Publications by authors named "Markus Schneider"

165 Publications

The Application of a CMR-B-Scalar Sensor for the Investigation of the Electromagnetic Acceleration of Type II Superconductors.

Sensors (Basel) 2021 Feb 11;21(4). Epub 2021 Feb 11.

French-German Research Institute of Saint-Louis, 68300 Saint-Louis, France.

In this paper, we investigated the behavior of a type II superconducting armature when accelerated by a pulsed magnetic field generated by a single-stage pancake coil. While conducting this investigation, we performed a numerical finite element simulation and an experimental study of the magnetic field dynamics at the edge of the pancake coil when the payload was a superconducting disc made from YBaCuO, cooled down to 77 K. The magnetic field measurements were performed using a CMR-B-scalar sensor, which was able to measure the absolute magnitude of the magnetic field and was specifically manufactured in order to increase the sensor's sensitivity up to 500 mT. It was obtained that type II superconducting armatures can outperform normal metals when the launch conditions are tailored to their electromagnetic properties.
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http://dx.doi.org/10.3390/s21041293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917592PMC
February 2021

The Role of Changing Loop Conformations in Streptavidin Versions Engineered for High-affinity Binding of the Strep-tag II Peptide.

J Mol Biol 2021 Feb 24;433(9):166893. Epub 2021 Feb 24.

Lehrstuhl für Biologische Chemie, Technische Universität München, 85354 Freising, Germany. Electronic address:

The affinity system based on the artificial peptide ligand Strep-tag® II and engineered tetrameric streptavidin, known as Strep-Tactin®, offers attractive applications for the study of recombinant proteins, from detection and purification to functional immobilization. To further improve binding of the Strep-tag II to streptavidin we have subjected two protruding loops that shape its ligand pocket for the peptide - instead of D-biotin recognized by the natural protein - to iterative random mutagenesis. Sequence analyses of hits from functional screening assays revealed several unexpected structural motifs, such as a disulfide bridge at the base of one loop, replacement of the crucial residue Trp120 by Gly and a two-residue deletion in the second loop. The mutant m1-9 (dubbed Strep-Tactin XT) showed strongly enhanced affinity towards the Strep-tag II, which was further boosted in case of the bivalent Twin-Strep-tag®. Four representative streptavidin mutants were crystallized in complex with the Strep-tag II peptide and their X-ray structures were solved at high resolutions. In addition, the crystal structure of the complex between Strep-Tactin XT and the Twin-Strep-tag was elucidated, indicating a bivalent mode of binding and explaining the experimentally observed avidity effect. Our study illustrates the structural plasticity of streptavidin as a scaffold for ligand binding and reveals interaction modes that would have been difficult to predict. As result, Strep-Tactin XT offers a convenient reagent for the kinetically stable immobilization of recombinant proteins fused with the Twin-Strep-tag. The possibility of reversibly dissociating such complexes simply with D-biotin as a competing ligand enables functional studies in protein science as well as cell biology.
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http://dx.doi.org/10.1016/j.jmb.2021.166893DOI Listing
February 2021

Low adherence to CKD-specific dietary recommendations associates with impaired kidney function, dyslipidemia, and inflammation.

Eur J Clin Nutr 2021 Feb 2. Epub 2021 Feb 2.

Division of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany.

Background/objectives: A diet following chronic kidney disease (CKD)-specific recommendations is considered essential for optimal management of patients with CKD. However, data on the adherence to these recommendations and its implications for health-relevant biomarkers are lacking. The objectives were to estimate adherence to CKD-specific dietary recommendations, to identify characteristics and lifestyle variables associated with poor adherence, and to investigate the relationship of adherence with biomarkers.

Methods: In this cross-sectional analysis, average dietary intake was estimated in 3193 participants with moderately severe CKD enrolled into the observational multicenter German CKD study using a food frequency questionnaire. A CKD diet score was developed to assess adherence to CKD-specific dietary recommendations based on intake of sodium, potassium, fiber, protein, sugar, and cholesterol. The associations of dietary adherence with characteristics, lifestyle variables, and biomarker levels were determined.

Results: Logistic regression analysis revealed younger age, higher body mass index, male gender, lower educational attainment, various lifestyle variables (cigarette smoking, infrequent alcohol consumption, low physical activity), and lower estimated glomerular filtrate rate associated with lower adherence to dietary recommendations. Low adherence to dietary recommendations was further associated with dyslipidemia, higher uric acid, and C-reactive protein levels. Associations between low dietary adherence and biomarkers were mostly driven by low intake of fiber and potassium, and high intake of sugar and cholesterol.

Conclusions: This study revealed differential characteristics and biomarkers associated with lower adherence to CKD-specific dietary recommendations. Promotion of CKD-specific dietary recommendations may help to mitigate the adverse prognosis in CKD patients.
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http://dx.doi.org/10.1038/s41430-020-00849-3DOI Listing
February 2021

Incorporating kidney disease measures into cardiovascular risk prediction: Development and validation in 9 million adults from 72 datasets.

EClinicalMedicine 2020 Oct 14;27:100552. Epub 2020 Oct 14.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.

Background: Chronic kidney disease (CKD) measures (estimated glomerular filtration rate [eGFR] and albuminuria) are frequently assessed in clinical practice and improve the prediction of incident cardiovascular disease (CVD), yet most major clinical guidelines do not have a standardized approach for incorporating these measures into CVD risk prediction. "CKD Patch" is a validated method to calibrate and improve the predicted risk from established equations according to CKD measures.

Methods: Utilizing data from 4,143,535 adults from 35 datasets, we developed several "CKD Patches" incorporating eGFR and albuminuria, to enhance prediction of risk of atherosclerotic CVD (ASCVD) by the Pooled Cohort Equation (PCE) and CVD mortality by Systematic COronary Risk Evaluation (SCORE). The risk enhancement by CKD Patch was determined by the deviation between individual CKD measures and the values expected from their traditional CVD risk factors and the hazard ratios for eGFR and albuminuria. We then validated this approach among 4,932,824 adults from 37 independent datasets, comparing the original PCE and SCORE equations (recalibrated in each dataset) to those with addition of CKD Patch.

