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Temporal resolution needed for Japanese speech communication was measured. A new experimental paradigm that can reflect the spectro-temporal resolution necessary for healthy listeners to perceive speech is introduced. As a first step, we report listeners' intelligibility scores of Japanese speech with a systematically degraded temporal resolution, so-called \"mosaic speech\": speech mosaicized in the coordinates of time and frequency. The results of two experiments show that mosaic speech cut into short static segments was almost perfectly intelligible with a temporal resolution of 40 ms or finer. Intelligibility dropped for a temporal resolution of 80 ms, but was still around 50%-correct level. The data are in line with previous results showing that speech signals separated into short temporal segments of <100 ms can be remarkably robust in terms of linguistic-content perception against drastic manipulations in each segment, such as partial signal omission or temporal reversal. The human perceptual system thus can extract meaning from unexpectedly rough temporal information in speech. The process resembles that of the visual system stringing together static movie frames of ~40 ms into vivid motion.

Although infection by SARS-CoV-2, the causative agent of coronavirus pneumonia disease (COVID-19), is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked Middle East respiratory syndrome coronavirus (MERS-CoV) S protein-mediated cell fusion by targeting transmembrane serine protease 2 (TMPRSS2), and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein, angiotensin I converting enzyme 2 (ACE2) and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an effective concentration (EC)50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. On the other hand, a significantly higher dose (EC50 around 30 μM) was required for VeroE6/TMPRSS2 cells, where the TMPRSS2-independent but cathepsin-dependent endosomal infection pathway likely predominates. Together, our study shows that nafamostat mesylate potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and also inhibits SARS-CoV-2 infection in vitro in a cell-type-dependent manner. These findings, together with accumulated clinical data regarding nafamostat’s safety, make it a likely candidate drug to treat COVID-19.

We recently reported that circular RNA is efficiently translated by a rolling circle amplification (RCA) mechanism in a cell-free Escherichia coli translation system. Recent studies have shown that circular RNAs composed of exonic sequences are abundant in human cells. However, whether these circular RNAs can be translated into proteins within cells remains unclear. In this study, we prepared circular RNAs with an infinite open reading frame and tested their translation in eukaryotic systems. Circular RNAs were translated into long proteins in rabbit reticulocyte lysate in the absence of any particular element for internal ribosome entry, a poly-A tail, or a cap structure. The translation systems in eukaryote can accept much simpler RNA as a template for protein synthesis by cyclisation. Here, we demonstrated that the circular RNA is efficiently translated in living human cells to produce abundant protein product by RCA mechanism. These findings suggest that translation of exonic circular RNAs present in human cells is more probable than previously thought.

We measured dietary salt intake in 26 patients with primary aldosteronism treated with mineralocorticoid receptor antagonists and evaluated whether plasma renin levels were affected by dietary salt intake pre-treatment and post 6 months of mineralocorticoid receptor antagonist treatment. The dietary salt intake level was calculated using spot urine sodium and creatinine concentrations, body weight, height, and age. The clinical parameters pre- and post- treatment were compared. The systolic and diastolic blood pressure levels decreased, and the serum potassium and active renin concentration increased significantly. Although the dietary salt intake did not change after treatment, the differences in dietary salt intake and active renin concentration pre- and post- treatment were inversely correlated (r = -0.418, p = 0.03). The 26 patients were divided into two groups with active renin concentration levels ≥5 pg/mL (Group 1) and <5 pg/mL (Group 2) after treatment. The Group parameters did not differ pre- and post- treatment. Group 1 evidenced improvements in systolic and diastolic blood pressures, and the potassium level and active renin concentration over time; Group 2 did not. Group 1 evidenced no significant correlation between the differences in dietary salt intake and active renin concentration levels (r = -0.481, p = 0.11) but Group 2 showed a strong inverse correlation (r = -0.7599, p = 0.01). In conclusion, we found that an active renin concentration level <5 pg/mL post-mineralocorticoid receptor antagonist treatment may indicate that salt sensitivity has not adequately improved, emphasizing the importance of measuring plasma renin levels after such treatment.

