Locus heterogeneity in the mechanism underlying the superior fermentation performances of phylogenetically distant sake yeasts.

Sake yeasts, Saccharomyces cerevisiae strains isolated from Japanese sake fermentation tanks, exhibit superior fermentation performance to that of other yeast strains. Although the exceptional abilities of the modern sake yeast strain K701 have been extensively investigated, those of phylogenetically distant classical sake yeasts remain largely understudied. In this study, we aimed to clarify the mechanism underlying the superior fermentation ability of the classical sake yeast strain Km67 by comparing its genetic and physiological properties with those of the laboratory strains X2180 and K701.

Amino acid-dependent TSC2 dephosphorylation by lysosome-PP2A regulates mTORC1 signaling transduction.

The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, composed of amino acid (AA)-sensing (Ragulator/LAMTOR-Rag) and growth factor (GF)-sensing (AKT-TSC1/2-Rheb) axes, pivotally regulates intracellular anabolism and catabolism. mTORC1 deregulation is associated with various metabolic diseases, including cancer and diabetes. As a key regulator of nutrient signaling, mTORC1 integrates a variety of nutrient signals.

Lifestyle-attributable burden of young-onset stroke in Chinese and global populations aged 20-54 years: A three decades comparative study (1990-2021) using Global Burden of Disease study data.

Introduction: Young-onset stroke represents a growing public health crisis globally along with rapid lifestyle changes. This study investigated the mortality and disability burden of young-onset stroke attributable to modifiable lifestyle factors in China compared with global trends, aiming to identify critical intervention targets.

Methods: Utilizing Global Burden of Disease 1990-2021 data, we analyzed age-stratified mortality and disability-adjusted life years for four lifestyle risk factors (tobacco, high alcohol use, dietary risk, and low physical activity).

Coronary Cannulation Following Transcatheter Aortic Valve Replacement With Self-Expanding Evolut FX+ System: The CANNULATE TAVR II Study.

•The CANNULATE TAVR II is the first prospective study evaluating coronary cannulation following implantation of the self-expanding Evolut FX+ valve, offering a direct comparison with patients treated using the previous-generation Evolut FX platform.•A novel geometric analysis using preprocedural and postprocedural computed tomography imaging was introduced to assess the spatial relationship between valve apertures and coronary ostia, incorporating the left coronary artery-right coronary artery angle and coronary height differences.•Mean time for the cannulation of the right coronary artery was faster with the newer Evolut FX+ platform compared to the previous generation, despite an experienced operator performing the procedures.

Impact of renal function on the efficacy of low-voltage area ablation after pulmonary vein isolation: A sub-analysis of the SUPPRESS-AF trial.

Background And Aims: The SUPPRESS-AF trial showed that pulmonary vein isolation (PVI) plus low-voltage area (LVA) ablation may reduce atrial fibrillation (AF) recurrence in some subgroups. Renal dysfunction is a cause of LVAs due to atrial cardiomyopathy and is also a risk factor for AF recurrence after catheter ablation. The aim of this study was to investigate the efficacy of LVA ablation after PVI stratified by renal function.

HLA-B*15:01-positive severe COVID-19 patients lack CD8 T cell pools with highly expanded public clonotypes.

Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8 T-cells directed against HLA-B*15:01-restricted Spike-derived S peptide (B15/SCD8 T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8 T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19.

The crystal structure of Thermus thermophilus UMP kinase complexed with a phosphoryl group acceptor and donor.

Nucleoside monophosphate kinases play crucial roles in biosynthesis and regeneration of nucleotides. Prokaryotic UMP kinase belongs to a family of amino acid kinases but not to other nucleoside monophosphate kinases. Although many structures of prokaryotic UMP kinase have been determined, limited structural information has been available on the conformational changes along the reaction and allosteric pathways.

Gender differences in higher-order aberrations and refractive error in Japanese school children: the Kyoto Childhood Refractive Error Study (KRES).

Purpose: To investigate and analyze gender-related differences in myopia prevalence and factors associated with myopia progression in school-aged children.

