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Phosphorylated derivatives of phosphatidylinositol, collectively referred to as phosphoinositides, occur in the cytoplasmic leaflet of cellular membranes and regulate activities such as vesicle transport, cytoskeletal reorganization and signal transduction (1,2). Recent studies have indicated an important role for phosphoinositide metabolism in the aetiology of diseases such as cancer, diabetes, myopathy and inflammation (3-5). Although the biological functions of the phosphatases that regulate phosphatidylinosito (1-3,4,5) trisphosphate (PtdIns(3,4,5)[P.sub.3]) have been well characterized, little is known about the functions of the phosphatases regulating the closely related molecule phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)[P.sub.2]). Here we show that inositol polyphosphate phosphatase 4A (INPP4A), a PtdIns(3,4)[P.sub.2] phosphatase, is a suppressor of glutamate excitotoxicity in the central nervous system. Targeted disruption of the Inpp4a gene in mice leads to neurodegeneration in the striatum, the input nucleus of the basal ganglia that has a central role in motor and cognitive behaviours. Notably, [Inpp4a.sup.-/-] mice show severe involuntary movement disorders. In vitro, Inpp4a gene silencing via short hairpin RNA renders cultured primary striatal neurons vulnerable to cell death mediated by N-methyl-Daspartate-type glutamate receptors (NMDARs). Mechanistically, INPP4A is found at the postsynaptic density and regulates synaptic NMDAR localization and NMDAR-mediated excitatory postsynaptic current. Thus, INPP4A protects neurons from excitotoxic cell death and thereby maintains the functional integrity of the brain. Our study demonstrates that PtdIns(3,4)[P.sub.2], PtdIns(3,4,5)[P.sub.3] and the phosphatases acting on them can have distinct regulatory roles, and provides insight into the unique aspects and physiological significance of PtdIns(3,4)[P.sub.2] metabolism. INPP4A represents, to our knowledge, the first signalling protein with a function in neurons to suppress excitotoxic cell death. The discovery of a direct link between PtdIns(3,4)[P.sub.2] metabolism and the regulation of neurodegeneration and involuntary movements may aid the development of new approaches for the treatment of neurodegenerative disorders., PtdIns(3,4)[P.sub.2] and PtdIns(3,4,5)[P.sub.3] are phosphoinositides that are thought to be highly similar in terms of their scarce abundance and proposed biological functions (6,7). Production of PtdIns(3,4)[P.sub.2] and PtdIns(3,4,5)[P.sub.3] depends on [...]

Escherichia coli harboring polyketide synthase (pks + E. coli) has been suggested to contribute to colorectal cancer development. Physical activity is strongly associated with lower colorectal cancer risks, but its effects on pks + E. coli remain unclear. The aim of this study was to investigate the association between pks + E. coli prevalence and physical activity. A cross-sectional study was conducted on 222 Japanese adults (27-79-years-old, 73.9% female). Triaxial accelerometers were used to measure light-intensity physical activity, moderate-to-vigorous intensity physical activity, the physical activity level, step-count, and time spent inactive. Fecal samples collected from participants were used to determine the prevalence of pks + E. coli. Multivariate logistic regression analysis and restricted cubic spline curves were used to examine the association between pks + E. coli prevalence and physical activity. The prevalence of pks + E. coli was 26.6% (59/222 participants). The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the highest tertile with reference to the lowest tertile of physical activity variables were as follows: light-intensity physical activity (OR 0.63; 95% CI 0.26-1.5), moderate-to-vigorous intensity physical activity (OR 0.85; 95% CI 0.39-1.87), physical activity level (OR 0.69; 95% CI 0.32-1.51), step-count (OR 0.92; 95% CI 0.42-2.00) and time spent inactive (OR 1.30; 95% CI 0.58-2.93). No significant dose-response relationship was found between all physical activity variables and pks + E. coli prevalence. Our findings did not suggest that physical activity has beneficial effects on the prevalence of pks + E. coli. Longitudinal studies targeting a large population are needed to clarify this association., (© 2023. The Author(s).)

This study aimed to identify the modifiable cardiovascular risk factors associated with longitudinal changes, which are nine functional and structural biological vascular aging indicators (BVAIs), to propose an effective method to prevent biological vascular aging. We conducted a longitudinal study of 697 adults (a maximum of 3636 BVAI measurements) who were, at baseline, aged between 26 and 85 years and whose BVAIs were measured at least twice between 2007 and 2018. The nine BVAIs were measured using vascular testing and an ultrasound device. Covariates were assessed using validated questionnaires and devices. During the mean follow-up period of 6.7 years, the average number of BVAI measurements ranged from 4.3 to 5.3. The longitudinal analysis showed a moderate positive correlation between the common carotid intima-media thickness (IMT) and chronological age in both men (r = 0.53) and women (r = 0.54). In the multivariate analysis, BVAIs were associated with factors such as age, sex, residential area, smoking status, blood clinical chemistry test levels, number of comorbidities, physical fitness, body mass, physical activity, and dietary intake. The IMT is the most useful BVAI. Our findings suggest that modifiable cardiovascular risk factors are associated with longitudinal changes in BVAI as represented by IMT., (© 2023. The Author(s).)

