Refine
Year of publication
- 2017 (3204) (remove)
Document Type
- Article (1229)
- Part of Periodical (582)
- Part of a Book (303)
- Book (235)
- Doctoral Thesis (182)
- Review (160)
- Contribution to a Periodical (151)
- Working Paper (129)
- Report (112)
- Preprint (64)
Language
- English (1689)
- German (1396)
- Portuguese (44)
- Spanish (21)
- French (20)
- Multiple languages (16)
- Turkish (13)
- Ukrainian (2)
- Catalan (1)
- Hebrew (1)
Is part of the Bibliography
- no (3204) (remove)
Keywords
- taxonomy (65)
- Deutsch (60)
- Literatur (58)
- Financial Institutions (41)
- new species (40)
- Rezeption (28)
- Literaturwissenschaft (26)
- Fremdsprachenunterricht (24)
- Vergleichende Literaturwissenschaft (23)
- Banking Supervision (22)
Institute
- Medizin (381)
- Präsidium (285)
- Physik (236)
- Wirtschaftswissenschaften (215)
- Gesellschaftswissenschaften (196)
- Sustainable Architecture for Finance in Europe (SAFE) (163)
- Frankfurt Institute for Advanced Studies (FIAS) (115)
- Biowissenschaften (105)
- Neuere Philologien (105)
- Informatik (91)
Recently, Aumüller and Dietzfelbinger proposed a version of a dual-pivot Quicksort, called "Count", which is optimal among dual-pivot versions with respect to the average number of key comparisons required. In this master's thesis we provide further probabilistic analysis of "Count". We derive an exact formula for the average number of swaps needed by "Count" as well as an asymptotic formula for the variance of the number of swaps and a limit law. Also for the number of key comparisons the asymptotic variance and a limit law are identified. We also consider both complexity measures jointly and find their asymptotic correlation.
Binding free energy calculations that make use of alchemical pathways are becoming increasingly feasible thanks to advances in hardware and algorithms. Although relative binding free energy (RBFE) calculations are starting to find widespread use, absolute binding free energy (ABFE) calculations are still being explored mainly in academic settings due to the high computational requirements and still uncertain predictive value. However, in some drug design scenarios, RBFE calculations are not applicable and ABFE calculations could provide an alternative. Computationally cheaper end-point calculations in implicit solvent, such as molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations, could too be used if one is primarily interested in a relative ranking of affinities. Here, we compare MMPBSA calculations to previously performed absolute alchemical free energy calculations in their ability to correlate with experimental binding free energies for three sets of bromodomain–inhibitor pairs. Different MMPBSA approaches have been considered, including a standard single-trajectory protocol, a protocol that includes a binding entropy estimate, and protocols that take into account the ligand hydration shell. Despite the improvements observed with the latter two MMPBSA approaches, ABFE calculations were found to be overall superior in obtaining correlation with experimental affinities for the test cases considered. A difference in weighted average Pearson () and Spearman () correlations of 0.25 and 0.31 was observed when using a standard single-trajectory MMPBSA setup ( = 0.64 and = 0.66 for ABFE; = 0.39 and = 0.35 for MMPBSA). The best performing MMPBSA protocols returned weighted average Pearson and Spearman correlations that were about 0.1 inferior to ABFE calculations: = 0.55 and = 0.56 when including an entropy estimate, and = 0.53 and = 0.55 when including explicit water molecules. Overall, the study suggests that ABFE calculations are indeed the more accurate approach, yet there is also value in MMPBSA calculations considering the lower compute requirements, and if agreement to experimental affinities in absolute terms is not of interest. Moreover, for the specific protein–ligand systems considered in this study, we find that including an explicit ligand hydration shell or a binding entropy estimate in the MMPBSA calculations resulted in significant performance improvements at a negligible computational cost.
The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation are promising targets to regulate tumor development. Bromodomains act as epigenetic readers by recognizing lysine acetylation on histone tails and boosting gene expression in order to regulate tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), we showed that RSV at 100 µM increased the melting temperature (∆Tm) of BET bromodomains by around 2.0 °C. The micromolar dissociation constant (Kd) range was characterized using Isothermal Titration Calorimetry (ITC). The RSV Kd value accounted to 6.6 µM in case of BRD4(1). Molecular docking proposed the binding mode of RSV against BRD4(1) mimicking the acetyl-lysine interactions. All these results suggest that RSV can also recognize epigenetic readers domains by interacting with BET bromodomains.
