Affectivity and Relational Awareness in Pedagogy and Education: moments of hesitation in intersubjective encounters

In this article, we put forward the concept ‘relational awareness’ to describe a conscious awareness of the experience of relational responsivity and dynamics of change in stressful intersubjective encounters in pedagogy and education. This concept is inspired by phenomenology and cultural-historical theory. We introduce the theories of extended affectivity, embodied resonance and intersubjectivity and relate these to cultural-historical psychology in order to explore how people appraise and understand situations related to societal goals, motives, practices and mediating means. Relational awareness, which involves being consciously aware of embodied, pre-reflective relational responsivity, is specific to the cultural context, to the mediating means, and the lived experiences of the person. Relational awareness and responsivity can be objects of reflection and education when educational practices include deliberate work on embodied experience and mediational means to reflect on and change experienced intercorporeity. Relational awareness differs from interpersonal perception in that it involves embodied activity mediated by embodied knowledge and social means of language and discourse.Our conceptualisation of relational awareness is empirically driven by two qualitative studies of preschool teachers’ and teachers’ embodied practices to become presently aware during intersubjective encounters with children in stressful everyday conditions. The embodied practices in the study were inspired by exercises in mindfulness and compassion, which were adjusted according to how the participants experienced their significance. The flexibly adjusted exercises and discourses appeared to provide participants with the mediational embodied and discoursive means to become relationally aware in difficult encounters. Biesta’s conceptualisation of ‘moments of hesitation’ contributes to the discussion of ‘relational awareness’ in education and care

Transforming growth factor-β in the pathogenesis of breast cancer metastasis and fibrosis

Since the discovery and cloning of TGF-_ tremendous scientific effort has led to a so- phisticated understanding of the multifunctional actions of this pleiotropic growth factor. TGF-_ regulates a myriad of processes in normal tissues and in disease pathogenesis. In cancer, TGF-_ often suppress early tumorigenesis and later enhance tumor progres- sion. The pathogenic role of TGF-_ signaling is an attractive target for therapeutical intervention. However, in order to specifically direct therapy to this branch of TGF-__ signaling a deeper understanding of its cellular actions in specific contextual settings is crucial. Several studies are presented in this thesis, which aim at unraveling the molec- ular mechanisms of TGF-_ in the pathogenesis of breast cancer, bone metastasis and in renal fibrosis.AstraZeneca NovartisUBL - phd migration 201

Transforming growth factor-β employs HMGA2 to elicit epithelial–mesenchymal transition

Epithelial–mesenchymal transition (EMT) occurs during embryogenesis, carcinoma invasiveness, and metastasis and can be elicited by transforming growth factor-β (TGF-β) signaling via intracellular Smad transducers. The molecular mechanisms that control the onset of EMT remain largely unexplored. Transcriptomic analysis revealed that the high mobility group A2 (HMGA2) gene is induced by the Smad pathway during EMT. Endogenous HMGA2 mediates EMT by TGF-β, whereas ectopic HMGA2 causes irreversible EMT characterized by severe E-cadherin suppression. HMGA2 provides transcriptional input for the expression control of four known regulators of EMT, the zinc-finger proteins Snail and Slug, the basic helix-loop-helix protein Twist, and inhibitor of differentiation 2. We delineate a pathway that links TGF-β signaling to the control of epithelial differentiation via HMGA2 and a cohort of major regulators of tumor invasiveness and metastasis. This network of signaling/transcription factors that work sequentially to establish EMT suggests that combinatorial detection of these proteins could serve as a new tool for EMT analysis in cancer patients

Linker Flexibility Facilitates Module Exchange in Fungal Hybrid PKS-NRPS Engineering

Polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) each give rise to a vast array of complex bioactive molecules with further complexity added by the existence of natural PKS-NRPS fusions. Rational genetic engineering for the production of natural product derivatives is desirable for the purpose of incorporating new functionalities into pre-existing molecules, or for optimization of known bioactivities. We sought to expand the range of natural product diversity by combining modules of PKS-NRPS hybrids from different hosts, hereby producing novel synthetic natural products. We succeeded in the construction of a functional cross-species chimeric PKS-NRPS expressed in Aspergillus nidulans. Module swapping of the two PKS-NRPS natural hybrids CcsA from Aspergillus clavatus involved in the biosynthesis of cytochalasin E and related Syn2 from rice plant pathogen Magnaporthe oryzae lead to production of novel hybrid products, demonstrating that the rational re-design of these fungal natural product enzymes is feasible. We also report the structure of four novel pseudo pre-cytochalasin intermediates, niduclavin and niduporthin along with the chimeric compounds niduchimaeralin A and B, all indicating that PKS-NRPS activity alone is insufficient for proper assembly of the cytochalasin core structure. Future success in the field of biocombinatorial synthesis of hybrid polyketide-nonribosomal peptides relies on the understanding of the fundamental mechanisms of inter-modular polyketide chain transfer. Therefore, we expressed several PKS-NRPS linker-modified variants. Intriguingly, the linker anatomy is less complex than expected, as these variants displayed great tolerance with regards to content and length, showing a hitherto unreported flexibility in PKS-NRPS hybrids, with great potential for synthetic biology-driven biocombinatorial chemistry

Dereplication Guided Discovery of Secondary Metabolites of Mixed Biosynthetic Origin from<i> Aspergillus aculeatus</i>

Investigation of the chemical profile of the industrially important black filamentous fungus Aspergillus aculeatus by UHPLC-DAD-HRMS and subsequent dereplication has led to the discovery of several novel compounds. Isolation and extensive 1D and 2D NMR spectroscopic analyses allowed for structural elucidation of a dioxomorpholine, a unique okaramine, an aflavinine and three novel structures of mixed biosynthetic origin, which we have named aculenes A–C. Moreover, known analogues of calbistrins, okaramines and secalonic acids were detected. All novel compounds were tested for antifungal activity against Candida albicans, however all showed only weak or no activity. Aspergillus aculeatus IBT 21030 was additionally shown to be capable of producing sclerotia. Examination of the sclerotia revealed a highly regulated production of metabolites in these morphological structures

Isolation, Structural Analyses and Biological Activity Assays against Chronic Lymphocytic Leukemia of Two Novel Cytochalasins - Sclerotionigrin A and B

Two new cytochalasins, sclerotionigrin A (1) and B (2) were isolated together with the known proxiphomin (3) from the filamentous fungus Aspergillus sclerotioniger. The structures and relative stereochemistry of 1 and 2 were determined based on comparison with 3, and from extensive 1D and 2D NMR spectroscopic analysis, supported by high resolution mass spectrometry (HRMS). Compounds 2 and 3 displayed cytotoxic activity towards chronic lymphocytic leukemia cells in vitro, with 3 being the most active