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The deposition of beta-amyloid (Aβ) in the brain precedes the onset of symptoms such as cognitive impairment in Alzheimer’s disease (AD); therefore, the early detection of Aβ accumulation is crucial. We previously reported the applicability of the QPLEXTM Alz plus assay kit for the prescreening of Aβ accumulation. Here, we tested the specific application of the kit in a large cohort of cognitively normal (CN) individuals of varying ages for the early detection of Aβ accumulation. We included a total of 221 CN participants with or without brain Aβ. The QPLEXTM biomarkers were characterized based on age groups (1st–3rd tertile) and across various brain regions with cerebral amyloid deposition. The 3rd tertile group (>65 years) was found to be the most suitable age group for the application of our assay kit. Receiver operating characteristic curve analysis showed that the area under the curve (AUC, discrimination power) was 0.878 with 69.7% sensitivity and 98.4% specificity in the 3rd tertile group. Additionally, specific correlations between biomarkers and cerebral amyloid deposition in four different brain regions revealed an overall correlation with general amyloid deposition, consistent with previous findings. Furthermore, the combinational panel with plasma Aβ1–42 levels maximized the discrimination efficiency and achieved an AUC of 0.921 with 95.7% sensitivity and 67.3% specificity. Thus, we suggest that the QPLEXTM Alz plus assay is useful for prescreening brain Aβ levels in CN individuals, especially those aged >65 years, to prevent disease progression via the early detection of disease initiation.

We investigate the choice of endogenous timing by managerial firms in the presence of network externalities under Bertrand competition. Contrast to the results of sequentiality in equilibrium, we demonstrate that when managers are being delegated both the market and timing decision, there exists a unique simultaneous move in equilibrium regardless of network externalities. However, when the choice of timing remains in the owners’ hands, if the network externalities are weak, it involves one owner of firm producing as a leader and the other owner of firm as a follower while there exists a unique simultaneous move in equilibrium if the network externalities are strong. Thus, the strength of network externalities plays an important role in both firms’ choice of roles and consensus between owner and manager. Consequently, from the viewpoint of social welfare and consumer surplus, Pareto superiority can be obtained endogenously when the strength of network externalities is strong under either consumers’ fulfilled or rational expectation.

Different stem cell-based strategies, especially induced pluripotent stem cells (iPSCs), have been exploited to regenerate teeth or restore biological and physiological functions after tooth loss. Further research is needed to establish an optimized protocol to effectively differentiate human iPSCs (hiPSCs) into dental epithelial cells (DECs). In this study, various factors were precisely modulated to facilitate differentiation of hiPSCs into DECs, which are essential for the regeneration of functional teeth. Embryoid bodies (EBs) were formed from hiPSCs as embryo-like aggregates, retinoic acid (RA) was used as an early ectodermal inducer, and bone morphogenic protein 4 (BMP4) activity was manipulated. The characteristics of DECs were enhanced and preserved after culture in keratinocyte serum-free medium (K-SFM). The yielded cell population exhibited noticeable DEC characteristics, consistent with the expression of epithelial cell and ameloblast markers. DECs demonstrated odontogenic abilities by exerting an inductive effect on human dental pulp stem cells (hDPSCs) and forming a tooth-like structure with the mouse tooth mesenchyme. Overall, our differentiation protocol provides a practical approach for applying hiPSCs for tooth regeneration.

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is accompanied by cognitive impairment and shows representative pathological features, including senile plaques and neurofibrillary tangles in the brain. Recent evidence suggests that several systemic changes outside the brain are associated with AD and may contribute to its pathogenesis. Among the factors that induce systemic changes in AD, the gut microbiota is increasingly drawing attention. Modulation of gut microbiome, along with continuous attempts to remove pathogenic proteins directly from the brain, is a viable strategy to cure AD. Seeking a holistic understanding of the pathways throughout the body that can affect the pathogenesis, rather than regarding AD solely as a brain disease, may be key to successful therapy. In this review, we focus on the role of the gut microbiota in causing systemic manifestations of AD. The review integrates recently emerging concepts and provides potential mechanisms about the involvement of the gut-brain axis in AD, ranging from gut permeability and inflammation to bacterial translocation and cross-seeding.

