Monitoring-Oriented Programming: A Tool-Supported Methodology for Higher Quality Object-Oriented Software

This paper presents a tool-supported methodological paradigm for object-oriented software development, called monitoring-oriented programming and abbreviated MOP, in which runtime monitoring is a basic software design principle. The general idea underlying MOP is that software developers insert specifications in their code via annotations. Actual monitoring code is automatically synthesized from these annotations before compilation and integrated at appropriate places in the program, according to user-defined configuration attributes. This way, the specification is checked at runtime against the implementation. Moreover, violations and/or validations of specifications can trigger user-defined code at any points in the program, in particular recovery code, outputting or sending messages, or raising exceptions. The MOP paradigm does not promote or enforce any specific formalism to specify requirements: it allows the users to plug-in their favorite or domain-specific specification formalisms via logic plug-in modules. There are two major technical challenges that MOP supporting tools unavoidably face: monitor synthesis and monitor integration. The former is heavily dependent on the specification formalism and comes as part of the corresponding logic plug-in, while the latter is uniform for all specification formalisms and depends only on the target programming language. An experimental prototype tool, called Java-MOP, is also discussed, which currently supports most but not all of the desired MOP features. MOP aims at reducing the gap between formal specification and implementation, by integrating the two and allowing them together to form a system

M3 muscarinic acetylcholine receptor facilitates the endocytosis of mu opioid receptor mediated by morphine independently of the formation of heteromeric complexes

Morphine inefficiency to induce the internalization of mu opioid (MOP) receptors observed in numerous experimental models constitutes a paradigm of G-protein coupled receptor (GPCR) functional selectivity. We recently described that activation of Gαq/11 proteins through 5-HT2A serotonin receptors co-expressed in the same cells facilitates MOP receptor endocytosis promoted by morphine. In order to explore whether a different Gαq/11 coupled GPCR would emulate this effect, a double stable Flp-In T-REx HEK293 cell line permanently expressing MOP-YFP receptors along with FLAG-M3-Cerulean receptors expressed in an inducible manner was generated. Fluorescence microscopy examination of these cells revealed a co-distribution of both receptors mainly compartmentalized in plasma membrane. Concurrent stimulation with carbachol and morphine promoted MOP receptor internalization, desensitization and down-regulation and this facilitation was not dependent on PKC activation. Co-immunoprecipitation experiments demonstrated that FLAG-M3-Cerulean/MOP-YFP receptors interact forming heteromeric complexes in a time depending manner, i.e. the strongest interaction was detected after 96h of FLAG-M3-Cerulean induced expression. Under these experimental conditions, treatment of cells with carbachol plus morphine resulted in the internalization of both receptors within separated endocytic vesicles as visualized by confocal microscopy. This trafficking segregation observed for FLAG-M3-Cerulean and MOP-YFP receptors upon agonist stimulation suggests that this protein-protein interaction presents temporal and dynamic properties. Moreover, MOP-YFP receptor internalization facilitated by FLAG-M3-Cerulean receptors is independent of the constitution of heteromeric complexes. [Abstract copyright: Copyright © 2017. Published by Elsevier Inc.

BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates

© 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.Background: The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. Methods: A series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. Results: After systemic administration, BU10038 (0.001–0.01 mg kg −1 ) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10–30-fold higher dose (0.01–0.1 mg kg −1 ). After intrathecal administration, BU10038 (3 μg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. Conclusions: These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.Peer reviewedFinal Published versio

Pressure-induced Superconductivity in the Three-component Fermion Topological Semimetal Molybdenum Phosphide

