Parallel synthesis of a bis-triazoles library as psammaplin A analogues: A new wave of antibiofilm compounds?

Synthesis of psammaplin A analogues is described. Screening for antibiofilm activity of the targeted library afford some interesting elements in terms of structure-activity relationships. Some compounds exhibited EC50 in the range of ampicillin against three strains of gramnegative bacteria without toxic effect.     

Origin of a Core Bacterial Gene via Co-option and Detoxification of a Phage Lysin

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Eimeria tenella ROP kinase EtROP1 induces G0/G1 cell cycle arrest and inhibits host cell apoptosis

Coccidia are obligate intracellular protozoan parasites responsible for human and veterinary diseases. Eimeria tenella, the aetiologic agent of caecal coccidiosis, is a major pathogen of chickens. In Toxoplasma gondii, some kinases from the rhoptry compartment (ROP) are key virulence factors. ROP kinases hijack and modulate many cellular functions and pathways, allowing T. gondii survival and development. E. tenella's kinome comprises 28 putative members of the ROP kinase family; most of them are predicted, as pseudokinases and their functions have never been characterised. One of the predicted kinase, EtROP1, was identified in the rhoptry proteome of E. tenella sporozoites. Here, we demonstrated that EtROP1 is active, and the N‐terminal extension is necessary for its catalytic kinase activity. Ectopic expression of EtROP1 followed by co‐immunoprecipitation identified cellular p53 as EtROP1 partner. Further characterisation confirmed the interaction and the phosphorylation of p53 by EtROP1. E. tenella infection or overexpression of EtROP1 resulted both in inhibition of host cell apoptosis and G0/G1 cell cycle arrest. This work functionally described the first ROP kinase from E. tenella and its noncanonical structure. Our study provides the first mechanistic insight into host cell apoptosis inhibition by E. tenella. EtROP1 appears as a new candidate for coccidiosis control.     

Female reproduction bears no survival cost in captivity for gray mouse lemurs

The survival cost of reproduction has been revealed in many free‐ranging vertebrates. However, recent studies on captive populations failed to detect this cost. Theoretically, this lack of survival/reproduction trade‐off is expected when resources are not limiting, but these studies may have failed to detect the cost, as they may not have fully accounted for potential confounding effects, in particular interindividual heterogeneity. Here, we investigated the effects of current and past reproductive effort on later survival in captive females of a small primate, the gray mouse lemur. Survival analyses showed no cost of reproduction in females; and the pattern was even in the opposite direction: the higher the reproductive effort, the higher the chances of survival until the next reproductive event. These conclusions hold even while accounting for interindividual heterogeneity. In agreement with aforementioned studies on captive vertebrates, these results remind us that reproduction is expected to be traded against body maintenance and the survival prospect only when resources are so limiting that they induce an allocation trade‐off. Thus, the cost of reproduction has a major extrinsic component driven by environmental conditions.     

Assembly of the <Emphasis Type="Italic">Tc1</Emphasis> and <Emphasis Type="Italic">mariner</Emphasis> transposition initiation complexes depends on the origins of their transposase DNA binding domains

In this review, we focus on the assembly of DNA/protein complexes that trigger transposition in eukaryotic members of the IS630–Tc1–mariner (ITm) super-family, the Tc1- and mariner-like elements (TLEs and MLEs). Elements belonging to this super-family encode transposases with DNA binding domains of different origins, and recent data indicate that the chimerization of functional domains has been an important evolutionary aspect in the generation of new transposons within the ITm super-family. These data also reveal that the inverted terminal repeats (ITRs) at the ends of transposons contain three kinds of motif within their sequences. The first two are well known and correspond to the cleavage site on the outer ITR extremities, and the transposase DNA binding site. The organization of ITRs and of the transposase DNA binding domains implies that differing pathways are used by MLEs and TLEs to regulate transposition initiation. These differences imply that the ways ITRs are recognized also differ leading to the formation of differently organized synaptic complexes. The third kind of motif is the transposition enhancers, which have been found in almost all the functional MLEs and TLEs analyzed to date. Finally, in vitro and in vivo assays of various elements all suggest that the transposition initiation complex is not formed randomly, but involves a mechanism of oriented transposon scanning. Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at . An erratum to this article can be found at     

Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression

Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD has not been elucidated, but weight loss, associated with chorea and cognitive decline, is a characteristic feature of the disease that is accessible to investigation. We, therefore, performed a multiparametric study exploring body weight and the mechanisms of its loss in 32 presymptomatic carriers and HD patients in the early stages of the disease, compared to 21 controls. We combined this study with a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance ((1)H NMR) spectroscopy. We report evidence of an early hypermetabolic state in HD. Weight loss was observed in the HD group even in presymptomatic carriers, although their caloric intake was higher than that of controls. Inflammatory processes and primary hormonal dysfunction were excluded. (1)H NMR spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and presymptomatic carriers from controls. This distinction was attributable to low levels of the branched chain amino acids (BCAA), valine, leucine and isoleucine. BCAA levels were correlated with weight loss and, importantly, with disease progression and abnormal triplet repeat expansion size in the HD1 gene. Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group. Therefore, early weight loss in HD is associated with a systemic metabolic defect, and BCAA levels may be used as a biomarker, indicative of disease onset and early progression. The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.     

Yield, chemical composition and gel strength of agarocolloids of Gracilaria gracilis, Gracilariopsis longissima and the newly reported Gracilaria cf. vermiculophylla from Roscoff (Brittany, France)

Agarocolloids were extracted from field samples of Gracilaria gracilis, Gracilariopsis longissima and the newly reported Gracilaria cf. vermiculophylla harvested at different periods of the year near Roscoff (France). Native and alkali modified extracts were characterized by GLC, HPLC and FT-IR spectroscopy. The main components of agarocolloids isolated by freeze-thawing method, were 3,6-anhydrogalactose and galactose. In addition, minor components (6-O-methyl-galactose, 4-O-methyl-galactose and sulfate groups ranging from 4.4 up to 6.6% [w/w]) were detected. The highest rate of 6-O-methylgalactose was observed in agarocolloids from vermiculophylla (14 mole%). Sulfates were mainly branched on C4 of the D-galactose in gracilis and Gs. longissima agarocolloids. G. vermiculophylla agaroids isolated by EtOH and NaCl precipitations from the syneresis water were characterized by a high sulfation on C6 of galactose and a low sulfation on C2 of 3,6-anhydrogalactose. Native agarocolloid gel strengths from Gracilaria species were clearly higher than those of Gracilariopsis. Alkali treatments reduced the sulfate levels but increased slightly the gel strengths. An approximation of the polymer sizes carried out with colorimetric assays indicated that the polymer sizes were higher in G. gracilis than observed in Gs. longissima. This revised version was published online in June 2006 with corrections to the Cover Date.     

Dynamics of the endoplasmic reticulum during early development of Drosophila melanogaster

In this study, we analyze for the first time endoplasmic reticulum (ER) dynamics and organization during oogenesis and embryonic divisions of Drosophila melanogaster using a Protein Disulfide Isomerase (PDI) GFP chimera protein. An accumulation of ER material into the oocyte takes place during the early steps of oogenesis. The compact organization of ER structures undergoes a transition to an expanded reticular network at fertilization. At the syncytial stage, this network connects to the nuclear envelope as each nucleus divides. Time-lapse confocal microscopy on PDI transgenic embryos allowed us to characterize a rapid redistribution of the ER during the mitotic phases. The ER network is massively recruited to the spindle poles in prophase. During metaphase most of the ER remains concentrated at the spindle poles and shortly thereafter forms several layers of membranes along the ruptured nuclear envelope. Later, during telophase an accumulation of ER material occurs at the spindle equator. We also analyzed the subcellular organization of the ER network at the ultrastructural level, allowing us to corroborate the results from confocal microscopy studies. This dynamic redistribution of ER suggests an unexpected regulatory function for this organelle during mitosis.     

C-terminal half of human centrin 2 behaves like a regulatory EF-hand domain

Human centrin 2 (HsCen2) is an EF-hand protein that plays a critical role in the centrosome duplication and separation during cell division. We studied the structural and Ca(2+)-binding properties of two C-terminal fragments of this protein: SC-HsCen2 (T94-Y172), covering two EF-hands, and LC-HsCen2 (M84-Y172), having 10 additional residues. Both fragments are highly disordered in the apo state but become better structured (although not conformationally homogeneous) in the presence of Ca(2+) and depending on the nature of the cations (K(+) or Na(+)) in the buffer. Only the longer C-terminal domain, in the Ca(2+)-saturated state and in the presence of Na(+) ions, was amenable to structure determination by nuclear magnetic resonance. The solution structure of LC-HsCen2 reveals an open two EF-hand structure, similar to the conformation of related Ca(2+)-saturated regulatory domains. Unexpectedly, the N-terminal helix segment (F86-T94) lies over the exposed hydrophobic cavity. This unusual intramolecular interaction increases considerably the Ca(2+) affinity and constitutes a useful model for the target binding.