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Chloroplasts are usually considered spheroid organelles, but this is not the only shape of chloroplasts. The chloroplast of Chlamydomonas has been typically described as cup-shaped. However, in old studies, it was also modeled as a complex shape with "perforations" or windows. Here, we reconstructed the cellular architecture of Chlamydomonas reinhardtii and C. applanata using an array tomography system installed on a field emission scanning electron microscope. C. reinhardtii chloroplasts resembled a baseball glove or a cup without a side, featuring numerous large and small holes that may facilitate the transport of metabolites and proteins produced in the Golgi apparatus fitted in the holes. In a lipid-accumulating, high-light condition, the chloroplast volume increased by filling the side cleft with an entire wall. Many accumulated large lipid droplets were accommodated within the chloroplast holes, which could have been considered as "chloroplast lipid droplets." Mitochondrial meshworks surrounded the chloroplast. C. applanata chloroplasts appeared like a folded starfish or a cup with many side clefts and a few holes. There was a single mitochondrion or two that branched in a complex form. Tight contacts of various organelles were also found in C. applanata. These reconstructions illustrate the complexity of chloroplast shape, which necessitates a revised understanding of the localization of lipid droplets and the evolution of chloroplasts: The prevailing image of the spheroid chloroplasts that reminds us of the similarity between chloroplasts and cyanobacteria is no longer tenable.

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BACKGROUND: Steroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed. METHODS: In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed. RESULTS: Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P = 0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P = 0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia. CONCLUSIONS: In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. (Funded by Bayer; FINEARTS-HF ClinicalTrials.gov number, NCT04435626.).

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Plastids in vascular plants have various differentiated forms, among which amyloplasts are crucial for starch storage and plant productivity. Despite the vast knowledge of the binary-fission mode of chloroplast division, our understanding of the replication of non-photosynthetic plastids, including amyloplasts, remains limited. Recent studies have suggested the involvement of stromules (stroma-filled tubules) in plastid replication when the division apparatus is faulty. However, details of the underlying mechanism(s) and their relevance to normal processes have yet to be elucidated. Here, we developed a live analysis system for studying amyloplast replication using Arabidopsis (Arabidopsis thaliana) ovule integuments. We showed the full sequence of amyloplast development and demonstrated that wild-type amyloplasts adopt three modes of replication, binary fission, multiple fission, and stromule-mediated fission, via multi-way placement of the FtsZ ring. The minE mutant, with severely inhibited chloroplast division, showed marked heterogeneity in amyloplast size, caused by size-dependent but wild-type modes of plastid fission. The dynamic properties of stromules distinguish the wild-type and minE phenotypes. In minE cells, extended stromules from giant amyloplasts acquired stability, allowing FtsZ ring assembly and constriction, as well as the growth of starch grains therein. Despite hyper-stromule formation, amyloplasts did not proliferate in the ftsZ null mutant. These data clarify the differences between amyloplast and chloroplast replication and demonstrate that the structural plasticity of amyloplasts underlies the multiplicity of their replication processes. Furthermore, this study shows that stromules can generate daughter plastids via the assembly of the FtsZ ring.

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AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

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Evaluating neutron output is important to ensure proper dose delivery for patients in boron neutron capture therapy (BNCT). It requires efficient quality assurance (QA) and quality control (QC) while maintaining measurement accuracy. This study investigated the optimal measurement conditions for QA/QC of activation measurements using a high-purity germanium (HP-Ge) detector in an accelerator-based boron neutron capture therapy (AB-BNCT) system employing a lithium target. The QA/QC uncertainty of the activation measurement was evaluated based on counts, reproducibility, and standard radiation source uncertainties. Measurements in a polymethyl methacrylate (PMMA) cylindrical phantom using aluminum-manganese (Al-Mn) foils and aluminum-gold (Al-Au) foils and measurements in a water phantom using gold wire with and without cadmium cover were performed to determine the optimal measurement conditions. The QA/QC uncertainties of the activation measurements were 4.5% for Au and 4.6% for Mn. The optimum irradiation proton charge and measurement time were determined to be 36 C and 900 s for measurements in a PMMA cylindrical phantom, 7.0 C and 900 s for gold wire measurements in a water phantom, and 54 C and 900 s at 0-2.2 cm depth and 3,600 s at deeper depths for gold wire measurements with cadmium cover. Our results serve as a reference for determining measurement conditions when performing QA/QC of activation measurements using HP-Ge detectors at an AB-BNCT employing a lithium target.

