Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma

PIM kinase expression in human lymphomas can influence the outcome of chemotherapy, and blocking cap-dependent translation can reverse PIM-mediated rapamycin resistance in murine lymphomas

Is a posthumanist bildung possible? Reclaiming the promise of bildung for contemporary higher education

My central argument in this article is that the notion of Bildung may offer conceptual sustenance to those who wish to develop educative practices to supplement or contest the prevalence and privileging of market and economic imperatives in higher education, which configure teaching and learning as an object available to measurement. I pursue this argument by making the case for an ethical posthuman Bildung which recognises the inseparability of knowing and being, the materiality of educative relations, and the need to install an ecology of ethical relations at the centre of educational practice in higher education. Such a re-conceptualisation situates Bildung not purely as an individual goal but as a process of ecologies and relationships. The article explores Bildung as a flexible concept, via three theoretical lenses, and notes that it has always been subject to continuing revision in response to changing social and educational contexts. In proposing the possibility of, and need for, a posthuman Bildung, the articles offers a critical review of the promise of Bildung and outlines some of the radical ways that a posthuman Bildung might reinvigorate conceptualisations of contemporary higher education. Keywords : Bildung; posthumanism; higher education; ethics; ecology

Identification of Human IKK-2 Inhibitors of Natural Origin (Part I): Modeling of the IKK-2 Kinase Domain, Virtual Screening and Activity Assays

BACKGROUND: Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits. METHODOLOGY/PRINCIPAL FINDINGS: We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2. CONCLUSIONS/SIGNIFICANCE: We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing new inhibitors for hIKK-2, a target of great interest in medicinal chemistry. Additionally, all the tools developed during the current study (i.e., the homology model for the hIKK-2 kinase domain and the pharmacophore) will be made available to interested readers upon request