PAI-1 secretion of endometrial and endometriotic cells is Smad2/3- and ERK1/2-dependent and influences cell adhesion

In the endometrium transforming growth factor-betas (TGF-ßs) are involved mainly in menstruation and endometriosis. After binding of the ligands to the high-affinity receptors, TGF-ß receptors (TBR1 and TBR2), TGF-ßs activate Smad signaling to modulate gene expression and cellular functions. However, recently also Smad-independent pathways have been studied in more details. To evaluate both pathways, we have analyzed TGF-ß signaling in human endometrial and endometriotic cells. Although endometrial and endometriotic cells secrete TGF-ß1, secretion by stromal cells was higher compared to epithelial cells. In contrast, secretion of TGF-ß2 was higher in endometriotic stromal and endometriotic epithelial cells compared to normal endometrial cells. Treatment of endometrial and endometriotic stromal and epithelial cells with TGF-ß1 or TGF-ß2 increased Smad-dependent secretion of plasminogen activator inhibitor-1 (PAI-1) dramatically in all three cell lines. Of note, endometriotic cells secreted clearly higher levels of PAI-1 compared to endometrial cells. Whereas a TBR1 kinase inhibitor completely blocked the TGF-ß1 or TGF-ß2-induced PAI-1 secretion, an ERK1/2 inhibitor only partially reduced PAI-1 secretion. This inhibition was not dependent on epidermal growth factor receptor (EGFR) activation by phosphorylation but on kinase activity of the TBR1. Finally, treatment of endometrial and endometriotic cell lines with recombinant PAI-1 showed reduced cell adhesion, especially of the endometrial cells. In summary, our results demonstrate that both Smad-dependent and TBR1-dependent ERK1/2 pathways are necessary for TGF-ß-dependent high level secretion of PAI-1, which might increase cellular deadhesion

GEMS: Galaxy Evolution from Morphologies and SEDs

GEMS, Galaxy Evolution from Morphologies and SEDs, is a large-area (800 arcmin2) two-color (F606W and F850LP) imaging survey with the Advanced Camera for Surveys on HST. Centered on the Chandra Deep Field South, it covers an area of ~28'x28', or about 120 Hubble Deep Field areas, to a depth of m_AB(F606W)=28.3 (5sigma and m_AB(F850LP)=27.1 (5sigma) for compact sources. In its central ~1/4, GEMS incorporates ACS imaging from the GOODS project. Focusing on the redshift range 0.2<=z<=1.1, GEMS provides morphologies and structural parameters for nearly 10,000 galaxies where redshift estimates, luminosities and SEDs exist from COMBO-17. At the same time, GEMS contains detectable host galaxy images for several hundred faint AGN. This paper provides an overview of the science goals, the experiment design, the data reduction and the science analysis plan for GEMS.Comment: 24 pages, TeX with 6 eps Figures; to appear in ApJ Supplement. Low resolution figures only. Full resolution at http://zwicky.as.arizona.edu/~rix/Misc/GEMS.ps.g

Skyrmionic order and magnetically induced polarization change in lacunar spinel compounds GaV4_{4}S8_{8} and GaMo4_{4}S8_{8}: comparative theoretical study

We show how low-energy electronic models derived from the first-principles electronic structure calculations can help to rationalize the magnetic properties of two lacunar spinel compounds GaM4S8 with light (M=V) and heavy (M=Mo) transition-metal elements, which are responsible for different spin-orbit interaction strength. In the model, each magnetic lattice point was associated with the M4S4 molecule, and the model itself was formulated in the basis of molecular Wannier functions constructed for three magnetic t2 bands. The effects of rhombohedral distortion, spin-orbit interaction, band filling, and the screening of Coulomb interactions in the t2 bands are discussed in details. The electronic model is further treated in the superexchange approximation, which allows us to derive an effective spin model for the energy and electric polarization ($P$) depending on the relative orientation of spins in the bonds, and study the properties of this model by means of classical Monte Carlo simulations with the emphasis on the possible formation of the skyrmionic phase. While isotropic exchange interactions clearly dominate in GaV4S8, all types of interactions -- isotropic, antisymmetric, and symmetric anisotropic -- are comparable in the case of GaMo4S8. Particularly, large uniaxial exchange anisotropy has a profound effect on the properties of GaMo4S8. On the one hand, it raises the Curie temperature by opening a gap in the spectrum of magnon excitations. On the other hand, it strongly affects the skyrmionic phase by playing the role of a molecular field, which facilitates the formation of skyrmions, but makes them relatively insensitive to the external magnetic field in the large part of the phase diagram. We predict reversal of the magnetic dependence of $P$ in the case of GaMo4S8 caused by the reversal of direction of the rhombohedral distortion.Comment: 13 pages, 9 figure

