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Institute
Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.
Background: In the revision of the Diagnostic and Statistical Manual (DSM-5), "Identity" is an essential diagnostic criterion for personality disorders (self-related personality functioning) in the alternative approach to the diagnosis of personality disorders in Section III of DSM-5. Integrating a broad range of established identity concepts, AIDA (Assessment of Identity Development in Adolescence) is a new questionnaire to assess pathology-related identity development in healthy and disturbed adolescents aged 12 to 18 years. Aim of the present study is to investigate differences in identity development between adolescents with different psychiatric diagnoses.
Methods: Participants were 86 adolescent psychiatric in- and outpatients aged 12 to 18 years. The test set includes the questionnaire AIDA and two semi-structured psychiatric interviews (SCID-II, K-DIPS). The patients were assigned to three diagnostic groups (personality disorders, internalizing disorders, externalizing disorders). Differences were analyzed by multivariate analysis of variance MANOVA.
Results: In line with our hypotheses, patients with personality disorders showed the highest scores in all AIDA scales with T>70. Patients with externalizing disorders showed scores in an average range compared to population norms, while patients with internalizing disorders lay in between with scores around T=60. The AIDA total score was highly significant between the groups with a remarkable effect size of f= 0.44.
Conclusion: Impairment of identity development differs between adolescent patients with different forms of mental disorders. The AIDA questionnaire is able to discriminate between these groups. This may help to improve assessment and treatment of adolescents with severe psychiatric problems.
Targeting self-renewal and tumorigenicity has been proposed as a potential strategy against cancer stem cells (CSCs). Epigenetic proteins are key modulators of gene expression and cancer development contributing to regulation and maintenance of self-renewal and tumorigenicity. Here, we have screened a small-molecule epigenetic inhibitor library using 3D in vitro models in order to determine potential epigenetic targets associated with self-renewal and tumorigenicity in Canine Mammary Cancer (CMC) cells. We identified inhibition of BET proteins as a promising strategy to inhibit CMC colonies and tumorspheres formation. Low doses of (+)-JQ1 were able to downregulate important genes associated to self-renewal pathways such as WNT, NOTCH, Hedgehog, PI3K/AKT/mTOR, EGF receptor and FGF receptor in CMC tumorspheres. In addition, we observed downregulation of ZEB2, a transcription factor important for the maintenance of self-renewal in canine mammary cancer cells. Furthermore, low doses of (+)-JQ1 were not cytotoxic in CMC cells cultured in 2D in vitro models but induced G2/M cell cycle arrest accompanied by upregulation of G2/M checkpoint-associated genes including BTG2 and CCNG2. Our work indicates the BET inhibition as a new strategy for canine mammary cancers by modulating the self-renewal phenotype in tumorigenic cells such as CSCs.
A plethora of data has highlighted the role of epigenetics in the development of cancer. Initiation and progression of different cancer types are associated with a variety of changes of epigenetic mechanisms, including aberrant DNA methylation, histone modifications, and miRNA expression. At the same time, advances in the available epigenetic tools allow to investigate and reverse these epigenetic changes and form the basis for the development of anticancer drugs in human oncology. Although human and canine cancer shares several common features, only recently that studies emerged investigating the epigenetic landscape in canine cancer and applying epigenetic modulators to canine cancer. This review focuses on the existing studies involving epigenetic changes in different types of canine cancer and the use of small-molecule inhibitors in canine cancer cells.
Emotional instability, difficulties in social adjustment, and disinhibited behavior are the most common symptoms of the psychiatric comorbidities in juvenile myoclonic epilepsy (JME). This psychopathology has been associated with dysfunctions of mesial-frontal brain circuits. The present work is a first direct test of this link and adapted a paradigm for probing frontal circuits during empathy for pain. Neural and psychophysiological parameters of pain empathy were assessed by combining functional magnetic resonance imaging (fMRI) with simultaneous pupillometry in 15 JME patients and 15 matched healthy controls. In JME patients, we observed reduced neural activation of the anterior cingulate cortex (ACC), the anterior insula (AI), and the ventrolateral prefrontal cortex (VLPFC). This modulation was paralleled by reduced pupil dilation during empathy for pain in patients. At the same time, pupil dilation was positively related to neural activity of the ACC, AI, and VLPFC. In JME patients, the ACC additionally showed reduced functional connectivity with the primary and secondary somatosensory cortex, areas fundamentally implicated in processing the somatic cause of another's pain. Our results provide first evidence that alterations of mesial-frontal circuits directly affect psychosocial functioning in JME patients and draw a link of pupil dynamics with brain activity during emotional processing. The findings of reduced pain empathy related activation of the ACC and AI and aberrant functional integration of the ACC with somatosensory cortex areas provide further evidence for this network's role in social behavior and helps explaining the JME psychopathology and patients' difficulties in social adjustment.