This study examines the endogenous vertical structure in which each manufacturer sells its product to its exclusive retailer who sells network goods to consumers (i.e. a duopoly in the upstream market) under Bertrand competition and Cournot competition with network externalities. We show that with strong (weak) network externalities under Bertrand competition, (a) it is a dominant strategy for each manufacturer to integrate (separate) its retailer; (b) with strong network externalities, the manufacturers’ profits, consumers’ surplus and social welfare are higher under vertical integration than under vertical separation. Under Cournot competition, (a) vertical separation is a unique subgame perfect Nash equilibrium; (b) with strong network externalities, the manufacturers’ profits, consumers’ surplus and social welfare are higher under vertical separation than under vertical integration.

We examine the endogenous determination of a vertical market in an import‐competing market with import tariff. We show that if firms commit to vertical organization before the government's commitment to trade policy, the home and foreign firms choose vertical separation and vertical integration, respectively, at equilibrium under Bertrand competition. Under Cournot competition, the subgame perfect Nash equilibrium entails both firms separating their retailers. Comparing profits between Bertrand competition to Cournot competition, we find that upstream manufacturer's profit can be higher under Bertrand competition with integration than under Cournot competition with separation when comparing foreign upstream manufacturer's profit.

We revisit firms’ strategic delegation in a Cournot game. We consider a market comprising two consumer groups, with either a high or low willingness to pay. In this market, we first consider firms’ identical marginal costs and show that either/both firms’ owners may strategically abandon the delegation option to avoid price collapse. We find three types of delegation decisions with either/both/no firm delegating in equilibrium. We further consider firms’ asymmetric marginal costs and show that the asymmetric equilibrium wherein only the less efficient firm delegates will exist in a wider parameter range, compared to that wherein only the more efficient firm delegates. Moreover, delegation may enable the less efficient firm to achieve a higher profit than her rival.

Alzheimer's disease (AD) is the most prevalent type of dementia. Reports have revealed that the peripheral immune system is linked to neuropathology; however, little is known about the contribution of B lymphocytes in AD. For this longitudinal study, 133 participants are included at baseline and second-year follow-up. Also, we analyze B cell receptor (BCR) repertoire data generated from a public dataset of three normal and 10 AD samples and perform BCR repertoire profiling and pairwise sharing analysis. As a result, longitudinal increase in B lymphocytes is associated with increased cerebral amyloid deposition and hyperactivates induced pluripotent stem cell-derived microglia with loss-of-function for beta-amyloid clearance. Patients with AD share similar class-switched BCR sequences with identical isotypes, despite the high somatic hypermutation rate. Thus, BCR repertoire profiling can lead to the development of individualized immune-based therapeutics and treatment. We provide evidence of both quantitative and qualitative changes in B lymphocytes during AD pathogenesis.

This study investigates capacity choice in a vertical structure in which each downstream firm makes its capacity decision, then a monopolistic upstream firm proposes the input price or two‐part tariff contract. Finally, each downstream firm chooses its output (or price). Contrary to the conventional wisdom that both firms hold excess capacity in an Cournot competition, we find that each downstream firm always chooses undercapacity regardless of both the nature of goods and the competition modes. Second, we also show that capacity efficiency is higher under Cournot competition than under Bertrand competition. Third, even though there are double marginalization distortion and rent‐extracting effect, we can achieve the monopoly equilibrium of the vertically integrated firm though two‐part tariff contract.

ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

The deposition of beta-amyloid (Aβ) in the brain precedes the onset of symptoms such as cognitive impairment in Alzheimer's disease (AD); therefore, the early detection of Aβ accumulation is crucial. We previously reported the applicability of the QPLEX

Tooth transplantation is one of the treatment options for extracted teeth that can be considered before dental implantation. Although the success rate of tooth transplantation is lower than that of implantation, tooth replantation and transplantation have the great advantage of using natural teeth. Tooth replantation might be considered a promising option in some cases. In present study, the expression patterns of revascularization and pulpal healing, which are the most important for the pulp viability, were analyzed after tooth replantation and allograft in mice. The inflammatory response and root dentin resorption were observed and not different between replantation and allograft in initiation of healing process. However, bonelike tissue formation, pulp revascularization and pulp healing were faster in replantation. The difference of healing patterns between tooth replantation and allograft found in present study will be helpful to select the treatment option and to understand healing mechanism., Highlights • The expression of healing markers begins in root canal and moves to pulp cavity. • Pulp healing response becomes normal in 7 days after tooth replantation. • Overall healing process in tooth replantation is faster than allograft.

