Association of Cancer and Its Interaction with Conventional Risk Factors on Cardiovascular Disease Risk.

Introduction We sought to examine the association of cancer history with the incidence of individual cardiovascular disease events and to clarify whether the history of cancer modifies the relationship between conventional cardiovascular risk factors and incident cardiovascular disease. Methods This retrospective cohort study used the JMDC Claims Database, including 3,531,683 individuals. The primary endpoint was the composite cardiovascular disease outcome, which included myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation. Results During a follow-up, 144,162 composite endpoints were recorded. Individuals with a history of cancer had a higher risk of developing composite cardiovascular disease events (HR 1.26, 95% CI 1.22-1.29). The HRs for myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation were 1.11 (95% CI 0.98-1.27), 1.15 (95% CI 1.10-1.20), 1.11 (95% CI 1.05-1.18), 1.39 (95% CI 1.34-1.44), and 1.22 (95% CI 1.13-1.32), respectively. Individuals who required chemotherapy for cancer had a higher risk of developing cardiovascular disease. Although conventional risk factors (e.g., overweight/obesity, hypertension, and diabetes) were associated with incident composite cardiovascular disease even in individuals with a history of cancer, the total population-attributable fractions of conventional risk factors were less in individuals with a history of cancer. Conclusion Individuals with a history of cancer (particularly those requiring chemotherapy) have a higher risk of cardiovascular disease. Traditional risk factors are important in the development of cardiovascular disease in individuals with and without a history of cancer. In individuals with a history of cancer, however, the total population-attributable fractions of conventional risk factors decreased.

Glucolipids and lipoteichoic acids affect the activity of SigI, an alternative sigma factor, and WalKR, an essential two-component system, in Bacillus subtilis.

In a Bacillus subtilis ugtP mutant lacking glucolipids, SigI was activated in the log phase, and the activation of SigI in the mutant was suppressed by the expression of native ugtP. By contrast, SigI was inhibited in a yfnI mutant lacking one of the lipoteichoic acid (LTA) synthase genes, and the inhibition was suppressed by the expression of yfnI. A series of mutation analyses of the sigI promoter revealed that the two WalR binding sites were involved in the increase of PsigI -lacZ activity in the ugtP mutant and decrease of the lacZ activity in the yfnI mutant. Transcription from the SigI recognition sequence was enhanced in the ugtP mutant, whereas yfnI disruption inhibited the transcription from the SigA recognition sequence in the sigI promoter. We found that not only SigI but also WalKR, the essential two-component system, was activated in the ugtP mutant and inhibited in the yfnI mutant. The walK mutants with activated WalR exhibited abnormal morphology, but this phenotype was suppressed by the addition of MgSO4 . We conclude that glucolipids and LTA are key compounds in the maintenance of normal cell surface structure in B. subtilis.

Association of four health behaviors in Life's Essential 8 with the incidence of hypertension and diabetes mellitus.

BACKGROUND: The association between health behaviors and the risk of developing hypertension and diabetes is not fully understood. We aimed to examine the association between four health behaviors involved in Life's Essential 8, the American Heart Association's key measures for improving and maintaining cardiovascular health, and the incidence of hypertension and diabetes. METHODS: This observational cohort study used the JMDC Claims Database between 2005 and 2021, which is a health check-up and claims database. We analyzed 2,912,183 participants without a history of hypertension, diabetes, cardiovascular disease, or renal failure. Non-ideal health behaviors included smoking, slow gait speed, eating fast, and poor sleep quality. RESULTS: During 1140 ± 877 days, 201,385 hypertension and 142,156 diabetes events were recorded. In a multivariable Cox regression analysis, the risk of hypertension and diabetes increased with an increasing number of non-ideal health behaviors. The hazard ratios (HRs) (95% confidence interval [CI]) per 1-point increase in non-ideal health behavior components for hypertension and diabetes were 1.11 (1.10-1.11) and 1.08 (1.08-1.09), respectively. Each health behavior was independently associated with the incidence of hypertension and diabetes. A 1-point improvement in health behaviors was associated with a lower risk of developing hypertension (HR 0.94, 95% CI 0.93-0.95) and diabetes (HR 0.95, 95% CI 0.94-0.96). CONCLUSION: Factors that can be substituted for the four health behaviors involved in Life's Essential 8 can stratify the risk of hypertension and diabetes, and improving these health behaviors is useful in preventing hypertension and diabetes in general population.

