Interactions between endothelial cells and HIV-1.

Endothelial cells (EC) participate in inflammatory and immune reactions by producing and responding to soluble mediators. Human immunodeficiency virus (HIV)-1 profoundly alters the features of EC. In some anatomical districts, they are infected by the virus and may represent a relevant reservoir. During lymphomononuclear cell diapedesis, EC activate virus replication in crossing cells. Direct or indirect damage of EC is particularly relevant in central nervous system, where blood-brain barrier perturbation is pivotal in neuronal degeneration. The observed alterations of EC adhesive properties contribute in altered leukocyte traffic from blood to lymphoid organs and tissues and play a role in the onset of immune surveillance alteration. These alterations of EC functions are relevant for the general vasculopathy, which marks the acquired immunodeficiency syndrome, and in particular are instrumental in the pathogenesis of Kaposi's sarcoma. Here we discuss the biological and molecular activation of EC in HIV-1 infection that represents the basis to understand the pathogenesis of HIV-1 associated vascular diseases

Stable interaction between α5β1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1

During angiogenic remodeling, Ang-1, the ligand of Tie2 tyrosine kinase, is involved in vessel sprouting and stabilization through unclear effects on nascent capillaries and mural cells. In our study, we hypothesized that the Ang-1/Tie2 system could crosstalk with integrins, and be influenced by the dynamic interactions between extracellular matrix and endothelial cells (ECs). Here, we show that α5β1 specifically sensitizes and modulates Tie2 receptor activation and signaling, allowing EC survival at low concentrations of Ang-1 and inducing persistent EC motility. Tie2 and α5β1 interact constitutively; α5β1 binding to fibronectin increases this association, whereas Ang-1 stimulation recruits p85 and FAK to this complex. Furthermore, we demonstrate that Ang-1 is able to mediate selectively α5β1 outside-in FAK phosphorylation. Thus, Ang-1 triggers signaling pathways through Tie2 and α5β1 receptors that could crosstalk when Tie2/α5β1 interaction occurs in ECs plated on fibronectin. By using blocking antibodies, we consistently found that α5β1, but not αvβ3 activation, is essential to Ang-1-dependent angiogenesis in vivo. © The Rockefeller University Press

Integrins: A flexible platform for endothelial vascular tyrosine kinase receptors.

Compared to lower metazoans, vertebrates built up an exclusively new set of adhesion-related genes involved in the tissue development and in their functions. They include a large variety of extracellular matrix proteins and their heterodimeric integrin adhesive receptors. Integrins control the adhesive state of the cell through complex molecular mechanisms. Outside-in signalling informs the cell about the extracellular matrix environment, while Inside-out signalling results in changes in integrin functional activity. In the last 10 years it has well established a reciprocal integration of signals originating from integrins and receptors for soluble growth factors. This review summarizes the current understanding of this connection in vascular endothelial cells and highlights how integrins regulate a genetic program triggered by angiogenic inducers during embryo development and in adult life

Gravitational Geons in 1+1 Dimensions

It is well known that general relativity does not admit gravitational geons that are stationary, asymptotically flat, singularity free and topologically trivial. However, it is likely that general relativity will receive corrections at large curvatures and the modified field equations may admit solutions corresponding to this type of geon. If geons are produced in the early universe and survive until today they could account for some of the dark matter that has been "observed" in galaxies and galactic clusters. In this paper I consider gravitational geons in 1+1 dimensional theories of gravity. I show that the Jackiw-Teitelboim theory with corrections proportional to $R^2$ and $\Box R$ admits gravitational geons. I also show that gravitational geons exist in a class of theories that includes Lagrangians proportional to $R^{2/3}$.Comment: 8 pages, a comment added, two references corrected, to appear in Classical and Quantum Gravit

