HIV-1 Nef-Src Family Kinase Interaction: A Novel Target for the Inhibition of HIV-1 Pathogenesis

Human immunodeficiency virus-1 (HIV-1) is a lentivirus responsible for development of AIDS. In addition to typical retroviral proteins (Gag, Pol and Env), primate lentiviruses like HIV-1 encode two regulatory (Tat and Rev) and four accessory proteins (Vif, Vpu, Vpr and Nef). The HIV-1 accessory factor Nef is essential for high-titer viral replication and AIDS progression. Nef function requires interaction with many host cell proteins, including specific members of the Src kinase family. In this dissertation project, I explored whether Src-family kinase (SFK) activation is a conserved property of nef alleles from a wide range of primary HIV-1 isolates and its sensitivity to selective pharmacological inhibitors. Representative Nef proteins from the major HIV-1 subtypes A1, A2, B, C, F1, F2, G, H, J and K strongly activated Hck and Lyn as well as c-Src to a lesser extent, demonstrating for the first time that SFK activation is a highly conserved property of primary M-group HIV-1 Nef isolates. Moreover, patient-derived Nef proteins also strongly activated Hck. Recently, our group identified 4-amino diphenylfuranopyrimidines (DFPs) and diphenylpyrazolyldiazene (PPD-B9) compounds that selectively inhibit Nef-dependent SFK activation as well as HIV replication. To determine whether these novel compounds exhibit broad-spectrum Nef-dependent antiretroviral activity against HIV-1, I first constructed chimeric forms of the viral strain NL4-3 expressing the same 10 primary nef alleles. The infectivity and replication of these Nef chimeras was indistinguishable from that of wild-type in three distinct cell lines (MT2, U87MG and CEM-T4). Importantly, the 4-aminopropanol and 4-aminobutanol derivatives of DFP as well as PPD-B9 potently inhibited the replication of all chimeric forms of HIV-1 in both U87MG and CEM-T4 cells in a Nef-dependent manner. The effects of these compounds against HIV replication correlated with inhibition of Nef-dependent activation of endogenous SFKs. My results demonstrate that the activation of Hck, Lyn and c-Src by Nef is highly conserved among all major clades of HIV-1 and that selective targeting of this pathway uniformly inhibits HIV-1 replication. My results have strong public health significance for developing therapeutics against current drug resistant variants of HIV-1

A Bird view on Heat Transfer Enhancement in a Tube with Twisted Tape Insert

Different kinds of methods used to enhance heat transfer rate of heat exchanger without influencing overall performance of the heat exchanger referred as heat transfer enhancement techniques. This technique are categorized into three types i.e. active technique, passive technique, and compound technique Some of the application of heat exchanger which require enhancement in heat transfer are – Air conditioning equipments, radiators, refrigerators, thermal Power plants etc. The intention of enhanced heat transfer is to encourage high heat fluxes, this result in reduction in size of heat exchanger. The present paper is a review of research work in last decade on heat transfer enhancement in a Heat Exchanger DOI: 10.17762/ijritcc2321-8169.15037

NANOFILLERS IN SURFACE COATINGS: A REVIEW

Nanofillers since many years have a high significance in various polymer based industries. Nanocoatings are coatings that are produced by usage of some component at nanoscale to obtain desired properties. Much research is being done to develop effective material combinations of polymer nanocomposites with tailored properties. Nanocomposite is a multiphase solid material where at least one of the phases should have dimensions of less than 100 nm. The properties of composites are largely dependent on the area of interface surface and the intensity of intermolecular interaction between the materials of the matrix and the filler. Nanoscale dispersion of filler or controlled nanostructures in the composite can introduce new physical properties and novel behaviors that are absent in the unfilled matrices. This paper reviews various types of fillers used for different applications in coatings such as anticorrosion resistant paints, ceramic coatings, super hydrophobic coatings, self-healing coatings, sol gel coatings, etc

POLYMERIC PARTICLE BOARD:A SUSTAINABLE SUBSTITUTE TO WOODEN BOARDS

The aim of this paper is to give overview about particleboards and its development.Particle boards are wood composite prepared from wood waste , stalks, wood shaving, etc and polymeric resin.Urea-Formaldehyde(UF) and Phenol Formaldehye (PF) being widely used resin for preparation of particle board.Here we discuss about different types wood and resin used for manufacture of particleboard.The effect of different woods and resin on properties like internal bond strength, thickness swelling, modulus of rupture, modulus of elasticity and water absorption.Various chemical additives used to modify the properties of particle board and also fire retardant property of particle board.World is leading towards sustainable development thus use of particle board can help us in achieving a small part of it.

HIV-1 Nef interaction influences the ATP-binding site of the Src-family kinase, Hck

Background: Nef is an HIV-1 accessory protein essential for viral replication and AIDS progression. Nef interacts with a multitude of host cell signaling partners, including members of the Src kinase family. Nef preferentially activates Hck, a Src-family kinase (SFK) strongly expressed in macrophages and other HIV target cells, by binding to its regulatory SH3 domain. Recently, we identified a series of kinase inhibitors that preferentially inhibit Hck in the presence of Nef. These compounds also block Nef-dependent HIV replication, validating the Nef-SFK signaling pathway as an antiretroviral drug target. Our findings also suggested that by binding to the Hck SH3 domain, Nef indirectly affects the conformation of the kinase active site to favor inhibitor association. Results: To test this hypothesis, we engineered a "gatekeeper" mutant of Hck with enhanced sensitivity to the pyrazolopyrimidine tyrosine kinase inhibitor, NaPP1. We also modified the RT loop of the Hck SH3 domain to enhance interaction of the kinase with Nef. This modification stabilized Nef:Hck interaction in solution-based kinase assays, as a way to mimic the more stable association that likely occurs at cellular membranes. Introduction of the modified RT loop rendered Hck remarkably more sensitive to activation by Nef, and led to a significant decrease in the K mssssfor ATP as well as enhanced inhibitor potency. Conclusions: These observations suggest that stable interaction with Nef may induce Src-family kinase active site conformations amenable to selective inhibitor targeting. © 2012 Pene-Dumitrescu et al; licensee BioMed Central Ltd

The effect of maleinized linseed oil (MLO) on mechanical performance of poly(lactic acid)-thermoplastic starch (PLA-TPS) blends

[EN] In this work, poly(lactic acid), PLA and thermoplastic starch, TPS blends (with a fixed content of 30 wt.% TPS) were prepared by melt extrusion process to increase the low ductile properties of PLA. The TPS used contains an aliphatic/aromatic biodegradable polyester (AAPE) that provides good resistance to aging and moisture. This blend provides slightly improved ductile properties with an increase in elongation at break of 21.5% but phase separation is observed due to the lack of strong interactions between the two polymers. Small amounts of maleinized linseed oil (MLO) can positively contribute to improve the ductile properties of these blends by a combined plasticizing-compatibilizing effect. The elongation at break increases over 160% with the only addition of 6 phr MLO. One of the evidence of the plasticizing-compatibilizing effect provided by MLO is the change in the glass transition temperature (Tg) with a decrease of about 10 °C. Field emission scanning electron microscopy (FESEM) of PLA-TPS blends with varying amounts of maleinized linseed oil also suggests an increase in compatibility.This research was supported by the Ministry of Economy and Competitiveness-MINECO, Ref: MAT2014-59242-C2-1-R. Authors also thank to "Conselleria d'Educacio, Cultura i Esport"-Generalitat Valenciana, Ref: GV/2014/008 for financial support.Ferri Azor, JM.; García García, D.; Sánchez Nacher, L.; Fenollar Gimeno, OÁ.; Balart Gimeno, RA. (2016). The effect of maleinized linseed oil (MLO) on mechanical performance of poly(lactic acid)-thermoplastic starch (PLA-TPS) blends. Carbohydrate Polymers. 147:60-68. https://doi.org/10.1016/j.carbpol.2016.03.082S606814

Discovery of a diaminoquinoxaline benzenesulfonamide antagonist of HIV-1 Nef function using a yeast-based phenotypic screen

Background: HIV-1 Nef is a viral accessory protein critical for AIDS progression. Nef lacks intrinsic catalytic activity and binds multiple host cell signaling proteins, including Hck and other Src-family tyrosine kinases. Nef binding induces constitutive Hck activation that may contribute to HIV pathogenesis by promoting viral infectivity, replication and downregulation of cell-surface MHC-I molecules. In this study, we developed a yeast-based phenotypic screen to identify small molecules that inhibit the Nef-Hck complex. Results: Nef-Hck interaction was faithfully reconstituted in yeast cells, resulting in kinase activation and growth arrest. Yeast cells expressing the Nef-Hck complex were used to screen a library of small heterocyclic compounds for their ability to rescue growth inhibition. The screen identified a dihydrobenzo-1,4-dioxin-substituted analog of 2-quinoxalinyl-3-aminobenzene-sulfonamide (DQBS) as a potent inhibitor of Nef-dependent HIV-1 replication and MHC-I downregulation in T-cells. Docking studies predicted direct binding of DQBS to Nef which was confirmed in differential scanning fluorimetry assays with recombinant purified Nef protein. DQBS also potently inhibited the replication of HIV-1 NL4-3 chimeras expressing Nef alleles representative of all M-group HIV-1 clades.Conclusions: Our findings demonstrate the utility of a yeast-based growth reversion assay for the identification of small molecule Nef antagonists. Inhibitors of Nef function discovered with this assay, such as DQBS, may complement the activity of current antiretroviral therapies by enabling immune recognition of HIV-infected cells through the rescue of cell surface MHC-I. © 2013 Trible et al.; licensee BioMed Central Ltd