The estimation of coronary artery calcium thickness by computed tomography angiography based on optical coherence tomography measurements.

Optical coherence tomography (OCT) is recommended to be the most appropriate modality in assessing calcium thickness, however, it has limitations associated with infrared attenuation. Although coronary computed tomography angiography (CCTA) detects calcification, it has low resolution and hence not recommended to measure the calcium size. The aim of this study was to devise a simple algorithm to estimate calcium thickness based on the CCTA image. A total of 68 patients who had CCTA for suspected coronary artery disease and subsequently went on to have OCT were included in the study. 238 lesions of them divided into derivation and validation dataset at 2:1 ratio (47 patients with 159 lesions and 21 with 79, respectively) were analyzed. A new method was developed to estimate calcium thickness from the maximum CT density within the calcification and compared with calcium thickness measured by OCT. Maximum Calcium density and measured calcium-border CT density had a good correlation with a linear equation of y = 0.58x + 201 (r = 0.892, 95% CI 0.855-0.919, p < 0.001). The estimated calcium thickness derived from this equation showed strong agreement with measured calcium thickness in validation and derivation dataset (r2 = 0.481 and 0.527, 95% CI 0.609-0.842 and 0.497-0.782, p < 0.001 in both, respectively), more accurate than the estimation by full width at half maximum and inflection point method. In conclusion, this novel method provided the estimation of calcium thickness more accurately than conventional methods.

Subjective Gait Speed and Risk of Developing Cardiovascular Events in 56,589 Cancer Survivors.

Despite having a higher risk of cardiovascular disease (CVD), there are currently limited data for stratifying CVD risk among cancer survivors. The purpose of this study was to uncover the relationship of subjective gait speed with incident CVD among cancer survivors.This retrospective observational cohort study analyzed data from the JMDC Claims Database between 2005 and 2021 including 56,589 patients with a prior history of breast, colorectal, or stomach cancer but no history of CVD. Gait speed was evaluated using information from self-reported questionnaires collected during health checkups. The primary endpoint was composite CVD outcome, which included heart failure, myocardial infarction, angina pectoris, and stroke.The median (interquartile range) age was 54 (48-61) years, and 20,981 (37.1%) were male. Among them, 25,933 patients (45.8%) reported fast gait speed. During a mean follow-up period of 1002 ± 803 days, 3,221 composite CVD outcomes were recorded. In multivariate Cox regression analysis, slow gait speed was associated with a higher risk of developing CVD compared with fast gait speed (hazard ratio, 1.14, 95% confidence interval, 1.06-1.22). This association was consistent across a variety of sensitivity analyses.We demonstrated that subjective slow gait speed was associated with a greater risk of CVD development among cancer survivors. This suggests the potential value of gait speed assessment for the CVD risk stratification of cancer patients as well as the clinical importance of maintaining exercise capacity among patients living with cancer.

Impact of mitochondria on local calcium release in murine sinoatrial nodal cells.

