Metabolomic Profiling in Patients with Heart Failure and Exercise Intolerance: Kynurenine as a Potential Biomarker

Aims: Metabolic and structural perturbations in skeletal muscle have been found in patients with heart failure (HF) both with preserved (HFpEF) and reduced (HFrEF) ejection fraction in association with reduced muscle endurance (RME). We aimed in the current study to create phenotypes for patients with RME and HFpEF compared to RME HFrEF according to their metabolomic profiles and to test the potential of Kynurenine (Kyn) as a marker for RME. Methods: Altogether, 18 HFrEF, 17 HFpEF, and 20 healthy controls (HC) were prospectively included in the current study. The following tests were performed on all participants: isokinetic muscle function tests, echocardiography, spiroergometry, and varied blood tests. Liquid chromatography tandem mass spectrometry was used to quantify metabolites in serum. Results: Except for aromatic and branched amino acids (AA), patients with HF showed reduced AAs compared to HC. Further perturbations were elevated concentrations of Kyn and acylcarnitines (ACs) in HFpEF and HFrEF patients ( p < 0.05). While patients with HFpEF and RME presented with reduced concentrations of ACs (long- and medium-chains), those with HFrEF and RME had distorted AAs metabolism ( p < 0.05). With an area under the curve (AUC) of 0.83, Kyn shows potential as a marker in HF and RME (specificity 70%, sensitivity 83%). In a multiple regression model consisting of short-chain-ACs, spermine, ornithine, glutamate, and Kyn, the latest was an independent predictor for RME (95% CI: −13.01, −3.30, B: −8.2 per 1 µM increase, p = 0.001). Conclusions: RME in patients with HFpEF vs. HFrEF proved to have different metabolomic profiles suggesting varied pathophysiology. Kyn might be a promising biomarker for patients with HF and RME

Children Base Their Investment on Calculated Pay-Off

To investigate the rise of economic abilities during development we studied children aged between 3 and 10 in an exchange situation requiring them to calculate their investment based on different offers. One experimenter gave back a reward twice the amount given by the children, and a second always gave back the same quantity regardless of the amount received. To maximize pay-offs children had to invest a maximal amount with the first, and a minimal amount with the second. About one third of the 5-year-olds and most 7- and 10-year-olds were able to adjust their investment according to the partner, while all 3-year-olds failed. Such performances should be related to the rise of cognitive and social skills after 4 years

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

Peer reviewe

Quantification of Bile Acids in Cerebrospinal Fluid: Results of an Observational Trial

(1) Background: Bile acids, known as aids in intestinal fat digestion and as messenger molecules in serum, can be detected in cerebrospinal fluid (CSF), although the blood–brain barrier is generally an insurmountable obstacle for bile acids. The exact mechanisms of the occurrence, as well as possible functions of bile acids in the central nervous system, are not precisely understood. (2) Methods: We conducted a single-center observational trial. The concentrations of 15 individual bile acids were determined using an in-house LC-MS/MS method in 54 patients with various acute and severe disorders of the central nervous system. We analyzed CSF from ventricular drainage taken within 24 h after placement, and blood samples were drawn at the same time for the presence and quantifiability of 15 individual bile acids. (3) Results: At a median time of 19.75 h after a cerebral insult, the concentration of bile acids in the CSF was minute and almost negligible. The CSF concentrations of total bile acids (TBAs) were significantly lower compared to the serum concentrations (serum 0.37 µmol/L [0.24, 0.89] vs. 0.14 µmol/L [0.05, 0.43]; p = 0.033). The ratio of serum-to-CSF bile acid levels calculated from the respective total concentrations were 3.10 [0.94, 14.64] for total bile acids, 3.05 for taurocholic acid, 14.30 [1.11, 27.13] for glycocholic acid, 0.0 for chenodeoxycholic acid, 2.19 for taurochenodeoxycholic acid, 1.91 [0.68, 8.64] for glycochenodeoxycholic acid and 0.77 [0.0, 13.79] for deoxycholic acid; other bile acids were not detected in the CSF. The ratio of CSF-to-serum S100 concentration was 0.01 [0.0, 0.02]. Serum total and conjugated (but not unconjugated) bilirubin levels and serum TBA levels were significantly correlated (total bilirubin p = 0.031 [0.023, 0.579]; conjugated bilirubin p = 0.001 [0.193, 0.683]; unconjugated p = 0.387 [−0.181, 0.426]). No correlations were found between bile acid concentrations and age, delirium, intraventricular blood volume, or outcome measured on a modified Rankin scale. (4) Conclusions: The determination of individual bile acids is feasible using the current LC-MS/MS method. The results suggest an intact blood–brain barrier in the patients studied. However, bile acids were detected in the CSF, which could have been achieved by active transport across the blood–brain barrier

Serum Metabolome Signatures Characterizing Co-Infection of <i>Plasmodium falciparum</i> and HBV in Pregnant Women

