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Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness.
Numerous cell–cell and cell–matrix interactions within the bone marrow microenvironment enable the controlled lifelong self-renewal and progeny of hematopoietic stem and progenitor cells (HSPCs). On the cellular level, this highly mutual interaction is granted by cell adhesion molecules (CAMs) integrating differentiation, proliferation, and pro-survival signals from the surrounding microenvironment to the inner cell. However, cell–cell and cell–matrix interactions are also critically involved during malignant transformation of hematopoietic stem/progenitor cells. It has become increasingly apparent that leukemia-associated gene products, such as activated tyrosine kinases and fusion proteins resulting from chromosomal translocations, directly regulate the activation status of adhesion molecules, thereby directing the leukemic phenotype. These observations imply that interference with adhesion molecule function represents a promising treatment strategy to target pre-leukemic and leukemic lesions within the bone marrow niche. Focusing on myeloid leukemia, we provide a current overview of the mechanisms by which leukemogenic gene products hijack control of cellular adhesion to subsequently disturb normal hematopoiesis and promote leukemia development.
IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.
Background: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia.
Methods: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7–28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL.
Results: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects’ underlying diseases.
Conclusion: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation.
Trial registration: ClinicalTrials.gov identifier: NCT01716234
In this note, we first highlight different developments for banks under direct ECB supervision within the SSM that may prompt further investigation by supervisors. We find that banks that were weakly capitalized at the start of direct ECB supervision (1) still face elevated levels of non-performing loans, (2) are less cost-efficient and (3) reduced their share of subordinated debt financing over the last years. We then stress the importance of continuous and ongoing cost-benefit analysis regarding banking supervision in Europe. We also encourage processes to question existing supervisory practices to ensure a lean and efficient banking supervision. Finally, we underline the need of continuous and intensified coordination among regulatory bodies in the Banking Union since the efficacy of European bank supervision rests on its interplay with many different institutions.
This document was requested by the European Parliament's Committee on Economic and Monetary Affairs. It was originally published on the European Parliament’s webpage.
Nach der 2008 startenden Finanzmarktkrise sind Maßnahmen zur Regulierung und Stabilisierung der Finanzmärkte in das Zentrum der politischen und der gesellschaftlichen Aufmerksamkeit gerückt. Insbesondere die hohen fiskalischen Kosten der Staaten zur Stützung ihrer Bankensysteme sowie die volkswirtschaftlichen Kosten infolge des Einbruchs des Wirtschaftswachstums in den Jahren nach der Insolvenz der US Investmentbank Lehman Brothers hatten einen globalen Konsens über die Notwendigkeit neuer Regulierungsmaßnahmen zur Folge. Im Ergebnis wurden das internationale Regulierungswerk Basel III sowie weitere nationale Maßnahmen zur Stabilisierung des Finanzsektors neu konzipiert und in Europa im Wege einer in nationales Recht umzusetzenden Richtlinie (die Capital Require-ments Directive IV - CRD IV) sowie einer Verordnung (die Capital Requirements Regulation CRR, welche unmittelbar geltendes Recht darstellt) eingeführt.
Vor diesem Hintergrund analysiert das vorliegende interdisziplinäre Gutachten die Auswirkungen der Regulierungsmaßnahmen, die zwischen 2008 bis zu Beginn des Jahres 2018 umgesetzt wurden auf dem deutschen Finanzsektor.
In diesem explorativen Beitrag machen wir uns Gedanken über die Zukunft von Deutscher Bank und Commerzbank und entwickeln einen neuen Zugang zu dem Thema: Statt einer Fusion von DB und CB schlagen wir eine Teilfusion nur der Datenzentren vor – es entsteht auf diese Weise die Grundlage für eine Open Banking Plattform als „utility“, also als Betrieb im Eigentum der Nutzer, an der perspektivisch weitere Finanzinstitute teilnehmen können. Die über die Daten kooperierenden Institute bleiben mit Blick auf Produkte und Dienstleistungen unverändert Konkurrenten – „national champions“ entstehen auf diese Weise nicht. Aber es wird damit in Europa die Basis für einen erfolgversprechenden Wettbewerb mit den großen Datenplattformen aus USA und China (Facebook, Amazon, Alipay) gelegt, die früher oder später in den Finanzmarkt eindringen werden. Das von uns vorgeschlagene Modell einer offenen Datenplattform für Banken verhindert das Entstehen von „national champions“ und schützt damit auch das Kernanliegen der Bankenunion: Die Schaffung eines Finanzsystems, dessen Banken jede für sich ausscheiden können ohne eine systemische Krise auszulösen, und ohne den Steuerzahler zu einer Rettungsaktion zu zwingen