Roles of mitochondria in sinoatrial nodal cells (SANCs) have not been fully clarified. We have previously demonstrated that mitochondrial Ca2+ efflux through the Na+-Ca2+ exchanger, NCXm, modulates sarcoplasmic reticulum (SR) Ca2+ content and automaticity of HL-1 cardiomyocytes. In this study, we extended this line of investigation to clarify the spatial and functional association between mitochondria and local calcium release (LCR) from the SR in murine SANCs. High-speed two dimensional (2D) and confocal line-scan imaging of SANCs revealed that LCRs in the early phase of the Ca2+ transient cycle length (CL) appeared with a higher probability near mitochondria. Although LCR increased toward the late phase of CL, no significant difference was noted in the occurrence of late LCRs near and distant from mitochondria. LCRs, especially in the late phase of CL, induced temporal and spatial heterogeneity of the Ca2+ transient amplitude. Attenuating mitochondrial Ca2+ efflux using an NCXm inhibitor, CGP-37157 (1 µM), reduced the amplitude, duration and size of LCR. It also attenuated early LCR occurrence, and simultaneously prolonged LCR period and CL. Additionally, CGP-37157 reduced caffeine-induced Ca2+ transient. Therefore, the inhibitory effect on LCR was attributable to the reduction of the SR Ca2+ content through NCXm inhibition. No obvious off-target effects of 1 µM CGP-37157 were found on T- and L-type voltage-gated Ca2+ currents and hyperpolarization-activated inward current. Taken together, these results suggest that mitochondria are involved in LCR generation by modulating the SR Ca2+ content through NCXm-mediated Ca2+ efflux in murine SANCs.

Kidney outcomes in patients with diabetes mellitus did not differ between individual sodium-glucose cotransporter-2 inhibitors.

Data comparing kidney outcomes between individual sodium-glucose cotransporter-2 (SGLT2) inhibitors are limited. Here, we aimed to compare the subsequent risk of developing kidney outcomes between individual inhibitors. This would be the first study to compare kidney outcomes of patients with diabetes mellitus who were newly treated with individual SGLT2 inhibitors using a large-scale real-world dataset. To do this, we analyzed results from 12,100 patients with diabetes mellitus who were taking different SGLT2 inhibitors (2,573 with empagliflozin; 2,214 with dapagliflozin; 2,100 with canagliflozin; and 5,213 with other such inhibitors). The primary outcome was the rate of estimated glomerular filtration rate (eGFR) decline as assessed using a linear mixed-effects model with an unstructured covariance. The median age of the patients was 53 years, and 84.4% of the patients were men. The median fasting plasma glucose and HbA1c levels were 147 (interquartile range 126-178) mg/dL and 7.5 (6.9-8.4)%, respectively. The median eGFR was 78 mL/min/1.73 m2 (interquartile range 68-90). The mean follow-up period was 773 days. The annual eGFR slopes of empagliflozin, dapagliflozin, canagliflozin, and other SGLT2 inhibitors were -1.15 (95% confidence interval, -1.33 to -0.96), -1.14 (-1.32 to -0.96), -1.24 (-1.44 to -1.04), and -1.06 (-1.18 to -0.94) ml/min/1.73 m2, respectively. No significant interaction was detected between the SGLT2 inhibitors and time using a linear mixed-effects model. A multitude of sensitivity analyses confirmed the robustness of our primary results. Thus, we found that there was no significant difference in the annual eGFR decline slopes between patients taking different SGLT2 inhibitors.

Glycemic status and the association of change in blood pressure with incident cardiovascular disease.

