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Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
Folgender Aufsatz analysiert die verschiedenen Bedeutungsebenen der Form und Funktion von Erzählung in Johann Wolfgang von Goethes „Reineke Fuchs“. Primäre Bezugspunkte des Reimversepos sind Homers „Ilias“ und Gottscheds „Reineke Fuchs“. Besonders augenfällig ist die Bedeutung der Inter- und Intratextualität in Goethes Text. Die Erzählungen des Protagonisten Reineke besitzen mindestens vier verschiedene Funktionen, welche sowohl das Wohlergehen von Reineke als auch die Interaktion zwischen Erzähler und Hörer umfassen. Ein weiterer wesentlicher Gesichtspunkt von Goethes Epos ist der Zusammenhang zwischen Leben und Dichtung. Ebenso werden die Fragen der sozialen Ordnung und Stabilität im Hinblick auf eine gelungene Individuation des Einzelnen thematisiert.
Die Analyse von E.T.A. Hoffmanns Erzählung Der Magnetiseur (1814) will textimmanente Komponenten mit kontextanalytischen Teilen verbinden. Die textimmanente Analyse umfasst konventionelle erzähltextanalytische Fragen wie z.B. diejenigen nach den Erzählsituationen und der Figurenanlage und Figurenkonstellation. Der Magnetiseur ist in der Forschung eher marginal behandelt worden, vielleicht nicht zuletzt, weil Der Magnetiseur hinsichtlich des Merkmals der Poetizität als eher minderwertig eingeschätzt wurde. So finden sich in der Sekundärliteratur auch häufig eher vereinzelte Hinweise über die Komposition und das Thema des Kunstwerks Der Magnetiseur. Eine kohärente, nach literaturwissenschaftlichen Maßstäben vorgenommene Gesamtinterpretation, welche auch kontextuelle Fragen berücksichtigt, steht noch aus. Die rein textimmanent verfahrende Analyse sollte aber, um den wünschenswerten Analyseertrag zu erbringen, durch eine Kontext-Analyse ergänzt werden, welche um den Themenbereich des Mesmerismus bzw. Magnetismus und der Traumforschung der Anthropologie der Romantik kreist. Ein innovativer Aspekt des Aufsatzes liegt demnach darin, dass dezidiert und en detail ein wesentliches Element des Kontextes der Hoffmann-Erzählung in die Analyse einbezogen wird. Der angesprochene Kontext besteht aus Schuberts Magnetismus-Theorie, welche Hoffmann nachweislich bekannt war und ihm in schriftlicher Form vorgelegen hat. Die hier vorgenommene Kontext-Analyse berücksichtigt folglich Schuberts wissenschaftliche Arbeiten zum Thema des Magnetismus, bezieht sie auf den Hoffmann’schen Text und zeichnet sich somit für einen guten Teil der Gesamtinterpretation verantwortlich.
Der folgende Beitrag beschäftigt sich mit Wim Wenders Film Hammett, wobei die im Film aufgeworfene Frage der Überlappung zwischen fikti-ver und realer Identität des amerikanischen Schriftstellers und Pinkerton-Detektivs Hammett fokussiert wird. Thematisiert wird die Künstlerprob-lematik in einem „Kunstwerk“ bzw. Kunstwerken. Denn Wim Wenders Filmkunstwerk Hammett handelt von einem Schriftsteller, der sich in ei-nem künstlerischen Produktionsprozess befindet. Müsste man dieses Phänomen mit einem Schlagwort zusammenfassen, dann könnte man von einer im Film und Hammetts Literatur auftauchenden und themati-sierten „Selbstreflexivität der Kunst“ sprechen. Ein wesentliches Thema im Wenderschen Schaffen, die Selbstreflexivität der Kunst, wird also im Film Hammett in den Mittelpunkt gerückt. In diesem Punkt ist ein gravie-render Unterschied zu den meisten anderen Filmen von Wim Wenders festzustellen: wird dort nur über das Medium des Films selbst reflektiert, so wird in Hammett der Produktionsprozess der erzählenden Kunst her-ausgestellt. Zu diesem Thema gehören auch im filmischen Medium die Aspekte der Inter- und Intratextualität. Im Zuge des Booms kulturwis-senschaftlicher Ansätze käme heute ggf. eine andere Terminologie zur Anwendung, man müsste von inner- und außerliterarischen bzw. –künstlerischen Kontexten zu Film und Texten sprechen.
