Extracting Imperative Programs from Proofs: In-place Quicksort

The process of program extraction is primarily associated with functional programs with less focus on imperative program extraction. In this paper we consider a standard problem for imperative programming: In-place Quicksort. We formalize a proof that every array of natural numbers can be sorted and apply a realizability interpretation to extract a program from the proof. Using monads we are able to exhibit the inherent imperative nature of the extracted program. We see this as a first step towards an automated extraction of imperative programs. The case study is carried out in the interactive proof assistant Minlog

Fucoidan and cancer: A multifunctional molecule with anti-tumor potential

There is a wide variety of cancer types yet, all share some common cellular and molecular behaviors. Most of the chemotherapeutic agents used in cancer treatment are designed to target common deregulated mechanisms within cancer cells. Many healthy tissues are also affected by the cytotoxic effects of these chemical agents. Fucoidan, a natural component of brown seaweed, has anti-cancer activity against various cancer types by targeting key apoptotic molecules. It also has beneficial effects as it can protect against toxicity associated with chemotherapeutic agents and radiation. Thus the synergistic effect of fucoidan with current anti-cancer agents is of considerable interest. This review discusses the mechanisms by which fucoidan retards tumor development, eradicates tumor cells and synergizes with anti-cancer chemotherapeutic agents. Challenges to the development of fucoidan as an anti-cancer agent will also be discussed

Mouse Model of Devil Facial Tumour Disease Establishes That an Effective Immune Response Can be Generated Against the Cancer Cells

The largest carnivorous marsupial in Australia, the Tasmanian devil (Sarcophilus harrisii) is facing extinction in the wild due to a transmissible cancer known as Devil Facial Tumour Disease (DFTD). DFTD is a clonal cell line transmitted from host to host with 100% mortality and no known immunity. While it was first considered that low genetic diversity of the population of devils enabled the allograft transmission of DFTD recent evidence reveals that genetically diverse animals succumb to the disease. The lack of an immune response against the DFTD tumor cells may be due to a lack of immunogenicity of the tumor cells. This could facilitate transmission between devils. To test immunogenicity, mice were injected with viable DFTD cells and anti-DFTD immune responses analyzed. A range of antibody isotypes against DFTD cells was detected, indicating that as DFTD cells can induce an immune response they are immunogenic. This was supported by cytokine production, when splenocytes from mice injected with DFTD cells were cultured in vitro with DFTD cells and the supernatant analyzed. There was a significant production of IFN-γ and TNF-α following the first injection with DFTD cells and a significant production of IL-6 and IL-10 following the second injection. Splenocytes from naïve or immunized mice killed DFTD cells in in vitro cytotoxicity assays. Thus they are also targets for immunological destruction. We conclude that as an immune response can be generated against DFTD cells they would be suitable targets for a vaccine

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii) facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY) ligand-binding motif and the CTLA-4 (GVYVKM) inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs) in genes and protein domains that have not been previously reported in any species. This checkpoint molecule analysis and review of salient features for each of the molecules presented here can serve as road map for the development of a Tasmanian devil facial tumor disease immunotherapy. Finally, the strategies can be used as a guide for veterinarians, ecologists, and other researchers willing to venture into the nascent field of wild immunology

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On kHz oscillations and characteristic frequencies of accreting magnetospheres

When an accreting star is close to rotational equilibrium between the dipole component of the stellar magnetic field and the accretion disk, the star's rotation rate is roughly of the order of the Keplerean rotation rate at the inner boundary of the disk, estimated as the conventional Alfven radius. A range of frequencies higher than this equilibrium rotation frequency can naturally arise if the accretion flow is channeled by higher multipoles of the star's magnetic field. The higher multipole components of the magnetic field will balance the material stresses of the accretion flow at radii closer to the star. The Kepler frequencies associated with these generalized Alfven radii increase with the order of the multipole. Other frequency bands, like the epicyclic frequencies associated with the accretion flow, may in turn be higher than the Kepler frequencies. We present expressions for the spectrum of higher frequencies arising due to these effects. Kilohertz quasi-periodic oscillation frequencies that are much higher than the rotation rate of the neutron star, as observed from the recently discovered 11 Hz (P = 90 ms) X-ray pulsar IGR J17480-2446 in the globular cluster Terzan 5, may be due to modulation of the accretion rate by the excitation of these modes in the accretion flow. The very high QPO frequencies observed from the soft gamma repeaters SGR 1806-20 (P = 5.2 s) and SGR 1900+14 (P = 7.5 s) may also correspond to these characteristic frequencies if SGRs accrete from fallback disks around them.Comment: 8 pages, 1 figure. Accepted for publication in MNRA

THE EFFECT OF TONE ON THE SUCCESSIVE COMPARISON OF BRIGHTNESS

Last updated: 6/12/200

The Lopsidedness of Present-Day Galaxies: Connections to the Formation of Stars, the Chemical Evolution of Galaxies, and the Growth of Black Holes

We have used the Sloan Digital Sky Survey (SDSS) to undertake an investigation of lopsidedness in a sample of ~25,000 nearby galaxies (z < 0.06). We use the m=1 azimuthal Fourier mode between the 50% and 90% light radii as our measure of lopsidedness. The SDSS spectra are used to measure the properties of the stars, gas, and black hole in the central-most few-kpc-scale region. We show that there is a strong link between lopsidedness in the outer parts of the galactic disk and the youth of the stellar population in the central region. This link is independent of the other structural properties of the galaxy. These results provide a robust statistical characterization of the connections between accretion/interactions/mergers and the resulting star formation. We also show that residuals in the galaxy mass-metallicity relation correlate with lopsidedness (at fixed mass, the more metal-poor galaxies are more lopsided). This suggests that the events causing lopsidedness and enhanced star formation deliver lower metallicity gas into the galaxy's central region. Finally, we find that there is a trend for the more powerful active galactic nuclei to be hosted by more lopsided galaxies (at fixed galaxy mass, density, or concentration). However if we compare samples matched to have both the same structures and central stellar populations, we then find no difference in lopsidedness between active and non-active galaxies. This leads to the following picture. The presence of cold gas in the central region of a galaxy (irrespective of its origin) is essential for both star-formation and black hole growth. The delivery of cold gas is aided by the processes that produce lopsidedness. Other processes on scales smaller than we can probe with our data are required to transport the gas to the black hole.Comment: 39 pages, 16 figures, 3 tables, accepted to ApJ. Updated author affiliation

Intravesical rAd-IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study.

Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 10(11) viral particles (vp)/mL or 3 × 10(11) vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNα/Syn3 (1 × 10(11) vp/mL, n = 21; 3 × 10(11) vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd-IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy