Catalysis by dienelactone hydrolase: A variation on the protease mechanism

Dienelactone hydrolase (DLH), an enzyme from the β-ketoadipate pathway, catalyzes the hydrolysis of dienelactone to maleylacetate. Our inhibitor binding studies suggest that its substrate, dienelactone, is held in the active site by hydrophobic interactions around the lactone ring and by the ion pairs between its carboxylate and Arg-81 and Arg-206. Like the cysteine/serine proteases, DLH has a catalytic triad (Cys-123, His-202, Asp-171) and its mechanism probably involves the formation of covalently bound acyl intermediate via a tetrahedral intermediate. Unlike the proteases, DLH seems to protonate the incipient leaving group only after the collapse of the first tetrahedral intermediate, rendering DLH incapable of hydrolyzing amide analogues of its ester substrate. In addition, the triad His probably does not protonate the leaving group (enolate) or deprotonate the water for deacylation; rather, the enolate anion abstracts a proton from water and, in doing so, supplies the hydroxyl for deacylation. © 1993 Wiley-Liss, Inc.     

Temporal fluctuations and experimental effects in desert plant communities

In the Chihuahuan Desert of the southwestern United States we monitored responses of both winter and summer annual plant communities to natural environmental variation and to experimental removal of seed-eating rodents and ants for 13 years. Analyses of data on population densities of the species by principal component analysis (PCA) followed by repeated measures analysis of variance (rmANOVA) on PCA scores showed that: (1) composition of both winter and summer annual communities varied substantially from year to year, presumably in response to interannual climatic variation, and (2) community composition of winter annuals was also significantly affected by the experimental manipulations of seed-eating animals, but the composition of the summer annual community showed no significant response to these experimental treatments. Canonical discriminant analysis (CDA) was then applied to the data for winter annuals to more clearly identify the responses to the different classes of experimental manipulations. This analysis showed that removing rodents or ants or both taxa caused distinctive changes in species composition. There was a tendency for large-seeded species to increase on rodent removal plots and to decrease on ant removal plots, and for small-seeded species to change in the opposite direction. In the winter annual community there was a significant time x treatment interaction: certain combinations of species that responded differently to removal of granivores also showed opposite fluctuations in response to long-term climatic variation. The large year-to-year variation in the summer annual community was closely and positively correlated across all experimental treatments. The use of multivariate analysis in conjunction with long-term monitoring and experimental manipulation shows how biotic interactions interact with variation in abiotic conditions to affect community dynamics.     

Ciudadanía activa y personas mayores: viejos conceptos,nuevos abordajes. Una revisión sistemática y metasíntesis cualitativa

The politics of active ageing present active citizenship of the elderly as a key challenge for the coming years. Active citizenship has been defined in different ways (as complimentary in most cases), outlining an eclecticism of participatory activities that includes political engagement in a participatory and deliberative manner, as well as community and voluntary action. This term is found in different contexts such as formal politics, work, civil society, and the home. This paper, based on a systematic review, identifies the context in which this concept emerges in relation to older people and people with dementia. It also analyses the different expressions of active citizenship used, and provides key elements to be taken into account in the formulation of policies in a context of accelerated demographic ageing and where dementia is a public health priority. The notion of active citizenship in old age is a step forward from active ageing to a broader concept that integrates the principle of equality between people irrespective of gender, age and the need for support.     

Thiosulfinate Tolerance Is a Virulence Strategy of an Atypical Bacterial Pathogen of Onion

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Conjugation of phosphonoacetic acid to nucleobase promotes a mechanism-based inhibition

Small molecule inhibitors have a powerful blocking action on viral polymerases. The bioavailability of the inhibitor, nevertheless, often raise a significant selectivity constraint and may substantially limit the efficacy of therapy. Phosphonoacetic acid has long been known to possess a restricted potential to block DNA biosynthesis. In order to achieve a better affinity, this compound has been linked with natural nucleotide at different positions. The structural context of the resulted conjugates has been found to be crucial for the acquisition by DNA polymerases. We show that nucleobase-conjugated phosphonoacetic acid is being accepted, but this alters the processivity of DNA polymerases. The data presented here not only provide a mechanistic rationale for a switch in the mode of DNA synthesis, but also highlight the nucleobase-targeted nucleotide functionalization as a route for enhancing the specificity of small molecule inhibitors.     

Amino acid prodrugs of NVR3-778: Design,synthesis and anti-HBV activity

A series of amino acid prodrugs of NVR3-778, a potent anti-HBV candidate currently under phase II clinical trial, were designed and synthesized as new anti-HBV agents. Except for 1e, all of them displayed roughly comparable anti-HBV activity (IC₅₀, 0.28–0.56 µM) to NVR3-778 (IC₅₀, 0.26 µM). Compound 1a, a l-valine ester prodrug of NVR3-778, was found to show significantly improved water solubility (0.7 mg/mL, pH 2) as we expected, and lower cytotoxicity (CC₅₀ > 10 µM) than NVR3-778 (CC₅₀, 4.81 µM). Moreover, 1a also exhibited acceptable PK properties and comparable in vivo efficacy in HBV DNA hydrodynamic mouse model to that of NVR3-778, suggesting it may serve as a promising lead compound for further anti-HBV drug discovery.     

Understanding Performance Degradation in Cation‐Disordered Rock‐Salt Oxide Cathodes

The collective redox activities of transition‐metal (TM) cations and oxygen anions have been shown to increase charge storage capacity in both Li‐rich layered and cation‐disordered rock‐salt cathodes. Repeated cycling involving anionic redox is known to trigger TM migration and phase transformation in layered Li‐ and Mn‐rich (LMR) oxides, however, detailed mechanistic understanding on the recently discovered Li‐rich rock‐salt cathodes is largely missing. The present study systematically investigates the effect of oxygen redox on a Li_1.3Nb_0.3Mn_0.4O₂ cathode and demonstrates that performance deterioration is directly correlated to the extent of oxygen redox. It is shown that voltage fade and hysteresis begin only after initiating anionic redox at high voltages, which grows progressively with either deeper oxidation of oxygen at higher potential or extended cycling. In contrast to what is reported on layered LMR oxides, extensive TM reduction is observed but phase transition is not detected in the cycled oxide. A densification/degradation mechanism is proposed accordingly which elucidates how a unique combination of extensive chemical reduction of TM and reduced quality of the Li percolation network in cation‐disordered rock‐salts can lead to performance degradation in these newer cathodes with 3D Li migration pathways. Design strategies to achieve balanced capacity and stability are also discussed.