Primary aldosteronism (PA) is typically managed with mineralocorticoid receptor antagonists (MRAs) barring adrenalectomy. The efficacy of esaxerenone, a nonsteroidal MRA, were explored in patients with PA. Various parameters such as the urinary albumin to creatinine ratio (UACR) and serum levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were evaluated in 25 PA patients before and 3 and 6 months after esaxerenone treatment. Systolic and diastolic blood pressure (BP), and the estimated glomerular filtration rate decreased after treatment, while serum levels of potassium and active renin increased. Significant reductions were observed in UACR 3 and 6 months after treatment. A significant decrease in NT-proBNP was evident at 6 months but not 3 months after treatment. Correlation analysis indicated that the reductions in BP and UACR at 3 months were independent of estimated daily salt intake. Furthermore, the effect of esaxerenone treatment on lowering UACR and NT-proBNP levels was independent of BP reduction. Responders whose systolic BP decreased 6 months after esaxerenone treatment by more than 10 mmHg compared to pretreatment had higher pretreatment NT-proBNP and similar UACR before and after treatment when compared with nonresponders. Esaxerenone improved mental, physical, and social quality of life (QOL) 6 months after treatment compared to healthy controls and increased over time. No patients discontinued treatment due to severe hyperkalemia or renal dysfunction. In conclusion, esaxerenone is a safe and effective MRA for PA treatment, offering significant benefits in terms of hypertension, albuminuria, NT-proBNP levels, and QOL improvement. Esaxerenone effectively lowers BP, UACR, and serum levels of NT-proBNP independent of dietary salt intake in mild PA patients. ARC active renin concentration, DBP diastolic blood pressure, MR mineralocorticoid receptor, MRA mineralocorticoid receptor antagonist, NT-proBNP N-terminal pro-brain natriuretic peptide, PA primary aldosteronism, QOL quality of life,  SBP systolic blood pressure,  SF-36  Medical Outcomes Study 36-Item Short-Form Health Survey,  UACR urinary albumin to creatinine ratio. Esaxerenone effectively lowers BP, UACR, and serum levels of NT-proBNP independent of dietary salt intake in mild PA patients. ARC active renin concentration, DBP diastolic blood pressure, MR mineralocorticoid receptor, MRA mineralocorticoid receptor antagonist, NT-proBNP N-terminal pro-brain natriuretic peptide, PA primary aldosteronism, QOL quality of life,  SBP systolic blood pressure,  SF-36  Medical Outcomes Study 36-Item Short-Form Health Survey,  UACR urinary albumin to creatinine ratio.

We investigated the influence of the menstrual cycle (MC) on leukocyte response after exercise-induced muscle damage (EIMD). During the early follicular (E-FP, n = 12) or mid-luteal phase (M-LP, n = 12), 24 untrained females with eumenorrhea performed 60 eccentric exercises using nondominant arms. Blood samples were collected at pre- and 4, 48, and 96 h postexercise to analyze estradiol and progesterone concentrations, leukocyte count and fractionation, and creatine kinase (CK) activity. We also assessed the maximal voluntary isometric contraction torque of elbow flexion, range of motion in the elbow joint, upper-arm circumference, and muscle soreness as indirect muscle damage markers at pre-; immediately post-; and 4, 48, and 96 h postexercise. The percent change in neutrophil counts from pre- to 4 h postexercise was lower in M-LP than in E-FP (E-FP, 30.7% [15.9–65.7%] vs. M-LP, 10.3% [−2.3–30.0%]; median [interquartile range: 25–75%]; p = 0.068). Progesterone concentration at pre-exercise was significantly negatively correlated with the percent change in neutrophil counts from pre- to 4 h postexercise in M-LP (r = −0.650, p = 0.022). MC did not affect CK activity or other muscle damage markers. Thus, progesterone concentration rather than MC may be related to neutrophil response following EIMD.