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PURPOSE: Bleeding complication is a critical risk factor for outcomes of acute heart failure patients requiring mechanical circulatory support (MCS), including percutaneous catheter-type heart pumps (Impella). The Japanese registry for Percutaneous Ventricular Assist Device (J-PVAD) is an ongoing, large-scale, real-world registry to characterize Japanese patients requiring Impella. Here we analyzed bleeding complication profiles in patients who received Impella. METHODS: All consecutive Japanese patients who received Impella from October 2017 to January 2020 were enrolled. The 30-day survival and bleeding complications were analyzed. RESULTS: A total of 1344 patients were included: 653 patients received Impella alone, 685 patients received a combination of veno-arterial extracorporeal membrane oxygenation and Impella (ECPELLA), and 6 patients had failed Impella delivery. Overall 30-day survival was 67.0%, with Impella alone at 81.9% and ECPELLA at 52.7%. Overall bleeding/hematoma adverse events with a relation or not-excluded relation to Impella was 6.92%. Among them, the rates of hematoma and bleeding from medical device access sites were 1.41% and 4.09%, respectively. There was no difference between etiologies for these events. CONCLUSION: This study represents the first 3-year survival and the safety profile focused on bleeding adverse events from the J-PVAD registry. The results show that the real-world frequency of bleeding adverse events for patients who received Impella was an expected range from previous reports, and future real-world studies should aim to expand this data set to improve outcomes and adverse events.

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Fulminant myocarditis requiring peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has a high mortality rate. We investigated clinical outcomes of combined use of VA-ECMO and percutaneous left ventricular assist device (VAD) (Impella) for fulminant myocarditis in 104 consecutive patients enrolled in the Japan Registry for Percutaneous VAD (J-pVAD) between October 2017 and January 2020. Patients were followed until hospital discharge and predictors of survival were analyzed with a Cox proportional hazards model. The median support duration of combined use of VA-ECMO and Impella (ECMO/Impella) was 6 days, and the median left ventricular ejection fraction improved from 15% to 52% during support ( p < 0.0001). Overall, 66 patients (63%) survived to discharge. Multivariate analysis revealed ECMO/Impella support at a transplant center as an independent predictor of survival ( p = 0.0231). Patients treated at transplant centers had better 60 days survival rates when compared to nontransplant centers (83% vs. 55%, p = 0.005). However, baseline characteristics and treatment strategies differed between the two groups. This real-world national registry database suggested the difference in survival after ECMO/Impella support for fulminant myocarditis between transplant and nontransplant centers, which may indicate hospital variations regarding patient management, although further controlled studies are needed.

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BACKGROUND/AIM: Interfractional anatomical variations cause considerable differences between planned and actual radiotherapy doses. This study aimed to investigate the efficacy of robust and planning target volume (PTV) margin-based optimizations for the anatomical variations in helical tomotherapy for prostate cancer. PATIENTS AND METHODS: Ten patients underwent treatment-planning kilovolt computed tomography (kVCT) and daily megavolt computed tomography (MVCT). Two types of nominal plans, with a prescription of 60 Gy/20 fractions, were created using robust and PTV margin-based optimizations on kVCT for each patient. Subsequently, the daily estimated doses were recalculated using nominal plans, and all available MVCTs modified the daily patient-setup errors. Due to the difference in dose calculation accuracy between kVCT and MVCT, three scenarios with dose corrections of 1, 2, and 3% were considered in the recalculation process. The dosimetric metrics, including target coverage with the prescription dose, Paddick's conformity index, homogeneity index, and mean dose to the rectum, were analyzed. RESULTS: A dosimetric comparison of the nominal plans demonstrated that the robust plans had better dose conformity, lower target coverage, and dose homogeneity than the PTV plans. In the daily estimated doses of any dose-corrected scenario, the target coverage and dose sparing to the rectum in the robust plans were significantly higher than those in the PTV plans, whereas dose conformity and homogeneity were identical to those of the nominal case. CONCLUSION: Robust optimization is recommended as it accounts for anatomical variations during treatment regarding target coverage in helical tomotherapy plans for prostate cancer.

