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Heterogametic sex chromosomes have evolved independently in various lineages of vertebrates. Such sex chromosome pairs often contain nonrecombining regions, with one of the chromosomes harboring a master sex-determining (SD) gene. It is hypothesized that these sex chromosomes evolved from a pair of autosomes that diverged after acquiring the SD gene. By linkage and association mapping of the SD locus in fugu (Takifugu rubripes), we show that a SNP (C/G) in the anti-Müllerian hormone receptor type II (Amhr2) gene is the only polymorphism associated with phenotypic sex. This SNP changes an amino acid (His/Asp384) in the kinase domain. While females are homozygous (His/His384), males are heterozygous. Sex in fugu is most likely determined by a combination of the two alleles of Amhr2. Consistent with this model, the medaka hotei mutant carrying a substitution in the kinase domain of Amhr2 causes a female phenotype. The association of the Amhr2 SNP with phenotypic sex is conserved in two other species of Takifugu but not in Tetraodon. The fugu SD locus shows no sign of recombination suppression between X and Y chromosomes. Thus, fugu sex chromosomes represent an unusual example of proto-sex chromosomes. Such undifferentiated X-Y chromosomes may be more common in vertebrates than previously thought.

The tiger pufferfish (fugu) is one of the most important food fishes in East Asia. Since its testes are regarded as a delicacy, sex determination is economically relevant. Previous studies have identified a missense single-nucleotide polymorphism (SNP) in the Amhr2 ( anti-Müllerian hormone receptor type II ) gene as a strong candidate for a master sex-determining polymorphism. To distinguish genotypic sex efficiently, we developed a high-resolution melting (HRM) assay for this SNP site. By screening 396 fish from two independent crosses reared under controlled conditions, we observed perfect concordance between the SNP genotype and phenotypic sex. Thus, this method holds great potential for use in high-throughput sexing. When analyzing 293 progeny from a third cross reared under unknown conditions, we unexpectedly found that 25 % of phenotypic males exhibited female genotype. These results suggest that environmental factors such as rearing conditions could influence the sex-determination pathway in pufferfish. Alternatively, genetic modifiers might override the signals from Amhr2 . This finding raises a concern regarding enhanced stock management of this species, because sex-reversed fish could compromise the sex ratio in subsequent generations. The HRM assay will also be useful for monitoring the degree of sex reversal before release.

Hypofrontality is a state of decreased cerebral blood flow in the prefrontal cortex during executive function performance; it is commonly observed in patients with schizophrenia. Cognitive dysfunction, as well as the psychological symptoms of schizophrenia, influences the ability of patients to reintegrate into society. The current study investigated the effects of an interactive sports video game (IVG; Nintendo Wii™ Sports Resort) on frontal lobe function of patients with schizophrenia. A sample of eight patients (6 male and 2 female; mean age = 46.7 years, standard deviation (SD) = 13.7) engaged in an IVG every week for 3 months in a controlled, single-blind, crossover study. Before and after the intervention we examined frontal lobe blood-flow volume using functional near-infrared spectroscopy (fNIRS), and assessed functional changes using the Frontal Assessment Battery, Health-Related Quality of Life scale, and behaviorally-assessed physical function tests. fNIRS revealed that prefrontal activity during IVG performance significantly increased in the IVG period compared with the control period. Furthermore, significant correlations between cerebral blood flow changes in different channels were observed during IVG performance. In addition, we observed intervention-related improvement in health-related quality of life following IVG. IVG intervention was associated with increased prefrontal cortex activation and improved health-related quality of life performance in patients with schizophrenia. Patients with chronic schizophrenia are characterized by withdrawal and a lack of social responsiveness or interest in others. Interventions using IVG may provide a useful low-cost rehabilitation method for such patients, without the need for specialized equipment.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are increasingly recommended as first-line treatment for type 2 diabetes mellitus (T2DM), but head-to-head data comparing them with metformin, the canonical biguanide, remain sparse in Japan. To compare the long-term effectiveness and cost of initiating treatment with a biguanide versus an SGLT2 inhibitor, excluding the alternative class for 12 months but permitting other antidiabetic drugs, on a composite of major cardio-cerebrovascular events and all-cause death, and a composite of diabetic complications. We emulated a new-user cohort trial using the Shizuoka Kokuho Database (2014-2021). Patients initiating treatment with either a biguanide or an SGLT2 inhibitor, while avoiding the alternative class during the first 12 months but allowing other glucose-lowering agents, were included. Follow-up began at treatment initiation; those who received the comparator drug within 12 months were excluded. After 1:1 propensity-score matching on demographic, clinical, laboratory, and lifestyle variables, cause-specific Cox models estimated hazard ratios (HRs). Daily medication costs were compared. After matching, 1,246 patients (623 per group) were followed for a median of 2.9 years (maximum 7.2 years). Cardio-cerebrovascular composite: 44/623 biguanide users (7.1%) and 35/623 SGLT2 inhibitor users (5.6%) experienced a first event (HR 0.80, 95% CI 0.51-1.24). Diabetic complications: 86/623 (13.8%) vs. 78/623 (12.5%) (HR 0.88, 95% CI 0.70-1.13). Median daily drug cost was 124.7 JPY for biguanides and 184.0 JPY for SGLT2 inhibitors (P < 0.001). Using a large-scale regional database from Japan, we found that among adults with type 2 diabetes without prior major cardiac or renal disease, first-line treatment with an SGLT2 inhibitor did not reduce risks of cardio-cerebrovascular events, mortality, or complications compared with metformin, and cost about 50% more.

