We present spontaneous scalarization of charged black holes (BHs) which is induced by the coupling of the scalar field to the electromagnetic field strength and the double-dual Riemann tensor ...LμναβFμνFαβ in a scalar-vector-tensor theory. In our model, the scalarization can be realized under the curved background with a nontrivial electromagnetic field, such as Reissner-Nordström black holes (RN BHs). First, we investigate the stability of the constant scalar field around RN BHs in the model, and show that the scalar field can suffer a tachyonic instability. Secondly, the bound state solution of the test scalar field around a RN BH and its stability is discussed. Finally, we construct scalarized BH solutions, and investigate their stability.
Aim: Cardiovascular disease (CVD) is the second largest cause of death in Japanese women. Pregnancy and childbirth are events that put a strain on the cardiovascular system. When postpartum weight ...retention is insufficient, weight gain due to fat deposition during pregnancy might lead to obesity. Thus, we examined the effects of body mass index (BMI) in middle and older ages and the number of children on CVD and metabolic disorders.Methods: From the Tohoku Medical Megabank database, we used data from 32,000 women aged ≥ 50 years. This database contains obstetrical history, medical history, and laboratory data obtained once from 2013 to 2015.Results: The mean age of participants was 64.2 years, and 47.7% of women had two children. Compared with nulliparous women, those who had a higher number of children had higher BMI and systolic blood pressure. The prevalence of CVD was highest in obese class I (30 kg/m2 ≤ BMI) women with three or more children and the prevalence of hypertension was high in pre-obese (25 kg/m2 ≤ BMI ＜30 kg/m2) and obese class I women with children. Conversely, the prevalence of diabetes and proportion of women whose HbA1c values were ＞6.5% was highest in obese class I women with no children.Conclusion: In this study, we found that not only BMI but also the number of children influenced the health status of middle- and older-aged women, suggesting the importance of childbirth history in the health management of women.
In recent decades, phage therapy has been overshadowed by the widespread use of antibiotics in Western countries. However, it has been revitalized as a powerful approach due to the increasing ...prevalence of antimicrobial-resistant bacteria. Although bacterial resistance to phages has been reported in clinical cases, recent studies on the fitness trade-offs between phage and antibiotic resistance have revealed new avenues in the field of phage therapy. This strategy aims to restore the antibiotic susceptibility of antimicrobial-resistant bacteria, even if phage-resistant variants develop. Here, we summarize the basic virological properties of phages and their applications within the context of antimicrobial resistance. In addition, we review the occurrence of phage resistance in clinical cases, and examine fitness trade-offs between phage and antibiotic sensitivity, exploring the potential of an evolutionary fitness cost as a countermeasure against phage resistance in therapy. Finally, we discuss future strategies and directions for phage-based therapy from the aspect of fitness trade-offs. This approach is expected to provide robust options when combined with antibiotics in this era of phage ‘re’-discovery.
The prevalence of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), is currently a major public health concern due to the lack of efficient ...disease-modifying therapeutic options. Recent evidence suggests that mitochondrial dysfunction and nitrosative/oxidative stress are key common mediators of pathogenesis. In this review, we highlight molecular mechanisms linking NO-dependent post-translational modifications, such as cysteine S-nitrosylation and tyrosine nitration, to abnormal mitochondrial metabolism. We further discuss the hypothesis that pathological levels of NO compromise brain energy metabolism via aberrant S-nitrosylation of key enzymes in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, contributing to neurodegenerative conditions. A better understanding of these pathophysiological events may provide a potential pathway for designing novel therapeutics to ameliorate neurodegenerative disorders.
Neurons are particularly sensitive to dysfunction in mitochondrial metabolism due to their high energy demands.
Excessive production of NO-related species is linked to mitochondrial metabolic defects in neurodegenerative diseases.
Aberrant protein S-nitrosylation (producing SNO-proteins) mediates pathological NO signaling cascades, contributing to mitochondrial metabolic dysfunction.
A wide range of aberrantly S-nitrosylated mitochondrial proteins that may contribute to neurodegenerative diseases has been identified; these SNO proteins include enzymes involved in the TCA cycle, the ETC, and mitochondrial dynamics.
