Hsp90 and associated co-chaperones of the Malaria parasite

Heat shock protein 90 (Hsp90) is one of the major guardians of cellular protein homeostasis, through its specialized molecular chaperone properties. While Hsp90 has been extensively studied in many prokaryotic and higher eukaryotic model organisms, its structural, functional, and biological properties in parasitic protozoans are less well defined. Hsp90 collaborates with a wide range of co-chaperones that fine-tune its protein folding pathway. Co-chaperones play many roles in the regulation of Hsp90, including selective targeting of client proteins, and the modulation of its ATPase activity, conformational changes, and post-translational modifications. Plasmodium falciparum is responsible for the most lethal form of human malaria. The survival of the malaria parasite inside the host and the vector depends on the action of molecular chaperones. The major cytosolic P. falciparum Hsp90 (PfHsp90) is known to play an essential role in the development of the parasite, particularly during the intra-erythrocytic stage in the human host. Although PfHsp90 shares significant sequence and structural similarity with human Hsp90, it has several major structural and functional differences. Furthermore, its co-chaperone network appears to be substantially different to that of the human host, with the potential absence of a key homolog. Indeed, PfHsp90 and its interface with co-chaperones represent potential drug targets for antimalarial drug discovery. In this review, we critically summarize the current understanding of the properties of Hsp90, and the associated co-chaperones of the malaria parasite

Revisiting Jon McKenzie?s Perform or else: Performance, labour and pedagogy

Tim Edkins and Stevphen Shukaitis interviewed Jon McKenzie on 24 March 2013 about his book Perform or else: From discipline to performance (2001a), its current resonance and his recent research. We begin by asking about Perform or else?s playful tone and composition. Then we ask about contemporary labour struggles, including in the state of Wisconsin where he is based as a Professor of English and Director of DesignLab at University of Wisconsin. We end by discussing how he sees the current role of the university. We focus on how DesignLab forms part of his applied research program, based on the multifaceted conception of performance theorised in Perform or else and instantiated in higher education

The potential benefits of outcome based assessments of infrastructure performance

The human race’s progress as a species has involved the creation of many types of artefact with arguably one of the most important being the construction of physical infrastructures. From working out how to build our own shelters and securing water supplies, we have identified and pursued the creation of the technologies and networks that we need to allow us to function in ever larger groups and communities. Thus, as a society we have generated a paradigm comprising both players and principles for assessing which infrastructure to invest in based on a combination of political decision making and a rationalist economic assessment, where measurable estimates of both the benefits and costs are evaluated. The traditional focus of regulators on the magnitude and quality of resources needed (inputs) to deliver a particular level of service or improvements to services (outputs) is now being challenged by an alternative view which assesses higher-level objectives that infrastructure investments seek to achieve, often in terms of customer experience and utility. Such Outcome based evaluations specify the outcome required but leaves the specific measures to achieve that outcome up to the discretion of the infrastructure builder and operator. Through the use of cases and examples from a number of sectors we review the different forms of benefit which infrastructure provides to our communities and examine what performance might mean in the context of such physical systems. This narrative prefaces an analysis of three particularly challenging aspects of outcomes based infrastructure evaluation: Who’s outcomes are to be valued? What constitutes an outcome? and How are we to deal with the temporality of outcome realisation? The nuances around these debates will shape both the nature of outcome metrics and arrangements for their auditing

Immunoglobulin G; structure and functional implications of different subclass modifications in initiation and resolution of allergy.

IgE and not IgG is usually associated with allergy. IgE lodged on mast cells in skin or gut and basophils in the blood allows for the prolonged duration of allergy through the persistent expression of high affinity IgE receptors. However, many allergic reactions are not dependent on IgE and are generated in the absence of allergen specific and even total IgE. Instead, IgG plasma cells are involved in induction of, and for much of the pathogenesis of, allergic diseases. The pattern of IgG producing plasma cells in atopic children and the tendency for direct or further class switching to IgE are the principle factors responsible for long-lasting sensitization of mast cells in allergic children. Indirect class switching from IgG producing plasma cells has been shown to be the predominant pathway for production of IgE while a Th2 microenvironment, genetic predisposition, and the concentration and nature of allergens together act on IgG plasma cells in the atopic tendency to undergo further immunoglobulin gene recombination. The seminal involvement of IgG in allergy is further indicated by the principal role of IgG4 in the natural resolution of allergy and as the favourable immunological response to immunotherapy. This paper will look at allergy through the role of different antibodies than IgE and give current knowledge of the nature and role of IgG antibodies in the start, maintenance and resolution of allergy

