Structural specializations of α4β7\alpha_4 \beta_7, an integrin that mediates rolling adhesion

The lymphocyte homing receptor integrin $\alpha_4 \beta_7$ is unusual for its ability to mediate both rolling and firm adhesion. $\alpha_4 \beta_1$ and $\alpha_4 \beta_7$ are targeted by therapeutics approved for multiple sclerosis and Crohn’s disease. Here, we show by electron microscopy and crystallography how two therapeutic Fabs, a small molecule (RO0505376), and mucosal adhesion molecule-1 (MAdCAM-1) bind α4β7. A long binding groove at the $\alpha_4 -\beta_7$interface for immunoglobulin superfamily domains differs in shape from integrin pockets that bind Arg-Gly-Asp motifs. RO0505376 mimics an Ile/Leu-Asp motif in $\alpha_4$ ligands, and orients differently from Arg-Gly-Asp mimics. A novel auxiliary residue at the metal ion–dependent adhesion site in $\alpha_4 \beta_7$ is essential for binding to MAdCAM-1 in $Mg^{2+}$ yet swings away when RO0505376 binds. A novel intermediate conformation of the $\alpha_4 \beta_7$ headpiece binds MAdCAM-1 and supports rolling adhesion. Lack of induction of the open headpiece conformation by ligand binding enables rolling adhesion to persist until integrin activation is signaled

Skap2 is required for β2 integrin-mediated neutrophil recruitment and functions.

Integrin activation is required for neutrophil functions. Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency (LAD) syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. The Src kinase-associated phosphoprotein 2 (Skap2) is involved in integrin functions in different leukocyte subtypes. However, the role of Skap2 in β2 integrin activation and neutrophil recruitment is unknown. In this study, we demonstrate the crucial role of Skap2 in regulating actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin cytoplasmic domain, thereby being indispensable for β2 integrin activation and neutrophil recruitment. The direct interaction of Skap2 with the Wiskott-Aldrich syndrome protein via its SH3 domain is critical for integrin activation and neutrophil recruitment in vivo. Furthermore, Skap2 regulates integrin-mediated outside-in signaling events and neutrophil functions. Thus, Skap2 is essential to activate the β2 integrins, and loss of Skap2 function is sufficient to cause a LAD-like phenotype in mice

The marginated pool

The pulmonary circulation harbors a large intravascular reservoir of leukocytes refered to as the Marginated Pool. This marginated pool is balanced by propeling and retaining forces acting on leukocytes during their passage through the pulmonary circulation. The present paper discusses these factors and their underlying mechanisms. Copyright (C) 2002 S. Karger AG, Basel

Development of flow focusing device for the visualization of leukocyte rolling adhesion

La microfluídica es un área de la microtecnología basada en chips de PDMS que está siendo utilizada cada vez más en multitud de aplicaciones. Una de estas aplicaciones es la investigación biomédica. La microfluídica o “Lab on a Chip” se ha convertido en una manera de realizar experimentos biomédicos y diagnósticos de una manera barata, rápida y eficaz. Cuando se realizan estudios sobre la extravasación leucocitaria utilizando chips microfluídicos, podemos observar la inconsistencia en la trayectoria de rodadura de los leucocitos debido a un flujo laminar. En este trabajo de fin de grado presentamos un método para centrar la interfaz de células en el centro de canal microfluídico. Cuando las células circulan por los sistemas microfluídicos, las células tienden a circular de manera aleatoria por los canales. Por tanto, con el sistema propuesto en este trabajo, dichas células serán redirigidas a la porción central del canal con el fin de recrear el fenómeno de rodadura presente en nuestro sistema circulatorio y así obtener información más detallada. Los resultados de este trabajo muestran la utilidad y la versatilidad de este dispositivo para experimentos relacionados

Carbon Nanotube Initiated Formation of Carbon Nanoscrolls

The unique topology and exceptional properties of carbon nanoscrolls (CNSs) have inspired unconventional nano-device concepts, yet the fabrication of CNSs remains rather challenging. Using molecular dynamics simulations, we demonstrate the spontaneous formation of a CNS from graphene on a substrate, initiated by a carbon nanotube (CNT). The rolling of graphene into a CNS is modulated by the CNT size, the carbon-carbon interlayer adhesion, and the graphene-substrate interaction. A phase diagram emerging from the simulations can offer quantitative guideline toward a feasible and robust physical approach to fabricating CNSs.Comment: 12 pages, 3 figure