Narracyjne i antynarracyjne modele egzystencji w naukach humanistycznych i praktyce literackiej

Wydział Nauk Społecznych

Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.

Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of caspase activation and tyrosine kinase/adaptor protein signaling to forge a unique approach for selectively killing leukemic cells through the forcible induction of apoptosis. We have engineered caspase variants that can directly be activated in response to BCR-ABL. Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells, this approach selectively eliminates leukemic cells regardless of drug-resistant mutations.

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.

Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.

Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets.

Stimulated CD4(+) T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with specific immunological roles. We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model. These data demonstrate that CD4(+) T cell subsets require distinct metabolic programs that can be manipulated in vivo to control Treg and Teff development in inflammatory diseases.

'Work and Emancipatory Practice: Towards a Recovery of Human Beings' Productive Capacities,'

This article argues that productive work represents a mode of human flourishing unfortunately neglected in much current political theorizing. Focusing on Habermasian critical theory, I contend that Habermas’s dualist theory of society, on account of the communicative versus instrumental reason binary which underpins it, excludes work and the economy from ethical reflection. To avoid this uncritical turn, we need a concept of work that retains a core emancipatory referent. This, I claim, is provided by Alasdair MacIntyre’s notion of ‘practice’. The notion of ‘practice’ is significant in suggesting an alternative conception of human productivity that is neither purely instrumental nor purely communicative, but rather both simultaneously, a form of activity which issues in material products and yet presumes a community of workers engaged in intersubjective self-transformation. However, we can endorse MacIntyre’s notion of ‘practice’ only if we reject his totalizing anti-modernism and insist on the emancipatory potentialities of modern institutions.

Justice as Fairness in Planning Policy-Making

This paper considers a moral basis for planning theory and endeavours to establish principles of justice which might be relevant to the regulation of development. Whilst the investigation recognises that there is a need for a deeper understanding of the dynamics of governance, it suggests that many of the inefficiencies, inequities and public disquiet concerns relating to planning centre on a drift from a perception that the system is both fair and just, and that practice needs to be anchored on founding values concerned with redistribution and equality. In this context, John Rawls’ theory of justice is employed as a vehicle to capture moral ideas of equality and liberty within a constitutional democracy and as a basis for scrutinising emerging justice based issues which impact upon planning. Using National Policy Statements as a case study, the paper concludes that, whilst there are serious concerns over current policymaking practices, the principles of justice offer a foundation for practical critique which can help overcome problems of mistrust.

Conundrums in Conservation: Complexity in Control

The departure point for this investigation is to highlight the centrality of regulation theory as a praxis in planning enforcement. The value of the conceptual framework is demonstrated by application in the problematic arena of conservation regulatory compliance, where there is currently a dearth of investigation. It is evidenced that this thematic approach provides a lens to scrutinise problematic areas of control and provides a deeper understanding of the difficulties faced by planning enforcement operational practice generally and heritage regimes specifically. The utility of the proposed mechanism is that it remedies the current well documented pitfalls of disjointed, piecemeal strategies by providing a framework for robust, coherent decision making not only in planning but in the wider regulatory arena.

Pitfalls in Protection: How Theory Can Enrich Our Understanding of Regulatory Compliance Problems in Planning Practice

This paper responds to demands for greater academic investigation into environmental protection, specifically the practical and structural problems which underpin regulatory compliance in the planning system. It critiques traditional theories of regulation and answers calls for the development of a thematic lens to facilitate the scrutiny of not only operational practice, but also the broader institutional regime. An empirical investigation builds upon the construct of really responsive regulation to study planning control and it becomes apparent that not only are there significant procedural planning difficulties facing regulatory compliance, but also that a much wider raft of issues must be considered if the complex equation is to be solved. The findings demonstrate how theory can be applied to enrich our rudimentary understanding of deep-seated problems and foster insights into areas of structural importance which are relevant to both planning and the wider regulatory arena.

Evidence-based policymaking and the public interest: lessons in legitimacy

This paper draws upon an analysis of regional spatial planning to highlight the centrality of ethics in praxis. In this context political liberalism is particularly helpful in developing a deeper understanding of the activities of those engaged in planning decision making. At the most basic level it demonstrates the importance of not only using shared liberal values as the foundation for public discourses but also achieving consensus through the development of an inclusive evidence base, derived from both lay and professional knowledge. Specifically, political liberalism provides a practical critique, enabling judgments to be made on problems which pervade operational planning practice and an evaluation to be conducted of the dynamic between and actions of participants.