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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.

Lower corrected calcium (cCa) levels are associated with a better prognosis among incident dialysis patients. However, cCa frequently overestimates ionized calcium (iCa) levels. The prognostic importance of the true calcium status defined by iCa remains to be revealed. We conducted a retrospective cohort study of incident hemodialysis patients. We collected data of iCa levels immediately before the first dialysis. We divided patients into three categories: apparent hypocalcemia (low iCa; <1.15 mmol/L and low cCa; <8.4 mg/dL), hidden hypocalcemia (low iCa despite normal or high cCa), and normocalcemia (normal iCa). The primary outcome was the composite of all-cause death and cardiovascular diseases after hospital discharge. Among the enrolled 332 patients, 75% of the patients showed true hypocalcemia, defined as iCa <1.15 mmol/L, 61% of whom showed hidden hypocalcemia. In multivariate Cox models including other potential risk factors, true hypocalcemia was a significant risk factor (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.03–5.34), whereas hypocalcemia defined as corrected calcium <8.4 mg/dL was not. Furthermore, hidden hypocalcemia was significantly associated with an increased risk of the outcome compared with normocalcemia (HR, 2.56; 95% CI, 1.11–5.94), while apparent hypocalcemia was not. Patients with hidden hypocalcemia were less likely to receive interventions to correct hypocalcemia, such as increased doses of active vitamin D or administration of calcium carbonate, than patients with apparent hypocalcemia (odds ratio, 0.45; 95% CI, 0.23–0.89). Hidden hypocalcemia was a strong predictor of death and cardiovascular events, suggesting the importance of measuring iCa.

The prognostic value of electrocardiograms (ECGs) has been reported in predialysis patients but not in incident hemodialysis patients with overhydration and electrolyte disturbances, both of which potentially affect ECG results. We performed a retrospective multicenter cohort study involving incident hemodialysis patients and examined whether ECG parameters immediately before hemodialysis initiation can predict subsequent cardiovascular disease (CVD) using Cox proportional hazards models. We explored potential effect modifications by several electrolytes on the predictive power of ECG abnormalities. Among the 618 enrolled patients, 16%, 10%, 46%, and 22% showed a PR interval ≥ 200 ms, QRS interval ≥120 ms, QTc interval ≥ 450/460 ms (male/female), and left ventricular hypertrophy (LVH) by voltage criteria, respectively. Over a median 3-year follow-up, 19% and 16% of the patients developed atherosclerotic and nonatherosclerotic CVD, respectively. The Cox regression model results revealed that the sum of the number of abnormalities in PR, QRS, and QT intervals was a significant risk factor for nonatherosclerotic CVD (hazard ratios (HRs) [95% confidence interval (CI)]: 1.58 [1.24-2.01] per number of abnormalities). The predictive value of LVH for atherosclerotic CVD was attenuated over time. At up to 36 months, although the proportional hazards assumption was met, LVH was significantly associated with atherosclerotic CVD (HR [95% CI]: 1.89 [1.15-3.11]). The adjusted HR was particularly high (HR [95% CI]: 4.02 [1.68-9.60]) among patients who were in the lowest tertile of serum magnesium levels (P for interaction = 0.04). PR, QRS, and QT prolongation additively predicted nonatherosclerotic CVD, while LVH predicted atherosclerotic CVD in the short term.

The bovine genetic variant A2 beta-casein is associated with fewer digestive and absorption issues compared to A1 beta-casein, leading to increased global demand for A2 milk. However, contamination with the A1 variant during collection, transportation, or sterilization of A2 milk poses a risk, necessitating a verification test to ensure A2 milk does not contain A1 beta-casein. We developed an A1-specific monoclonal antibody (mAb) and a general mAb that reacts with both A1 and A2 variants, using the iliac lymph node method. A sandwich ELISA was created using the general mAb as the capture antibody and the A1-specific mAb as the detection antibody to identify A1 beta-casein in milk. This ELISA successfully detected A1 beta-casein in raw and pasteurized A2 milk, including ultra-high temperature treated milk. The test identified A1 beta-casein when the A1 spike in A2 milk exceeded 1% in volume, indicating its capability to detect contamination from one A1A1 cow in a herd of one hundred A2A2 cows. The developed A1 beta-casein ELISA is suitable for high-throughput analysis and valuable for monitoring A1 beta-casein contamination in commercially produced A2 milk.

Getting stuck is an inevitable part of learning programming. Long-term stuck decreases the learner’s motivation and learning efficiency. The current approach to supporting learning in lectures involves teachers finding students who are getting stuck, reviewing their source code, and solving the problems. However, it is difficult for teachers to grasp every learner’s stuck situation and to distinguish stuck or deep thinking only by their source code. Teachers should advise learners only when there is no progress and they are psychologically stuck. This paper proposes a method for detecting when learners get stuck during programming by using multi-modal data, considering both their source code and psychological state measured by a heart rate sensor. The evaluation results of the proposed method show that it can detect more stuck situations than the method that uses only a single indicator. Furthermore, we implemented a system that aggregates the stuck situation detected by the proposed method and presents them to a teacher. In evaluations during the actual programming lecture, participants rated the notification timing of application as suitable and commented that the application was useful. The questionnaire survey showed that the application can detect situations where learners cannot find solutions to exercise problems or express them in programming.