Western guidelines often recommend biguanides as the first-line treatment for diabetes. However, dipeptidyl peptidase-4 (DPP-4) inhibitors, alongside biguanides, are increasingly used as the first-line therapy for type 2 diabetes (T2DM) in Japan. However, there have been few studies comparing the effectiveness of biguanides and DPP-4 inhibitors with respect to diabetes-related complications and cardio-cerebrovascular events over the long term, as well as the costs associated. We aimed to compare the outcomes of patients with T2DM who initiate treatment with a biguanide versus a DPP-4 inhibitor and the long-term costs associated. We performed a cohort study between 2012 and 2021 using a new-user design and the Shizuoka Kokuho database. Patients were included if they were diagnosed with T2DM. The primary outcome was the incidence of cardio-cerebrovascular events or mortality from the initial month of treatment; and the secondary outcomes were the incidences of related complications (nephropathy, renal failure, retinopathy, and peripheral neuropathy) and the daily cost of the drugs used. Individuals who had experienced prior events during the preceding year were excluded, and events within 6 months of the start of the study period were censored. Propensity score matching was performed to compare between two groups. The matched 1:5 cohort comprised 529 and 2,116 patients who were initially treated with a biguanide or a DPP-4 inhibitor, respectively. Although there were no significant differences in the incidence of cardio-cerebrovascular events or mortality and T2DM-related complications between the two groups (p = 0.139 and p = 0.595), daily biguanide administration was significantly cheaper (mean daily cost for biguanides, 61.1 JPY; for DPP-4 inhibitors, 122.7 JPY; p<0.001). In patients with T2DM who initiate pharmacotherapy, there were no differences in the long-term incidences of cardio-cerebrovascular events or complications associated with biguanide or DPP-4 use, but the former was less costly.

The high susceptibility of the Ti–6Al–2Sn–4Zr–6Mo wt pct (Ti6246) alloy to microstructural changes stands as a challenge when processed by the laser powder bed fusion (LPBF) technology. However, leveraging the capabilities of the LPBF process to successfully control the microstructure (and/or crystallographic texture) of the Ti6246 could improve mechanical properties, particularly at elevated temperatures. In this study, the creep performance (at 500 °C) of Ti6246 fabricated from three different LPBF processing conditions and heat-treated (HT) at 885 °C were investigated. In the as-built state, all the LPBFed-Ti6246 exhibited columnar microstructures with crystallographic lamellar-like microstructure (CLM), a near-single crystal-like microstructure (SCM), and polycrystalline microstructure (PCM) textures, respectively. At low applied stresses (100–300 MPa), diffusional creep was the dominant deformation mechanism and its resistance depended on grain size. The reference β -forged-HT Ti6246, characterized by large equiaxed grains, exhibited the lowest strain rate compared to the columnar microstructure of SX1 (CLM)-HT, SX2 (SCM)-HT, and SX3 (PCM)-HT. Conversely, dislocation slip governed deformation at high applied stresses (400–580 MPa) and its efficacy depended on the α/ β interfaces in the microstructures. Disjointed columnar grains in SX1 (CLM)-HT and the deformation of the polycrystalline grains in SX3 (PCM)-HT indicated that the melt pool boundaries were unstable in the LPBFed-Ti6246. SX2 (SCM)-HT exhibited the longest creep life due to the relatively stable melt pool boundaries and the near < 001 > SCM crystallographic texture parallel to the applied stresses. Shallow ductile dimples and tears and the observation of laser scan tracks characterized the fracture surfaces of the LPBFed-Ti6246. These indicated that failure occurred by intergranular ductile fracture resulting from the formation of microvoids at the melt pool boundaries.