Die Reihe „Papers of Excellence 2.0: Ausgewählte Arbeiten aus den Fachdidaktiken und Bildungswissenschaften der Goethe-Universität Frankfurt a.M.“ ist eine neue, erweiterte und zusätzliche Auflage der bekannten Reihe „Papers of Excellence: Ausgewählte Arbeiten aus den Fachdidaktiken“, welche seit 2010 von Daniela Elsner und Anja Wildemann im Shaker-Verlag herausgegeben wird. In alter Tradition werden auch in der ab sofort zusätzlich zur Printausgabe erscheinenden Online Version dieser Buchreihe herausragende Examens- und Masterarbeiten, die sich durch eine ausgewiesene empirische, fachdidaktische Auseinandersetzung mit einem Thema auszeichnen, zusammenfassend vorgestellt. Neu ist, dass die Online Version nun auch Arbeiten mit einem bildungswissenschaftlichen Fokus aufnimmt und solche, die an der Schnittstelle zwischen Fachdidaktik und Bildungswissenschaften an-gelegt sind. Die Papers of Excellence 2.0, die derzeit nur Studien integriert, die an der Goethe Universität Frankfurt am Main angefertigt wurden, werden von Astrid Jurecka (Bildungswissenschaften) und Daniela Elsner (Fachdidaktik) herausgegeben und sind kostenfrei zugänglich.
BRAF V600E mutations occur frequently in malignant melanoma, but are rare in most malignant glioma subtypes. Besides, more benign brain tumors such as ganglioglioma, dysembryoblastic neuroepithelial tumours and supratentorial pilocytic astrocytomas, only pleomorphic xanthoastrocytomas (50-78%) and epitheloid glioblastoma (50%) regularly exhibit BRAF mutations. In the present study, we report on three patients with recurrent malignant gliomas harbouring a BRAF V600E mutation. All patients presented with markedly disseminated leptomeningeal disease at recurrence and had progressed after radiotherapy and alkylating chemotherapy. Therefore, estimated life expectancy at recurrence was a few weeks. All three patients received dabrafenib as a single agent and all showed a complete or nearly complete response. Treatment is ongoing and patients are stable for 27 months, 7 months and 3 months, respectively. One patient showed a dramatic radiologic and clinical response after one week of treatment. We were able to generate an ex vivo tumor cell culture from CSF in one patient. Treatment of this cell culture with dabrafenib resulted in reduced cell density and inhibition of ERK phosphorylation in vitro. To date, this is the first series on adult patients with BRAF-mutated malignant glioma and leptomeningeal dissemination treated with dabrafenib monotherapy. All patients showed a dramatic response with one patient showing an ongoing response for more than two years.
We explored the characteristics and motivations of people who, having obtained their genetic or genomic data from Direct-To-Consumer genetic testing (DTC-GT) companies, voluntarily decide to share them on the publicly accessible web platform openSNP. The study is the first attempt to describe open data sharing activities undertaken by individuals without institutional oversight. In the paper we provide a detailed overview of the distribution of the demographic characteristics and motivations of people engaged in genetic or genomic open data sharing. The geographical distribution of the respondents showed the USA as dominant. There was no significant gender divide, the age distribution was broad, educational background varied and respondents with and without children were equally represented. Health, even though prominent, was not the respondents’ primary or only motivation to be tested. As to their motivations to openly share their data, 86.05% indicated wanting to learn about themselves as relevant, followed by contributing to the advancement of medical research (80.30%), improving the predictability of genetic testing (76.02%) and considering it fun to explore genotype and phenotype data (75.51%). Whereas most respondents were well aware of the privacy risks of their involvement in open genetic data sharing and considered the possibility of direct, personal repercussions troubling, they estimated the risk of this happening to be negligible. Our findings highlight the diversity of DTC-GT consumers who decide to openly share their data. Instead of focusing exclusively on health-related aspects of genetic testing and data sharing, our study emphasizes the importance of taking into account benefits and risks that stretch beyond the health spectrum. Our results thus lend further support to the call for a broader and multi-faceted conceptualization of genomic utility.
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
El libro Serve the Power(s), Serve the State, editado por los historiadores Juan Carlos Garavaglia, Michael Braddick y Christian Lamouroux en el año 2016, es una apuesta por estudiar sistemáticamente la historia del Estado y de aproximarse a nuevas y diversas lecturas historiográficas al tema, el cual ha ocupado un lugar importante en las reflexiones académicas de las últimas décadas. Esta preocupación por el Estado y su proceso de formación, no sólo ha sido objeto de reflexión desde la Historia, sino además, desde otras disciplinas como la Ciencia Política, la Sociología y la Antropología, entre otras. Así, esta publicación en la que participan quince diferentes autores, con diferentes trayectorias e intereses, surge de la Conferencia Internacional llevada a cabo en el 2011 en la Universidad Pompeu Fabra en Barcelona, la cual estuvo fundada en la reflexión sobre el Estado como problema y objeto de estudio desde una perspectiva histórica. ...
