Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process

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Structural characterization of the α-N-acetylglucosaminidase,a key enzyme in the pathogenesis of Sanfilippo syndrome B

Mucopolysaccharidosis III B (MPS III-B) is a rare lysosomal storage disorder caused by deficiencies in Alpha-N-acetylglucosaminidase (NAGLU) for which there is currently no cure, and present treatment is largely supportive. Understanding the structure of NAGLU may allow for identification of novel therapeutic targets for MPS III-B. Here we describe the first crystal structure of human NAGLU, determined to a resolution of 2.3?Å. The crystal structure reveals a novel homotrimeric configuration, maintained primarily by hydrophobic and electrostatic interactions via domain II of three contiguous domains from the N- to C-terminus. The active site cleft is located between domains II and III. Catalytic glutamate residues, E316 and E446, are located at the top of the (α/β)₈ barrel structure in domain II. We utilized the three-dimensional structure of NAGLU to map several MPS III-B mutations, and hypothesize their functional consequences. Revealing atomic level structural information about this critical lysosomal enzyme paves the way for the design of novel therapeutics to target the underlying causes of MPS III-B.     

Pharmacological characterization of 3H-LSD binding sites in mouse brain in vivo.

In mice receiving i.v. low doses of ³H-LSD the accumulation of radioactivity in brain appears to reflect a selective binding to high affinity sites as indicated by the heterogenous regional distribution (paralleling that observed in in vitro binding studies) and by the saturable character of the process (ED₅₀ around 30μg.kg^?1 in cerebral cortex).The identity of the binding sites was assessed in various regions by administration of agonists or antagonists of different neurotransmitters. In cortex specific accumulation of ³H-LSD was easily prevented by administration of serotonin antagonists (cyproheptadine, methysergide, methiothepin) or by tryptamine derivatives (psilocin, psilocybin, dimethyltryptamine) and 5-hydroxytryptophan + pargyline. Among neuroleptics some prevented ³H-LSD binding (spiperone, haloperidol) whereas 1mg.kg^?1 pimozide was ineffective. In addition a large variety of agents (adrenergic, cholinergic, morphine) were ineffective. These data suggest a selective binding to cortical serotonin receptors.     

Genomic and RT-qPCR analysis of trimethoprim-sulfamethoxazole and meropenem resistance in Burkholderia pseudomallei clinical isolates

BackgroundMelioidosis is an endemic disease in southeast Asia and northern Australia caused by the saprophytic bacteria Burkholderia pseudomallei, with a high mortality rate. The clinical presentation is multifaceted, with symptoms ranging from acute septicemia to multiple chronic abscesses. Here, we report a chronic case of melioidosis in a patient who lived in Malaysia in the 70s and was suspected of contracting tuberculosis. Approximately 40 years later, in 2014, he was diagnosed with pauci-symptomatic melioidosis during a routine examination. Four strains were isolated from a single sample. They showed divergent morphotypes and divergent antibiotic susceptibility, with some strains showing resistance to trimethoprim-sulfamethoxazole and fluoroquinolones. In 2016, clinical samples were still positive for B. pseudomallei, and only one type of strain, showing atypical resistance to meropenem, was isolated.Principal findingsWe performed whole genome sequencing and RT-qPCR analysis on the strains isolated during this study to gain further insights into their differences. We thus identified two types of resistance mechanisms in these clinical strains. The first one was an adaptive and transient mechanism that disappeared during the course of laboratory sub-cultures; the second was a mutation in the efflux pump regulator amrR, associated with the overexpression of the related transporter.ConclusionThe development of such mechanisms may have a clinical impact on antibiotic treatment. Indeed, their transient nature could lead to an undiagnosed resistance. Efflux overexpression due to mutation leads to an important multiple resistance, reducing the effectiveness of antibiotics during treatment.     

Determining the Cellular Structure of Two Cereal Food Foams by X-ray Micro-Tomography

The cellular structure of two products, an extruded breakfast cereal and a short dough biscuit, was characterized by two different X-ray micro computed tomographic systems. Acquisitions were made by a compact desktop system Skyscan 1174 (Bruker μCT, Belgium) and at the European Synchrotron Radiation Facility (ESRF, beamline ID19, France) at different resolutions (voxel size of 6.5 μm, 7.5 μm, 16.2 μm and 25.8 μm). 3D images were processed for the density, the connectivity index and the granulometry of cells and cell walls. These experiments underlined the importance of the resolution for determination of quantitative measurements such as densities and thicknesses. The median width calculated for the cell walls distribution in the biscuit dropped from 141 to 50 μm when the voxel size changed from 25.8 to 7.5 μm. Images well showed that even though the food products had close values of porosity 0.6 and 0.7 for biscuit and extruded breakfast cereal respectively, their cellular structures were very different. The biscuit had small cells (median value of the distribution varied from 125 to 152 μm, according to resolution) and larger cell walls (50–141 μm) than the extrudate (32–109 μm) which, on the contrary, exhibited very large cells (307–400 μm). Beyond methodological issues, these differences could be clearly attributed to the differences of compositions and processes.     

Riverscape genetics in brook lamprey: genetic diversity is less influenced by river fragmentation than by gene flow with the anadromous ecotype

Understanding the effect of human-induced landscape fragmentation on gene flow and evolutionary potential of wild populations has become a major concern. Here, we investigated the effect of riverscape fragmentation on patterns of genetic diversity in the freshwater resident European brook lamprey (Lampetra planeri) that has a low ability to pass obstacles to migration. We tested the hypotheses of (i) asymmetric gene flow following water current and (ii) an effect of gene flow with the closely related anadromous river lamprey (L. fluviatilis) ecotype on L. planeri genetic diversity. We genotyped 2472 individuals, including 225 L. fluviatilis, sampled from 81 sites upstream and downstream barriers to migration, in 29 western European rivers. Linear modelling revealed a strong positive relationship between genetic diversity and the distance from the river source, consistent with expected patterns of decreased gene flow into upstream populations. However, the presence of anthropogenic barriers had a moderate effect on spatial genetic structure. Accordingly, we found evidence for downstream-directed gene flow, supporting the hypothesis that barriers do not limit dispersal mediated by water flow. Downstream L. planeri populations in sympatry with L. fluviatilis displayed consistently higher genetic diversity. We conclude that genetic drift and slight downstream gene flow drive the genetic make-up of upstream L. planeri populations whereas gene flow between ecotypes maintains higher levels of genetic diversity in L. planeri populations sympatric with L. fluviatilis. We discuss the implications of these results for the design of conservation strategies of lamprey, and other freshwater organisms with several ecotypes, in fragmented dendritic river networks.Subject terms: Conservation biology, Ecological genetics, Evolutionary genetics, Genetic variation