Findings: We confirmed the prediction improvement with the CKD Patch for CVD mortality beyond SCORE and ASCVD beyond PCE in validation datasets (Δc-statistic 0.027 [95% CI 0.018-0.036] and 0.010 [0.007-0.013] and categorical net reclassification improvement 0.080 [0.032-0.127] and 0.056 [0.044-0.067], respectively). The median (IQI) of the ratio of predicted risk for CVD mortality with CKD Patch vs. the original prediction with SCORE was 2.64 (1.89-3.40) in very high-risk CKD (e.g., eGFR 30-44 ml/min/1.73m with albuminuria ≥30 mg/g), 1.86 (1.48-2.44) in high-risk CKD (e.g., eGFR 45-59 ml/min/1.73m with albuminuria 30-299 mg/g), and 1.37 (1.14-1.69) in moderate risk CKD (e.g., eGFR 60-89 ml/min/1.73m with albuminuria 30-299 mg/g), indicating considerable risk underestimation in CKD with SCORE. The corresponding estimates for ASCVD with PCE were 1.55 (1.37-1.81), 1.24 (1.10-1.54), and 1.21 (0.98-1.46).

Interpretation: The "CKD Patch" can be used to quantitatively enhance ASCVD and CVD mortality risk prediction equations recommended in major US and European guidelines according to CKD measures, when available.

Funding: US National Kidney Foundation and the NIDDK.
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http://dx.doi.org/10.1016/j.eclinm.2020.100552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599294PMC
October 2020

Total motorized spiral enteroscopy: first prospective clinical feasibility trial.

Gastrointest Endosc 2020 Nov 2. Epub 2020 Nov 2.

Department of Internal Medicine and Gastroenterology, Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany.

Background And Aims: Motorized spiral enteroscopy (MSE) was recently introduced into clinical practice and shown to be safe and effective for antegrade enteroscopy. The aim of the current trial was to prospectively study the efficacy and safety of MSE for visualization of the entire small bowel.

Methods: All consecutive patients with indications for complete enteroscopy meeting the inclusion criteria were enrolled in a prospective observational bicentric trial, starting with antegrade MSE; a retrograde approach was performed if MSE remained incomplete from antegrade. The primary objective was to ascertain the total enteroscopy rate (TER); secondary objectives were diagnostic yield, procedural success, time, depth of maximum insertion (DMI), therapeutic yield, and adverse events (AEs).

Results: Thirty patients (16 women, 14 men; median age 64 years [range, 37-100]) were enrolled. Technical success rate of antegrade MSE (advancement beyond the ligament of Treitz) and retrograde MSE (advancement beyond the ileocecal valve [ICV]) were 100% and 100%, respectively. Overall TER was 70%: 16.6% antegrade approach alone and 53.4% bidirectional approach. Median antegrade DMI distal from the ligament of Treitz was 490 cm (range, 160-600); median insertion time 26 minutes (range, 15-110). The median retrograde DMI beyond the ICV was 120 cm (range, 40-600), and median insertion time was 17 minutes (range, 1-68). Overall diagnostic and therapeutic yields were 80% and 86.7%, respectively. Overall AE rate was 16.7%. No serious AEs occurred.

Conclusions: This prospective study showed that complete enteroscopy is feasible with MSE, either from antegrade alone or bidirectionally, with high success rates and short procedural duration. These results justify further evaluation of MSE in a large prospective multicenter study, preferably with inclusion of a control group. (Clinical trial registration number: NCT03438695.).
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http://dx.doi.org/10.1016/j.gie.2020.10.028DOI Listing
November 2020

A Process Analytical Concept for In-Line FTIR Monitoring of Polysiloxane Formation.

Polymers (Basel) 2020 Oct 25;12(11). Epub 2020 Oct 25.

School of Applied Chemistry, Reutlingen University, 72762 Reutlingen, Germany.

The chemical synthesis of polysiloxanes from monomeric starting materials involves a series of hydrolysis, condensation and modification reactions with complex monomeric and oligomeric reaction mixtures. Real-time monitoring and precise process control of the synthesis process is of great importance to ensure reproducible intermediates and products and can readily be performed by optical spectroscopy. In chemical reactions involving rapid and simultaneous functional group transformations and complex reaction mixtures, however, the spectroscopic signals are often ambiguous due to overlapping bands, shifting peaks and changing baselines. The univariate analysis of individual absorbance signals is hence often only of limited use. In contrast, batch modelling based on the multivariate analysis of the time course of principal components (PCs) derived from the reaction spectra provides a more efficient tool for real-time monitoring. In batch modelling, not only single absorbance bands are used but information over a broad range of wavelengths is extracted from the evolving spectral fingerprints and used for analysis. Thereby, process control can be based on numerous chemical and morphological changes taking place during synthesis. "Bad" (or abnormal) batches can quickly be distinguished from "normal" ones by comparing the respective reaction trajectories in real time. In this work, FTIR spectroscopy was combined with multivariate data analysis for the in-line process characterization and batch modelling of polysiloxane formation. The synthesis was conducted under different starting conditions using various reactant concentrations. The complex spectral information was evaluated using chemometrics (principal component analysis, PCA). Specific spectral features at different stages of the reaction were assigned to the corresponding reaction steps. Reaction trajectories were derived based on batch modelling using a wide range of wavelengths. Subsequently, complexity was reduced again to the most relevant absorbance signals in order to derive a concept for a low-cost process spectroscopic set-up which could be used for real-time process monitoring and reaction control.
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http://dx.doi.org/10.3390/polym12112473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693933PMC
October 2020

The Tumor Suppressive mir-148a Is Epigenetically Inactivated in Classical Hodgkin Lymphoma.

Cells 2020 10 14;9(10). Epub 2020 Oct 14.

Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland.

