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Fibrosis occurs during progression of osteoarthritis (OA), and myofibroblasts are considered a key effector to drive the fibrotic response. Macrophages also play critical roles in OA progression. However, whether macrophage polarization is involved in OA-related fibrosis has not been adequately defined. Here, we investigated the effect of M2-like macrophages compared to M1-like macrophages on the myofibroblast differentiation of human synovial fibroblasts (HSFs). M1- and M2-like macrophages differentiated from the human monocytic THP-1 cells were co-cultured with HSFs for 72 h. Alpha-smooth muscle actin (α-SMA) positive cells and gene expression of pro-fibrotic and anti-fibrotic factors were quantified. The concentration of transforming growth factor-beta1 (TGF-β1) in the culture supernatant was also analyzed, and its effect on the regulation of the TGF-β/SMAD signaling pathway was further investigated. We found that, cocultured with M2-like macrophages increased the number of α-SMA positive cells and expression of pro-fibrotic genes and decreased the expression of anti-fibrotic genes in HSFs. TGF‑β1 was highly secreted by M2‑like macrophages and accelerated the phosphorylation of SMAD2/3 in HSF cells. Our results indicate the pro-fibrotic effects of M2-like macrophages in myofibroblast differentiation of HSFs, in association with the TGF-β1/SMAD2/3 signaling pathway activation. Thus, M2-like macrophages may play a role in OA fibrogenesis and its progression.

In orthopedics and dentistry, there is an urgent need to obtain low-stiffness implants that suppress the stress shielding caused by the use of metallic implants. In this study, we aimed to fabricate alloys that can reduce the stiffness by increasing the strength while maintaining a low Young’s modulus based on the metastable β-Ti alloy. We designed alloys in which Ti was partially replaced by Zr based on the ISO-approved metastable β-Ti alloy Ti-15Mo-5Zr-3Al. All alloys prepared by arc melting and subsequent solution treatment showed a single β-phase solid solution, with no formation of the ω-phase. The alloys exhibited a low Young’s modulus equivalent to that of Ti-15Mo-5Zr-3Al and a high strength superior to that of Ti-15Mo-5Zr-3Al and Ti-6Al-4V. This strengthening was presumed to be due to solid-solution strengthening. The biocompatibility of the alloys was as good as or better than that of Ti-6Al-4V. These alloys have potential as metallic materials suitable for biomedical applications.

Several studies have been conducted on the fatigue behavior of copper and 7-3, and 6-4 brasses. However, there have been fewer studies on the fatigue behavior and fatigue crack growth (FCG) properties of free-cutting brass, primarily because emphasis has been placed on the development of lead-free free-cutting brass. In this study, fatigue experiments were performed in the atmosphere at room temperature using three types of free-cutting, two types of bismuth (Bi)-based (with different grain sizes), and lead (Pb)-based brasses. It was found that lead-free Bi-based free-cutting brass had approximately the same fatigue performance as that of Pb-based free-cutting brass. It was also clarified that the addition of Bi or Pb initiated fatigue cracks, and that the crack growth period occupied most of the fatigue life. Differences in the FCG behavior of the three free-cutting brasses were observed in the low ΔK range. The modified linear fracture mechanics parameter M was used to quantitatively analyze the fatigue life and FCG behavior (short surface cracks). A comparison between the calculated and experimental results showed that M was useful.

