MiR203 Mediates Subversion of Stem Cell Properties During Mammary Epithelial Differentiation via Repression of ΔNP63α and Promotes Mesenchymal-to-Epithelial Transition

During reproductive life, the mammary epithelium undergoes consecutive cycles of proliferation, differentiation and apoptosis. Doing so relies on the retained proliferative capacity, prolonged lifespan and developmental potency of mammary stem cells (MaSCs). ΔNp63α, the predominant TP63 isoform in mammary epithelia, is robustly expressed in MaSCs and is required for preservation of self-renewing capacity in diverse epithelial structures. However, the mechanism(s) underlying subversion of this activity during forfeiture of self-renewing capacity are poorly understood. MicroRNAs (miRNAs) govern critical cellular functions including stem cell maintenance, development, cell cycle regulation and differentiation by disrupting translation of target mRNAs. Data presented here indicate that expression of miR203, a miRNA that targets ΔNp63α and ΔNp63β is activated during luminal epithelial differentiation and that this pattern is observed in the murine mammary hierarchy. In addition, we present evidence that the transcription factor Zeb1 represses miR203 expression, thus enhancing ΔNp63α protein levels. Furthermore, ectopic miR203 suppresses ΔNp63α expression, proliferation and colony formation. The anti-clonogenic effects mediated by miR203 require suppression of ΔNp63α. In addition, ectopic miR203 promotes mesenchymal-to-epithelial transition and disrupts activities associated with epithelial stem cells. These studies support a model in which induction of miR203 mediates forfeiture of self-renewing capacity via suppression of ΔNp63α and may also have anti-tumorigenic activity through its reduction of EMT and cancer stem cell populations

Gamma-ray observations of the Crab Region using a coded-aperture telescope

The region of the Galactic anticenter, including the Crab Nebula, was observed during a balloon flight of the University of New Hampshire Directional Gamma-Ray Telescope employing the coded-aperture imaging technique to image celestial gamma-radiation between 160 keV and 9.3 MeV. The background systematics are treated with a simple and relatively straightforward correction procedure. The results demonstrate that the coded-aperture procedure is a viable approach for imaging not only point sources of radiation, but also extended sources of emission. The results for the Crab\u27s photon spectrum are consistent with a power-law spectrum. Upper limits on the flux levels of line emission at 405 keV and 1050 keV and on the flux from the X-ray binary source A0535 + 26 and diffuse Galactic emission from the anticenter region are derived

ASSESSING AND REDUCING SOYBEAN CROP LOSSES FROM DEER: AN INTERDISCIPLINARY, MULTI-AGENCY EFFORT

Damage from white-tailed deer (Odocoileus virginianus) has become a common complaint of soybean (Glycine max) producers in many areas of the Southeast. Both short- and long-term, single-field and community-wide solutions to this problem are needed. This paper describes a multi-agency, multi-state effort, involving agronomists, wildlife biologists, producers, and other landowners, to assess soybean losses from deer and to evaluate potential solutions. One phase of this work, which is supported by soybean producer checkoff funds, involves evaluating agronomic practices for reducing crop losses. These include drilled (rather than wide-row) plantings and use of insect-resistant or dense-pubescent cultivars (varieties) which may deter browsing, especially where deer pressure is light to moderate. Evaluations of these practices, in comparison with conventional ones, are being conducted in producer’s fields in SC, NC, and VA. The other phase of this work is a cooperative project involving Clemson University, the SC Wildlife and Marine Resources Department, soybean producers and’ other landowners in a 7500-acre tract in Hampton and Jasper Cos., SC. The deer population in this tract will be monitored and reduced over a 3-year period, and the resulting effects on soybean crop losses and herd quality will be assessed

ASSESSING AND REDUCING SOYBEAN CROP LOSSES FROM DEER: AN INTERDISCIPLINARY, MULTI-AGENCY EFFORT

Damage from white-tailed deer (Odocoileus virginianus) has become a common complaint of soybean (Glycine max) producers in many areas of the Southeast. Both short- and long-term, single-field and community-wide solutions to this problem are needed. This paper describes a multi-agency, multi-state effort, involving agronomists, wildlife biologists, producers, and other landowners, to assess soybean losses from deer and to evaluate potential solutions. One phase of this work, which is supported by soybean producer checkoff funds, involves evaluating agronomic practices for reducing crop losses. These include drilled (rather than wide-row) plantings and use of insect-resistant or dense-pubescent cultivars (varieties) which may deter browsing, especially where deer pressure is light to moderate. Evaluations of these practices, in comparison with conventional ones, are being conducted in producer’s fields in SC, NC, and VA. The other phase of this work is a cooperative project involving Clemson University, the SC Wildlife and Marine Resources Department, soybean producers and’ other landowners in a 7500-acre tract in Hampton and Jasper Cos., SC. The deer population in this tract will be monitored and reduced over a 3-year period, and the resulting effects on soybean crop losses and herd quality will be assessed

Gamma-ray observations of Cygnus X-1 and Cygnus X-3 using a coded-aperture telescope

A balloon-borne coded-aperture telescope, measuring gamma-ray photons in the 160 keV to 9.3 MeV range, was used to observe the Cygnus region of the sky on October 1 and 2, 1984. In the 2-9.3-MeV band, evidence is found for a hard spectral component with a mean flux level at the top of the atmosphere of 7.4 + or - 2.5 x 10 to the -7th photons/sq cm per s per keV, inconsistent with the predictions of the inverse Compton models normally used to describe the X-ray emission. Both Cyg X-1 and Cyg X-3 could be observed simultaneously with the telescope. The results are used to establish 1-sigma upper flux limits on the spectral emission from Cyg X-3

Mapping Children's Discussions of Evidence in Science to Assess Collaboration and Argumentation

