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  • 1801.
    Abdulla, Parosh
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Ben Henda, Noomene
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Deneux, Johann
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Jonsson, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Reidmar, Tomas
    Report on Dataflow Dependencies in Billing Processing Systems2004In: Proc. ISoLA '04: 1st International Symposium on Leveraging Applications of Formal Methods, 2004Conference paper (Refereed)
  • 1802.
    Abdulla, Parosh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Ben Henda, Noomene
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Mayr, Richard
    Decisive Markov Chains2007In: Logical Methods in Computer Science, ISSN 1860-5974, E-ISSN 1860-5974, Vol. 3, no 4, p. 1-32Article in journal (Refereed)
    Abstract [en]

    We consider qualitative and quantitative verification problems for infinite-state Markov chains. We call a Markov chain decisive w.r.t. a given set of target states F if it almost certainly eventually reaches either F or a state from which F can no longer be reached. While all finite Markov chains are trivially decisive (for every set F), this also holds for many classes of infinite Markov chains. Infinite Markov chains which contain a finite attractor are decisive w.r.t. every set F. In particular, this holds for probabilistic lossy channel systems (PLCS). Furthermore, all globally coarse Markov chains are decisive. This class includes probabilistic vector addition systems (PVASS) and probabilistic noisy Turing machines (PNTM). We consider both safety and liveness problems for decisive Markov chains, i.e., the probabilities that a given set of states F is eventually reached or reached infinitely often, respectively. 1. We express the qualitative problems in abstract terms for decisive Markov chains, and show an almost complete picture of its decidability for PLCS, PVASS and PNTM. 2. We also show that the path enumeration algorithm of Iyer and Narasimha terminates for decisive Markov chains and can thus be used to solve the approximate quantitative safety problem. A modified variant of this algorithm solves the approximate quantitative liveness problem. 3. Finally, we show that the exact probability of (repeatedly) reaching F cannot be effectively expressed (in a uniform way) in Tarski-algebra for either PLCS, PVASS or (P)NTM.

  • 1803. Abdulla, Parosh
    et al.
    Ben Henda, Noomene
    Mayr, Richard
    Sandberg, Sven
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology.
    Eager Markov Chains2006In: Proceedings of the 4th International Symposium on Automated Technology for Verification and Analysis (ATVA 2006), 2006, p. 24-38Chapter in book (Other academic)
  • 1804.
    Abdulla, Parosh
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. DoCS.
    Ben Henda, Noomene
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. DoCS.
    Mayr, Richard
    Sandberg, Sven
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datalogi.
    Eager Markov Chains: Eager Markov Chains2006In: Proceedings of the fourth international symposium on Automated Technology for Verification and Analysis (ATVA), 2006, p. 24-38Conference paper (Refereed)
    Abstract [en]

    We consider infinite-state discrete Markov chains which are eager:

    the probability of avoiding a defined set of final states for more than n steps is bounded by some exponentially decreasing function f(n).

    We prove that eager Markov chains include those induced by Probabilistic Lossy Channel Systems, Probabilistic Vector Addition Systems with States, and Noisy Turing Machines, and that the bounding function f(n) can be effectively constructed for them.

    Furthermore, we study the problem of computing the expected reward (or cost) of runs until reaching the final states, where rewards are assigned to individual runs by computable reward functions.

    For eager Markov chains, an effective path exploration scheme,

    based on forward reachability analysis, can be used to approximate the expected reward up-to an arbitrarily small error.

  • 1805. Abdulla, Parosh
    et al.
    Ben Henda, Noomene
    Mayr, Richard
    Sandberg, Sven
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology.
    Limiting Behavior of Markov Chains with Eager Attractors2006In: Proceedings of the 3rd International Conference on the Quantitative Evaluation of SysTems (QEST 2006), 2006, p. 253--262Chapter in book (Other academic)
  • 1806.
    Abdulla, Parosh
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. DoCS.
    Ben Henda, Noomene
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. DoCS.
    Mayr, Richard
    Sandberg, Sven
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datalogi.
    Limiting Behavior of Markov Chains with Eager Attractors2006In: Third International Conference on the Quantitative Evaluation of Systems (QEST), 2006, p. 253-262Conference paper (Refereed)
  • 1807.
    Abdulla, Parosh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Ciobanu, Radu
    Univ Edinburgh, Edinburgh, Midlothian, Scotland..
    Mayr, Richard
    Univ Edinburgh, Edinburgh, Midlothian, Scotland..
    Sangnier, Arnaud
    Univ Paris Diderot, CNRS, LIAFA, Sorbonne Paris Cite, Paris, France..
    Sproston, Jeremy
    Univ Turin, Turin, Italy..
    Qualitative Analysis of VASS-Induced MDPs2016In: Foundations Of Software Science And Computation Structures (FOSSACS 2016) / [ed] Jacobs, B Loding, C, 2016, p. 319-334Conference paper (Refereed)
    Abstract [en]

    We consider infinite-state Markov decision processes (MDPs) that are induced by extensions of vector addition systems with states (VASS). Verification conditions for these MDPs are described by reachability and Buchi objectives w.r.t. given sets of control-states. We study the decidability of some qualitative versions of these objectives, i.e., the decidability of whether such objectives can be achieved surely, almostsurely, or limit-surely. While most such problems are undecidable in general, some are decidable for large subclasses in which either only the controller or only the random environment can change the counter values (while the other side can only change control-states).

  • 1808.
    Abdulla, Parosh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Delporte, Carole
    Univ Paris Diderot, Paris, France.
    Special Issue on NETYS'20162019In: Computing, ISSN 0010-485X, E-ISSN 1436-5057, Vol. 101, no 1, p. 1-2Article in journal (Other academic)
  • 1809.
    Abdulla, Parosh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Delzanno, Giorgio
    Rezine, Ahmed
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Parameterized Verification of Infinite-state Processes with Global Conditions2007In: Computer Aided Verification, Proceedings / [ed] Damm W, Hermanns H, 2007, p. 145-157Conference paper (Refereed)
    Abstract [en]

    We present a simple and effective approximated backward reachability algorithm for parameterized systems with existentially and universally quantified global conditions. The individual processes operate on unbounded local variables ranging over the natural numbers. In addition, processes may communicate via broadcast, rendez-vous and shared variables. We apply the algorithm to verify mutual exclusion for complex protocols such as Lamport's bakery algorithm both with and without atomicity conditions, a distributed version of the bakery algorithm, and Ricart-Agrawala's distributed mutual exclusion algorithm.

  • 1810.
    Abdulla, Parosh
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Deneux, Johann
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Mahata, Pritha
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Multi-Clock Timed Networks2004In: LICS'2004, 18th IEEE Int. Symp. on Logic in Computer Science, 2004Conference paper (Refereed)
  • 1811. Abdulla, Parosh
    et al.
    Deneux, Johann
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology.
    Mahata, Pritha
    Networks of Identical Multi-Clock Timed ProcessesArticle in journal (Refereed)
  • 1812.
    Abdulla, Parosh
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Deneux, Johann
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Mahata, Pritha
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Open, Closed and Robust Timed Networks.2004In: CONCUR 2004 -- Concurrency Theory: 15th International Conference, London, UK, August 31 - September 3, 2004, Proceedings, 2004, p. 529-Conference paper (Refereed)
  • 1813.
    Abdulla, Parosh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Deneux, Johann
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Mahata, Pritha
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Nylén, Aletta
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Forward Reachability Analysis of Timed Petri Nets2004In: FORMATS-FTRTFT'04, 2004, 2004Conference paper (Refereed)
  • 1814. Abdulla, Parosh
    et al.
    Deneux, Johann
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology.
    Ouaknine, Joël
    Worrell, James
    Decidability and Complexity Results for Timed Automata via Channel Machines2005In: LNCS, Vol. 3580Article in journal (Refereed)
  • 1815.
    Abdulla, Parosh
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Deneux, Johann
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Åkerlund, Ove
    Designing Safe, Reliable Systems using Scade2004In: Proc. ISoLA '04: International Symposium on Leveraging Applications of Formal Methods, 2004Conference paper (Refereed)
  • 1816.
    Abdulla, Parosh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Haziza, Frédéric
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Holík, Lukás
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Brno Univ Technol, Brno, Czech Republic..
    Jonsson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Rezine, Ahmed
    Linköping Univ, Linköping, Sweden..
    An integrated specification and verification technique for highly concurrent data structures for highly concurrent data structures2017In: International Journal on Software Tools for Technology Transfer (STTT), ISSN 1433-2779, E-ISSN 1433-2787, Vol. 19, no 5, p. 549-563Article in journal (Refereed)
    Abstract [en]

    We present a technique for automatically verifying safety properties of concurrent programs, in particular programs that rely on subtle dependencies of local states of different threads, such as lock-free implementations of stacks and queues in an environment without garbage collection. Our technique addresses the joint challenges of infinite-state specifications, an unbounded number of threads, and an unbounded heap managed by explicit memory allocation. Our technique builds on the automata-theoretic approach to model checking, in which a specification is given by an automaton that observes the execution of a program and accepts executions that violate the intended specification. We extend this approach by allowing specifications to be given by a class of infinite-state automata. We show how such automata can be used to specify queues, stacks, and other data structures, by extending a data-independence argument. For verification, we develop a shape analysis, which tracks correlations between pairs of threads, and a novel abstraction to make the analysis practical. We have implemented our method and used it to verify programs, some of which have not been verified by any other automatic method before.

