708 research outputs found

    Case-Linked Jurisdiction and Busybody States

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    Environmental benefits of chemical propulsion

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    This paper identifies the necessity of chemical propulsion to satellite usage and some of the benefits accrued through monitoring global resources and patterns, including the Global Climate Change Model (GCM). The paper also summarized how the satellite observations are used to affect national and international policies. Chemical propulsion, like all environmentally conscious industries, does provide limited, controlled pollutant sources through its manufacture and usage. However, chemical propulsion is the sole source which enables mankind to launch spacecraft and monitor the Earth. The information provided by remote sensing directly affects national and international policies designed to protect the environment and enhance the overall quality of life on Earth. The resultant of chemical propulsion is the capability to reduce overall pollutant emissions to the benefit of mankind

    Electromagnetic waves around dilatonic stars and naked singularities

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    We study the propagation of classical electromagnetic waves on the simplest four-dimensional spherically symmetric metric with a dilaton background field. Solutions to the relevant equations are obtained perturbatively in a parameter which measures the strength of the dilaton field (hence parameterizes the departure from Schwarzschild geometry). The loss of energy from outgoing modes is estimated as a back-scattering process against the dilaton background, which would affect the luminosity of stars with a dilaton field. The radiation emitted by a freely falling point-like source on such a background is also studied by analytical and numerical methods.Comment: 9 pages, 1 figur

    All-sky convolution for polarimetry experiments

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    We discuss all-sky convolution of the instrument beam with the sky signal in polarimetry experiments, such as the Planck mission which will map the temperature anisotropy and polarization of the cosmic microwave background (CMB). To account properly for stray light (from e.g. the galaxy, sun, and planets) in the far side-lobes of such an experiment, it is necessary to perform the beam convolution over the full sky. We discuss this process in multipole space for an arbitrary beam response, fully including the effects of beam asymmetry and cross-polarization. The form of the convolution in multipole space is such that the Wandelt-Gorski fast technique for all-sky convolution of scalar signals (e.g. temperature) can be applied with little modification. We further show that for the special case of a pure co-polarized, axisymmetric beam the effect of the convolution can be described by spin-weighted window functions. In the limits of a small angle beam and large Legendre multipoles, the spin-weight 2 window function for the linear polarization reduces to the usual scalar window function used in previous analyses of beam effects in CMB polarimetry experiments. While we focus on the example of polarimetry experiments in the context of CMB studies, we emphasise that the formalism we develop is applicable to anisotropic filtering of arbitrary tensor fields on the sphere.Comment: 8 pages, 1 figure; Minor changes to match version accepted by Phys. Rev.

    The effects of social service contact on teenagers in England

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    Objective: This study investigated outcomes of social service contact during teenage years. Method: Secondary analysis was conducted of the Longitudinal Survey of Young People in England (N = 15,770), using data on reported contact with social services resulting from teenagers’ behavior. Outcomes considered were educational achievement and aspiration, mental health, and locus of control. Inverse-probability-weighted regression adjustment was used to estimate the effect of social service contact. Results: There was no significant difference between those who received social service contact and those who did not for mental health outcome or aspiration to apply to university. Those with contact had lower odds of achieving good exam results or of being confident in university acceptance if sought. Results for locus of control were mixed. Conclusions: Attention is needed to the role of social services in supporting the education of young people in difficulty. Further research is needed on the outcomes of social services contact

    A covalent p97/VCP ATPase inhibitor can overcome resistance to CB-5083 and NMS-873 in colorectal cancer cells

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    Small-molecule inhibitors of p97 are useful tools to study p97 function. Human p97 is an important AAA ATPase due to its diverse cellular functions and implication in mediating the turnover of proteins involved in tumorigenesis and virus infections. Multiple p97 inhibitors identified from previous high-throughput screening studies are thiol-reactive compounds targeting Cys522 in the D2 ATP-binding domain. Thus, these findings suggest a potential strategy to develop covalent p97 inhibitors. We first used purified p97 to assay several known covalent kinase inhibitors to determine if they can inhibit ATPase activity. We evaluated their selectivity using our dual reporter cells that can distinguish p97 dependent and independent degradation. We selected a β-nitrostyrene scaffold to further study the structure-activity relationship. In addition, we used p97 structures to design and synthesize analogues of pyrazolo[3,4-d]pyrimidine (PP). We incorporated electrophiles into a PP-like compound 17 (4-amino-1-tert-butyl-3-phenyl pyrazolo[3,4-d]pyrimidine) to generate eight compounds. A selective compound 18 (N-(1-(tert-butyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)acrylamide, PPA) exhibited excellent selectivity in an in vitro ATPase activity assay: IC50 of 0.6 μM, 300 μM, and 100 μM for wild type p97, yeast Cdc48, and N-ethylmaleimide sensitive factor (NSF), respectively. To further examine the importance of Cys522 on the active site pocket during PPA inhibition, C522A and C522T mutants of p97 were purified and shown to increase IC50 values by 100-fold, whereas replacement of Thr532 of yeast Cdc48 with Cysteine decreased the IC50 by 10-fold. The molecular modeling suggested the hydrogen bonds and hydrophobic interactions in addition to the covalent bonding at Cys522 between WT-p97 and PPA. Furthermore, tandem mass spectrometry confirmed formation of a covalent bond between Cys522 and PPA. An anti-proliferation assay indicated that the proliferation of HCT116, HeLa, and RPMI8226 was inhibited by PPA with IC50 of 2.7 μM, 6.1 μM, and 3.4 μM, respectively. In addition, PPA is able to inhibit proliferation of two HCT116 cell lines that are resistant to CB-5083 and NMS-873, respectively. Proteomic analysis of PPA-treated HCT116 revealed Gene Ontology enrichment of known p97 functional pathways such as the protein ubiquitination and the ER to Golgi transport vesicle membrane. In conclusion, we have identified and characterized PPA as a selective covalent p97 inhibitor, which will allow future exploration to improve the potency of p97 inhibitors with different mechanisms of action
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