Int J Tuberc Lung Dis

BackgroundTherapeutic effects of antiretroviral therapy (ART) in patients with multidrug resistant tuberculosis (MDR-TB) and HIV infection have not been established.ObjectiveThe objective of this study was to assess therapeutic outcomes of ART integration with MDR-TB treatment.DesignA subgroup of MDR-TB patients from the SAPiT study, a randomized controlled trial, conducted in an out-patient clinic in Durban, South Africa from 2008\u20132012MethodsClinical outcomes at 18 months were compared in patients randomized to receive ART within 12 weeks of standard first-line tuberculosis treatment initiation with those who commenced ART after completing tuberculosis treatment.ResultsMycobacterium tuberculosis drug susceptibility was available in 489 (76%) of 642 SAPiT patients; 23 had MDR-TB, 14 in the integrated treatment arm and 9 in the sequential treatment arm. At 18 months, the mortality rate was 11.9/100 person-years (95% confidence interval (CI): 1.4\u201342.8) in the combined integrated treatment arm and 56.0/100 person-years (95%CI: 18.2\u2013130.8) in the sequential treatment arm, (Hazard Ratio adjusted for baseline CD4 count and whether MDR-TB treatment was initiated: 0.14; 95% CI: 0.02\u20130.94; P=0.04).ConclusionDespite the small sample size, the 86% reduction in mortality due to early initiation of ART in MDR-TB patients was statistically significant.D43TW00231/TW/FIC NIH HHS/United StatesD43 TW000231/TW/FIC NIH HHS/United States5U26PS001350/PS/NCHHSTP CDC HHS/United StatesU19 AI051794/AI/NIAID NIH HHS/United StatesU2G PS001350/PS/NCHHSTP CDC HHS/United StatesPEPFAR/United States2016-02-29T00:00:00Z24429305PMC47700138583vault:1580

Optimality in Self-Organized Molecular Sorting

We introduce a simple physical picture to explain the process of molecular sorting, whereby specific proteins are concentrated and distilled into submicrometric lipid vesicles in eukaryotic cells. To this purpose, we formulate a model based on the coupling of spontaneous molecular aggregation with vesicle nucleation. Its implications are studied by means of a phenomenological theory describing the diffusion of molecules toward multiple sorting centers that grow due to molecule absorption and are extracted when they reach a sufficiently large size. The predictions of the theory are compared with numerical simulations of a lattice-gas realization of the model and with experimental observations. The efficiency of the distillation process is found to be optimal for intermediate aggregation rates, where the density of sorted molecules is minimal and the process obeys simple scaling laws. Quantitative measures of endocytic sorting performed in primary endothelial cells are compatible with the hypothesis that these optimal conditions are realized in living cells

Temporal and spatial modulation of Rho GTPases during in vitro formation of capillary vascular network. Adherens junctions and myosin light chain as targets of Rac1 and RhoA

Endothelial cells (ECs) self-organize into capillary networks when plated on extracellular matrix. In this process, Rho GTPases-mediated cytoskeletal dynamics control cell movement and organization of cell-to-matrix and cell-to-cell contacts. Time course analysis of RhoA and Rac1 activation matches specific morphological aspects of nascent pattern. RhoA-GTP increases early during EC adhesion and accumulates at sites of membrane ruffling. Rac1 is activated later and localizes in lamellipodia and at cell-to-cell contacts of organized cell chains. When ECs stretch and remodel to form capillary structures, RhoA-GTP increases again and associates with stress fibers running along the major cell axis. N17Rac1 and N19RhoA mutants impair pattern formation. Cell-to-cell contacts and myosin light chains (MLC) are targets of Rac1 and RhoA, respectively. N17Rac1 reduces the shift of beta-catenin and vascular endothelial cadherin to Triton X-100-insoluble fraction and impairs beta-catenin distribution at adherens junctions, suggesting that Rac1 controls the dynamics of cadherin-catenin complex with F-actin. During the remodeling phase of network formation, ECs show an intense staining for phosphorylated MLC along the plasma membrane; in contrast, MLC is less phosphorylated and widely diffused in N19RhoA ECs. Both N17Rac1 and N19RhoA have been used to investigate the role of wild type molecules in the main steps characterizing in vitro angiogenesis: (i) cell adhesion to the substrate, (ii) cell movement, and (iii) mechanical remodeling of matrix. N17Rac1 has a striking inhibitory effect on haptotaxis, whereas N19RhoA slightly inhibits EC adhesion and motility but more markedly Matrigel contraction. We conclude that different Rho GTPases control distinct morphogenetic aspects of vascular morphogenesis