  • 1817.
    Abdulla, Parosh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Iyer, Purushothaman
    Nylén, Aletta
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    SAT-solving the Coverability Problem for Unbounded Petri Nets2004In: Formal methods in system design, ISSN 0925-9856, E-ISSN 1572-8102, Vol. 24, no 1, p. 25-43Article in journal (Refereed)
  • 1818.
    Abdulla, Parosh
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology.
    Jonsson, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology.
    On the existence of network invariants for verifying parameterized systems1999In: Correct System Design: Recent Insights and Advances, Springer-Verlag, Berlin , 1999, p. 180-197Chapter in book (Refereed)
  • 1819.
    Abdulla, Parosh
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Jonsson, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Nilsson, Marcus
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    d'Orso, Julien
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Saksena, Mayank
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Regular Model Checking for LTL(MSO)2004In: Computer Aided Verification, 2004, p. 348-360Conference paper (Refereed)
    Abstract [en]

    Regular model checking is a form of symbolic model checking for parameterized and infinite-state systems whose states can be represented as words of arbitrary length over a finite alphabet, in which regular sets of words are used to represent sets of states. We present $\logic$, a combination of the logics MSO and LTL as a natural logic for expressing temporal properties to be verified in regular model checking. $\logic$ is a two-dimensional modal logic, where MSO is used for specifying properties of system states and transitions, and LTL is used for specifying temporal properties. In addition, the first-order quantification in MSO can be used to express properties parameterized on a position or process.

    We give a technique for model checking $\logic$, which is adapted from the automata-theoretic approach: a formula is translated to a (\buchi) transducer with a regular set of accepting states, and regular model checking techniques are used to search for models. We have implemented the technique and show its application to a number of parameterized algorithms from the literature.

  • 1820.
    Abdulla, Parosh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Jonsson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Nilsson, Marcus
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    d'Orso, Julien
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Saksena, Mayank
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Regular model checking for LTL(MSO)2012In: International Journal on Software Tools for Technology Transfer (STTT), ISSN 1385-4879, E-ISSN 1571-8115, Vol. 14, no 2, p. 223-241Article in journal (Refereed)
    Abstract [en]

    Regular model checking is a form of symbolic model checking for parameterized and infinite-state systems whose states can be represented as words of arbitrary length over a finite alphabet, in which regular sets of words are used to represent sets of states. We present LTL(MSO), a combination of the logics MSO and LTL as a natural logic for expressing temporal properties to be verified in regular model checking. In other words, LTL(MSO) is a natural specification language for both the system and the property under consideration. LTL(MSO) is a two-dimensional modal logic, where MSO is used for specifying properties of system states and transitions, and LTL is used for specifying temporal properties.  In addition, the first-order quantification in MSO can be used to express properties parameterized on a position or process.  We give a technique for model checking LTL(MSO), which is adapted from the automata-theoretic approach: a formula is translated to a Buechi regular transition system with a regular set of accepting states, and regular model checking techniques are used to search for models. We have implemented the technique, and show its application to a number of parameterized algorithms from the literature.

  • 1821.
    Abdulla, Parosh
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. datorteknik.
    Jonsson, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. datorteknik.
    Nilsson, Marcus
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. datorteknik.
    Saksena, Mayank
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. datorteknik.
    A Survey of Regular Model Checking.2004In: CONCUR 2004 - Concurrency Theory: 15th International Conference, London, UK, August 31 - September 3, 2004, Proceedings., 2004, p. 35-48Conference paper (Refereed)
    Abstract [en]

    Regular model checking is being developed for algorithmic verification of several classes of infinite-state systems whose configurations can be modeled as words over a finite alphabet. Examples include parameterized systems consisting of an arbitrary number of homogeneous finite-state processes connected in a linear or ring-formed topology, and systems that operate on queues, stacks, integers, and other linear data structures. The main idea is to use regular languages as the representation of sets of configurations, and finite-state transducers to describe transition relations. In general, the verification problems considered are all undecidable, so the work has consisted in developing semi-algorithms, and decidability results for restricted cases. This paper provides a survey of the work that has been performed so far, and some of its applications.

  • 1822.
    Abdulla, Parosh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Jonsson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Trinh, Cong Quy
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Automated Verification of Linearization Policies2016In: Automated Verification of Linearization Policies: 23rd International Symposium, SAS 2016, Edinburgh, UK, September 8-10, 2016, Proceedings, 2016Conference paper (Other academic)
    Abstract [en]

    We present a novel framework for automated verification of linearizability for concurrent data structures that implement sets, stacks, and queues. The framework requires the user to provide a linearization policy, which describes how linearization point placement in different concurrent threads affect each other; such linearization policies are often provided informally together with descriptions of new algorithms. We present a specification formalism for linearization policies which allows the user to specify, in a simple and concise manner, complex patterns including non-fixed linearization points. To automate verification, we extend thread-modular reasoning to bound the number of considered threads, and use a novel symbolic representation for unbounded heap structures that store data from an unbounded domain. We have implemented our framework in a tool and successfully used it to prove linearizability for a wide range of algorithms, including all implementations of concurrent sets, stacks, and queues based on singly-linked lists that are known to us from the literature.

  • 1823.
    Abdulla, Parosh
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Mathematics and Computer Science, Department of Information Technology, Computer Systems. Datorteknik.
    Mahata, Pritha
    Datorteknik.
    Mayr, Richard
    Decidability of Zenoness, Token Liveness, and Boundedness for Dense-Timed Petri Nets.2004In: FSTTCS' 04: 24th Conference on Foundations of Software Technology and Theoretical Computer Science, 2004Conference paper (Refereed)
  • 1824.
    Abdulla, Parosh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Ouaknine, Joel
    Quaas, Karin
    Worrell, James
    Zone-Based Universality Analysis for Single-Clock Timed Automata2007In: International Symposium on Fundamentals of Software Engineering, Proceedings / [ed] Arbab F; Sirjani M, 2007, p. 98-112Conference paper (Refereed)
    Abstract [en]

    During the last years, timed automata have become a popular model for describing the behaviour of real-time systems. In particular, there has been much research on problems such as language inclusion and universality. It is well-known that the universality problem is undecidable for the class of timed automata with two or more clocks. Recently, it was shown that the problem becomes decidable if the automata are restricted to operate on a single clock variable. However, existing algorithms use a region-based constraint system and suffer from constraint explosion even for small examples. In this paper, we present a zone-based algorithm for solving the universality problem for single-clock timed automata. We apply the theory of better quasi-orderings, a refinement of the theory of well quasi-orderings, to prove termination of the algorithm. We have implemented a prototype based on our method, and checked universality for a number of timed automata. Comparisons with a region-based prototype confirm that zones are a more succinct representation, and hence allow a much more efficient implementation of the universality algorithm.

  • 1825.
    Abdulla, Salim
    et al.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania..
    Adam, Ishag
    Univ Khartoum, Fac Med, Khartoum, Sudan..
    Adjei, George O.
    Univ Ghana, Sch Med, Ctr Trop Clin Pharmacol & Therapeut, Accra, Ghana..
    Adjuik, Martin A.
    INDEPTH Network Secretariat, Accra, Ghana..
    Alemayehu, Bereket
    Int Ctr AIDS Care & Treatment Programs, Addis Ababa, Ethiopia..
    Allan, Richard
    MENTOR Initiat, Crawley, England..
    Arinaitwe, Emmanuel
    Infect Dis Res Collaborat, Kampala, Uganda..
    Ashley, Elizabeth A.
    Epictr, Paris, France..
    Ba, Mamadou S.
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Barennes, Hubert
    Ctr Muraz, Bobo Dioulasso, Burkina Faso.;French Foreign Affairs, Biarritz, France..
    Barnes, Karen I.
    WorldWide Antimalarial Resistance Network WWARN, Cape Town, South Africa.;Univ Cape Town, Dept Med, Div Clin Pharmacol, ZA-7925 Cape Town, South Africa..
    Bassat, Quique
    Ctr Invest Saude Manhica, Manhica, Mozambique.;Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Hosp Clin, Barcelona, Spain..
    Baudin, Elisabeth
    MENTOR Initiat, Crawley, England..
    Berens-Riha, Nicole
    Univ Munich LMU, Med Ctr, Div Infect Dis & Trop Med, Munich, Germany.;LMU, German Ctr Infect Res DZIF, Munich, Germany..
    Bjoerkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden..
    Bompart, Francois
    Sanofi Aventis, Direct Acces Med Access Med, Gentilly, France..
    Bonnet, Maryline
    Epictr, Geneva, Switzerland..
    Borrmann, Steffen
    Wellcome Trust Res Programme, Kenya Med Res Inst, Kilifi, Kenya.;Univ Tubingen, Inst Trop Med, Tubingen, Germany.;German Ctr Infect Res, Tubingen, Germany..
    Bousema, Teun
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Infect & Immun, London WC1, England.;Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Njimegen, Netherlands..
    Brasseur, Philippe
    IRD, Dakar, Senegal..
    Bukirwa, Hasifa
    Uganda Malaria Surveillance Project, Kampala, Uganda..
    Checchi, Francesco
    Epictr, Paris, France..
    Dahal, Prabin
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    D'Alessandro, Umberto
    Inst Trop Med, Unit Malariol, B-2000 Antwerp, Belgium.;MRC Unit, Fajara, Gambia.;London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Dis Control, London WC1, England..
    Desai, Meghna
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA..
    Dicko, Alassane
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali.;Univ Bamako, Fac Med Pharm & Dent, Dept Publ Hlth, Bamako, Mali..
    Djimde, Abdoulaye A.
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali..
    Dorsey, Grant
    Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA..
    Doumbo, Ogobara K.
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali..
    Drakeley, Chris J.
    German Ctr Infect Res, Tubingen, Germany..
    Duparc, Stephan
    Med Malaria Venture, Geneva, Switzerland..
    Eshetu, Teferi
    Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Hosp Clin, Barcelona, Spain.;Jimma Univ, Dept Med Lab Sci & Pathol, Jimma, Ethiopia..
    Espie, Emmanuelle
    Epictr, Paris, France..
    Etard, Jean-Francois
    Epictr, Paris, France.;IRD, Montpellier, France..
    Faiz, Abul M.
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand..
    Falade, Catherine O.
    Univ Ibadan, Coll Med, Dept Pharmacol & Therapeut, Ibadan, Nigeria..
    Fanello, Caterina I.
    Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand..
    Faucher, Jean-Francois
    IRD, Mother & Child Hlth Trop Res Unit, Paris, France.;Univ Paris 05, PRES Sorbonne Paris Cite, Paris, France.;Univ Besancon, Med Ctr, Dept Infect Dis, F-25030 Besancon, France..
    Faye, Babacar
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Faye, Oumar
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Filler, Scott
    Global Fund Fight AIDS TB & Malaria, Geneva, Switzerland..
    Flegg, Jennifer A.
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Monash Univ, Sch Math Sci, Melbourne, Vic 3004, Australia.;Monash Univ, Monash Acad Cross & Interdisciplinary Math Applic, Melbourne, Vic 3004, Australia..
    Fofana, Bakary
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali..
    Fogg, Carole
    Univ Portsmouth, Portsmouth Hosp NHS Trust, Portsmouth, Hants, England..
    Gadalla, Nahla B.
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Infect & Immun, London WC1, England.;Natl Res Ctr, Res Inst Trop Med, Dept Epidemiol, Khartoum, Sudan.;NIAID, Rockville, MD USA..
    Gaye, Oumar
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Genton, Blaise
    Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland.;Univ Lausanne Hosp, Div Infect Dis, Lausanne, Switzerland.;Univ Lausanne Hosp, Dept Ambulatory Care & Community Med, Lausanne, Switzerland..
    Gething, Peter W.
    Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England..
    Gil, Jose P.
    Karolinska Inst, Pharmacogenet Sect, Drug Resistance Unit, Dept Physiol & Pharmacol, Stockholm, Sweden.;Univ Lisbon, Fac Sci, Biosyst & Integrat Sci Inst BioISI, P-1699 Lisbon, Portugal.;SUNY Binghamton, Harpur Coll Arts & Sci, Binghamton, NY USA..
    Gonzalez, Raquel
    Ctr Invest Saude Manhica, Manhica, Mozambique.;Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Hosp Clin, Barcelona, Spain..
    Grandesso, Francesco
    Epictr, Paris, France..
    Greenhouse, Bryan
    Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA..
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Dis Control, London WC1, England..
    Grivoyannis, Anastasia
    Univ Washington, Div Emergency Med, Seattle, WA 98195 USA..
    Guerin, Philippe J.
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Guthmann, Jean-Paul
    Inst Veille Sanit, Dept Malad Infect, St Maurice, France..
    Hamed, Kamal
    Novartis Pharmaceut, E Hanover, NJ USA..
    Hamour, Sally
    Royal Free Hosp, UCL Ctr Nephrol, London NW3 2QG, England..
    Hay, Simon I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.;NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA..
    Hodel, Eva Maria
    Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland.;Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England..
    Humphreys, Georgina S.
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Hwang, Jimee
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA.;Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA..
    Ibrahim, Maman L.
    Ctr Rech Med & Sanit, Niamey, Niger..
    Jima, Daddi
    Fed Minist Hlth, Addis Ababa, Ethiopia..
    Jones, Joel J.
    Minist Hlth & Social Welf, Natl Malaria Control Programme, Monrovia, Liberia..
    Jullien, Vincent
    Univ Paris 05, AP HP, Paris, France..
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya..
    Kachur, Patrick S.
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA..
    Kager, Piet A.
    Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, Div Infect Dis Trop Med & AIDS, NL-1105 AZ Amsterdam, Netherlands..
    Kamugisha, Erasmus
    Catholic Univ Hlth & Allied Sci, Mwanza, Tanzania..
    Kamya, Moses R.
    Makerere Univ, Coll Hlth Sci, Kampala, Uganda..
    Karema, Corine
    Minist Hlth, Malaria & Other Parasit Dis Div RBC, Kigali, Rwanda..
    Kayentao, Kassoum
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali..
    Kiechel, Jean-Rene
    Drugs Neglected Dis initiat, Geneva, Switzerland..
    Kironde, Fred
    Makerere Univ, Dept Biochem, Kampala, Uganda..
    Kofoed, Poul-Erik
    Projecto Saude Bandim, Bissau, Guinea Bissau.;Kolding Cty Hosp, Dept Paediat, Kolding, Denmark..
    Kremsner, Peter G.
    Univ Tubingen, Inst Trop Med, Tubingen, Germany.;Ctr Rech Med Lambarene, Lambarene, Gabon..
    Krishna, Sanjeev
    Univ London, Inst Infect & Immun, London, England. Operat Ctr Barcelona Athens, Med Sans Frontieres, Barcelona, Spain..
