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

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