Aberrant S-nitrosylation of specific proteins may represent a key mediator of both T2DM/MetS and neurodegenerative disorders such as AD.
Mitochondria are highly dynamic organelles that continuously undergo two opposite processes, fission and fusion. Mitochondrial dynamics influence not only mitochondrial morphology, but also ...mitochondrial biogenesis, mitochondrial distribution within the cell, cell bioenergetics, and cell injury or death. Drp1 mediates mitochondrial fission, whereas Mfn1/2 and Opa1 control mitochondrial fusion. Neurons require large amounts of energy to carry out their highly specialized functions. Thus, mitochondrial dysfunction is a prominent feature in a variety of neurodegenerative diseases. Mutations of Mfn2 and Opa1 lead to neuropathies such as Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. Moreover, both Aβ peptide and mutant huntingtin protein induce mitochondrial fragmentation and neuronal cell death. In addition, mutants of Parkinson's disease-related genes also show abnormal mitochondrial morphology. This review highlights our current understanding of abnormal mitochondrial dynamics relevant to neuronal synaptic loss and cell death in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease.
Although radical surgery is recommended for patients not meeting the curative criteria for endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) because of the potential risk of lymph ...node metastasis (LNM), this recommendation may be overestimated and excessive. We aimed to establish a simple scoring system for decision making after ESD.
This multicenter retrospective study consisted of two stages. First, the risk-scoring system for LNM was developed using multivariate logistic regression analysis in 1,101 patients who underwent radical surgery after having failed to meet the curative criteria for ESD of EGC. Next, the system was internally validated by survival analysis in another 905 patients who also did not meet the criteria and did not receive additional treatment after ESD.
In the development stage, based on accordant regression coefficients, five risk factors for LNM were weighted with point values: three points for lymphatic invasion and 1 point each for tumor size >30 mm, positive vertical margin, venous invasion, and submucosal invasion ≥500 μm. Then, the patients were categorized into three LNM risk groups: low (0-1 point: 2.5% risk), intermediate (2-4 points: 6.7%), and high (5-7 points: 22.7%). In the validation stage, cancer-specific survival differed significantly among these groups (99.6, 96.0, and 90.1%, respectively, at 5 years; P<0.001). The C statistic of the system for cancer-specific mortality was 0.78.
This scoring system predicted cancer-specific survival in patients who did not meet the curative criteria after ESD for EGC. ESD without additional treatment may be an acceptable option for patients at low risk.
Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a ...gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.
At high altitudes, the hypoxic atmosphere decreases the oxygen partial pressure in the body, inducing several metabolic changes in tissues and cells. Furthermore, it exerts potent anorectic effects, ...thus causing an energy deficit. Two decades ago, a marked increase in the resting level of plasma cholecystokinin (CCK) was observed in humans at the Mt. Kanchenjunga basecamp, located at 5100 m above the sea level, compared to sea-level control values. Interestingly, acute exercise also raises plasma CCK and exerts potent anorectic effects under normoxic conditions. However, the transcriptional regulations of Cck gene underlying these effects have not yet been established. Here, we employed acute electrical pulse stimulation (EPS) followed by microarray analysis to discover novel myokines in 3D-engineered muscle. Acute EPS affects the contractile function, inducing a decline in the contractile force. Surprisingly, microarray analysis revealed an EPS-induced activation of cholecystokinin receptor (CCKR)-mediated signaling. Furthermore, Cck was constitutively upregulated in 3D-engineered muscle, and its expression increased under hypoxic conditions. Notably, a hypoxia-responsive element was detected in the Cck promoters of mice and humans. Our results suggested that hypoxia transactivated Cck expression in 3D-engineered muscle. Furthermore, the elevation in plasma CCK levels following acute exercise or at high altitude might be partly attributed to myogenic cells.
•Acute electrical pulse stimulation (EPS) induced cholecystokinin CCK signaling.•Cck was constitutively upregulated in 3D-engineered muscle.•Cck expression increased under hypoxic conditions.•Myogenic cells might partly elevate plasma CCK at high altitude.
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