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Liver cancer is a major health-care concern and its oncogenic mechanisms are still largely unclear. Persistent hepatocyte cell death is a common feature among various chronic liver diseases, the blocking of which presents as logical treatment. Therefore, we aimed at investigating tumor development in mice with hepatocyte-specific Bid depletion – a BH3-only Bcl-2 family member that amplifies apoptotic death signals. Hepatocyte-specific conditional Bid-knockout mice (Bid Δhep ) were injected with 25 mg/kg diethylnitrosamine (DEN) at 14 days of age, and liver tumorigenesis was investigated 9 months later. Additionally, different models of acute liver injury were used including: acute high-dose DEN challenge, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and carbon tetrachloride (CCL4) injection. Bid Δhep mice developed significantly fewer tumors, showed smaller maximal and average tumor size and reduced tumor incidence. In the acute DEN model, 48 h post injection we observed a significant reduction in liver injury in Bid Δhep animals, assessed via serum transaminases and liver histopathology. Furthermore, TNF- α , IL-1ß, cJUN and IL-6 mRNA expression was reduced. These findings were accompanied by reduced compensatory hepatocyte proliferation in Bid Δhep mice when compared with controls by immunohistochemistry for Ki67 and proliferating cell nuclear antigen 48 h after DEN injection. In the acute CCL4 model, Bid Δhep mice displayed reductions in liver injury and inflammation when compared with controls. No differences in liver injury and serum bilirubin levels were detected in Bid Δhep and Bid flo/flo mice fed with DDC, which induces bile duct injury and a ductular reaction. Our study demonstrates that in DEN-induced hepatocellular carcinoma, the inhibition of hepatocyte death pathways through Bid deletion protects animals from tumorigenesis. These results suggest that reducing hepatocyte cell death, liver inflammation and compensatory proliferation has a stronger beneficial effect than the potential side effect of enhancing tumor cell survival.

Bovine mastitis is primarily treated with antimicrobial agents. Anti-inflammatory agents are also used to alleviate clinical symptoms or reduce antimicrobial use. Glycyrrhizin is an anti-inflammatory agent used in the treatment of bovine mastitis, but its effects are not fully understood. We therefore examined the anti-inflammatory effects of glycyrrhizin both in vivo and in vitro. We first tested whether glycyrrhizin exerts anti-inflammatory effects using MAC-T cells, an immortalized bovine mammary epithelial cell line. Glycyrrhizin decreased the expression of interleukin (IL)-1β mRNA in a concentration-dependent manner in MAC-T cells stimulated with lipoteichoic acid (LTA). We then investigated the effects of glycyrrhizin in bovine mammary epithelial cells (bMECs), which seem to retain more of the characteristics of actual mammary epithelial cells. Stimulation with LTA or lipopolysaccharide significantly increased cytokine mRNA expression in bMECs. Glycyrrhizin exhibited a slight inhibitory effect, but no significant difference was observed. The effect of glycyrrhizin on LTA-induced mastitis was examined in lactating cows. Quarters were divided into test and control areas (test quarter: n=8, control quarter: n=7). All quarters were stimulated with LTA at the start of the trial (0 h). In the test quarter group, glycyrrhizin was administered via intramammary infusion. The somatic cell count and relative gene expression of IL-1β and tumor necrosis factor–α were significantly lower in test quarters than control quarters. Both the in vitro and in vivo studies showed that glycyrrhizin reduces the expression of proinflammatory cytokine genes in response to LTA-induced inflammation and partially revealed the mechanism of the anti-inflammatory effect of glycyrrhizin on mastitis. Further investigations involving field cases of mastitis with bacterial infections are needed to demonstrate the anti-inflammatory effect of glycyrrhizin on bovine mastitis.

Background Well-being, encompassing psychological, social, and physical dimensions, is vital for healthy ageing. The concept of flourishing provides a comprehensive framework that integrates multiple domains essential for overall well-being. Gardening, a multicomponent activity, has been associated with well-being; however, few studies have comprehensively assessed associations with multidimensional well-being. This study examined the association between gardening and flourishing among older adults in Tokyo. Methods In 2023, a postal survey was conducted among 2,088 adults aged ≥65 years (mean age: 74.8 ± 6.2 years) in Tokyo. Gardening status was categorised as gardening or non-gardening. 12 items were used to assess key domains of individual flourishing: (1) happiness and life satisfaction, (2) mental and physical health, (3) meaning and purpose, (4) character and virtue, (5) close social relationships, (6) financial and material stability. Overall flourishing was calculated as the average of domains 1-5, while secure flourishing included all six domains. Covariates included sex, age, education, income, marital status, employment and housing type. Multiple imputation was used for missing data. Associations were estimated using robust regression models with Bonferroni correction, and standardised coefficients (β) with 95% confidence intervals (CI) were calculated. Results 46.6% of the participants were gardeners. Gardening was positively associated with all flourishing domains: 1: β = 0.36 (95% CI: 0.16-0.55), 2: 0.28 (0.10-0.47), 3: 0.38 (0.18-0.57), 4: 0.45 (0.26-0.64), 5: 0.38 (0.18-0.58), and 6: 0.38 (0.14-0.62). Gardeners also had significantly higher overall flourishing: 0.37 (0.18-0.55) and secure flourishing: 0.36 (0.18-0.55) than non-gardeners. All associations remained significant after Bonferroni correction. Conclusions Overall, gardening was associated with better multidimensional well-being, including flourishing outcomes among older adults in Tokyo. Key messages • Gardening was associated with higher scores across all flourishing domains, including overall and secure flourishing, among older adults. • Gardening could support multidimensional well-being, including flourishing in ageing populations.