    Lameyre, Valerie
    Sanofi Aventis, Direct Acces Med Access Med, Gentilly, France..
    Lell, Bertrand
    Univ Tubingen, Inst Trop Med, Tubingen, Germany.;Ctr Rech Med Lambarene, Lambarene, Gabon..
    Lima, Angeles
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Makanga, Michael
    European & Dev Countries Clin Trials Partnership, Cape Town, South Africa..
    Malik, ElFatih M.
    Fed Minist Hlth, Khartoum, Sudan..
    Marsh, Kevin
    Wellcome Trust Res Programme, Kenya Med Res Inst, Kilifi, Kenya.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden..
    Massougbodji, Achille
    Univ Abomey Calavi, FSS, CERPAGE, Cotonou, Benin..
    Menan, Herve
    Univ Cocody, Fac Pharm, Dept Parasitol, Abidjan, Cote Ivoire..
    Menard, Didier
    Inst Pasteur Cambodia, Malaria Mol Epidemiol Unit, Phnom Penh, Cambodia..
    Menendez, Clara
    Ctr Invest Saude Manhica, Manhica, Mozambique.;Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Hosp Clin, Barcelona, Spain..
    Mens, Petra F.
    Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, Div Infect Dis Trop Med & AIDS, NL-1105 AZ Amsterdam, Netherlands.;KIT Biomed Res, Royal Trop Inst, Amsterdam, Netherlands..
    Meremikwu, Martin
    Univ Calabar, Dept Paediat, Calabar, Nigeria.;Inst Trop Dis Res & Prevent, Calabar, Nigeria..
    Moreira, Clarissa
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Nabasumba, Carolyn
    Epictr, Paris, France.;Mbarara Univ Sci & Technol, Fac Med, Mbarara, Uganda..
    Nambozi, Michael
    Trop Dis Res Ctr, Ndola, Zambia..
    Ndiaye, Jean-Louis
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania.;Karolinska Inst, Dept Med Solna, Infect Dis Unit, Malaria Res, Stockholm, Sweden..
    Nikiema, Frederic
    Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso..
    Nsanzabana, Christian
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Ntoumi, Francine
    Univ Tubingen, Inst Trop Med, Tubingen, Germany.;Univ Marien Ngouabi, FCRM, Fac Sci Sante, Brazzaville, Congo..
    Oguike, Mary
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Infect & Immun, London WC1, England..
    Ogutu, Bernhards R.
    United States Army Med Res Unit, Kenya Med Res Inst, Kisumu, Kenya..
    Olliaro, Piero
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;UNICEF UNDP World Bank WHO Special Programme Res, Geneva, Switzerland..
    Omar, Sabah A.
    Kenya Govt Med Res Ctr, Ctr Biotechnol Res & Dev, Nairobi, Kenya..
    Ouedraogo, Jean-Bosco
    Ctr Muraz, Bobo Dioulasso, Burkina Faso.;Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso..
    Owusu-Agyei, Seth
    Kintampo Hlth Res Ctr, Kintampo, Ghana..
    Penali, Louis K.
    WorldWide Antimalarial Resistance Network WWARN W, Dakar, Senegal..
    Pene, Mbaye
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Peshu, Judy
    Wellcome Trust Res Programme, Kenya Med Res Inst, Kilifi, Kenya..
    Piola, Patrice
    Inst Pasteur Madagascar, Epidemiol Unit, Antananarivo, Madagascar..
    Plowe, Christopher V.
    Univ Maryland, Sch Med, Howard Hughes Med Inst, Ctr Vaccine Dev, Baltimore, MD 21201 USA..
    Premji, Zul
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania..
    Price, Ric N.
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Menzies Sch Hlth Res, Darwin, NT, Australia.;Charles Darwin Univ, Darwin, NT 0909, Australia..
    Randrianarivelojosia, Milijaona
    Inst Pasteur Madagascar, Malaria Res Unit, Antananarivo, Madagascar..
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Karolinska Inst, Karolinska Univ Hosp, Infect Dis Unit, Malaria Res Lab,Dept Med, Stockholm, Sweden.;Malarsjukhuset, Dept Infect Dis, S-63188 Eskilstuna, Sweden..
    Roper, Cally
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Pathogen Mol Biol, London WC1, England..
    Rosenthal, Philip J.
    Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA..
    Sagara, Issaka
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali..
    Same-Ekobo, Albert
    Ctr Hosp Univ Yaounde, Fac Med & Sci Biomed, Yaounde, Cameroon..
    Sawa, Patrick
    Int Ctr Insect Physiol & Ecol, Human Hlth Div, Mbita, Kenya..
    Schallig, Henk D. F. H.
    KIT Biomed Res, Royal Trop Inst, Amsterdam, Netherlands..
    Schramm, Birgit
    Epictr, Paris, France..
    Seck, Amadou
    WorldWide Antimalarial Resistance Network WWARN W, Dakar, Senegal..
    Shekalaghe, Seif A.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania.;Kilimanjaro Christian Med Ctr, Kilimanjaro Clin Med Res Inst, Moshi, Tanzania..
    Sibley, Carol H.
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA..
    Sinou, Vronique
    Aix Marseille Univ, Fac Pharm, UMR MD3, Marseille, France..
    Sirima, Sodiomon B.
    CNRFP, Ouagadougou, Burkina Faso..
    Som, Fabrice A.
    Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso..
    Sow, Doudou
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Staedke, Sarah G.
    Infect Dis Res Collaborat, Kampala, Uganda.;London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Clin Res, London WC1, England..
    Stepniewska, Kasia
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Sutherland, Colin J.
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Infect & Immun, London WC1, England..
    Swarthout, Todd D.
    Med Sans Frontieres, London, England..
    Sylla, Khadime
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Talisuna, Ambrose O.
    East Africa Reg Ctr, WorldWide Antimalarial Resistance Network WWARN, Nairobi, Kenya.;Univ Oxford, KEMRI, Wellcome Trust Res Programme, Nairobi, Kenya..
    Taylor, Walter R. J.
    UNICEF UNDP World Bank WHO Special Programme Res, Geneva, Switzerland.;Hop Cantonal Univ Geneva, Serv Med Int & Humanitaire, Geneva, Switzerland..
    Temu, Emmanuel A.
    MENTOR Initiat, Crawley, England.;Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland.;Univ Basel, Basel, Switzerland..
    Thwing, Julie I.
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA..
    Tine, Roger C. K.
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Tinto, Halidou
    Ctr Muraz, Bobo Dioulasso, Burkina Faso.;Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso..
    Tommasini, Silva
    Sigma Tau Ind Farmaceut Riunite SpA, Rome, Italy..
    Toure, Offianan A.
    Inst Pasteur Cote Ivoire, Malariol Dept, Abidjan, Cote Ivoire..
    Ursing, Johan
    Projecto Saude Bandim, Bissau, Guinea Bissau.;Karolinska Inst, Dept Med Solna, Infect Dis Unit, Malaria Res, Stockholm, Sweden..
    Vaillant, Michel T.
    CRP Sante, Ctr Hlth Studies, Methodol & Stat Unit, Luxembourg, Luxembourg.;Univ Bordeaux 2, Unite Bases Therapeut Inflammat & Infect 3677, F-33076 Bordeaux, France..
    Valentini, Giovanni
    Sigma Tau Ind Farmaceut Riunite SpA, Rome, Italy..
    Van den Broek, Ingrid
    Med Sans Frontieres, London, England.;Natl Inst Publ Hlth & Environm, Ctr Infect Dis Control, NL-3720 BA Bilthoven, Netherlands..
    Van Vugt, Michele
    Univ Amsterdam, Acad Med Ctr, Ctr Trop Med & Travel Med, Div Infect Dis, NL-1012 WX Amsterdam, Netherlands..
    Ward, Stephen A.
    Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England..
    Winstanley, Peter A.
    Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England..
    Yavo, William
    Univ Cocody, Fac Pharmaceut & Biol Sci, Dept Parasitol & Mycol, Abidjan, Cote Ivoire.;Natl Inst Publ Hlth, Malaria Res & Control Ctr, Abidjan, Cote Ivoire..
    Yeka, Adoke
    Uganda Malaria Surveillance Project, Kampala, Uganda..
    Zolia, Yah M.
    Minist Hlth & Social Welf, Natl Malaria Control Programme, Monrovia, Liberia..
    Zongo, Issaka
    Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso..
    Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data2015In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 13, article id 212Article, review/survey (Refereed)
    Abstract [en]

    Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 degrees C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

  • 1826.
    Abdulla, Salim
    et al.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania..
    Ashley, Elizabeth A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Bassat, Quique
    Univ Barcelona, Ctr Invest Saude Manhica Manhica Mozamb & ISGloba, Barcelona Ctr Int Hlth Res CRESIB, Hosp Clin, Barcelona, Spain..
    Bethell, Delia
    AFRIMS, Dept Immunol & Med, Bangkok, Thailand..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Borrmann, Steffen
    Kenya Govt Med Res Ctr, Wellcome Trust Res Programme, Kilifi, Kenya.;Univ Magdeburg, Sch Med, D-39106 Magdeburg, Germany..
    D'Alessandro, Umberto
    Inst Trop Med, Unit Malariol, B-2000 Antwerp, Belgium.;MRC Unit, Fajara, Gambia..
    Dahal, Prabin
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Day, Nicholas P.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Diakite, Mahamadou
    Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali..
    Djimde, Abdoulaye A.
    Dondorp, Arjen M.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Duong, Socheat
    Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Edstein, Michael D.
    Fairhurst, Rick M.
    NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA..
    Faiz, M. Abul
    Malaria Res Grp MRG & Dev Care Fdn, Dhaka, Bangladesh..
    Falade, Catherine
    Univ Ibadan, Coll Med, Ibadan, Nigeria..
    Flegg, Jennifer A.
    Monash Univ, Sch Math Sci, Clayton, Vic 3800, Australia..
    Fogg, Carole
    Univ Portsmouth, Portsmouth, Hants, England..
    Gonzalez, Raquel
    Ctr Invest Saude Manhica Manhica Mozamb, Barcelona, Spain.;CRESIB, Barcelona, Spain..
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England..
    Guerin, Philippe J.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Guthmann, Jean-Paul
    Epicentre, Paris, France..
    Hamed, Kamal
    Novartis Pharmaceut, E Hanover, NJ USA..
    Hien, Tran Tinh
    Htut, Ye
    Dept Med Res, Lower Myanmar, Yangon, Myanmar..
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya..
    Lim, Pharath
    NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA.;US & Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Dept Microbiol Cell & Tumour Biol, Dept Publ Hlth Sci, Malaria Res, Stockholm, Sweden..
    Mayxay, Mayfong
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahosot Hosp, Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit LOMWRU, Viangchan, Laos.;Univ Hlth Sci, Fac Postgrad Studies, Viangchan, Laos..
    Mokuolu, Olugbenga A.
    Univ Ilorin, Dept Paediat & Child Hlth, Ilorin, Nigeria..
    Moreira, Clarissa
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Newton, Paul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahosot Hosp, Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit LOMWRU, Viangchan, Laos..
    Noedl, Harald
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria..
    Nosten, Francois
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Bangkok 10700, Thailand..
    Ogutu, Bernhards R.
    Kenya Govt Med Res Ctr, US Army Med Res Unit, Kisumu, Kenya..
    Onyamboko, Marie A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO..
    Owusu-Agyei, Seth
    Kintampo Hlth Res Ctr, Kintampo, Ghana..
    Phyo, Aung Pyae
    Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Bangkok 10700, Thailand..
    Premji, Zul
    Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania..
    Price, Ric N.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia.;Charles Darwin Univ, Darwin, NT 0909, Australia..
    Pukrittayakamee, Sasithon
    Mahidol Univ, Fac Trop Med, Bangkok 10700, Thailand..
    Ramharter, Michael
    Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med 1, Vienna, Austria.;Univ Tubingen, Inst Tropenmed, Tubingen, Germany.;Ctr Rech Med Lambarene, Lambarene, Gabon..
    Sagara, Issaka
    Univ Bamako, Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali..
    Se, Youry
    AFRIMS, Phnom Penh, Cambodia..
    Suon, Seila
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Stepniewska, Kasia
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Ward, Stephen A.
    Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England..
    White, Nicholas J.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Winstanley, Peter A.
    Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England..
    Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 359Article in journal (Refereed)
    Abstract [en]

    Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

  • 1827.
    Abdullah, Jakaria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Dai, Gaoyang
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Guan, Nan
    Northeastern Univ, Shenyang, Liaoning, Peoples R China..
    Mohaqeqi, Morteza
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Wang, Yi
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Towards a Tool: TIMES-Pro for Modeling, Analysis, Simulation and Implementation of Cyber-Physical Systems2017In: MODELS, ALGORITHMS, LOGICS AND TOOLS: ESSAYS DEDICATED TO KIM GULDSTRAND LARSEN ON THE OCCASION OF HIS 60TH BIRTHDAY / [ed] Aceto, L Bacci, G Bacci, G Ingolfsdottir, A Legay, A Mardare, R, SPRINGER INTERNATIONAL PUBLISHING AG , 2017, p. 623-639Conference paper (Refereed)
    Abstract [en]

    We consider a Cyber-Physical System (CPS) as a network of components that are either physical plants with continuous behaviors or discrete controllers. To build CPS's in a systematic manner, the TIMES-Pro tool is designed to support modeling, analysis and code generation for real-time simulation and final deployment. In this paper, we present our decisions in designing the modeling language, the tool architecture and features of TIMES-Pro, and also a case study to demonstrate its applicability.

  • 1828.
    Abdullah, Jakaria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Dai, Gaoyang
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Mohaqeqi, Morteza
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Yi, Wang
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Schedulability Analysis and Software Synthesis for Graph-Based Task Models with Resource Sharing2018In: Proc. 24th Real-Time and Embedded Technology and Applications Symposium, IEEE Computer Society, 2018, p. 261-270Conference paper (Refereed)
  • 1829.
    Abdullah, Jakaria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Dai, Gaoyang
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Computer Systems.
    Wang, Yi
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Worst-Case Cause-Effect Reaction Latency in Systems with Non-Blocking Communication2019In: 2019 Design, Automation & Test in Europe Conference & Exhibition (DATE), IEEE, 2019, p. 1625-1630Conference paper (Refereed)
    Abstract [en]

    In real-time embedded systems, a system functionality is often implemented using a data-flow chain over a set of communicating tasks. A critical non-functional requirement in such systems is to restrict the amount of time, i.e. cause-effect latency, for an input to impact its corresponding output. The problem of estimating the worst-case cause-effect latency is well-studied in the context of blocking inter-task communication. Recent research results show that non-blocking communication preserving functional semantics is critical for the model-based design of dynamically updatable systems. In this paper, we study the worst-case cause-effect reaction latency estimation problem in the context of non-blocking inter-task communication. We present a computationally efficient algorithm that tightly over-approximates the exact worst-case reaction latency in cause-effect data-flow chains.

  • 1830.
    Abdullah, Jakaria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Mohaqeqi, Morteza
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Yi, Wang
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Synthesis of Ada code from graph-based task models2017In: Proc. 32nd ACM Symposium on Applied Computing, New York: ACM Press, 2017, p. 1467-1472Conference paper (Refereed)
  • 1831.
    Abdullah, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Validering av narkotikahanteringen för morfin, oxikodon och ketobemidon vid Astrid Lindgrens Barnsjukhus2016Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Validering av narkotikahanteringen för morfin, oxikodon och ketobemidon vid Astrid Lindgrens Barnsjukhus

    Sarah Abdullah

    Fördjupningsprojekt i farmakoterapi 30 hp, Apotekarprogrammet

    Institution för farmaceutisk biovetenskap, Handledare: Per Nydert, Examinator: Margareta Hammalund- Udenaes

