Expression of DEP-1, a receptor-like protein-tyrosine-phosphatase, is enhanced with increasing cell density

cDNA encoding a receptor-like protein-tyrosine-phosphatase (PTP) termed DEP-1 was isolated from a HeLa cell library. The cDNA predicts an enzyme consisting of an extracellular segment containing eight fibronectin type III repeats, a single transmembrane segment, and a single intracellular PTP domain. Following expression of DEP-1 cDNA in COS cells a glycoprotein of 180 kDa was detected and PTP activity was demonstrated in immunocomplexes with a C-terminal peptide antiserum. Endogenous DEP-1 was detected in WI-38 human embryonic lung fibroblasts by immunoblotting and immunocomplex PTP assays. Immunoblot analysis of DEP-1 expression in WI-38 cells revealed dramatically increased levels and activity of the PTP in dense cultures relative to sparse cultures. Also, DEP-1 activity, detected in PTP assays of immunocomplexes, was increased is dense cell cultures. In contrast, the expression levels of PTP-1B did not change with cell density. This enhancement of DEP-1 expression with increasing cell density was also observed in another fibroblast cell line, AG1518. The increase in DEP-1 occurs gradually with increasing cell contact and is initiated before saturation cell density is reached. These observations suggest that DEP-1 may contribute to the mechanism of contact inhibition of cell growth

Clinical Outcomes to Exercise Training in Type 1 Diabetes: A Systematic Review and Meta-Analysis.

AIMS: To establish the relationship between exercise training and clinical outcomes in people with type I diabetes. METHODS: Studies were identified through a MEDLINE search strategy, Cochrane Controlled Trials Registry, CINAHL, SPORTDiscus and Science Citation Index. The search strategy included a mix of key concepts related to exercise training; type 1 diabetes; glycaemic control for trials of exercise training in people with type 1 diabetes. Searches were limited to prospective randomized or controlled trials of exercise training in humans with type 1 diabetes lasting 12 weeks or more. RESULTS: In exercised adults there were significant improvements in body mass Mean Difference (MD): -2.20 kg, 95% Confidence Interval (CI) -3.79 -0.61, p=0.007; body mass index (BMI) MD: -0.39 kg/m2, 95% CI -0.75 -0.02, p=0.04; Peak VO2MD: 4.08 ml/kg/min, 95% CI 2.18 5.98, p<0.0001; and, low-density lipoprotein cholesterol (LDL) MD: -0.21 mmol/L, 95% CI -0.33 -0.08, p=0.002. In exercised children there were significant improvements in insulin dose MD: -0.23 IU/kg, 95% CI -0.37 -0.09, p=0.002; waist circumference MD: -5.40 cm, 95% CI -8.45 -2.35, p=0.0005; LDL MD: -0.31 mmol/L, 95% CI -0.55 -0.06, p=0.02; and, triglycerides MD: -0.21 mmol/L, 95% CI -0.42 -0.0, p=0.04. There were no significant changes in glycosylated haemoglobin (HbA1C%), fasting blood glucose, resting heart rate, resting systolic blood pressure or high density lipoproteins in either group. CONCLUSIONS: Exercise training improves some markers of type 1 diabetes severity; particularly body mass, BMI, Peak VO2and LDL in adults and insulin dose, waist circumference, LDL and triglycerides in children

Signatures of photon and axion-like particle mixing in the gamma-ray burst jet

Photons couple to Axion-Like Particles (ALPs) or more generally to any pseudo Nambu-Goldstone boson in the presence of an external electromagnetic field. Mixing between photons and ALPs in the strong magnetic field of a Gamma-Ray Burst (GRB) jet during the prompt emission phase can leave observable imprints on the gamma-ray polarization and spectrum. Mixing in the intergalactic medium is not expected to modify these signatures for ALP mass > 10^(-14) eV and/or for < nG magnetic field. We show that the depletion of photons due to conversion to ALPs changes the linear degree of polarization from the values predicted by the synchrotron model of gamma ray emission. We also show that when the magnetic field orientation in the propagation region is perpendicular to the field orientation in the production region, the observed synchrotron spectrum becomes steeper than the theoretical prediction and as detected in a sizable fraction of GRB sample. Detection of the correlated polarization and spectral signatures from these steep-spectrum GRBs by gamma-ray polarimeters can be a very powerful probe to discover ALPs. Measurement of gamma-ray polarization from GRBs in general, with high statistics, can also be useful to search for ALPs.Comment: 17 pages, 3 figures. Accepted for publication in JCAP with minor change

