The quiet editor: Ivan Vladislavić and South African cultural production

This article examines the literary and sociological significance of Ivan Vladislavić’s "double life” (Lahire, 2010: n.p.) as both editor and writer. With reference to a number of his editorial roles as well as the joint projects he has worked on with writers and visual artists, the article considers how Vladislavić’s work with others spreads symbolic value. Described by one of his clients as the “quiet editor”, Vladislavić can be read as a new kind of author; what he terms “creative editing” (Steyn, 2012: n.p.) as a new kind of writing, through which more traditional models of authorship and literary production are thrown into question — less Bourdieu’s (1984) “field of literary production” or Casanova’s (2004: 82) “world literary space”, red in tooth and claw, amd more Howard Becker’s “art world”: a convivial “network of cooperating people, all of whose work is essential to the final outcome” (1982: 25)

Y2Y4 Receptor Double Knockout Protects Against Obesity Due to a High-Fat Diet or Y1 Receptor Deficiency in Mice

Neuropeptide Y receptors are critical regulators of energy homeostasis, but the functional interactions and relative contributions of Y receptors and the environment in this process are unknown. We measured the effects of an ad libitum diet of normal or high-fat food on energy balance in mice with single, double, or triple deficiencies of Y1, Y2, or Y4 receptors. Whereas wild-type mice developed diet-induced obesity, Y2Y4 double knockouts did not. In contrast, Y1 knockout or Y1Y2 or Y1Y4 receptor double knockout mice developed an exacerbated diet-induced obesity syndrome. Remarkably, the antiobesity effect of Y2Y4 deficiency was stronger than the obesogenic effect of Y1 deficiency, since Y1Y2Y4 triple knockouts did not develop obesity on the high-fat diet. Resistance to diet-induced obesity in Y2Y4 knockouts was associated with reduced food intake and improved glucose tolerance in the absence of changes in total physical activity. Fecal concentration of free fatty acids was significantly increased in Y2Y4 knockouts in association with a significantly reduced bile acid pool and marked alterations in intestinal morphology. In addition, hypothalamic proopiomelanocortin expression was decreased in diet-induced obesity (in both wild-type and Y1 receptor knockout mice) but not in obesity-resistant Y2Y4 receptor knockout mice fed a high-fat diet. Therefore, deletion of Y2 and Y4 receptors synergistically protects against diet-induced obesity, at least partially via changes in food intake and hypothalamic proopiomelanocortin expression

CRLF3 plays a key role in the final stage of platelet genesis and is a potential therapeutic target for thrombocythemia.

The process of platelet production has so far been understood to be a 2-stage process: megakaryocyte maturation from hematopoietic stem cells followed by proplatelet formation, with each phase regulating the peripheral blood platelet count. Proplatelet formation releases into the bloodstream beads-on-a-string preplatelets, which undergo fission into mature platelets. For the first time, we show that preplatelet maturation is a third, tightly regulated, critical process akin to cytokinesis that regulates platelet count. We show that deficiency in cytokine receptor-like factor 3 (CRLF3) in mice leads to an isolated and sustained 25% to 48% reduction in the platelet count without any effect on other blood cell lineages. We show that Crlf3-/- preplatelets have increased microtubule stability, possibly because of increased microtubule glutamylation via the interaction of CRLF3 with key members of the Hippo pathway. Using a mouse model of JAK2 V617F essential thrombocythemia, we show that a lack of CRLF3 leads to long-term lineage-specific normalization of the platelet count. We thereby postulate that targeting CRLF3 has therapeutic potential for treatment of thrombocythemia

The DARS (Dopamine Augmented Rehabilitation in Stroke) trial: protocol for a randomised controlled trial of Co-careldopa treatment in addition to routine NHS occupational and physical therapy after stroke

Background: Stroke has a huge impact, leaving more than a third of affected people with lasting disability and rehabilitation remains a cornerstone treatment in the National Health Service (NHS). Recovery of mobility and arm function post-stroke occurs through re-learning to use the affected body parts and/or learning to compensate with the lesser affected side. Promising evidence suggests that the addition of Co-careldopa to physical therapy and occupational therapy may improve the recovery of arm and leg movement and lead to improved function. Methods/design: Dopamine Augmented Rehabilitation in Stroke (DARS) is a multi-centre double-blind, randomised, placebo, controlled clinical trial of Co-careldopa in addition to routine NHS occupational therapy and physical therapy as part of early stroke rehabilitation. Participants will be randomised on a 1:1 basis to either Co-careldopa or placebo. The primary objective of the trial is to determine whether the addition of six weeks of Co-careldopa treatment to rehabilitation therapy can improve the proportion of patients who can walk independently eight weeks post-randomisation. Discussion: The DARS trial will provide evidence as to whether Co-careldopa, in addition to routine NHS occupational and physical therapy, leads to a greater recovery of motor function, a reduction in carer dependency and advance rehabilitation treatments for people with stroke. Trial registration: ISRCTN99643613 assigned on 4 December 2009

