Human naive CD8 T cells down-regulate expression of the WNT pathway transcription factors lymphoid enhancer binding factor 1 and transcription factor 7 (T cell factor-1) following antigen encounter in vitro and in vivo

Abstract The transcription factors lymphoid enhancer binding factor 1 (LEF1) and transcription factor 7 (TCF7) (T cell factor-1 (TCF-1)) are downstream effectors of the WNT signaling pathway, which is a critical regulator of T cell development in the thymus. In this study, we show that LEF1 and TCF7 (TCF-1) are not only expressed in thymocytes, but also in mature T cells. Our data demonstrate that Ag encounter in vivo and engagement of the TCR or IL-15 receptor in vitro leads to the down-regulation of LEF1 and TCF7 (TCF-1) expression in human naive CD8 T cells. We further show that resting T cells preferentially express inhibitory LEF1 and TCF7 (TCF-1) isoforms and that T cell activation changes the isoform balance in favor of stimulatory TCF7 (TCF-1) isoforms. Altogether, our study suggests that proteins involved in the WNT signaling pathway not only regulate T cell development, but also peripheral T cell differentiation.</jats:p

Epidermal growth factor-mediated T-cell factor/lymphoid enhancer factor transcriptional activity is essential but not sufficient for cell cycle progression in nontransformed mammary epithelial cells

Because beta-catenin target genes such as cyclin D1 are involved in cell cycle progression, we examined whether beta-catenin has a more pervasive role in normal cell proliferation, even upon stimulation by non-Wnt ligands. Here, we demonstrate that epidermal growth factor (EGF) stimulates T-cell factor/lymphoid enhancer factor (Tcf/Lef) transcriptional activity in nontransformed mammary epithelial cells (MCF-10A) and that its transcriptional activity is essential for EGF-mediated progression through G(1)/S phase. Thus, expression of dominant-negative Tcf4 blocks EGF-mediated Tcf/Lef transcriptional activity and bromodeoxyuridine uptake. In fact, the importance of EGF-mediated Tcf/Lef transcriptional activity for cell cycle progression may lie further upstream at the G(1)/S phase transition. We demonstrate that dominant-negative Tcf4 inhibits a reporter of cyclin D1 promoter activity in a dose-dependent manner. Importantly, dominant-negative Tcf4 suppresses EGF- mediated cell cycle activity specifically by thwarting EGF- mediated Tcf/Lef transcriptional activity, not by broader effects on EGF signaling. Thus, although expression of dominant-negative Tcf4 blocks EGF- mediated TOPFLASH activation, it has no effect on either EGF receptor or ERK phosphorylation, further underscoring the fact that Tcf/ Lef-mediated transcription is essential for cell cycle progression, even when other pro-mitogenic signals are at normal levels. Yet, despite its essential role, Tcf/Lef transcriptional activity alone is not sufficient for cell cycle progression. Serum also stimulates Tcf/ Lef transcriptional activation in MCF-10A cells but is unable to promote DNA synthesis. Taken together, our data support a model wherein EGF promotes Tcf/ Lef transcriptional activity, and this signal is essential but not sufficient for cell cycle activity

APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis.

Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis

Random raman fiber laser based on a twin-core fiber with FBGs inscribed by femtosecond radiation

Narrowband Raman lasing in a polarization-maintaining two-core fiber (TCF) is demonstrated. Femtosecond point-by-point inscription of fiber Bragg gratings (FBGs) in individual cores produces a half-open cavity with random distributed feedback. The laser linewidth in the cavity with a single FBG inscribed in one core of the TCF reduced by ∼2 times with respect to the cavity with a fiber loop mirror. It is shown that the inscription of two FBGs in different cores leads to the formation of a Michelson-type interferometer, leading to the modulation of generation spectra near threshold. This technique offers new possibilities for spectral filtering or multi-wavelength generation

Systematic co-occurrence of tail correlation functions among max-stable processes

The tail correlation function (TCF) is one of the most popular bivariate extremal dependence measures that has entered the literature under various names. We study to what extent the TCF can distinguish between different classes of well-known max-stable processes and identify essentially different processes sharing the same TCF.Comment: 31 pages, 4 Tables, 5 Figure

