Active regulator of SIRT1 is required for cancer cell survival but not for SIRT1 activity

The NAD+-dependent deacetylase SIRT1 is involved in diverse cellular processes, and has also been linked with multiple disease states. Among these, SIRT1 expression negatively correlates with cancer survival in both laboratory and clinical studies. Active regulator of SIRT1 (AROS) was the first reported post-transcriptional regulator of SIRT1 activity, enhancing SIRT1-mediated deacetylation and downregulation of the SIRT1 target p53. However, little is known regarding the role of AROS in regulation of SIRT1 during disease. Here, we report the cellular and molecular effects of RNAi-mediated AROS suppression, comparing this with the role of SIRT1 in a panel of human cell lines of both cancerous and non-cancerous origins. Unexpectedly, AROS is found to vary in its modulation of p53 acetylation according to cell context. AROS suppresses p53 acetylation only following the application of cell damaging stress, whereas SIRT1 suppresses p53 under all conditions analysed. This supplements the original characterization of AROS but indicates that SIRT1 activity can persist following suppression of AROS. We also demonstrate that knockdown of AROS induces apoptosis in three cancer cell lines, independent of p53 activation. Importantly, AROS is not required for the viability of three non-cancer cell lines indicating a putative role for AROS in specifically promoting cancer cell survival

Law-Based Arguments and Messages to Advocate for Later School Start Time Policies in the United States

The increasing scientific evidence that early school start times are harmful to the health and safety of teenagers has generated much recent debate about changing school start times policies for adolescent students. Although efforts to promote and implement such changes have proliferated in the United States in recent years, they have rarely been supported by law-based arguments and messages that leverage the existing legal infrastructure regulating public education and child welfare in the United States. Furthermore, the legal bases to support or resist such changes have not been explored in detail to date. This article provides an overview of how law-based arguments and messages can be constructed and applied to advocate for later school start time policies in U.S. public secondary schools. The legal infrastructure impacting school start time policies in the United States is briefly reviewed, including descriptions of how government regulates education, what legal obligations school officials have concerning their students\u27 welfare, and what laws and public policies currently exist that address adolescent sleep health and safety. On the basis of this legal infrastructure, some hypothetical examples of law-based arguments and messages that could be applied to various types of advocacy activities (e.g., litigation, legislative and administrative advocacy, media and public outreach) to promote later school start times are discussed. Particular consideration is given to hypothetical arguments and messages aimed at emphasizing the consistency of later school start time policies with existing child welfare law and practices, legal responsibilities of school officials and governmental authorities, and societal values and norms

Experimental Wear Modelling of Lifeboat Slipway Launches

It is necessary to use an inclined slipway to launch lifeboats in locations where there is no natural harbour. Slipway stations consist of an initial roller section followed by an inclined keelway, the lifeboat is released from the top of the slipway and proceeds under its own weight into the water. Contact is between the lifeboat keel and a lined, greased keelway and this that determines the friction along the slipway. This paper describes a bench test methodology to investigate this contact. The selection of a modified TE57 reciprocating tribometer and design of a modified pin on plate arrangement is discussed. A test schedule for both the original nickel/chromium coated steel lining and the new low-friction jute fibre/phenolic resin composite lining is developed to accurately reflect real world conditions including environmental contamination such as seawater or wind-blown sand. Environmentally conscious lubricants including water and bio-greases are investigated and compared for their effects in reducing slipway panel friction and wear. Experimental data is collected to establish wear mechanisms, wear volumes and friction characteristics for a range of lubricants and environmental contaminants for the two most common lifeboat keelway lining materials. Implications of this research for future lifeboat slipway design are discussed

Polarization-dependence of anomalous scattering in brominated DNA and RNA molecules, and importance of crystal orientation in single- and multiple-wavelength anomalous diffraction phasing

In this paper the anisotropy of anomalous scattering at the Br K-absorption edge in brominated nucleotides is investigated, and it is shown that this effect can give rise to a marked directional dependence of the anomalous signal strength in X-ray diffraction data. This implies that choosing the correct orientation for crystals of such molecules can be a crucial determinant of success or failure when using single- and multiple-wavelength anomalous diffraction (SAD or MAD) methods to solve their structure. In particular, polarized absorption spectra on an oriented crystal of a brominated DNA molecule were measured, and were used to determine the orientation that yields a maximum anomalous signal in the diffraction data. Out of several SAD data sets, only those collected at or near that optimal orientation allowed interpretable electron density maps to be obtained. The findings of this study have implications for instrumental choices in experimental stations at synchrotron beamlines, as well as for the development of data collection strategy programs

Appendix to paper ?on essential oil of sage.?

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Guanylate cyclase C as a target for prevention, detection, and therapy in colorectal cancer.

INTRODUCTION: Colorectal cancer remains the second leading cause of cancer death in the United States, and new strategies to prevent, detect, and treat the disease are needed. The receptor, guanylate cyclase C (GUCY2C), a tumor suppressor expressed by the intestinal epithelium, has emerged as a promising target. Areas covered: This review outlines the role of GUCY2C in tumorigenesis, and steps to translate GUCY2C-targeting schemes to the clinic. Endogenous GUCY2C-activating ligands disappear early in tumorigenesis, silencing its signaling axis and enabling transformation. Pre-clinical models support GUCY2C ligand supplementation as a novel disease prevention paradigm. With the recent FDA approval of the GUCY2C ligand, linaclotide, and two more synthetic ligands in the pipeline, this strategy can be tested in human trials. In addition to primary tumor prevention, we also review immunotherapies targeting GUCY2C expressed by metastatic lesions, and platforms using GUCY2C as a biomarker for detection and patient staging. Expert commentary: Results of the first GUCY2C targeting schemes in patients will become available in the coming years. The identification of GUCY2C ligand loss as a requirement for colorectal tumorigenesis has the potential to change the treatment paradigm from an irreversible disease of genetic mutation, to a treatable disease of ligand insufficiency