Implications of Action-Oriented Paradigm Shifts in Cognitive Science

An action-oriented perspective changes the role of an individual from a passive observer to an actively engaged agent interacting in a closed loop with the world as well as with others. Cognition exists to serve action within a landscape that contains both. This chapter surveys this landscape and addresses the status of the pragmatic turn. Its potential influence on science and the study of cognition are considered (including perception, social cognition, social interaction, sensorimotor entrainment, and language acquisition) and its impact on how neuroscience is studied is also investigated (with the notion that brains do not passively build models, but instead support the guidance of action). A review of its implications in robotics and engineering includes a discussion of the application of enactive control principles to couple action and perception in robotics as well as the conceptualization of system design in a more holistic, less modular manner. Practical applications that can impact the human condition are reviewed (e.g., educational applications, treatment possibilities for developmental and psychopathological disorders, the development of neural prostheses). All of this foreshadows the potential societal implications of the pragmatic turn. The chapter concludes that an action-oriented approach emphasizes a continuum of interaction between technical aspects of cognitive systems and robotics, biology, psychology, the social sciences, and the humanities, where the individual is part of a grounded cultural system

The transcription factors islet and lim3 combinatorially regulate ion channel gene expression

Expression of appropriate ion channels is essential to allow developing neurons to form functional networks. Our previous studies have identified LIM-homeodomain (HD) transcription factors (TFs), expressed by developing neurons, that are specifically able to regulate ion channel gene expression. In this study, we use the technique of DNA adenine methyltransferase identification (DamID) to identify putative gene targets of four such TFs that are differentially expressed in Drosophila motoneurons. Analysis of targets for Islet (Isl), Lim3, Hb9, and Even-skipped (Eve) identifies both ion channel genes and genes predicted to regulate aspects of dendritic and axonal morphology. Significantly, some ion channel genes are bound by more than one TF, consistent with the possibility of combinatorial regulation. One such gene is Shaker (Sh), which encodes a voltage-dependent fast K(+) channel (K(v1.1)). DamID reveals that Sh is bound by both Isl and Lim3. We used body wall muscle as a test tissue because in conditions of low Ca(2+), the fast K(+) current is carried solely by Sh channels (unlike neurons in which a second fast K(+) current, Shal, also contributes). Ectopic expression of isl, but not Lim3, is sufficient to reduce both Sh transcript and Sh current level. By contrast, coexpression of both TFs is additive, resulting in a significantly greater reduction in both Sh transcript and current compared with isl expression alone. These observations provide evidence for combinatorial activity of Isl and Lim3 in regulating ion channel gene expression

Soft drug-inhibitors for the epigenetic targets Lysine-Specific Demethylase 1 (LSD1) and Histone Deacetylases (HDACs)

Epigenetic modulators such as Lysine-specific Demethylase 1 (LSD1) and Histone Deacetylases (HDACs), are drug targets for cancer, neuropsychiatric disease or inflammation but inhibitors of these enzymes exhibit considerable side effects. For a potential local treatment with reduced systemic toxicity, we present here soft drug candidates as new LSD1 and HDAC inhibitors. A soft drug is a compound that is degraded in vivo to less active metabolites, after having achieved its therapeutic function. This has been successfully applied for corticosteroids in the clinic but soft drugs targeting epigenetic enzymes are scarce, with the HDAC inhibitor remetinostat being the only example. We have developed new methyl ester containing inhibitors targeting LSD1 respectively HDACs and compared the biological activity of these to their respective carboxylic acids cleavage products. In vitro activity assays, cellular experiments, and a stability assay identified potent HDAC and LSD1 soft drug candidates that are superior to their corresponding carboxylic acids in cellular models

Implications of action-oriented paradigm shifts in cognitive science

Dominey PF, Prescott TJ, Bohg J, et al. Implications of action-oriented paradigm shifts in cognitive science. In: Engel AK, Friston KJ, Kragic D, eds. The pragmatic turn. Toward Action-Oriented Views in Cognitive Science. Strüngmann Forum Reports. Vol 18. Cambridge: MIT Press; 2016: 333-356

EULAR study group on 'MHC-I-opathy':identifying disease-overarching mechanisms across disciplines and borders

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.Publisher PDFPeer reviewe