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Background: Lactate dehydrogenase C (LDHC) is specifically expressed in male germ cells and plays critical roles in glycolysis. Glycolysis is required to supply energy for sperm motility. Previous studies showed that Ldhc knock‐out mice exhibit impaired sperm motility. Objectives: We established human LDHC knock‐in (hLDHC KI) mice and examined whether hLDHC KI mice can be used to assess LDHC‐targeting drugs. Material and methods: HLDHC was knocked‐in to the mouse Ldhc (mLdhc) allele using the CRISPR/Cas9 system. Mating tests, sperm motility examinations with a computer‐assisted sperm analysis (CASA) system, and in vitro fertilization (IVF) were performed. Furthermore, the effect of an LDH inhibitor was analyzed with CASA and IVF. Results: HLDHC was detected at the protein level in hLDHC KI spermatozoa. hLDHC KI mice exhibited comparable sperm motility and male fertility to wild‐type (WT) mice. When we performed IVF using the LDH inhibitor more specific to hLDHC than mLDHC, fertilization rates were reduced in hLDHC KI mice but not in WT mice. Discussion and conclusion: Our results reveal that hLDHC can rescue the absence of mLDHC. Differences in the effect of the LDH inhibitor between WT and hLDHC KI mice indicate that hLDHC KI mice can be a good model to assess hLDHC inhibitors for preclinical contraceptive studies. [ABSTRACT FROM AUTHOR]

Introduction: Gastroesophageal reflux disease is a common condition, and proton pump inhibitors (PPIs) are the mainstays of treatment. However, concerns have been raised about the safety of PPIs. A potassium‐competitive acid blocker (P‐CAB), vonoprazan (VPZ), was recently introduced, which may provide clinical benefits. This study was performed to investigate the cost‐effectiveness of alternative long‐term strategies including continuous and discontinuous treatment with VPZ for the management of reflux esophagitis in Japan. Methods: A health state transition model was developed to capture the long‐term management of reflux esophagitis. Four different strategies were compared: (a) intermittent PPI using lansoprazole (LPZ); (b) intermittent P‐CAB; (c) maintenance PPI using LPZ; and (d) maintenance P‐CAB. Results: Intermittent P‐CAB was the most cost‐effective, and the number of days for which medication was required with this strategy was fewest. Maintenance PPI was more efficacious, but more costly than intermittent P‐CAB. Maintenance P‐CAB was more efficacious, but more costly than maintenance PPI. Co‐payments were higher for maintenance PPI than for intermittent P‐CAB, and for maintenance P‐CAB than for maintenance PPI, which were considered reasonable for the majority of patients to improve symptoms. Conclusions: Intermittent P‐CAB appears to be the strategy of choice for the majority of reflux esophagitis patients in clinical practice. If a patient is not satisfied with the symptom control of the current strategy, switching to a more effective strategy appears to be a reasonable option for the majority of patients. [ABSTRACT FROM AUTHOR]

Abstract: The drs gene is an apoptosis-inducing tumor suppressor. By using drs-knockout (KO) mouse embryonic fibroblasts (MEFs), we showed that drs is involved in the host defense against viral infection. In drs-KO MEFs infected with vesicular stomatitis virus, the viral replication and protein synthesis were markedly enhanced without the upregulation of the cellular protein synthesis. Phosphorylation of S6K, S6, 4EBP1 and TSC2 proteins was closely correlated with the enhanced viral replication in drs-KO MEFs. Drs protein could associate with stress-inducible GADD34 to form a complex with TSC1/2, which suppresses mTOR activity. These findings indicate that Drs suppresses viral replication via mTOR-dependent pathway. [Copyright &y& Elsevier]

Ribonucleoprotein (RNP) granules are membraneless electron-dense structures rich in RNAs and proteins, and involved in various cellular processes. Two RNP granules in male germ cells, intermitochondrial cement and the chromatoid body (CB), are associated with PIWI-interacting RNAs (piRNAs) and are required for transposon silencing and spermatogenesis. Other RNP granules in male germ cells, the reticulated body and CB remnants, are also essential for spermiogenesis. In this study, we disrupted FBXO24, a testis-enriched F-box protein, in mice and found numerous membraneless electron-dense granules accumulated in sperm flagella. Fbxo24 knockout (KO) mice exhibited malformed flagellar structures, impaired sperm motility, and male infertility, likely due to the accumulation of abnormal granules. The amount and localization of known RNP granule-related proteins were not disrupted in Fbxo24 KO mice, suggesting that the accumulated granules were distinct from known RNP granules. Further studies revealed that RNAs and two importins, IPO5 and KPNB1, abnormally accumulated in Fbxo24 KO spermatozoa and that FBXO24 could ubiquitinate IPO5. In addition, IPO5 and KPNB1 were recruited to stress granules, RNP complexes, when cells were treated with oxidative stress or a proteasome inhibitor. These results suggest that FBXO24 is involved in the degradation of IPO5, disruption of which may lead to the accumulation of abnormal RNP granules in sperm flagella., Competing Interests: YK, HM, ZX, KS, MK, TN, CE, MI No competing interests declared, (© 2024, Kaneda et al.)

Purpose: This study evaluated the dysregulation of TCF4 isoforms and differential exon usage (DEU) in corneal endothelial cells (CECs) of Fuchs endothelial corneal dystrophy (FECD) with or without trinucleotide repeat (TNR) expansion in the intron region of the TCF4 gene., Methods: Three RNA-Seq datasets of CECs (our own and two other previously published datasets) derived from non-FECD control and FECD subjects were analyzed to identify TCF4 isoforms and DEU events dysregulated in FECD by comparing control subjects to those with FECD with TNR expansion and FECD without TNR expansion., Results: Our RNA-Seq data demonstrated upregulation of three TCF4 isoforms and downregulation of two isoforms in FECD without TNR expansion compared to the controls. In FECD with TNR expansion, one isoform was upregulated and one isoform was downregulated compared to the control. Additional analysis using two other datasets identified that the TCF4-277 isoform was upregulated in common in all three datasets in FECD with TNR expansion, whereas no isoform was dysregulated in FECD without TNR expansion. DEU analysis showed that one exon (E174) upstream of the TNR, which only encompassed TCF4-277, was upregulated in common in all three datasets, whereas eight exons downstream of the TNR were downregulated in common in all three datasets in FECD with TNR expansion., Conclusions: This study identified TCF4-277 as a dysregulated isoform in FECD with TNR expansion, suggesting a potential contribution of TCF4-277 to FECD pathophysiology.

Pancreatobiliary endoscopic interventions using balloon-assisted endoscopes have been widely acknowledged as the first-line therapy for pancreatobiliary diseases in postoperative patients with reconstructed gastrointestinal anatomy (excluding the Billroth I procedure). However, there are many technical difficulties, and the procedural completion rates vary in a wide range among institutions, indicating the procedural technique is yet to be standardized. This article aims to provide technical tips of procedures and insights into the advanced aspects, including the management of extremely difficult cases and troubleshooting of endoscopic retrograde cholangiopancreatography using balloon endoscopy, along with a review of recent advancements in this field., Competing Interests: The authors disclose no conflicts of interest., (© 2023 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)