Enabled Negatively Regulates Diaphanous-Driven Actin Dynamics In Vitro and In Vivo

Actin regulators facilitate cell migration by controlling cell protrusion architecture and dynamics. As the behavior of individual actin regulators becomes clear, we must address why cells require multiple regulators with similar functions and how they cooperate to create diverse protrusions. We characterized Diaphanous (Dia) and Enabled (Ena) as a model, using complementary approaches: cell culture, biophysical analysis, and Drosophila morphogenesis. We found that Dia and Ena have distinct biochemical properties that contribute to the different protrusion morphologies each induces. Dia is a more processive, faster elongator, paralleling the long, stable filopodia it induces in vivo, while Ena promotes filopodia with more dynamic changes in number, length, and lifetime. Acting together, Ena and Dia induce protrusions distinct from those induced by either alone, with Ena reducing Dia-driven protrusion length and number. Consistent with this, EnaEVH1 binds Dia directly and inhibits DiaFH1FH2-mediated nucleation in vitro. Finally, Ena rescues hemocyte migration defects caused by activated Dia

Specific Class I HLA Supertypes but Not HLA Zygosity or Expression Are Associated with Outcomes following HLA-Matched Allogeneic Hematopoietic Cell Transplant: HLA Supertypes Impact Allogeneic HCT Outcomes

Maximizing the probability of antigen presentation to T cells through diversity in HLAs can enhance immune responsiveness and translate into improved clinical outcomes, as evidenced by the association of heterozygosity and supertypes at HLA class I loci with improved survival in patients with advanced solid tumors treated with immune checkpoint inhibitors. We investigated the impact of HLA heterozygosity, supertypes, and surface expression on outcomes in adult and pediatric patients with acute myeloid leukemia (AML), myelodysplastic syndrome, acute lymphoblastic leukemia, and non-Hodgkin lymphoma who underwent 8/8 HLA-matched, T cell replete, unrelated, allogeneic hematopoietic cell transplant (HCT) from 2000 to 2015 using patient data reported to the Center for International Blood and Marrow Transplant Research. HLA class I heterozygosity and HLA expression were not associated with overall survival, relapse, transplant-related mortality (TRM), disease-free survival (DFS), and acute graft-versus-host disease following HCT. The HLA-B62 supertype was associated with decreased TRM in the entire patient cohort (hazard ratio [HR], 0.79; 95% CI, 0.69 to 0.90; P = .00053). The HLA-B27 supertype was associated with worse DFS in patients with AML (HR = 1.21; 95% CI, 1.10 to 1.32; P = .00005). These findings suggest that the survival benefit of HLA heterozygosity seen in solid tumor patients receiving immune checkpoint inhibitors does not extend to patients undergoing allogeneic HCT. Certain HLA supertypes, however, are associated with TRM and DFS, suggesting that similarities in peptide presentation between supertype members play a role in these outcomes. Beyond implications for prognosis following HCT, these findings support the further investigation of these HLA supertypes and the specific immune peptides important for transplant outcomes

Postscript: Beirut Life and Debt Version 2.016

This essay continues a project begun a decade ago with the article, “A Matter of Life and Debt: The Untold Costs of Rafiq Hariri’s New Beirut.” This new article, or “Postscript,” begins by examining the reception of that first investigation and responds to one criticism directed at the original essay: that it proffers an unfairly pessimistic profile of the reconstruction effort generally and of its prime mover specifically, the now-deceased Prime Minister Rafiq Hariri. This paper follows a cost/benefits analysis of the project and the company behind it, Solidere, and examines two other Solidere-styled developments abroad, both results of the company’s attempts to monetize its so-called “brand.” The first of these, “Abdali,” is in Amman. The second of these comprises a trio of projects that SI prepared for Sheikh Zayed City in metropolitan Cairo. The paper argues that Solidere’s failure to disclose the dubious financial dealings behind such projects further erodes the credibility of a company for whom the notion of “business as usual” works first and foremost to benefit the few at the expense of the many

Influence of physico-chemical properties, macro- and microstructure on osteoinductive potential of calcium-phosphate ceramics

Osteoinduction by biomaterials that initially do not contain bone morphogenetic proteins and other growth factors has been shown to be a real phenomenon by many investigators in the past two decades. Although it is well-known that a material needs to meet very specific requirements in terms of physico-chemical and structural properties in order to be osteoinductive, the underlying mechanism of osteoinduction is not fully unraveled yet. In the present study we investigated parameters which are of importance for the osteoinductive potential of biomaterials by comparing four biphasic calcium-phosphate and a carbonated apatite ceramic. The results showed that the presence of micropores, by which the specific surface area of a material is increased, is essential for the material's osteoinductivity. However, if the surface area is too high, or material is too resorbable because of its chemical composition, the implant might degrade and lose its shape. In that case, ectopic bone formation does not occur, as a relatively stable surface is needed to facilitate new bone growth

Osteoinduction by biomaterials - Physicochemical and structural influences

Osteoincluction by biomaterials has been shown to be a real phenomenon by many investigators in the last decade. The exact mechanism of this phenomenon is, however, still largely unknown. This in vivo study in goats was performed to get insight into processes governing the phenomenon of osteoinduction by biomaterials and had four main goals: (i) to further investigate the influence of physicochemical properties and structure on biomaterial osteoinductive potential, (ii) to investigate the influence of implant size on the amount of induced bone, (iii) to investigate implantation site dependence, and (iv) to investigate changes occurring on the surface of the material after implantation. Intramuscular implantations of four different biphasic calcium phosphate ceramics, consisting of hydroxyapatite and beta-tricalcium phosphate and a carbonated apatite ceramic, indicated that, for a maximal osteoinductive potential, there is an optimal specific surface area for each material type. It was further shown that a decrease of the implant size with a half significantly decreased the relative amount of induced bone. In addition, subcutaneous implantation did not give rise to ectopic bone formation in any of the animals, while bone was induced in most animals intramuscularly. Analysis of the surfaces of the materials after subcutaneous implantation inside diffusion chambers indicated that the increased specific surface area leads to more surface reactivity, which is hypothesized to be essential for osteoinductivity by biomaterials. (c) 2006 Wiley Periodicals, Inc