Topological semimetal, a novel state of quantum matter hosting exotic emergent quantum phenomena dictated by the non-trivial band topology, has emerged as a new frontier in condensed-matter physics. Very recently, a coexistence of triply degenerate points of band crossing and Weyl points near the Fermi level was theoretically predicted and immediately experimentally verified in single crystalline molybdenum phosphide (MoP). Here we show in this material the high-pressure electronic transport and synchrotron X-ray diffraction (XRD) measurements, combined with density functional theory (DFT) calculations. We report the emergence of pressure-induced superconductivity in MoP with a critical temperature Tc of about 2 K at 27.6 GPa, rising to 3.7 K at the highest pressure of 95.0 GPa studied. No structural phase transitions is detected up to 60.6 GPa from the XRD. Meanwhile, the Weyl points and triply degenerate points topologically protected by the crystal symmetry are retained at high pressure as revealed by our DFT calculations. The coexistence of three-component fermion and superconductivity in heavily pressurized MoP offers an excellent platform to study the interplay between topological phase of matter and superconductivity.Comment: 27 pages, 10 figures, 1 tabl

MOP /Matrix Operation Programs system/

MOP /Matrix Operation Programs/ system consists of a set of FORTRAN 4 subroutines which are related through a small common allocation. The system accomplishes all matrix algebra operations plus related input-output and housekeeping details

Economic impacts of a premature nuclear phase-out in Switzerland

This paper investigates the economic impacts of two policy proposals: "Strom ohne Atom" (SOA) and "Moratorium Plus" (MOP), both of which contain a premature phase-out of nuclear power in Switzerland. While MOP restricts business-as-usual operation time of existing nuclear power plants to 40 years, which results in a cutback of 10-20 years, SOA foresees a reduction in operation time of 20-30 years and administers combined heat and power to substitute for nuclear energy. Based on simulations with an intertemporal multi-sector general equilibrium model of the Swiss economy, we quantify the price tags for risk reduction from nuclear power operation given additional constraints on back-up technologies. Costs of accelerating the phase-out of nuclear power for an average household amount to 200 CHF/a over the next 45 years under SOA and drop to 60 CHF/a in the case of MOP. If Switzerland were to assure carbon neutrality of a premature phase-out by the use of carbon taxes, adjustment costs would increase to 230 CHF under SOA and 110 CHF under MOP. --nuclear phase-out,computable general equilibrium

Multiple orthogonal polynomial ensembles

Multiple orthogonal polynomials are traditionally studied because of their connections to number theory and approximation theory. In recent years they were found to be connected to certain models in random matrix theory. In this paper we introduce the notion of a multiple orthogonal polynomial ensemble (MOP ensemble) and derive some of their basic properties. It is shown that Angelesco and Nikishin systems give rise to MOP ensembles and that the equilibrium problems that are associated with these systems have a natural interpretation in the context of MOP ensembles.Comment: 20 pages, no figure

Nilai – Nilai Budaya dalam Memandang Metode Kontrasepsi Medis Operasi Pria di Kabupaten Demak Tahun 2013

Vasektomi atau medis operasi pria (MOP) merupakan tindakan penutupan (pemotongan, pengikatan, penyumbatan) kedua saluran mani pria sebelah kanan dan kiri, yang terdapat dalam kantung buah zakar. Sehingga pada ejakulasi, cairan mani yang keluar tidak lagi mengandung sperma sehingga mencegahkehamilanpadasaatkoitus. Jumlah akseptor MOP di Kabupaten Demak pada bulan februari 2013 sangat rendah dibandingkan dengan alat kontrasepsi lainnya yaitu sebesar 0,00% PB (peserta baru) dan 0,53% PA (peserta aktif). Tujuan dilakukan penelitian ini adalah menggambarkan nilai – nilai budaya dalam memandang metode kontrasepsi Medis operasi Pria (MOP) di masyarakat Kabupaten Demak tahun 2013. Jenis Penelitian ini adalah penelitian kualitatif dengan metode wawancara mendalam kepada subjek penelitian yaitu bagi yang melakukan MOP dan yang tidak melakukan MOP, ditentukan dengan teknik purposive sampling. Sampel yang digunakan sebanyak 6 pria yaitu: 4 pria yang menggunakan MOP dan 2 pria yang tidak menggunakan MOP. Keabsahan data dilakukan dengan triangulasi sumber yaitu keluarga (istri), tokoh agama, PLKB (Petugas Lapangan Keluarga Berencana), Kasubid KB dan Kepala Unit Pelaksanaan Teknis Badan Pemberdayaan Masyarakat Keluarga Berencana. Hasil penelitian menunjukan sebagian besar subjek penelitian memikirkan dan merasakan KB MOP untuk mengurangi jumlah kelahiran, mereka melakukan MOP dengan suka rela, siap, mantap, yakin dan merasa nyaman setelah melakukan MOP. Bagi yang tidak melakukan MOP masih adanya keraguan. Perilaku tokoh agama tidak mempengaruhi SP untuk melakukan MOP. Baik bagi suami yang melakukan MOP dan tidak melakukan MOP masih memandang nilai budaya KB diperuntukkan untuk perempuan (istri) dan merasa cukup 2 anak. Perilaku penggunaan MOP bagi yang melakukan MOP untuk memperingan istri, sedangkan bagi yang tidak melakukan MOP karena sibuk bekarja dan istri sudah ikut KB. Disarankan bagi petugas kesehatan (PLKB) yang dibina oleh bapermas dan KB untuk melakukan penyuluhan kepada para pria bahwa KB tidak hanya untuk wanita tapi ada KB untuk pria yaitu MOP