DNA methylation was shown previously to be a crucial mechanism responsible for transcriptional deregulation in the pathogenesis of classical Hodgkin lymphoma (cHL). To identify epigenetically inactivated miRNAs in cHL, we have analyzed the set of miRNAs downregulated in cHL cell lines using bisulfite pyrosequencing. We focused on miRNAs with promoter regions located within or <1000 bp from a CpG island. Most promising candidate miRNAs were further studied in primary Hodgkin and Reed-Sternberg (HRS) cells obtained by laser capture microdissection. Last, to evaluate the function of identified miRNAs, we performed a luciferase reporter assay to confirm miRNA: mRNA interactions and therefore established cHL cell lines with stable overexpression of selected miRNAs for proliferation tests. We found a significant reverse correlation between DNA methylation and expression levels of mir-339-3p, mir-148a-3p, mir-148a-5p and mir-193a-5 demonstrating epigenetic regulation of these miRNAs in cHL cell lines. Moreover, we demonstrated direct interaction between miR-148a-3p and and transcripts as well as between mir-148a-5p and and transcripts. Furthermore, mir-148a overexpression resulted in reduced cell proliferation in the KM-H2 cell line. In summary, we report that mir-148a is a novel tumor suppressor inactivated in cHL and that epigenetic silencing of miRNAs is a common phenomenon in cHL.
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http://dx.doi.org/10.3390/cells9102292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602210PMC
October 2020

Extended interaction networks with HCV protease NS3-4A substrates explain the lack of adaptive capability against protease inhibitors.

J Biol Chem 2020 10 3;295(40):13862-13874. Epub 2020 Aug 3.

Department of Internal Medicine 1, Goethe University Hospital Frankfurt, Frankfurt, Germany; University Center for Infectious Diseases, Goethe University Hospital Frankfurt, Frankfurt, Germany. Electronic address:

Inhibitors against the NS3-4A protease of hepatitis C virus (HCV) have proven to be useful drugs in the treatment of HCV infection. Although variants have been identified with mutations that confer resistance to these inhibitors, the mutations do not restore replicative fitness and no secondary mutations that rescue fitness have been found. To gain insight into the molecular mechanisms underlying the lack of fitness compensation, we screened known resistance mutations in infectious HCV cell culture with different genomic backgrounds. We observed that the Q41R mutation of NS3-4A efficiently rescues the replicative fitness in cell culture for virus variants containing mutations at NS3-Asp To understand how the Q41R mutation rescues activity, we performed protease activity assays complemented by molecular dynamics simulations, which showed that protease-peptide interactions far outside the targeted peptide cleavage sites mediate substrate recognition by NS3-4A and support protease cleavage kinetics. These interactions shed new light on the mechanisms by which NS3-4A cleaves its substrates, viral polyproteins and a prime cellular antiviral adaptor protein, the mitochondrial antiviral signaling protein MAVS. Peptide binding is mediated by an extended hydrogen-bond network in NS3-4A that was effectively optimized for protease-MAVS binding in Asp variants with rescued replicative fitness from NS3-Q41R. In the protease harboring NS3-Q41R, the N-terminal cleavage products of MAVS retained high affinity to the active site, rendering the protease susceptible for potential product inhibition. Our findings reveal delicately balanced protease-peptide interactions in viral replication and immune escape that likely restrict the protease adaptive capability and narrow the virus evolutionary space.
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http://dx.doi.org/10.1074/jbc.RA120.013898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535904PMC
October 2020

Motorized spiral enteroscopy-assisted ERCP after Roux-en-Y reconstructive surgery and bilioenteric anastomosis: first clinical case.

VideoGIE 2020 Jul 14;5(7):311-313. Epub 2020 May 14.

Department of Gastroenterology and Interventional Endoscopy, Evangelisches Krankenhaus Düsseldorf, Germany.

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http://dx.doi.org/10.1016/j.vgie.2020.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332831PMC
July 2020

Exposure of Patient-Derived Mesenchymal Stromal Cells to TGFB1 Supports Fibrosis Induction in a Pediatric Acute Megakaryoblastic Leukemia Model.

Mol Cancer Res 2020 10 8;18(10):1603-1612. Epub 2020 Jul 8.

Department of Pediatric Hematology and Oncology, University Children's Hospital Essen, Essen, Germany.

Bone marrow fibrosis (BMF) is a rare complication in acute leukemia. In pediatrics, it predominantly occurs in acute megakaryoblastic leukemia (AMKL) and especially in patients with trisomy 21, called myeloid leukemia in Down syndrome (ML-DS). Defects in mesenchymal stromal cells (MSC) and cytokines specifically released by the myeloid blasts are thought to be the main drivers of fibrosis in the bone marrow niche (BMN). To model the BMN of pediatric patients with AMKL in mice, we first established MSCs from pediatric patients with AMKL ( = 5) and ML-DS ( = 9). Healthy donor control MSCs ( = 6) were generated from unaffected children and adolescents ≤18 years of age. Steady-state analyses of the MSCs revealed that patient-derived MSCs exhibited decreased adipogenic differentiation potential and enrichment of proliferation-associated genes. Importantly, TGFB1 exposure promoted early profibrotic changes in all three MSC entities. To study BMF induction for longer periods of time, we created an humanized artificial BMN subcutaneously in immunodeficient NOD.Cg-Prkdc Il2rg/SzJ mice, using a mixture of MSCs, human umbilical vein endothelial cell, and Matrigel. Injection of AMKL blasts as producers of TGFB1 into this BMN after 8 weeks induced fibrosis grade I/II in a dose-dependent fashion over a time period of 4 weeks. Thus, our study developed a humanized mouse model that will be instrumental to specifically examine leukemogenesis and therapeutic targets for AMKL blasts in future. IMPLICATIONS: TGFB1 supports fibrosis induction in a pediatric AMKL model generated with patient-derived MSCs. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/10/1603/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0091DOI Listing
October 2020

Systematic Investigation of Polyurethane Biomaterial Surface Roughness on Human Immune Responses .

Biomed Res Int 2020 11;2020:3481549. Epub 2020 May 11.

NMI, Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany.

