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Ribosome biogenesis is one cell function-defining process. It depends on efficient transcription of rDNAs in the nucleolus as well as on the cytosolic synthesis of ribosomal proteins. For newly transcribed rRNA modification and ribosomal protein assembly, so-called small nucleolar RNAs (snoRNAs) and ribosome biogenesis factors (RBFs) are required. For both, an inventory was established for model systems like yeast and humans. For plants, many assignments are based on predictions. Here, RNA deep sequencing after nuclei enrichment was combined with single molecule species detection by northern blot and in vivo fluorescence in situ hybridization (FISH)-based localization studies. In addition, the occurrence and abundance of selected snoRNAs in different tissues were determined. These approaches confirm the presence of most of the database-deposited snoRNAs in cell cultures, but some of them are localized in the cytosol rather than in the nucleus. Further, for the explored snoRNA examples, differences in their abundance in different tissues were observed, suggesting a tissue-specific function of some snoRNAs. Thus, based on prediction and experimental confirmation, many plant snoRNAs can be proposed, while it cannot be excluded that some of the proposed snoRNAs perform alternative functions than are involved in rRNA modification
Complexome profiling is an emerging ‘omics approach that systematically interrogates the composition of protein complexes (the complexome) of a sample, by combining biochemical separation of native protein complexes with mass-spectrometry based quantitation proteomics. The resulting fractionation profiles hold comprehensive information on the abundance and composition of the complexome, and have a high potential for reuse by experimental and computational researchers. However, the lack of a central resource that provides access to these data, reported with adequate descriptions and an analysis tool, has limited their reuse. Therefore, we established the ComplexomE profiling DAta Resource (CEDAR, www3.cmbi.umcn.nl/cedar/), an openly accessible database for depositing and exploring mass spectrometry data from complexome profiling studies. Compatibility and reusability of the data is ensured by a standardized data and reporting format containing the “minimum information required for a complexome profiling experiment” (MIACE). The data can be accessed through a user-friendly web interface, as well as programmatically using the REST API portal. Additionally, all complexome profiles available on CEDAR can be inspected directly on the website with the profile viewer tool that allows the detection of correlated profiles and inference of potential complexes. In conclusion, CEDAR is a unique, growing and invaluable resource for the study of protein complex composition and dynamics across biological systems.
Background: Culture-derived mesenchymal stromal cells (MSCs) exhibit variable characteristics when manufactured using different methods and different source materials. The purpose of this study was to assess the impact on MSC characteristics when different laboratories propagated MSCs from cultures initiated with BM aliquots derived from the same donor source material.
Methods and Methods: Five aliquots from each of three different BM donors were distributed to five independent laboratories. Three laboratories plated whole BM and two laboratories a mononuclear BM cell fraction. Four laboratories cultured in media supplemented with fetal bovine serum (FBS) and one laboratory used human platelet lysate (hPL). Initial cell seeding densities (i.e., P0) ranged from 19.7 × 103/cm2–282 × 103/cm2 and for second seeding (i.e., P1) 0.05 × 103–5.1 × 103 cells/cm2. Post-thawed MSCs from each laboratory were analyzed for cell viability, immunophenotype, tri-lineage differentiation, fibroblast colony-forming units (CFU-F), gene expression, and immunosuppressive activity.
Results: Transit times from BM collection to receipt by laboratories located in the United States ranged from 16.0–30.0 h and from 41.5–71.5 h for a laboratory in Asia. Post-thaw culture derived MSCs rom BM #1, #2, and #3 exhibited viabilities that ranged from 74–92%, 61–96%, and 23–90%, respectively. CFU activity from BM #1, #2, and #3 per 200 MSCs plated averaged 45.1 ± 21.4, 49.3 ± 26.8 and 14.9 ± 13.3, respectively. No substantial differences were observed in immunophenotype, and immunosuppressive activities. Global gene expression profiles of MSCs revealed transcriptome differences due to different inter-laboratory methods and to donor source material with the center effects showing greater molecular differences than source material.
Conclusion: Functional and molecular differences exist among MSCs produced by different centers even when the same BM starting material is used to initiate cultures. These results indicated that manufacturing of MSCs by five independent centers contributed more to MSC variability than did the source material of the BM used in this study. Thus, emphasizing the importance of establishing worldwide standards to propagate MSCs for clinical use.