Study Design: Observational study.

Methods: This study involved 2,298 eyes (boys = 1194 eyes; girls=1104 eyes) of 1149 school children (597 boys; 552 girls) in two elementary/junior high schools in Kyoto Japan, examined from 2013 through 2022.

Catalytic Residue Reprogramming Enhances Enzyme Activity at Alkaline pH via Phenolate-Mediated Proton Transfer.

Achieving efficient enzyme catalysis under extreme pH conditions remains a major challenge in biocatalysis and synthetic biology. To address this, we present an enzyme engineering strategy that integrates rational redesign of catalytic residues with directed evolution to enable robust enzyme function at alkaline pH. The core principle involves replacing the conserved general base with an ionizable residue of higher intrinsic p, shifting the proton transfer mechanism from carboxylate- to phenolate-mediated catalysis.

Dissociable impacts of physical and psychological factors on side effects after COVID-19 vaccination in Japan: A within-subject repeated measures design.

Background: Although vaccination has significantly contributed to controlling the coronavirus disease 2019 (COVID-19) infections, a high risk of side effects has resulted in vaccination hesitancy. Nevertheless, as COVID-19 has become common but still has a severe impact on vulnerable people, we might need to follow a long-term vaccination routine. Therefore, elucidating the characteristics of individuals who may exhibit either vulnerability or resilience to the side effects associated with COVID-19 vaccinations is of the utmost importance for the vaccination plan against COVID-19.

Clinical significance of severe proteinuria in preeclampsia: a multicenter study of maternal and neonatal outcomes.

This study aimed to determine the association between proteinuria severity and maternal/neonatal outcomes among preeclamptic women with hypertension with proteinuria. We retrospectively assessed 721 women at 11 institutions. All participants had singleton pregnancies and delivered at ≥22 gestational weeks.

Impaired lysosomal proteolysis in developing neurons induces protein aggregation and disrupts morphogenesis and neuromaturation.

Lysosomes play a central role in the degradation of intracellular substances. Through this degradative capacity, lysosomes contribute to biological homeostasis and are particularly critical for the maintenance and function of neurons. Deficiencies in various lysosomal proteins cause a group of conditions known as lysosomal storage disorders, which often present with developmental delay and other neurological symptoms.

Efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer: a FRESCO-2 subgroup analysis of patients enrolled in Japan.

Background: In the phase 3 FRESCO-2 study, fruquintinib plus best supportive care (BSC) significantly improved overall survival (OS) versus placebo plus BSC in patients with refractory metastatic colorectal cancer (mCRC). We present the results of a FRESCO-2 post hoc subgroup analysis evaluating outcomes of patients enrolled in Japan.

Methods: In FRESCO-2, patients had previously received all standard chemotherapies, anti-VEGF and anti-EGFR therapies if indicated, and had progressed on, or were intolerant to trifluridine-tipiracil and/or regorafenib.

A reappraisal of association between ventilator-associated events and mortality among critically ill patients using marginal structural model: multicenter observational study.

Purpose: Ventilator-associated events (VAEs), developed by the US Centers for Disease Control and Prevention (CDC), are considered a new medical quality indicator associated with poor outcomes. However, previous studies failed to adjust for changes in patient severity, leaving open the possibility that VAEs are just a surrogate for severity. This study aimed to reevaluate the association between VAEs and mortality, adjusting for changes in severity over time.

Infrared and ultraviolet spectroscopic characterization of a key intermediate during DNA repair by (6-4) photolyase.

Ultraviolet (UV) irradiation of DNA causes genotoxic photolesions, such as carcinogenic pyrimidine(6-4)pyrimidone photoproducts ((6-4)PPs). In many organisms, (6-4)PPs are repaired by (6-4) photolyases, which contain a flavin chromophore and use blue light energy to initiate the catalytic reaction. Although (6-4)PP repair has been shown to require the input of two successive photons, details of the mechanism remain elusive.

CSF1R-Dependent Microglial Repopulation and Contact-Dependent Inhibition of Proliferation In Vitro.