Plasmodium falciparum (P. falciparum) and hepatitis B virus (HBV) co-infection is on the rise among pregnant women in northern Ghana. Mono-infection with either of these two pathogens results in unique metabolic alterations. Thus, we aimed to explicate the effects of this co-infection on the metabolome signatures of pregnant women, which would indicate the impacted metabolic pathways and provide useful prognostic or diagnostic markers. Using an MS/MS-based targeted metabolomic approach, we determined the serum metabolome in pregnant women with P. falciparum mono-infection, HBV mono-infection, P. falciparum, and HBV co-infection and in uninfected (control) women. We observed significantly decreased sphingolipid concentrations in subjects with P. falciparum mono-infection, whereas amino acids and phospholipids were decreased in subjects with HBV mono-infection. Co-infections were found to be characterized distinctively by reduced concentrations of phospholipids and hexoses (mostly glucose) as well as altered pathways that contribute to redox homeostasis. Overall, PC ae C40:1 was found to be a good discriminatory metabolite for the co-infection group. PC ae C40:1 can further be explored for use in the diagnosis and treatment of malaria and chronic hepatitis B co-morbidity as well as to distinguish co-infections from cases of mono-infections

RIPK3 promoter hypermethylation in hepatocytes protects from bile acid-induced inflammation and necroptosis

Abstract Necroptosis facilitates cell death in a controlled manner and is employed by many cell types following injury. It plays a significant role in various liver diseases, albeit the cell-type-specific regulation of necroptosis in the liver and especially hepatocytes, has not yet been conceptualized. We demonstrate that DNA methylation suppresses RIPK3 expression in human hepatocytes and HepG2 cells. In diseases leading to cholestasis, the RIPK3 expression is induced in mice and humans in a cell-type-specific manner. Overexpression of RIPK3 in HepG2 cells leads to RIPK3 activation by phosphorylation and cell death, further modulated by different bile acids. Additionally, bile acids and RIPK3 activation further facilitate JNK phosphorylation, IL-8 expression, and its release. This suggests that hepatocytes suppress RIPK3 expression to protect themselves from necroptosis and cytokine release induced by bile acid and RIPK3. In chronic liver diseases associated with cholestasis, induction of RIPK3 expression may be an early event signaling danger and repair through releasing IL-8

Metabolomic profiling of patients with high gradient aortic stenosis undergoing transcatheter aortic valve replacement

Aim!#!Aim of our study was to evaluate metabolic changes in patients with aortic stenosis (AS) before and after transcatheter aortic valve replacement (TAVR) and to assess whether this procedure reverses metabolomic alterations.!##!Methods!#!188 plasma metabolites of 30 patients with severe high-gradient aortic valve stenosis (pre-TAVR and 6 weeks post-TAVR) as well as 20 healthy controls (HC) were quantified by liquid chromatography tandem mass spectrometry. Significantly altered metabolites were then correlated to an extensive patient database of clinical parameters at the time of measurement.!##!Results!#!Out of the determined metabolites, 26.6% (n = 50) were significantly altered in patients with AS pre-TAVR compared to HC. In detail, 5/40 acylcarnitines as well as 10/42 amino acids and biogenic amines were mainly increased in AS, whereas 29/90 glycerophospholipids and 6/15 sphingomyelins were mainly reduced. In the post-TAVR group, 10.1% (n = 19) of metabolites showed significant differences when compared to pre-TAVR. Moreover, we found nine metabolites revealing reversible concentration levels. Correlation with clinically important parameters revealed strong correlations between sphingomyelins and cholesterol (r = 0.847), acylcarnitines and brain natriuretic peptide (r = 0.664) and showed correlation of acylcarnitine with an improvement of left ventricular (LV) ejection fraction (r = - 0.513) and phosphatidylcholines with an improvement of LV mass (r = - 0.637).!##!Conclusion!#!Metabolic profiling identified significant and reversible changes in circulating metabolites of patients with AS. The correlation of circulating metabolites with clinical parameters supports the use of these data to identify novel diagnostic as well as prognostic markers for disease screening, pathophysiological studies as well as patient surveillance

Sodium channels as gateable non-photonic sensors for membrane-delimited reactive species

AbstractReactive oxygen species (ROS) and reactive oxygen intermediates (ROI) play crucial roles in physiological processes. While excessive ROS damages cells, small fluctuations in ROS levels represent physiological signals important for vital functions. Despite the physiological importance of ROS, many fundamental questions remain unanswered, such as which types of ROS occur in cells, how they distribute inside cells, and how long they remain in an active form. The current study presents a ratiometric sensor of intracellular ROS levels based on genetically engineered voltage-gated sodium channels (roNaV). roNaV can be used for detecting oxidative modification that occurs near the plasma membrane with a sensitivity similar to existing fluorescence-based ROS sensors. Moreover, roNaV has several advantages over traditional sensors because it does not need excitation light for sensing, and thus, can be used to detect phototoxic cellular modifications. In addition, the ROS dynamic range of roNaV is easily manipulated in real time by means of the endogenous channel inactivation mechanism. Measurements on ROS liberated from intracellular Lucifer Yellow and genetically encoded KillerRed have revealed an assessment of ROS lifetime in individual mammalian cells. Flashlight-induced ROS concentration decayed with two major time constants of about 10 and 1000ms