HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus

Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Angst Springs Eternal:Dangerous Times and the Dangers of Timing the “Arab Spring”

Various reflections on the ‘Arab Spring’ evince a common view of the relationship between change and time that imbues events with a sense of intrinsic peril. Based on a framework developed from Norbert Elias’s concept of timing, this article elaborates the relationship between time and the ‘Arab Spring’ by unpacking and explaining three rhetorical tropes prevalent in academic responses to the revolts. The first two construct a problem to which the third proffers a solution. First, analysts treat time itself as a problematic force confounding stability and progress. Second, they deploy fluvial metaphors to present dynamic events as inherently insecure. Third, they use temporal Othering to retrofit the ‘Arab Spring’ to the familiar arc of liberal democracy, which renders the revolts intelligible and amenable to external intervention. These moves prioritize certainty and order over other considerations and constrain open-ended transformations within a familiar rubric of political progress. They also constitute an active timing effort based on a conservative standard, with important implications for our understanding of security and for scholarly reflexivity. The article concludes with three temporal alternatives for engaging novel changes like the ‘Arab Spring’

Exenatide Improves Glucose Homeostasis and Prolongs Survival in a Murine Model of Dilated Cardiomyopathy

There is growing awareness of secondary insulin resistance and alterations in myocardial glucose utilization in congestive heart failure. Whether therapies that directly target these changes would be beneficial is unclear. We previously demonstrated that acute blockade of the insulin responsive facilitative glucose transporter GLUT4 precipitates acute decompensated heart failure in mice with advanced dilated cardiomyopathy. Our current objective was to determine whether pharmacologic enhancement of insulin sensitivity and myocardial glucose uptake preserves cardiac function and survival in the setting of primary heart failure.The GLP-1 agonist exenatide was administered twice daily to a murine model of dilated cardiomyopathy (TG9) starting at 56 days of life. TG9 mice develop congestive heart failure and secondary insulin resistance in a highly predictable manner with death by 12 weeks of age. Glucose homeostasis was assessed by measuring glucose tolerance at 8 and 10 weeks and tissue 2-deoxyglucose uptake at 75 days. Exenatide treatment improved glucose tolerance, myocardial GLUT4 expression and 2-deoxyglucose uptake, cardiac contractility, and survival over control vehicle-treated TG9 mice. Phosphorylation of AMP kinase and AKT was also increased in exenatide-treated animals. Total myocardial GLUT1 levels were not different between groups. Exenatide also abrogated the detrimental effect of the GLUT4 antagonist ritonavir on survival in TG9 mice.In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal. An incretin-based therapy, which addresses these changes, appears beneficial

Microarray analysis of immediate-type allergy in KU812 cells in response to fulvic acid

Fulvic acid (FA) is class of compounds of humic substances formed through the degradation of organic substances by chemical and biological processes. FA has been utilized in traditional Chinese medicine and possesses various pharmacological properties. Previously, we reported that FA extracted from solubilized excess sludge (SS-FA) had an inhibitory effect on β-hexosaminidase release in human leukemia basophilic (KU812) cells. In this study, we investigated the effects of SS-FA on the immediate-type allergic reaction and studied its possible mechanisms of action in KU812 cells following activation with phorbol myristate acetate (20 nmol L−1) plus calcium ionophore A23187 (1 μmol L−1) (PMACI). The inhibitory effect of SS-FA on degranulation in PMACI-stimulated KU812 cells was examined using histamine release assay. SS-FA significantly decreased the histamine release in KU812 cells at concentrations of 0.1–10.0 μg mL−1. To gain more information regarding the mechanism of the suppression of degranulation following SS-FA treatment, microarray was conducted to determine which genes were differentially expressed in response to SS-FA in PMACI-activated KU812 cells. From a total of 201 genes in the DNA chip, 28 genes were up-regulated and 173 genes were down-regulated in cells pretreated with SS-FA for 15 min and stimulated with PMACI. From the 71 genes that showed more than two fold change in expression, 16 genes were significantly down-regulated that were subjected to hierarchical clustering. SS-FA affected the expression of genes that were involved in the following pathways: signal transduction, cytokine–cytokine receptor interaction, immune response, cell adhesion molecules and IgE receptor β subunit response

Insulin modulates the frequency of Ca2+ oscillations in mouse pancreatic islets

Pancreatic islets can adapt to oscillatory glucose to produce synchronous insulin pulses. Can islets adapt to other oscillatory stimuli, specifically insulin? To answer this question, we stimulated islets with pulses of exogenous insulin and measured their Ca2+ oscillations. We observed that sufficiently high insulin (> 500 nM) with an optimal pulse period (~ 4 min) could make islets to produce synchronous Ca2+ oscillations. Glucose and insulin, which are key stimulatory factors of islets, modulate islet Ca2+ oscillations differently. Glucose increases the active-to-silent ratio of phases, whereas insulin increases the period of the oscillation. To examine the dual modulation, we adopted a phase oscillator model that incorporated the phase and frequency modulations. This mathematical model showed that out-of-phase oscillations of glucose and insulin were more effective at synchronizing islet Ca2+ oscillations than in-phase stimuli. This finding suggests that a phase shift in glucose and insulin oscillations can enhance inter-islet synchronization