BACKGROUND: The clinical benefit of blood pressure (BP) reduction in individuals with diabetes has not been fully elucidated. We sought to identify the clinical impact of BP reduction on incident cardiovascular disease in people having diabetes and hypertension. METHODS: We conducted a retrospective cohort study including 754,677 individuals (median age 47 years, 75.8 % men) with stage 1/stage 2 hypertension. Participants were categorized using fasting plasma glucose (FPG) at baseline as normal FPG (FPG < 100 mg/dL) (n = 517,372), prediabetes (FPG:100-125 mg/dL) (n = 197,836), or diabetes mellitus (FPG ≥126 mg/dL) (n = 39,469). The primary outcome was heart failure (HF), and the secondary outcomes included ischemic heart disease (IHD) including myocardial infarction and angina pectoris, and stroke. RESULTS: Over a mean follow-up of 1111 ± 909 days, 18,429 HFs, 17,058 IHDs, and 8,795 strokes were recorded. Reduction in BP of< 120/80 mmHg at 1year was associated with a lower risk of developing HF (HR:0.77, 95% CI:0.72-0.82), IHD (HR:0.84, 95% CI:0.79-0.89), and stroke (HR:0.75, 95% CI:0.69-0.82) in individuals with normal FPG, whereas it was not associated with a risk of developing HF (HR:0.98, 95% CI:0.81-1.17) and stroke (HR:0.82, 95% CI:0.62-1.09) in those with DM. Interaction analyses showed that the influence of BP reduction on incident HF was attenuated with people with prediabetes or DM. A multitude of sensitivity analyses confirmed our results. CONCLUSIONS: The association of BP reduction with the risk of developing HF was attenuated with deteriorating glucose tolerance. The optimal management strategy for hypertensive people with prediabetes or DM for the prevention of developing cardiovascular disease (particularly HF) is needed to be established.

Comparison of cardiovascular outcomes between SGLT2 inhibitors in diabetes mellitus.

BACKGROUND: There have been scarce data comparing cardiovascular outcomes between individual sodium-glucose cotransporter-2 (SGLT2) inhibitors. We aimed to compare the subsequent cardiovascular risk between individual SGLT2 inhibitors. METHODS: We analyzed 25,315 patients with diabetes mellitus (DM) newly taking SGLT2 inhibitors (empagliflozin: 5302, dapagliflozin: 4681, canagliflozin: 4411, other SGLT2 inhibitors: 10,921). We compared the risks of developing heart failure (HF), myocardial infarction (MI), angina pectoris (AP), stroke, and atrial fibrillation (AF) between individual SGLT2 inhibitors. RESULTS: Median age was 52 years, and 82.5% were men. The median fasting plasma glucose and HbA1c levels were 149 (Q1-Q3:127-182) mg/dL and 7.5 (Q1-Q3:6.9-8.6) %. During a mean follow-up of 814 ± 591 days, 855 HF, 143 MI, 815 AP, 340 stroke, and 139 AF events were recorded. Compared with empagliflozin, the risk of developing HF, MI, AP, stroke, and AF was not significantly different in dapagliflozin, canagliflozin, and other SGLT inhibitors. For developing HF, compared with empagliflozin, hazard ratios of dapagliflozin, canagliflozin, and other SGLT2 inhibitors were 1.02 (95% confidence interval [CI] 0.81-1.27), 1.08 (95% CI 0.87-1.35), and 0.88 (95% CI 0.73-1.07), respectively. Wald tests showed that there was no significant difference in the risk of developing HF, MI, AP, stroke, and AF among individual SGLT2 inhibitors. We confirmed the robustness of these results through a multitude of sensitivity analyses. CONCLUSION: The risks for subsequent development of HF, MI, AP, stroke, and AF were comparable between individual SGLT2 inhibitors. This is the first study comparing the wide-range cardiovascular outcomes of patients with DM treated with individual SGLT2 inhibitors using large-scale real-world data.

Threshold of BMI for the Development of Hypertension among Japanese Adults.