Background Senescence is a well-known risk factor for several diseases, such as neurodegenerative disorders. Therefore, studies exploring the mechanisms underlying aging are expected to guide the discovery of novel drug targets and biomarkers for these diseases. However, a comprehensive overview of the metabolic and lipidomic changes in healthy aging mammals is lacking. To understand the changes of metabolism with aging, especially lipid metabolism, we analyzed the metabolomes and lipidomes of the cerebral cortex, liver, femoral muscle, and epididymal fat in young and aged mice. Results Two-dimensional cluster analysis revealed clear separation between the metabolite profiles of the aged and young groups. Deoxydihydroceramide (doxDHCer), deoxyceramide (doxCer), and ether-linked diacylglycerol (DAG) levels were elevated during aging. Conclusion This is the first report of age-related variations in deoxysphingolipid and ether-linked DAG levels in mice. DoxCer, doxDHCer, and ether-linked DAGs may be associated with senescence in mammalian tissues.

Background Volume overload is common and associated with high mortality in patients on peritoneal dialysis (PD). Traditional strategies including diuretics, water/salt restriction, and icodextrin-based solutions cannot always fully correct this condition, necessitating novel alternative strategies. Recent studies confirmed the expression of sodium–glucose cotransporter 2 (SGLT2) in the human peritoneum. Experimental data suggest that SGLT2 inhibitors decrease glucose absorption from the PD solution, thereby increasing the ultrafiltration volume. This trial aims to assess whether SGLT2 inhibitors increase the ultrafiltration volume in patients on PD. Methods The EMPOWERED trial (trial registration: jRCTs051230081) is a multicenter, randomized, double-blind, placebo-controlled, crossover trial. Patients with clinically diagnosed chronic heart failure are eligible regardless of the presence of diabetes if they use at least 3 L/day glucose-based PD solutions. Participants will be randomly assigned (1:1) to receive empagliflozin 10 mg once daily and then placebo or vice versa. Each treatment period will last 8 weeks with a 4-week washout period. This study will recruit at least 36 randomized participants. The primary endpoint is the change in the daily ultrafiltration volume from baseline to week 8 in each intervention period. The key secondary endpoints include changes in the biomarkers of drained PD solutions, renal residual function, and anemia-related parameters. Conclusions This trial aims to assess the benefit of SGLT2 inhibitors in fluid management with a novel mechanism of action in patients on PD. It will also provide insights into the effects of SGLT2 inhibitors on solute transport across the peritoneal membrane and residual renal function.

Electron Cyclotron Resonance Ion Sources (ECRIS) are essential for generating highly charged heavy ions in accelerator facilities. However, maintaining stable and high beam intensity remains a challenge due to complex and time-dependent fluctuations in ion source conditions. In this study, we propose a novel beam intensity prediction method that integrates plasma chamber images with numerical operational data using a convolutional neural network (ResNet50). Experiments were conducted using two ion sources HyperECRIS (14 GHz) and R28G-K (28 GHz)—to evaluate the model’s performance. The results demonstrate that incorporating image data significantly improves prediction accuracy, especially in scenarios where numerical parameters remain constant but beam intensity varies. Furthermore, we show that retraining the model with recent data enables robust long-term operation, reducing the need for initial startup data.

In the Japan Dialysis Active Vitamin D (J-DAVID) trial, oral alfacalcidol numerically, but not significantly, increased the risk of cardiovascular events among patients undergoing hemodialysis. Because the cardiovascular effect of alfacalcidol could be modulated by bone turnover status, this post-hoc analysis of the J-DAVID examined how alkaline phosphatase (ALP), a more precise marker of bone turnover than parathyroid hormone (PTH), modifies the impact of alfacalcidol. The J-DAVID was a 48-month, open-label, randomized controlled trial comparing oral alfacalcidol with no vitamin D receptor activators use in terms of cardiovascular events among 976 hemodialysis patients without secondary hyperparathyroidism. This post-hoc analysis included 959 patients with available data on baseline ALP. The median [25–75th percentile] baseline ALP level was 234 [183–296] U/L. In a Cox proportional hazards model, ALP did not significantly modify the effect of alfacalcidol on the rate of cardiovascular events or all-cause death ( P for effect modification = 0.54 and 0.74, respectively). The effect of alfacalcidol on time-series changes in calcium, phosphate, and intact PTH were similar across ALP subgroups. In conclusion, oral alfacalcidol did not significantly affect cardiovascular outcomes irrespective of bone turnover status.

Background Hemoglobin levels usually decline before dialysis initiation. The influence of overhydration on anemia progression and iron sequestration is poorly documented. Furthermore, clinical implications of anemia at dialysis initiation remain to be elucidated. Methods This multicenter retrospective cohort study enrolled incident dialysis patients. The patients were stratified by tertiles of overhydration rate (OH-R) defined by (BW − DW)/DW*100 (BW: body weight just before dialysis initiation, DW: dry weight). Time courses (6 months before, to 1 month after, dialysis initiation) of hemoglobin, C-reactive protein (CRP), and iron sequestration index (ISI) were examined using mixed effects models. We used Cox models to identify anemia parameters predicting subsequent cardiovascular disease (CVD). Results Among the 905 enrolled patients, hemoglobin levels gradually decreased before dialysis initiation and rapidly increased thereafter. An inverse V-shaped time course was observed for CRP and ISI with an increase during dialysis initiation. Patients with a higher OH-R showed lower hemoglobin levels along with higher CRP and ISI levels before dialysis initiation. Mean corpuscular hemoglobin concentration (MCHC) was more stable before dialysis initiation than were mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Low MCHC (< 32 g/dL) was independently associated with the incidence of nonatherosclerotic CVD. Patients with low MCHC tended to have increased left ventricular wall thickness and left atrial diameter. Conclusions Progression of anemia before dialysis among overhydrated patients may mainly occur through hemodilution and iron sequestration partly induced by inflammation. Low MCHC reflects left atrial overload and left ventricular hypertrophy and hence may predict nonatherosclerotic CVD. Graphic abstract