LFA-1 and Kindlin-3 enable the collaborative transport of SLP-76 microclusters by myosin and dynein motors

Integrin engagement within the immune synapse enhances T cell activation, but our understanding of this process is incomplete. In response to T cell receptor (TCR) ligation, SLP-76 (LCP2), ADAP (FYB), and SKAP-55 (SKAP1) are recruited into microclusters and activate integrins via the effectors Talin-1 and Kindlin-3. We postulated that integrins influence the centripetal transport and signaling of SLP-76 microclusters via these linkages. We show that contractile myosin filaments surround and are co-transported with SLP-76 microclusters, and that TCR ligand density governs the centripetal movement of both structures. Centripetal transport requires formin activity, actomyosin contraction, microtubule integrity, and dynein motor function. Although immobilized VLA-4 (a4b1) and LFA-1 (aLb2) ligands arrest the centripetal movement of SLP-76 microclusters and myosin filaments, VLA-4 acts distally, while LFA-1 acts in the lamellum. Integrin b2, Kindlin-3, and Zyxin are required for complete centripetal transport, while integrin b1 and Talin-1 are not. CD69 upregulation is similarly dependent on integrin b2, Kindlin-3, and Zyxin, but not Talin-1. These findings highlight the integration of cytoskeletal systems within the immune synapse and reveal extracellular ligand-independent roles for LFA-1 and Kindlin-3.

THE REFLECTION OF OWN ABSENCE IN THE WORLD BY LYRICAL SUBJECTS OF LATE WORKS BY EGOR LETOV

t. The article is dedicated to the late works of Yegor Letov and explores the lyrical subject’s perception of the world in which he himself and people like him will no longer exist. The topic touches on the theme of death which is clearly manifesting itself in all works of the rock poet. It reveals that Letov’s lyrical subject fixes his absence in the world turning to images of nature that remain unchanged, to elements of people’s everyday life that persist without him and to the space of artistic work the contemporary to the poet. In parallel there is the self-reflection of Letov’s lyrical subject as a people’s rock poet who values living life and does not aim for pecuniary well-being. The lyrical subject of Letov when thinking about the life that will continue after the passing of his generation realizes that the world will turn upside down and become uncomfortable and unacceptable for him. The world of a deceased person will separate from the big world and begin a centripetal movement while the reverse of return will no longer be possible. An important motive is the distortion of memory about a real person, which will inevitably occur after an individual leaves the general world. Human himself will not be able to influence his posthumous fate. However shortly before his death Letov comes to a rather optimistic conclusion that he managed to transmit to living humans an undistorted healthy element of his world vision.

Macrophage centripetal migration drives spontaneous healing process after spinal cord injury

Traumatic spinal cord injury (SCI) brings numerous inflammatory cells, including macrophages, from the circulating blood to lesions, but pathophysiological impact resulting from spatiotemporal dynamics of macrophages is unknown. Here, we show that macrophages centripetally migrate toward the lesion epicenter after infiltrating into the wide range of spinal cord, depending on the gradient of chemoattractant C5a. However, macrophages lacking interferon regulatory factor 8 (IRF8) cannot migrate toward the epicenter and remain widely scattered in the injured cord with profound axonal loss and little remyelination, resulting in a poor functional outcome after SCI. Time-lapse imaging and P2X/YRs blockade revealed that macrophage migration via IRF8 was caused by purinergic receptors involved in the C5a-directed migration. Conversely, pharmacological promotion of IRF8 activation facilitated macrophage centripetal movement, thereby improving the SCI recovery. Our findings reveal the importance of macrophage centripetal migration via IRF8, providing a novel therapeutic target for central nervous system injury.

ASEAN in the Age of Anti-Globalization: Compartmentalized Regionalism(s) and Three Trajectories

This essay attempts to examine the prospect of ASEAN integration in the age of anti-globalization by understanding ASEAN as a compartmentalized regionalism. It argues that discussions on the prospect of ASEAN are actually discussions on the trajectories of two separate regional projects: economic regionalism and political security regionalism. It must be noted that we often have difficulties separating the two because their evolution has so far been marked by centripetal movement towards liberal tradition in the two regional projects. However, since we are entering the age of anti-globalization, this is changing. To make an educated guess on the future of ASEAN regionalism(s), I argue that we should focus our attention to three main indicators: (1) Structural: will the international system be cooperative or competitive multipolar system? (2) National elite orientation: will the liberal elites and technocracy in ASEAN countries remain liberal, or will nationalist elites take charge?; and (3) Public sentiment: how big is the positive or negative sentiment towards economic liberalization?

The HIV-1 protein Vpr impairs phagosome maturation by controlling microtubule-dependent trafficking

Human immunodeficiency virus type 1 (HIV-1) impairs major functions of macrophages but the molecular basis for this defect remains poorly characterized. Here, we show that macrophages infected with HIV-1 were unable to respond efficiently to phagocytic triggers and to clear bacteria. The maturation of phagosomes, defined by the presence of late endocytic markers, hydrolases, and reactive oxygen species, was perturbed in HIV-1–infected macrophages. We showed that maturation arrest occurred at the level of the EHD3/MICAL-L1 endosomal sorting machinery. Unexpectedly, we found that the regulatory viral protein (Vpr) was crucial to perturb phagosome maturation. Our data reveal that Vpr interacted with EB1, p150Glued, and dynein heavy chain and was sufficient to critically alter the microtubule plus end localization of EB1 and p150Glued, hence altering the centripetal movement of phagosomes and their maturation. Thus, we identify Vpr as a modulator of the microtubule-dependent endocytic trafficking in HIV-1–infected macrophages, leading to strong alterations in phagolysosome biogenesis.