BACKGROUND: The optimal value of BMI for the development of hypertension and the influence of BMI on the development of stage 1 or stage 2 hypertension remain unclear. OBJECTIVES: We sought to identify the BMI threshold for the prevention of hypertension and how changes in BMI would influence the risk of developing hypertension. METHODS: We analyzed 1,262,356 participants (median age: 43 y; 50.9% men) with normal blood pressure [BP; systolic BP (SBP) <120 mmHg and diastolic BP (DBP) <80 mmHg] or elevated BP (SBP: 120-129 mmHg and DBP <80 mmHg). The primary outcome was stage 1 (SBP 130-139 mmHg or DBP 80-89 mmHg) or stage 2 hypertension (SBP ≥140 mmHg or DBP ≥90 mmHg). We analyzed the relation between baseline BMI, change in BMI, and the risk of developing hypertension using generalized additive models with a smoothing spline. RESULTS: During the median follow-up of 851 d, 341,212 cases of stage 1 hypertension and 70,968 cases of stage 2 hypertension were detected. The risk of developing stage 1 or stage 2 hypertension increased steeply after BMI (kg/m2) exceeded 20. The annual change in BMI was positively correlated with the risk of developing stage 1 or 2 hypertension. Contour mapping using generalized additive models demonstrated an additive increase in the risk of developing hypertension with higher baseline BMI and increases in BMI over 1 y. Body-weight gain increases the risk of developing hypertension even in underweight or normal-weight individuals based on the WHO classification. CONCLUSIONS: In Japanese adults with normal or elevated BP, the risk of developing hypertension increased with BMI when baseline BMI was >20. Body-weight gain additively interacted with baseline BMI during hypertension development. Our results underscore the importance of maintaining body weight in preventing the development of hypertension.

Semiquantitative assessed proteinuria and risk of heart failure: analysis of a nationwide epidemiological database.

BACKGROUND: Heart failure (HF) is increasing in prevalence worldwide. We explored whether adults with trace and positive proteinuria were at a high risk for incident HF compared with those with negative proteinuria using a nationwide epidemiological database. METHODS: This is an observational cohort study using the JMDC Claims Database collected between 2005 and 2020. This is a population-based sample [n = 1 021 943; median age 44 years (interquartile range 37-52); 54.8% men]. No participants had a known history of cardiovascular disease (CVD). Each participant was categorized into three groups according to the urine dipstick test results: negative proteinuria (n = 902 273), trace proteinuria (n = 89 599) and positive proteinuria (≥1+; n = 30 071). The primary outcome was HF. The secondary outcomes were myocardial infarction (MI), stroke and atrial fibrillation (AF). We performed multivariable Cox regression analyses to identify the association between the proteinuria category and incident HF and other CVD events. RESULTS: Over a mean follow-up of 1150 ± 920 days, 17 182 incident HF events occurred. After multivariable adjustment, hazard ratios for HF events were 1.09 [95% confidence interval (CI) 1.03-1.15] and 1.59 (95% CI 1.49-1.70) for trace proteinuria and positive proteinuria versus negative proteinuria, respectively. This association was present irrespective of clinical characteristics. A stepwise increase in the risk of MI, stroke and AF with proteinuria category was also observed. Our primary results were confirmed in participants after multiple imputations for missing values and in those having no medications for hypertension, diabetes mellitus and dyslipidemia. The discriminative predictive value for HF events improved by adding the results of urine dipstick tests to traditional risk factors [net reclassification improvement 0.0497 (95% CI 0.0346-0.0648); P < 0.001]. CONCLUSIONS: Not only positive proteinuria, but also trace proteinuria was associated with a greater incidence of HF in the general population. Semiquantitative assessment of proteinuria would be informative for the risk stratification of HF.

Biomarkers associated with coronary high-risk plaques.

Vascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary high-risk plaques defined according to intravascular imaging have not been systematically studied. A total of 69 patients with coronary artery disease who underwent both optical coherence tomography and intravascular ultrasound imaging, and who provided blood specimens were included. Comprehensive biomarkers for inflammation, lipid, and coagulation were analyzed. Composite models sought biomarker patterns associated with thin-cap fibroatheroma (TCFA) and "high-risk plaques" (TCFA and large plaque burden). Two different composite models were developed for TCFA, based on the finding that high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1, fibrinogen, IL-6, homocysteine and amyloid A levels were elevated, and high-density lipoprotein cholesterol (HDL) and bile acid levels were decreased in these patients. Both composite models were highly accurate for detecting patients with TCFA (area under curve [AUC]: 0.883 in model-A and 0.875 in model-B, both p < 0.001). In addition, creatinine, hsCRP, fibrinogen, tumor necrosis factor-α, IL-6, homocysteine, amyloid A, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques". Two composite models were highly accurate for detection of patients with "high-risk plaques" (AUC: 0.925 in model-A and 0.947 in model-B, both p < 0.001). Biomarkers useful for detection of patients with high-risk coronary plaques defined according to intravascular imaging have been identified. These biomarkers may be useful to risk stratify patients and to develop targeted therapy.Clinical Trial Registration https://www.umin.ac.jp/ctr/ , UMIN000041692. Biomarkers and high-risk plaques hsCRP, PAI-1, fibrinogen, IL-6, homocysteine, amyloid A, HDL, and bile acid were useful for detecting patients with TCFA. hsCRP, fibrinogen, IL-6, homocysteine, amyloid A, creatinine, TNFα, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques" (plaque which has both TCFA and large plaque burden). White arrowhead denotes TCFA. Red and green dashed lines denote lumen area and external elastic membrane area, respectively.

The impact of chronic kidney disease severity on clinical outcomes after current generation drug-eluting stent implantation for left main distal bifurcation lesions: the Milan and New-Tokyo registry.

Objectives. The impact of chronic kidney disease (CKD) on clinical outcomes after percutaneous coronary intervention (PCI) for unprotected left main distal bifurcation lesions (ULMD) is not fully understood in current generation drug eluting stent (cDES) era. We assessed clinical outcomes after PCI using cDES for ULMD according to CKD severity based on estimated glomerular filtration rate (eGFR). Design. We identified 720 consecutive patients who underwent PCI using cDES for ULMD at three high volume centers between January 2005 and December 2015. We divided those patients to the following five groups according to eGFR. Each group was defined as follows: no CKD (60 mL/min/1.73 m2 ≤ eGFR), mild CKD (45 ≤ eGFR < 60 mL/min/1.73 m2), moderate CKD (30 ≤ eGFR < 45 mL/min/1.73 m2), severe CKD (15 ≤ eGFR < 30 mL/min/1.73 m2) and hemodialysis (HD). The primary endpoint was target lesion failure (TLF) at 3 years. TLF was defined as a composite of cardiac death, target lesion revascularization (TLR) and myocardial infarction (MI). Results. TLF occurred more frequently in severe CKD and HD group compared with other three groups. Conclusions. The patients who have severe CKD or are on HD, were extremely associated with worse clinical outcomes after PCI for ULMD even with cDES.

Impact of directional coronary atherectomy followed by drug-coated balloon strategy to avoid the complex stenting for bifurcation lesions.

Although the simple single stenting rather than complex double stenting is recommended on percutaneous coronary intervention (PCI) for bifurcation lesions, double stenting cannot always be avoided. We investigated the impact of directional coronary atherectomy (DCA), followed by drug-coated balloon (DCB) treatment to reduce the number of stents and avoid complex stenting in PCI for bifurcation lesions and short-term patency. DCA treatment without stents was attempted for 27 bifurcation lesions in 25 patients, of those, 26 bifurcation lesions in 24 patients were successfully treated and 3-month follow-up angiography and optical coherence tomography (OCT) were performed. Sixteen lesions (59.3%) were related to left main trunk distal bifurcations, and 7 (25.9%) were true bifurcation lesions. Among the true bifurcation lesions, 4 lesions (57.1%) needed 1 stent, and the other 3 lesions (42.9%) needed no stents. Among the non-true bifurcation lesions, 1 lesion (5.0%) needed bailout stent and other lesions (95.0%) needed no stents. According to DCA followed by DCB treatment, the angiographic mean diameter stenosis improved from 65.5 ± 15.0% to 7.8 ± 9.8%, and the mean plaque area in intravascular ultrasound improved from 80.4 ± 10.5% to 39.0 ± 11.5%, respectively. Angiographic and OCT late lumen loss values were 0.2 ± 0.6 mm and 1.4 ± 1.9 mm, respectively. No patient had in-hospital major adverse cardiac events (MACE) and 3-month MACE. In conclusion, compared with standard provisional side branch stenting strategy, DCA followed by DCB treatment might reduce the number of stents, avoid complex stenting for major bifurcation lesions and provide good short-term outcomes.