A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome

Intelligence testing in children with intellectual disabilities (ID) has significant limitations. The normative samples of widely used intelligence tests, such as the Wechsler Intelligence Scales, rarely include an adequate number of subjects with ID needed to provide sensitive measurement in the very low ability range, and they are highly subject to floor effects. The IQ measurement problems in these children prevent characterization of strengths and weaknesses, poorer estimates of cognitive abilities in research applications, and in clinical settings, limited utility for assessment, prognosis estimation, and planning intervention. Here, we examined the sensitivity of the Wechsler Intelligence Scale for Children (WISC-III) in a large sample of children with fragile X syndrome (FXS), the most common cause of inherited ID. The WISC-III was administered to 217 children with FXS (age 6–17 years, 83 girls and 134 boys). Using raw norms data obtained with permission from the Psychological Corporation, we calculated normalized scores representing each participant’s actual deviation from the standardization sample using a z-score transformation. To validate this approach, we compared correlations between the new normalized scores versus the usual standard scores with a measure of adaptive behavior (Vineland Adaptive Behavior Scales) and with a genetic measure specific to FXS (FMR1 protein or FMRP). The distribution of WISC-III standard scores showed significant skewing with floor effects in a high proportion of participants, especially males (64.9%–94.0% across subtests). With the z-score normalization, the flooring problems were eliminated and scores were normally distributed. Furthermore, we found correlations between cognitive performance and adaptive behavior, and between cognition and FMRP that were very much improved when using these normalized scores in contrast to the usual standardized scores. The results of this study show that meaningful variation in intellectual ability in children with FXS, and probably other populations of children with neurodevelopmental disorders, is obscured by the usual translation of raw scores into standardized scores. A method of raw score transformation may improve the characterization of cognitive functioning in ID populations, especially for research applications

Mapping differential interactomes by affinity purification coupled with data independent mass spectrometry acquisition

Characterizing changes in protein-protein interactions associated with sequence variants (e.g. disease-associated mutations or splice forms) or following exposure to drugs, growth factors or hormones is critical to understanding how protein complexes are built, localized and regulated. Affinity purification (AP) coupled with mass spectrometry permits the analysis of protein interactions under near-physiological conditions, yet monitoring interaction changes requires the development of a robust and sensitive quantitative approach, especially for large-scale studies where cost and time are major considerations. To this end, we have coupled AP to data-independent mass spectrometric acquisition (SWATH), and implemented an automated data extraction and statistical analysis pipeline to score modulated interactions. Here, we use AP-SWATH to characterize changes in protein-protein interactions imparted by the HSP90 inhibitor NVP-AUY922 or melanoma-associated mutations in the human kinase CDK4. We show that AP-SWATH is a robust label-free approach to characterize such changes, and propose a scalable pipeline for systems biology studies

An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations

Protein-protein interactions govern almost all cellular functions. These complex networks of stable and transient associations can be mapped by affinity purification mass spectrometry (AP-MS) and complementary proximity-based labeling methods such as BioID. To exploit the advantages of both strategies, we here design and optimize an integrated approach combining AP-MS and BioID in a single construct, which we term MAC-tag. We systematically apply the MAC-tag approach to 18 subcellular and 3 sub-organelle localization markers, generating a molecular context database, which can be used to define a protein's molecular location. In addition, we show that combining the AP-MS and BioID results makes it possible to obtain interaction distances within a protein complex. Taken together, our integrated strategy enables the comprehensive mapping of the physical and functional interactions of proteins, defining their molecular context and improving our understanding of the cellular interactome.Peer reviewe

Life, time, and the organism:Temporal registers in the construction of life forms

In this paper, we articulate how time and temporalities are involved in the making of living things. For these purposes, we draw on an instructive episode concerning Norfolk Horn sheep. We attend to historical debates over the nature of the breed, whether it is extinct or not, and whether presently living exemplars are faithful copies of those that came before. We argue that there are features to these debates that are important to understanding contemporary configurations of life, time and the organism, especially as these are articulated within the field of synthetic biology. In particular, we highlight how organisms are configured within different material and semiotic assemblages that are always structured temporally. While we identify three distinct structures, namely the historical, phyletic and molecular registers, we do not regard the list as exhaustive. We also highlight how these structures are related to the care and value invested in the organisms at issue. Finally, because we are interested ultimately in ways of producing time, our subject matter requires us to think about historiographical practice reflexively. This draws us into dialogue with other scholars interested in time, not just historians, but also philosophers and sociologists, and into conversations with them about time as always multiple and never an inert background

Application guide for omics approaches to cell signaling

Research in signal transduction aims to identify the functions of different signaling pathways in physiological and pathological states. Traditional techniques using biochemical, genetic or cell biological approaches have made important contributions to our understanding of cellular signaling. However, the single-gene approach does not take into account the full complexity of cell signaling. With the availability of omics techniques, great progress has been made in understanding signaling networks. Omics approaches can be classified into two categories: 'molecular profiling', including genomic, proteomic, post-translational modification and interactome profiling; and 'molecular perturbation', including genetic and functional perturbations