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The effect of prehospital factors on favorable neurological outcomes remains unclear in patients with witnessed out-of-hospital cardiac arrest (OHCA) and a shockable rhythm. We developed a decision tree model for these patients by using prehospital factors. Using a nationwide OHCA registry database between 2005 and 2020, we retrospectively analyzed a cohort of 1,930,273 patients, of whom 86,495 with witnessed OHCA and an initial shockable rhythm were included. The primary endpoint was defined as favorable neurological survival (cerebral performance category score of 1 or 2 at 1 month). A decision tree model was developed from randomly selected 77,845 patients (development cohort) and validated in 8650 patients (validation cohort). In the development cohort, the presence of prehospital return of spontaneous circulation was the best predictor of favorable neurological survival, followed by the absence of adrenaline administration and age. The patients were categorized into 9 groups with probabilities of favorable neurological survival ranging from 5.7 to 70.8% (areas under the receiver operating characteristic curve of 0.851 and 0.844 in the development and validation cohorts, respectively). Our model is potentially helpful in stratifying the probability of favorable neurological survival in patients with witnessed OHCA and an initial shockable rhythm.

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Objective: Most large-vessel occlusions (LVOs) amenable to acute recanalization occur in the internal carotid or middle cerebral artery. However, few LVOs with a multivessel disease can be difficult to treat. This study aimed to determine the outcomes of mechanical thrombectomy in patients with both anterior and middle cerebral artery occlusions. Methods: We retrospectively collected data for patients who had undergone mechanical thrombectomy since January 2016 at Fukushima Medical University and its affiliated institutions (10 institutions). Patients with occluded vessels in the anterior and middle cerebral arteries were selected, and patient background, treatment course, and outcomes were reviewed. Results: A total of 341 mechanical thrombectomies were performed during the study period. Seven patients had occlusions involving both anterior and middle cerebral arteries. In these seven patients, the median time from onset to imaging, imaging to puncture, and puncture to recanalization was 106, 60, and 74 min, respectively. Only one patient (14%) had a modified Rankin Scale of 0-2 at 90 days. Conclusion: Comorbid anterior cerebral artery occlusion may worsen the outcome of patients with middle cerebral artery occlusion.

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The order Parmales (class Bolidophyceae) is a minor group of pico-sized eukaryotic marine phytoplankton that contains species with cells surrounded by silica plates. Previous studies revealed that Parmales is a member of ochrophytes and sister to diatoms (phylum Bacillariophyta), the most successful phytoplankton group in the modern ocean. Therefore, parmalean genomes can serve as a reference to elucidate both the evolutionary events that differentiated these two lineages and the genomic basis for the ecological success of diatoms vs. the more cryptic lifestyle of parmaleans. Here, we compare the genomes of eight parmaleans and five diatoms to explore their physiological and evolutionary differences. Parmaleans are predicted to be phago-mixotrophs. By contrast, diatoms have lost genes related to phagocytosis, indicating the ecological specialization from phago-mixotrophy to photoautotrophy in their early evolution. Furthermore, diatoms show significant enrichment in gene sets involved in nutrient uptake and metabolism, including iron and silica, in comparison with parmaleans. Overall, our results suggest a strong evolutionary link between the loss of phago-mixotrophy and specialization to a silicified photoautotrophic life stage early in diatom evolution after diverging from the Parmales lineage.