100 Jahre Dieter Janz
(2020)
The 20 April 2020 marks the centenary of Dieter Janz’s birth. This issue of Zeitschrift für Epileptologie is published in his honor with the aim of tracing the work of Dieter Janz over the last five decades and summarizing new findings on the Janz syndrome (Juvenile Myoclonic Epilepsy), which is named after him.
Introduction: Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments. Areas covered: This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones for DS treatment, together with the latest findings of other pharmacotherapies in development. In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are generally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies. Expert opinion: Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs.
Highlights
• German patients with LGS identified using most specific algorithm to date.
• Prevalence of probable LGS with epilepsy diagnosis before age 6 was 6.5 per 100,000.
• High healthcare costs of €22,787 PPY; mostly due to inpatient and home nursing care.
• Costs were greater in patients prescribed rescue medications.
• Over 10 years, LGS patients had significant mortality vs. controls (2.88 vs. 0.01%).
Abstract
Objective: This retrospective study examined patients with probable Lennox-Gastaut syndrome (LGS) identified from German healthcare data.
Methods: This 10-year study (2007–2016) assessed healthcare insurance claims information from the Vilua Healthcare research database. A selection algorithm considering diagnoses and drug prescriptions identified patients with probable LGS. To increase the sensitivity of the identification algorithm, two populations were defined: all patients with probable LGS (broadly defined) and only those with a documented epilepsy diagnosis before 6 years of age (narrowly defined). This specific criterion was used as LGS typically has a peak seizure onset between age 3 and 5 years. Primary analyses were prevalence and demographics; secondary analyses included healthcare costs, hospitalization rate and length of stay (LOS), medication use, and mortality.
Results: In the final year of the study, 545 patients with broadly defined probable LGS (mean [range] age: 31.4 [2–89] years; male: 53%) were identified. Using the narrowly defined probable LGS definition, the number of patients was reduced to 102 (mean [range] age: 7.4 [2–14] years; male: 52%). Prevalence of broadly defined and narrowly defined probable LGS was 39.2 and 6.5 per 100,000 people. During the 10-year study, 208 patients with narrowly defined probable LGS were identified and followed up for 1379 patient-years. The mean annual cost of healthcare was €22,787 per patient-year (PPY); greatest costs were attributable to inpatient care (33%), home nursing care (13%), and medication (10%). Mean annual healthcare costs were significantly greater for those with prescribed rescue medication (45% of patient-years) versus those without (€33,872 vs. €13,785 PPY, p < 0.001). Mean (standard deviation [SD]) annual hospitalization rate was 1.6 (2.0) PPY with mean (SD) annual LOS of 22.7 (46.0) days. Annual hospitalization rate was significantly greater in those who were prescribed rescue medication versus those who were not (2.2 [2.3] vs. 1.1 [1.6] PPY, p < 0.001). The mean (SD) number of different medications prescribed was 11.3 (7.3) PPY and 33.8 (17.0) over the entire observable time per patient (OET); antiepileptic drugs only accounted for 2.1 (1.1) of the medications prescribed PPY and 3.8 (2.0) OET. Over the 10-year study period, mortality in patients with narrowly defined probable LGS was significantly higher than the matched control population (six events [2.88%] vs. one event [0.01%], p < 0.001).
Conclusion: Annual healthcare costs incurred by patients with probable LGS in Germany were substantial, and mostly attributable to inpatient care, home nursing care, and medication. Patients prescribed with rescue medication incurred significantly greater costs than those who were not. Patients with narrowly defined probable LGS had a higher mortality rate versus control populations.
