Bile Acid Metabolites in Serum: Intraindividual Variation and Associations with Coronary Heart Disease, Metabolic Syndrome and Diabetes Mellitus

Bile acids (BAs) regulate glucose and lipid metabolism. In longitudinal and case-control-studies, we investigated the diurnal variation of serum concentrations of the 15 major BAs as well as the biosynthetic precursor 7α-hydroxy-4-cholesten-3-one (C4) and their associations, respectively, with coronary artery disease (CAD), diabetes mellitus type 2 (T2DM), and non-diabetic metabolic syndrome (MetS). In hourly taken blood samples of four healthy probands, the intraindividual 24 h variation of C4, conjugated and unconjugated BAs ranged from 42% to 72%, from 23% to 91%, and from 49% to 90%, respectively. Conjugated BA concentrations mainly increased following food intake. Serum levels of C4 and unconjugated BAs changed with daytime with maxima varying interindividually between 20h00 and 1h00 and between 3h00 and 8h00, respectively. Comparisons of data from 75 CAD patients with 75 CAD-free controls revealed no statistically significant association of CAD with BAs or C4. Comparisons of data from 50 controls free of T2DM or MetS, 50 MetS patients, and 50 T2DM patients revealed significantly increased fasting serum levels of C4 in patients with MetS and T2DM. Multiple regression analysis revealed body mass index (BMI) and plasma levels of triglycerides (TG) as independent determinants of C4 levels. Upon multivariate and principle component analyses the association of C4 with T2DM and/or MetS was not independent of or superior to the canonical MetS components. In conclusion, despite large intra- and interindividual variation, serum levels of C4,are significantly increased in patients with MetS and T2DM but confounded with BMI and TG

Original experimental data and code for the Paper ”Quantum spins and hybridization in artificially-constructed chains of magnetic adatoms on a superconductor“

Magnetic adatom chains on surfaces constitute fascinating quantum spin systems. Superconducting substrates suppress interactions with bulk electronic excitations but couple the adatom spins to a chain of subgap Yu-Shiba-Rusinov (YSR) quasiparticles. Using a scanning tunneling microscope, we investigate such correlated spin-fermion systems by constructing Fe chains adatom by adatom on superconducting NbSe2. The adatoms couple entirely via the substrate, retaining their quantum spin nature. In dimers, we observe that the deepest YSR state undergoes a quantum phase transition due to Ruderman-Kittel-Kasuya-Yosida interactions, a distinct signature of quantum spins. Chains exhibit coherent hybridization and band formation of the YSR excitations, indicating ferromagnetic coupling. Longer chains develop separate domains due to coexisting charge-density-wave order of NbSe2. Despite the spin-orbit-coupled substrate, we find no signatures of Majoranas, possibly because quantum spins reduce the parameter range for topological superconductivity. We suggest that adatom chains are versatile systems for investigating correlated-electron physics and its interplay with topological superconductivity

Quantum spins and hybridization in artificially-constructed chains of magnetic adatoms on a superconductor

Magnetic adatom chains on surfaces constitute fascinating quantum spin systems. Superconducting substrates suppress interactions with bulk electronic excitations but couple the adatom spins to a chain of subgap Yu-Shiba-Rusinov (YSR) quasiparticles. Using a scanning tunneling microscope, we investigate such correlated spin-fermion systems by constructing Fe chains adatom by adatom on superconducting NbSe$_2$. The adatoms couple entirely via the substrate, retaining their quantum spin nature. In dimers, we observe that the deepest YSR state undergoes a quantum phase transition due to Ruderman-Kittel-Kasuya-Yosida interactions, a distinct signature of quantum spins. Chains exhibit coherent hybridization and band formation of the YSR excitations, indicating ferromagnetic coupling. Longer chains develop separate domains due to coexisting charge-density-wave order of NbSe$_2$. Despite the spin-orbit-coupled substrate, we find no signatures of Majoranas, possibly because quantum spins reduce the parameter range for topological superconductivity. We suggest that adatom chains are versatile systems for investigating correlated-electron physics and its interplay with topological superconductivity

Nanoparticle shapes of LiMnPO4, Li+ diffusion orientation and diffusion coefficients for high volumetric energy Li+ ion cathodes

