The swelling ratio of the dried PVA hydrogels decreased from 6.7 to 2.6 as the saponification degree increased from 95 to 99.9, whereas the storage modulus and tear strength increased from 17 to 400 kPa and from 0.5 to 10 N mm⁻¹, respectively. The dimensional ratios of the inner- and outer-diameter and the length of the dried tube-shaped hydrogels (saponification degree of 98.5) prepared by simple air drying isotropically increased 1.4–1.5 times in physiological saline. Meanwhile, the dimensional ratios of the dried hydrogels prepared by drying under extension increased by twice, whereas the length decreased slightly, indicating anisotropic swelling. The radial force of the reswollen tube-shaped hydrogels (6.6 ± 0.6 mN mm⁻²) was significantly higher than that of a conventional metallic stent (4.4 ± 0.3 mN mm⁻²), suggesting that PVA hydrogels were applicable as self-expandable stents. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48851.     

Epigenetic Regulation of ALS and CMT: A Lesson from Drosophila Models

Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disorder and is sometimes associated with frontotemporal dementia. Charcot–Marie–Tooth disease (CMT) is one of the most commonly inherited peripheral neuropathies causing the slow progression of sensory and distal muscle defects. Of note, the severity and progression of CMT symptoms markedly vary. The phenotypic heterogeneity of ALS and CMT suggests the existence of modifiers that determine disease characteristics. Epigenetic regulation of biological functions via gene expression without alterations in the DNA sequence may be an important factor. The methylation of DNA, noncoding RNA, and post-translational modification of histones are the major epigenetic mechanisms. Currently, Drosophila is emerging as a useful ALS and CMT model. In this review, we summarize recent studies linking ALS and CMT to epigenetic regulation with a strong emphasis on approaches using Drosophila models.     

Electrical Properties of Nonconventional Bi-Ba-Cu-O Glasses

Electrical properties of Bi-Ba-Cu-O glasses have been systematically investigated, and possible conduction mechanisms are discussed. Conductivity behavior is described by a small-polaron hopping mechanism. log σ_o, the slope of the log σ- W straight line, and the magnitude of the polaron bandwidth reveal that adiabatic hopping is dominant in the glasses. The Seebeck coefficient, S , of the Bi₁₆BaCu₃O_y glass is positive, indicating that the glass is a p -type hole conductor. The positive deviation of the observed S value from the theoretical S value is explained by assuming that the only oxygens bonded to both Cu²⁺ and Cu⁺ ions mediate indirect Cu⁺-O-Cu²⁺ hopping.     

Thioamide-Bridged Nucleic Acid (thioAmNA) Containing Thymine or 2-Thiothymine: Duplex-Forming Ability,Base Discrimination,and Enzymatic Stability

Oligonucleotides containing bridged nucleic acids (BNAs) show high duplex-forming ability towards target single-stranded RNA, so many BNAs have been developed for antisense applications. Amide-bridged nucleic acids (AmNAs), which are BNA analogues bearing an amide bond at the bridge, exhibit high duplex-forming ability, enzymatic stability, and antisense activity; thus, the AmNA motif represents a promising BNA scaffold. The high enzymatic stability of the AmNA motif is presumably attributable to the bulky amide structure, because it inhibits the access of nucleases to the phosphodiester linkage. Here, to improve enzymatic stability further, we designed thioAmNAs: thioamide-bridged nucleotides that have a bulkier bridge structure than AmNA. The synthesis of thioAmNAs bearing either thymine (thioAmNA-T) or 2-thiothymine (thioAmNA-S²T) bases was successful, and the obtained monomers were introduced into designed oligonucleotides without noticeable by-product generation. The thioAmNA-T- and thioAmNA-S²T-modified oligonucleotides showed strong binding affinity toward complementary single-stranded RNA, with the thioAmNA-S²T-modified oligonucleotide displaying excellent base-discrimination capability. Moreover, both thioAmNA-T and thioAmNA-S²T endowed oligonucleotides with higher resistance to enzymatic degradation than AmNA-T. These results indicate that thioAmNAs are potentially useful chemical modifications for oligonucleotide-based therapeutics.     