Objective: Severely injured patients frequently develop an immunological imbalance following the traumatic insult, which might result in infectious complications evoked by a persisting immunosuppression. Regulatory T cells (Tregs) maintain the immune homeostasis by suppressing proinflammatory responses, however, their functionality after trauma is unclear. Here, we characterized the role of Tregs in regulating the proliferation of CD4+ lymphocytes in traumatized patients (TP). Methods: Peripheral blood was obtained daily from 29 severely injured TP (Injury Severity Score, ISS ≥16) for ten days following admission to the emergency department (ED). Ten healthy volunteers (HV) served as controls. The frequency and activity of Tregs were assessed by flow cytometry. Proliferation of CD4+ cells was analyzed either in presence or absence of Tregs, or after blocking of either IL-10 or IL-10R1. Results: The frequencies of CD4+CD25high and CD4+CD25+CD127− Tregs were significantly decreased immediately upon admission of TP to the ED and during the following 10 post-injury days. Compared with HV CD4+ T cell proliferation in TP increased significantly upon their admission and on the following days. As expected, CD4+CD25+CD127− Tregs reduced the proliferation of CD4+ cells in HV, nevertheless, CD4+ proliferation in TP was increased by Tregs. Neutralization of IL-10 as well as blocking the IL-10R1 increased further CD4+ T cell proliferation in Tregs-depleted cultures, thereby confirming an IL-10-mediated mechanism of IL-10-regulated CD4+ T cell proliferation. Neutralization of IL-10 in TP decreased CD4+ T cell proliferation in Tregs-depleted cultures, whereas blocking of the IL-10R1 receptor had no significant effects. Conclusions: The frequency of Tregs in the CD4+ T lymphocyte population is reduced after trauma; however, their inductiveness is increased. The mechanisms of deregulated influence of Tregs on CD4+ T cell proliferation are mediated via IL-10 but not via the IL-10R1.
CO2 has been electrochemically reduced to the intermediate formate, which was subsequently used as sole substrate for the production of the polymer polyhydroxybutyrate (PHB) by the microorganism Cupriavidus necator. Faradaic efficiencies (FE) up to 54 % have been reached with Sn‐based gas‐diffusion electrodes in physiological electrolyte. The formate containing electrolyte can be used directly as drop‐in solution in the following biological polymer production by resting cells. 56 mg PHB L−1 and a ratio of 34 % PHB per cell dry weight were achieved. The calculated overall FE for the process was as high as 4 %. The direct use of the electrolyte as drop‐in media in the bioconversion enables simplified processes with a minimum of intermediate purification effort. Thus, an optimal coupling between electrochemical and biotechnological processes can be realized.
Persönliches Feedback bei Vorlesungen mit Hunderten Studierenden erscheint bisher utopisch – auch nach dem Digitalisierungsschub in Corona-Zeiten. Tools aus dem Forschungsgebiet der »Learning Analytics« könnten künftig den Studierenden Rückmeldung geben und zugleich den Betreuern Hinweise liefern, wo noch Hilfestellung nötig ist.
Eine lebenswerte, schöne Stadt mit viel Grün und kurzen Wegen – das wünschen sich eigentlich alle. Wie wir dorthin kommen können, daran forscht die Arbeitsgruppe des Mobilitätsforschers Martin Lanzendorf. Im Fokus steht dabei der Mensch: Wie verhält er sich im öffentlichen Raum, was sind seine Beweggründe, Ziele und Wünsche – und wie ließe sich sein Verhalten beeinflussen?
So far, personal feedback in the case of lectures with hundreds of students still seems utopic – even after the digitalization boom in times of the coronavirus. Tools from the research field of »learning analytics« could in future give students feedback and at the same time provide their supervisors with clues about where help is still needed.
Since the introduction of rental E-scooters in Germany in mid-June 2019, the safety of this new means of transport has been the subject of extensive public debate. However, valid data on injuries and usage habits are not yet available. This retrospective two-center study included a total of 76 patients who presented to the emergency department following E-scooter-related accidents. The mean age was 34.3 ± 12.4 years and 69.7% of the patients were male. About half of the patients were admitted by ambulance (42.1%). Fractures were found in 48.6% of patients, and 27.6% required surgical treatment due to a fracture. The upper extremities were the most commonly affected body region, followed by injuries to the lower extremity and to the head and face. Only one patient had worn a helmet. In-hospital treatment was necessary for 26.3% of the cases. Patients presented to the emergency department mainly during the weekend and on-call times. This is the first report on E-scooter-related injuries in Germany. Accidents with E-scooters can cause serious injuries and, therefore, represent a further burden to emergency departments. The use of E-scooters appears to be mostly recreational, and the rate of use of protective gear is low.