Purpose The objective of the present study was to ascertain the effect of immediate occlusal loading after implant placement on osseointegration and the micro/nanostructure of the surrounding bone. Methods After extraction of a rat maxillary right second molar, an implant was placed immediately with initial fixation (2 N< ). The implants were placed to avoid occlusal loading due to mastication, and in the loaded group, a superstructure was fabricated and subjected to occlusal loading. Bone morphometry, collagen fiber anisotropy, and biological apatite (BAp) crystallite alignment were quantitatively evaluated in both groups after extraction and fixation of the jaw bone at Days 7 and 21 after surgery. Results Osseointegration was observed in both groups. Bone morphometry showed significant differences in bone volume, trabecular number, trabecular thickness and bone mineral density (BMD) at Days 21 postoperatively ( P  < 0.05). A significant difference was also found in the trabecular separation at Days 7 postoperatively ( P  < 0.05). In the evaluation of collagen fiber anisotropy, collagen fiber bundles running differently from the existing bone were observed in both groups. In terms of BAp crystallite alignment, a specific structure was observed in the reconstructed new bone after implantation, and preferential orientation of BAp crystallite alignment was observed in the longitudinal direction of the implants in the Day 21 postoperative loaded group. Conclusion When sufficient initial fixation is achieved at the time of dental implant placement, then the applied masticatory load may contribute to rapidly achieving not only bone volume, but also adequate bone quality after implant placement.

Background There are many unclear points regarding local structural characteristics of the bone surrounding the implant reflecting the mechanical environment. Purpose The purpose of this study is to quantitatively evaluate bone quality surrounding implants placed into the femurs of mice in an unloading model, and to determine the influence of the mechanical environment on bone quality. Methods Twenty 12-week-old male C57BL6/NcL mice ( n = 5/group) were used as experimental animals. The mice were divided into two groups: the experimental group ( n = 10) which were reared by tail suspension, and the control group ( n = 10) which were reared normally. An implant was placed into the femur of a tail-suspended mouse, and after the healing period, they were sacrificed and the femur was removed. After micro-CT imaging, Villanueva osteochrome bone stain was performed. It was embedded in unsaturated polyester resin. The polymerized block was sliced passing through the center of the implant body. Next, 100-μm-thick polished specimens were prepared with water-resistant abrasive paper. In addition to histological observation, morphometric evaluation of cancellous bone was performed, and the anisotropy of collagen fibers and biological apatite (BAp) crystals was analyzed. Results As a result, the femoral cortical bone thickness and new peri-implant bone mass showed low values in the tail suspension group. The uniaxial preferential orientation of BAp c -axis in the femoral long axis direction in the non-implant groups, but biaxial preferential orientation of BAp c -axis along the long axis of implant and femoral long axis direction were confirmed in new bone reconstructed by implant placement. Collagen fiber running anisotropy and orientation of BAp c -axis in the bone surrounding the implant were not significantly different due to tail suspension. Conclusions From the above results, it was clarified that bone formation occurs surrounding the implant even under extremely low load conditions, and bone microstructure and bone quality adapted to the new mechanical environment are acquired.

In this study, we aimed to elucidate the effects and mechanism of action of valproic acid on hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells. Human induced pluripotent stem cells were differentiated into endodermal cells in the presence of activin A and then into hepatic progenitor cells using dimethyl sulfoxide. Hepatic progenitor cells were matured in the presence of hepatocyte growth factor, oncostatin M, and dexamethasone with valproic acid that was added during the maturation process. After 25 days of differentiation, cells expressed hepatic marker genes and drug-metabolizing enzymes and exhibited drug-metabolizing enzyme activities. These expression levels and activities were increased by treatment with valproic acid, the timing and duration of which were important parameters to promote differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells into hepatocytes. Valproic acid inhibited histone deacetylase activity during differentiation of human induced pluripotent stem cells, and other histone deacetylase inhibitors also enhanced differentiation into hepatocytes. In conclusion, histone deacetylase inhibitors such as valproic acid can be used to promote hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells.