SLI-1 Cbl Inhibits the Engulfment of Apoptotic Cells in C. elegans through a Ligase-Independent Function

The engulfment of apoptotic cells is required for normal metazoan development and tissue remodeling. In Caenorhabditis elegans, two parallel and partially redundant conserved pathways act in cell-corpse engulfment. One pathway, which includes the small GTPase CED-10 Rac and the cytoskeletal regulator ABI-1, acts to rearrange the cytoskeleton of the engulfing cell. The CED-10 Rac pathway is also required for proper migration of the distal tip cells (DTCs) during the development of the C. elegans gonad. The second pathway includes the receptor tyrosine kinase CED-1 and might recruit membranes to extend the surface of the engulfing cell. Cbl, the mammalian homolog of the C. elegans E3 ubiquitin ligase and adaptor protein SLI-1, interacts with Rac and Abi2 and modulates the actin cytoskeleton, suggesting it might act in engulfment. Our genetic studies indicate that SLI-1 inhibits apoptotic cell engulfment and DTC migration independently of the CED-10 Rac and CED-1 pathways. We found that the RING finger domain of SLI-1 is not essential to rescue the effects of SLI-1 deletion on cell migration, suggesting that its role in this process is ubiquitin ligase-independent. We propose that SLI-1 opposes the engulfment of apoptotic cells via a previously unidentified pathway.National Cancer Institute (U.S.) (Award K08CA104890

Clinical Use and Therapeutic Potential of IVIG/SCIG, Plasma-Derived IgA or IgM, and Other Alternative Immunoglobulin Preparations

Intravenous and subcutaneous immunoglobulin preparations, consisting of IgG class antibodies, are increasingly used to treat a broad range of pathological conditions, including humoral immune deficiencies, as well as acute and chronic inflammatory or autoimmune disorders. A plethora of Fab- or Fc-mediated immune regulatory mechanisms has been described that might act separately or in concert, depending on pathogenesis or stage of clinical condition. Attempts have been undertaken to improve the efficacy of polyclonal IgG preparations, including the identification of relevant subfractions, mild chemical modification of molecules, or modification of carbohydrate side chains. Furthermore, plasma-derived IgA or IgM preparations may exhibit characteristics that might be exploited therapeutically. The need for improved treatment strategies without increase in plasma demand is a goal and might be achieved by more optimal use of plasma-derived proteins, including the IgA and the IgM fractions. This article provides an overview on the current knowledge and future strategies to improve the efficacy of regular IgG preparations and discusses the potential of human plasma-derived IgA, IgM, and preparations composed of mixtures of IgG, IgA, and IgM

Quantifying the Proteolytic Release of Extracellular Matrix-Sequestered VEGF with a Computational Model

BACKGROUND: VEGF proteolysis by plasmin or matrix metalloproteinases (MMPs) is believed to play an important role in regulating vascular patterning in vivo by releasing VEGF from the extracellular matrix (ECM). However, a quantitative understanding of the kinetics of VEGF cleavage and the efficiency of cell-mediated VEGF release is currently lacking. To address these uncertainties, we develop a molecular-detailed quantitative model of VEGF proteolysis, used here in the context of an endothelial sprout. METHODOLOGY AND FINDINGS: To study a cell's ability to cleave VEGF, the model captures MMP secretion, VEGF-ECM binding, VEGF proteolysis from VEGF165 to VEGF114 (the expected MMP cleavage product of VEGF165) and VEGF receptor-mediated recapture. Using experimental data, we estimated the effective bimolecular rate constant of VEGF165 cleavage by plasmin to be 328 M(-1) s(-1) at 25 degrees C, which is relatively slow compared to typical MMP-ECM proteolysis reactions. While previous studies have implicated cellular proteolysis in growth factor processing, we show that single cells do not individually have the capacity to cleave VEGF to any appreciable extent (less than 0.1% conversion). In addition, we find that a tip cell's receptor system will not efficiently recapture the cleaved VEGF due to an inability of cleaved VEGF to associate with Neuropilin-1. CONCLUSIONS: Overall, VEGF165 cleavage in vivo is likely to be mediated by the combined effect of numerous cells, instead of behaving in a single-cell-directed, autocrine manner. We show that heparan sulfate proteoglycans (HSPGs) potentiate VEGF cleavage by increasing the VEGF clearance time in tissues. In addition, we find that the VEGF-HSPG complex is more sensitive to proteases than is soluble VEGF, which may imply its potential relevance in receptor signaling. Finally, according to our calculations, experimentally measured soluble protease levels are approximately two orders of magnitude lower than that needed to reconcile levels of VEGF cleavage seen in pathological situations