Hepatitis Delta virus (HDV) is a satellite of Hepatitis B virus with a single-stranded circular RNA genome. HDV RNA genome synthesis is carried out in infected cells by cellular RNA polymerases with the assistance of the small hepatitis delta antigen (S-HDAg). Here we show that S-HDAg binds the bromodomain (BRD) adjacent to zinc finger domain 2B (BAZ2B) protein, a regulatory subunit of BAZ2B-associated remodeling factor (BRF) ISWI chromatin remodeling complexes. shRNA-mediated silencing of BAZ2B or its inactivation with the BAZ2B BRD inhibitor GSK2801 impairs HDV replication in HDV-infected human hepatocytes. S-HDAg contains a short linear interacting motif (SLiM) KacXXR, similar to the one recognized by BAZ2B BRD in histone H3. We found that the integrity of the S-HDAg SLiM sequence is required for S-HDAg interaction with BAZ2B BRD and for HDV RNA replication. Our results suggest that S-HDAg uses a histone mimicry strategy to co-activate the RNA polymerase II-dependent synthesis of HDV RNA and sustain HDV replication.
Rezensionen [2021]
(2021)
Verzeichnis
Einzelrezensionen
146 Benner, Julia/Schneider-Kempf, Barbara/Putjenter, Sigrun (Hg.): Schauplatz der Künste – Bild und Text im Kinderbuch. Festgabe
für Carola Pohlmann zum 60. Geburtstag (Claudia Blei-Hoch)
147 Conrad, Maren (Hg.): Moderne Märchen. Populäre Variationen in jugendkulturellen Literatur- und Medienformaten der Gegenwart (Ernst Seibert)
149 Dettmar, Ute/Roeder, Caroline/Tomkowiak, Ingrid (Hg.): Schnittstellen der Kinder- und Jugendmedienforschung. Aktuelle Positionen und Perspektiven (Nicola König)
151 Dettmar, Ute/Pecher, Claudia Maria/Anker, Martin (Hg.): Bilder zu»Klassikern« (Annette Kliewer)
152 Ewers, Hans-Heino (Hg.): Michael Ende. Zur Aktualität eines Klassikers von internationalem Rang (Thomas Boyken)
154 Frickel, Daniela A. /Kagelmann, Andre/Seidler, Andreas /Glasenapp, Gabriele von (Hg.): Kinder- und Jugendmedien im inklusiven Blick. Analytische und didaktische Perspektiven (Susanne Blumesberger)
156 Gansel, Carsten/Ächtler, Norman/KümmerlingMeibauer, Bettina (Hg.): Erzählen über Kindheit und Jugend in der Gegenwartsliteratur (Nadine Bieker)
158 Giuriato, Davide: Grenzenlose Bestimmbarkeit. Kindheiten in der Literatur der Moderne (Julia Boog-Kaminski)
160 Hodkinson, Owen/ Lovatt, Helen (Hg.): Classical Reception and Children’s Literature. Greece, Rome and Childhood Transformation
(Ludger Scherer)
162 Jantzen, Christoph/Ritter, Alexandra/Ritter, Michel (Hg.): Faszination Zauberwelt. Neue Perspektiven auf die Fantastik in Kinder- und Jugendmedien (Ernst Seibert)
164 Josting, Petra/Kruse, Iris (Hg.): Karen-Susan Fessel. Bielefelder Poet in Residence 2018 (Kirsten Kumschlies)
165 Kalbermatten, Manuela: »The match that lights the fire«. Gesellschaft und Geschlecht in Future-Fiction für Jugendliche (Sabine Planka)
167 Kurwinkel, Tobias /Norrick-Rühl, Corinna/ Schmerheim, Philipp (Hg.): Die Welt im Bild erfassen. Multidisziplinäre Perspektiven auf
das Bilderbuch (Sonja Müller-Carstens)
169 Kurwinkel, Tobias /Schmerheim, Philipp (Hg.): Handbuch Kinder- und Jugendliteratur. Unter Mitarbeit von Stefanie Jakobi
(Thomas Boyken)
171 Lexe, Heidi (Hg.): Time Warp und Taschenuhr. Zeit in der Kinder- und Jugendliteratur (Inger Lison)
173 Lötscher, Christine: Die Alice-Maschine. Figurationen der Unruhe in der Populärkultur (Astrid Henning-Mohr)
175 Marciniak, Katarzyna (Hg.): Chasing Mythical Beasts. The Reception of Ancient Monsters in Children’s and Young Adults’ Culture (Thomas Kullmann)
177 Oetken, Mareile/Vach, Karin/Weinkauff, Gina (Hg.): Klaus Ensikat, Stefanie Harjes, Susanne Janssen. Heidelberger Kinderliteraturgespräche 2017/18 (Heinz-Jürgen und Ursula Kliewer)
179 Schäfer, Iris (Hg.): Zur Ästhetik psychischer Krankheiten in kinder- und jugendliterarischen Medien. Psychoanalytische und tiefenpsychologische Analysen – transdisziplinär erweitert (Kirsten Kumschlies)
180 Stemmann, Anna: Räume der Adoleszenz. Deutschsprachige Jugendliteratur der Gegenwart in topographischer Perspektive (Sabine Planka)
Sammelrezensionen
182 Pugh, Tison: Harry Potter and Beyond. On J. K. Rowling’s Fantasies and Other Fictions Jarazo-Álvarez, Rubén/Alderete-Diez, Pilar (Hg.): Cultural Politics in Harry Potter. Life, Death and the Politics of Fear (Thomas Hardtke)