It has been widely shown that biomaterial surface topography can modulate host immune response, but a fundamental understanding of how different topographies contribute to pro-inflammatory or anti-inflammatory responses is still lacking. To investigate the impact of surface topography on immune response, we undertook a systematic approach by analyzing immune response to eight grades of medical grade polyurethane of increasing surface roughness in three models of the human immune system. Polyurethane specimens were produced with defined roughness values by injection molding according to the VDI 3400 industrial standard. Specimens ranged from 0.1 m to 18 m in average roughness (Ra), which was confirmed by confocal scanning microscopy. Immunological responses were assessed with THP-1-derived macrophages, human peripheral blood mononuclear cells (PBMCs), and whole blood following culture on polyurethane specimens. As shown by the release of pro-inflammatory and anti-inflammatory cytokines in all three models, a mild immune response to polyurethane was observed, however, this was not associated with the degree of surface roughness. Likewise, the cell morphology (cell spreading, circularity, and elongation) in THP-1-derived macrophages and the expression of CD molecules in the PBMC model on T cells (HLA-DR and CD16), NK cells (HLA-DR), and monocytes (HLA-DR, CD16, CD86, and CD163) showed no influence of surface roughness. In summary, this study shows that modifying surface roughness in the micrometer range on polyurethane has no impact on the pro-inflammatory immune response. Therefore, we propose that such modifications do not affect the immunocompatibility of polyurethane, thereby supporting the notion of polyurethane as a biocompatible material.
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http://dx.doi.org/10.1155/2020/3481549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240656PMC
February 2021

[Highlights of the "Spine Section" in the journal Pain Medicine].

Schmerz 2020 Aug;34(4):355-356

AlphaMed, Bamberg, Deutschland.

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http://dx.doi.org/10.1007/s00482-020-00482-wDOI Listing
August 2020

Motorised spiral enteroscopy: first prospective clinical feasibility study.

Gut 2021 Feb 24;70(2):261-267. Epub 2020 Apr 24.

Department of Gastroenterology, Evangelisches Krankenhaus Dusseldorf, Dusseldorf, Nordrhein-Westfalen, Germany.

Objective: Currently available methods for small bowel endoscopy are often time consuming; motorised PowerSpiral Enteroscopy (PSE) is a further development of spiral enteroscopy to facilitate the approach to the small bowel. The aim of this bicentric prospective trial was to study feasibility and yield of peroral PSE.

Design: Consecutive patients with suspected small bowel disease and indication for antegrade enteroscopy were included in two tertiary referral centres. Primary objective was diagnostic yield of antegrade PSE. Secondary objectives included technical success (defined as successful endoscope insertion at least to ligament of Treitz), depth of maximum insertion (DMI), median insertion time to DMI, rate of therapeutic procedures and adverse events.

Results: During a 30-month period, 140 procedures were performed on 132 patients (58 female, 74 male; median age: 68 (20-100) years) under general anaesthesia. Overall diagnostic yield of PSE was 74.2%; with 68.2% of procedures including some form of endotherapy. Technical success rate of PSE was 97%; median DMI was 450 cm (0-600) with a median insertion time to DMI of 25 min (3-122). Antegrade panenteroscopy to the cecum was achieved in 14 cases (10.6%). Overall adverse event (AE) rate was 14.4%; two major serious AEs occurred (1.5%), one delayed perforation, one bleeding from Mallory-Weiss lesion.

Conclusion: This pilot clinical trial demonstrates that PSE is effective for diagnostic and therapeutic antegrade enteroscopy and may compare favourably with traditional methods of deep enteroscopy in ease of use and procedural duration. More comparative data are required to assess clinical application and safety of PSE.

Trial Registration Number: NCT02965209.
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http://dx.doi.org/10.1136/gutjnl-2019-319908DOI Listing
February 2021

Association of Serum Uromodulin with Death, Cardiovascular Events, and Kidney Failure in CKD.

Clin J Am Soc Nephrol 2020 05 14;15(5):616-624. Epub 2020 Apr 14.

Department of Nephrology and Clinical Immunology, Hospital Munich-Harlaching, Teaching Hospital of the Ludwig Maximilian University of Munich, Munich, Germany.

Background And Objectives: Uromodulin is exclusively produced by tubular epithelial cells and released into urine and serum. Higher serum uromodulin has been associated with lower risk for kidney failure in Chinese patients with CKD and with lower risk for mortality in the elderly and in patients undergoing coronary angiography. We hypothesized that lower serum uromodulin is associated with mortality, cardiovascular events, and kidney failure in white patients with CKD.

Design, Setting, Participants, & Measurements: We measured serum uromodulin in 5143 participants enrolled in the German CKD (GCKD) study. The associations of baseline serum uromodulin with all-cause mortality, major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, nonfatal myocardial infarction or stroke, or incident peripheral vascular disease), and kidney failure (dialysis or transplantation) were evaluated using multivariable Cox proportional hazard regression analyses in a cohort study design, adjusting for demographics, eGFR, albuminuria, cardiovascular risk factors, and medication.

Results: The mean age of participants was 60±12 years, 60% were male. Mean serum uromodulin concentration was 98±60 ng/ml, eGFR was 49±18 ml/min per 1.73 m, and 78% had eGFR <60 ml/min per 1.73 m. Participants in lower serum uromodulin quartiles had lower eGFR and higher albuminuria, prevalence of diabetes, hypertension, coronary artery disease, and more frequent history of stroke at baseline. During a follow-up of 4 years, 335 participants died, 417 developed MACE, and 229 developed kidney failure. In multivariable analysis, the highest serum uromodulin quartile was associated with lower hazard for mortality (hazard ratio [HR], 0.57; 95% CI, 0.38 to 0.87), MACE (HR, 0.63; 95% CI, 0.45 to 0.90), and kidney failure (HR, 0.24; 95% CI, 0.10 to 0.55) compared with the lowest quartile.

Conclusions: Higher serum uromodulin is independently associated with lower risk for mortality, cardiovascular events, and kidney failure in white patients with CKD.

Clinical Trial Registry Name And Registration Number: Deutsches Register für Klinische Studien (DRKS; German national database of clinical studies), DRKS00003971.
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http://dx.doi.org/10.2215/CJN.11780919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269219PMC
May 2020

Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signalling.

Cardiovasc Res 2021 Feb;117(3):930-941

Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Altenberger Strasse 69, 4040 Linz, Austria.

Aims: Uromodulin is produced exclusively in the kidney and secreted into both urine and blood. Serum levels of uromodulin are correlated with kidney function and reduced in chronic kidney disease (CKD) patients, but physiological functions of serum uromodulin are still elusive. This study investigated the role of uromodulin in medial vascular calcification, a key factor associated with cardiovascular events and mortality in CKD patients.

