Activated leukocyte cell adhesion molecule (ALCAM) has been proposed to mediate leukocyte migration across the blood-brain barrier (BBB) in multiple sclerosis or experimental autoimmune encephalomyelitis (EAE). Here, we confirmed vascular ALCAM expression in human brain tissue samples in situ and on two different human in vitro BBB models. Antibody-mediated inhibition of ALCAM reduced diapedesis of human CD4 Th1 but not of Th17 cells across the human BBB in vitro. In accordance to human Th1 cells, mouse Th1 cells showed reduced diapedesis across an ALCAM in vitro BBB model under static but no longer under flow conditions. In contrast to the limited role of ALCAM in T cell extravasation across the BBB, we found a contribution of ALCAM to rolling, adhesion, and diapedesis of human CD14 monocytes across the human BBB under flow and static conditions. Taken together, our study highlights the potential differences in the CNS expression of ALCAM in mouse and human and supports a prominent role for ALCAM in the multi-step extravasation of monocytes across the BBB.
Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy.
A suite of zwitterionic pyridylidene-based merocyanines that contain no interconnecting p-bridge between the donor and acceptor rings has been synthesised and their second-order NLO properties evaluated largely by semi-empirical computational methods (MOPAC 97/AM1). Contrary to expectation, increasing the degree of inter-ring twist (h), at least up to 55u, in these new pyridylideneazolone chromophores is found to have little or no effect on the figure of merit [mb( 0 )]. An X-ray crystallographic appraisal of one of these chromophores, 14, reveals however that the twist angle (albeit in the solid state) is greater than that predicted by computation and that all other features are consistent with the highly zwitterionic nature of these systems. In spite of this, a combination of factors-insufficient acceptor strength, insufficient extent of conjugation and perhaps insufficient twist angle, in particular-clearly leads to the low values of the quadratic hyperpolarisabilities. The trade-off between targeting a more modest b from a minimum of p-conjugating framework between D and A (and therefore synthetic expediency) and seeking a moderate-to-high dipole moment has therefore resulted in only low figures of merit for these systems.Calculations performed on a suite of readily accessible, isoelectronic cyanines, in which the acceptor is a stabilised cyclopentadienide carbocycle rather than a heterocycle, have revealed the potential that these systems, exemplified by 27, have as NLO chromophores. Representative polymer-tetherable derivatives of this system have been prepared as have the corresponding TDI-based polyurethanes.
Kaposi sarcoma is the most common human herpesvirus 8 (HHV-8)-related disease described after solid organ transplantation. Multicentric Castleman disease and hemophagocytic syndrome are other potential HHV-8-induced entities but are less frequently reported. We describe the case of a liver transplant recipient who presented with an acute febrile illness 1 year after transplantation with a rapidly fatal outcome. Autopsy revealed 3 distinct HHV-8-related entities: Kaposi sarcoma, HHV-8-associated multicentric Castleman disease with microlymphomas and a severe hemophagocytic syndrome. Retrospective serologic tests suggested that HHV-8 was likely transmitted by the seropositive donor at the time of transplantation. To our knowledge, this is the first case of copresentation of 3 clinical presentations of HHV-8-mediated human disease in the post-transplant setting. Considering the absence of systematic screening of organ donors/recipients for HHV-8 infection, HHV-8-related illness should be suspected in transplant recipients who present with acute febrile illness, systemic symptoms, lymphadenopathies, and/or multiorgan failure to rapidly document the diagnosis and provide timely an adequate treatment.
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