The effect of maleinized linseed oil as biobased plasticizer in poly (lactic acid)-based formulations

[EN] The use of maleinized linseed oil (MLO) as a potential biobased plasticizer for poly(lactic acid) (PLA) industrial formulations with improved toughness was evaluated. MLO content varied in the range 0-20 phr (parts by weight of MLO per hundred parts by weight of PLA). Mechanical, thermal and morphological characterizations were used to assess the potential of MLO as an environmentally friendly plasticizer for PLA formulations. Dynamic mechanical thermal analysis and differential scanning calorimetry revealed anoticeable decrease in the glass transition temperature of about 6.5 degrees C compared to neat PLA. In addition, the cold crystallization process was favoured with MLO content due to the increased chain mobility that the plasticizer provides. PLA toughness was markedly improved in formulations with 5 phr MLO, while maximum elongation at break was obtained for PLA formulations plasticized with MLO content in the range 15-20 phr. Scanning electron microscopy revealed evidence of plastic deformation. Nevertheless, phase separation was detected in plasticized PLA formulations with high MLO content (above 15-20 phr MLO), which had a negative effect on overall toughness. (C) 2017 Society of Chemical IndustryThis research was funded by the Ministry of Economy and Competitiveness - MINECO, ref. MAT2014-59242-C2-1-R. The authors also thank Conselleria d'Educacio, Cultura i Esport - Generalitat Valenciana, ref. GV/2014/008, for financial support. DG-G thanks the Spanish Ministry of Education, Culture and Sports for financial support through an FPU grant (FPU13/06011).Ferri, J.; Garcia-Garcia, D.; Montanes, N.; Fenollar, O.; Balart, R. (2017). The effect of maleinized linseed oil as biobased plasticizer in poly (lactic acid)-based formulations. Polymer International. 66(6):882-891. https://doi.org/10.1002/pi.5329S88289166

Nef Alleles from All Major HIV-1 Clades Activate Src-Family Kinases and Enhance HIV-1 Replication in an Inhibitor-Sensitive Manner

The HIV-1 accessory factor Nef is essential for high-titer viral replication and AIDS progression. Nef function requires interaction with many host cell proteins, including specific members of the Src kinase family. Here we explored whether Src-family kinase activation is a conserved property of Nef alleles from a wide range of primary HIV-1 isolates and their sensitivity to selective pharmacological inhibitors. Representative Nef proteins from the major HIV-1 subtypes A1, A2, B, C, F1, F2, G, H, J and K strongly activated Hck and Lyn as well as c-Src to a lesser extent, demonstrating for the first time that Src-family kinase activation is a highly conserved property of primary M-group HIV-1 Nef isolates. Recently, we identified 4-amino substituted diphenylfuropyrimidines (DFPs) that selectively inhibit Nef-dependent activation of Src-family kinases as well as HIV replication. To determine whether DFP compounds exhibit broad-spectrum Nef-dependent antiretroviral activity against HIV-1, we first constructed chimeric forms of the HIV-1 strain NL4-3 expressing each of the primary Nef alleles. The infectivity and replication of these Nef chimeras was indistinguishable from that of wild-type virus in two distinct cell lines (U87MG astroglial cells and CEM-T4 lymphoblasts). Importantly, the 4-aminopropanol and 4-aminobutanol derivatives of DFP potently inhibited the replication of all chimeric forms of HIV-1 in both U87MG and CEM-T4 cells in a Nef-dependent manner. The antiretroviral effects of these compounds correlated with inhibition of Nef-dependent activation of endogenous Src-family kinases in the HIV-infected cells. Our results demonstrate that the activation of Hck, Lyn and c-Src by Nef is highly conserved among all major clades of HIV-1 and that selective targeting of this pathway uniformly inhibits HIV-1 replication