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Background Exercise intolerance in heart failure arises from multifactorial pathophysiological mechanisms. Hepatokines, liver‐synthesized molecules, regulate systemic metabolisms in peripheral tissues. We previously identified the hepatokine fetuin‐A as being linked to liver hypoperfusion in heart failure. Here, we investigated the role of fetuin‐A in connecting cardiac–hepatic–peripheral interaction. Methods and Results We conducted a prospective study involving 202 consecutive hospitalized patients (mean age, 56.8 years; 76.2% men) with heart failure who underwent cardiopulmonary exercise testing. We measured the serum concentration of fetuin‐A by ELISA. Correlation analysis revealed a negative association between fetuin‐A levels and the ratio of minimum minute ventilation to carbon dioxide production, its slope, and a tendency toward a positive correlation with peak oxygen uptake. Patients with impaired exercise tolerance exhibited lower fetuin‐A levels. During a median follow‐up of 1045 days, 18.3% experienced cardiac events, including 4 cardiac deaths and 33 cases of worsening heart failure. Classification and regression tree analysis identified a high‐risk subgroup with lower fetuin‐A (

Organisms adapt to changes in their environment to survive. The emergence of predators is an example of environmental change, and organisms try to change their external phenotypic systems and physiological mechanisms to adapt to such changes. In general, prey exhibit different phenotypes to predators owing to historically long-term prey-predator interactions. However, when presented with a novel predator, the extent and rate of phenotypic plasticity in prey are largely unknown. Therefore, exploring the physiological adaptive response of organisms to novel predators is a crucial topic in physiology and evolutionary biology. Counterintuitively, Xenopus tropicalis tadpoles do not exhibit distinct external phenotypes when exposed to new predation threats. Accordingly, we examined the brains of X. tropicalis tadpoles to understand their response to novel predation pressure in the absence of apparent external morphological adaptations. Principal component analysis of fifteen external morphological parameters showed that each external morphological site varied nonlinearly with predator exposure time. However, the overall percentage change in principal components during the predation threat (24 h) was shown to significantly (p < 0.05) alter tadpole morphology compared with that during control or 5-day out treatment (5 days of exposure to predation followed by 5 days of no exposure). However, the adaptive strategy of the altered sites was unknown because the changes were not specific to a particular site but were rather nonlinear in various sites. Therefore, RNA-seq, metabolomic, Ingenuity Pathway Analysis, and Kyoto Encyclopedia of Genes and Genomes analyses were performed on the entire brain to investigate physiological changes in the brain, finding that glycolysis-driven ATP production was enhanced and ß-oxidation and the tricarboxylic acid cycle were downregulated in response to predation stress. Superoxide dismutase was upregulated after 6 h of exposure to new predation pressure, and radical production was reduced. Hemoglobin was also increased in the brain, forming oxyhemoglobin, which is known to scavenge hydroxyl radicals in the midbrain and hindbrain. These suggest that X. tropicalis tadpoles do not develop external morphological adaptations that are positively correlated with predation pressure, such as tail elongation, in response to novel predators; however, they improve their brain functionality when exposed to a novel predator.

Abstract Growth hormone (GH) transgenesis can be used to manipulate the growth performance of fish and mammals. In this study, homozygous and hemizygous GH-transgenic amago salmon (Oncorhynchus masou ishikawae) derived from a single female exhibited hypoglycemia. Proteomic and signal network analyses using iTRAQ indicated a decreased NAD+/NADH ratio in transgenic fish, indicative of reduced mitochondrial ND1 function and ROS levels. Mitochondrial DNA sequencing revealed that approximately 28% of the deletion mutations in the GH homozygous- and hemizygous-female-derived mitochondrial DNA occurred in ND1. These fish also displayed decreased ROS levels. Our results indicate that GH transgenesis in amago salmon may induce specific deletion mutations that are maternally inherited over generations and alter energy production.