Objectives The treatment of ameloblastoma, an odontogenic epithelial tumour destroying jawbone, mainly depends on radical destructive resections. Other therapeutic options are limited by the characteristics of ameloblastoma, such as high recurrence rates and resistance to radiation and chemotherapy, which implies possible existence of cancer stem cells (CSCs) in ameloblastoma. Here, we identified a putative CSC population in immortalized and primary human ameloblastoma cells and examined possible therapeutic reagents to reduce the CSC population. Methods We investigated subpopulations of AM‐1 cell line and human ameloblastoma cells using immunocytochemistry and flow cytometry and the effects of Wnt signalling activators on the 2‐ and 3‐dimensional cultured ameloblastoma cells using molecular biological analyses. Result Among heterogenous ameloblastoma cells, small‐sized and round‐shaped cells were found to be proliferative and expressed a marker of dental epithelial stem cells, SRY‐box 2 (Sox2). Exogenous activation of Wnt signalling using glycogen synthase kinase 3β inhibitors, lithium chloride (LiCl) and valproic acid (VPA), increased the cell size and decreased proliferation of cells and expression of Sox2 in 2 dimensionally cultured AM‐1 and human primary ameloblastoma cells. Furthermore, the growth of 3 dimensionally cultured AM‐1 cells as suspended or embedded in gel was suppressed by treatment with Wnt signalling activators, VPA and CHIR99021, or antibodies to sclerostin, an antagonist of Wnt signalling. Conclusion We suggest that Wnt signalling activators are potential drug candidates to suppress CSCs in ameloblastoma., Ameloblastoma, a benign tumour of the odontogenic epithelium, presents significant recurrence rates and resistance to radiotherapy and chemotherapy, which compel patients to undergo radical resections, potentially causing surgical morbidity. In this study, we found that the exogenous activation of Wnt signalling using antibody (α‐SOST antibody) or chemicals (LiCl, VPA or CHIR9902) increases β‐catenin (β‐cat) in ameloblastoma, leading to an increase in β‐cathigh and Sox2‐ cells and decrease in β‐catlow and Sox2+ cells, the putative cancer stem cells (CSCs). This change of sub‐population in ameloblastoma results in the suppression of spheroid‐forming activity and invasiveness. The results suggest that Wnt signalling activators may serve as potential drug candidates to suppress CSCs in ameloblastoma.

We theoretically investigate spin-orbit torques in insulator/ferromagnet/normal-metal structures with a focus on interfacial spin-orbit coupling effect at an insulator/ferromagnet interface. Based on the spin drift-diffusion formalism generalized to consider transverse spin currents in a ferromagnet and the boundary condition to consider transverse spin currents leaving from a ferromagnet, we find that interfacial spin-orbit coupling at the insulator/ferromagnet interface contributes to dampinglike spin-orbit torque, which is important for current-driven magnetization dynamics, even when the interfacial spin-orbit coupling generates the only fieldlike component. We also calculate spin-orbit torques in a single ferromagnet sandwiched by two dissimilar insulators, which provides additional information about interfacial spin-orbit interaction at insulator/ferromagnet interfaces.

We investigate the effects of interfacial oxidation on the perpendicular magnetic anisotropy, magnetic damping, and spin-orbit torques in heavy-metal (Pt)/ferromagnet (Co or NiFe)/capping (MgO/Ta, HfOx, or TaN) structures. At room temperature, the capping materials influence the effective surface magnetic anisotropy energy density, which is associated with the formation of interfacial magnetic oxides. The magnetic damping parameter of Co is considerably influenced by the capping material (especially MgO) while that of NiFe is not. This is possibly due to extra magnetic damping via spin-pumping process across the Co/CoO interface and incoherent magnon generation (spin fluctuation) developed in the antiferromagnetic CoO. It is also observed that both antidamping and field-like spin-orbit torque efficiencies vary with the capping material in the thickness ranges we examined. Our results reveal the crucial role of interfacial oxides on the perpendicular magnetic anisotropy, magnetic damping, and spin-orbit torques.

Hypoxia is a state of inadequate supply of oxygen. Increasing evidence indicates that a hypoxic environment is strongly associated with abnormal organ development. Oxygen nanobubbles (ONBs) are newly developed nanomaterials that can deliver oxygen to developing tissues, including hypoxic cells. However, the mechanisms through which nanobubbles recover hypoxic tissues, such as developing tooth germs remain to be identified. In this study, tooth germs were cultured in various conditions: CO2chamber, hypoxic chamber, and with 20% ONBs for 3 h. The target stages were at the cap stage (all soft tissue) and bell stage (hard tissue starts to form). Hypoxic tooth germs were recovered with 20% ONBs in the media, similar to the tooth germs incubated in a CO2chamber (normoxic condition). The tooth germs under hypoxic conditions underwent apoptosis both at the cap and bell stages, and ONBs rescued the damaged tooth germs in both the cap and bell stages. Using kidney transplantation for hard tissue formationin vivo, amelogenesis and dentinogenesis imperfecta in hypoxic conditions at the bell stage were rescued with ONBs. Furthermore, glucose uptake by tooth germs was highly upregulated under hypoxic conditions, and was restored with ONBs to normoxia levels. Our findings indicate that the strategies to make use of ONBs for efficient oxygen targeted delivery can restore cellular processes, such as cell proliferation and apoptosis, glucose uptake, and hypomineralization in hypoxic environments.