    Introduktion: Kontrollerad narkotikaanvändning leder till mindre risk för läkemedelshanteringsfel vilket bidrar till ökad personal- och patientsäkerhet. Syfte: Validering av datauttag från TakeCare samt validering av hanteringen av morfin, oxikodon och ketobemidon på avdelning Q84 och B78 på Astrid Lindgrens Barnsjukhus. Material och metoder: Uttag i narkotikaloggen jämfördes med administreringar i journalsystemet TakeCare. Detta utfördes retrospektivt under 11,5 månader i den kvantitativa studien och prospektivt under ca. en månad i den kvalitativa studien där även orsaker till avvikelserna har studerats. Dessutom jämfördes den dokumenterade kassationen mot den uppskattade kassationen. Resultat: I den retrospektiva studieperioden ingick 93 patienter. Av alla doser i narkotikaloggen fanns på Q84 78,6 % (95 % KI 73,5-83,2) och på B78 85,9 % (95 % KI 81,8-89,4) av doserna i TakeCare. Av totala antalet doser saknades på Q84 21 % (95 % KI 17,0-25,6)* och på B78 5,2 % (95 % KI 3,2-7,99) av doserna i narkotikaloggen. Dessutom förekom det under den retrospektiva studien 38 avvikelser i behållningen vilket var signifikant högre jämfört med fem avvikelser på B78. De huvudsakliga orsakerna till avvikelser mellan uttag och administrering var vård utanför avdelningen (29 % resp. 36 % av alla avvikelser), administrering skedde ur tidigare patientuttag (14 % resp. 14 %), opioidinfusion (34 % resp. 0 %) och behov saknades (0 % resp. 36 %) för Q84 resp. B78. Under hela studieperioden utgjorde den dokumenterade kassationen 0,39 % på Q84 och 0,93 % på B78 av den uppskattade kassationen. Konklusion: Antal doser i TakeCare av alla doser i narkotikaloggen var inte signifikant skild mellan avdelningarna. Däremot var antalet doser som saknades i narkotikaloggen av alla doser signifikant högre på Q84. Detta indikerar att narkotikaloggen var mer välskött på B78. Antalet avvikelser i behållningen var signifikant högre på Q84, vilket indikerar att läkemedelsautomaten på B78 leder till en mer kontrollerad narkotikahantering. Både på avdelning Q84 och B78 var kassationen bristfälligt dokumenterad.

  • 1832.
    Abdullah, Syed Md Jakaria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Lampka, Kai
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Yi, Wang
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Improving performance by monitoring while maintaining worst-case guarantees2016In: Proc. 19th Conference on Design, Automation and Test in Europe, Piscataway, NJ: IEEE, 2016, p. 257-260Conference paper (Refereed)
  • 1833.
    Abdullahi Elmi, Salma
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of History of Science and Ideas.
    Evolutionary Ethics and Idealism: The idealists Henry Jones and Andrew Seth Pringle-Pattison in dialog with Darwinism concerning evolution and ethics.2018Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 1834.
    Abdulmahdi, Rasha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Statinanvändning hos äldre hypertonipatienter med nedsatt njurfunktion2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Statinanvändning hos äldre hypertonipatienter med nedsatt njurfunktion

    Rasha Abdulmahdi

    Handledare: Björn Wettermark, Docent, Apotekare, Utvecklingsavdelningen, SLL. Yvonne Freund-Levi, MD PhD Överläkare KI. Tero Shemiekka, överläkare Avdelningen för E-hälsa, SLL. Examinator: Margareta Hammarlund-Udenaes, Professor i farmakokinetik och farmakodynamik. Institutionen för farmaceutisk biovetenskap. Examensarbete i Farmakoterapi D, 30hp, Uppsala universitet.

     

    Introduktion: Äldre patienter löper större risk att utveckla läkemedelsbiverkningar p.g.a. avtagande njurfunktion. Flera publicerade studier tyder på att många patienter läggs in akut på sjukhus för att de använder läkemedel som inte anpassas efter deras njurfunktion. Syfte: Att kartlägga förskrivning av statiner hos äldre hypertonipatienter med avseende på njurfunktion i Skaraborg och sydvästra Stockholms Län. Material och metoder: En tvärsnittstudie baserad på data hämtade från SPCCD (Swedish Primary Care Cardiovascular Database). Patienter ≥ 65 år som hade minst ett registrerat S-kreatinin under år 2006-2008 inkluderades och andelen som hämtade ut statiner under perioden 2006-2009 analyserades. GFR (Glomerular Filtration Rate) beräknades med CKD-EPI-formeln (Chronic Kidney Disease Epidemiology Collaboration). Läkemedelssubstanserna lämplighet eller behov av dosjustering i relation till njurfunktion granskades enligt RenBase, en databas med dokumentation av läkemedel vid nedsatt njurfunktion. Resultat. Totalt identifierades 38 239 individer och av dessa hade 23,8 % behandlats med statiner. De mest förskrivna statinerna var simvastatin (84,2 %) och atorvastatin (10,5 %). Det var signifikant färre (95 % C.I.) som behandlades med de båda statinerna vid en jämförelse mellan GFR < 30 och >30. Det fanns ingen korrelation mellan snittdosering (mg/dag) och njurfunktion. Konklusion: Många äldre hypertonipatienter i primärvården med nedsatt njurfunktion får statinbehandling. Det förefaller dock som om simvastatin inte dosjusteras hos patienter med svårt nedsatt njurfunktion.

                 

  • 1835. Abdul-Majid, KB
    et al.
    Stefferl, A
    Bourquin, C
    Lassmann, H
    Linington, C
    Olsson, T
    Kleinau, S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Harris, RA
    Fc receptors are critical for autoimmune inflammatory damage to the central nervous system in experimental autoimmune encephalomyelitis.2002In: Scand J Immunol, Vol. 55, p. 70-Article in journal (Refereed)
  • 1836.
    Abdulrahim, Jihan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Theology, Department of Theology.
    Religion och politik, hot mot demokratin?: En kvalitativ studie om imamers perspektiv på muslimers religiösa politiska åsikter i den svenska offentliga sfären2019Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
  • 1837.
    Abdulrahim, Muhanad Adnan Abdulrahim
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Informatics and Media.
    Investigating the requirements for an e-service that provide relevant online information for newly arrived immigrants in Sweden2014Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    There is a huge need for information when you arrive as an immigrant in a new country. The purpose of the study is to find out recommendations for an information portal for newly arrived immigrants in Sweden.

    First, a survey was conducted to the webmasters of relevant authorities online resources regarding their ways of considering the needs of immigrant users. The answers showed that the webmasters of the official websites showed interest in considering the needs of immigrants in their websites by including pages in different languages, but most of them considered this to be difficult, expensive and problematic.

    To know more about a particular user group, a survey, interviews and observations have been done.

    A survey to newly arrived immigrants showed that their ICT skills are comparable to the average of Swedish citizens. In spite of differences within the immigrant group, like age, gender and cultural factors, they also shared common characteristics. Most of the immigrants trusted Swedish websites and Swedish authorities websites as reliable information resources more than websites in their mother-tongue.

    Test-persons were faced with the task of finding information about the possibility to borrow money for furniture for the first home in Sweden, our observations showed that very few of the test-persons managed to find their way to the correct authority webpage (Studiemedels-nämnden). Most test-persons tried by using many ways to search for the information, but all except two gave up. None of the test-persons managed to find the pages that were translated to their mother-tongue.

    The study points out the need for a systematical approach to web information for newly arrived immigrants to help them with their integration process and benefit from Swedish e-government services. A central multilingual portal website should be the heart of this program.

    This approach can be introduced in SFI schools given that all SFI schools are supplied with computers.

  • 1838.
    Abdulrahman, Hazha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mach, Aaron
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Does photographic documentation of the position of the recording electrodes decrease motor amplitude variation in electroneurography?2009Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    It is known that there is an intraindividual amplitude variation in motor electroneurography when the same person is examined at different times. This variation affects the evaluation the status of the patient. The aim of this study was to investigate if the intraindividual amplitude variation decreased by photographing the electrode position, that later is used in the follow-up study. Twenty test persons were examined by four laboratory scientists. The nerves that were examined were median, ulnar, peroneal and tibial nerve. At the first examination the laboratory scientists used method guidelines and took photographs of the electrode position. The photographs were then used in the follow-up. The results showed that there was an indication of decreased of the intraindividual amplitude variation when photographic documentation was used instead of method guidelines.

  • 1839.
    Abdulrahman Majid, Shokhan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    En studie om svårigheter för flerspråkiga elever i matematikundervisningen2013Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Många studier pekar på att flerspråkiga barn har sämre resultat än barnen med svensk bakgrund. Syftet med studien är att studera flerspråkiga barns svårigheter och deras möte med texter i matematikutbildningen. Vidare syftar studien att ta reda på om signalord har betydelse för flerspråkiga barns svårigheter vid lösning av de olika matematiska textuppgifterna. Signalord betyder ord som signalerar vilken typ av räknesätt man ska välja.  Deltagarna i den här studien är barn i årskurs tre.