The research reported in this paper concerns the development of children's skills of interpreting and evaluating evidence in science. Previous studies have shown that school teaching often places limited emphasis on the development of these skills, which are necessary for children to engage in scientific debate and decision-making. The research, undertaken in the UK, involved four collaborative decision-making activities to stimulate group discussion, each was carried out with five groups of four children (10-11 years old). The research shows how the children evaluated evidence for possible choices and judged whether their evidence was sufficient to support a particular conclusion or the rejection of alternative conclusions. A mapping technique was developed to analyse the discussions and identify different "levels" of argumentation. The authors conclude that suitable collaborative activities that focus on the discussion of evidence can be developed to exercise children's ability to argue effectively in making decisions

Understandings of sustainable corporate governance by Australian managed investment schemes and some implications for small-scale forestry in Australia

This study reveals that managers of Australian managed investment schemes understand sustainable corporate governance as a mix of financial, natural environment and social outcomes. The managers that were interviewed prioritized financial aspects of business performance but acknowledged that sustained financial performance was only possible if positive natural environment outcomes and positive social outcomes were also sustained. In this context, the managers expressed qualified support for the development of small-scale forestry in Australia

Pregnancy Induces Persistent Changes that Potentiate Apoptotic Signaling and Responses to DNA Damage

A full-term pregnancy reduces the lifetime risk of breast cancer by up to 50%. This effect is mediated, in part, by p53-dependent pathways. Gene expression profiling was used to investigate the mechanisms that alter apoptotic responses to DNA damage in the mammary gland. Radiation-induced responses in BALB/c-Trp53+/+ and BALB/c-Trp53-/- mice identified 121 genes that were altered by radiation and p53 status (p53-IR). To determine the effect of parity, mice were mated, force-weaned and mammary glands were allowed to involute for 21 days (parous) and compared with age-matched nulliparous mice. Gene expression profiles were determined in mammary tissues from nulliparous (N), parous (P), irradiated nulliparous (N-IR) and irradiated parous (P-IR) mice. The p53-IR gene signature did not differ among the N-IR and P-IR groups indicating that transcriptional activity of p53 was not altered by parity. However, expression profiles of apoptosis-related genes differed significantly in the parous group. The alterations in parous mammary tissues was accompanied by over-representation of biological processes that included “signal transduction” (e=1.69E-05). Within this set, Wnt signaling was especially pronounced (e Parity-regulated genes collaborate with p53-dependent targets, which act as a “switch”, to elicit apoptosis following ionizing radiation. The epigenetic states of the parity-regulated genes Tgfb2 and Wnt5a provide a mechanism for the persistent alterations in gene expression and apoptosis in parous mammary epithelial cells

Estrogen receptor beta selectively restricts proliferation and favors surveillance in mammary epithelial cells

Estrogen (17β-estradiol) has paradoxical effects in both promoting and preventing breast cancer as estrogen activates proliferation, but also promotes p53-mediated surveillance pathways. Estrogen mediates its effects in target tissues through the activation of estrogen receptor subtypes: ERα and ERβ. To examine the capability of these receptors in mediating surveillance as opposed to proliferation, selective estrogen receptor agonists were compared with 17β-estradiol for induction of proliferation and radiation induced apoptosis in vivo. Transcriptional regulation of estrogen-responsive genes was also compared in mouse mammary epithelium in vivo and in the human mammary MCF7 cell line transduced with a repressible ERβ. Selective activation of ERβ with the agonist diarylpropionitrile (DPN) in vivo enhances p53-mediated apoptosis in the mouse mammary epithelium without stimulating proliferation. In addition, radiation-induced apoptosis is significantly reduced in mice lacking ERβ (βERKO). As expected, 17β-estradiol or selective activation of ERα with pyrazole triol (PPT) induced the expression of estrogen-response genes including progesterone receptor, amphiregulin and trefoil factor 1. DPN and ERβ failed to induce the expression of these genes. Interestingly, the ERβ agonist DPN selectively induced the expression of genes that repress proliferation including TGFβ2 while inhibiting proliferative canonical wnt signaling via beta-catenin by inducing WNT5a and AXIN2. DPN was also more potent in stimulating the expression of EGR1, a modulator of p53 activity. These results suggest that ERα and ERβ have distinct roles in gene regulation. In addition, the ability of DPN and ERβ to potentiate surveillance pathways while limiting proliferation suggests that ERβ agonists may have therapeutic and chemopreventive value in breast cancer

The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM

The activation of ATR-ATRIP in response to double-stranded DNA breaks (DSBs) depends upon ATM in human cells and Xenopus egg extracts. One important aspect of this dependency involves regulation of TopBP1 by ATM. In Xenopus egg extracts, ATM associates with TopBP1 and thereupon phosphorylates it on S1131. This phosphorylation enhances the capacity of TopBP1 to activate the ATR-ATRIP complex. We show that TopBP1 also interacts with the Mre11-Rad50-Nbs1 (MRN) complex in egg extracts in a checkpoint-regulated manner. This interaction involves the Nbs1 subunit of the complex. ATM can no longer interact with TopBP1 in Nbs1-depleted egg extracts, which suggests that the MRN complex helps to bridge ATM and TopBP1 together. The association between TopBP1 and Nbs1 involves the first pair of BRCT repeats in TopBP1. In addition, the two tandem BRCT repeats of Nbs1 are required for this binding. Functional studies with mutated forms of TopBP1 and Nbs1 suggested that the BRCT-dependent association of these proteins is critical for a normal checkpoint response to DSBs. These findings suggest that the MRN complex is a crucial mediator in the process whereby ATM promotes the TopBP1-dependent activation of ATR-ATRIP in response to DSBs