Localized practices and globalized futures: challenges for Alaska coastal community youth

An article from Maritime Studies (2015) 14:

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 μM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg−1, NU7026 underwent rapid plasma clearance (0.108 l h−1) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg−1 was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg−1 i.p. in order to obtain the drug exposure required for radiosensitisation

The Role of the Transitional Leader : A Comparative Analysis of Adolfo Suárez and Boris Yeltsin

The role of leadership in transitional regimes is an issue that requires closer examination, given the ability of the leader to shape and determine the direction of the regime. This paper seeks to delineate some common features of leadership during such regimes and the factors influencing the ability of leaders to manipulate and shift the direction of the process. To illustrate, it adopts a comparative analysis of the leadership of Adolfo Suárez (Spain) and Boris Yeltsin (Russia). It will be shown that, despite the different outcomes of these cases, there are clear similarities that point to the existence of a form of transitional leadership. Central to the paper is an adoption of the notion of structure and agency to determine the extent actors in this position can affect change within the constraints faced

Understanding Ion Binding Affinity and Selectivity in β‑Parvalbumin Using Molecular Dynamics and Mean Spherical Approximation Theory

Parvalbumin (PV) is a globular calcium (Ca²⁺)-selective protein expressed in a variety of biological tissues. Our computational studies of the rat β-parvalbumin (β-PV) isoform seek to elucidate the molecular thermodynamics of Ca²⁺ versus magnesium (Mg²⁺) binding at the protein’s two EF-hand motifs. Specifically, we have utilized molecular dynamics (MD) simulations and a mean-field electrolyte model (mean spherical approximation (MSA) theory) to delineate how the EF-hand scaffold controls the “local” thermodynamics of Ca²⁺ binding selectivity over Mg²⁺. Our MD simulations provide the probability density of metal-chelating oxygens within the EF-hand scaffolds for both Ca²⁺ and Mg²⁺, as well the conformational strain induced by Mg²⁺ relative to Ca²⁺ binding. MSA theory utilizes the binding domain oxygen and charge distributions to predict the chemical potential of ion binding, as well as their corresponding concentrations within the binding domain. We find that the electrostatic and steric contributions toward ion binding were similar for Mg²⁺ and Ca²⁺, yet the latter was 5.5 kcal/mol lower in enthalpy when internal strain within the EF hand was considered. We therefore speculate that beyond differences in dehydration energies for the Ca²⁺ versus Mg²⁺, strain induced in the β-PV EF hand by cation binding significantly contributes to the nearly 10,000-fold difference in binding affinity reported in the literature. We further complemented our analyses of local factors governing cation binding selectivity with whole-protein (global) contributions, such as interhelical residue–residue contacts and solvent exposure of hydrophobic surface. These contributions were found to be comparable for both Ca²⁺- and Mg²⁺-bound β-PV, which may implicate local factors, EF-hand strain, and dehydration, in providing the primary means of selectivity. We anticipate these methods could be used to estimate metal binding thermodynamics across a broad range of PV sequence homologues and EF-hand-containing, Ca²⁺ binding proteins