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An accelerator-based boron neutron capture therapy (AB-BNCT) system was installed at the Shonan Kamakura General Hospital (SKGH). We confirmed that a stable operation was possible for 1 h at a current of 30 mA. The evaluated thermal neutron flux was 2.8 × 109 cm-2 s-1 and in good agreement (±5%) with the calculated values. The daily variation was within ±2%. The ambient dose rate due to residual radioactivity after irradiation was approximately 5 µSv/h using a lead shutter.

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Natriuretic peptides, brain (B-type) natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up-to-date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptides-guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions.

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Natriuretic peptides, brain (B-type) natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor-neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up-to-date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptide-guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions.

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Clostridium butyricum TO-A, Enterococcus faecium T-110, and Bacillus subtilis TO-A are sold as oral probiotic preparations and reportedly exhibit many beneficial effects on the health of hosts, including humans and livestock. In this study, we compared the ability of these clinically applied probiotic bacteria with Escherichia coli OP50 in extending the lifespan of Caenorhabditis elegans. To compare the C. elegans lifespan-extending effects of the three bacteria, experiments were performed using a nematode growth medium containing a small amount of trypticase soy agar. The maximum lifespans of worms fed C. butyricum TO-A, E. faecium T-110, or B. subtilis TO-A increased by 11, 12, and 26%, respectively, compared with worms fed E. coli OP50. In addition, we conducted a metabolomic analysis of methanol extracts of B. subtilis TO-A cells, which exhibited the strongest lifespan-extending effect on C. elegans among the probiotic bacteria tested in this study. As a result, 59 candidate substances involved in extending the lifespan of C. elegans were identified in B. subtilis TO-A cells.

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AIM: There is a need for a cognitive function test that is less burdensome to perform cognitive function tests used to date and can detect mild changes in the cognitive function and mild cognitive impairment (MCI). We developed a cognitive function examination using a virtual reality device (VR-E). The purpose of this study was to verify its usability. METHODS: Seventy-seven participants (29 males and 48 females, average age 75.1 years old) were classified according to their Clinical Dementia Rating (CDR). To estimate the validity of VR-E in measuring cognitive function, we used the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment-Japanese version (MoCA-J) scores as benchmarks. The MMSE was performed for all subjects, while the MoCA-J was performed for subjects with an MMSE score ≥20. RESULTS: VR-E scores were highest in the CDR 0 group (0.77±0.15, mean±SD), decreasing for subsequent groups (CDR 0.5: 0.65±0.19, CDR 1-3: 0.22±0.21). The receiver operating characteristic analysis showed that all three methods were able to distinguish CDR groups. For CDR 0 vs. 0.5, the areas under the curve for MMSE/MoCA-J/VR-E were 0.85/0.80/0.70, respectively, and those for CDR 0.5 vs. 1-3 were 0.89/0.92/0.90, respectively. The time required to complete VR-E was approximately 5 minutes. Of the 77 subjects, 12 were difficult to assess using the VR-E due to poor understanding or eye diseases or Meniere's syndrome. CONCLUSIONS: The present findings suggested that the VR-E can be used as a cognitive function test that correlates with existing standard assessments for dementia and MCI.

