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

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

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

Site-selective quantum correlations revealed by magnetic anisotropy in the tetramer system SeCuO3

We present the investigation of a monoclinic compound SeCuO3 using x-ray powder diffraction, magnetization, torque and electron-spin-resonance (ESR). Structurally based analysis suggests that SeCuO3 can be considered as a 3D network of tetramers. The values of intra-tetramer exchange interactions are extracted from the temperature dependence of the susceptibility and amount to ~200 K. The inter-tetramer coupling leads to the development of long-range antiferromagnetic order at TN = 8 K. An unusual temperature dependence of the effective g-tensors is observed, accompanied with a rotation of macroscopic magnetic axes. We explain this unique observation as due to site-selective quantum correlations

APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis.

Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis

Competing Jahn Teller distortions and ferrimagnetic ordering in the geometrically frustrated system Ni1 xCuxCr2O4

Competing Jahn Teller distortions combined with geometrical frustration give rise to a rich phase diagram as a function of x Cu and temperature in the spinel system Ni1 xCuxCr2O4. The Jahn Teller distortion of the end members acts in opposite ways, with an elongation of the NiO4 tetrahedra resulting in a structural transition at TS1 317K in NiCr2O4, but a flattening in the CuO4 tetrahedra at TS1 846K in CuCr2O4. In both cases the symmetry is lowered from cubic Fd 3m to tetragonal I41 amd on cooling. In order to follow the influence of Jahn Teller active Ni2 and Cu2 ions on the structural and magnetic properties of chromium spinels, we have investigated a series of samples of Ni1 xCuxCr2O4 by x ray and neutron powder diffraction. In the critical range 0.10 lt; x Cu lt; 0.20, strong orthorhombic distortions were observed, where competing Jahn Teller activities between the Cu2 and Ni2 ions result in distortions along both the a and c axes. For Ni0.85Cu0.15Cr2O4, the orthorhombic structure Fddd is stabilized up to TS2 368 2 K, close to the first structural phase transition at TS1 374 2 K. A ferrimagnetic spin alignment of the Ni Cu and chromium atoms sets in at much lower temperature TC 95K in this compound. The end members NiCr2O4 and CuCr2O4 undergo this ferrimagnetic transition at TC 74 and 135 K, respectively. These transitions are accompanied by the structural change to the orthorhombic symmetry which relieves the frustration. NiCr2O4 and Ni0.85Cu0.15Cr2O4 undergo a second magnetic transition at TM2 24 and 67K due to a superimposed antiferromagnetic ordering of the Cr moments resulting in a noncollinear magnetic structure. In the system Ni1 xCuxCr2O4, the magnetic transitions TC and TM2 merge with increasing copper content up to x Cu similar to 0.5. For the Ni rich chromites, geometrical frustration causes a strong reduction of the chromium moments, where magnetic long range order coexists with a disordered spin liquid like or a reentrant spin glass like state. This paper provides insight into the interplay between the Jahn Teller effect, geometrical frustration, and long range magnetic order in these complex system

GUCY2C maintains intestinal LGR5+ stem cells by opposing ER stress

Long-lived multipotent stem cells (ISCs) at the base of intestinal crypts adjust their phenotypes to accommodate normal maintenance and post-injury regeneration of the epithelium. Their long life, lineage plasticity, and proliferative potential underlie the necessity for tight homeostatic regulation of the ISC compartment. In that context, the guanylate cyclase C (GUCY2C) receptor and its paracrine ligands regulate intestinal epithelial homeostasis, including proliferation, lineage commitment, and DNA damage repair. However, a role for this axis in maintaining ISCs remains unknown. Transgenic mice enabling analysis of ISCs (Lgr5-GFP) in the context of GUCY2C elimination (Gucy2c-/-) were combined with immunodetection techniques and pharmacological treatments to define the role of the GUCY2C signaling axis in supporting ISCs. ISCs were reduced in Gucy2c-/- mice, associated with loss of active Lgr5+ cells but a reciprocal increase in reserve Bmi1+ cells. GUCY2C was expressed in crypt base Lgr5+ cells in which it mediates canonical cyclic (c) GMPdependent signaling. Endoplasmic reticulum (ER) stress, typically absent from ISCs, was elevated throughout the crypt base in Gucy2c-/- mice. The chemical chaperone tauroursodeoxycholic acid resolved this ER stress and restored the balance of ISCs, an effect mimicked by the GUCY2C effector 8Br-cGMP. Reduced ISCs in Gucy2c-/-mice was associated with greater epithelial injury and impaired regeneration following sub-lethal doses of irradiation. These observations suggest that GUCY2C provides homeostatic signals that modulate ER stress and cell vulnerability as part of the machinery contributing to the integrity of ISCs. © Kraft et al