Dendrites display a striking variety of neuronal type-specific morphologies, but the mechanisms and principles underlying such diversity remain elusive. A major player in defining the morphology of dendrites is the neuronal cytoskeleton, including evolutionarily conserved actin-modulatory proteins (AMPs). Still, we lack a clear understanding of how AMPs might support developmental phenomena such as neuron-type specific dendrite dynamics. To address precisely this level of in vivo specificity, we concentrated on a defined neuronal type, the class III dendritic arborisation (c3da) neuron of Drosophila larvae, displaying actin-enriched short terminal branchlets (STBs). Computational modelling reveals that the main branches of c3da neurons follow a general growth model based on optimal wiring, but the STBs do not. Instead, model STBs are defined by a short reach and a high affinity to grow towards the main branches. We thus concentrated on c3da STBs and developed new methods to quantitatively describe dendrite morphology and dynamics based on in vivo time-lapse imaging of mutants lacking individual AMPs. In this way, we extrapolated the role of these AMPs in defining STB properties. We propose that dendrite diversity is supported by the combination of a common step, refined by a neuron type-specific second level. For c3da neurons, we present a molecular model of how the combined action of multiple AMPs in vivo define the properties of these second level specialisations, the STBs.
p53 regulates the cellular response to genotoxic damage and prevents carcinogenic events. Theoretical and experimental studies state that the p53-Mdm2 network constitutes the core module of regulatory interactions activated by cellular stress induced by a variety of signaling pathways. In this paper, a strategy to control the p53-Mdm2 network regulated by p14ARF is developed, based on the pinning control technique, which consists into applying local feedback controllers to a small number of nodes (pinned ones) in the network. Pinned nodes are selected on the basis of their importance level in a topological hierarchy, their degree of connectivity within the network, and the biological role they perform. In this paper, two cases are considered. For the first case, the oscillatory pattern under gamma-radiation is recovered; afterward, as the second case, increased expression of p53 level is taken into account. For both cases, the control law is applied to p14ARF (pinned node based on a virtual leader methodology), and overexpressed Mdm2-mediated p53 degradation condition is considered as carcinogenic initial behavior. The approach in this paper uses a computational algorithm, which opens an alternative path to understand the cellular responses to stress, doing it possible to model and control the gene regulatory network dynamics in two different biological contexts. As the main result of the proposed control technique, the two mentioned desired behaviors are obtained.
Reliable and efficient recording of the error-related negativity with a speeded Eriksen Flanker task
(2020)
There is accumulating evidence that the error-related negativity (ERN), an event-related potential elicited after erroneous actions, is altered in different psychiatric disorders and may help to guide treatment options. Thus, the ERN is a promising candidate as a psychiatric biomarker. Basic methodological requirements for a biomarker are standardized and reliable measurements. Additional psychiatry specific requirements are time efficiency and patient-friendliness.
The aim of the present study is to establish ERN acquisition in a reliable, time-efficient and patient-friendly way for use in clinical practice.
Healthy subjects (N=27) performed a modified Eriksen Flanker Task with adaptive reaction time window and only incongruent stimuli that maximizes the number of errors. All participants were tested for mental health by the Mini International Neuropsychiatric Interview (M.I.N.I.). The first N=12 subjects were part of a pilot study and further N=14 subjects were included for analysis (one subject was excluded due to technical problems). In a test-retest design with two sessions separated by 28 days the reliability of the ERN has been assessed. To ensure external validity, we aimed to replicate previously reported correlation patterns of ERN amplitude with (1) number of errors and (2) negative affect. State affect of each subject was measured by the Positive and Negative Affect Schedule. In order to optimize the clinical use of the task, we determined to which extent the task can be shortened while keeping reliability >0.80.
We found excellent reliability of the ERN (intraclass correlation coefficient =0.806-0.947) and replicated specific correlation patterns (ERN amplitude with relative number of errors: r=0.394; p=0.082; ERN amplitude with negative affect: r=-0.583, p=0.014). The task can be shortened to a patient-friendly and clinically feasible length of only 8 minutes keeping reliability >0.80.