Glucocorticoid Receptor β Acts As a Co-activator of T-Cell Factor 4 and Enhances Glioma Cell Proliferation

We previously reported that glucocorticoid receptor β (GRβ) regulates injury-mediated astrocyte activation and contributes to glioma pathogenesis via modulation of β-catenin/T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activity. The aim of this study was to characterize the mechanism behind cross-talk between GRβ and β-catenin/TCF in the progression of glioma. Here, we reported that GRβ knockdown reduced U118 and Shg44 glioma cell proliferation in vitro and in vivo. Mechanistically, we found that GRβ knockdown decreased TCF/LEF transcriptional activity without affecting β-catenin/TCF complex. Both GRα and GRβ directly interact with TCF-4, while only GRβ is required for sustaining TCF/LEF activity under hormone-free condition. GRβ bound to the N-terminus domain of TCF-4 its influence on Wnt signaling required both ligand- and DNA-binding domains (LBD and DBD, respectively). GRβ and TCF-4 interaction is enough to maintain the TCF/LEF activity at a high level in the absence of β-catenin stabilization. Taken together, these results suggest a novel cross-talk between GRβ and TCF-4 which regulates Wnt signaling and the proliferation in gliomas

Time to Virological Failure of 3 Classes of Antiretrovirals after Initiation of Highly Active Antiretroviral Therapy: Results from the EuroSIDA Study Group

Objective. The purpose of the present study was to determine the prevalence and incidence of virological triple drug-class failure (TCF) and to summarize the clinical outcome for patients who started receiving highly active antiretroviral therapy (HAART). Methods. The present study is an observational longitudinal study of 3496 treatment-experienced (TE) and treatment-naive (TN) patients monitored from the time they started receiving HAART (baseline) until TCF occurred (as determined on the basis of viral loads), until AIDS was newly diagnosed, or until death. Results. Four hundred forty-five patients (12.7%) had TCF; 370 (16.6%) of 2230 patients were TE, and 75 (5.9%) of 1266 patients were TN. At 6 years after starting HAART, 21.4% of TE and 11.2% of TN patients had TCF (P < .0001). The prevalence of TCF at or after 2002 was 15.5% in TE patients and 4.8% in TN patients. TN patients had a 32% annual increase in the incidence of TCF (95% confidence interval [CI], 14%-54%; P < .0001); at 5 years after starting HAART, the rate was comparable for TE and TN patients (3.3 and 3.4 cases/100 person-years of follow-up [PYFU], respectively). The incidence of new cases of AIDS or death was 2.7 cases/100 PYFU in patients who did not experience TCF and 5.0 cases/100 PYFU in patients who did experience TCF, an estimated 36% increase with each category of TCF (95% CI, 19%-56%; P < .0001). Conclusion. The prevalence of TCF was low after patients started receiving HAART, particularly among TN patients. Despite the influx of patients who had started receiving HAART more recently, the prevalence of TCF increased over calendar time. Patients with TCF had a higher incidence of newly diagnosed AIDS or death. Treatment of patients with TCF deserves further investigatio

LES-CMC simulations of different auto-ignition regimes of hydrogen in a hot turbulent air Co-flow

Large-Eddy Simulation (LES) results in combination with first-order Conditional Moment Closure (CMC) are presented for a hydrogen jet, diluted with nitrogen, issued into a turbulent co-flowing hot air stream. The fuel mixes with the co-flow air, ignites and forms a lifted-like flame. Global trends in the experimental observations are in general well reproduced: the auto-ignition length decreases with increase in co-flow temperature and increases with increase in co-flow velocity. In the experiments, the co-flow temperature was varied, so that different auto-ignition regimes, including low Damkohler number situations, were obtained (no ignition, random spots, flashback and lifted flame). All regimes are recovered in the simulations. Auto-ignition is found to be the stabilizing mechanism. The impact of different detailed chemistry mechanisms on the auto-ignition predictions is discussed. With increasing air temperature, the differences between the mechanisms considered diminish. The evolution of temperature, H2O, H, HO2 and OH from inert to burning conditions is discussed in mixture fraction space