Spermatogenesis is an important cellular differentiation process that produces the male gametes and remains active throughout the individual's lifespan. Sertoli cell-only syndrome (SCO) refers to the dysfunction of the male reproductive system, including infertility. Accurate self-renewal of spermatogonial stem cells (SSCs) is essential to prevent SCO syndrome. This study investigated the role of microtubule-associated serine/threonine kinase family member 4 (MAST4) in spermatogenesis in mice. MAST4 was localized in Sertoli cells before puberty, providing a somatic niche for spermatogenesis in mice and MAST4 expression shifted to Leydig cells and spermatids throughout puberty. Mast4 knockout (KO) testes were reduced in size compared to wild-type testes, and germ cell depletion associated with an increase in apoptosis and subsequent loss of tubular structure were similar to the SCO phenotype. In addition, MAST4 phosphorylated the Ets-related molecule (ERM), specifically the serine 367 residue. The phosphorylation of ERM ultimately controls the transcription of ERM target genes related to SSC self-renewal. The expression of spermatogenesis-associated proteins was significantly decreased whereas Sertoli cell markers were increased in Mast4 KO testes, which was well-founded by RNA-sequencing analysis. Therefore, MAST4 is associated with the fibroblast growth factor 2 (FGF2)/ERM pathway and this association helps us explore the capacity of SSCs to maintain a vertebrate stem cell niche.

Cleft palate is one of the most common craniofacial defects in newborn babies. The characteristics of this genetic disease produce soft and hard tissue defects on the lip and maxilla, which cause not only aesthetic but also functional problems with speech, eating, and breathing. Bone grafts using autologous cancellous bone have been a standard treatment to repair the hard tissue defect in cleft palates. However, such grafts do not fully integrate into host bone and undergo resorption. To overcome engraftment problems, it is common to engineer new tissues with a combination of multipotent cells and biomaterial frameworks. Here, we manufactured cell sheets for bone repair of cleft palates derived from two osteogenic cell sources, human mesenchymal stem cells (hMSCs) and stem cells from human exfoliated deciduous teeth (SHEDs). Cell sheets made from hMSCs and SHEDs gave rise to in vitro calcification, which indicated the osteogenic potential of these cells. The cell sheets of hMSCs and SHEDs expressed the bone-specific osteogenic markers, osterix, osteocalcin, and osteopontin, following insertion into ex vivo-cultured embryonic palatal shelves and in ovo culture. In conclusion, we showed that osteogenic stem cell sheets have mineralization potential and might represent a new alternative to autologous bone transplantation in the reconstruction of cleft palates.

The skin wound healing ability of animals differs depending on the environment. The gerbil wound model showed a different wound healing mechanism than was known thus far. Many other wound healing mechanisms have been found to involve transforming growth factor-beta 1 (TGF-β1). However, in the wound healing of gerbil skin, the expression of TGF-β1 seems to be not enough compared to mouse. In this study, we compared the wound healing process of gerbil and mouse back skin. At 3 days after wounding, the TGF-β1 level was downregulated in gerbil skin wound healing compared mouse. In addition, gerbils have fewer integrin signals related to the regulation of TGF-β activation and signaling. Despite lacking these factors, the wound healing results in the gerbil are similar to those for skin wound healing in mice. In contrast, in gerbil skin wound healing, the basal skin layer showed hyperplasia in re-epithelialization, more production of hair follicles, and low probability of collagen infiltration at the late stages of wound healing. These data suggest that different wound healing mechanisms are present in the mammals.

This paper compares vertical integration and vertical separation with network externalities. Contrary to conventional wisdom, if network effects are stronger than the threshold level of the network externality parameter, manufacturers’ strategic choices of wholesale prices move in opposite directions (i.e., wholesale prices may be strategic substitutes under Bertrand competition). Second, if the strength of network effects is strong enough, both profits and outputs are larger under vertical separation than under integration. Finally, if network effects are strong (weak), outputs (wholesale prices, retail prices), consumer surplus, and social welfare are higher (lower) under separation than integration.