Cardiovascular disease (CVD) is a global health burden in the world. Although low-carbohydrate diets (LCDs) have beneficial effects on CVD risk, their preventive effects remain elusive. We investigated whether LCDs ameliorate heart failure (HF) using a murine model of pressure overload. LCD with plant-derived fat (LCD-P) ameliorated HF progression, whereas LCD with animal-derived fat (LCD-A) aggravated inflammation and cardiac dysfunction. In the hearts of LCD-P-fed mice but not LCD-A, fatty acid oxidation-related genes were highly expressed, and peroxisome proliferator-activated receptor α (PPARα), which regulates lipid metabolism and inflammation, was activated. Loss- and gain-of-function experiments indicated the critical roles of PPARα in preventing HF progression. Stearic acid, which was more abundant in the serum and heart of LCD-P-fed mice, activated PPARα in cultured cardiomyocytes. We highlight the importance of fat sources substituted for reduced carbohydrates in LCDs and suggest that the LCD-P-stearic acid-PPARα pathway as a therapeutic target for HF., (© 2023. The Author(s).)

The phase angle (PhA), measured via bioelectrical impedance analysis, is considered an indicator of cellular health, where higher values reflect higher cellularity, cell membrane integrity, and better cell function. This study aimed to examine the relationship between PhA and exercise habits or objectively measured physical activity. We included 115 people aged 32-69 years. The body composition and PhA were measured using a bioelectrical impedance device. Physical activity and sedentary behavior (SB) were assessed using a triaxial accelerometer. Exercise habits were also obtained through structured interviews, and participants were categorized into the no exercise habit (No-Ex), resistance training exercise habit (RT), or aerobic training exercise habit (AT) groups. Objectively measured moderate-to-vigorous physical activity or step count significantly correlated with PhA, independent of age, sex, height, percent body fat, body cell mass, and leg muscle power. In contrast, SB was not significant determinants of PhA. People who exercised regularly (RT or AT) had significantly higher PhA values than did those in the No-Ex group. Furthermore, the PhA was not significantly different between the RT and AT groups. Regularly engaging in exercise with moderate-to-vigorous intensity may improve or maintain muscle cellular health and muscle quality., (© 2022. The Author(s).)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary cardiomyopathy that results in fatal arrhythmias and heart failure. Herein, we report a Japanese patient with ARVC whose parents were blood relatives. Genetic testing identified a homozygous rare variant, c.1592T > G (p.Phe531Cys), of DSG2 that is presumed to be a founder variant among East Asians. Genetic counseling sessions with precise risk assessment and appropriate follow-up programs were provided to the patient and family members., (© 2022. The Author(s).)

Hereditary leiomyomatosis and renal cell carcinoma caused by loss-of-function germline variants of the FH gene can develop into aggressive renal cell carcinoma (RCC). We report the case of a 27-year-old man who died of RCC. Genetic testing revealed a novel pathogenic variant of FH, NM_000143.3:c.1013_1014del (p.Ile338Serfs*3), that was also identified in healthy siblings. Identification of genetic causes in the proband helped us to provide relatives with precise genetic counseling and appropriate surveillance programs., (© 2021. The Author(s).)

2p15p16.1 microdeletion syndrome is a recently recognized congenital disorder characterized by developmental delay and dysmorphic features. RP2-associated retinal disorder (RP2-RD) is an X-linked inherited retinal disease with a childhood onset caused by a loss-of-function variant in the RP2 gene. Here, we describe a 14-year-old boy with double diagnoses of 2p15p16.1 microdeletion syndrome and RP2-RD. The recurrence risk of each condition and the indication for potential therapeutic options for RP2-RD are discussed., (© 2021. The Author(s).)

Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through β-arrestin as a biased receptor. As several β-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a β-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited β-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a β-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.

Some clinical trials showed that omega-3 fatty acid (FA) reduced cardiovascular events, but it remains unknown whether omega-3 FA supplementation changes the composition of FAs and their metabolites in the heart and how the changes, if any, exert beneficial effects on cardiac structure and function. To clarify these issues, we supplied omega-3 FA to mice exposed to pressure overload, and examined cardiac structure and function by echocardiography and a proportion of FAs and their metabolites by gas chromatography and liquid chromatography-tandem mass spectrometry, respectively. Pressure overload induced cardiac hypertrophy and dysfunction, and reduced concentration of all FAs' components and increased free form arachidonic acid and its metabolites, precursors of pro-inflammatory mediators in the heart. Omega-3 FA supplementation increased both total and free form of eicosapentaenoic acid, a precursor of pro-resolution mediators and reduced free form arachidonic acid in the heart. Omega-3 FA supplementation suppressed expressions of pro-inflammatory cytokines and the infiltration of inflammatory cells into the heart and ameliorated cardiac dysfunction and fibrosis. These results suggest that omega-3 FA-induced changes of FAs composition in the heart have beneficial effects on cardiac function via regulating inflammation.