Spatial and Functional Crosstalk between the Mitochondrial Na+-Ca2+ Exchanger NCLX and the Sarcoplasmic Reticulum Ca2+ Pump SERCA in Cardiomyocytes.

The mitochondrial Na+-Ca2+ exchanger, NCLX, was reported to supply Ca2+ to sarcoplasmic reticulum (SR)/endoplasmic reticulum, thereby modulating various cellular functions such as the rhythmicity of cardiomyocytes, and cellular Ca2+ signaling upon antigen receptor stimulation and chemotaxis in B lymphocytes; however, there is little information on the spatial relationships of NCLX with SR Ca2+ handling proteins, and their physiological impact. Here we examined the issue, focusing on the interaction of NCLX with an SR Ca2+ pump SERCA in cardiomyocytes. A bimolecular fluorescence complementation assay using HEK293 cells revealed that the exogenously expressed NCLX was localized in close proximity to four exogenously expressed SERCA isoforms. Immunofluorescence analyses of isolated ventricular myocytes showed that the NCLX was localized to the edges of the mitochondria, forming a striped pattern. The co-localization coefficients in the super-resolution images were higher for NCLX-SERCA2, than for NCLX-ryanodine receptor and NCLX-Na+/K+ ATPase α-1 subunit, confirming the close localization of endogenous NCLX and SERCA2 in cardiomyocytes. The mathematical model implemented with the spatial and functional coupling of NCLX and SERCA well reproduced the NCLX inhibition-mediated modulations of SR Ca2+ reuptake in HL-1 cardiomyocytes. Taken together, these results indicated that NCLX and SERCA are spatially and functionally coupled in cardiomyocytes.

Digital transformation of droplet/aerosol infection risk assessment realized on "Fugaku" for the fight against COVID-19.

The fastest supercomputer in 2020, Fugaku, has not only achieved digital transformation of epidemiology in allowing end-to-end, detailed quantitative modeling of COVID-19 transmissions for the first time but also transformed the behavior of the entire Japanese public through its detailed analysis of transmission risks in multitudes of societal situations entailing heavy risks. A novel aerosol simulation methodology was synthesized out of a combination of a new CFD methods meeting industrial demands in the solver, CUBE (Jansson et al., 2019), which not only allowed the simulations to scale massively with high resolution required for micrometer virus-containing aerosol particles but also enabled extremely rapid time-to-solution due to its ability to generate the digital twins representing multitudes of societal situations in a matter of minutes, attaining true overall application high performance; such simulations have been running for the past 1.5°years on Fugaku, cumulatively consuming top supercomputer-class resources and the communicated by the media as well as becoming the basis for official public policies.

Integration of mitochondrial energetics in heart with mathematical modelling.

It has been an unsolved question how cardiac mitochondrial energetics is regulated during working transition. Mathematical modelling is a powerful tool for exploring the complicated networks of mitochondrial metabolism. We summarize the recent progress and remaining questions about mitochondrial energetics in heart, especially focusing on approaches utilizing mathematical modelling. Feedback activation by ADP and/or inorganic phosphate is an old but still attractive hypothesis for explaining the regulation mechanisms of cardiac mitochondrial energetics. However, this hypothesis has not been fully validated by experiments because rises of ADP and/or inorganic phosphate concentrations during cardiac workload increase have not been detected in many experiments. The hypothesis of intracellular energetic units is an extended version of feedback activation, which has a similar problem. The each-step activation hypothesis beautifully reproduces metabolite constancy, although such master regulators have not been identified yet. Ca2+ has been the most plausible candidate because some of the mitochondrial dehydrogenases are activated by it. Recent experimental and simulation studies, however, throw doubt on its physiological relevance. Finally, we discuss issues to be solved to obtain a better view of cardiac mitochondrial energetics.