To conclude, the present modified task provides reliable and efficient recording of the ERN, facilitating its use as a psychiatric biomarker.
This study was performed to identify Peronosclerospora species found in Indonesia based on sequence analysis of the cox2 gene. In addition, sequence data in total, 26 isolates of Peronosclerospora were investigated in this study. They were obtained from 7 provinces in Indonesia, namely Lampung, Jawa Timur, Jawa Barat, Sumatera Utara, Jawa Tengah, Yogyakarta, and Sulawesi Selatan. Sequence analysis of cox2 and phylogenetic inference were performed on all the 26 isolates. A set of primers developed in this study, PCOX2F and PCOX2R, was used for PCR amplification. Phylogenetic analyses showed that all the Indonesian isolates were divided into two groups. Group I contained 13 isolates; 9 isolates obtained from Lampung, 3 isolates from Sumatera Utara, and 1 isolate from Jawa Barat. Group II consisted of 13 isolates; 7 isolates from Jawa Timur, 2 isolates from Jawa Tengah, 1 isolate from Yogyakarta, and 3 isolates from Sulawesi Selatan. All the members of group I clustered with the ex-type sequence of P. australiensis. Meanwhile, all members of Group II formed the sister clade of isolates obtained from Timor-Leste and may represent P. maydis.
Introduction: Recommendations for venous thromboembolism and deep venous thrombosis (DVT) prophylaxis using graduated compression stockings (GCS) is historically based and has been critically examined in current publications. Existing guidelines are inconclusive as to recommend the general use of GCS.
Patients/Methods: 24 273 in-patients (general surgery and orthopedic patients) undergoing surgery between 2006 and 2016 were included in a retrospectively analysis from a single center. From January 2006 to January 2011 perioperative GCS was employed additionally to drug prophylaxis and from February 2011 to March 2016 patients received drug prophylaxis alone. According to german guidelines all patients received venous thromboembolism prophylaxis with weight-adapted LMWH. Risk stratification (low risk, moderate risk, high risk) was based on the guideline of the American College of Chest Physicians. Data analysis was performed before and after propensity matching (PM). The defined primary endpoint was the incidence of symptomatic or fatal pulmonary embolism (PE). A secondary endpoint was the incidence of deep venous thromboembolism (DVT).
Results: After risk stratification (low risk n = 16 483; moderate risk n = 4464; high risk n = 3326) a total of 24 273 patient were analyzed. Before to PM the relative risk for the occurrence of a PE or DVT was not increased by abstaining from GCS. After PM two groups of 11 312 patients each, one with and one without GCS application, were formed. When comparing the two groups, the relative risk (RR) for the occurrence of a pulmonary embolism was: Low Risk 0.99 [CI95% 0.998–1.000]; Moderate Risk 0.999 [CI95% 0.95–1.003]; High Risk 0.996 [CI95% 0.992–1.000] (p > 0.05). The incidence of PE in the total group LMWH alone was 0.1% (n = 16). In the total group using LMWH + GCS, the incidence was 0.3% (n = 29). RR after PM was 0.999 [CI95% 0.998–1.00].
Conclusion: In comparison to prior studies with only small numbers of patients our trial shows in a large group of patients with moderate and high risk developing VTE we can support the view that abstaining from GCS-use does not increase the incidence of symptomatic or fatal PE and symptomatic DVT.
A myriad of signaling molecules in a heuristic network of the tumor microenvironment (TME) pose a challenge and an opportunity for novel therapeutic target identification in human cancers. MicroRNAs (miRs), due to their ability to affect signaling pathways at various levels, take a prominent space in the quest of novel cancer therapeutics. The role of miRs in cancer initiation, progression, as well as in chemoresistance, is being increasingly investigated. The canonical function of miRs is to target mRNAs for post-transcriptional gene silencing, which has a great implication in first-order regulation of signaling pathways. However, several reports suggest that miRs also perform non-canonical functions, partly due to their characteristic non-coding small RNA nature. Examples emerge when they act as ligands for toll-like receptors or perform second-order functions, e.g., to regulate protein translation and interactions. This review is a compendium of recent advancements in understanding the role of miRs in cancer signaling and focuses on the role of miRs as novel regulators of the signaling pathway in the TME.