Prominent Role Of Platelets In The Formation Of Circulating Neutrophil-red Cell Heterocellular Aggregates In Sickle Cell Anemia

[No abstract available]9911e214e217Hidalgo, A., Chang, J., Jang, J.E., Peired, A.J., Chiang, E.Y., Frenette, P.S., Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury (2009) Nat Med, 15 (4), pp. 384-391Turhan, A., Jenab, P., Bruhns, P., Ravetch, J.V., Coller, B.S., Frenette, P.S., Intravenous immune globulin prevents venular vaso-occlusion in sickle cell mice by inhibiting leukocyte adhesion and the interactions between sickle erythrocytes and adherent leukocytes (2004) Blood, 103 (6), pp. 2397-2400Turhan, A., Weiss, L.A., Mohandas, N., Coller, B.S., Frenette, P.S., Primary role for adherent leukocytes in sickle cell vascular occlusion: A new paradigm (2002) Proc Natl Acad Sci USA, 99 (5), pp. 3047-3051May, A.E., Langer, H., Seizer, P., Bigalke, B., Lindemann, S., Gawaz, M., Platelet-leukocyte interactions in inflammation and atherothrombosis (2007) Semin Thromb Hemost, 33 (2), pp. 123-127Gawaz, M., Fateh-Moghadam, S., Pilz, G., Gurland, H.J., Werdan, K., Platelet activation and interaction with leucocytes in patients with sepsis or multiple organ failure (1995) Eur J Clin Invest, 25 (11), pp. 843-851Polanowska-Grabowska, R., Wallace, K., Field, J.J., Chen, L., Marshall, M.A., Figler, R., P-selectin-mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease (2010) Art Thromb Vascular Biol, 30 (12), pp. 2392-2399Brittain, J.E., Knoll, C.M., Ataga, K.I., Orringer, E.P., Parise, L.V., Fibronectin bridges monocytes and reticulocytes via integrin alpha4beta1 (2008) Br J Haematol, 141 (6), pp. 872-881Chaar, V., Picot, J., Renaud, O., Bartolucci, P., Nzouakou, R., Bachir, D., Aggregation of mononuclear and red blood cells through an {alpha}4{beta}1-Lu/basal cell adhesion molecule interaction in sickle cell disease (2010) Haematologica, 95 (11), pp. 1841-1848Finnegan, E.M., Turhan, A., Golan, D.E., Barabino, G.A., Adherent leukocytes capture sickle erythrocytes in an in vitro flow model of vasoocclusion (2007) Am J Hematol, 82 (4), pp. 266-275Wun, T., Paglieroni, T., Tablin, F., Welborn, J., Nelson, K., Cheung, A., Platelet activation and platelet-erythrocyte aggregates in patients with sickle cell anemia (1997) J Lab Clin Med, 129 (5), pp. 507-516Hynes, R.O., Integrins: Versatility, modulation, and signaling in cell adhesion (1992) Cell, 69 (1), pp. 11-25Novelli, E.M., Kato, G.J., Ragni, M.V., Zhang, Y., Hildesheim, M.E., Nouraie, M., Plasma thrombospondin-1 is increased during acute sickle cell vaso-occlusive events and associated with acute chest syndrome, hydroxyurea therapy, and lower hemolytic rates (2012) Am J Hematol, 87 (3), pp. 326-330Proenca-Ferreira, R., Brugnerotto, A.F., Garrido, V.T., Dominical, V.M., Vital, D.M., Ribeiro Mde, F., Endothelial activation by platelets from sickle cell anemia patients (2014) PloS one, 9 (2)Kutlar, A., Ataga, K.I., McMahon, L., Howard, J., Galacteros, F., Hagar, W., A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease (2012) Am J Hematol, 87 (5), pp. 536-539Telen, M.J., Wun, T., McCavit, T.L., De Castro, L.M., Krishnamurti, L., Lanzkron, S., GMI 1070: Reduction In Time To Resolution Of Vaso-Occlusive Crisis and Decreased Opioid Use In a Prospective, Randomized, Multi-Center Double Blind, Adaptive Phase 2 Study In Sickle Cell Disease (2013) Blood, 122 (21), p. 7. , Abstrac

Short report: 2014 Pacific meeting on implementation of the International Health Regulations (2005)

From 24 to 26 November 2014, 44 delegates representing 20 of the 22 Pacific island countries and areas, programme directors and technical experts from the World Health Organization (WHO) Regional Office for the Western Pacific and development partners met in the tranquil setting of Denarau Island, Fiji to attend the third biannual Pacific Meeting on Implementation of the International Health Regulations (2005)

Abstract 11332: Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes

Congenital heart disease (CHD) is present in 1% of live births, yet despite large-scale genomic sequencing efforts, identification of causal mutations remains a challenge. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of GATA4 and TBX5, two transcription factors whose mutation cause CHDs. Defining the GATA4 or TBX5 interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating the results with genetic data from the Pediatric Cardiac Genomic Consortium revealed an enrichment of de novo variants associated with CHD. A consolidative score that prioritized interactome members based on variant, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the GLYR1 missense variant identified disrupted interaction with GATA4 and impaired transcriptional co-regulation in cardiomyocyte differentiation in vitro and cardiogenesis in vivo. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in disease

Integration of Protein Interactome Networks With Congenital Heart Disease Variants Reveals Candidate Disease Genes

Congenital heart disease (CHD) is present in 1% of live births, yet despite large-scale genomic sequencing efforts, identification of causal mutations remains a challenge. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of GATA4 and TBX5, two transcription factors whose mutation cause CHDs. Defining the GATA4 or TBX5 interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating the results with genetic data from the Pediatric Cardiac Genomic Consortium revealed an enrichment of de novo variants associated with CHD. A consolidative score that prioritized interactome members based on variant, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the GLYR1 missense variant identified disrupted interaction with GATA4 and impaired transcriptional co-regulation in cardiomyocyte differentiation in vitro and cardiogenesis in vivo. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in disease

Transcription factor protein interactomes reveal genetic determinants in heart disease.

Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease

Transcription factor protein interactomes reveal genetic determinants in heart disease

Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease