Takasaki University of Health and Welfare (高崎健康福祉大学, Takasaki kenkō fukushi daigaku) is a private university in Takasaki, Gunma, Japan, established in 2001. The predecessor of the school was founded in 1936..
To safeguard global food security against rapid population growth and a warming world, the effective genetic improvement of cereals is imperative. Flower opening time (FOT) critically affects the seed setting rate. In this study, we identified a gene, EARLY-MORNING FLOWERING 3 (EMF3), in which single-nucleotide substitutions strongly modulate FOT in rice in a semi-dominant manner, resulting in wide variation in FOT from earlier to later FOT than the wild-type. EMF3 knock-out mutants showed significantly reduced FOT synchrony and disrupted anther dehiscence, leading to fertilisation failure. EMF3 encodes a plasma membrane-localised polypeptide of 723 amino acids with an armadillo repeat fold and four transmembrane segments. Furthermore, EMF3 is specifically expressed in the anthers starting from nighttime on the day of flowering, with substantial impacts on the transcriptomes of both anther and lodicule, which suggested an exclusive role of EMF3 in flowering events. Modifying EMF3 alleles of O. sativa enabled the adjustment of FOT among Oryza species and subspecies, potentially facilitating cross-fertilisation by overcoming one of the major challenges of inter-specific hybridisation to exploit heterosis. Introducing the EMF3 alleles with the earlier FOT into popular rice cultivars resulted in flowering at an earlier time of day when the temperature was cooler, efficiently increasing seed setting rate under heat stress. This discovery unveils the novel mechanism of anther control of flower opening time through the EMF3 gene, while also enabling the use of EMF3 alleles in breeding strategies for efficient fertilisation for increasing hybrid rice seed production and mitigating future heat-stress damage at flowering.
Organic anion-transporting polypeptide transporters (SLCO/OATPs) function as cellular gatekeepers, regulating intestinal absorption, hepatic and renal clearance, and the tissue distribution of drugs and metabolites in the human body. However, the mechanisms underlying substrate selection within the SLCO superfamily remain unclear, hampering efforts to rationalize the interaction of drugs and metabolites with these transporters. SLCO2A1 (also known as OATP2A1) is responsible for the distribution of eicosanoids, including prostaglandins (PGs) and thromboxanes, throughout the body, in addition to several families of nonsteroidal anti-inflammatory drugs (NSAIDs). Here, we present cryogenic electron microscopy structures of SLCO2A1 bound to endogenous PGs and to four widely prescribed medications for treating inflammation, chronic asthma, and Parkinson's disease (PD). Complementary molecular dynamics and in vivo cellular assays elucidate the molecular basis for PG and drug recognition. Our study reports essential mechanistic details that underpin substrate selection and subfamily adaptation within the broader SLCO superfamily of drug and metabolite transporters.
Abstract Background Polymorphisms in voltage-gated sodium channel (SCN) genes have been implicated in oxaliplatin-induced peripheral neuropathy (OXAIPN). However, their association with chronic OXAIPN in Japanese patients remains unclear. This study investigated the association between SCN gene polymorphisms and patient-reported chronic OXAIPN outcomes in Japanese patients with colorectal cancer. Methods Seventy-six Japanese patients with colorectal cancer who received oxaliplatin-containing adjuvant chemotherapy were included. Seven polymorphisms, namely SCN4A rs2302237, SCN5A rs11720524, SCN9A rs6746030 and rs6754031, SCN10A rs6800541 and rs12632942, and GSTP1 rs1695, were analyzed. Chronic OXAIPN was assessed using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (FACT/GOG-Ntx) score as the primary endpoint, while symptom severity assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was evaluated as a key secondary endpoint. Assessments were conducted at treatment completion (0 M) and 6 months after treatment completion (6 M). Results The mean age of the patients was 64.6 ± 9.9 years, and 50 patients (65.8%) were male. The mean cumulative oxaliplatin dose was 792 ± 184 mg/m². In multivariate analyses, carriers of the SCN4A rs2302237 variant allele had lower FACT/GOG-Ntx scores than non-carriers at both 0 M (B = − 4.385, 95% confidence interval [CI]: −7.938 to − 0.831, p = 0.016) and 6 M (B = − 5.150, 95% CI: −8.975 to − 1.326, p = 0.009), indicating a lower patient-reported neuropathy-related symptom burden. In contrast, carriers of the SCN10A rs6800541 variant allele had higher FACT/GOG-Ntx scores at 0 M (B = 4.564, 95% CI: 0.393 to 8.735, p = 0.032); however, no similar association was observed at 6 M. PRO-CTCAE severity analyses showed similar trends for SCN4A rs2302237 and SCN10A rs6800541. Conclusions In this exploratory study of Japanese patients with colorectal cancer, SCN4A rs2302237 was consistently associated with a lower neuropathy-related symptom burden at both 0 M and 6 M. These findings suggest that SCN4A rs2302237 may be a candidate marker associated with patient-reported chronic OXAIPN symptom burden; however, larger validation studies are needed to confirm its clinical significance.