185 Clermont, Philippe/Henky, Danièle (Hg.):Transmédialités du conte Freeman, Matthew/Rampazzo Gambarato, Renira (Hg.): The Routledge Companion to Transmedia Studies (Ludger Scherer)
Objectives: There is promising evidence that mindfulness-based interventions are effective in reducing the symptoms of posttraumatic stress disorder (PTSD). However, until now, studies have often lacked a full clinical PTSD assessment, and interventions are often administered in addition to other interventions. This study examined the feasibility of mindfulness-based stress reduction (MBSR) as a standalone intervention in patients with PTSD who have experienced mixed traumatic events.
Method: Fourteen patients participated in 8 weeks of MBSR. The patients were assessed prior to treatment, post-treatment and at a 1-month follow-up through self-ratings (e.g., the Davidson Trauma Scale) and the Clinician-Administered PTSD Scale to determine the effects of the intervention. Furthermore, after the intervention, the patients participated in qualitative interviews regarding their experiences with MBSR and their ideas for future improvements.
Results: Nine patients finished the program, and these patients considered the exercises to be applicable and helpful. In the Clinician-Administered PTSD Scale, we found large effects regarding the reduction of PTSD symptoms among completers (Cohen's d = 1.2). In the Davidson Trauma Scale, the effect sizes were somewhat lower (Cohen's d = 0.6) but nevertheless confirmed the efficacy of MBSR in reducing PTSD symptoms. In the qualitative interviews, the patients reported an augmentation of wellbeing and improvement regarding the handling of difficult situations and more distance from the traumatic event.
Conclusion: Despite the large effects, the high dropout rates and the results of the post-treatment interviews suggest that the intervention should be better adapted to the needs of PTSD patients, e.g., by giving more information regarding the exercises and by including shorter exercises to manage acute distress.
The Kinase Chemogenomic Set (KCGS): an open science resource for kinase vulnerability identification
(2021)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Background: Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active ‘probe’ molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors. Here we describe the use of a high-content cellular immunofluorescence assay as a method for demonstrating target engagement in cells.
Results: A panel of assays for the Jumonji C subfamily of KDMs was developed to encompass all major branches of the JmjC phylogenetic tree. These assays compare compound activity against wild-type KDM proteins to a catalytically inactive version of the KDM, in which residues involved in the active-site iron coordination are mutated to inactivate the enzyme activity. These mutants are critical for assessing the specific effect of KDM inhibitors and for revealing indirect effects on histone methylation status. The reported assays make use of ectopically expressed demethylases, and we demonstrate their use to profile several recently identified classes of KDM inhibitors and their structurally matched inactive controls. The generated data correlate well with assay results assessing endogenous KDM inhibition and confirm the selectivity observed in biochemical assays with isolated enzymes. We find that both cellular permeability and competition with 2-oxoglutarate affect the translation of biochemical activity to cellular inhibition.
Conclusions: High-content-based immunofluorescence assays have been established for eight KDM members of the 2-oxoglutarate-dependent oxygenases covering all major branches of the JmjC-KDM phylogenetic tree. The usage of both full-length, wild-type and catalytically inactive mutant ectopically expressed protein, as well as structure-matched inactive control compounds, allowed for detection of nonspecific effects causing changes in histone methylation as a result of compound toxicity. The developed assays offer a histone lysine demethylase family-wide tool for assessing KDM inhibitors for cell activity and on-target efficacy. In addition, the presented data may inform further studies to assess the cell-based activity of histone lysine methylation inhibitors.