We envisioned that the rumen of Kitasato Yakumo beef cattle would contain unique microorganisms which produce bioactive compounds as their defense response to the external environment. The variety of microorganisms were collected from the feces of Kitasato Yakumo beef cattle. We evaluated the biological activity of the culture broth of the isolated strains, proving the utility of our approach. [ABSTRACT FROM AUTHOR]

In this paper, we describe our discovery of burnettiene A (1) as an antimalarial compound from the culture broth of Lecanicillium primulinum (current name: Flavocillium primulinum) FKI-6715 strain utilizing our original multidrug-sensitive yeast system. This polyene-decalin polyketide natural product was originally isolated as an antifungal active compound from Aspergillus burnettii. However, the antifungal activity of 1 has been revealed in only one fungal species, and the mechanism of action of 1 remains unknown. After the validation of mitochondrial function inhibitory of 1 , we envisioned a new antimalarial drug discovery platform based on mitochondrial function inhibitory activity. We evaluated antimalarial activity and 1 showed antimalarial activity against Plasmodium falciparum FCR3 (chloroquine sensitive) and the K1 strain (chloroquine resistant). Our study revealed the utility of our original screening system based on a multidrug-sensitive yeast and mitochondrial function inhibitory activity for the discovery of new antimalarial drug candidates. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension is characterized by increased pulmonary arterial pressure, driven in part by inflammatory infiltrates. Here, the authors show that in mice, transgenic expression of mutant JAK2 leads to clonal hematopoiesis and lung accumulation of elastase- and cytokine-expressing neutrophils, and that the phenotype can be reversed by ALK1 inhibition.

Background: Tartrate-resistant acid phosphatase type 5b (TRACP5b) is derived from osteoclasts, and has been used as a marker of osteoporosis (bone resorption). Although heart failure (HF) is associated with catabolic bone remodelling, serum TRACP5b levels have not been rigourously examined in patients with HF. Methods: We conducted a prospective observational study of 688 decompensated HF patients who had been discharged and whose TRACP5b had been measured. These patients were divided into tertiles on the basis of serum TRACP5b levels: first (TRACP5b < 316 mU/dL, n = 229), second (TRACP5b 316-489 mU/dL, n = 229), and third (TRACP5b ≥ 490 mU/dL, n = 230). We compared the patient baseline characteristics, exercise capacity, and their postdischarge prognosis, including cardiac mortality and cardiac events such as cardiac death and worsening HF. Results: Age was significantly higher, and prevalence of female sex and anemia was significantly higher in the third tertile than in the first and second tertiles (P < 0.05, respectively). Circulating TRACP5b levels were correlated with peak breath-by-breath oxygen consumption, but not with left ventricular ejection fraction. In the Kaplan-Meier analysis (mean follow-up, 426 days), cardiac mortality and cardiac event rates progressively increased from the first to the third tertiles (P < 0.05, respectively). In the multivariable Cox proportional hazard analysis, the third tertile was an independent predictor of cardiac mortality and cardiac events (cardiac mortality hazard ratio, 2.493; P = 0.040; cardiac events hazard ratio, 1.687; P = 0.030). Conclusions: High serum levels of TRACP5b, a marker of bone resorption, are associated with high cardiac mortality and cardiac events, accompanied by impaired exercise capacity. Résumé: Introduction: La TRACP5b (de l’anglais, tartrate-resistant acid phosphatase type 5b, soit l’isoforme 5 b de la phosphatase acide résistante au tartrate) qui est dérivée des ostéoclastes a été utilisée comme marqueur de l’ostéoporose (la résorption de l’os). Bien que l’insuffisance cardiaque (IC) soit associée au remodelage osseux catabolique, les concentrations sériques de TRACP5b n’ont pas été rigoureusement examinées chez les patients atteints d’IC. Méthodes: Nous avons mené une étude prospective observationnelle auprès de 688 patients atteints d’IC décompensée qui avaient obtenu leur sortie de l’hôpital et pour lesquels nous avions les mesures de TRACP5b. Nous avons réparti ces patients en tertiles en fonction des concentrations sériques de TRACP5b : le premier (TRACP5b < 316 mU/dL, n = 229), le deuxième (TRACP5b 316-489 mU/dL, n = 229) et le troisième (TRACP5b ≥ 490 mU/dL, n = 230). Nous avons comparé les caractéristiques initiales des patients, leur capacité à l’effort et leur pronostic après la sortie de l’hôpital, à savoir la mortalité d’origine cardiaque et les événements cardiaques tels que la mort cardiaque et l’aggravation de l’IC. Résultats: L’âge était significativement plus élevé, et la prévalence du sexe féminin et de l’anémie était significativement plus élevée dans le troisième tertile que dans les premier et deuxième tertiles (P < 0,05, respectivement). Les concentrations circulantes de TRACP5b corrélaient avec la consommation d’oxygène maximale « respiration par respiration », mais non avec la fraction d’éjection ventriculaire gauche. Dans l’analyse de Kaplan-Meier (durée moyenne de suivi, 426 jours), les taux de mortalité d’origine cardiaque et d’ événements cardiaques augmentaient progressivement du 1er tertile au 3e tertile (P < 0,05, respectivement). Dans l’analyse multivariable selon le modèle des risques proportionnels de Cox, le 3e tertile était un prédicteur indépendant de la mortalité d’origine cardiaque et des événements cardiaques (rapport de risque de mortalité d’origine cardiaque, 2,493; P = 0,040; rapport de risque d’événements cardiaques, 1,687; P = 0,030). Conclusions: Les concentrations sériques élevées de TRACP5b, un marqueur de la résorption de l’os, sont associées à la hausse des taux de mortalité d’origine cardiaque et d’ événements cardiaques, accompagnés de la diminution de la capacité à l’effort.