Background/Objectives: Carbon-ion radiotherapy (CIRT) is a promising treatment option for unresectable locally recurrent rectal cancer (LRRC). However, CIRT is contraindicated in cases where recurrent tumors are attached to the intestine. To address this limitation, we developed a novel treatment strategy involving curative-dose CIRT to recurrent tumors, including the adjacent intestine, without dose constraints, followed by surgical resection of the irradiated intestine. This study aimed to assess the feasibility of this approach. Methods: Patients were eligible for this study if the distance between the unresectable recurrent tumor and the adjacent intestines was less than 3 mm. Between 2019 and 2023, twelve patients were enrolled. CIRT was administered at curative doses of 70.4 or 73.6 Gy (relative biologic effectiveness (RBE)), including the adjacent intestines, without dose constraints. Surgical resection was not intended to excise the tumor itself, but was performed solely to remove the irradiated intestines. Irradiated intestine resection was planned within eight weeks after the completion of CIRT. Results: All patients completed the scheduled treatment course. The median interval between completing CIRT and surgery was 4 (3–8) weeks. No patients experienced acute AEs related to CIRT. Regarding late AEs, two patients developed Grade I sciatic neuralgia, and one patient developed Grade III neuralgia. We considered this symptom, which later resulted in a limp in his left leg, acceptable because this patient could ambulate with assistance. Clavien–Dindo Grade III postoperative complications occurred in one patient. The median follow-up duration was 40 (20–60) months. One patient was diagnosed with in-field recurrence, and three patients were diagnosed with out-of-field recurrence. These patients received reirradiation with CIRT. Four patients experienced lung recurrence, and one patient died from rectal-cancer-specific causes. Conclusions: This novel treatment strategy may provide favorable outcomes for patients with unresectable LRRC. This approach can be applied to the currently accepted indications for CIRT, and we believe that CIRT is a feasible treatment option for future patients.

In women, fat oxidation during exercise changes with the menstrual cycle. This study aimed to investigate the effect of green tea extract (GTE) ingestion on fat oxidation during exercise depending on the menstrual cycle phase. Ten women with regular menstrual cycles participated in this randomized, double-blind, crossover study. GTE or placebo was administered during the menstrual cycle’s follicular phase (FP) and luteal phase (LP). Participants cycled for 30 min at 50% maximal workload, and a respiratory gas analysis was performed. Serum estradiol, progesterone, free fatty acid, plasma noradrenaline, blood glucose, and lactate concentrations were assessed before, during, and after the exercise. Fat oxidation, carbohydrate oxidation, and the respiratory exchange ratio (RER) were calculated using respiratory gas. Fat oxidation during the exercise was significantly higher in the FP than in the LP with the placebo (p < 0.05) but did not differ between the phases with GTE. Carbohydrate oxidation, serum-free fatty acid, plasma noradrenaline, blood glucose, and lactate concentrations were not significantly different between the phases in either trial. Our results suggest that GTE ingestion improves the decrease in fat oxidation in the LP.

The incidence and long-term clinical impact of stent fracture (SF) occurred beyond 1 year after sirolimus-eluting stent (SES) implantation remains unclear. From April 2004 to March 2008, 985 consecutive patients with 1,307 lesions were treated only with SES. Of these, 868 patients (88.1%) with 1,140 lesions underwent follow-up angiography within 1 year after the index procedure, and 646 patients (65.6%) with 872 lesions underwent it both within and beyond 1 year after the index procedure. According to the diagnosed timing of SF, we divided the patients into the 2 groups: early SF (<1 year after the index procedure) and late-acquired SF (>1 year after the index procedure). Early- and late-acquired SFs were observed in 64 of 868 patients (7.4%) and 66 of 1,140 lesions (5.8%); 12 of 646 patients (1.9%) and 12 of 872 lesions (1.4%), respectively. Cumulative 10-year incidence of clinically driven target lesion revascularization and definite stent thrombosis were numerically higher in the early- and late-acquired SF groups than in the non-SF group (41.6% vs 45.5% vs 19.0%; 8.0% vs 8.3% vs 2.0%, respectively). In conclusion, late-acquired SF after SES implantation occurred in 1.4% of lesions, which was lower than that of early SF. However, both early- and late-acquired SFs appeared to be associated with clinically driven target lesion revascularization and stent thrombosis during the long-term follow-up.

As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.