Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets

Although tissue factor (TF), the principial initiator of physiological coagulation and pathological thrombosis, has recently been proposed to be present in human blood, the functional significance and location of the intravascular TF is unknown. In the plasma portion of blood, we found TF to be mainly associated with circulating microvesicles. By cell sorting with the specific marker CD42b, platelet-derived microvesicles were identified as a major location of the plasma TF. This was confirmed by the presence of full-length TF in microvesicles acutely shedded from the activated platelets. TF was observed to be stored in the α-granules and the open canalicular system of resting platelets and to be exposed on the cell surface after platelet activation. Functional competence of the blood-based TF was enabled when the microvesicles and platelets adhered to neutrophils, as mediated by P-selectin and neutrophil counterreceptor (PSGL-1, CD18 integrins) interactions. Moreover, neutrophil-secreted oxygen radical species supported the intravascular TF activity. The pools of platelet and microvesicle TF contributed additively and to a comparable extent to the overall blood TF activity, indicating a substantial participation of the microvesicle TF. Our results introduce a new concept of TF-mediated coagulation crucially dependent on TF associated with microvesicles and activated platelets, which principally enables the entire coagulation system to proceed on a restricted cell surface

Overexpression of the urokinase receptor splice variant uPAR-del4/5 in breast cancer cells affects cell adhesion and invasion in a dose-dependent manner and modulates transcription of tumor-associated genes

mRNA levels of the urokinase receptor splice variant uPAR-del4/5 are associated with prognosis in breast cancer. Its overexpression in cancer cells affects tumor biologically relevant processes. In the present study, individual breast cancer cell clones displaying low vs. high uPAR-del4/5 expression were analyzed demonstrating that uPAR-del4/5 leads to reduced cell adhesion and invasion in a dose-dependent manner. Additionally, matrix metalloproteinase-9 (MMP-9) was found to be strongly upregulated in uPAR-del4/5 overexpressing compared to vector control cells. uPAR-del4/5 may thus play an important role in the regulation of the extracellular proteolytic network and, by this, influence the metastatic potential of breast cancer cells

A Bosonic Model of Hole Pairs

We numerically investigate a bosonic representation for hole pairs on a two-leg t-J ladder where hard core bosons on a chain represent the hole pairs on the ladder. The interaction between hole pairs is obtained by fitting the density profile obtained with the effective model to the one obtained with the \tj model, taking into account the inner structure of the hole pair given by the hole-hole correlation function. For these interactions we calculate the Luttinger liquid parameter, which takes the universal value $K_{\rho}=1$ as half filling is approached, for values of the rung exchange $J'$ between strong coupling and the isotropic case. The long distance behavior of the hole-hole correlation function is also investigated. Starting from large $J'$, the correlation length first increases as expected, but diminishes significantly as $J'$ is reduced and bound holes sit mainly on adjacent rungs. As the isotropic case is approached, the correlation length increases again. This effect is related to the different kind of bonds in the region between the two holes of a hole pair when they move apart.Comment: 11 page

Rab31 expression levels modulate tumor-relevant characteristics of breast cancer cells

BACKGROUND: Rab proteins constitute a large family of monomeric GTP-binding proteins that regulate intracellular vesicle transport. Several Rab proteins, including rab31, have been shown to affect cancer progression and are related with prognosis in various types of cancer including breast cancer. Recently, the gene encoding rab31 was found to be overexpressed in estrogen receptor-positive breast cancer tissue. In a previous study we found a significant association of high rab31 mRNA expression with poor prognosis in node-negative breast cancer patients. In the present study, we aimed to investigate the impact of rab31 (over)-expression on important aspects of tumor progression in vitro and in vivo. METHODS: Breast cancer cells displaying low (MDA-MB-231) or no (CAMA-1) endogenous rab31 expression were stably transfected with a rab31 expression plasmid. Batch-transfected cells as well as selected cell clones, expressing different levels of rab31 protein, were analyzed with regard to proliferation, cell adhesion, the invasive capacity of tumor cells, and in vivo in a xenograft tumor model. Polyclonal antibodies directed to recombinantly expressed rab31 were generated and protein expression analyzed by immunohistochemistry, Western blot analysis, and a newly developed sensitive ELISA. RESULTS: Elevated rab31 protein levels were associated with enhanced proliferation of breast cancer cells. Interestingly, weak to moderate overexpression of rab31 in cell lines with no detectable endogenous rab31 expression was already sufficient to elicit distinct effects on cell proliferation. By contrast, increased expression of rab31 in breast cancer cells led to reduced adhesion towards several extracellular matrix proteins and decreased invasive capacity through Matrigel(TM). Again, the rab31-mediated effects on cell adhesion and invasion were dose-dependent. Finally, in a xenograft mouse model, we observed a significantly impaired metastatic dissemination of rab31 overexpressing MDA-MB-231 breast cancer cells to the lung. CONCLUSIONS: Overexpression of rab31 in breast cancer cells leads to a switch from an invasive to a proliferative phenotype as indicated by an increased cell proliferation, reduced adhesion and invasion in vitro, and a reduced capacity to form lung metastases in vivo

