Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response

The pattern recognition receptor RIG-I is critical for Type-I interferon production. However, the global regulation of RIG-I signaling is only partially understood. Using a human genome-wide RNAi-screen, we identified 226 novel regulatory proteins of RIG-I mediated interferon-β production. Furthermore, the screen identified a metabolic pathway that synthesizes the inositol pyrophosphate 1-IP7 as a previously unrecognized positive regulator of interferon production. Detailed genetic and biochemical experiments demonstrated that the kinase activities of IPPK, PPIP5K1 and PPIP5K2 (which convert IP5 to1-IP7) were critical for both interferon induction, and the control of cellular infection by Sendai and influenza A viruses. Conversely, ectopically expressed inositol pyrophosphate-hydrolases DIPPs attenuated interferon transcription. Mechanistic experiments in intact cells revealed that the expression of IPPK, PPIP5K1 and PPIP5K2 was needed for the phosphorylation and activation of IRF3, a transcription factor for interferon. The addition of purified individual inositol pyrophosphates to a cell free reconstituted RIG-I signaling assay further identified 1-IP7 as an essential component required for IRF3 activation. The inositol pyrophosphate may act by β-phosphoryl transfer, since its action was not recapitulated by a synthetic phosphonoacetate analogue of 1-IP7. This study thus identified several novel regulators of RIG-I, and a new role for inositol pyrophosphates in augmenting innate immune responses to viral infection that may have therapeutic applications

Bio-Geo-Graphy: Landscape, Dwelling, and the Political Ecology of Human-Elephant Relations

The relation between the bio and the geo has been amongst geography's most enduring concerns. This paper contributes to ongoing attempts in human geography to politicise the dynamics and distribution of life. Drawing upon postcolonial environmental history, animal ecology, and more-than-human geography, the paper examines how humans and elephants cohabit with and against the grain of cartographic design. Through fieldwork in northeast India, it develops a ‘dwelt political ecology’ that reanimates landscape as a dwelt achievement whilst remaining sensitive to postcolonial histories and subaltern concerns. The paper conceptualises and deploys a methodology of ‘tracking’ through which archival material, elephant ecology, and voices of the marginalised can be integrated and mapped. It concludes by discussing the implications of this work for fostering new conversations between more-than-human geography and subaltern political ecology

Endoscopic procedures for removal of foreign bodies of the aerodigestive tract: The Bugando Medical Centre experience

<p>Abstract</p> <p>Background</p> <p>Foreign bodies in the aerodigestive tract continue to be a common problem that contributes significantly to high morbidity and mortality worldwide. This study was conducted to describe our own experience with endoscopic procedures for removal of foreign bodies in the aerodigestive tract, in our local setting and compare with what is described in literature.</p> <p>Methods</p> <p>This was a prospective descriptive study which was conducted at Bugando Medical Centre between January 2008 and December 2009. Data were collected using a structured questionnaire and analyzed using SPSS computer software version 15.</p> <p>Results</p> <p>A total of 98 patients were studied. Males outnumbered females by a ratio of 1.1:1. Patients aged 2 years and below were the majority (75.9%). The commonest type of foreign bodies in airways was groundnuts (72.7%) and in esophagus was coins (72.7%). The trachea (52.2%) was the most common site of foreign body's lodgment in the airways, whereas cricopharyngeal sphincter (68.5%) was the commonest site in the esophagus. Rigid endoscopy with forceps removal under general anesthesia was the main treatment modality performed in 87.8% of patients. The foreign bodies were successfully removed without complications in 90.8% of cases. Complication rate was 7.1% and bronchopneumonia was the most common complication accounting for 42.8% of cases. The mean duration of hospital stay was 3.4 days and mortality rate was 4.1%.</p> <p>Conclusion</p> <p>Aerodigestive tract foreign bodies continue to be a significant cause of childhood morbidity and mortality in our setting. Rigid endoscopic procedures under general anesthesia are the main treatment modalities performed. Prevention is highly recommended whereby parents should be educated to keep a close eye on their children and keep objects which can be foreign bodies away from children's reach.</p