Constraints on the CMB temperature redshift dependence from SZ and distance measurements

The relation between redshift and the CMB temperature, $T_{CMB}(z)=T_0(1+z)$ is a key prediction of standard cosmology, but is violated in many non-standard models. Constraining possible deviations to this law is an effective way to test the $\Lambda$CDM paradigm and search for hints of new physics. We present state-of-the-art constraints, using both direct and indirect measurements. In particular, we point out that in models where photons can be created or destroyed, not only does the temperature-redshift relation change, but so does the distance duality relation, and these departures from the standard behaviour are related, providing us with an opportunity to improve constraints. We show that current datasets limit possible deviations of the form $T_{CMB}(z)=T_0(1+z)^{1-\beta}$ to be $\beta=0.004\pm0.016$ up to a redshift $z\sim 3$. We also discuss how, with the next generation of space and ground-based experiments, these constraints can be improved by more than one order of magnitude.Comment: 27 pages, 11 figure

A complete 3D numerical study of the effects of pseudoscalar-photon mixing on quasar polarizations

We present the results of three-dimensional simulations of quasar polarizations in the presence of pseudoscalar-photon mixing in the intergalactic medium. The intergalactic magnetic field is assumed to be uncorrelated in wave vector space but correlated in real space. Such a field may be obtained if its origin is primordial. Furthermore we assume that the quasars, located at cosmological distances, have negligible initial polarization. In the presence of pseudoscalar-photon mixing we show, through a direct comparison with observations, that this may explain the observed large scale alignments in quasar polarizations within the framework of big bang cosmology. We find that the simulation results give a reasonably good fit to the observed data.Comment: 15 pages, 8 figures, significant changes, to appear in EPJ

Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model

Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs. © 2011 Yang et al

JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length

C-Jun NH2-terminal kinases (JNKs) are essential during brain development, when they regulate morphogenic changes involving cell movement and migration. In the adult, JNK determines neuronal cytoarchitecture. To help uncover the molecular effectors for JNKs in these events, we affinity purified JNK-interacting proteins from brain. This revealed that the stathmin family microtubule-destabilizing proteins SCG10, SCLIP, RB3, and RB3' interact tightly with JNK. Furthermore, SCG10 is also phosphorylated by JNK in vivo on sites that regulate its microtubule depolymerizing activity, serines 62 and 73. SCG10-S73 phosphorylation is significantly decreased in JNK1-/- cortex, indicating that JNK1 phosphorylates SCG10 in developing forebrain. JNK phosphorylation of SCG10 determines axodendritic length in cerebrocortical cultures, and JNK site-phosphorylated SCG10 colocalizes with active JNK in embryonic brain regions undergoing neurite elongation and migration. We demonstrate that inhibition of cytoplasmic JNK and expression of SCG10-62A/73A both inhibited fluorescent tubulin recovery after photobleaching. These data suggest that JNK1 is responsible for regulation of SCG10 depolymerizing activity and neurite elongation during brain development

Cumulative Risk, Age at Onset, and Sex-Specific Differences for Developing End-Stage Renal Disease in Young Patients With Type 1 Diabetes: A Nationwide Population-Based Cohort Study