The political import of deconstruction—Derrida’s limits?: a forum on Jacques Derrida’s specters of Marx after 25 Years, part I

Jacques Derrida delivered the basis of The Specters of Marx: The State of the Debt, the Work of Mourning, & the New International as a plenary address at the conference ‘Whither Marxism?’ hosted by the University of California, Riverside, in 1993. The longer book version was published in French the same year and appeared in English and Portuguese the following year. In the decade after the publication of Specters, Derrida’s analyses provoked a large critical literature and invited both consternation and celebration by figures such as Antonio Negri, Wendy Brown and Frederic Jameson. This forum seeks to stimulate new reflections on Derrida, deconstruction and Specters of Marx by considering how the futures past announced by the book have fared after an eventful quarter century. Maja Zehfuss, Antonio Vázquez-Arroyo and Dan Bulley and Bal Sokhi-Bulley offer sharp, occasionally exasperated, meditations on the political import of deconstruction and the limits of Derrida’s diagnoses in Specters of Marx but also identify possible paths forward for a global politics taking inspiration in Derrida’s work of the 1990s

Halogenated oxindole and indoles from the South African marine ascidian Distaplia skoogi:

The known 3,6-dibromoindole (1), 6-bromo-3-chloroindole (2) and 6-bromo-2-oxindole (3) were isolated from the marine ascidian (sea squirt) Distapia skoogi collected from Algoa Bay, South Africa. Standard spectroscopic techniques were used to elucidate the structures of 1-3. All three compounds were found to be moderately cytotoxic to metastatic MDA-MB-231 breast cancer cells

Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia

Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal (EMT) transcription factor, confers properties of ‘stemness’, such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in adult stem cells. Here, we used the hematopoietic system, as a well-established paradigm of stem cell biology, to evaluate Zeb1 mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1-Cre system to specifically knockout (KO) Zeb1 in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zeb1 led to rapid onset thymic atrophy and apoptosis driven loss of thymocytes and T cells. A profound cell-autonomous self-renewal defect and multi-lineage differentiation block was observed in Zeb1 KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multi-lineage differentiation genes, and of cell polarity, consisting of cytoskeleton, lipid metabolism/lipid membrane and cell adhesion related genes. Notably, Epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1 KO HSCs, which correlated with enhanced cell survival, diminished mitochondrial metabolism, ribosome biogenesis, and differentiation capacity and an activated transcriptomic signature associated with acute myeloid leukemia (AML) signaling. ZEB1 expression was downregulated in AML patients and Zeb1 KO in the malignant counterparts of HSCs - leukemic stem cells (LSCs) - accelerated MLL-AF9 and Meis1a/Hoxa9-driven AML progression, implicating Zeb1 as a tumor suppressor in AML LSCs. Thus, Zeb1 acts as a transcriptional regulator in hematopoiesis, critically co-ordinating HSC self-renewal, apoptotic and multi-lineage differentiation fates required to suppress leukemic potential in AML

'Memory Must Be Defended': Beyond the Politics of Mnemonical Security

This article supplements and extends the ontological security theory in International Relations (IR) by conceptualizing the notion of mnemonical security. It engages critically the securitization of memory as a means of making certain historical remembrances secure by delegitimizing or outright criminalizing others. The securitization of historical memory by means of law tends to reproduce a sense of insecurity among the contesters of the ‘memory’ in question. To move beyond the politics of mnemonical security, two lines of action are outlined: (i) the ‘desecuritization’ of social remembrance in order to allow for its repoliticization, and (ii) the rethinking of the self–other relations in mnemonic conflicts. A radically democratic, agonistic politics of memory is called for that would avoid the knee-jerk reactive treatment of identity, memory and history as problems of security. Rather than trying to secure the unsecurable, a genuinely agonistic mnemonic pluralism would enable different interpretations of the past to be questioned, in place of pre-defining national or regional positions on legitimate remembrance in ontological security terms