This paper presents an extension of the GLL parsing algorithm for context-free grammars which also supports parsing expression grammars with ordered choice and lookahead. The new PEGLL algorithm retains support for unordered choice, and thus parses a common superset of context-free grammars and parsing expression grammars. As part of this work, the authors have modified an existing GLL parser-generator to support parsing expression grammars, adding operators for common parsing expressions and modifying the lexer algorithm to better support ordered choice.

This paper presents a new derivative parsing algorithm for parsing expression grammars; this new algorithm is both simpler and faster than the existing parsing expression derivative algorithm presented by Moss. This new algorithm improves on the worst-case space and runtime bounds of the previous algorithm by a linear factor, as well as decreasing runtime by about half in practice. A proof of correctness for the new algorithm is included in this paper, a result not present in earlier work.

SummaryThe C programming language is a foundational technology for modern computing with millions of lines of code implementing everything from hobby projects to commercial operating systems. This installation base and the programmers producing it represent a massive software engineering investment spanning decades and likely to continue for decades more. Nevertheless, C, which was first standardized almost 30 years ago, lacks many features that make programming in more modern languages safer and more productive. The goal of the C project (pronounced “C for all”) is to create an extension of C that provides modern safety and productivity features while still ensuring strong backward compatibility with C and its programmers. Prior projects have attempted similar goals but failed to honor the C programming style; for instance, adding object‐oriented or functional programming with garbage collection is a nonstarter for many C developers. Specifically, C is designed to have an orthogonal feature set based closely on the C programming paradigm, so that C features can be added incrementally to existing C code bases, and C programmers can learn C extensions on an as‐needed basis, preserving investment in existing code and programmers. This paper presents a quick tour of C features, showing how their design avoids shortcomings of similar features in C and other C‐like languages. Experimental results are presented to validate several of the new features.

This paper introduces a new derivative parsing algorithm for recognition of parsing expression grammars. Derivative parsing is shown to have a polynomial worst-case time bound, an improvement on the exponential bound of the recursive descent algorithm. This work also introduces asymptotic analysis based on inputs with a constant bound on both grammar nesting depth and number of backtracking choices; derivative and recursive descent parsing are shown to run in linear time and constant space on this useful class of inputs, with both the theoretical bounds and the reasonability of the input class validated empirically. This common-case constant memory usage of derivative parsing is an improvement on the linear space required by the packrat algorithm.

Ribavirin is used for the treatment of hepatitis C virus (HCV) infection. The equilibrative nucleoside transporter 1 (ENT1) expressed in hepatocytes transports ribavirin into the liver, the site of efficacy of the drug. However, it is still unclear whether ENT1 plays a dominant role in the hepatic distribution of the drug in vivo. In addition, due to fetal toxicity, administration of ribavirin to pregnant women with HCV infection is contraindicated. ENT1 might play a role in the fetal distribution and therefore the fetal toxicity of ribavirin. The aim of the present study was to investigate the in vivo contribution of ENT1 to the tissue distribution of ribavirin. When compared with that in Ent1(+/+) mice, the ribavirin tissue to plasma concentration ratio (including phosphorylated metabolites) in Ent1(-/-) mice at 15 min and 6 h after intravenous [(3) H]-ribavirin (3 mg/kg) administration was consistently and significantly decreased in the liver and the pancreas. Likewise, when compared with the Ent1(+/+) mice, the fetal distribution of ribavirin at 15 min after administration was significantly reduced in Ent1(-/-) fetuses and placenta. In contrast, there was no significant difference between Ent1(+/+), Ent1(+/-) and Ent1(-/-) mice in the fetal or placental to maternal plasma ribavirin concentration ratio at 2 h after ribavirin administration. The findings in the present study suggest that ENT1 plays a pivotal role in the distribution of ribavirin into tissues including the liver and pancreas, but affects only the rate, but not the extent, of ribavirin distribution into the fetus. Copyright © 2016 John Wiley & Sons, Ltd.

Given a symmetry group acting on the hyperplanes of an arrangement, our goal is to report a single basis from each orbit of bases induced by this group. In this paper we extend previous techniques for finding the (feasible) bases of polyhedra up to symmetry, and for computing the symmetry groups of polyhedra, to the setting of hyperplane arrangements. We present some preliminary experiments with a C++ implementation of these techniques called Basil. These results show substantial speedups compared to a previous polyhedra only system using the computer algebra system GAP. We also measure the speedup due to a Gram matrix invariant, and show that the overhead of symmetry testing, while substantial, is dominated by the savings in reduced pivoting.