Methods And Results : Experiments were performed in primary human (HAoSMCs) and mouse (MOVAS) aortic smooth muscle cells, cholecalciferol overload and subtotal nephrectomy mouse models and serum from CKD patients. In three independent cohorts of CKD patients, serum uromodulin concentrations were inversely correlated with serum calcification propensity. Uromodulin supplementation reduced phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. In human serum, pro-inflammatory cytokines tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) co-immunoprecipitated with uromodulin. Uromodulin inhibited TNFα and IL-1β-induced osteo-/chondrogenic signalling and activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated β cells (NF-kB) as well as phosphate-induced NF-kB-dependent transcriptional activity in HAoSMCs. In vivo, adeno-associated virus (AAV)-mediated overexpression of uromodulin ameliorated vascular calcification in mice with cholecalciferol overload. Conversely, cholecalciferol overload-induced vascular calcification was aggravated in uromodulin-deficient mice. In contrast, uromodulin overexpression failed to reduce vascular calcification during renal failure in mice. Carbamylated uromodulin was detected in serum of CKD patients and uromodulin carbamylation inhibited its anti-calcific properties in vitro.

Conclusions : Uromodulin counteracts vascular osteo-/chondrogenic transdifferentiation and calcification, at least in part, through interference with cytokine-dependent pro-calcific signalling. In CKD, reduction and carbamylation of uromodulin may contribute to vascular pathology.
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http://dx.doi.org/10.1093/cvr/cvaa081DOI Listing
February 2021

Novel Biomarkers in Patients with Chronic Kidney Disease: An Analysis of Patients Enrolled in the GCKD-Study.

J Clin Med 2020 Mar 24;9(3). Epub 2020 Mar 24.

Department of Internal Medicine III, Friedrich Schiller University Jena, 07743 Jena, Germany.

Chronic kidney disease (CKD) and cardiovascular diseases (CVD) often occur concomitantly, and CKD is a major risk factor for cardiovascular mortality. Since some of the most commonly used biomarkers in CVD are permanently elevated in patients with CKD, novel biomarkers are warranted for clinical practice. Plasma concentrations of five cardiovascular biomarkers (soluble suppression of tumorigenicity (sST2), growth differentiation factor 15 (GDF-15), heart-type fatty acid-binding protein (H-FABP), insulin-like growth factor-binding protein 2 (IGF-BP2), and soluble urokinase plasminogen activator receptor) were analyzed by means of enzyme-linked immunosorbent assay (ELISA) in 219 patients with CKD enrolled in the German Chronic Kidney Disease (GCKD) study. Except for sST2, all of the investigated biomarkers were significantly elevated in patients with CKD (2.0- to 4.4-fold increase in advanced CKD (estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m² body surface area (BSA)) and showed a significant inverse correlation with eGFR. Moreover, all but H-FABP and sST2 were additionally elevated in patients with micro- and macro-albuminuria. Based on our findings, sST2 appears to be the biomarker whose diagnostic performance is least affected by decreased renal function, thus suggesting potential viability in the management of patients with CVD and concomitant CKD. The predictive potential of sST2 remains to be proven in endpoint studies.
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http://dx.doi.org/10.3390/jcm9030886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141541PMC
March 2020

Systematic analysis of the binding behaviour of UHRF1 towards different methyl- and carboxylcytosine modification patterns at CpG dyads.

PLoS One 2020 21;15(2):e0229144. Epub 2020 Feb 21.

Center for Integrated Protein Science Munich at the TUM School of Life Sciences, Technische Universität München, Freising, Germany.

The multi-domain protein UHRF1 is essential for DNA methylation maintenance and binds DNA via a base-flipping mechanism with a preference for hemi-methylated CpG sites. We investigated its binding to hemi- and symmetrically modified DNA containing either 5-methylcytosine (mC), 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), or 5-carboxylcytosine (caC). Our experimental results indicate that UHRF1 binds symmetrically carboxylated and hybrid methylated/carboxylated CpG dyads in addition to its previously reported substrates. Complementary molecular dynamics simulations provide a possible mechanistic explanation of how the protein could differentiate between modification patterns. First, we observe different local binding modes in the nucleotide binding pocket as well as the protein's NKR finger. Second, both DNA modification sites are coupled through key residues within the NKR finger, suggesting a communication pathway affecting protein-DNA binding for carboxylcytosine modifications. Our results suggest a possible additional function of the hemi-methylation reader UHRF1 through binding of carboxylated CpG sites. This opens the possibility of new biological roles of UHRF1 beyond DNA methylation maintenance and of oxidised methylcytosine derivates in epigenetic regulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229144PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034832PMC
May 2020

[Evidence-based interventional pain medicine : Progress over the past 10 years].

Schmerz 2020 Apr;34(2):123-126

AlphaMed, Kärntenstr. 2, 96052, Bamberg, Deutschland.

Interventional pain medicine plays an important role in pain therapy for neck and back pain. However, spine interventions are characterized by controversy between its proponents and its detractors. Detractors variously assert that the procedures practiced lack validity, are not effective, or produce complications that impugn the procedures. The Spine Intervention Society (SIS) published several articles over the last decade that answer and refute these criticisms.
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http://dx.doi.org/10.1007/s00482-019-00440-1DOI Listing
April 2020

Association Between Dietary Patterns and Kidney Function in Patients With Chronic Kidney Disease: A Cross-Sectional Analysis of the German Chronic Kidney Disease Study.

J Ren Nutr 2020 07 21;30(4):296-304. Epub 2019 Nov 21.

Division of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany. Electronic address:

Objective: In the general population, "healthy" dietary patterns are associated with improved health outcomes, but data on associations between observance of specific dietary patterns and kidney function in patients with chronic kidney disease (CKD) are sparse.

Methods: Dietary intake was evaluated using food frequency questionnaires in patients with moderately severe CKD under nephrology care enrolled into the observational multicenter German CKD study. The Dietary Approaches to Stop Hypertension (DASH) diet score, Mediterranean diet score, and German Food Pyramid Index (GFPI) were calculated and their association with estimated glomerular filtration rate (eGFR) and albuminuria was assessed by multivariable linear regression analysis, adjusted for gender, age, body mass index, energy intake, smoking status, alcohol intake, education, high-density lipoprotein-cholesterol (HDL- cholesterol), low-density lipoprotein-cholesterol (LDL-cholesterol), hypertension, and diabetes mellitus.

