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

Inactivation of the antibacterial and cytotoxic properties of silver ions by biologically relevant compounds

There has been a recent surge in the use of silver as an antimicrobial agent in a wide range of domestic and clinical products, intended to prevent or treat bacterial infections and reduce bacterial colonization of surfaces. It has been reported that the antibacterial and cytotoxic properties of silver are affected by the assay conditions, particularly the type of growth media used in vitro. The toxicity of Ag+ to bacterial cells is comparable to that of human cells. We demonstrate that biologically relevant compounds such as glutathione, cysteine and human blood components significantly reduce the toxicity of silver ions to clinically relevant pathogenic bacteria and primary human dermal fibroblasts (skin cells). Bacteria are able to grow normally in the presence of silver nitrate at >20-fold the minimum inhibitory concentration (MIC) if Ag+ and thiols are added in a 1:1 ratio because the reaction of Ag+ with extracellular thiols prevents silver ions from interacting with cells. Extracellular thiols and human serum also significantly reduce the antimicrobial activity of silver wound dressings Aquacel-Ag (Convatec) and Acticoat (Smith & Nephew) to Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli in vitro. These results have important implications for the deployment of silver as an antimicrobial agent in environments exposed to biological tissue or secretions. Significant amounts of money and effort have been directed at the development of silver-coated medical devices (e.g. dressings, catheters, implants). We believe our findings are essential for the effective design and testing of antimicrobial silver coatings

The role of renal transporters and novel regulatory interactions in the TAL that control blood pressure

Hypertension (HTN), a major public health issue is currently the leading factor in the global burden of disease, where associated complications account for 9.4 million deaths worldwide every year (98). Excessive dietary salt intake is among the environmental factors that contribute to HTN, known as salt sensitivity. The heterogeneity of salt sensitivity and the multiple mechanisms that link high salt intake to increases in blood pressure are of upmost importance for therapeutic application. A continual increase in the kidney's reabsorption of sodium (Na+) relies on sequential actions at various segments along the nephron. When the distal segments of the nephron fail to regulate Na+, the effects on Na+ homeostasis are unfavourable. We propose that the specific nephron region where increased active uptake occurs as a result of variations in Na+ reabsorption is at the thick ascending limb of the loop of Henle (TAL). The purpose of this review is to urge the consideration of the TAL that contributes to the pathophysiology of salt sensitive HTN. Further research in this area will enable development of a therapeutic application for targeted treatment

The Purple Haze of Eta Carinae: Binary-Induced Variability?

Asymmetric variability in ultraviolet images of the Homunculus obtained with the Advanced Camera for Surveys/High Resolution Camera on the Hubble Space Telescope suggests that Eta Carinae is indeed a binary system. Images obtained before, during, and after the recent ``spectroscopic event'' in 2003.5 show alternating patterns of bright spots and shadows on opposite sides of the star before and after the event, providing a strong geometric argument for an azimuthally-evolving, asymmetric UV radiation field as one might predict in some binary models. The simplest interpretation of these UV images, where excess UV escapes from the secondary star in the direction away from the primary, places the major axis of the eccentric orbit roughly perpendicular to our line of sight, sharing the same equatorial plane as the Homunculus, and with apastron for the hot secondary star oriented toward the southwest of the primary. However, other orbital orientations may be allowed with more complicated geometries. Selective UV illumination of the wind and ejecta may be partly responsible for line profile variations seen in spectra. The brightness asymmetries cannot be explained plausibly with delays due to light travel time alone, so a single-star model would require a seriously asymmetric shell ejection.Comment: 8 pages, fig 1 in color, accepted by ApJ Letter

On the Nature of “Good” Goods and the Ethical Role of Marketing

The purpose of this essay is to elaborate on an important section of a document titled, Vocation of the Business Leader, published by the Pontifical Council for Justice and Peace. Subtitled “A Reflection,” this document is an 87 paragraph, 13,000 word (in English) statement about the ideals of business leadership as inspired by Christian values and ethics. It was sponsored by Peter K.A. Cardinal Turkson and Bishop Mario Toso in consultation with assorted educators, theologians, economists, and philosophers. The document developed from reflections and discussions on Pope Benedict XVI’s social encyclical Caritas in Veritate, particularly a seminar organized by the Pontifical Council for Justice and Peace in February 2011. As such, it extends Caritas in Veritate, especially with regard to economics and business

Religion-motivated Enterprises in the Marketplace: A Macromarketing Inquiry

This exploratory essay identifies and examines a variety of religiously affiliated or inspired enterprises operating in otherwise secular marketplaces. While explicitly recognizing that some marketplace manifestations of religion can be controversial, even dysfunctional, it argues for the evident macromarketing relevance of this project. The approach for analyzing what this paper refers to as “religion-motivated enterprises” (RMEs) consists of (1) a nominal classification scheme to illustrate and categorize the diversity of RME examples; (2) some foundational principles shared among major faith traditions that provide a basis for an RME ethos; and (3) basic propositions that, with future empirical testing, may explain the contributions of these organizations to improved market performance. Our commentary includes environmental factors that prompted the establishment of many RMEs, the nature of their sustainability, and the importance of mission statements to their operations. Finally, we identify opportunities for additional research and summarize the macromarketing contributions of this article

Sequential primed kinases create a damage-responsive phosphodegron on Eco1.

Sister-chromatid cohesion is established during S phase when Eco1 acetylates cohesin. In budding yeast, Eco1 activity falls after S phase due to Cdk1-dependent phosphorylation, which triggers ubiquitination by SCF(Cdc4). We show here that Eco1 degradation requires the sequential actions of Cdk1 and two additional kinases, Cdc7-Dbf4 and the GSK-3 homolog Mck1. These kinases recognize motifs primed by previous phosphorylation, resulting in an ordered sequence of three phosphorylation events on Eco1. Only the latter two phosphorylation sites are spaced correctly to bind Cdc4, resulting in strict discrimination between phosphates added by Cdk1 and by Cdc7. Inhibition of Cdc7 by the DNA damage response prevents Eco1 destruction, allowing establishment of cohesion after S phase. This elaborate regulatory system, involving three independent kinases and stringent substrate selection by a ubiquitin ligase, enables robust control of cohesion establishment during normal growth and after stress