Characterization of a new pathway that activates lumisterol <i>in vivo</i> to biologically active hydroxylumisterols

Abstract Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non-genomic VDR site. Inhibition of RORα and RORγ transactivation activities in a Tet-on CHO cell reporter system, RORα co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORα and RORγ as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved

Opportunities in Software Engineering Research for Web API Consumption

Nowadays, invoking third party code increasingly involves calling web services via their web APIs, as opposed to the more traditional scenario of downloading a library and invoking the library's API. However, there are also new challenges for developers calling these web APIs. In this paper, we highlight a broad set of these challenges and argue for resulting opportunities for software engineering research to support developers in consuming web APIs. We outline two specific research threads in this context: (1) web API specification curation, which enables us to know the signatures of web APIs, and (2) static analysis that is capable of extracting URLs, HTTP methods etc. of web API calls. Furthermore, we present new work on how we combine (1) and (2) to provide IDE support for application developers consuming web APIs. As web APIs are used broadly, research in supporting the consumption of web APIs offers exciting opportunities.Comment: Erik Wittern and Annie Ying are both first author

Advanced Transport Operating System (ATOPS) Flight Management/Flight Controls (FM/FC) software description

The flight software developed for the Flight Management/Flight Controls (FM/FC) MicroVAX computer used on the Transport Systems Research Vehicle for Advanced Transport Operating Systems (ATOPS) research is described. The FM/FC software computes navigation position estimates, guidance commands, and those commands issued to the control surfaces to direct the aircraft in flight. Various modes of flight are provided for, ranging from computer assisted manual modes to fully automatic modes including automatic landing. A high-level system overview as well as a description of each software module comprising the system is provided. Digital systems diagrams are included for each major flight control component and selected flight management functions

Advanced Transport Operating System (ATOPS) control display unit software description

The software created for the Control Display Units (CDUs), used for the Advanced Transport Operating Systems (ATOPS) project, on the Transport Systems Research Vehicle (TSRV) is described. Module descriptions are presented in a standardized format which contains module purpose, calling sequence, a detailed description, and global references. The global reference section includes subroutines, functions, and common variables referenced by a particular module. The CDUs, one for the pilot and one for the copilot, are used for flight management purposes. Operations performed with the CDU affects the aircraft's guidance, navigation, and display software

Advanced transport operating system software upgrade: Flight management/flight controls software description

The Flight Management/Flight Controls (FM/FC) software for the Norden 2 (PDP-11/70M) computer installed on the NASA 737 aircraft is described. The software computes the navigation position estimates, guidance commands, those commands to be issued to the control surfaces to direct the aircraft in flight based on the modes selected on the Advanced Guidance Control System (AGSC) mode panel, and the flight path selected via the Navigation Control/Display Unit (NCDU)

Products of Vitamin D3 or 7-Dehydrocholesterol Metabolism by Cytochrome P450scc Show Anti-Leukemia Effects, Having Low or Absent Calcemic Activity

BACKGROUND. Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)2D3, as well as 1-hydroxyvitamin D3 to 1a,20-dihydroxyvitamin D3 (1,20(OH)2D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL). METHODS AND FINDINGS. To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH)2D3 being either equipotent or slightly less potent than 1,25(OH)2D3, while 1,20(OH)2D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH)2D3 was the most potent, 20(OH)D3, 20,23(OH)2D3 and 1,20(OH)2D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 µg/kg, whereas, 1,20(OH)2D3 was slightly to moderately calcemic and 1,25(OH)2D3 had strong calcemic activity. CONCLUSIONS. We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.National Institutes of Health (R01A052190

NLO photon parton parametrization using ee and ep data

An NLO photon parton parametrization is presented based on the existing $F_2^\gamma$ measurements from $e^+e^-$ data and the low-$x$ proton structure function from $ep$ interactions. Also included in the extraction of the NLO parton distribution functions are the dijets data coming from $\gamma p \to j_1 + j_2 +X$. The new parametrization is compared to other NLO parametrizations.Comment: 22 pages, 7 figures, 2 table

On parton distributions in a photon gas

In some cases it may be useful to know parton distributions in a photon gas. This may be relevant, e.g., for the analysis of interactions of high energy cosmic ray particles with the cosmic microwave background radiation. The latter can be considered as a gas of photons with an almost perfect blackbody spectrum. An approach to finding such parton distributions is described. The survival probability of ultra-high energy neutrinos traveling through this radiation is calculated.Comment: 5 pages, 4 figures, EPJ style files. Some changes in the text. Two new sections discussing ultra-high energy neutrino damping in the cosmic microwave background radiation are include

Implications of a W^+W^- (ZZ) - Higgs - t c-bar$ Interaction for e^+e^- -> t c-bar \nu_e \nu_e-bar, t c-bar e^+ e^-, t c-bar Z and for t -> cW^+W^-, cZZ in a Two Higgs Doublet Model

The Standard Model with one extra Higgs doublet may give rise to enhanced TREE-LEVEL flavor-changing-scalar coupling of a neutral Higgs to a pair of top-charm quarks. This coupling may drive a large TREE-LEVEL effective W^+W^-(ZZ) - Higgs - t c-bar interaction. As a result we find that the reactions e^+e^- -> t c-bar \nu_e \nu_e-bar, t c-bar e^+ e^-, t c-bar Z and the two rare top decays t -> cW^+W^-, t -> cZZ become very sensitive probes of such an effective interaction. The most promising ones, e^+e^- -> t c-bar \nu_e \nu_e-bar, t c-bar e^+ e^-, may yield several hundreds and up to thousands of such events at the Next Linear Collider with a center of mass energy of \sqrt{s}=0.5 - 2 TeV if the mass of the lightest neutral Higgs is a few hundred GeV. The rare decays t -> cW^+W^- and t -> cZZ may be accessible at the LHC if the mass of the lightest neutral Higgs lies in the narrow window 150 GeV < m_h < 200 GeV.Comment: 18 pages, plain latex, 12 figures embadded in the text using epsfi

Combined QCD and electroweak analysis of HERA data

A simultaneous fit of parton distribution functions (PDFs) and electroweak parameters to HERA data on deep inelastic scattering is presented. The input data are the neutral current and charged current inclusive cross sections which were previously used in the QCD analysis leading to the HERAPDF2.0 PDFs. In addition, the polarisation of the electron beam was taken into account for the ZEUS data recorded between 2004 and 2007. Results on the vector and axial-vector couplings of the Z boson to u- and d-type quarks, on the value of the electroweak mixing angle and the mass of the W boson are presented. The values obtained for the electroweak parameters are in agreement with Standard Model predictions.Comment: 32 pages, 10 figures, accepted by Phys. Rev. D. Small corrections from proofing process and small change to Fig. 12 and Table