Universität Heidelberg
  • Heidelberg, Germany
Recent publications
Myeloid/lymphoid neoplasms with eosinophilia (MLN-eos) are rare haematological neoplasms primarily affecting adults. The heterogeneous clinical picture and the rarity of the disease, especially in children, may delay an early diagnosis. MLN-eos are characterized by constitutive tyrosine kinase (TK) activity due to gene fusions. It is thus of importance to obtain a prompt genetic diagnosis to start a specific therapy. Here, we outline the clinical, genetic, and biochemical background of TK driven MLN-eos and report two extremely rare paediatric cases of MLN-eo, the used diagnostic methods, therapy and clinical outcomes. Our results demonstrate that, standard cytogenetic and molecular methods may not be sufficient to diagnose MLN-eo due to cytogenetically cryptic aberrations. We therefore recommend performing additional evaluation with fluorescence in-situ hybridization and molecular genetic methods (array-based comparative genomic hybridization and RNA sequencing) which will lead to the correct diagnosis. Following this diagnostic route we detected a TNIP1::PDGFRB and a PCM1::FGFR1 fusion in our patients. Thus, genetic diagnosis must be precise and quick in order to initiate adequate therapies with tyrosine kinase inhibitors or HSCT.
The FeIVO complexes of bispidines (3,7-diazabicyclo[3.3.1]nonane derivatives) are known to be highly reactive oxidants - with the tetradentate bispidine, the so far most reactive ferryl complex has been reported and two isomeric pentadentate ligands also lead to very reactive high-valent oxidants. With a series of 4 new bispidine derivatives we now try to address the question why the bispidine scaffold in general leads to very reactive oxidants and how this can be tuned by ligand modifications. The study is based on a full structural, spectroscopic and electrochemical analysis of the iron(II) precursors, spectroscopic data of the iron(IV)-oxido complexes, a kinetic analysis of the stoichiometric oxidation of thioanisole by five different bispidine‑iron(IV)-oxido complexes and on product analyses of reactions by the five ferryl oxidants with thioanisole, β-methylstyrene and cis-stilbene as substrates.
The initial treatment of acute and subacute portal vein thrombosis, which is the most common cause of portal vein occlusion, consists of intravenous anticoagulation with heparin, but there is still a huge uncertainty among physicians regarding the role of more invasive therapies. We report a 61-year-old male patient, who presented in our emergency room with a subacute complete thrombosis of the intra- and extrahepatic portal vein, mesenteric vein, with associated venous congestion of 20-30 cm length of the small intestine with a quick and complete remission of the portal vein thrombosis under sole i.v. heparin-perfusor therapy without any complications. Molecular genetic analysis found combined genetic mutations of the gene factor 2 (c.20210G>A, heterozygotic), SERPINE1 (-675 5G>4G, heterozygotic), and the MTHFR gene. Along with this interesting case, we also present the recent status of portal vein thrombosis and portal vein occlusion in the literature.
Purpose: Hepatic steatosis is often diagnosed non-invasively. Various measures and accompanying diagnostic thresholds based on contrast-enhanced CT and virtual non-contrast images have been proposed. We compare these established criteria to novel and fully automated measures. Method: CT data sets of 197 patients were analyzed. Regions of interest (ROIs) were manually drawn for the liver, spleen, portal vein, and aorta to calculate four established measures of liver-fat. Two novel measures capturing the deviation between the empirical distributions of HU measurements across all voxels within the liver and spleen were calculated. These measures were calculated with both manual ROIs and using fully automated organ segmentations. Agreement between the different measures was evaluated using correlational analysis, as well as their ability to discriminate between fatty and healthy liver. Results: Established and novel measures of fatty liver were at a high level of agreement. Novel methods were statistically indistinguishable from the established ones when taking established diagnostic thresholds or physicians' diagnoses as ground truth and this high performance level persisted for automatically selected ROIs. Conclusion: Automatically generated organ segmentations led to comparable results as manual ROIs, suggesting that the implementation of automated methods can prove to be a valuable tool for incidental diagnosis. Differences in the distribution of HU measurements across voxels between liver and spleen can serve as surrogate markers for the liver-fat-content. Novel measures do not exhibit a measurable disadvantage over established methods based on simpler measures such as across-voxel averages in a population with low incidence of fatty liver.
Eukaryotic cells use clathrin-mediated endocytosis to take up a large range of extracellular cargo. During endocytosis, a clathrin coat forms on the plasma membrane, but it remains controversial when and how it is remodeled into a spherical vesicle. Here, we use 3D superresolution microscopy to determine the precise geometry of the clathrin coat at large numbers of endocytic sites. Through pseudo-temporal sorting, we determine the average trajectory of clathrin remodeling during endocytosis. We find that clathrin coats assemble first on flat membranes to 50% of the coat area before they become rapidly and continuously bent, and this mechanism is confirmed in three cell lines. We introduce the cooperative curvature model, which is based on positive feedback for curvature generation. It accurately describes the measured shapes and dynamics of the clathrin coat and could represent a general mechanism for clathrin coat remodeling on the plasma membrane.
Mosquito-borne flaviviruses including Zika virus (ZIKV) represent a public health problem in some parts of the world. Although ZIKV infection is predominantly asymptomatic or associated with mild symptoms, it can lead to neurological complications. ZIKV infection can also cause antibody-dependent enhancement (ADE) of infection with similar viruses, warranting further studies of virion assembly and the function of envelope (E) protein-specific antibodies. Although extracellular vesicles (EVs) from flavivirus-infected cells have been reported to transmit infection, this interpretation is challenged by difficulties in separating EVs from flavivirions due to their similar biochemical composition and biophysical properties. In the present study, a rigorous EV-virion separation method combining sequential ultracentrifugation and affinity capture was developed to study EVs from ZIKV-infected cells. We find that these EVs do not transmit infection, but EVs display abundant E proteins which have an antigenic landscape similar to that of virions carrying E. ZIKV E-coated EVs attenuate antibody-dependent enhancement mediated by ZIKV E-specific and DENV-cross-reactive antibodies in both cell culture and mouse models. We thus report an alternative route for Flavivirus E protein secretion. These results suggest that modulation of E protein release via virions and EVs may present a new approach to regulating flavivirus-host interactions.
Early Cretaceous rift basins of the incipient South Atlantic have been the focus of intense hydrocarbon exploration and production activities and host some large oil accumulations in sections predating an interval of major salt deposition, particularly in the central segment of the South Atlantic. Understanding the timing (and associated uncertainties) of source rock and reservoir deposition and their relationship with rift evolution is critical for successful exploration. However, there are still many unresolved issues and data gaps regarding the precise age and duration of salt deposition. Better chronological constraints are particularly needed to determine the timing of deposition of Pre-Salt reservoirs and the primary evaporites, as well as the secondary phase of halokinensis that resulted in variable reservoir sealing potential. To help address this gap, stable carbon isotope (δ¹³C) records from bulk organic matter and insoluble kerogen were generated for the Early Cretaceous salt and Pre-Salt intervals from two exploration wells offshore of Gabon. The bulk organic δ¹³C stratigraphies for the two wells were then integrated with palynological and ostracod biostratigraphy and placed within a sequence stratigraphic and regional tectonic framework, providing new constraints on the timing of rift lake evolution and salt deposition. The good correlation between the offshore Gabon δ¹³C record with other published sections calibrated to the current Geologic Time Scale as well as other regional sections from NE Brazil, supports the reliability of our new Gabon δ¹³C record. Several δ¹³C excursions are identified in the Pre-Salt sequence and are correlated with the Valanginian Weissert event and Early Aptian δ¹³C event(s). Salt deposition on the Gabon margin is interpreted to have occurred during an interval straddling the Early-Late Aptian boundary (∼118.4–116.8 Ma). These findings are comparable with other published estimates for salt deposition from northeast Brazil but differ from published estimates from the Campos-Santos basins; the latter are critically discussed. This study provides an important stratigraphic dataset for offshore Gabon and contributes to the ongoing debate regarding the timing of rifting and salt deposition in the Early Cretaceous of the South Atlantic passive margin system.
