Characterization of functional and structural integrity in experimental focal epilepsy: reduced network efficiency coincides with white matter changes

Background

Although focal epilepsies are increasingly recognized to affect multiple and remote neural systems, the underlying spatiotemporal pattern and the relationships between recurrent spontaneous seizures, global functional connectivity, and structural integrity remain largely unknown.

Methodology/Principal Findings

Here we utilized serial resting-state functional MRI, graph-theoretical analysis of complex brain networks and diffusion tensor imaging to characterize the evolution of global network topology, functional connectivity and structural changes in the interictal brain in relation to focal epilepsy in a rat model. Epileptic networks exhibited a more regular functional topology than controls, indicated by a significant increase in shortest path length and clustering coefficient. Interhemispheric functional connectivity in epileptic brains decreased, while intrahemispheric functional connectivity increased. Widespread reductions of fractional anisotropy were found in white matter regions not restricted to the vicinity of the epileptic focus, including the corpus callosum.

Conclusions/Significance

Our longitudinal study on the pathogenesis of network dynamics in epileptic brains reveals that, despite the locality of the epileptogenic area, epileptic brains differ in their global network topology, connectivity and structural integrity from healthy brains.     

Higher temperature reduces the effects of litter quality on decomposition by aquatic fungi

1. We investigated the effects of riparian plant diversity (species number and identity) and temperature on microbially mediated leaf decomposition by assessing fungal biodiversity, fungal reproduction and leaf mass loss. 2. Leaves of five riparian plant species were first immersed in a stream to allow microbial colonisation and were then exposed, alone or in all possible combinations, at 16 or 24 °C in laboratory microcosms. 3. Fungal biodiversity was reduced by temperature but was not affected by litter diversity. Temperature altered fungal community composition with species of warmer climate, such as Lunulospora curvula, becoming dominant. 4. Fungal reproduction was affected by litter diversity, but not by temperature. Fungal reproduction in leaf mixtures did not differ or was lower than that expected from the weighted sum of fungal sporulation on individual leaf species. At the higher temperature, the negative effect of litter diversity on fungal reproduction decreased with the number of leaf species. 5. Leaf mass loss was affected by the identity of leaf mixtures (i.e. litter quality), but not by leaf species number. This was mainly explained by the negative correlation between leaf decomposition and initial lignin concentration of leaves. 6. At 24 °C, the negative effects of lignin on microbially mediated leaf decomposition diminished, suggesting that higher temperatures may weaken the effects of litter quality on plant litter decomposition in streams. 7. The reduction in the negative effects of lignin at the higher temperature resulted in an increased microbially mediated litter decomposition, which may favour invertebrate‐mediated litter decomposition leading to a depletion of litter stocks in streams.     

Distinct States of Methionyl-tRNA Synthetase Indicate Inhibitor Binding by Conformational Selection

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Highlights? Complexes of MetRS from T. brucei with its substrate, intermediate, and inhibitors ? In crystals, substrate-bound MetRS undergoes extensive changes with inhibitor binding ? The inhibitor-bound conformation is surprisingly similar to the ligand-free state ? This indicates inhibitor binding occurs via conformational selection not by induced fit     

Psychosocial functioning, self-perception and body image and their auxologic correlates in growth hormone and oestrogen-treated young adult women with Turner syndrome