Zeitgenossen und Nachfolger Wagners griffen die von ihm selbst akzeptierte Inszenierungsstrategie als nationaler Kulturheros auf. Wagners "außerordentliche Verflechtung mit der deutschen Geschichte" war von ihm selbst beabsichtigt und vom Ehrgeiz bestimmt, "mit seinem Werk an der Nationwerdung der Deutschen im 19. Jahrhundert mitzuwirken. Dies ist ihm in einem Ausmaß gelungen, wie es bei keiner anderen Gestalt der deutschen Kulturgeschichte seit Luther festzustellen ist." Das Wagnersche Werk wie seine Selbstinszenierungen wurzeln sowohl in der europäischen Moderne als auch im spezifisch deutschen kulturell-politischen Kontext des 19. und frühen 20. Jahrhunderts. Beide Bereiche verraten allerdings eine gewisse interne Brüchigkeit, wie sie schon Adorno als Wagners Grundmerkmal diagnostiziert hatte. Er konstatierte eine den Wagnerschen künstlerisch-theatralischen und politisch-selbstrepräsentativen Gesten inhärente Tendenz zur Selbstde(kon)struktion. Nachfolgend wird diese Brüchigkeit analysiert, die sich in die Produktionsbedingungen seiner als heroische Kulturtaten konstruierten Werke eingeschrieben hat.
Obwohl mit dem "Personenkult" um Josef Stalin (1878−1953) vor allem die Inszenierungen seiner Macht und sein Führungsstil bezeichnet werden, ging der Kult um seine Person über den Rahmen des Politischen hinaus: Stalin wurde mit der Zeit zunehmend zu einer kulturstiftenden Figur, ja gar zu einem kulturellen Symbol stilisiert, das eine ganze Epoche prägte. Wenn überhaupt von einem "Gesamtkunstwerk Stalin" (Boris Groys) die Rede sein kann, dann bezeichnet dieser Begriff gleichermaßen die Epoche Stalins wie ihren Hauptprotagonisten, dessen Selbstinszenierungen als ein Kulturphänomen, ein 'Kunstwerk' der Zeit betrachtet werden können. In diesem "Gesamtkunstwerk" erscheint er sowohl als ein demiurgischer Herrscher als auch als ein prometheischer Heros - als Befreier und Kulturstifter. Der "Führer", der die sowjetischen Völker zum Siege führt, ist zugleich der "Lehrer", der lehrt was richtig und was falsch ist. [...] Er ist eine Figur der Revolution, berufen, sein Land aus dem Chaos zu führen und eine neue Ordnung herzustellen. Diese neue Ordnung reicht über das Machtpolitische hinaus ins Kulturelle: Der revolutionäre Heros ist ein Kulturstifter, dessen Mission eine prometheische Tat, und zwar die Erschaffung eines neuen Menschen ist. Die Herrscher, die als Kulturheroen inszeniert werden, sind vor allem nationale Heroen und werden mit einer Nation identifiziert, die sie vertreten. Im Falle Stalins ist dieses Modell komplizierter, denn er steht an der Spitze des Vielvölkerstaates, der sich als eine "Völkerfamilie" darstellt. Daher muss er als Heros für alle Völker der UdSSR gleichermaßen gelten. Zugleich ist er aber ein Georgier und diese Tatsache beschert seinem Geburtsland eine symbolische Sonderstellung, sie verleiht Stalin als kulturheroischer Figur gewissermaßen zwei Gesichter: das allgemeinsowjetische und das national-georgische.
Exposure to community violence through witnessing or being directly victimized has been associated with conduct problems in a range of studies. However, the relationship between community violence exposure (CVE) and conduct problems has never been studied separately in healthy individuals and individuals with conduct disorder (CD). Therefore, it is not clear whether the association between CVE and conduct problems is due to confounding factors, because those with high conduct problems also tend to live in more violent neighborhoods, i.e., an ecological fallacy. Hence, the aim of the present study was: (1) to investigate whether the association between recent CVE and current conduct problems holds true for healthy controls as well as adolescents with a diagnosis of CD; (2) to examine whether the association is stable in both groups when including effects of aggression subtypes (proactive/reactive aggression), age, gender, site and socioeconomic status (SES); and (3) to test whether proactive or reactive aggression mediate the link between CVE and conduct problems. Data from 1178 children and adolescents (62% female; 44% CD) aged between 9 years and 18 years from seven European countries were analyzed. Conduct problems were assessed using the Kiddie-Schedule of Affective Disorders and Schizophrenia diagnostic interview. Information about CVE and aggression subtypes was obtained using self-report questionnaires (Social and Health Assessment and Reactive-Proactive aggression Questionnaire (RPQ), respectively). The association between witnessing community violence and conduct problems was significant in both groups (adolescents with CD and healthy controls). The association was also stable after examining the mediating effects of aggression subtypes while including moderating effects of age, gender and SES and controlling for effects of site in both groups. There were no clear differences between the groups in the strength of the association between witnessing violence and conduct problems. However, we found evidence for a ceiling effect, i.e., individuals with very high levels of conduct problems could not show a further increase if exposed to CVE and vice versa. Results indicate that there was no evidence for an ecological fallacy being the primary cause of the association, i.e., CVE must be considered a valid risk factor in the etiology of CD.