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AIM OF THE STUDY: Defibrillation plays a crucial role in early return of spontaneous circulation (ROSC) and survival of patients with out-of-hospital cardiac arrest (OHCA) and shockable rhythm. Prehospital adrenaline administration increases the probability of prehospital ROSC. However, little is known about the relationship between number of prehospital defibrillation attempts and neurologically favourable survival in patients treated with and without adrenaline. METHODS: Using a nationwide Japanese OHCA registry database from 2006 to 2020, 1,802,084 patients with OHCA were retrospectively analysed, among whom 81,056 with witnessed OHCA and initial shockable rhythm were included. The relationship between the number of defibrillation attempts before hospital admission and neurologically favourable survival rate (cerebral performance category score of 1 or 2) at 1 month was evaluated with subgroup analysis for patients treated with and without adrenaline. RESULTS: At 1 month, 18,080 (22.3%) patients had a cerebral performance category score of 1 or 2. In the study population, the probability of prehospital ROSC and favourable neurological survival rate were inversely associated with number of defibrillation attempts. Similar trends were observed in patients treated without adrenaline, whereas a greater number of defibrillation attempts was counterintuitively associated with favourable neurological survival rate in patients treated with prehospital adrenaline. CONCLUSIONS: Overall, a greater number of prehospital defibrillation attempts was associated with lower neurologically favourable survival at 1 month in patients with OHCA and shockable rhythm. However, an increasing number of shocks (up to the 4th shock) was associated with better neurological outcomes when considering only patients treated with adrenaline.

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BACKGROUND: The Impella®percutaneous left ventricular assist device has been available in Japan since 2017. This is the first large-scale registry study to analyze the efficacy and safety of Impella in Japanese patients with acute myocardial infarction with cardiogenic shock (AMICS).Methods and Results: The Japanese registry for Percutaneous Ventricular Assist Device (J-PVAD) has registered all consecutive Japanese patients treated with Impella. We extracted data for 593 AMICS patients from J-PVAD and analyzed 30-day survival and safety profiles. Overall 30-day survival was 63.1%. The 30-day survival of the Impella alone and Impella plus venoarterial extracorporeal membrane oxygenation (ECPELLA) groups was 80.9% and 45.7%, respectively. The Impella alone group was older and had a lower rate of cardiac arrest, milder consciousness disturbance, less inotrope use, lower serum lactate concentrations, higher B-type natriuretic peptide concentrations, and higher left ventricular ejection fraction (LVEF) than the ECPELLA group. Cox regression analysis revealed that older age and comorbid renal disturbance were common risk factors affecting 30-day mortality in both groups. Major adverse events were hemolysis (10.8%), hemorrhage/hematoma (7.6%), peripheral ischemia (4.4%), stroke (1.3%), and thrombosis (0.7%). LVEF improved in both groups during support. CONCLUSIONS: AMICS treatment with Impella showed favorable 30-day survival and safety profiles. The survival rate of patients treated with Impella alone was particularly high. Further studies are needed to improve outcomes of patients with ECPELLA support.

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Catheter-based micro-axial ventricular assist device Impella® (Abiomed, Danvers, MA) has been used in Japanese patients with drug-refractory acute heart failure (AHF) since 2017. This is the first interim analysis of the ongoing Japan Registry for Percutaneous Ventricular Assist Device (J-PVAD) to investigate the safety and efficacy of Impella support. Between October 2017 and January 2020, 823 Japanese patients, who were treated with the Impella 2.5, CP, or 5.0 pump, were enrolled. The primary endpoints were safety profiles and cumulative 30-day survival. Among them, 44.8% of patients were acute myocardial infarction with cardiogenic shock. The Impella pumps were unable to implant in 4 patients. The Impella 2.5, CP, and 5.0 pumps were used in 72.4%, 6.2%, and 16.6%, respectively, and mean support duration was 8.1 ± 10.2 days. Combination use of Impella and venoarterial extracorporeal membrane oxygenation (VA-ECMO) was applied for 387 patients (47.3%). Pump stop occurred 22 patients (2.7%). Major adverse events included hemolysis (11.2%), hemorrhage/hematoma (6.1%), peripheral ischemia (1.6%), and stroke (1.6%). The overall 30-day survival was 62.2%. Survival of patients with single Impella support was significantly higher than patients with Impella combined with VA-ECMO support (81.1% vs 49.6%; p < 0.01), who had lower blood pressure, lower left ventricular ejection fraction, and higher degree of inotropic support. Results suggest that short-term outcome of Impella support for Japanese patients was favorable with acceptable safety profiles.

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