In this work we discuss the deformed relativistic wave equations, namely the Klein–Gordon and Dirac equations in a Doubly Special Relativity scenario. We employ what we call a geometric approach, based on the geometry of a curved momentum space, which should be seen as complementary to the more spread algebraic one. In this frame we are able to rederive well-known algebraic expressions, as well as to treat yet unresolved issues, to wit, the explicit relation between both equations, the discrete symmetries for Dirac particles, the fate of covariance, and the formal definition of a Hilbert space for the Klein–Gordon case.
Colorectal cancer (CRC) incidence and mortality are higher among men than among women. We aimed to estimate overall and age-specific risk advancement periods (RAPs) for men compared to women, which quantify how many years earlier comparable levels of risk are reached by men. RAPs were derived by Cox regression models among 331,224 participants aged 40-69 at baseline of the UK Biobank with no previous diagnosis of CRC and no previous CRC screening examination who were followed with respect to CRC incidence for up to 13 years. Men were at substantially higher risk of CRC than women in age groups 50-59 and 60-69, with RAPs (95% confidence intervals) as high as 8.7 (4.5-13.0) and 6.2 (4.5-7.9), respectively. These RAPs were higher than those for family history of CRC in these age groups. By contrast, no significant sex difference but a major impact of family history was seen in age group 40-49 (p-value for interaction between sex and age = 0.00079). The observed patterns suggest that consideration of gender-specific starting ages of screening might be warranted in countries in which screening offers start at ages above 50 years.
Background Pulmonary fibrosis (PF) is caused by a heterogeneous group of diseases, with a high inter-individual variability in disease trajectory. Identifying disease progression in patients with PF has impact on clinical management decisions. However, strategies to early identify and predict disease progression for these patients are currently lacking. In this study, we aim to assess long-term FVC change in patients with PF measured with home spirometry, and evaluate the feasibility of a multinational patient-led registry in PF. In addition, we will assess validity of patient-reported outcomes (PROMs) for the different subgroups of patients with PF. Methods In this international, prospective, multicenter, observational study, we aim to include 700 patients across seven European countries. Patients will monitor their disease course for a period of two years using an online home monitoring program (I-FILE), which includes home spirometry, pulse oximetry, and PROMs. Results will be directly sent to the hospital via the online application. Patients will be asked to perform daily home spirometry and pulse oximetry in the first three months, followed by once weekly measurements for a period of two years. PROMs will be completed in the online I-FILE application every six months, including the King’s brief Interstitial Lung Disease Health Status, The EuroQol five dimensions five-level, Visual Analogue Scales on cough, dyspnea, fatigue and general complaints, Leicester Cough Questionnaire, Fatigue Assessment Scale, Work Productivity and Activity Impairment Questionnaire, Global Rating of Change Scale, and Living with Pulmonary Fibrosis questionnaire. Discussion This study will provide much needed insights in disease trajectories of the different subgroups of patients with PF. Simultaneously, the I-FILE study will yield valuable information on the use and feasibility of home-based data collection. This international patient-led registry will facilitate trans-border collaboration to further optimize care and research for patients with PF. Trial registration: The study was registered on the 12th of March 2020 in the International Clinical Trial Registry, www.clinicaltrials.gov; Identifier: NCT04304898.
