Contribution of Flooded Soils to Sediment and Nutrient Fluxes in a Hydropower Reservoir (Sarrans,Central France)

Ecosystems - When a water reservoir is created, the pre-existing soils and vegetation are flooded. Here, we took advantage of the complete emptying of the Sarrans Reservoir, which was flooded...     

Kallikrein 5 inhibitors identified through structure based drug design in search for a treatment for Netherton Syndrome

Netherton syndrome (NS) is a rare and debilitating severe autosomal recessive genetic skin disease with high mortality rates particularly in neonates. NS is caused by loss-of-function SPINK5 mutations leading to unregulated kallikrein 5 (KLK5) and kallikrein 7 (KLK7) activity. Furthermore, KLK5 inhibition has been proposed as a potential therapeutic treatment for NS. Identification of potent and selective KLK5 inhibitors would enable further exploration of the disease biology and could ultimately lead to a treatment for NS. This publication describes how fragmentation of known trypsin-like serine protease (TLSP) inhibitors resulted in the identification of a series of phenolic amidine-based KLK5 inhibitors 1. X-ray crystallography was used to find alternatives to the phenol interaction leading to identification of carbonyl analogues such as lactam 13 and benzimidazole 15. These reversible inhibitors, with selectivity over KLK1 (10–100 fold), provided novel starting points for the guided growth towards suitable tool molecules for the exploration of KLK5 biology.     

Comparative Analysis of Nucleotide Fluorescent Analogs for Registration of DNA Conformational Changes Induced by Interaction with Formamidopyrimidine-DNA Glycosylase Fpg

Russian Journal of Bioorganic Chemistry - DNA-substrates containing fluorescent DNA base analogs are widely used to study protein–nucleic acid interactions. In the case of DNA-recognizing...     

Growth of an anaerobic sulfate-reducing bacterium sustained by oxygen respiratory energy conservation after O2-driven experimental evolution

Desulfovibrio species are representatives of microorganisms at the boundary between anaerobic and aerobic lifestyles, since they contain the enzymatic systems required for both sulfate and oxygen reduction. However, the latter has been shown to be solely a protective mechanism. By implementing the oxygen-driven experimental evolution of Desulfovibrio vulgaris Hildenborough, we have obtained strains that have evolved to grow with energy derived from oxidative phosphorylation linked to oxygen reduction. We show that a few mutations are sufficient for the emergence of this phenotype and reveal two routes of evolution primarily involving either inactivation or overexpression of the gene encoding heterodisulfide reductase. We propose that the oxygen respiration for energy conservation that sustains the growth of the O₂-evolved strains is associated with a rearrangement of metabolite fluxes, especially NAD⁺/NADH, leading to an optimized O₂ reduction. These evolved strains are the first sulfate-reducing bacteria that exhibit a demonstrated oxygen respiratory process that enables growth.     

Mapping quantitative trait Loci underlying fitness-related traits in a free-living sheep population

We searched for quantitative trait loci (QTL) underlying fitness-related traits in a free-living pedigree of 588 Soay sheep in which a genetic map using 251 markers with an average spacing of 15 cM had been established previously. Traits examined included birth date and weight, considered both as maternal and offspring traits, foreleg length, hindleg length, and body weight measured on animals in August and jaw length and metacarpal length measured on cleaned skeletal material. In some cases the data were split to consider different age classes separately, yielding a total of 15 traits studied. Genetic and environmental components of phenotypic variance were estimated for each trait and, for those traits showing nonzero heritability (N= 12), a QTL search was conducted by comparing a polygenic model with a model including a putative QTL. Support for a QTL at genome-wide significance was found on chromosome 11 for jaw length; suggestive QTL were found on chromosomes 2 and 5 (for birth date as a trait of the lamb), 8 (birth weight as a trait of the lamb), and 15 (adult hindleg length). We discuss the prospects for refining estimates of QTL position and effect size in the study population, and for QTL searches in free-living pedigrees in general.     

Molecular and structural discrimination of proline racemase and hydroxyproline-2-epimerase from nosocomial and bacterial pathogens

The first eukaryotic proline racemase (PRAC), isolated from the human Trypanosoma cruzi pathogen, is a validated therapeutic target against Chagas' disease. This essential enzyme is implicated in parasite life cycle and infectivity and its ability to trigger host B-cell nonspecific hypergammaglobulinemia contributes to parasite evasion and persistence. Using previously identified PRAC signatures and data mining we present the identification and characterization of a novel PRAC and five hydroxyproline epimerases (HyPRE) from pathogenic bacteria. Single-mutation of key HyPRE catalytic cysteine abrogates enzymatic activity supporting the presence of two reaction centers per homodimer. Furthermore, evidences are provided that Brucella abortus PrpA [for 'proline racemase' virulence factor A] and homologous proteins from two Brucella spp are bona fide HyPREs and not 'one way' directional PRACs as described elsewhere. Although the mechanisms of aminoacid racemization and epimerization are conserved between PRAC and HyPRE, our studies demonstrate that substrate accessibility and specificity partly rely on constraints imposed by aromatic or aliphatic residues distinctively belonging to the catalytic pockets. Analysis of PRAC and HyPRE sequences along with reaction center structural data disclose additional valuable elements for in silico discrimination of the enzymes. Furthermore, similarly to PRAC, the lymphocyte mitogenicity displayed by HyPREs is discussed in the context of bacterial metabolism and pathogenesis. Considering tissue specificity and tropism of infectious pathogens, it would not be surprising if upon infection PRAC and HyPRE play important roles in the regulation of the intracellular and extracellular amino acid pool profiting the microrganism with precursors and enzymatic pathways of the host.