Earthquake forecasting in Italy, before and after Umbria-Marche seismic sequence 1997. A review of the earthquake occurrence modeling at different spatio-temporal-magnitude scales.

The main goal of this work is to review the scientific researches carried out before and after the Umbria-Marche sequence related to the earthquake forecasting/prediction in Italy. In particular, I focus the attention on models that aim addressing three main practical questions: was (is) Umbria-Marche a region with high probability of occurrence of a destructive earthquake? Was a precursory activity recorded before the mainshock(s)? What was our capability to model the spatio-temporal-magnitude evolution of that seismic sequence? The models are reviewed pointing out what we have learned after the Umbria-Marche earthquakes, in terms of physical understanding of earthquake occurrence process, and of improving our capability to forecast earthquakes and to track in real-time seismic sequences

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

Insights into the Molecular Flexibility of θ‑Defensins by NMR Relaxation Analysis

θ-Defensins are mammalian cyclic peptides that have antimicrobial activity and show potential as stable scaffolds for peptide-based drug design. The cyclic cystine ladder structural motif of θ-defensins has been characterized using NMR spectroscopy and is important for their structure and stability. However, the effect of the pronounced elongated topology of θ-defensins on their molecular motion is not yet understood. Studies of molecular motion by NMR relaxation measurements have been facilitated by the recent development of a semirecombinant method for producing cyclic peptides that allows for isotopic labeling. Here we have undertaken a multifield ¹⁵N NMR relaxation analysis of the anti-HIV θ-defensin, HTD-2, and interpreted the experimental data using various models of overall and internal molecular motion. We found that it was necessary to apply a model that includes internal motion to account for the variations in the experimental T₁ and NOE data at different backbone amide sites in the peptide. Although an isotropic model with internal motion was the simplest model that provided a satisfactory fit with the experimental data, we cannot exclude the possibility that overall motion is anisotropic, especially considering the strikingly elongated topology of θ-defensins. The presence of flexible side chains, self-association, interactions with solvent, and internal motions are all potential contributors to the observed relaxation data. Internal motion consistent with the constraints imposed by the cyclic cystine ladder was observed in that the order parameters, <i>S</i>², show that residues in the turns are more flexible than those in the β-sheet. This study provides insights into the dynamics of θ-defensins and information that might be useful in their application as scaffolds in drug design

Althusser and the Critique of Political Economy

Two disulfide-containing peptides, barrettides A (<b>1</b>) and B (<b>2</b>), from the cold-water marine sponge <i>Geodia barretti</i> are described. Those 31 amino acid residue long peptides were sequenced using mass spectrometry methods and structurally characterized using NMR spectroscopy. The structure of <b>1</b> was confirmed by total synthesis using the solid-phase peptide synthesis approach that was developed. The two peptides were found to differ only at a single position in their sequence. The three-dimensional structure of <b>1</b> revealed that these peptides possess a unique fold consisting of a long β-hairpin structure that is cross-braced by two disulfide bonds in a ladder-like arrangement. The peptides are amphipathic in nature with the hydrophobic and charged residues clustered on separate faces of the molecule. The barrettides were found not to inhibit the growth of either <i>Escherichia coli</i> or <i>Staphylococcus aureus</i> but displayed antifouling activity against barnacle larvae (<i>Balanus improvisus</i>) without lethal effects in the concentrations tested

Understanding the Molecular Basis of Toxin Promiscuity: The Analgesic Sea Anemone Peptide APETx2 Interacts with Acid-Sensing Ion Channel 3 and hERG Channels via Overlapping Pharmacophores

The sea anemone peptide APETx2 is a potent and selective blocker of acid-sensing ion channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure–activity relationship study of APETx2. Determination of a high-resolution structure of APETx2 combined with scanning mutagenesis revealed a cluster of aromatic and basic residues that mediate its interaction with ASIC3. We show that APETx2 also inhibits the off-target hERG channel by reducing the maximal current amplitude and shifting the voltage dependence of activation to more positive potentials. Electrophysiological screening of selected APETx2 mutants revealed partial overlap between the surfaces on APETx2 that mediate its interaction with ASIC3 and hERG. Characterization of the molecular basis of these interactions is an important first step toward the rational design of more selective APETx2 analogues

Elliott et al. (2014). Plant Cell 10.1105/tpc.114.123620 Supplemental Data

Supplemental Figures 1-24, Supplemental Tables 1-11, Supplemental Methods, Supplemental Dataset 1-