Emodin Suppresses Migration and Invasion through the Modulation of CXCR4 Expression in an Orthotopic Model of Human Hepatocellular Carcinoma

10.1371/journal.pone.0057015PLoS ONE83

Loss of Caveolin-1 Accelerates Neurodegeneration and Aging

The aged brain exhibits a loss in gray matter and a decrease in spines and synaptic densities that may represent a sequela for neurodegenerative diseases such as Alzheimer's. Membrane/lipid rafts (MLR), discrete regions of the plasmalemma enriched in cholesterol, glycosphingolipids, and sphingomyelin, are essential for the development and stabilization of synapses. Caveolin-1 (Cav-1), a cholesterol binding protein organizes synaptic signaling components within MLR. It is unknown whether loss of synapses is dependent on an age-related loss of Cav-1 expression and whether this has implications for neurodegenerative diseases such as Alzheimer's disease.We analyzed brains from young (Yg, 3-6 months), middle age (Md, 12 months), aged (Ag, >18 months), and young Cav-1 KO mice and show that localization of PSD-95, NR2A, NR2B, TrkBR, AMPAR, and Cav-1 to MLR is decreased in aged hippocampi. Young Cav-1 KO mice showed signs of premature neuronal aging and degeneration. Hippocampi synaptosomes from Cav-1 KO mice showed reduced PSD-95, NR2A, NR2B, and Cav-1, an inability to be protected against cerebral ischemia-reperfusion injury compared to young WT mice, increased Aβ, P-Tau, and astrogliosis, decreased cerebrovascular volume compared to young WT mice. As with aged hippocampi, Cav-1 KO brains showed significantly reduced synapses. Neuron-targeted re-expression of Cav-1 in Cav-1 KO neurons in vitro decreased Aβ expression.Therefore, Cav-1 represents a novel control point for healthy neuronal aging and loss of Cav-1 represents a non-mutational model for Alzheimer's disease

Caveolin contributes to the modulation of basal and β-adrenoceptor stimulated function of the adult rat ventricular myocyte by simvastatin: A novel pleiotropic effect

The number of people taking statins is increasing across the globe, highlighting the Importance of fully understanding statins effects on the cardiovascular system. The beneficial impact of statins extends well beyond regression of atherosclerosis to include direct effects on tissues of the cardiovascular system (pleiotropic effects). Pleiotropic effects on the cardiac myocyte are often overlooked. Here we consider the contribution of the caveolin protein, whose expression and cellular distribution is dependent on cholesterol, to statin effects on the cardiac myocyte. Caveolin is a structural and regulatory component of caveolae, and is a key regulator of cardiac contractile function and adrenergic responsiveness. We employed an experimental model in which inhibition of myocyte HMG CoA reductase could be studied in the absence of paracrine influences from non-myocyte cells. Adult rat ventricular myocytes were treated with 10 μM simvastatin for 2 days. Simvastatin treatment reduced myocyte cholesterol, caveolin 3 and caveolar density. Negative inotropic and positive lusitropic effects (with corresponding changes in [Ca2]¡) were seen in statin-treated cells. Simvastatin significantly potentiated the inotropic response to β2-, but not β1-, adrenoceptor stimulation. Under conditions of β2-adrenoceptor stimulation, phosphorylation of phospholamban at Ser16and troponin I at Ser23/24was enhanced with statin treatment. Simvastatin increased NO production without significant effects on eNOS expression or phosphorylation (Ser1177), consistent with the reduced expression of caveolin 3, its constitutive Inhibitor. In conclusion, statin treatment can reduce caveolin 3 expression, with functional consequences consistent with the known role of caveolae in the cardiac cell. These data are likely to be of significance, particularly during the early phases of statin treatment, and in patients with heart failure who have altered ß-adrenoceptor signalling. In addition, as caveolin is ubiquitously expressed and has myriad tissue-specific functions, the impact of statin-dependent changes in caveolin is likely to have many other functional sequelae