Results: A total of 2,813 patients (41% women; age 60.1 ± 11.6 years) were included in the analysis. High DASH diet score and GFPI were associated with lower systolic blood pressure and lower intake of antihypertensive medication, higher HDL, and lower uric acid levels. Mediterranean-style diet was associated with lower prevalence of diabetes mellitus. Higher DASH and Mediterranean diet scores were associated with higher eGFR (β-coefficient = 1.226, P < .001; β-coefficient = 0.932, P = .007, respectively). In contrast, GFPI was not associated with eGFR. For the individual components of the dietary patterns, higher intake of nuts and legumes, cereals, fish, and polyunsaturated fats was associated with higher eGFR and higher intake of dairy, composed of low- and whole-fat dairy, was associated with lower eGFR. No association was found between dietary patterns and albuminuria.

Conclusion: Higher observance of the DASH or Mediterranean diet, but not German food pyramid recommendations, was associated with higher eGFR among patients with CKD. Improving dietary habits may offer an opportunity to better control comorbidities and kidney function decline in patients with CKD.
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http://dx.doi.org/10.1053/j.jrn.2019.09.008DOI Listing
July 2020

Impact of C-reactive protein on osteo-/chondrogenic transdifferentiation and calcification of vascular smooth muscle cells.

Aging (Albany NY) 2019 08 3;11(15):5445-5462. Epub 2019 Aug 3.

Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany.

Medial vascular calcification occurs during the aging process and is strongly accelerated by chronic kidney disease (CKD). Elevated C-reactive protein (CRP) levels are associated with vascular calcification, cardiovascular events and mortality in CKD patients. CRP is an important promoter of vascular inflammation. Inflammatory processes are critically involved in initiation and progression of vascular calcification. Thus, the present study explored a possible impact of CRP on vascular calcification. We found that CRP promoted osteo-/chondrogenic transdifferentiation and aggravated phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of primary human aortic smooth muscle cells (HAoSMCs). These effects were paralleled by increased cellular oxidative stress and corresponding pro-calcific downstream-signaling. Antioxidants or p38 MAPK inhibition suppressed CRP-induced osteo-/chondrogenic signaling and mineralization. Furthermore, silencing of Fc fragment of IgG receptor IIa (FCGR2A) blunted the pro-calcific effects of CRP. Vascular CRP expression was increased in the klotho-hypomorphic mouse model of aging as well as in HAoSMCs during calcifying conditions. In conclusion, CRP augments osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells through mechanisms involving FCGR2A-dependent induction of oxidative stress. Thus, systemic inflammation may actively contribute to the progression of vascular calcification.
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http://dx.doi.org/10.18632/aging.102130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710049PMC
August 2019

Device-assisted enteroscopy: A review of available techniques and upcoming new technologies.

World J Gastroenterol 2019 Jul 14;25(27):3538-3545. Epub 2019 Jul 14.

Department of Internal Medicine and Gastroenterology, Evangelisches Krankenhaus Düsseldorf, Düsseldorf 40217, Germany.

The advent of video capsule endoscopy into clinical routine more than 15 years ago led to a substantial change in the diagnostic approach to patients with suspected small bowel diseases, often indicating a deep enteroscopy procedure for diagnostical confirmation or endoscopic treatment. Device assisted enteroscopy was developed in 2001 and for the first time established a practicable, safe and effective method for evaluation of the small bowel. Currently with double-balloon enteroscopy, single-balloon enteroscopy and spiral enteroscopy three different platforms are available in clinical routine. Summarizing, double-balloon enteroscopy seems to offer the deepest insertion depth to the small bowel going hand in hand with the disadvantage of a longer procedural duration. Manual spiral enteroscopy seems to be a faster procedure but without reaching the depth of the DBE in currently available data. Finally, single-balloon enteroscopy seems to be the least complicated procedure to perform. Despite substantial improvements in the field of direct enteroscopy, even nowadays deep endoscopic access to the small bowel with all available methods is still a complex procedure, cumbersome and time-consuming and requires high endoscopic skills. This review will give an overview of the currently available techniques and will further discuss the role of the upcoming new technology of the motorized spiral enteroscopy (PowerSpiral).
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http://dx.doi.org/10.3748/wjg.v25.i27.3538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658397PMC
July 2019

[Risk Scores in Patients with Chronic Kidney Disease].

Dtsch Med Wochenschr 2019 06 4;144(11):739-742. Epub 2019 Jun 4.

Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin, Charité - Universitätsmedizin Berlin.

Assessing the risk of adverse outcomes associated with chronic kidney disease (CKD) is important for physicians and affected patients alike. Categorizing CKD according to the cause-GFR category-albuminuria category (CGA)-classification system proposed by KDIGO already provides a semi-quantitative assessment of risks. The more recent development of the "Tangri"-formula provides a means to quantify the risk of progression for patients with CKD stage G3a-G5 (eGFR 10 - 59 ml/min/1.73 m) to kidney failure requiring kidney replacement therapy. To use this formula, the variables age, sex, eGFR and albuminuria are required (4-variable equation). An extended formula with the additional parameters calcium, phosphate, bicarbonate and albumin (8-variable equation) allows an even more precise estimation of progression risk. In patients with advanced CKD, stage G4 or higher (GFR category ≥ 4, i. e. eGFR < 30 ml/min/1.73 m), models recently developed by the CKD-prognosis consortium can not only be used to predict the risk of kidney failure but also the risk of cardiovascular disease events and death. The risk estimators can be accessed through websites (http://kidneyfailurerisk.com, http://www.ckdpcrisk.org/lowgfrevents/) and via downloading of the respective "apps". These novel tools may prove useful for health care decisions and as a basis for discussions with CKD patients.
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http://dx.doi.org/10.1055/a-0641-9625DOI Listing
June 2019

Ceramides bind VDAC2 to trigger mitochondrial apoptosis.