Abstract Frameshifts in the Calreticulin (CALR) exon 9 provide a recurrent driver mutation of essential thrombocythemia (ET) and primary myelofibrosis among myeloproliferative neoplasms (MPNs). Here, we generated knock-in mice with murine Calr exon 9 mimicking the human CALR mutations, using the CRISPR-Cas9 method. Knock-in mice with del10 [Calr del10/WT (wild−type) mice] exhibited an ET phenotype with increases of peripheral blood (PB) platelets and leukocytes, and accumulation of megakaryocytes in bone marrow (BM), while those with ins2 (Calr ins2/WT mice) showed a slight splenic enlargement. Phosphorylated STAT3 (pSTAT3) was upregulated in BM cells of both knock-in mice. In BM transplantation (BMT) recipients from Calr del10/WT mice, although PB cell counts were not different from those in BMT recipients from Calr WT/WT mice, Calr del10/WT BM-derived macrophages exhibited elevations of pSTAT3 and Endothelin-1 levels. Strikingly, BMT recipients from Calr del10/WT mice developed more severe pulmonary hypertension (PH)—which often arises as a comorbidity in patients with MPNs—than BMT recipients from Calr WT/WT mice, with pulmonary arterial remodeling accompanied by an accumulation of donor-derived macrophages in response to chronic hypoxia. In conclusion, our murine model with the frameshifted murine Calr presented an ET phenotype analogous to human MPNs in molecular mechanisms and cardiovascular complications such as PH.

Objectives: Cytomegalovirus (CMV) reactivation in patients with severe drug eruption on immunosuppressive therapy often leads to fulminant disease and even mortality, yet there are no biomarkers to accurately predict CMV reactivation either before or after immunosuppressive therapy. We aimed to assess whether patients who develop CMV reactivation (CMV-positive cases) have distinct immunological profiles from CMV-negative cases before and after immunosuppressive therapy. Methods: We performed serial cytokine/chemokine and regulatory T cells (Tregs) assessments of 45 patients with drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic syndrome (DRESS) during a follow-up period of nearly three years after onset. Results: Elevated IL-8, IL-10, IL-12p40, IL-15, TNF-α, G-CSF, and MIP-1α levels at baseline were associated with later development of CMV reactivation, while after starting treatment, IL-10 and IL-15 levels were associated with the onset of CMV reactivation; the use of corticosteroids obscured the large differences in these cytokines at baseline. CMV-positive cases were found to have normal Tregs frequencies at baseline, while negative cases had elevated frequencies. Higher eotaxin, IL-10, and G-CSF levels and lower IL-12p40 levels at baseline might be used for predicting the development of lethal CMV disease. Conclusions: The algorithm based on these results showed an accurate association with CMV reactivation.