OBJECTIVE This study aimed to estimate the current cumulative risk of end-stage renal disease (ESRD) due to diabetic nephropathy in a large, nationwide, population-based prospective type 1 diabetes cohort and specifically study the effects of sex and age at onset. RESEARCH DESIGN AND METHODS In Sweden, all incident cases of type 1 diabetes aged 0-14 years and 15-34 years are recorded in validated research registers since 1977 and 1983, respectively. These registers were linked to the Swedish Renal Registry, which, since 1991, collects data on patients who receive active uremia treatment. Patients with years duration of type 1 diabetes were included (n = 11,681). RESULTS During a median time of follow-up of 20 years, 127 patients had developed ESRD due to diabetic nephropathy. The cumulative incidence at 30 years of type 1 diabetes duration was low, with a male predominance (4.1% [95% CI 3.1-5.3] vs. 2.5% [1.7-3.5]). In both male and female subjects, onset of type I diabetes before 10 years of age was associated with the lowest risk of developing ESRD. The highest risk of ESRD was found in male subjects diagnosed at age 20-34 years (hazard ratio 3.0 [95% CI 1.5-5.7]). In female subjects with onset at age 20-34 years, the risk was similar to patients diagnosed before age 10 years. CONCLUSIONS The cumulative incidence of ESRD is exceptionally low in young type 1 diabetic patients in Sweden. There is a striking difference in risk for male compared with female patients. The different patterns of risk by age at onset and sex suggest a role for puberty and sex hormones

NOX4-dependent ROS production by stromal mammary cells modulates epithelial MCF-7 cell migration

BACKGROUND: The influence of the stromal microenvironment on the progression of epithelial cancers has been demonstrated. Unravelling the mechanisms by which stromal cells affect epithelial behaviour will contribute in understanding cellular malignancy. It has been proposed that redox environment has a role in the acquisition of malignancy. In this work, we studied the influence of epithelial cells on the stromal redox status and the consequence of this phenomenon on MCF-7 cell motility. METHODS: We analysed in a co-culture system, the effect of RMF-EG mammary stromal cells on the migratory capacity of MCF-7 cell line. To test whether the NOX-dependent stromal redox environment influences the epithelial migratory behaviour, we knocked down the expression of NOX4 using siRNA strategy. The effect of TGF-b1 on NOX4 expression and activity was analysed by qPCR, and intracellular ROS production was measured by a fluorescent method. RESULTS: Migration of MCF-7 breast epithelial cells was stimulated when co-cultured with RMF-EG cells. This effect depends on stromal NOX4 expression that, in turn, is enhanced by epithelial soluble factors. Pre-treatment of stromal cells with TGF-b1 enhanced this migratory stimulus by elevating NOX4 expression and intracellular ROS production. TGF-b1 seems to be a major component of the epithelial soluble factors that stimulate NOX4 expression. CONCLUSIONS: Our results have identified that an increased stromal oxidative status, mainly provided by an elevated NOX4 expression, is a permissive element in the acquisition of epithelial migratory properties. The capacity of stromal cells to modify their intracellular ROS production, and accordingly, to increase epithelial motility, seems to depend on epithelial soluble factors among which TGF-b1 have a decisive role.This work was supported by the grant (1080196 to JM) from the Fondo Nacional de Ciencia y Tecnologı´a (FONDECYT) of Chile

Downregulation of TGF-beta receptor types II and III in oral squamous cell carcinoma and oral carcinoma-associated fibroblasts

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to assess the expression levels for TβRI, TβRII, and TβRIII in epithelial layers of oral premalignant lesions (oral leukoplakia, OLK) and oral squamous cell carcinoma (OSCC), as well as in oral carcinoma-associated fibroblasts (CAFs), with the final goal of exploring the roles of various types of TβRs in carcinogenesis of oral mucosa.</p> <p>Methods</p> <p>Normal oral tissues, OLK, and OSCC were obtained from 138 previously untreated patients. Seven primary human oral CAF lines and six primary normal fibroblast (NF) lines were established successfully via cell culture. The three receptors were detected using immunohistochemical (IHC), quantitative RT-PCR, and Western blot approaches.</p> <p>Results</p> <p>IHC signals for TβRII and TβRIII in the epithelial layer decreased in tissue samples with increasing disease aggressiveness (P < 0.05); no expression differences were observed for TβRI, in OLK and OSCC (P > 0.05); and TβRII and TβRIII were significantly downregulated in CAFs compared with NFs, at the mRNA and protein levels (P < 0.05). Exogenous expression of TGF-β1 led to a remarkable decrease in the expression of TβRII and TβRIII in CAFs (P < 0.05).</p> <p>Conclusion</p> <p>This study provides the first evidence that the loss of TβRII and TβRIII expression in oral epithelium and stroma is a common event in OSCC. The restoration of the expression of TβRII and TβRIII in oral cancerous tissues may represent a novel strategy for the treatment of oral carcinoma.</p