Viscoelastic phase separation in polymer blends

In this paper, the dynamics and morphology of viscoelastic phase separation in polymer blends is investigated based on the two-fluid model in two dimensions. At critical composition, we have carefully checked the role of shear modulus, without taking account of bulk modulus. The results show that the higher shear modulus component tends to form a dispersed phase in the intermediate stage of phase separation, if the difference between the shear moduli of the components is large enough. This is opposite to the role of bulk modulus, that the higher bulk modulus component forms a networklike pattern without taking account of the shear modulus even if it is the minority phase. The morphological formation is determined by the competition of opposite effects of shear modulus and bulk modulus. For polymer blends at critical composition, the bulk modulus difference leads to a networklike pattern formed by the higher modulus component in the intermediate stage of phase separation. But if the difference between the shear moduli of the components is large enough, a co-continuous structure is observed, resulting from the competition between shear and bulk moduli. For off-critical composition, difference in bulk modulus also leads to a networklike pattern of the component with higher bulk modulus in the intermediate stage of phase separation, but phase inversion is observed rapidly. A small difference between the shear moduli of the components can support the networklike pattern to continue for longer time. But the networklike pattern does not occur for large difference between shear moduli

Preparation of oriented liquid-crystalline/isotropic block copolymer films with parallel or perpendicular arrangement of smectic layers and lamellar microdomains

Communication: Films of a symmetric liquid- crystalline/isotropic block copolymer consisting of a smectic LC side-chain polymer and polystyrene were prepared by solvent casting from solution and from the isotropic melt. By annealing the solvent-cast film in the S-A phase an oriented microphase- separated film of lamellar morphology was obtained in which both the lamellae of the block copolymer and the smectic layers of the LC block were oriented parallel to the film surface. A lamellar morphology with perpendicular orientation of lamellae and smectic layers was generated by cooling the block copolymer from the melt

Preparation of oriented liquid-crystalline/isotropic block copolymer films with parallel or perpendicular arrangement of smectic layers and lamellar microdomains

Communication: Films of a symmetric liquid- crystalline/isotropic block copolymer consisting of a smectic LC side-chain polymer and polystyrene were prepared by solvent casting from solution and from the isotropic melt. By annealing the solvent-cast film in the S-A phase an oriented microphase- separated film of lamellar morphology was obtained in which both the lamellae of the block copolymer and the smectic layers of the LC block were oriented parallel to the film surface. A lamellar morphology with perpendicular orientation of lamellae and smectic layers was generated by cooling the block copolymer from the melt

Rheologische und rheooptische Untersuchung der Phaseninversion in reaktiven Kautschuk/Thermoplast Blends - Einfluss von Viskositaet, Grenzflaechenspannung und Viskoelastizitaet Schlussbericht

SIGLEAvailable from TIB Hannover: F03B895 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekArbeitsgemeinschaft Industrieller Forschungsvereinigungen 'Otto von Guericke' e.V. (AIF), Koeln (Germany); Bundesministerium fuer Wirtschaft und Technologie (BMWi), Berlin (Germany)DEGerman

Entwicklung einer rheooptischen Methode zur Kontrolle der Morphologie von Polymerblends in der Scherstroemung Schlussbericht

Available from TIB Hannover: DtF QN1(66,44) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEArbeitsgemeinschaft Industrieller Forschungsvereinigungen 'Otto von Guericke' e.V. (AIF), Koeln (Germany)DEGerman