From logical forms to SPARQL query with GETARUNS

We present a system for Question Answering which computes a prospective answer from Logical Forms produced by a full-fledged NLP for text understanding, and then maps the result onto schemata in SPARQL to be used for accessing the Semantic Web. As an intermediate step, and whenever there are complex concepts to be mapped, the system looks for a corresponding amalgam in YAGO classes. It is just by the internal structure of the Logical Form that we are able to produce a suitable and meaningful context for concept disambiguation. Logical Forms are the final output of a complex system for text understanding - GETARUNS - which can deal with different levels of syntactic and semantic ambiguity in the generation of a final structure, by accessing computational lexical equipped with sub-categorization frames and appropriate selectional restrictions applied to the attachment of complements and adjuncts. The system also produces pronominal binding and instantiates the implicit arguments, if needed, in order to complete the required Predicate Argument structure which is licensed by the semantic component

Delineation of the Unbinding Pathway of α-Conotoxin ImI from the α7 Nicotinic Acetylcholine Receptor

α-Conotoxins potently and specifically inhibit isoforms of nicotinic acetylcholine receptors (nAChRs) and are used as molecular probes and as drugs or drug leads. Interactions occurring during binding and unbinding events are linked to binding kinetics, and knowledge of these interactions could help in the development of α-conotoxins as drugs. Here, the unbinding process for the prototypical α-conotoxin ImI/α7-nAChR system was investigated theoretically, and three exit routes were identified using random accelerated molecular dynamics simulations. The route involving the smallest conformation perturbation was further divided into three subpathways, which were studied using steered molecular dynamics simulations. Of the three subpathways, two had better experimental support and lower potential of mean force, indicating that they might be sampled more frequently. Additionally, these subpathways were supported by previous experimental studies. Several pairwise interactions, including a cation-π interaction and charge and hydrogen bond interactions, were identified as potentially playing important roles in the unbinding event

Flowchart describing the operation of NMRdyn.

<p>Panel A shows that the system being studied may be a monomeric protein or may include oligomers. The types of parameters that describe the dynamics of the system are labeled. In the monomeric case, relaxation data are usually measured at different magnetic field strengths and at one concentration, for a series of n nuclei (typically the backbone amide nitrogen for each amino acid, or backbone/sidechain ¹³C labeled sites) as shown in panel B. To study self-association, data at multiple concentrations are required. Relaxation data, molecular parameters, and physical constants are used as input into NMRdyn. Panel C (left side) shows that in the case of a monomeric protein, NMRdyn performs a ‘classical’ analysis, where the AIC value is minimized until it and all microdynamic parameters converge with model optimization and model selection performed at each minimization step. For studies of protein self-association (Panel C, right side), a grid-search approach can be applied, resulting in a set of microdynamic parameters describing the monomeric protein and the oligomer.</p

Comparison of order parameters (<i>S²</i>) computed by NMRdyn (open circles) and relax [5] (crosses) for a relaxation analysis on micelle-bound neuropeptide Y [8].

<p>The original set of relaxation data used was downloaded from the Biological Magnetic Resonance Bank <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003820#pone.0003820-Ulrich1" target="_blank">[20]</a>. <i>S²</i> describes the flexibility of a given residue, with a value close to 1 indicative of high local order, and is one of the most informative parameters from a relaxation analysis. The agreement between the results from NMRdyn and relax validates NMRdyn's implementation.</p

Model-free models and associated parameters.

<p>Model-free models and associated parameters.</p

Fixed stoichiometry analysis of kalata B1, the prototypical cyclotide, assuming a monomer-tetramer equilibrium.

<p>NMRdyn was used to perform a search over different association constants. The overall Akaike's Information Criteria (AIC) score was used to judge the goodness of the fit, with the aim of obtaining the minimum AIC score. The results indicate that an association constant of approximately 3×10⁷ M⁻³ can be used to describe the formation of the kalata B1 tetramer in solution.</p

Determination of the α‑Conotoxin Vc1.1 Binding Site on the α9α10 Nicotinic Acetylcholine Receptor

α-Conotoxin Vc1.1 specifically and potently inhibits the nicotinic acetylcholine receptor subtype α9α10 (α9α10 nAChR) and is a potential novel treatment for neuropathic pain. Here, we used a combination of computational modeling and electrophysiology experiments to determine the Vc1.1 binding site on the α9α10 nAChR. Interactions of Vc1.1 with two probable binding sites, α9α10 and α10α9, were modeled. Mutational energies calculated by assuming specific interactions in the α10α9 binding site correlated better with electrophysiological recordings than those assuming interactions with the α9α10 binding site. Two novel Vc1.1 analogues, [N9F]­Vc1.1 and [N9W]­Vc1.1, were predicted to have large differences in affinity between the two binding sites. Data from functional studies were consistent with computational predictions that assumed preferred binding of Vc1.1 to the α10α9 pocket. Moreover, our modeling study suggested that a single hydrogen bond formed between Vc1.1 and position 59 of the α10α9 pocket confers specificity to rat versus human α9α10 nAChRs

Design of a Cyclotide Antagonist of Neuropilin‑1 and -2 That Potently Inhibits Endothelial Cell Migration

Neuropilin-1 and -2 are critical regulators of angiogenesis, lymphangiogenesis, and cell survival as receptors for multiple growth factors. Disulfide-rich peptides that antagonize the growth factor receptors neuropilin-1 and neuropilin-2 were developed using bacterial display libraries. Peptide ligands specific for the VEGFA binding site on neuropilin-1 were identified by screening a library of disulfide-rich peptides derived from the thermostable, protease-resistant cyclotide kalata B1. First generation ligands were subjected to one cycle of affinity maturation to yield acyclic peptides with affinities of 40–60 nM and slow dissociation rate constants (∼1 × 10^–3 s^–1). Peptides exhibited equivalent affinities for human and mouse neuropilin-1 and cross-reacted with human neuropilin-2 with lower affinity. A C-to-N cyclized variant (cyclotide) of one neuropilin ligand retained high affinity, exhibited increased protease resistance, and conferred improved potency for inhibiting endothelial cell migration <i>in vitro</i> (EC₅₀ ≈ 100 nM). These results demonstrate that potent, target-specific cyclotides can be created by evolutionary design and that backbone cyclization can confer improved pharmacological properties

Structural Characterization of the Cyclic Cystine Ladder Motif of θ‑Defensins

The θ-defensins are, to date, the only known ribosomally synthesized cyclic peptides in mammals, and they have promising antimicrobial bioactivities. The characteristic structural motif of the θ-defensins is the cyclic cystine ladder, comprising a cyclic peptide backbone and three parallel disulfide bonds. In contrast to the cyclic cystine knot, which characterizes the plant cyclotides, the cyclic cystine ladder has not been as well described as a structural motif. Here we report the solution structures and nuclear magnetic resonance relaxation properties in aqueous solution of three representative θ-defensins from different species. Our data suggest that the θ-defensins are more rigid and structurally defined than previously thought. In addition, all three θ-defensins were found to self-associate in aqueous solution in a concentration-dependent and reversible manner, a property that might have a role in their mechanism of action. The structural definition of the θ-defensins and the cyclic cystine ladder will help to guide exploitation of these molecules as structural frameworks for the design of peptide drugs

The E15R Point Mutation in Scorpion Toxin Cn2 Uncouples Its Depressant and Excitatory Activities on Human Na_V1.6

We report the chemical synthesis of scorpion toxin Cn2, a potent and highly selective activator of the human voltage-gated sodium channel Na_V1.6. In an attempt to decouple channel activation from channel binding, we also synthesized the first analogue of this toxin, Cn2­[E15R]. This mutation caused uncoupling of the toxin’s excitatory and depressant activities, effectively resulting in a Na_V1.6 inhibitor. In agreement with the in vitro observations, Cn2­[E15R] is antinociceptive in mouse models of Na_V1.6-mediated pain