Numerous studies reported a strong link between working memory capacity (WMC) and fluid intelligence (Gf), although views differ in respect to how close these two constructs are related to each other. In the present study, we used a WMC task with five levels of task demands to assess the relationship between WMC and Gf by means of a new methodological approach referred to as fixed-links modeling. Fixed-links models belong to the family of confirmatory factor analysis (CFA) and are of particular interest for experimental, repeated-measures designs. With this technique, processes systematically varying across task conditions can be disentangled from processes unaffected by the experimental manipulation. Proceeding from the assumption that experimental manipulation in a WMC task leads to increasing demands on WMC, the processes systematically varying across task conditions can be assumed to be WMC-specific. Processes not varying across task conditions, on the other hand, are probably independent of WMC. Fixed-links models allow for representing these two kinds of processes by two independent latent variables. In contrast to traditional CFA where a common latent variable is derived from the different task conditions, fixed-links models facilitate a more precise or purified representation of the WMC-related processes of interest. By using fixed-links modeling to analyze data of 200 participants, we identified a non-experimental latent variable, representing processes that remained constant irrespective of the WMC task conditions, and an experimental latent variable which reflected processes that varied as a function of experimental manipulation. This latter variable represents the increasing demands on WMC and, hence, was considered a purified measure of WMC controlled for the constant processes. Fixed-links modeling showed that both the purified measure of WMC (β = .48) as well as the constant processes involved in the task (β = .45) were related to Gf. Taken together, these two latent variables explained the same portion of variance of Gf as a single latent variable obtained by traditional CFA (β = .65) indicating that traditional CFA causes an overestimation of the effective relationship between WMC and Gf. Thus, fixed-links modeling provides a feasible method for a more valid investigation of the functional relationship between specific constructs.
The article reports three simulation studies conducted to find out whether the effect of a time limit for testing impairs model fit in investigations of structural validity, whether the representation of the assumed source of the effect prevents impairment of model fit and whether it is possible to identify and discriminate this method effect from another method effect. Omissions due to the time limit for testing were not considered as missing data but as information on the participants’ processing speed. In simulated data the presence of a time-limit effect impaired comparative fit index and nonnormed fit index whereas normed chi-square, root mean square error of approximation, and standardized root mean square residual indicated good model fit. The explicit consideration of the effect due to the time limit by an additional component of the model improved model fit. Effect-specific assumptions included in the model of measurement enabled the discrimination of the effect due to the time limit from another possible method effect.
The paper outlines a method for investigating the speed effect due to a time limit in testing. It is assumed that the time limit enables latent processing speed to influence responses by causing omissions in the case of insufficient speed. Because of processing speed as additional latent source, the customary confirmatory factor model is enlarged by a second latent variable representing latent processing speed. For distinguishing this effect from other method effects, the factor loadings are fixed according to the cumulative normal distribution. With the second latent variable added, confirmatory factor analysis of reasoning data (N=518) including omissions because of a time limit yielded good model fit and discriminated the speed effect from other possible effects due to the item difficulty, the homogeneity of an item subset and the item positions. Because of the crucial role of the cumulative normal distribution for fixing the factor loadings a check of the normality assumption is also reported.
Can variances of latent variables be scaled in such a way that they correspond to eigenvalues?
(2017)
The paper reports an investigation of whether sums of squared factor loadings obtained in confirmatory factor analysis correspond to eigenvalues of exploratory factor analysis. The sum of squared factor loadings reflects the variance of the corresponding latent variable if the variance parameter of the confirmatory factor model is set equal to one. Hence, the computation of the sum implies a specific type of scaling of the variance. While the investigation of the theoretical foundations suggested the expected correspondence between sums of squared factor loadings and eigenvalues, the necessity of procedural specifications in the application, as for example the estimation method, revealed external influences on the outcome. A simulation study was conducted that demonstrated the possibility of exact correspondence if the same estimation method was applied. However, in the majority of realized specifications the estimates showed similar sizes but no correspondence.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.