Synthesis and Immunomodulatory Activity of Fluorine-Containing Bisphosphonates

Immune checkpoint blockade using anti-PD-1/PD-L1 or anti-CTLA-4 monoclonal antibodies (mAbs) has revolutionized cancer treatment. However, many types of cancer do not respond and for those that do, only a minority of patients achieve durable remissions. Therefore, oncoimmunologists are working to develop adoptive cell therapies for non-hematopoietic tumors by harnessing immune effector cells such as αβ T cells and γδ T cells. In contrast to conventional αβ T cells that recognize peptides in the context of MHC class I or II molecules, γδ T cells expressing Vγ2Vδ2 T cell receptors (also termed Vγ9Vδ2) are stimulated by isoprenoid metabolites (phosphoantigens) such as isopentenyl diphosphate in a butyrophilin-3A1-dependent manner. Vγ2Vδ2 T cells kill almost all types of tumor cells that have been treated with bisphosphonates. In this study, we synthesized a series of fluorine-containing bisphosphonates based on current drugs and found that they stimulated Vγ2Vδ2 T cell killing of tumor cells. A fluorine-containing prodrug analogue of zoledronate where phosphonate moieties were masked with pivaloyloxymethyl groups markedly enhanced Vγ2Vδ2 T-cell-mediated cytotoxicity, and also promoted the expansion of peripheral blood Vγ2Vδ2 T cells. These results demonstrate that a prodrug of a fluorine-containing zoledronate analogue can sensitize tumor cells for killing as well as expand Vγ2Vδ2 T cells for adoptive cell therapy.     

Reduction behaviors and catalytic properties for methanol steam reforming of Cu-based spinel compounds CuX2O4 (X=Fe,Mn, Al,La)

In this study, various Cu-based spinel compounds, i.e., CuFe₂O₄, CuMn₂O₄, CuAl₂O₄ and CuLa₂O₄, were fabricated by a solid-state reaction method. Reduction behaviors and morphological changes of these materials have been characterized by H₂ temperature-programmed reduction (H₂-TPR), X-ray diffraction (XRD), Scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Moreover, the catalytic properties for steam reforming of methanol (SRM) of these Cu-based spinel compounds were investigated. H₂-TPR results indicated that the reducibility of Cu-based spinel compounds was strongly dependent on the B-site component while the CuFe₂O₄ catalyst revealed the lowest reduction temperature (190 °C), followed respectively by CuAl₂O₄ (267 °C), CuMn₂O₄ (270 °C), and CuLa₂O₄ (326 °C). The reduced CuAl₂O₄ catalyst demonstrated the best performance in terms of catalytic activity. Based on the SEM and XRD results, pulverization of the CuAl₂O₄ particles due to gas evolution and a high concentration of nanosized Cu particles (≈50.9 nm) precipitated on the surfaces of the Al₂O₃ support were observed after reduction at 360 °C in H₂. The BET surface area of the CuAl₂O₄ catalyst escalated from 5.5 to 13.2 m²/g. Reduction of Cu-based spinel ferrites appear to be a potential synthesis route for preparing a catalyst with high catalytic activity and thermal stability. The catalytic performance of these copper-oxide composites was superior to those of conventional copper catalysts.     

Design and Synthesis of A‐Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors

Currently, pyripyropene A, which is isolated from the culture broth of Aspergillus fumigatus FO‐1289, is the only compound known to strongly and selectively inhibit the isozyme sterol O‐acyltransferase 2 (SOAT2). To aid in the development of new cholesterol‐lowering or anti‐atherosclerotic agents, new A‐ring simplified pyripyropene A analogues have been designed and synthesized based on total synthesis, and the results of structure–activity relationship studies of pyripyropene A. Among the analogues, two A‐ring simplified pyripyropene A analogues exhibited equally efficient SOAT2 inhibitory activity to that of natural pyripyropene A. These new analogues are the most potent and selective SOAT2 inhibitors to be used as synthetic compounds and attractive seed compounds for the development of drug for dyslipidemia, including atherosclerotic disease and steatosis.