Establishment of a cell-free translation system from rice callus extracts.

Eukaryotic in vitro translation systems require large numbers of protein and RNA components and thereby rely on the use of cell extracts. Here we established a new in vitro translation system based on rice callus extract (RCE). We confirmed that RCE maintains its initial activity even after five freeze-thaw cycles and that the optimum temperature for translation is around 20°C. We demonstrated that the RCE system allows the synthesis of hERG, a large membrane protein, in the presence of liposomes. We also showed that the introduction of a bicistronic mRNA based on 2A peptide to RCE allowed the production of two distinct proteins from a single mRNA. Our new method thus facilitates laboratory-scale production of cell extracts, making it a useful tool for the in vitro synthesis of proteins for biochemical studies.

Safety and efficacy of cold polypectomy compared to endoscopic mucosal resection and hot biopsy polypectomy.

Backgrounds: Recently, several studies have demonstrated the usefulness of cold polypectomy (CP), a safe and simple method for the removal of small polyps. We investigated the safety and efficacy of CP compared to that of endoscopic mucosal resection (EMR) and hot biopsy polypectomy (HB). Methods: We retrospectively examined 1713 colorectal polyps (size 1-9 mm) in 731 patients. CP, EMR, and HB were performed on 476, 997, and 240 lesions, respectively. We compared the region, size, morphology, the presence of delayed bleeding as overt bleeding 24 h after operation, number of clips, pathology, the presence of antithrombotic therapy, procedure time from detection of a polyp to resection and hemostasis, device cost including device and clips, and polyp remnants. Results: The delayed bleeding in the CP group (0/476) was significantly lower compared to that in the HB group (3/240) and EMR group (7/997). There were no cases of perforations. The procedure time was significantly shorter in the CP group than in the EMR group (91.3sec vs 290.1sec, p < .0001). The CP group had a significantly lower device cost than the HB and EMR groups (49.2USD vs 58.0 USD vs 91.3 USD, p < .0001) was not inferior in terms of polyp remnants to the EMR and HB groups. (1.4% vs 0.6% vs 6.1%, p = .1599) Conclusions: CP is a safe treatment that achieves less delayed bleeding. Moreover, CP is not inferior to other groups in terms of polyp remnants and offers a cost benefit. CP can be considered useful for colonic polypectomy.

Dysregulation of a potassium channel, THIK-1, targeted by caspase-8 accelerates cell shrinkage.

Activation of caspases is crucial for the execution of apoptosis. Although the caspase cascade associated with activation of the initiator caspase-8 (CASP8) has been investigated in molecular and biochemical detail, the physiological role of CASP8 is not fully understood. Here, we identified a two-pore domain potassium channel, tandem-pore domain halothane-inhibited K+ channel 1 (THIK-1), as a novel CASP8 substrate. The intracellular region of THIK-1 was cleaved by CASP8 in apoptotic cells. Overexpression of THIK-1, but not its mutant lacking the CASP8-target sequence in the intracellular portion, accelerated cell shrinkage in response to apoptotic stimuli. In contrast, knockdown of endogenous THIK-1 by RNA interference resulted in delayed shrinkage and potassium efflux. Furthermore, a truncated THIK-1 mutant lacking the intracellular region, which mimics the form cleaved by CASP8, led to a decrease of cell volume of cultured cells without apoptotic stimulation and excessively promoted irregular development of Xenopus embryos. Taken together, these results indicate that THIK-1 is involved in the acceleration of cell shrinkage. Thus, we have demonstrated a novel physiological role of CASP8: creating a cascade that advances the cell to the next stage in the apoptotic process.