Ribavirin is frontline treatment for hepatitis C virus infection. To determine the role of nucleoside transporters in the intestinal absorption of orally administered ribavirin, we perfused the intestines of Ent1(-/-) and wild-type mice, in situ, with [(3)H] ribavirin (20, 200, and 5000 μM) in the presence and absence of sodium. The decrease in luminal ribavirin concentration over 30 min was measured at 5 min intervals. Blood samples were collected approximately every 10 min. Ribavirin plus phosphorylated metabolite concentrations (hereafter referred to as ribavirin) were determined in tissue, blood, and plasma by HPLC fractionation and scintillation counting. There was no significant difference between wild-type and Ent1(-/-) mice in intestinal loss of ribavirin at any ribavirin concentration studied. Perfusions without sodium drastically reduced the intestinal loss of ribavirin in both wild-type and Ent1(-/-) mice. After 20 μM ribavirin perfusions, Ent1(-/-) intestinal tissue contained 8-fold greater ribavirin than wild-type mice (p < 0.01). Ribavirin concentrations in the wild-type intestinal tissue were 70-fold higher after 200 vs 20 μM perfusions (p < 0.001), indicating saturation of intestinal ribavirin efflux and possibly other processes as well. Ribavirin plasma concentrations were significantly higher in wild-type mice (2.7-fold) vs Ent1(-/-) mice at 30 min after the 20 μM perfusion (p < 0.01). These results suggest that, at lower intestinal concentrations of ribavirin, concentrative and equilibrative nucleoside transporters are important in the intestinal absorption of ribavirin. At higher intestinal concentrations, these transporters are saturated and other processes in the intestine (transport and/or metabolism) play an important role in the absorption of ribavirin.

This paper contains an investigation of how different kinds of computer interface controls facilitate users’ discovery and learning of the functionality afforded by these controls. To test these capabilities, I have developed a simple rich text editor with both a standard graphical interface and a more efficient keyboard-based interface which uses MediaWiki formatting markup. This study examined the utility of providing a syntax highlighting-based “live preview” of the formatted text for user efficiency, satisfaction, and education in the use of the more efficient typed formatting markup. Analysis of the data collected from the study suggests that the live preview feature is effective at improving user efficiency, but through reducing user invocation of the manual preview feature rather than by training users to utilize keyboard-entered formatting markup. In fact, the greater similarity of the live preview-enabled interface to common word processing software appeared to suggest to its users a greater similarity of behaviour as well. The experimental group of users, who were given a live preview-enabled interface, in fact showed less aptitude than a control group without the feature to discover the usage and functionality of the typed formatting markup.

Ribavirin [1-(beta-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide] is the treatment of choice for hepatitis C virus infection. Ribavirin is a substrate of several nucleoside transporters, including the equilibrative nucleoside transporter (Ent) and the concentrative nucleoside transporter 2. To determine the role of Ent1 in ribavirin absorption and erythrocyte distribution, we examined its pharmacokinetics in Ent1-null mice. After intravenous administration, we found that the erythrocyte area under the curve (AUC(0-12) (h)) was reduced 3.05-fold along with 2.63-fold reduction of erythrocyte versus plasma AUC ratio in the Ent1(-/-) mice, whereas there was no significant difference in the plasma AUC(0-12 h) between Ent1(+/+) and Ent1(-/-) mice. After 48 h, we found a similar fraction of ribavirin or total radioactivity excreted in the urine between the Ent1(+/+) and Ent1(-/-) mice. After oral administration of three different doses, 0.024, 0.24, and 6.1 mg/kg, we found that the dose-normalized plasma AUC(0-12 h) of ribavirin was 69.7 +/- 12.0, 20.7 +/- 1.5, and 18.3 +/- 2.7 min/l, respectively, in the Ent1(+/+) mice and 18.9 +/- 2.8, 13.0 +/- 0.5, and 12.2 +/- 1.0 min/l, respectively, in the Ent1(-/-) mice. It is interesting that at the highest dose, the dose-normalized plasma AUC(0-30) (min), AUC(0-12 h), and C-max in the Ent1(+/+) mice were decreased 4.0-, 3.8-, and 3.4-fold, respectively, compared with the lowest dose, suggesting absorption was saturated at the highest dose we used. The dose-normalized plasma AUC(0-12 h) was 3.7- and 1.5-fold lower at the lowest and the highest dose, respectively, in the Ent1(-/-) mice compared with those of the Ent1(+/+) mice. Our findings indicate that Ent1 plays a significant role in the oral absorption and erythrocyte distribution of ribavirin.