    Resultaten har visat att barnen som gjort uppgifterna fått stöd av de signalord som prövats och barnen tycker att matematiska textuppgifter med signalord är lättare än uppgifter utan signalord.  Barnen som behärskar svenska språket anser att signalord fungerar som stöd oavsett hur ”kognitivt” uppgifterna är. I intervjuer med barnen har jag kommit fram till att barnen har svårigheter med att hänga med och förklara textuppgifter och därför har de svårt att lösa uppgifterna. Studien visar även att man måste tänka på att inte formulera matematiska textuppgifter på samma sätt för elever med språkliga svårigheter och speciellt för nyinflyttade barn, och visar att det inte bara är ord som gör hinder för förståelse av textuppgifter utan uppfattningen av textuppgifters innehåll är också en avgörande faktor för hur barnen löser uppgiften.

    Alla barn som har deltagit i denna studie anser att matematiska textuppgifter är svåra och tråkiga. Detta stämmer överens med Cummins, Kintsch, Reusser & Weimers yttrande (1988) att matematiska textuppgifter är svårast speciellt för flerspråkiga barn. Enligt barnen ligger svårigheten i behovet av att läsa och förstå texterna för att kunna lösa uppgifterna, vilket inte är fallet med uppgifter med endast siffror i. Anledningen till att barnen tycker att uppgifter med siffror är lättare än uppgifter med text är att uppgifter med siffror inte kräver lika mycket av barnen att hålla information i arbetsminnet som uppgifter med texter eftersom barnen får stöd av siffror och symboler för att kunna lösa uppgiften. Barnen behöver endast veta vad symbolerna betyder men i textuppgifter krävs att barnen ska välja räkneoperationer och hålla textens matematiska innehåll kvar i arbetsminnet.

    En viktig punkt som kommit fram av intervjuerna är att utvecklingen av barnens lärande står i relation till hur mycket tid både matematiklärare och modersmålslärare kan ägna barnen.  Detta förklaras med att flerspråkiga barn anser att de inte får den hjälp de önskar vilket orsakar att de får sämre resultat i matematik. Resultatet visar även att det är viktigt för flerspråkiga barn att få matematisk undervisning på sitt modersmål för att få förståelse av de matematiska begreppen och inte förhindra matematisk utveckling. Speciellt barn som inte får någon hjälp hemma behöver mer hjälp som Leah Nillas (2002, s.97) visar; att en av de faktorer som påverkar flerspråkiga barns möjlighet att lyckas i matematik är att barnen får hjälp av sina föräldrar.

  • 1840.
    Abdulrasul, Ali
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurosteroids and Alzheimer’s disease: Mechanistic studies of neuroprotection and neurogenesis2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Alzheimer’s disease (AD) and its consequent memory and cognitive impairments continue to be unhaltable and incurable to this day. Yet, recent studies demonstrating neuroprotective effects of some neurosteroids have shown a potential of these steroids to modulate AD progression in vitro and in vivo. In the present study, the effects of neurosteroids were studied on hydrogen peroxide (H2O2), as well as staurosporine-induced toxicity in SH-SY5Y neuroblastoma cells. Moreover, underlying mechanisms were investigated. Cell viability was measured with MTT-assay. The results demonstrated that the neurosteroids investigated reduced hydrogen peroxide-induced toxicity. One of the neurosteroid even reduced staurosporine-induced toxicity. Moreover, the present study also showed neurogenic properties for one of the neurosteroid studied.  In conclusion, this report demonstrates that neurosteroids act neuroprotective against hydrogen peroxide-induced toxicity and that one of the neurosteroids studied even acts neuroprotective against staurosporine-induced toxicity and possesses neurogenic effects. 

  • 1841.
    Abdulreda, Alico
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Giba, Gabriela
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Generation Y: En studie om vad som motiverar yngre medarbetare2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Generation Y or Millennials are people born 1980-1999. They are raised with a more advanced technology like no other generation before them. The technology has affected the individuals from generation Y in a way which has led them to become impatience. Studies have shown that people in generation Y are very emotional compared to other generations before them. Individuals from generation Y are already entering the labour market. Studies have shown that if an organisation wants to have a bright future the employees are a very important access. A leader who knows how to motivate and lead his co-workers has a great asset which may have a positive impact on the organisation. The purpose of this study is to understand what motivates people who are included in generation Y and what kind of leadership suits them best. Most of the theoretical framework came from scientific articles with theories and models of motivation and leadership for generation Y. Semi-structured interviews were chosen for the research method to get right information. The result of the study showed that generation Y is mostly motivated by inner motivation and prefer a leader who can adapt to the many work situations that can occur in the organisations.

  • 1842.
    Abdul-Redah, T
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics.
    Streffer, RMF
    Chatzidimitriou-Dreismann, CA
    Hjörvarsson, Björgvin
    Karlsson, EB
    Mayers, J
    Anomalous neutron Compton scattering in metallic hydrides: new experiments2000In: PHYSICA B, ISSN 0921-4526, Vol. 276, p. 824-825Article in journal (Refereed)
    Abstract [en]

    The time-of-flight spectra of the neutron Compton scattering of solid palladium hydrides were measured at room temperature. This experiment, which was motivated by previous measurements on liquid H2O/D2O mixtures as mel as on niobium hydrides, showed anom

  • 1843. Abdurahman, S
    et al.
    Höglund, Stefan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Goobar-Larsson, L
    Vahlne, A
    Selected amino acid substitutions in the C-terminal region of human immunodeficiency virus type 1 capsid protein affect virus assembly and release2004In: J. gen. Virol, Vol. 85, p. 2903-2913Article in journal (Refereed)
  • 1844. Abdurahman, Samir
    et al.
    Höglund, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Höglund, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Vahlne, Anders
    Mutation in the loop C-terminal to the cyclophilin A binding site of HIV-1 capsid protein disrupts proper virus assembly and infectivity2007In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 4, p. 19-Article in journal (Refereed)
    Abstract [en]

    We have studied the effects associated with two single amino acid substitution mutations in HIV-1 capsid (CA), the E98A and E187G. Both amino acids are well conserved among all major HIV-1 subtypes. HIV-1 infectivity is critically dependent on proper CA cone formation and mutations in CA are lethal when they inhibit CA assembly by destabilizing the intra and/or inter molecular CA contacts, which ultimately abrogate viral replication. Glu98, which is located on a surface of a flexible cyclophilin A binding loop is not involved in any intra-molecular contacts with other CA residues. In contrast, Glu187 has extensive intra-molecular contacts with eight other CA residues. Additionally, Glu187 has been shown to form a salt-bridge with Arg18 of another N-terminal CA monomer in a N-C dimer. However, despite proper virus release, glycoprotein incorporation and Gag processing, electron microscopy analysis revealed that, in contrast to the E187G mutant, only the E98A particles had aberrant core morphology that resulted in loss of infectivity.

  • 1845. Abdurahman, Samir
    et al.
    Vegvari, Akos
    Levi, Michael
    Höglund, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Högberg, Marita
    Tong, Weimin
    Romero, Ivan
    Balzarini, Jan
    Vahlne, Anders
    Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology2009In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 6, p. 34-Article in journal (Refereed)
    Abstract [en]

    Background: Formation of an HIV-1 particle with a conical core structure is a prerequisite for the subsequent infectivity of the virus particle. We have previously described that glycineamide (G-NH2) when added to the culture medium of infected cells induces non-infectious HIV-1 particles with aberrant core structures. Results: Here we demonstrate that it is not G-NH2 itself but a metabolite thereof that displays antiviral activity. We show that conversion of G-NH2 to its antiviral metabolite is catalyzed by an enzyme present in bovine and porcine but surprisingly not in human serum. Structure determination by NMR suggested that the active G-NH2 metabolite was alpha-hydroxy-glycineamide (alpha-HGA). Chemically synthesized alpha-HGA inhibited HIV-1 replication to the same degree as G-NH2, unlike a number of other synthesized analogues of G-NH2 which had no effect on HIV-1 replication. Comparisons by capillary electrophoresis and HPLC of the metabolite with the chemically synthesized alpha-HGA further confirmed that the antiviral G-NH2-metabolite indeed was alpha-HGA. Conclusion: alpha-HGA has an unusually simple structure and a novel mechanism of antiviral action. Thus, alpha-HGA could be a lead for new antiviral substances belonging to a new class of anti-HIV drugs, i.e. capsid assembly inhibitors.