The relative contribution of diet to colorectal cancer (CRC) incidence is higher than that for other cancers. Animal models have revealed that Escherichia coli containing polyketide synthase (pks + E. coli) in the gut participates in CRC development. The purpose of this cross-sectional study was to examine the relationship between dietary intake and the prevalence of pks + E. coli isolated from the microbiota in faecal samples of 223 healthy Japanese individuals. Dietary intake was assessed using a previously validated brief-type self-administered diet history questionnaire. The prevalence of pks + E. coli was evaluated using faecal samples collected from participants and specific primers that detected pks + E. coli. The prevalence of pks + E. coli was 26.9%. After adjusting for baseline confounders, the prevalence of pks + E. coli was negatively associated with the intake of green tea (odds ratio [OR], 0.59 [95% confidence interval (CI) 0.30-0.88] per 100 g/1,000 kcal increment) and manganese (OR, 0.43 [95% CI 0.22-0.85] per 1 mg/1,000 kcal increment) and was positively associated with male sex (OR, 2.27 [95% CI 1.05-4.91]). While futher studies are needed to validate these findings, these results provide insight into potential dietary interventions for the prevention of CRC.

Faecal volume, form, colour, and odour are associated with various diseases, dietary habits, and the gut microbiome. Multifaceted assessment of faecal condition will be needed for future research and practice. Faecal observation has advantages, as it is non-invasive, frequent, and easy. We have developed and validated an illustrative card tool for comprehensively faecal assessment. In 38 healthy adults, observations of volume, form, colour, and odour of faeces using the tool were compared to the objective characteristics of the actual faeces determined using a weighing scale, moisture meter, hardness meter, colourimeter, and odour measuring device. A significant positive correlation (ρ = 0.778) was observed between the number of faecal model (2 cm × 10 cm) units and the actual weight. The Bristol Stool Form Scale showed a significant positive correlation with the moisture content (ρ = 0.717) and negative correlations with faecal hardness (ρ = -0.843) and adhesiveness (ρ = -0.761). The L*a*b* colour space values of the stool differed significantly among observational judgments using the colour card tool. No significant correlation was observed between the observation of odour and the measured odour index. In conclusion, the faecal volume, form, and colour can be estimated by observation using the multifaceted assessment card tool.

Metagenomic analysis based on the 16S rRNA gene is generally performed to examine the diversity and abundance of commensal bacteria in feces, which is now recognized to be associated with human health and diseases. Guanidine thiocyanate (GuSCN) solution is used as a less onerous way compared with a frozen method to transport and stock fecal samples at room temperature for DNA analysis; however, optimal methods to measure fecal bacterial composition in GuSCN solution remain to be investigated. Here, we examined the influence of various factors such as pretreatment (e.g., removing GuSCN solution and washing feces with phosphate-buffered saline (PBS) before mechanical lysis), fecal concentration in the GuSCN solution, storage time, and position of fecal subsampling on the 16S rRNA-based analysis of fecal bacteria in GuSCN solution. We found that pretreatment and fecal concentration affected the bacterial composition, and a little change was noted with subsampling position. Based on these results, we propose a basic protocol, including fecal sampling, sample storage, and DNA extraction, for the 16S rRNA-based analysis of bacterial composition in feces suspended in GuSCN solution.

A decrease in systemic arterial compliance (SAC) increases left ventricular load along with the demand for excessive myocardial oxygen consumption when the age-related reduction of SAC reaches a marked level, and consequently may depress left ventricular pump function. Reduced left ventricular pump function decreases aerobic capacity, and some study groups have shown that SAC and/or central arterial distensibility is correlated with maximal aerobic capacity in humans. We thus hypothesize that, once the age-related reduction of SAC reaches a marked level, the participation of SAC in aerobic capacity will be significant even during sub-maximal exercise. Thirty young humans and 46 elderly humans participated in this study. SAC, oxygen uptake at the ventilatory threshold (VO2VT), and the ratio of increase in oxygen uptake, in cardiac output, and in effective arterial elastance to increase in work rate (deltaVO2/deltaWR, deltaCO/deltaWR and deltaEa/deltaWR) were measured. SAC was significantly higher in young subjects compared with elderly subjects, and was significantly related to VO2VT in elderly subjects. SAC also significantly correlated with deltaVO2/deltaWR, deltaCO/deltaWR and deltaEa/deltaWR in elderly subjects. When total subjects were divided by the value of SAC into 6 groups, the VO2VT values in the 3 groups with lower SAC were significantly lower than those in the 3 groups with higher SAC, and gradually decreased with the reduction of SAC. There were no changes in VO2VT among the 3 groups with higher SAC. These results suggest that the participation of SAC in aerobic capacity is significant even during sub-maximal exercise in individuals who show a pronounced age-related reduction of SAC.