The polar nucleoside drug ribavirin is front-line treatment for chronic hepatitis C virus infection. The human equilibrative nucleoside transporter (ENT) 1 transports ribavirin into erythrocytes where it is phosphorylated. These phosphorylated metabolites accumulate in the erythrocytes and produce dose-limiting hemolytic anemia. Here, we examined the in vitro and ex vivo transport and metabolism of ribavirin by erythrocytes isolated from humans and Ent1-null mice. Ribavirin (2.4 microM) uptake was significantly higher (1044 +/- 255 amol/microg/10 s) into erythrocytes from Ent1(+/+) mice compared with that from Ent1(-/-) mice (76.48 +/- 11.20 amol/microg/10 s). Our results showed a saturable (K(m) of 382 +/- 75.1 microM) transport of [(3)H]ribavirin into erythrocytes from Ent1(+/+) mice. We found that ribavirin concentration rapidly (within 60 s) reached equilibrium in erythrocytes using a time course of [(3)H]ribavirin transport (2.5 microM) and metabolism in mouse and human erythrocytes for 8 h. However, total radioactivity of ribavirin was predominantly attributed to the phosphorylated metabolites ribavirin monophosphate and ribavirin triphosphate. Our findings allow us to estimate ribavirin transport, diffusion, and metabolic clearance and to predict in vivo accumulation of ribavirin phosphates in erythrocytes of both mice and humans. Our modeling of ribavirin in erythrocytes on long-term administration of ribavirin suggests that the accumulation of ribavirin inside the cells is dependent on ENT1/Ent1 transport and the rates of intracellular phosphorylation and the degradation of the phosphorylated metabolites. We predict that Ent1(+/+) and Ent1(-/-) mice will serve as excellent models to investigate the contribution of Ent1 to the pharmacokinetics and toxicity of ribavirin in vivo.

One under-addressed issue in the field of Web services composition is authentication between disparate services using different authentication methods or protocols. A single sign-on (SSO) framework reduces the burden on the end user to provide authentication credentials to these separate services; thus it is a desirable feature for systems and applications that are based on multiple Web services. However, true SSO is not feasible in a Web services context, as individual services can be provided by any parties; they may have arbitrary authentication methods, credential types, or protocols, and may not have an existing trust or federation arrangement with a given external authentication system. Due to these factors, it is valuable to provide a specialized service that can provide authentication information seamlessly to the services selected for a given service-enabled process. This paper introduces a unified authentication framework for accessing heterogeneous Web services. We propose a credential storage and retrieval mechanism to store authentication data and pass that data to corresponding Web services clients. Hence, this framework enables authenticated access to Web services implemented with arbitrary access control methods.

The aim of this current review is to summarize the present status of pharmacokinetics in Drug Discovery. The review is structured into four sections. The first section is a general overview of what we understand by pharmacokinetics and the different LADMET aspects: Liberation, Absorption, Distribution, Metabolism, Excretion, and Toxicity. The second section highlights the different computational or in silico approaches to estimate/predict one or several aspects of the pharmacokinetic profile of a discovery lead compound. The third section discusses the most commonly used in vitro methodologies. The fourth and last section examines the various approaches employed towards the pharmacokinetic assessment of discovery molecules; including all the LADME processes, discussing the different mathematical methodologies available to establish the PK profile of a test compound; what the main differences are and what should be the criteria for using one or another mathematical approach. The major conclusion of this review is that the use of the appropriate preclinical assays has a key role in the long-term viability of a pharmaceutical company since applying the right tools early in discovery will play a key role in determining the company's ability to discover novel safe and effective therapeutics to patients as quickly as possible. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:654–690, 2008