Abstract Aims Recently, B‐type natriuretic peptide (BNP) has been attracting attention as a predictor of stroke in patients with atrial fibrillation or those with prior stroke experience. However, the association between BNP and stroke has not been examined in patients with chronic heart failure (CHF). In the current study, we assessed whether BNP is associated with future occurrence of stroke in patients with CHF. Methods and results We prospectively studied 1803 consecutive patients who were admitted for decompensated HF and assessed the predictive value of circulating BNP levels for occurrence of post‐discharge stroke. A total of 69 (3.8%) patients experienced a stroke (the stroke group) during the post‐discharge follow‐up period of a median of 1150 days. The stroke group showed a higher CHADS2 score. With respect to past medical history, the stroke group had a higher prevalence of arterial hypertension, atrial fibrillation, prior stroke, and chronic kidney disease. Echocardiographic parameters showed no significant differences between the two groups. In contrast, BNP levels were significantly higher in the stroke group than in the non‐stroke group (452.1 vs. 222.7 pg/mL, P

BackgroundThe Patterns of non-Adherence to Anti-Platelet Regimen in Stented Patients (PARIS) thrombotic risk score has been proposed to estimate the risk of stent thrombotic events after percutaneous coronary intervention (PCI). However, the prognostic value of the PARIS thrombotic risk score for long term all-cause and cardiac mortalities, as well as hospitalization due to heart failure, has not yet been evaluated. Therefore, the aim of the present study was to evaluate the prognostic value of the PARIS thrombotic risk score for all-cause and cardiac mortalities and hospitalization due to heart failure following PCI.Methods and resultsConsecutive 1,061 patients who underwent PCI were divided into three groups based on PARIS thrombotic risk score; low- (n = 320), intermediate- (n = 469) and high-risk (n = 272) groups. We followed up on all three groups for all-cause mortality, cardiac mortality and hospitalization due to heart failure. Kaplan-Meier analysis showed that all outcomes were highest in the high-risk group (P < 0.001, P = 0.022 and P < 0.001, respectively). Multivariate Cox proportional hazard analysis, adjusted for confounding factors, showed that the risk of all-cause mortality and hospitalization due to heart failure of the high-risk group were higher than those of the low-risk group (hazard ratios 1.76 and 2.14, P = 0.005 and P = 0.017, respectively).ConclusionThe PARIS thrombotic risk score is a significant prognostic indicator for all-cause mortality and hospitalization due to heart failure in patients after PCI.

Background Blood‐based DNA methylation patterns are linked to types of diseases. FKBP prolyl isomerase 5 (FKBP5), a protein cochaperone, is known to be associated with the inflammatory response, but the regulatory mechanisms by leukocyte FKBP5 DNA methylation in patients with dilated cardiomyopathy (DCM) remain unclear. Methods and Results The present study enrolled patients with DCM (n=31) and age‐matched and sex‐matched control participants (n=43). We assessed FKBP5 CpG (cytosine‐phosphate‐guanine) methylation of CpG islands at the 5′ side as well as putative promoter regions by methylation‐specific quantitative polymerase chain reaction using leukocyte DNA isolated from the peripheral blood. FKBP5 CpG methylation levels at the CpG island of the gene body and the promoter regions were significantly decreased in patients with DCM. Leukocyte FKBP5 and IL‐1β (interleukin 1β) mRNA expression levels were significantly higher in patients with DCM than in controls. The protein expressions of DNMT1 (DNA methyltransferase 1) and DNMT3A (DNA methyltransferase 3A) in leukocytes were significantly reduced in patients with DCM. In vitro methylation assay revealed that FKBP5 promoter activity was inhibited at the methylated conditions in response to immune stimulation, suggesting that the decreased FKBP5 CpG methylation was functionally associated with elevation of FKBP5 mRNA expressions. Histological analysis using a mouse model with pressure overload showed that FKBP5‐expressing cells were substantially infiltrated in the myocardial interstitium in the failing hearts, indicating a possible role of FKBP5 expressions of immune cells in the cardiac remodeling. Conclusions Our findings demonstrate a link between specific CpG hypomethylation of leukocyte FKBP5 and DCM. Blood‐based epigenetic modification in FKBP5 may be a novel molecular mechanism that contributes to the pathogenesis of DCM.