Background The European Medicines Agency has a risk-management strategy to enhance the planning and implementation of pharmacovigilance and risk-minimization activities for new drugs. This system often requires additional postmarketing pharmacovigilance activities. Objective Our objective was to investigate safety concerns for products approved since the EU pharmacovigilance legislation took effect and to analyze associations between these safety concerns and the additional pharmacovigilance activities required. Methods We studied 49 new active substances approved in 2013 and 2014 in the EU. For these products, we extracted information from the European Public Assessment Reports on their characteristics, safety concerns, and additional pharmacovigilance activities and analyzed the associations between them. Results The 49 products involved 813 safety concerns, 418 of which were subject to additional pharmacovigilance activities, which were implemented for 57.5% of the potential and 38.8% of the identified risks. These additional pharmacovigilance activities included 143 clinical trials (47.7%), 73 non-interventional studies (24.3%), and 72 non-clinical studies (24.0%). Conclusions Our results suggest that both the type of additional pharmacovigilance activity required and whether or not they are implemented depend on the product characteristics and their related safety concerns. From the early stages of drug development, companies should consider the kind of safety information that will be required in the postmarketing stage based on what is already known about the product characteristics and anticipated safety concerns.

The role of the ligamentum flavum (LF) in the pathogenesis of adolescent idiopathic scoliosis (AIS) is not well understood. Using magnetic resonance imaging (MRI), we investigated the degrees of LF hypertrophy in 18 patients without scoliosis and on the convex and concave sides of the apex of the curvature in 22 patients with AIS. Next, gene expression was compared among neutral vertebral LF and LF on the convex and concave sides of the apex of the curvature in patients with AIS. Histological and microarray analyses of the LF were compared among neutral vertebrae (control) and the LF on the apex of the curvatures. The mean area of LF in the without scoliosis, apical concave, and convex with scoliosis groups was 10.5, 13.5, and 20.3 mm2, respectively. There were significant differences among the three groups (p < 0.05). Histological analysis showed that the ratio of fibers (Collagen/Elastic) was significantly increased on the convex side compared to the concave side (p < 0.05). Microarray analysis showed that ERC2 and MAFB showed significantly increased gene expression on the convex side compared with those of the concave side and the neutral vertebral LF cells. These genes were significantly associated with increased expression of collagen by LF cells (p < 0.05). LF hypertrophy was identified in scoliosis patients, and the convex side was significantly more hypertrophic than that of the concave side. ERC2 and MAFB genes were associated with LF hypertrophy in patients with AIS. These phenomena are likely to be associated with the progression of scoliosis.

Intervertebral disc (IVD) diseases are common spinal disorders that cause neck or back pain in the presence or absence of an underlying neurological disorder. IVD diseases develop on the basis of degeneration, and there are no established treatments for degeneration. IVD diseases may therefore represent a candidate for the application of regenerative medicine, potentially employing normal human dermal fibroblasts (NHDFs) induced to differentiate into nucleus pulposus (NP) cells. Here, we used a three-dimensional culture system to demonstrate that ectopic expression of MYC, KLF4, NOTO, SOX5, SOX6, and SOX9 in NHDFs generated NP-like cells, detected using Safranin-O staining. Quantitative PCR, microarray analysis, and fluorescence-activated cell sorting revealed that the induced NP cells exhibited a fully differentiated phenotype. These findings may significantly contribute to the development of effective strategies for treating IVD diseases.

Alcohol is a traditional social-bonding reinforcer; however, the neural mechanism underlying ethanol-driven social behaviors remains elusive. Here, we report that ethanol facilitates observational fear response. Observer mice exhibited stronger defensive immobility while observing cagemates that received repetitive foot shocks if the observer mice had experienced a brief priming foot shock. This enhancement was associated with an observation-induced recruitment of subsets of anterior cingulate cortex (ACC) neurons in the observer mouse that were responsive to its own pain. The vicariously activated ACC neurons projected their axons preferentially to the basolateral amygdala. Ethanol shifted the ACC neuronal balance toward inhibition, facilitated the preferential ACC neuronal recruitment during observation, and enhanced observational fear response, independent of an oxytocin signaling pathway. Furthermore, ethanol enhanced socially evoked fear response in autism model mice. Mice have been shown to display a fear response upon observing another mouse undergo fear conditioning. Here, the authors show that ethanol facilitates socially evoked fear memory recall, via pain-responsive neurons in the anterior cingulate cortex.