BACKGROUND: Few data are available on the psychosocial status of growth hormone (GH) and oestrogen treated women with Turner syndrome (TS). In this study, we evaluated psychosocial functioning, self-concept and body image in GH and oestrogen treated young adult women with TS and we studied the relationship with auxological parameters. PATIENTS AND METHODS: Thirty women with TS (mean +/- SD age: 22.1 +/- 2.4 years), all treated with GH and oestrogens if indicated, and an age-matched reference group of 44 non-Turner female students (age: 20.5 +/- 2.1 years) completed 3 questionnaires evaluating, respectively, behavioural and emotional problems (Young Adult Self Report), self-concept (Self Perception Profile for College Students) and body-image (Body Attitude Scale). RESULTS: TS patients did not report more behavioural and emotional problems compared to the non-TS females except for attention problems; they even reported fewer problems on some subscales (somatic complaints, thought problems, delinquent behaviour). TS patients did not differ from the non-TS female group in their bodily satisfaction. TS patients, particularly patients with a 45,X karyotype, perceived themselves as less socially competent. BMI was significantly related to the appraisal score of the Body Attitude Scale, whereas height was not related to any of the evaluated psychosocial parameters. CONCLUSION: The psychosocial adaptation of young adult women with TS, diagnosed at an early age and treated during childhood with GH and oestrogens if indicated, appears to be quite satisfactory. Follow-up of adult TS patients should not neglect the problem of overweight and associated psychosocial consequences.     

Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents

New dialkylimidazole based sterol 14α-demethylase inhibitors were prepared and tested as potential anti-Trypanosoma cruzi agents. Previous studies had identified compound 2 as the most potent and selective inhibitor against parasite cultures. In addition, animal studies had demonstrated that compound 2 is highly efficacious in the acute model of the disease. However, compound 2 has a high molecular weight and high hydrophobicity, issues addressed here. Systematic modifications were carried out at four positions on the scaffold and several inhibitors were identified which are highly potent (EC₅₀ <1 nM) against T. cruzi in culture. The halogenated derivatives 36j, 36k, and 36p, display excellent activity against T. cruzi amastigotes, with reduced molecular weight and lipophilicity, and exhibit suitable physicochemical properties for an oral drug candidate.     

Tissue distribution of a plasmid DNA encoding Hsp65 gene is dependent on the dose administered through intramuscular delivery

In order to assess a new strategy of DNA vaccine for a more complete understanding of its action in immune response, it is important to determine the in vivo biodistribution fate and antigen expression. In previous studies, our group focused on the prophylactic and therapeutic use of a plasmid DNA encoding the Mycobacterium leprae 65-kDa heat shock protein (Hsp65) and achieved an efficient immune response induction as well as protection against virulent M. tuberculosis challenge. In the present study, we examined in vivo tissue distribution of naked DNA-Hsp65 vaccine, the Hsp65 message, genome integration and methylation status of plasmid DNA. The DNA-Hsp65 was detectable in several tissue types, indicating that DNA-Hsp65 disseminates widely throughout the body. The biodistribution was dose-dependent. In contrast, RT-PCR detected the Hsp65 message for at least 15 days in muscle or liver tissue from immunized mice. We also analyzed the methylation status and integration of the injected plasmid DNA into the host cellular genome. The bacterial methylation pattern persisted for at least 6 months, indicating that the plasmid DNA-Hsp65 does not replicate in mammalian tissue, and Southern blot analysis showed that plasmid DNA was not integrated. These results have important implications for the use of DNA-Hsp65 vaccine in a clinical setting and open new perspectives for DNA vaccines and new considerations about the inoculation site and delivery system.     

Anion binding at the active site of trypanosomal triosephosphate isomerase. Monohydrogen phosphate does not mimic sulphate

The three-dimensional structure of triosephosphate isomerase complexed with the competitive inhibitor SO-4(2) was determined by X-ray crystallography to a resolution of 0.24 nm. A comparison with the native crystal structure, where SO-4(2) is bound, revealed five changes: (a) a 0.10-nm shift of the anion-binding site; (b) a further closing of the flexible loop of the enzyme; (c) a 'swinging in' of the side chain of the catalytic Glu, that is chi 1 changes from (+) to (-) synclinal; (d) an altered water structure; (e) a disappearance of the conformational heterogeneity at the C-terminus of strand beta 7. Some of these changes may be related to the different hydrogen-bond pattern about the two different anions. However, the distance of 0.10 nm between the sulphur and phosphorus positions is unexpected and remains intriguing.