Nanoparticles of LiMnPO₄ were fabricated in rod, elongated as well as cubic shapes. The 1D Li⁺ preferred diffusion direction for each shape was determined via electron diffraction spot patterns. The shape of nano-LiMnPO₄ varied the diffusion coefficient of Li⁺ because the Li⁺ diffusion direction and the path length were different. The particles with the shortest dimension along the b-axis provided the highest diffusion coefficient, resulting in the highest gravimetric capacity of 135, 100 and 60 mAh g⁻¹ at 0.05C, 1C and 10C, respectively. Using ball-milling, a higher loading of nano-LiMnPO₄ in the electrode was achieved, increasing the volumetric capacity to 263 mAh cm⁻³, which is ca. 3.5 times higher than the one obtained by hand-mixing of electrode materials. Thus, the electrochemical performance is governed by both the diffusion coefficient of Li⁺, which is dependent on the shape of LiMnPO₄ nanoparticles and the secondary composite structure

Quantification of the 15 major human bile acids and their precursor 7α-hydroxy-4-cholesten-3-one in serum by liquid chromatography-tandem mass spectrometry

Bile acids are increasingly gaining attention since they were discovered to be activators of the transcription factor farnesoid X receptor (FXR) in addition to their well-established role in dietary lipid emulsification. Moreover, the differential activation potency of bile acids on FXR, which is due to structural variation of the ligands, generates the need for new analytical tools that are sensitive and specific enough to quantify the individual species of this complex class of compounds. Because bile acids undergo enterohepatic circulation, the additional assessment of a bile acid precursor as a marker for bile acid biosynthesis is used to differentiate between newly synthesised bile acids and bile acids reabsorbed from the intestine. This paper describes two new methods using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantification of the major unconjugated bile acids in human serum (cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid and ursodeoxycholic acid) with their glycine- and taurine-conjugates as well as their precursor 7α-hydroxy-4-cholesten-3-one (C4). Intra- and inter-day variation was less than 12% and accuracy was between 84% and 102% for all analytes. Extraction recovery was between 78% and 100% for the bile acids whereas it was 62% for C4 and limit of quantification values ranged from 2nmol/l to 50nmol/l for all compounds. These two methods have the practical advantage of requiring low sample volume (100μl serum for each method) and identical eluents, stationary phase as well as ionisation technique, so that they can be used in a combined way. Moreover, they provide information on the composition of the bile acid pool on one hand and on the relative amount of newly synthesised bile acids on the other, which taken together, gives new insights in the investigation of bile acid metabolism

De novo expression of gastrokines in pancreatic precursor lesions impede the development of pancreatic cancer

Molecular events occurring in stepwise progression from pre-malignant lesions (pancreatic intraepithelial neoplasia; PanIN) to the development of pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Thus, characterization of early PanIN lesions may reveal markers that can help in diagnosing PDAC at an early stage and allow understanding the pathology of the disease. We performed the molecular and histological assessment of patient-derived PanINs, tumor tissues and pancreas from mouse models with PDAC (KC mice that harbor K-RAS mutation in pancreatic tissue), where we noted marked upregulation of gastrokine (GKN) proteins. To further understand the role of gastrokine proteins in PDAC development, GKN-deficient KC mice were developed by intercrossing gastrokine-deficient mice with KC mice. Panc-02 (pancreatic cancer cells of mouse origin) were genetically modified to express GKN1 for further in vitro and in vivo analysis. Our results show that gastrokine proteins were absent in healthy pancreas and invasive cancer, while its expression was prominent in low-grade PanINs. We could detect these proteins in pancreatic juice and serum of KC mice. Furthermore, accelerated PanIN and tumor development were noted in gastrokine deficient KC mice. Loss of gastrokine 1 protein delayed apoptosis during carcinogenesis leading to the development of desmoplastic stroma while loss of gastrokine 2 increased the proliferation rate in precursor lesions. In summary, we identified gastrokine proteins in early pancreatic precursor lesions, where gastrokine proteins delay pancreatic carcinogenesis

Polyglutamine-expanded ataxin-3: a target engagement marker for spinocerebellar ataxia type 3 in peripheral blood

Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. Objective: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). Methods: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. Results: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. Conclusions: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyFunding agencies: This project is supported by the EU Joint Programme—Neurodegenerative Disease Research (JPND) through the following funding organizations under the aegis of JPND: Germany, Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B); Netherlands, The Netherlands Organisation for Health Research and Development; Portugal, Foundation for Science and Technology (FCT, grant number JPCOFUND/0001/2015), and Regional Fund for Science and Technology of the Azores; and United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 643417. In addition, support has been received by the BIONIC project (number 733050822, which has been made possible by ZonMW as part of “Memorabel,” the research and innovation program for dementia, as part of the Dutch national “Deltaplan for Dementia”: zonmw.nl/dementiaresearch), the CAF[1]E project (the National Institutes of Health, USA, grant number 5R01NS104147-02), and a grant from the Selfridges Group Foundation (NR170024). The BIONIC project is a consortium of Radboudumc, LUMC, ADX Neurosciences, and Rhode Island University