Callous-unemotional traits are characterized by a lack of empathy, a disregard for others' feelings and shallow or deficient affect, such as a lack of remorse or guilt. Neuroanatomical correlates of callous-unemotional traits have been demonstrated in clinical samples (i.e., adolescents with disruptive behavior disorders). However, it is unknown whether callous-unemotional traits are associated with neuroanatomical correlates within normative populations without clinical levels of aggression or antisocial behavior. Here we investigated the relationship between callous-unemotional traits and gray matter volume using voxel-based morphometry in a large sample of typically-developing boys and girls (N = 189). Whole-brain multiple regression analyses controlling for site, total intracranial volume, and age were conducted in the whole sample and in boys and girls individually. Results revealed that sex and callous-unemotional traits interacted to predict gray matter volume when considering the whole sample. This interaction was driven by a significant positive correlation between callous-unemotional traits and bilateral anterior insula volume in boys, but not girls. Insula gray matter volume explained 19% of the variance in callous-unemotional traits for boys. Our results demonstrate that callous-unemotional traits are related to variations in brain structure beyond psychiatric samples. This association was observed for boys only, underlining the importance of considering sex as a factor in future research designs. Future longitudinal studies should determine whether these findings hold over childhood and adolescence, and whether the neuroanatomical correlates of callous-unemotional traits are predictive of future psychiatric vulnerability.
The release of RNA-containing extracellular vesicles (EV) into the extracellular milieu has been demonstrated in a multitude of different in vitro cell systems and in a variety of body fluids. RNA-containing EV are in the limelight for their capacity to communicate genetically encoded messages to other cells, their suitability as candidate biomarkers for diseases, and their use as therapeutic agents. Although EV-RNA has attracted enormous interest from basic researchers, clinicians, and industry, we currently have limited knowledge on which mechanisms drive and regulate RNA incorporation into EV and on how RNA-encoded messages affect signalling processes in EV-targeted cells. Moreover, EV-RNA research faces various technical challenges, such as standardisation of EV isolation methods, optimisation of methodologies to isolate and characterise minute quantities of RNA found in EV, and development of approaches to demonstrate functional transfer of EV-RNA in vivo. These topics were discussed at the 2015 EV-RNA workshop of the International Society for Extracellular Vesicles. This position paper was written by the participants of the workshop not only to give an overview of the current state of knowledge in the field, but also to clarify that our incomplete knowledge – of the nature of EV(-RNA)s and of how to effectively and reliably study them – currently prohibits the implementation of gold standards in EV-RNA research. In addition, this paper creates awareness of possibilities and limitations of currently used strategies to investigate EV-RNA and calls for caution in interpretation of the obtained data.
Androgen receptor deregulation drives bromodomain-mediated chromatin alterations in prostate cancer
(2017)
Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.
Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity. Treatment with these inhibitors inhibited SRPK1 activity and phosphorylation of serine/arginine splicing factor 1 (SRSF1), resulting in alternative splicing of VEGF-A from pro-angiogenic to antiangiogenic isoforms. This property resulted in potent inhibition of blood vessel growth in models of choroidal angiogenesis in vivo. This work identifies tool compounds for splice isoform selective targeting of pro-angiogenic VEGF, which may lead to new therapeutic strategies for a diversity of diseases where dysfunctional splicing drives disease development.
NEK family kinases are serine/threonine kinases that have been functionally implicated in the regulation of the disjunction of the centrosome, the assembly of the mitotic spindle, the function of the primary cilium and the DNA damage response. NEK1 shows pleiotropic functions and has been found to be mutated in cancer cells, ciliopathies such as the polycystic kidney disease, as well as in the genetic diseases short-rib thoracic dysplasia, Mohr-syndrome and amyotrophic lateral sclerosis. NEK1 is essential for the ionizing radiation DNA damage response and priming of the ATR kinase and of Rad54 through phosphorylation. Here we report on the structure of the kinase domain of human NEK1 in its apo- and ATP-mimetic inhibitor bound forms. The inhibitor bound structure may allow the design of NEK specific chemo-sensitizing agents to act in conjunction with chemo- or radiation therapy of cancer cells. Furthermore, we characterized the dynamic protein interactome of NEK1 after DNA damage challenge with cisplatin. Our data suggest that NEK1 and its interaction partners trigger the DNA damage pathways responsible for correcting DNA crosslinks.