111 research outputs found
Incremental QBF Solving
We consider the problem of incrementally solving a sequence of quantified
Boolean formulae (QBF). Incremental solving aims at using information learned
from one formula in the process of solving the next formulae in the sequence.
Based on a general overview of the problem and related challenges, we present
an approach to incremental QBF solving which is application-independent and
hence applicable to QBF encodings of arbitrary problems. We implemented this
approach in our incremental search-based QBF solver DepQBF and report on
implementation details. Experimental results illustrate the potential benefits
of incremental solving in QBF-based workflows.Comment: revision (camera-ready, to appear in the proceedings of CP 2014,
LNCS, Springer
Evaluating QBF Solvers: Quantifier Alternations Matter
We present an experimental study of the effects of quantifier alternations on
the evaluation of quantified Boolean formula (QBF) solvers. The number of
quantifier alternations in a QBF in prenex conjunctive normal form (PCNF) is
directly related to the theoretical hardness of the respective QBF
satisfiability problem in the polynomial hierarchy. We show empirically that
the performance of solvers based on different solving paradigms substantially
varies depending on the numbers of alternations in PCNFs. In related
theoretical work, quantifier alternations have become the focus of
understanding the strengths and weaknesses of various QBF proof systems
implemented in solvers. Our results motivate the development of methods to
evaluate orthogonal solving paradigms by taking quantifier alternations into
account. This is necessary to showcase the broad range of existing QBF solving
paradigms for practical QBF applications. Moreover, we highlight the potential
of combining different approaches and QBF proof systems in solvers.Comment: preprint of a paper to be published at CP 2018, LNCS, Springer,
including appendi
DepQBF 6.0: A Search-Based QBF Solver Beyond Traditional QCDCL
We present the latest major release version 6.0 of the quantified Boolean
formula (QBF) solver DepQBF, which is based on QCDCL. QCDCL is an extension of
the conflict-driven clause learning (CDCL) paradigm implemented in state of the
art propositional satisfiability (SAT) solvers. The Q-resolution calculus
(QRES) is a QBF proof system which underlies QCDCL. QCDCL solvers can produce
QRES proofs of QBFs in prenex conjunctive normal form (PCNF) as a byproduct of
the solving process. In contrast to traditional QCDCL based on QRES, DepQBF 6.0
implements a variant of QCDCL which is based on a generalization of QRES. This
generalization is due to a set of additional axioms and leaves the original
Q-resolution rules unchanged. The generalization of QRES enables QCDCL to
potentially produce exponentially shorter proofs than the traditional variant.
We present an overview of the features implemented in DepQBF and report on
experimental results which demonstrate the effectiveness of generalized QRES in
QCDCL.Comment: 12 pages + appendix; to appear in the proceedings of CADE-26, LNCS,
Springer, 201
Understanding and Extending Incremental Determinization for 2QBF
Incremental determinization is a recently proposed algorithm for solving
quantified Boolean formulas with one quantifier alternation. In this paper, we
formalize incremental determinization as a set of inference rules to help
understand the design space of similar algorithms. We then present additional
inference rules that extend incremental determinization in two ways. The first
extension integrates the popular CEGAR principle and the second extension
allows us to analyze different cases in isolation. The experimental evaluation
demonstrates that the extensions significantly improve the performance
A model for implementation of HACCP system for prevention and control of mycotoxins during the production of red dried chili pepper
Ontogeny of midazolam glucuronidation in preterm infants
Purpose: In preterm infants, the biotransformation of midazolam (M) to 1-OH-midazolam (OHM) by cytochrome P450 3A4 (CYP3A4) is developmentally immature, but it is currently unknown whether the glucuronidation of OHM to 1-OH-midazolam glucuronide (OHMG) is also decreased. The aim of our study was to investigate the urinary excretion of midazolam and its metabolites OHM and OHMG in preterm neonates following the intravenous (IV) or oral (PO) administration of a single M dose. Methods: Preterm infants (post-natal age 3-13 days, gestational age 26-34 4/7 weeks) scheduled to undergo a stressful procedure received a 30-min IV infusion (n=15) or a PO bolus dose (n=7) of 0.1 mg/kg midazolam. The percentage of midazolam dose excreted in the urine as M, OHM and OHMG up to 6 h post-dose was determined. Results: The median percentage of the midazolam dose excreted as M, OHM and OHMG in the urine during the 6-h interval after the IV infusion was 0.44% (range 0.02-1.39%), 0.04% (0.01-0.13%) and 1.57% (0.36-7.7%), respectively. After administration of the PO bolus dose, the median percentage of M, OHM and OHMG excreted in the urine was 0.11% (0.02-0.59%), 0.02% (0.00-0.10%) and 1.69% (0.58-7.31%), respectively. The proportion of the IV midazolam dose excreted as OHMG increased significantly with postconceptional age (r=0.73, p <0.05). Conclusion: The glucuronidation of OHM appears immature in preterm infants less than 2 weeks of age. The observed increase in urinary excretion of OHMG with postconceptional age likely reflects the combined maturation of glucuronidation and renal function
N-glycans of Human Protein C Inhibitor: Tissue-Specific Expression and Function
Protein C inhibitor (PCI) is a serpin type of serine protease inhibitor that is found in many tissues and fluids in human, including blood plasma, seminal plasma and urine. This inhibitor displays an unusually broad protease specificity compared with other serpins. Previous studies have shown that the N-glycan(s) and the NH2-terminus affect some blood-related functions of PCI. In this study, we have for the first time determined the N-glycan profile of seminal plasma PCI, by mass spectrometry. The N-glycan structures differed markedly compared with those of both blood-derived and urinary PCI, providing evidence that the N-glycans of PCI are expressed in a tissue-specific manner. The most abundant structure (m/z 2592.9) had a composition of Fuc3Hex5HexNAc4, consistent with a core fucosylated bi-antennary glycan with terminal Lewisx. A major serine protease in semen, prostate specific antigen (PSA), was used to evaluate the effects of N-glycans and the NH2-terminus on a PCI function related to the reproductive tract. Second-order rate constants for PSA inhibition by PCI were 4.3±0.2 and 4.1±0.5 M−1s−1 for the natural full-length PCI and a form lacking six amino acids at the NH2-terminus, respectively, whereas these constants were 4.8±0.1 and 29±7 M−1s−1 for the corresponding PNGase F-treated forms. The 7–8-fold higher rate constants obtained when both the N-glycans and the NH2-terminus had been removed suggest that these structures jointly affect the rate of PSA inhibition, presumably by together hindering conformational changes of PCI required to bind to the catalytic pocket of PSA
The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria
The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria
Preference of banana flavour and aroma are not affected by time of the year or 'winter' chilling
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