Artificial peptide-DNA complexes enable the transient expression of transgenes in mitochondria; however, the mechanism by which DNA is released from such complexes after delivery remains poorly understood. We previously established particle bombardment-assisted peptide-mediated gene transfer as a method for DNA delivery in plant mitochondria. In this study, we examined the effects of C-terminal modification of a mitochondria-targeting carrier peptide on transient gene expression in mitochondria. Plasmid DNA encoding NanoLuc (Nluc) was complexed with C-terminally amidated cytcox-KH (cytcox-KH-NH2) or non-amidated cytcox-KH (cytcox-KH-COOH) and delivered to Brassica campestris leaves. Introduction of the cytcox-KH-COOH-based complex considerably elevated transient Nluc activity compared to that of the cytcox-KH-NH2-based complex. Both peptides demonstrated comparable DNA-binding capacities, DNase I protection, and transcriptional activity, indicating similar interactions with plasmid DNA. However, the cytcox-KH-COOH-based complex exhibited increased susceptibility to trypsin digestion. This result demonstrates that C-terminal modification modulates transient gene expression in the mitochondria by altering the protease sensitivity of the peptide-DNA complexes. Consequently, controlled peptide degradability is a crucial parameter contributing to transient gene expression in mitochondria.
BACKGROUND:Item response theory (IRT), particularly the graded response model, provides a latent trait (θ) that reflects balance ability and offers a complementary framework for psychometric evaluation. Although IRT is recommended for estimating clinical thresholds, its application to cutoff determination for stroke populations remains limited. We hypothesized that IRT-based approaches will yield cutoff values that differ from those derived using classical test theory and provide additional methodological insight for cutoff determination. PURPOSE:To estimate and compare cutoff values for walking independence in inpatients with stroke using classical test theory and IRT. METHODS:Data from 165 inpatients with stroke were analyzed. Balance was assessed using the Brief Balance Evaluation Systems Test (Brief-BESTest). Cutoff scores were calculated using receiver operating characteristic (ROC), IRT combined with ROC (IRT+ROC), prevalence-based IRT method (old IRT), and embedded state-item IRT method (new IRT). Discriminative performance was evaluated using area under the ROC curve (AUC), sensitivity, specificity, likelihood ratios, and accuracy. RESULTS:The cutoff values for walking independence were 12.37 (ROC), 11.46 (IRT+ROC), 10.54 (old IRT), and 7.90 (new IRT). All methods demonstrated comparable performance, with AUC values ranging from 0.769 to 0.794, indicating good discriminative ability of the Brief-BESTest for identifying walking independence. The new IRT method achieved the highest AUC and sensitivity; ROC and IRT+ROC methods achieved similar AUCs. Although cutoff values and classification metrics differed slightly across methods, their confidence intervals overlapped. CONCLUSION:To our knowledge, this is the first study to directly compare cutoff estimation methods incorporating IRT in stroke rehabilitation, suggesting that IRT-based approaches can yield cutoff values with stability comparable to that of classical test theory and providing methodological insight for future research and clinical assessment scale development.