Murine microglia exhibit rapid self-renewal upon removal from the postnatal brain. However, the signaling pathways that regulate microglial repopulation remain largely unclear. To address this knowledge gap, we depleted microglia from mixed glial cultures using anti-CD11b magnetic particles and cultured them for 4 weeks to monitor their repopulation ability in vitro.

Serum magnesium and outcomes in heart failure with reduced ejection fraction: the GALACTIC-HF trial.

Background And Aims: The frequency and prognostic significance of abnormalities in serum magnesium concentrations have not been described in a contemporary HF population. The authors evaluated the prognostic significance of magnesium concentrations in patients with HFrEF enrolled in GALACTIC-HF trial.

Methods: GALACTIC-HF was a randomized, double-blind, multicentre, event-driven trial that investigated the efficacy and safety of omecamtiv mecarbil compared to placebo in HF patients with LVEF ≤35%.

Multi-omics analysis identifies an M-MDSC-like immunosuppressive phenotype in lineage-switched AML with KMT2A rearrangement.

Lineage switching (LS) is the conversion of cancer cell lineage during the course of a disease. LS in leukemia cell lineage facilitates cancer cells escaping targeting strategy like CD19 targeted immunotherapy. However, the genetic and biological mechanisms underlying immune evasion by LS leukemia cells are not well understood.

Single-cell transcriptomic reconstruction of the human hair cycle: Capturing the temporal dynamics of skin tissue remodeling.

The hair cycle is a valuable model for studying tissue remodeling processes in adult mammals. Time course single-cell transcriptomics offers a powerful approach for characterizing changes in cellular states and interactions; however, its application in human tissues remains challenging. Here, we performed single-cell RNA sequencing on 19 human skin tissues, each containing a single hair follicle.

Vaccine adjuvants as stand-alone immunoprophylaxis in strategies for 100-day rapid responses to future pandemics.

The COVID-19 pandemic accelerated vaccinology progress, driving rapid vaccine development for infectious and non-infectious diseases. However, challenges persist: malaria, HIV, and dengue lack fully effective vaccines, whereas influenza and tuberculosis face waning efficacy. Emerging pathogens and drug-resistant strains further highlight the need for improved vaccines, particularly those offering rapid deployment, broad immunogenicity, and durable protection against variants.

Loss of Angulin-1/LSR promotes vasculogenic mimicry and epithelial-mesenchymal transition in breast cancer.

Vasculogenic mimicry (VM) is a process by which tumor cells form vessel-like network to secure oxygen and nutrients essential for tumor growth. Intercellular junctions, including tight junctions, may play a critical role in this process, important for VM. Here, we investigated the role of angulin-1/LSR (Ang-1), a key component of tricellular tight junctions, in VM regulation.

Inhibition of N-myristoyltransferase in pluripotent stem cells promotes the naive state in mice and elicits trophectoderm and primitive endoderm markers in humans.

Naive and primed states represent distinct phases of pluripotency during early embryonic development, both of which can be captured and interconverted in vitro. To understand pluripotency regulation, we performed a recessive genetic screen using homozygous mutant mouse embryonic stem cells (mESCs) and identified N-myristoyltransferase (NMT) as a novel regulator. Disruption of Nmt1 in mESCs conferred resistance to differentiation, and NMT suppression in mouse epiblast stem cells (mEpiSCs) promoted the conversion from the primed to the naive state.

Lysine-Targeting Inhibitors of Amyloidogenic Protein Aggregation: A Promise for Neurodegenerative Proteinopathies.

Inhibition of amyloidogenic-protein oligomerization and aggregation is a promising therapy-development strategy for proteinopathies, such as Alzheimer's and Parkinson's diseases, in which proteins self-associate into a variety of abnormal, toxic assemblies. Despite discovery of numerous compounds modulating the self-assembly process in vitro, few have reached advanced clinical trials, and none have translated into effective therapy to date. A potential reason is a lack of clear mechanistic understanding of the interaction between the inhibitors/modulators and the target metastable protein assemblies.