This study examines the determinants of Merger and Acquisition (M & A) when manufacturing firms integrate with retailing firms. We examine a manufacturing duopoly in which each upstream firm sells the output to its exclusive retailing firm. In sequence of the timing of game, the strategic variables are set as Research and Development (R & D) investment, wholesale price by manufacturing firms and sales volume by retailing firms. The study concludes that degree of investment efficiency, product differentiation, and market size play important roles in vertical integration. Our conclusion shows that if product differentiation becomes greater, the vertical integration increases. Secondly, if the market size becomes larger, the vertical integration increases. Thirdly, the vertical integration increases when investment efficiency becomes higher. Our theoretical findings are also supported by the empirical results with the listed Japanese company data from 1996 to 2016.

Considering the interplay between intra-firms (own retailing firms) and inter-firms (rival retailing firms) competition in vertically related markets, we compare linear tariffs and two-part tariffs pricing. In contrast to previous results, we show that when both products are sufficiently close substitutes, there is a threshold level of the number of retailing firms, beyond which each manufacturing firm’s profits are larger under linear tariffs pricing than under two-part tariffs pricing. It shows the contradictions to the conventional wisdom that two-part tariffs pricing is always better than linear tariffs pricing from the viewpoint of manufacturing firms. We also show that the wholesale prices increase as the number of retailing firms increases under two-part tariffs pricing, regardless of the degree of product substitutability.

By incorporating port competition into a third-market model consisting of two exporting firms and one importing country, we demonstrate the endogenous choice of port structures (i.e. privatization or public ownership) under either Bertrand or Cournot competition. In contrast to previous studies on port competition, we analyze the port strategy in view of all trading countries (i.e. importing country and exporting countries). We find that regardless of transport cost, the port ownership strategy alters according to exporting firm’s competition mode. Under Bertrand competition, the choice of port ownership structure depends on the degree of imperfect substitutability. However, under Cournot competition, all trading countries choose same ownership structures of each port. By comparing equilibrium of each competition mode, we show that welfare of exporting country under Cournot competition is higher than under Bertrand competition if goods are sufficiently substitutes. In contrast, importing country p...

This study investigates the strategic disclosure of a downstream firm’s information regarding cost-reducing investment in a vertically related industry. Disclosing information affects an (common) upstream firm’s input price (i.e., vertical strategic effects) and a rival downstream firm’s output level (i.e., horizontal strategic effects). We show that the downstream firm is willing to withhold its information as the products become more differentiated because the horizontal strategic effects decrease with the products differentiation degree. This implies that non-disclosure, rather than disclosure, can convey an aggressive investment (i.e., lower marginal costs) to a rival downstream firm when the products are sufficiently differentiated. Moreover, we show that the downstream firm may disclose its information and pursue its investment at a minimum level when the products are extremely differentiated. In this case, they desire to reveal high marginal costs (i.e., a low investment level) to the upstream firm to reduce the input price, regardless of horizontal market competition.

In the presence of network externalities, we compare the stability of collusion under Bertrand and Cournot duopoly with differentiated products. Contrast to previous studies, we show that (i) firms have stronger incentive to collude under Bertrand competition than under Cournot competition in the sense of wide range of network externalities; (ii) collusion in prices (quantities) is more stable than in quantities (prices) if network externalities is strong (weak).

Fershtman and Judd (1987) show that profit-oriented owners delegate pricing decisions to managers through contracts that incentivize them to behave less aggressively. Hoernig (2012) extends their analysis to environments with network effects and finds that, when network effects are strong enough, the result is reversed and that optimal delegation contracts incentivize managers to behave more aggressively. This paper revisits Hoernig (2012) by assuming that consumers form expectations about network sizes before owners choose delegation contracts, in contrast with Hoernig’s (2012) assumption that expectations are formed after the contracts are chosen. That is, the current study employs fulfilled (or passive) expectations, while Hoernig (2012) uses rational (or responsive) expectations. We show that under the fulfilled expectations, Fershtman and Judd’s (1987) results hold, regardless of the strength of the network effect.

Considering the interplay between network externalities and the degree of product substitutability in a vertical structure, we compare the outcomes of vertical integration and vertical separation. In contrast to previous results, we show that when both products are sufficiently close substitutes, there is a threshold level of the network externality parameter, beyond which vertical separation is more efficient than vertical integration. This is due to the internalization of the network externality by a multiproduct monopolist, which, in the balance between the extensive and intensive margin, leads to higher output prices.