Nat Commun 2019 04 23;10(1):1832. Epub 2019 Apr 23.

Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076, Osnabrück, Germany.

Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity.
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http://dx.doi.org/10.1038/s41467-019-09654-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478893PMC
April 2019

Laser-Based Microdissection of Single Cells from Tissue Sections and PCR Analysis of Rearranged Immunoglobulin Genes from Isolated Normal and Malignant Human B Cells.

Methods Mol Biol 2019 ;1956:61-75

Senckenberg Institute of Pathology, University of Frankfurt, Frankfurt am Main, Germany.

Normal and malignant B cells carry rearranged immunoglobulin (Ig) variable region genes, which due to their practically limitless diversity represent ideal clonal markers for these cells. We describe here an approach to isolate single cells from frozen tissue sections by microdissection using a laser-based method. From the isolated cells, rearranged IgH and Igκ genes are amplified in a semi-nested PCR approach, using a collection of V gene subgroup-specific primers recognizing nearly all V genes together with primers for the J genes. By sequence analysis of V region genes from distinct cells, the clonal relationship of the B lineage cells can unequivocally be determined and related to the histological distribution of the cells. The approach is also useful to determine V, D, and J gene usage. Moreover, the presence and pattern of somatic Ig V gene mutations give valuable insight into the stage of differentiation of the B cells.
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http://dx.doi.org/10.1007/978-1-4939-9151-8_3DOI Listing
July 2019

Left Ventricular Structure in Patients With Mild-to-Moderate CKD-a Magnetic Resonance Imaging Study.

Kidney Int Rep 2019 Feb 11;4(2):267-274. Epub 2018 Oct 11.

Department of Nephrology and Hypertension, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.

Introduction: The high burden of left ventricular (LV) abnormalities in patients with advanced chronic kidney disease (CKD) is well established. However, less is known about the prevalence, patterns, and determinants of LV abnormalities in patients with early CKD.

Methods: We examined LV structure in 290 patients with a median estimated glomerular filtration rate (eGFR) of 51 ml/min per 1.73 m by magnetic resonance imaging (MRI). We explored associations with clinical and hemodynamic parameters, hydration (bioimpedance), endothelial function, inflammation (including C-reactive protein and tumor necrosis factor-α and its soluble receptors) and mineral bone disease (MBD) markers (including vitamin D, parathyroid hormone, α-klotho and fibroblast growth factor-23).

Results: Normal geometry was found in 56% of patients, dilation in 4%, concentric remodeling in 10%, and LV hypertrophy in 29%. Linear regression analysis revealed that greater LV mass was independently associated with male sex, greater body mass index (BMI), and higher 24-hour systolic blood pressure (24-hour SBP). Concentric remodeling was independently associated with age, male sex, higher 24-hour SBP, and greater hemoglobin levels. Surprisingly, neither hydration status, nor endothelial function, nor any of the inflammatory or MBD parameters added significantly to these models.

Conclusion: Abnormal LV structure was found in almost one-half of the patients. Reducing BMI and 24-hour SBP and avoiding high hemoglobin concentrations appear to be the key factors to prevent abnormal LV remodeling in patients with mild-to-moderate CKD.
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http://dx.doi.org/10.1016/j.ekir.2018.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365352PMC
February 2019

A randomized controlled trial of the effect of spironolactone on left ventricular mass in hemodialysis patients.

Kidney Int 2019 04 31;95(4):983-991. Epub 2019 Jan 31.

Comprehensive Heart Failure Center, University and University Hospital Würzburg, Würzburg, Germany; Department of Medicine I, Division of Nephrology, University Hospital Würzburg, Würzburg, Germany.

Mineralocorticoid receptor antagonists have beneficial effects on left ventricular remodeling, cardiac fibrosis, and arrhythmia in heart failure, but efficacy and safety in dialysis patients is less clear. We evaluated the effect of spironolactone on left ventricular mass (LVM), an independent predictor of all-cause and cardiovascular mortality, in hemodialysis patients. In this placebo-controlled, parallel-group trial, 97 hemodialysis patients (23% female; mean age 60.3 years) were randomized to spironolactone 50 mg once daily (n=50) or placebo (n=47). The primary efficacy endpoint was change in LVM index (LVMi) from baseline to 40 weeks as determined by cardiac magnetic resonance imaging. Safety endpoints were development of hyperkalemia and change in residual renal function. There was no significant change in LVMi in participants randomized to spironolactone compared to placebo (-2.86±11.87 vs. 0.41±10.84 g/m). There was also no difference in the secondary outcomes of mean 24-hour systolic or diastolic ambulatory blood pressure, left ventricular ejection fraction, 6-minute walk test distance, or New York Heart Association functional class. Moderate hyperkalemia (pre-dialysis potassium levels of 6.0-6.5 mmol/L) was more frequent with spironolactone treatment (155 vs. 80 events), but severe hyperkalemia (≥6.5 mmol/L) was not (14 vs. 24 events). Changes in residual urine volume and measured glomerular filtration rate did not differ between groups. There were no deaths in the spironolactone group and 4 deaths in the placebo group. Thus, treatment with 50 mg spironolactone did not change left ventricular mass index, cardiac function, or blood pressure in hemodialysis patients. Spironolactone increased the frequency of moderate hyperkalemia, but did not increase severe hyperkalemia.
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http://dx.doi.org/10.1016/j.kint.2018.11.025DOI Listing
April 2019

SpyGlass DS-guided lithotripsy for pancreatic duct stones in symptomatic treatment-refractory chronic calcifying pancreatitis.

Endosc Int Open 2019 Feb 17;7(2):E99-E103. Epub 2019 Jan 17.

Department of Gastroenterology, Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany.