  • 1846. Abdurahman, Samir
    et al.
    Vegvari, Akos
    Youssefi, Masoud
    Levi, Michael
    Höglund, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Andersson, Elin
    Horal, Peter
    Svennerholm, Bo
    Balzarini, Jan
    Vahlne, Anders
    Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 10, p. 3737-3744Article in journal (Refereed)
    Abstract [en]

    Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH2), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH2 itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.

  • 1847. Abdurahman, Samir
    et al.
    Youssefi, Masoud
    Höglund, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Vahlne, Anders
    Characterization of the invariable residue 51 mutations of human immunodeficiency virus type 1 capsid protein on in vitro CA assembly and infectivity2007In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 4, p. 69-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The mature HIV-1 conical core formation proceeds through highly regulated protease cleavage of the Gag precursor, which ultimately leads to substantial rearrangements of the capsid (CAp24) molecule involving both inter- and intra-molecular contacts of the CAp24 molecules. In this aspect, Asp51 which is located in the N-terminal domain of HIV-1 CAp24 plays an important role by forming a salt-bridge with the free imino terminus Pro1 following proteolytic cleavage and liberation of the CAp24 protein from the Pr55Gag precursor. Thus, previous substitution mutation of Asp51 to alanine (D51A) has shown to be lethal and that this invariable residue was found essential for tube formation in vitro, virus replication and virus capsid formation. RESULTS: We extended the above investigation by introducing three different D51 substitution mutations (D51N, D51E, and D51Q) into both prokaryotic and eukaryotic expression systems and studied their effects on in vitro capsid assembly and virus infectivity. Two substitution mutations (D51E and D51N) had no substantial effect on in vitro capsid assembly, yet they impaired viral infectivity and particle production. In contrast, the D51Q mutant was defective both for in vitro capsid assembly and for virus replication in cell culture. CONCLUSION: These results show that substitutions of D51 with glutamate, glutamine, or asparagine, three amino acid residues that are structurally related to aspartate, could partially rescue both in vitro capsid assembly and intra-cellular CAp24 production but not replication of the virus in cultured cells.

  • 1848.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Discovery and evaluation of direct acting antivirals against hepatitis C virus2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Until recently, the standard therapy for hepatitis C treatment has been interferon and ribavirin. Such treatment has only 50% efficacy and is not well tolerated. The emergence of new drugs has increased the treatment efficacy to 90%. Despite such an achievement, the success is limited since the virus mutates rapidly, causing the emergence of drug resistant forms. In addition, most new drugs were developed to treat genotype 1 infections. Thus, development of new potent antivirals is needed and drug discovery against hepatitis C is continued.

    In this thesis, a FRET-based protease assay was used to evaluate new pyrazinone based NS3 protease inhibitors that are structurally different to the newly approved and currently developing drugs. Several compounds in this series showed good potencies in the nanomolar range against NS3 proteases from genotype 1, 3, and the drug resistance variant R155K. We assume that these compounds can be further developed into drug candidates that possess activity against above mentioned enzyme variants.

    By using SPR technology, we analyzed interaction mechanisms and characteristics of allosteric inhibitors targeting NS5B polymerases from genotypes 1 and 3. The compounds exhibited different binding mechanisms and displayed a low affinity against NS5B from genotype 3.

    In order to evaluate the activity and inhibitors of the NS5B polymerase, we established an SPR based assay, which enables the monitoring of polymerization and its inhibition in real time. This assay can readily be implemented for the discovery of inhibitors targeting HCV.

    An SPR based fragment screening approach has also been established. A screen of a fragment library has been performed in order to identify novel scaffolds that can be used as a starting point for development of new allosteric inhibitors against NS5B polymerase. Selected fragments will be further elaborated to generate a new potent allosteric drug candidate.

    Alternative approaches have successfully been developed and implemented to the discovery of potential lead compounds targeting two important HCV drug targets.

    List of papers
    1. Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
    Open this publication in new window or tab >>Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
    Show others...
    2016 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, no 12, p. 2603-2620Article in journal (Refereed) Published
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

    Keywords
    Hepatitis C virus; Drug resistance; Pyrazinone; NS3 protease inhibitors; R155K
    National Category
    Organic Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-243315 (URN)10.1016/j.bmc.2016.03.066 (DOI)000376727800002 ()27160057 (PubMedID)
    Funder
    Swedish Research Council, D0571301
    Available from: 2015-02-08 Created: 2015-02-08 Last updated: 2017-12-04Bibliographically approved
    2. Pyrazinone based hepatitis C virus NS3 protease inhibitors targeting genotype 1a, 3a and the drug-resistant enzyme variant R155K
    Open this publication in new window or tab >>Pyrazinone based hepatitis C virus NS3 protease inhibitors targeting genotype 1a, 3a and the drug-resistant enzyme variant R155K
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265295 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
    3. Resolution of the Interaction Mechanisms and Characteristics of Non-nucleoside Inhibitors of Hepatitis C Virus Polymerase - Laying the Foundation for Discovery of Allosteric HCV Drugs
    Open this publication in new window or tab >>Resolution of the Interaction Mechanisms and Characteristics of Non-nucleoside Inhibitors of Hepatitis C Virus Polymerase - Laying the Foundation for Discovery of Allosteric HCV Drugs
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    2013 (English)In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 97, no 3, p. 356-368Article in journal (Other academic) Published
    Abstract [en]

    Development of allosteric inhibitors into efficient drugs is hampered by their indirect mode-of-action and complex structure-kinetic relationships. To enablethe design of efficient allosteric drugs targeting the polymerase of hepatitis C virus(NS5B), the interaction characteristics of three non-nucleoside compounds (filibuvir, VX-222, and tegobuvir) inhibiting HCV replication via NS5B have been analyzed. Since there was no logical correlation between the anti-HCV replicative and enzyme inhibitory effects of the compounds, surface plasmon resonance biosensor technology was used to resolve the mechanistic, kinetic, thermodynamic and chemodynamic features of their interactions with their target and their effect on itsinteraction with RNA. Tegobuvir could not be seen to interact with NS5B at all while filibuvir interacted in a single reversible step (except at low temperatures) and VX-222 in two serial steps, interpreted as an induced fit mechanism. Both filibuvir and VX-222 interfered with the interaction between NS5B and RNA. They competed for binding to the enzyme, suggesting that they had a common inhibition mechanism and identical or overlapping binding sites. The greater anti-HCV replicative activityof VX-222 over filibuvir is hypothesized to be due to a greater allosteric conformational effect, resulting in the formation of a less catalytically competent complex. In addition, the induced fit mechanism of VX-222 gives it a kinetic advantage over filibuvir, exhibited as a longer residence time. These insights have important consequences for the selection and optimization of new allosteric NS5Binhibitors.

    Keywords
    HCV, NS5B, filibuvir, VX-222, tegobuvir, allosteric inhibitor, induced fit, kinetics, chemodynamics, thermodynamics
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biochemistry; Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-171996 (URN)10.1016/j.antiviral.2012.12.027 (DOI)000317709400018 ()
    Available from: 2012-04-03 Created: 2012-03-31 Last updated: 2017-12-07Bibliographically approved
    4. Characterization of allosteric inhibitors of hepatitis C virus polymerase – a genotype comparative study
    Open this publication in new window or tab >>Characterization of allosteric inhibitors of hepatitis C virus polymerase – a genotype comparative study
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265287 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
    5. A time-resolved surface plasmon resonance based hepatitis C virus NS5B polymerase assay and its application for drug discovery
    Open this publication in new window or tab >>A time-resolved surface plasmon resonance based hepatitis C virus NS5B polymerase assay and its application for drug discovery
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265290 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
    6. Fragment library screening addressing Hepatitis C protein NS5B from genotypes 1 and 3 using an SPR-based approach
    Open this publication in new window or tab >>Fragment library screening addressing Hepatitis C protein NS5B from genotypes 1 and 3 using an SPR-based approach
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-265292 (URN)
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
  • 1849. Abdurakhmanov, Eldar
    et al.
    Danielson, Helena
    A time-resolved surface plasmon resonance based hepatitis C virus NS5B polymerase assay and its application for drug discoveryManuscript (preprint) (Other academic)
  • 1850.
    Abdurakhmanov, Eldar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Solbak, Sara
    Danielson, Helena
    Characterization of allosteric inhibitors of hepatitis C virus polymerase – a genotype comparative studyManuscript (preprint) (Other academic)
34353637383940 1801 - 1850 of 252464
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