Molecular hydrogen (H 2 ), as a new medical gas, has protective effects in neurological disorders including Parkinson’s disease (PD). In our previous report, the neuroprotective effect of drinking water with saturated H 2 (H 2 water) in PD mice might be due to stomach–brain interaction via release of gastric hormone, ghrelin. In the present study, we assessed the effect of H 2 -induced ghrelin more precisely. To confirm the contribution of ghrelin in H 2 water-drinking PD model mice, ghrelin-knock out (KO) mice were used. Despite the speculation, the effect of H 2 water was still observed in ghrelin-KO PD model mice. To further check the involvement of ghrelin, possible contribution of ghrelin-induced vagal afferent effect was tested by performing subdiaphragmatic vagotomy before treating with H 2 water and administration of MPTP (1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine). The protective effect of H 2 water was still observed in the vagotomized mice in substantia nigra, suggesting that stimulation of vagal afferent nerves is not involved in H 2 -induced neuroprotection. Other neuroprotective substitutes in ghrelin-KO mice were speculated because H 2 -induced neuroprotection was not cancelled by ghrelin receptor antagonist, D-Lys 3 GHRP-6, in ghrelin-KO PD model mice, unlike in wild-type PD model mice. Our results indicate that ghrelin may not be the only factor for H 2 -induced neuroprotection and other factors can substitute the role of ghrelin when ghrelin is absent, raising intriguing options of research for H 2 -responsive factors.

Circulating microRNAs in the blood may provide diagnostic and prognostic information about canine neoplastic diseases, and their profiles may be conserved between human and canine species. We performed RT-qPCR to obtain the profiles of circulating plasma microRNA-214 and -126 in total 181 cases of canine neoplastic diseases and healthy controls. MicroRNA-214 levels were high in 2 epithelial tumours (thyroid and mammary carcinomas) and 4 non-epithelial tumours (osteosarcoma, histiocytic sarcoma, chondrosarcoma, and hemangiosarcoma). In contrast, microRNA-126 levels were high in 6 epithelial tumours (mammary, hepatocellular, squamous cell, thyroid, transitional cell carcinomas, and adenocarcinoma) and 4 non-epithelial tumours (osteosarcoma, mast cell tumour, melanoma, and hemangiosarcoma). The diagnostic potential of microRNA-214 was relatively high in sarcomas, whereas that of microR-126 was high in most types of the tumours. MicroRNA-214 and -126 were prognostic predictors in 2 groups (adenocarcinoma and non-epithelial tumours except for osteosarcoma) and 3 groups (epithelial tumours, adenocarcinoma, and melanoma), respectively. Additionally, the microRNA levels did not show a strong correlation with the other clinical parameters. In conclusion, circulating microRNA-214 and -126 have the potential to be diagnostic and prognostic biomarkers for canine neoplastic diseases. Furthermore, their profiles may be key references as well for exploring novel biomarkers for human cancers.

Catharanthus roseus is a medicinal plant well known for producing bioactive compounds such as vinblastine and vincristine, which are classified as terpenoid indole alkaloids (TIAs). Although the leaves of this plant are the main source of these antitumour drugs, much remains unknown on how TIAs are biosynthesised from a central precursor, strictosidine, to various TIAs in planta. Here, we have succeeded in showing, for the first time in leaf tissue of C. roseus, cell-specific TIAs localisation and accumulation with 10 μm spatial resolution Imaging mass spectrometry (Imaging MS) and live single-cell mass spectrometry (single-cell MS). These metabolomic studies revealed that most TIA precursors (iridoids) are localised in the epidermal cells, but major TIAs including serpentine and vindoline are localised instead in idioblast cells. Interestingly, the central TIA intermediate strictosidine also accumulates in both epidermal and idioblast cells of C. roseus. Moreover, we also found that vindoline accumulation increases in laticifer cells as the leaf expands. These discoveries highlight the complexity of intercellular localisation in plant specialised metabolism.