 Endoscopic retrograde cholangiopancreatography (ERCP) and/or extracorporeal shock wave lithotripsy are first-line therapies for draining an obstructed pancreatic duct (PD) in painful chronic calcifying pancreatitis (CCP). Pancreaticoscopy has shown promising success rates in small series.  This study was a retrospective analysis of a clinical database. Included were all digital single-operator digital video (SOV) pancreaticoscopy-guided interventions (n = 23) on CCP patients (n = 20) between 2015 and 2017. Success and complication rates were collected from the database. Clinical success was determined by assessing pain level score (NRS) and quality of life (QoL) using standardized questionnaires.  Overall technical success rate (successful SOV-pancreaticoscopy and PD drainage) was 95 %. Adverse events occurred in 7 of 23 procedures (30 %) and included extravasation from the PD (n = 1), self-limiting post-sphincterotomy bleeding (n = 1) and post-ERCP pancreatitis (PEP) (n = 6). At 3- to 6-month follow-up, 95 % of patients reported improvement in symptoms and reduction in intake of analgesics. Mean NRS decreased from 5.4 (±1.6) to 2.8 (± 1.8) (  < 0.01). Clinical success was achieved in 95 % of patients.  Digital SOV-guided lithotripsy was found to be safe and effective in this highly selected population of CCP patients. PD decompression had a beneficial effect on pain reduction and QoL.
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http://dx.doi.org/10.1055/a-0808-4499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336461PMC
February 2019

Experimental and Numerical Study of a Thermal Expansion Gyroscope for Different Gases.

Sensors (Basel) 2019 Jan 17;19(2). Epub 2019 Jan 17.

Institut d'Électronique et des Systèmes, Université de Montpellier, IES, F-34090 Montpellier, France.

A new single-axis gas thermal gyroscope without proof mass is presented in this paper. The device was designed, manufactured and experimentally characterized. The obtained results were compared to numerical simulation. The working principle of the gyroscope is based on the deflection of a laminar gas flow caused by the Coriolis effect. A bidirectional hot air flow is generated by alternating activation of two suspended resistive micro-heaters. The heated gas is encapsulated in a semi-open cavity and the gas expands primarily inside the cavity. The thermal expansion gyroscope has a simple structure. Indeed, the device is composed of a micromachined cavity on which three bridges are suspended. The central bridge is electrically separated into two segments enabling to set up two heaters which may be supplied independently from each other. The two other bridges, placed symmetrically on each side of the central bridge, are equipped with temperature detectors which measure variations in gas temperature. The differential temperature depends on the rotational velocity applied to the system. Various parameters such as the heating duty cycle, the type of the gas and the power injected into the heaters have been studied to define the optimal working conditions required to obtain the highest level of sensitivity over a measurement range of around 1000°/s. The robustness of the device has also been tested and validated for a shock resistance of 10,000 g for a duration of 400 µs.
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http://dx.doi.org/10.3390/s19020360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359575PMC
January 2019

Drugs linked to plasma homoarginine in chronic kidney disease patients-a cross-sectional analysis of the German Chronic Kidney Disease cohort.

Nephrol Dial Transplant 2020 07;35(7):1187-1195

Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Background: Elevated plasma concentrations of symmetric and asymmetric dimethylarginine (SDMA and ADMA, respectively) and a lower plasma concentration of the structurally related homoarginine are commonly observed in patients with chronic kidney disease (CKD) and independently predict total mortality as well as progression of renal disease. We aimed to identify drugs that may alter this adverse metabolite pattern in a favourable fashion.

Methods: Plasma ADMA, SDMA, homoarginine and l-arginine were determined by liquid chromatography-tandem mass spectrometry in 4756 CKD patients ages 18-74 years with an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or an eGFR >60 mL/min/1.73 m2 and overt proteinuria who were enrolled in the German Chronic Kidney Disease (GCKD) study. Associations between laboratory, clinical and medication data were assessed.

Results: Intake of several commonly used drugs was independently associated with plasma concentrations of homoarginine and/or related metabolites. Among these, the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist fenofibrate was associated with the most profound differences in ADMA, SDMA and homoarginine plasma concentrations: 66 patients taking fenofibrate had a multivariable adjusted odds ratio (OR) of 5.83 [95% confidence interval (CI) 2.82-12.03, P < 0.001] to have a plasma homoarginine concentration above the median. The median homoarginine plasma concentration in patients taking fenofibrate was 2.30 µmol/L versus 1.55 in patients not taking the drug (P < 0.001). In addition, fibrates were significantly associated with lower plasma SDMA and higher l-arginine concentrations. In contrast, glucocorticoids were associated with lower plasma homoarginine, with adjusted ORs of 0.52 (95% CI 0.40-0.67, P < 0.001) and 0.53 (95% CI 0.31-0.90, P = 0.018) for prednisolone and methylprednisolone, respectively.

Conclusions: In a large cohort of CKD patients, intake of fenofibrate and glucocorticoids were independently associated with higher and lower plasma homoarginine concentrations, respectively. Effects on plasma homoarginine and methylarginines warrant further investigation as potential mechanisms mediating beneficial or adverse drug effects.
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http://dx.doi.org/10.1093/ndt/gfy342DOI Listing
July 2020

Chemical Cross-Linking Enables Drafting ClpXP Proximity Maps and Taking Snapshots of In Situ Interaction Networks.

Cell Chem Biol 2019 01 8;26(1):48-59.e7. Epub 2018 Nov 8.

Department of Chemistry, Chair of Organic Chemistry II, Center for Integrated Protein Science (CIPSM), Technische Universität München, Lichtenbergstraße 4, 85748 Garching, Germany. Electronic address:

Detection of dynamic protein-protein interactions within complexes and networks remains a challenging task. Here, we show by the example of the proteolytic ClpXP complex the utility of combined chemical cross-linking and mass spectrometry (XL-MS) to map interactions within ClpP and ClpX as well as across the enigmatic ClpX hexamer-ClpP heptamer interface. A few hot-spot lysines located in signature loops in ClpX were shown to be in proximity to several structural regions of ClpP providing an initial draft of the ClpX-ClpP interaction. Application of XL-MS further confirmed that Listeria monocytogenes ClpX interacts with the heterooligomeric ClpP1/2 complex solely via the ClpP2 apical site. Moreover, cellular interaction networks of human and bacterial proteases were elucidated via in situ chemical cross-linking followed by an antibody-based pull-down against ClpP. A subsequent mass spectrometric analysis demonstrated an up to 3-fold higher coverage compared with co-immunoprecipitation without cross-linker revealing unprecedented insight into intracellular ClpXP networks.
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http://dx.doi.org/10.1016/j.chembiol.2018.10.007DOI Listing
January 2019