Induktion von Apoptose und Signaltransduktion in leukämischen Zellen unter Tyrosinkinase-Inhibitor-Behandlung

Magdeburg, Univ., Fak. für Naturwiss., Diss., 2012von Marie-Christine Wagne

Qualitätsmanagement Lehrveranstaltungen : Empfehlungen für Konzipierung, Etablierung, Durchführung und Verwendung von Evaluationen

Um institutionell akkreditiert zu werden, müssen Hochschulen in der Schweiz die Qualitätsstandards für die institutionelle Akkreditierung der Richtlinien des Hochschulrates für die Akkreditierung im Hochschulbereich (Akkreditierungsrichtlinien HFKG, 2015) erfüllen. Mit der institutionellen Akkreditierung sind insbesondere das Bezeichnungsrecht „Universität“, „Fachhochschule“ oder „Pädagogische Hochschule“ und die Gewährung von Bundesbeiträgen verbunden. Die Qualitätsstandards für die institutionelle Akkreditierung sind auf einem relativ hohen Abstraktionsniveau formuliert, um einen Rahmen für das Qualitätsmanagement verschiedener Hochschulen und Hochschuleinheiten sowie Hochschultätigkeiten mit ihren charakteristischen Merkmalen und Bedingungen bieten zu können. Zweck dieses Dokuments ist es, die Qualitätsstandards für die institutionelle Akkreditierung auf das Qualitätsmanagement von Lehrveranstaltungen auszuführen. Zudem werden die Qualitätsstandards um die Evaluationsstandards der Schweizerischen Evaluationsgesellschaft (SEVAL, 2016) ergänzt. Die Evaluationsstandards bieten eine Grundlage und Hilfestellung für die Planung und Durchführung von professionellen Evaluationen

Adults with autism spectrum condition have atypical perception of ambiguous figures when bottom-up and top-down interactions are incongruous.

We examined the perception of an ambiguous squares stimulus evoking bistable perception in a sample of 31 individuals with autistic spectrum condition and 22 matched typical adults. The perception of the ambiguous figure was manipulated by adaptation to unambiguous figures and/or by placing the ambiguous figure into a context of unambiguous figures. This resulted in four conditions testing the independent and combined (congruent and incongruent) manipulations of adaptation (bottom-up) and spatial context (top-down) effects. The strength of perception, as measured by perception of the first reported orientation of the ambiguous stimulus, was affected comparably between groups. Nevertheless, the strength of perception, as measured by perceptual durations, was affected differently between groups: the perceptual effect was strongest for the autistic spectrum condition group when combined bottom-up and top-down conditions were congruent. In contrast, the strength of the perceptual effect in response to the same condition in the typical adults group was comparable to the adaptation, but stronger than both the context and the incongruent combined bottom-up and top-down conditions. Furthermore, the context condition was stronger than the incongruent combined bottom-up and top-down conditions for the typical adults group. Thus, our findings support the view of stimulus-specific top-down modulation in autistic spectrum condition

Reynolds number and humidity dependency of dropwise condensation in moist convective air flows

In moist air flows with phase transition is the convective flow strongly influenced by the sensible and the latent heat transfer. Additionally, the droplet shape (contact angle), the surface properties and the spatial distribution of the droplets also have a strong influence. Hence, empirical models or numerical calculations often fail to predict the heat and mass transfer due to the large number of parameters and the mutual interplay of the different heat transport mechanisms. To obtain a reliable prediction of the mass and the heat transfer, time-consuming and cost-intensive experiments or computationally expensive numerical simulations are necessary. Neither is feasible in the development and design process for industrial applications. It would be too costly and time consuming. Therefore, the method of predicting the droplet size distribution and the corresponding heat transfer by means of a scalar model is of vital interest. To overcome this issue we have been developing a prediction model based on the scaling of system characteristic numbers. Part of this approach is to investigate the effect of large-scale flow structures on the dynamics of the droplet size distribution and the corresponding sensible heat transfer and the condensation mass transfe

Rapid progression of prostate cancer in men with a BRCA2 mutation.

Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P<0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation

The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development

Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD. We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme. To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics. Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community's chances of successfully bringing new rare disease drugs to registration and ultimately to marke

Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in neuroanatomical phenotypes and unveils a male-specific role for the major vault protein

Background Using mouse genetic studies and systematic assessments of brain neuroanatomical phenotypes, we set out to identify which of the 30 genes causes brain defects at the autism-associated 16p11.2 locus. Results We show that multiple genes mapping to this region interact to regulate brain anatomy, with female mice exhibiting far fewer brain neuroanatomical phenotypes. In male mice, among the 13 genes associated with neuroanatomical defects (Mvp, Ppp4c, Zg16, Taok2, Slx1b, Maz, Fam57b, Bola2, Tbx6, Qprt, Spn, Hirip3, and Doc2a), Mvp is the top driver implicated in phenotypes pertaining to brain, cortex, hippocampus, ventricles, and corpus callosum sizes. The major vault protein (MVP), the main component of the vault organelle, is a conserved protein found in eukaryotic cells, yet its function is not understood. Here, we find MVP expression highly specific to the limbic system and show that Mvp regulates neuronal morphology, postnatally and specifically in males. We also recapitulate a previously reported genetic interaction and show that Mvp+/−;Mapk3+/− mice exhibit behavioral deficits, notably decreased anxiety-like traits detected in the elevated plus maze and open field paradigms. Conclusions Our study highlights multiple gene drivers in neuroanatomical phenotypes, interacting with each other through complex relationships. It also provides the first evidence for the involvement of the major vault protein in the regulation of brain size and neuroanatomy, specifically in male mice

Microbiome definition re-visited: old concepts and new challenges

peer-reviewedAbstract The field of microbiome research has evolved rapidly over the past few decades and has become a topic of great scientific and public interest. As a result of this rapid growth in interest covering different fields, we are lacking a clear commonly agreed definition of the term “microbiome.” Moreover, a consensus on best practices in microbiome research is missing. Recently, a panel of international experts discussed the current gaps in the frame of the European-funded MicrobiomeSupport project. The meeting brought together about 40 leaders from diverse microbiome areas, while more than a hundred experts from all over the world took part in an online survey accompanying the workshop. This article excerpts the outcomes of the workshop and the corresponding online survey embedded in a short historical introduction and future outlook. We propose a definition of microbiome based on the compact, clear, and comprehensive description of the term provided by Whipps et al. in 1988, amended with a set of novel recommendations considering the latest technological developments and research findings. We clearly separate the terms microbiome and microbiota and provide a comprehensive discussion considering the composition of microbiota, the heterogeneity and dynamics of microbiomes in time and space, the stability and resilience of microbial networks, the definition of core microbiomes, and functionally relevant keystone species as well as co-evolutionary principles of microbe-host and inter-species interactions within the microbiome. These broad definitions together with the suggested unifying concepts will help to improve standardization of microbiome studies in the future, and could be the starting point for an integrated assessment of data resulting in a more rapid transfer of knowledge from basic science into practice. Furthermore, microbiome standards are important for solving new challenges associated with anthropogenic-driven changes in the field of planetary health, for which the understanding of microbiomes might play a key role. Video Abstrac

Fgf9 and Wnt4 Act as Antagonistic Signals to Regulate Mammalian Sex Determination

The genes encoding members of the wingless-related MMTV integration site (WNT) and fibroblast growth factor (FGF) families coordinate growth, morphogenesis, and differentiation in many fields of cells during development. In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination. Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads. However, the relationship between these signals and the male sex-determining gene, Sry, was unknown. We show through gain- and loss-of-function experiments that fibroblast growth factor 9 (FGF9) and WNT4 act as opposing signals to regulate sex determination. In the mouse XY gonad, Sry normally initiates a feed-forward loop between Sox9 and Fgf9, which up-regulates Fgf9 and represses Wnt4 to establish the testis pathway. Surprisingly, loss of Wnt4 in XX gonads is sufficient to up-regulate Fgf9 and Sox9 in the absence of Sry. These data suggest that the fate of the gonad is controlled by antagonism between Fgf9 and Wnt4. The role of the male sex-determining switch— Sry in the case of mammals—is to tip the balance between these underlying patterning signals. In principle, sex determination in other vertebrates may operate through any switch that introduces an imbalance between these two signaling pathways