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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.

Parasite resistance traits in aquaculture species often have moderate heritability, indicating the potential for genetic improvements by selective breeding. However, parasite resistance is often synonymous with an undesirable negative correlation with body size. In this study, we first tested the feasibility of genomic selection (GS) on resistance to heterobothriosis, caused by the monogenean parasite Heterobothrium okamotoi , which leads to huge economic losses in aquaculture of the tiger pufferfish Takifugu rubripes. Then, using a simulation study, we tested the possibility of simultaneous improvement of parasite resistance, assessed by parasite counts on host fish (HC), and standard length (SL). Each trait showed moderate heritability (square-root transformed HC: h 2  = 0.308 ± 0.123, S.E.; SL: h 2  = 0.405 ± 0.131). The predictive abilities of genomic prediction among 12 models, including genomic Best Linear Unbiased Predictor (GBLUP), Bayesian regressions, and machine learning procedures, were also moderate for both transformed HC (0.248‒0.344) and SL (0.340‒0.481). These results confirmed the feasibility of GS for this trait. Although an undesirable genetic correlation was suggested between transformed HC and SL ( r g  = 0.228), the simulation study suggested the desired gains index can help achieve simultaneous genetic improvements in both traits.

BackgroundThe aim of this retrospective study was to determine the effect of skeletal muscle and body fat on liver function in patients with nonalcoholic fatty liver disease (NAFLD) diagnosed by liver biopsy.MethodsAmong the 219 patients with NAFLD enrolled in this study was a cohort of 139 patients who had their body composition measured with Inbody720 at baseline and at ≥ 1 year postbaseline, to elucidate the relationship between liver function and changes in skeletal muscle and body fat mass. Multivariate analysis was used to identify factors influencing low skeletal muscle mass index (SMI, defined as 7 kg/m2 in men, and 5.7 kg/m2 in women) and the skeletal muscle mass to body fat mass ratio (SF ratio).ResultsOf the 219 patients enrolled, 27 (12.3%) had a low SMI. Patient age (> 70 years) and female gender were identified as risk factors for low SMI. Hepatic fibrosis was not associated with SMI. In the cohort followed up at baseline and 12 months later, transaminase activity, body fat mass, and SMI significantly decreased over time. Changes in the SF ratio were significantly associated with changes in liver function. An increase in the SF ratio [hazard ratio (HR) 10.99 in men, 6.849 in women] was a predictor of reduced ALT, independent of age and other backgrounds.ConclusionsIn the patients with NAFLD, SMI was decreased, even in the early stages of NAFLD. Therapeutic strategies for NAFLD require a reduction in body fat mass and the maintenance of skeletal muscle is also needed.

The tiger pufferfish Takifugu rubripes is one of the most valuable aquaculture species in Japan. In this study, we investigated the genetic variation in resistance to heterobothriosis caused by a host-specific monogenean parasite, Heterobothrium okamotoi, in the tiger pufferfish, and examined the possibility of selective breeding for enhancing resistance traits. A total of 299 tiger pufferfish produced from ten males and one female caught from the wild were experimentally exposed to oncomiracidia of H. okamotoi. The number of parasites on the gills at 3 weeks post-infection ranged from 0 to 68, with great variation observed both within and between families. The estimated heritability for parasite density was small, but significantly different from zero (H2 = 0.098; 95% confidence interval: 0.025–0.201). Although we may have sampled a limited fraction of the genetic variance as the number of families was small, the results suggest that there are genetic components that affect heterobothriosis resistance in the species. A positive phenotypic correlation was observed between parasite count and standard length (r = 0.66). Further investigation of the genetic correlation between the two traits using larger families is needed to assess the impacts of selective breeding on heterobothriosis resistance in this species.

Background/Aims: The purpose of this study was to evaluate the safety and efficacy of gastric endoscopic submucosal dissection (ESD) using the Clutch Cutter (CC), a scissor-type knife, compared with those of procedures using conventional devices. Methods: This single-center retrospective study evaluated 237 patients with early gastric cancer: 83 who underwent ESD using the CC group and 154 who underwent ESD using the insulated-tip knife 2 (IT2 group). Clinicopathological features and technical outcomes were compared between the 2 groups using a propensity score-matched analysis. Results: In 61 pairs of matched patients, there was no significant difference in R0 resection, perforation, or postoperative bleeding between the CC and IT2 groups. Comparisons between the 2 groups showed similar treatment outcomes for an expert endoscopist. Nevertheless, there were significant differences between the 2 groups for nonexperts in terms of self-completion (61.7 and 24.5%, respectively, p < 0.001), mean procedure times (45 and 61 min, respectively, p = 0.002), and mean numbers of intraoperative bleeding points and bleeding points requiring hemostatic forceps (3 and 0 vs. 8 and 3, respectively, p < 0.001). Conclusion: Better self-completion rates and shorter procedure times were noted for gastric ESD using the CC by nonexperts than for that using IT2, probably due to hemostatic efficacy.