Neutralizing the RNA phosphodiester backbone enables delivery of siRNA across cell membranes. RNA interference (RNAi) has great potential to treat human disease 1 , 2 , 3 . However, in vivo delivery of short interfering RNAs (siRNAs), which are negatively charged double-stranded RNA macromolecules, remains a major hurdle 4 , 5 , 6 , 7 , 8 , 9 . Current siRNA delivery has begun to move away from large lipid and synthetic nanoparticles to more defined molecular conjugates 9 . Here we address this issue by synthesis of short interfering ribonucleic neutrals (siRNNs) whose phosphate backbone contains neutral phosphotriester groups, allowing for delivery into cells. Once inside cells, siRNNs are converted by cytoplasmic thioesterases into native, charged phosphodiester-backbone siRNAs, which induce robust RNAi responses. siRNNs have favorable drug-like properties, including high synthetic yields, serum stability and absence of innate immune responses. Unlike siRNAs, siRNNs avidly bind serum albumin to positively influence pharmacokinetic properties. Systemic delivery of siRNNs conjugated to a hepatocyte-specific targeting domain induced extended dose-dependent in vivo RNAi responses in mice. We believe that siRNNs represent a technology that will open new avenues for development of RNAi therapeutics.

ObjectivesThe COVID-19 pandemic has had variable effects on the rates of STIs reported across the globe. This study sought to assess how the number of STI reports changed during the pandemic in Japan.MethodsWe used national infectious disease surveillance data from the National Institute of Infectious Diseases (Tokyo, Japan) for the period between January 2013 and December 2021. We compared reported rates of chlamydia, gonorrhoea, condyloma acuminata and genital herpes, as well as total notifications for HIV/AIDS and syphilis during the pandemic versus previous years in Japan. We used a quasi-Poisson regression to determine whether any given week or month between January 2018 and December 2021 had a significant excess or deficit of STIs. Notification values above or below the 95% upper and lower prediction thresholds were considered as statistically significant. The start of the pandemic was defined as January 2020.ResultsChlamydia generally remained within predicted range during the pandemic period. Reporting of gonorrhoea was significantly higher than expected throughout early-to-mid 2021 but otherwise generally remained within predicted range prior to 2021. Condyloma, herpes and HIV/AIDS reporting were transiently significantly lower than expected throughout the pandemic period, but no significant periods of higher-than-expected reporting were detected. Syphilis showed widespread evidence of significantly lower-than-predicted reporting throughout 2020 but eventually reversed, showing significantly higher-than-predicted reporting in mid-to-late 2021.ConclusionsThe COVID-19 pandemic was associated with variable changes in the reporting of STIs in Japan. Higher-than-predicted reporting was more likely to be observed in the later phases of the pandemic. These changes may have been attributable to pandemic-related changes in sexual behaviour and decreased STI clinic attendance and testing, but further research on the long-term impact of the pandemic on STIs is necessary.

IntroductionMarriage, divorce and fertility are declining in Japan. There is concern that the COVID-19 pandemic may have accelerated the decrease in marriages and births while increasing the number of divorces. Changes in partnership behaviours and fertility have significant implications for mental health, well-being and population demographics.MethodsJapanese vital statistical data were collected for December 2011–May 2021. We used the Farrington algorithm on the daily numbers of marriages, divorces and births (per month) in order to determine whether any given month between January 2017 and May 2021 had a significant excess or deficit. Analyses were conducted at the national and regional levels.ResultsDuring the pandemic, significant deficits in the national number of marriages were noted in January 2020, April 2020, May 2020, July 2020, September 2020 and April 2021. Regional marriage patterns reflected national trends. Divorces were noted to be in deficit during April 2020, May 2020 and May 2021 at the country level. Regional analyses mirrored national divorce trends with the exception of Shikoku, which showed no deficits during the pandemic. Significant deficits in the number of total births were noted in December 2020, January 2021 and February 2021. Regionally, birth deficits were concentrated in Chubu, Kansai and Kanto. After the start of the pandemic, no significant excesses in marriages, divorces or births were noted at the national or regional level.ConclusionsMarriages and divorces declined during the pandemic in Japan, especially during state of emergency declarations. There were decreased births between December 2020 and February 2021, approximately 8–10 months after the first state of emergency, suggesting that couples altered their pregnancy intention in response to the pandemic. Metropolitan regions were more affected by the pandemic than their less metropolitan counterparts.