Cytochrome P450 CYP1B1 interacts with 8-<i>methoxypsoralen</i> (8-MOP) and influences psoralen-Ultraviolet A (PUVA) sensitivity

Background: There are unpredictable inter-individual differences in sensitivity to psoralen-UVA (PUVA) photochemotherapy, used to treat skin diseases including psoriasis. Psoralens are metabolised by cytochrome P450 enzymes (P450), and we hypothesised that variability in cutaneous P450 expression may influence PUVA sensitivity. We previously showed that P450 CYP1B1 was abundantly expressed in human skin and regulated by PUVA, and described marked inter-individual differences in cutaneous CYP1B1 expression.Objectives: We investigated whether CYP1B1 made a significant contribution to 8-methoxypsoralen (8-MOP) metabolism, and whether individuality in CYP1B1 activity influenced PUVA sensitivity.Methods: We used E. coli membranes co-expressing various P450s and cytochrome P450 reductase (CPR) to study 8-MOP metabolism and cytotoxicity assays in CYP1B1-expressing mammalian cells to assess PUVA sensitivity.Results: We showed that P450s CYP1A1, CYP1A2, CYP1B1, CYP2A6 and CYP2E1 influence 8-MOP metabolism. As CYP1B1 is the most abundant P450 in human skin, we further demonstrated that: (i) CYP1B1 interacts with 8-MOP (ii) metabolism of the CYP1B1 substrates 7-ethoxyresorufin and 17-b-estradiol showed concentration-dependent inhibition by 8-MOP and (iii) inhibition of 7-ethoxyresorufin metabolism by 8-MOP was influenced by CYP1B1 genotype. The influence of CYP1B1 on PUVA cytotoxicity was further investigated in a Chinese hamster ovary cell line, stably expressing CYP1B1 and CPR, which was more sensitive to PUVA than control cells, suggesting that CYP1B1 metabolises 8-MOP to a more phototoxicmetabolite(s).Conclusion: Our data therefore suggest that CYP1B1 significantly contributes to cutaneous 8-MOP metabolism, and that individuality in CYP1B1 expression may influence PUVA sensitivity

On the computational complexity of Data Flow Analysis

We consider the problem of Data Flow Analysis over monotone data flow frameworks with a finite lattice. The problem of computing the Maximum Fixed Point (MFP) solution is shown to be P-complete even when the lattice has just four elements. This shows that the problem is unlikely to be efficiently parallelizable. It is also shown that the problem of computing the Meet Over all Paths (MOP) solution is NL-complete (and hence efficiently parallelizable) when the lattice is finite even for non-monotone data flow frameworks. These results appear in contrast with the fact that when the lattice is not finite, solving the MOP problem is undecidable and hence significantly harder than the MFP problem which is polynomial time computable for lattices of finite height.Comment: 7 pages 4 figure