Background: Particle imaging can increase precision in proton and ion therapy. Interactions with nuclei in the imaged object increase image noise and reduce image quality, especially for multi-nucleon ions that can fragment, such as helium. Purpose: This work proposes a particle imaging filter, referred to as the Prior Filter, based on using prior information in the form of an estimated relative stopping power (RSP) map and the principles of electromagnetic interaction, to identify particles that have undergone nuclear interaction. The particles identified as having undergone nuclear interactions are then excluded from the image reconstruction, reducing the image noise. Methods: The Prior Filter uses Fermi-Eyges scattering and Tschalär straggling theories to determine the likelihood that a particle only interacts electromagnetically. A threshold is then set to reject those particles with a low likelihood. The filter was evaluated and compared with a filter that estimates this likelihood based on the measured distribution of energy and scattering angle within pixels, commonly implemented as the 3σ filter. Reconstructed radiographs from simulated data of a 20 cm water cylinder and an anthropomorphic chest phantom were generated with both protons and helium ions to assess the effect of the filters on noise reduction. The simulation also allowed assessment of secondary particle removal through the particle histories. Experimental data were acquired of the Catphan CTP 404 Sensitometry phantom using the U.S. proton CT (pCT) collaboration prototype scanner. The proton and helium images were filtered with both the prior filtering method and a state-of-the-art method including an implementation of the 3σ filter. For both cases a dE-E telescope filter, designed for this type of detector, was also applied. Results: The proton radiographs showed a small reduction in noise (1 mm of water equivalent thickness) but a larger reduction in helium radiographs (up to 5-6 mm of water equivalent thickness) due to better secondary filtering. The proton and helium CT images reflected this, with similar noise at the center of the phantom (0.02 RSP) for the proton images and an RSP noise of 0.03 for the proposed filter and 0.06 for the 3σ filter in the helium images. Images reconstructed from data with a dose reduction, up to a factor of 9, maintained a lower noise level using the Prior Filter over the state-of-the-art filtering method. Conclusions: The proposed filter results in images with equal or reduced noise compared to those that have undergone a filtering method typical of current particle imaging studies. This work also demonstrates that the proposed filter maintains better performance against the state of the art with up to a nine-fold dose reduction. This article is protected by copyright. All rights reserved.
Protein S-persulfidation (P-SSH) is recognized as a common posttranslational modification. It occurs under basal conditions and is often observed to be elevated under stress conditions. However, the mechanism(s) by which proteins are persulfidated inside cells have remained unclear. Here we report that 3-mercaptopyruvate sulfur transferase (MPST) engages in direct protein-to-protein transpersulfidation reactions beyond its previously known protein substrates thioredoxin and MOCS3/Uba4, associated with H2S generation and transfer RNA thiolation, respectively. We observe that depletion of MPST in human cells lowers overall intracellular protein persulfidation levels and identify a subset of proteins whose persulfidation depends on MPST. The predicted involvement of these proteins in the adaptation to stress responses supports the notion that MPST-dependent protein persulfidation promotes cytoprotective functions. The observation of MPST-independent protein persulfidation suggests that other protein persulfidases remain to be identified.
After ionization of an inner-valence electron of molecules, the resulting cation-radicals store substantial internal energy which, if sufficient, can trigger ejection of an additional electron in an Auger decay usually followed by molecule fragmentation. In the environment, intermolecular Coulombic decay (ICD) and electron-transfer mediated decay (ETMD) are also operative, resulting in one or two electrons being ejected from a neighbor, thus preventing the fragmentation of the initially ionized molecule. These relaxation processes are investigated theoretically for prototypical heterocycle-water complexes of imidazole, pyrrole, and pyridine. It is found that the hydrogen-bonding site of the water molecule critically influences the nature and energetics of the electronic states involved, opening or closing certain relaxation processes of the inner-valence ionized system. Our results indicate that the relaxation mechanisms of biologically relevant systems with inner-valence vacancies on their carbon atoms can strongly depend on the presence of the electron-density donating or accepting neighbor, either water or another biomolecule.
Background: Respiratory syncytial virus (RSV) is the most common cause of acute respiratory tract infection in infants and young children often leading to severe disease requiring hospitalization. However, validated tools for systematic assessment of disease severity are lacking. Methods: This study aimed at creating and validating a standardized, simple-to-use disease severity score for RSV infection in children - the RSV-CLASS. Therefore, data from over 700 RSV-infected children over six winter seasons (2014-2020) was analyzed using univariate and multiple regression analyses for the prediction of LRTI as a proxy for a severe course of disease. Results: Testing a broad range of respiratory symptoms, they eventually yielded seven items. Performing stepwise selection, these were reduced to the final four items: cough, tachypnoea, rales, and wheezing, each receiving one point in the proposed score named RSV-CLASS (Clinical Assessment Severity Score). The score was calculated for children in two cohorts A and B, one for development and one for validation, with an AUC of 0.90 and 0.87, respectively. With a score value of three or four, 97.8% and 100% of the children, respectively, were admitted with LRTI and classified correctly. Conclusions: The RSV-CLASS is a disease severity score based on a neutral, analytical approach using prospective data from a large study cohort. It will contribute to systematically assessing the disease severity of RSV infection and can be used for evidence-based clinical decision-making as well as for research settings. This article is protected by copyright. All rights reserved.
The notion of metacognitive myopia refers to a conspicuous weakness of the quality control of memory and reasoning processes. Although people are often remarkably sensitive even to complex samples of information when making evaluative judgments and decisions, their uncritical and naive tendency to take the validity of sampled information for granted constitutes a major obstacle to rational behavior. After illustrating this phenomenon with reference to prominent biases (base-rate neglect, misattribution, perseverance), we decompose metacognitive myopia into two distinct but intertwined functions, monitoring and control. We offer explanations for why effectively monitoring the biases resulting from information sampling in an uncertain world is so difficult and why the control function is severely restricted by the lack of volitional control over mental actions. Because of these and other difficulties, metacognitive myopia constitutes a major obstacle to rational judgment and decision making.
Endoscopic lung volume reduction procedure with valves is a well-studied treatment option for advanced lung emphysema to target lung hyperinflation in carefully selected patients with COPD. Before valve implantation, collateral ventilation (CV) of the target lobe needs to be assessed to obtain an optimal treatment effect. The analysis of CV according to current standards occurs via an in vivo assessment with the Chartis®system (PulmonX Inc., Redwood City, CA, USA) and a computed tomography (CT) scan of the thorax with interlobar fissure analysis. The focus of this review is to provide detailed information about the Chartis®procedure and interpretation of Chartis® phenotypes. As a main tool in the assessment of CV and being a safe procedure, the Chartis® assessment should be performed by default to confirm interlobar fissure analysis in most emphysema patients. Based on the obtained results, lung volume reduction therapy options should be discussed in an interdisciplinary emphysema conference.
Background The brain and muscle Arnt-like protein-1 ( BMAL1 ) gene is an important circadian clock gene and previous studies have found that certain polymorphisms are associated with type 2 diabetes in adults. However, it remains unknown if such polymorphisms can affect fasting glucose in children and if other factors modify the associations. Methods A school-based cross-sectional study with 947 Chinese children was conducted. A multivariable linear regression model was used to analyze the association between BMAL1 gene polymorphisms and fasting glucose level. Results After adjusting for age, sex, body mass index (BMI), physical activity, and unhealthy diet, GG genotype carriers of BMAL1 rs3789327 had higher fasting glucose than AA/GA genotype carriers ( b = 0.101, SE = 0.050, P = 0.045). Adjusting for the same confounders, rs3816358 was shown to be significantly associated with fasting glucose ( b = 0.060, SE = 0.028, P = 0.032). Furthermore, a significant interaction between rs3789327 and nutritional status on fasting glucose was identified ( P interaction = 0.009); rs3789327 was associated with fasting glucose in the overweight/obese subgroup ( b = 0.353, SE = 0.126, P = 0.006), but not in non-overweight/non-obese children. Conclusions BMAL1 polymorphisms were significantly associated with the fasting glucose level in children. Additionally, the observed interaction between nutritional status and BMAL1 supports promoting an optimal BMI in children genetically predisposed to higher glucose level. Impact Polymorphisms in the essential circadian clock gene BMAL1 were associated with fasting blood glucose levels in children. Additionally, there was a significant interaction between nutritional status and BMAL1 affecting fasting glucose levels. BMAL1 rs3789327 was associated with fasting glucose only in overweight/obese children. This finding could bring novel insights into mechanisms by which nutritional status influences fasting glucose in children.
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Claudia Seyler
  • Department of Medicine III: Cardiology, Angiology and Pneumology
Jan Larmann
  • Department of Anesthesiology
Joachim Funke
  • Institute of Psychology
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Prof. Dr. Bernhard Eitel
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