The T2K experiment presents new measurements of neutrino oscillation parameters using protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on and the impact of priors on the measurement. Both analyses prefer the normal mass ordering and upper octant of with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on from reactors, using Feldman-Cousins corrected intervals, and using constant intervals. The CP-violating phase is constrained to using Feldman-Cousins corrected intervals, and is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than credible level using a flat prior in and just below using a flat prior in When the external constraint on is removed, in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses.

The T2K experiment presents new measurements of neutrino oscillation parameters using $$19.7(16.3)\\times 10^{20}$$ 19.7(16.3)×1020 protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional $$4.7\\times 10^{20}$$ 4.7×1020 POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on $$\\sin ^2\\theta _{13}$$ sin2θ13 and the impact of priors on the $$\\delta _{\\textrm{CP}}$$ δCP measurement. Both analyses prefer the normal mass ordering and upper octant of $$\\sin ^2\\theta _{23}$$ sin2θ23 with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on $$\\sin ^2\\theta _{13}$$ sin2θ13 from reactors, $$\\sin ^2\\theta _{23}=0.561^{+0.021}_{-0.032}$$ sin2θ23=0.561-0.032+0.021 using Feldman–Cousins corrected intervals, and $$\\varDelta {}m^2_{32}=2.494_{-0.058}^{+0.041}\\times 10^{-3}~\\text {eV}^2$$ Δm322=2.494-0.058+0.041×10-3eV2 using constant $$\\varDelta \\chi ^{2}$$ Δχ2 intervals. The CP-violating phase is constrained to $$\\delta _{\\textrm{CP}}=-1.97_{-0.70}^{+0.97}$$ δCP=-1.97-0.70+0.97 using Feldman–Cousins corrected intervals, and $$\\delta _{\\textrm{CP}}=0,\\pi $$ δCP=0,π is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than $$2\\sigma $$ 2σ credible level using a flat prior in $$\\delta _{\\textrm{CP}},$$ δCP, and just below $$2\\sigma $$ 2σ using a flat prior in $$\\sin \\delta _{\\textrm{CP}}.$$ sinδCP. When the external constraint on $$\\sin ^2\\theta _{13}$$ sin2θ13 is removed, $$\\sin ^2\\theta _{13}=28.0^{+2.8}_{-6.5}\\times 10^{-3},$$ sin2θ13=28.0-6.5+2.8×10-3, in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses.

Home telemonitoring is becoming more important to home medical care for patients with heart failure. Since there are no data on home telemonitoring for Japanese patients with heart failure, we investigated its effect on cardiovascular outcomes. The HOMES-HF study was the first multicenter, open-label, randomized, controlled trial (RCT) to elucidate the effectiveness of home telemonitoring of physiological data, such as body weight, blood pressure, and pulse rate, for Japanese patients with heart failure (UMIN Clinical Trials Registry 000006839). The primary end-point was a composite of all-cause death or rehospitalization due to worsening heart failure. We analyzed 181 recently hospitalized patients with heart failure who were randomly assigned to a telemonitoring group (n = 90) or a usual care group (n = 91). The mean follow-up period was 15 (range 0–31) months. There was no statistically significant difference in the primary end-point between groups [hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.548–1.648; p = 0.572]. Home telemonitoring for Japanese patients with heart failure was feasible; however, beneficial effects in addition to those of usual care were not demonstrated. Further investigation of more patients with severe heart failure, participation of home medical care providers, and use of a more integrated home telemonitoring system emphasizing communication as well as monitoring of symptoms and physiological data are required.

Honey is natural nectar that honey bees gather from a variety of flowers. Honey is made up of many nutrients that are essential for the growth and development of various tissues and organs in all kinds of living organisms. The goal of the current study was to determine whether adding honey to diets of naked neck cocks would have a good impact on their semen quality, haematological profile, and immune system. A total of 90 naked neck cocks that were 75 weeks old were gathered for this purpose in March and April 2021 from the University of Agriculture Birds Stock. The birds were divided into 3 equal treatment groups: control, A and B, which each received a dose of 5 and 10 g of honey in 1 litre of water (w/v), respectively. The control group received no treatment. Five weeks of treatment were given, with one week serving as an adaptation period. One-way analysis of variance was applied to the recorded data for statistical analysis. The addition of honey to drinking water at a dose of 10 g (w/v) increased (p<0.05) sperm motility, followed by a dose of 5 g (w/v) and the control group, but the mean values of non-motile sperms were lowest (p<0.05) at a dose of 10 g (w/v), followed by a dose of 5 g (w/v), and the control group. However, there were no significant differences in semen volume, pH, or concentration across the treatment groups. The haematological parameters, such as haemoglobin, total leukocyte count, red blood cells, and packed cell volume, were not significantly affected by the addition of honey to the drinking water, but the ND titer of naked neck cocks treated with 10 g (w/v) honey was significantly (p<0.05) higher than that of the cocks in the 5 g (w/v) and control group. In conclusion, the addition of honey to drinking water at a dose of 10 g (w/v) may have positive effects on sperm motility and antibody titer against Newcastle disease in aged naked neck cocks. Furthermore, these results also suggest that the addition of honey to drinking water at a dose of 10 g (w/v) may rejuvenate naked neck cocks even at old age (75 week age).