BackgroundHepatic fibrosis is an independent risk factor for mortality and liver-related events in patients with nonalcoholic fatty liver disease (NAFLD). PNPLA3 rs738409 has been associated with fibrosis in viral and non-viral hepatitis. TLL1 rs17047200 also has been associated with developing hepatocellular carcinoma probably via hepatic fibrogenesis. We estimated the impact of these genetic polymorphisms on hepatic fibrosis in Japanese patients with NAFLD.MethodsWe analyzed the association between these genetic variants and the backgrounds of 817 individuals who received health checkups (health check cohort) from 2012 to 2014. Then, we investigated the relationship between genetic variants and liver histology in 258 consecutive patients with biopsy-proven NAFLD in Japan (NAFLD cohort) from 2012 to 2017 (UMIN000027399).ResultsThe prevalence of PNPLA3 CG/GG in the NAFLD cohort was higher than that in the health check cohort (p < 0.001). The prevalence of patients with advanced fibrosis (stages 3–4) was higher for PNPLA3 genotype CG/GG than CC (p = 0.048) and for TLL1 genotype AT/TT than AA (p = 0.044). The high-risk group which had at least two risk alleles of these variants was more likely to have advanced fibrosis (p = 0.004). Multivariate analysis identified body mass index [odds ratio (OR) 1.123, serum AST (OR 1.037, p = 0.004], serum albumin (OR 0.247, p = 0.032), and genetic high risk (OR 2.632, p = 0.026) as predictors of advanced fibrosis.ConclusionsIn Japanese patients with NAFLD, individuals with risk alleles of PNPLA3 and TLL1 may have a risk of advanced fibrosis.

Background: Management of antithrombotic agents during endoscopic treatment changed after the publishing of ­Japan Gastroenterological Endoscopy Society guidelines for gastroenterological endoscopy in antithrombotic drug users (GL-2012). Objectives: We aimed to evaluate the effect of implementing antithrombotic agent management guidelines (GL-2012) on postoperative bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) and on the prevention of thromboembolic events. Methods: A total of 1,264 patients who underwent ESD for EGC at Kyoto Prefectural University Hospital between June 2002 and March 2017 were enrolled and divided into 2 groups: 621 patients before the publication of GL-2012 (Pre-GL group) and 643 patients after (Post-GL group). Relationships between postoperative bleeding and various clinicopathological factors in each group were investigated through propensity score-matching analysis. Results: In the Pre-GL group, antihypertensive agent use (p < 0.01) and upper third of the stomach (p < 0.01) were significantly related to postoperative bleeding in univariate analysis. Antihypertensive agent use (OR 4.6, 95% CI 1.6–12.8) and upper third of the stomach (OR 4.9, 95% CI 1.8–13.4) were significantly related to postoperative bleeding in multivariate analysis. In the Post-GL group, antihypertensive agent use (p < 0.01), dual antiplatelet agents use (p < 0.01), anticoagulant agents use (p < 0.01), and heparin replacement therapy (p < 0.01) were significantly related to postoperative bleeding in univariate analysis. Antihypertensive agent use (OR 3.4, 95% CI 1.1–9.6), dual antiplatelet agents (OR 12.3, 95% CI 2.4–63.0), and heparin replacement therapy (OR 10.2, 95% CI 2.5–41.5) were significantly related to postoperative bleeding in multivariate analysis. Conclusions: The adherence to GL-2012 might reduce risk of thromboembolic events. On the other hand, dual antiplatelet agents therapy and heparin replacement therapy were the new independent risk factors for ESD postoperative bleeding in EGC after GL-2012. Especially as for heparin replacement therapy, uninterrupted warfarin or a temporary short interruption of direct oral anticoagulants without heparin replacement therapy might be recommended rather than heparin replacement therapy.

We investigated the influence of paternal effects on progeny survival of the fugu Takifugu rubripes when multiple families were reared in communal tanks. Four males were crossed with four females in a factorial cross to give 16 families, and the half-siblings sharing the same mother were reared together. Male parentage was determined using microsatellite markers at 35 days. Although the maternal and tank effects were large, it was possible to detect paternal effects in relative survival rate and standard length (standardized in each tank), which were found to be significantly correlated. Paternal effects on growth rate suggest the existence of family-based differences in competition for food. Furthermore, genetic differences affecting larval growth appeared to be partly responsible for the disparity in survival rate observed among families.

The tiger pufferfish (fugu), Takifugu rubripes, is a model fish that has had its genome entirely sequenced. By performing genomewide linkage analyses, we show that the sex of fugu is determined by a single chromosomal region on linkage group 19 in an XX–XY system.

Sodium-glucose cotransporter-2 inhibitors (SGLT2I) have been reported to have renal-protective effects in patients with type 2 diabetes (T2DM). This a retrospective study aimed to evaluate the effect of SGLT2I on renal function in patients with nonalcoholic fatty liver disease (NAFLD) and T2DM. We analyzed 69 consecutive patients with a biopsy-proven NAFLD and T2DM with an estimated glomerular filtration rate (eGFR) >60 mL/min. Of these 69 patients, 22 received SGLT2I and 47 were treated without SGLT2I. Liver function and eGFR were analyzed at baseline and after three years. Body mass index, liver function and HbA1c improved significantly in both groups. In the total population, the median eGFR declined from 80.7 mL/min at the baseline to 74.9 mL/min at the end of follow-up. The median eGFR at the baseline/end of follow-up was 81.2/80.4 mL/min in patients treated with SGLT2I and 80.2/70.8 mL/min in patients treated without SGLT2I. Multivariate analysis identified an increased FIB-4 index with an odds ratio (OR) of 4.721, (p = 0.045) and SGLT2I treatment (OR 0.263, p = 0.033) as predictive factors for decreased eGFR. SGLT2I treatment has a protective effect on the renal function for NAFLD with T2DM. A long-term, randomized, controlled trial is warranted to confirm the renal protective effect of SGLT2I in NAFLD patients with T2DM.