Differential regulation of cell motility and invasion by FAK

Cell migration and invasion are fundamental components of tumor cell metastasis. Increased focal adhesion kinase (FAK) expression and tyrosine phosphorylation are connected with elevated tumorigenesis. Null mutation of FAK results in embryonic lethality, and FAK−/− fibroblasts exhibit cell migration defects in culture. Here we show that viral Src (v-Src) transformation of FAK−/− cells promotes integrin-stimulated motility equal to stable FAK reexpression. However, FAK−/− v-Src cells were not invasive, and FAK reexpression, Tyr-397 phosphorylation, and FAK kinase activity were required for the generation of an invasive cell phenotype. Cell invasion was linked to transient FAK accumulation at lamellipodia, formation of a FAK–Src-p130Cas–Dock180 signaling complex, elevated Rac and c-Jun NH2-terminal kinase activation, and increased matrix metalloproteinase expression and activity. Our studies support a dual role for FAK in promoting cell motility and invasion through the activation of distinct signaling pathways

A Variant of TNFR2-Fc Fusion Protein Exhibits Improved Efficacy in Treating Experimental Rheumatoid Arthritis

Etanercept, a TNF receptor 2-Fc fusion protein, is currently being used for the treatment of rheumatoid arthritis (RA). However, 25% to 38% of patients show no response which is suspected to be partially due to insufficient affinity of this protein to TNFα. By using computational protein design, we found that residue W89 and E92 of TNFR2 were critical for ligand binding. Among several mutants tested, W89Y/E92N displayed 1.49-fold higher neutralizing activity to TNFα, as compared to that of Etanercept. Surface plasmon resonance (SPR) based binding assay revealed that the equilibrium dissociation constant of W89Y/E92N to TNFα was 3.65-fold higher than that of Etanercept. In a rat model of collagen-induced arthritis (CIA), W89Y/E92N showed a significantly better ability than Etanercept in reducing paw swelling and improvement of arthritic joint histopathologically. These data demonstrate that W89Y/E92N is potentially a better candidate with improved efficacy in treating RA and other autoimmune diseases

Highly transparent conductive AZO/Zr50Cu50/AZO films in wide range of visible and near infrared wavelength grown by pulsed laser deposition

Novel AZO/Zr50Cu50/AZO tri-layer transparent conductive films with excellent transmittance in both visible and near infrared region were successfully prepared by pulsed laser deposition on glass substrates. The electrical and optical properties were investigated at various Zr50Cu50 thicknesses. As the AZO thickness was fixed at 50 nm and Zr50Cu50 thickness was varied between 1 and 18 nm, it was found that AZO (50 nm)/Zr50Cu50/AZO (50 nm) tri-layer films exhibited good conductivity and high transmittance in both visible and near infrared wavelength. Additionally, both the electrical and optical properties of AZO (50 nm)/Zr50Cu50 (2 nm)/AZO (50 nm) tri-layer films were found to be sensitive to the growth temperature. In this work, the lowest sheet resistance (43 Ω/□) and relatively high transmittance (∼80%) in the range of 400–2000 nm were achieved while the growth temperature was 350 °C. Furthermore, the AZO (50 nm)/Zr50Cu50 (2 nm)/AZO (50 nm) thin film deposited at 350 °C exhibits the highest figure of merit of 1.42 × 10−3 Ω−1, indicating that the multilayer is promising for coated glasses and thin film solar cells. Keywords: Transparent conductive oxide, AZO, Zr50Cu50, Electrical and optical properties, Visible and near infrared transmittanc

Activation of Lipid Metabolism Contributes to Interleukin-8 Production during Chlamydia trachomatis Infection of Cervical Epithelial Cells

Chlamydia trachomatis infection is the most common cause of bacterial sexually transmitted diseases. Infection of the urogenital tract by C. trachomatis causes chronic inflammation and related clinical complications. Unlike other invasive bacteria that induce a rapid cytokine/chemokine production, chlamydial infection induces delayed inflammatory response and proinflammatory chemokine production that is dependent on bacterial growth. We present data here to show that the lipid metabolism required for chlamydial growth contributes to Chlamydia-induced proinflammatory chemokine production. By gene microarray profiling, validated with biochemical studies, we found that C. trachomatis LGV2 selectively upregulated PTGS2 (COX2) and PTGER4 (EP4) in cervical epithelial HeLa 229 cells. COX2 is an enzyme that catalyzes the rate-limiting step of arachidonic acid conversion to prostaglandins, including prostaglandin E2 (PGE2) and other eicosanoids, whereas EP4 is a subtype of cell surface receptors for PGE2. We show that Chlamydia infection induced COX2 protein expression in both epithelial cells and peripheral blood mononuclear cells and promoted PGE2 release. Exogenous PGE2 was able to induce interleukin-8 release in HeLa 229 epithelial cells. Finally, we demonstrated that interleukin-8 induction by Chlamydia infection or PGE2 treatment was dependent on extracellular signal-regulated kinase/mitogen-activated protein activity. Together, these data demonstrate that the host lipid remodeling process required for chlamydial growth contributes to proinflammatory chemokine production. This study also highlights the importance of maintaining a balanced habitat for parasitic pathogens as obligate intracellular organisms