The transition between hole-pairs and four-hole clusters in four-leg tJ ladders

Holes weakly doped into a four-leg \tj ladder bind in pairs. At dopings exceeding a critical doping of $\delta_c\simeq {1/8}$ four hole clusters are observed to form in DMRG calculations. The symmetry of the ground state wavefunction does not change and we are able to reproduce this behavior qualitatively with an effective bosonic model in which the four-leg ladder is represented as two coupled two-leg ladders and hole-pairs are mapped on hard core bosons moving along and between these ladders. At lower dopings, $\delta<\delta_c$, a one dimensional bosonic representation for hole-pairs works and allows us to calculate accurately the Luttinger liquid parameter \krho, which takes the universal value \krho=1 as half-filling is approached

Fibroblastic Reticular Cells From Lymph Nodes Attenuate T Cell Expansion by Producing Nitric Oxide

Adaptive immune responses are initiated when T cells encounter antigen on dendritic cells (DC) in T zones of secondary lymphoid organs. T zones contain a 3-dimensional scaffold of fibroblastic reticular cells (FRC) but currently it is unclear how FRC influence T cell activation. Here we report that FRC lines and ex vivo FRC inhibit T cell proliferation but not differentiation. FRC share this feature with fibroblasts from non-lymphoid tissues as well as mesenchymal stromal cells. We identified FRC as strong source of nitric oxide (NO) thereby directly dampening T cell expansion as well as reducing the T cell priming capacity of DC. The expression of inducible nitric oxide synthase (iNOS) was up-regulated in a subset of FRC by both DC-signals as well as interferon-γ produced by primed CD8+ T cells. Importantly, iNOS expression was induced during viral infection in vivo in both LN FRC and DC. As a consequence, the primary T cell response was found to be exaggerated in Inos−/− mice. Our findings highlight that in addition to their established positive roles in T cell responses FRC and DC cooperate in a negative feedback loop to attenuate T cell expansion during acute inflammation

Properties of lightly doped t-J two-leg ladders

We have numerically investigated the doped t-J ladder using exact diagonalization. We have studied both the limit of strong inter-chain coupling and isotropic coupling. The ladder scales to the Luther-Emery liquid regime in the strong inter-chain coupling limit. In this strong coupling limit there is a simple picture of the excitation spectrum that can be continued to explain the behavior at isotropic coupling. At J=0 we have indications of a ferromagnetic ground state. At a large $J/t$ the ladder is phase separated into holes and a Heisenberg ladder. At intermediate coupling the ground state shows hole pairing with a modified d-wave symmetry. The excitation spectrum separates into a limited number of quasiparticles which carry charge $+|e|$ and spin ${1\over 2}$ and a triplet magnon mode. At half-filling the former vanish but the latter evolves continuously into the magnon band of the spin liquid. At low doping the quasiparticles form a dilute Fermi gas with a strong attraction but simultaneously the Fermi wave vector, as would be measured in photoemission, is large. The dynamical structure factors are calculated and are found to be very similar to calculations on 2D clusters

Observation of dipole-mode vector solitons

We report on the first experimental observation of a novel type of optical vector soliton, a {\em dipole-mode soliton}, recently predicted theoretically. We show that these vector solitons can be generated in a photorefractive medium employing two different processes: a phase imprinting, and a symmetry-breaking instability of a vortex-mode vector soliton. The experimental results display remarkable agreement with the theory, and confirm the robust nature of these radially asymmetric two-component solitary waves.Comment: 4 pages, 8 figures; pictures in the PRL version are better qualit