Regional spread of HIV-1 M subtype B in middle-aged patients by random env-C2V4 region sequencing

A transmission cluster of HIV-1 M:B was identified in 11 patients with a median age of 52 (range 26–65) in North-East Germany by C2V4 region sequencing of the env gene of HIV-1, who—except of one—were not aware of any risky behaviour. The 10 male and 1 female patients deteriorated immunologically, according to their information made available, within 4 years after a putative HIV acquisition. Nucleic acid sequence analysis showed a R5 virus in all patients and in 7 of 11 a crown motif of the V3 loop, GPGSALFTT, which is found rarely. Analysis of formation of this cluster showed that there is still a huge discrepancy between awareness and behaviour regarding HIV transmission in middle-aged patients, and that a local outbreak can be detected by nucleic acid analysis of the hypervariable env region

Humoral and Cellular CMV Responses in Healthy Donors; Identification of a Frequent Population of CMV-Specific, CD4+ T Cells in Seronegative Donors

CMV status is an important risk factor in immune compromised patients. In hematopoeitic cell transplantations (HCT), both donor and recipient are tested routinely for CMV status by serological assays; however, one might argue that it might also be of relevance to examine CMV status by cellular (i.e., T lymphocyte) assays. Here, we have analyzed the CMV status of 100 healthy blood bank donors using both serology and cellular assays. About half (56%) were found to be CMV seropositive, and they all mounted strong CD8+ and/or moderate CD4+ T cell responses ex vivo against the immunodominant CMV protein, pp65. Of the 44 seronegative donors, only five (11%) mounted ex vivo T cell responses; surprisingly, 33 (75%) mounted strong CD4+ T cell responses after a brief in vitro peptide stimulation culture. This may have significant implications for the analysis and selection of HCT donors

Quality of Life as an outcome in Alzheimer's disease and other dementias- obstacles and goals

<p>Abstract</p> <p>Background</p> <p>The number of individuals at risk for dementia will probably increase in ageing societies as will the array of preventive and therapeutic options, both however within limited economic resources. For economic and medical purposes valid instruments are required to assess disease processes and the efficacy of therapeutic interventions for different forms and stages of illness. In principal, the impact of illness and success of an intervention can be assessed with biomedical variables, e.g. severity of symptoms or frequency of complications of a disease. However, this does not allow clear judgement on clinical relevance or comparison across different diseases.</p> <p>Discussion</p> <p>Outcome model variables such as quality of life (QoL) or health care resource utilization require the patient to appraise their own well-being or third parties to set preferences. In Alzheimer's disease and other dementias the evaluation process performed by the patient is subject to the disease process itself because over progress of the disease neuroanatomical structures are affected that mediate evaluation processes.</p> <p>Summary</p> <p>Published research and methodological considerations thus lead to the conclusion that current QoL-instruments, which have been useful in other contexts, are ill-suited and insufficiently validated to play a major role in dementia research, decision making and resource allocation. New models integrating biomedical and outcome variables need to be developed in order to meet the upcoming medical and economic challenges.</p

Somatostatin Inhibits Cell Migration and Reduces Cell Counts of Human Keratinocytes and Delays Epidermal Wound Healing in an Ex Vivo Wound Model

The peptide hormone somatostatin (SST) and its five G protein-coupled receptors (SSTR1-5) were described to be present in the skin, but their cutaneous function(s) and skin-specific signalling mechanisms are widely unknown. By using receptor specific agonists we show here that the SSTRs expressed in keratinocytes are functionally coupled to the inhibition of adenylate cyclase. In addition, treatment with SSTR4 and SSTR5/1 specific agonists significantly influences the MAP kinase signalling pathway. As epidermal hormone receptors in general are known to regulate re-epithelialization following skin injury, we investigated the effect of SST on cell counts and migration of human keratinocytes. Our results demonstrate a significant inhibition of cell migration and reduction of cell counts by SST. We do not observe an effect on apoptosis and necrosis. Analysis of signalling pathways showed that somatostatin inhibits cell migration independent of its effect on cAMP. Migrating keratinocytes treated with SST show altered cytoskeleton dynamics with delayed lamellipodia formation. Furthermore, the activity of the small GTPase Rac1 is diminished, providing evidence for the control of the actin cytoskeleton by somatostatin receptors in keratinocytes. While activation of all receptors leads to redundant effects on cell migration, only treatment with a SSTR5/1 specific agonist resulted in decreased cell counts. In accordance with reduced cell counts and impaired migration we observe delayed re-epithelialization in an ex vivo wound healing model. Consequently, our experiments suggest SST as a negative regulator of epidermal wound healing