5 research outputs found
Escaping the Kmara Box: Reframing the Role of Civil Society in Georgia’s Rose Revolution
No full textThis article examines the role of civic groups in Georgia’s Rose Revolution using Larry Diamond’s framework of the democratic functions of civil society. The author argues that the contribution of civil society to the peaceful transfer of power in 2003 is best understood by expanding the analytical focus out from the Kmara youth movement to include a larger set of organisations. Rather than focusing on the Kmara youth movement as the primary civil society actor in 2003, the author contends that Kmara was, in fact, a product of the coordinated involvement of a cohort of NGOs. The article stresses the highly interconnected nature of Georgian civic leaders and organisations, particularly regarding networks with other NGOs, opposition politicians, and journalists from the Rustavi 2 television station
Sensory processing subtypes in autism: association with adaptive behavior
No full textChildren with autism are frequently observed to experience difficulties in sensory processing. This study examined specific patterns of sensory processing in 54 children with autistic disorder and their association with adaptive behavior. Model-based cluster analysis revealed three distinct sensory processing subtypes in autism. These subtypes were differentiated by taste and smell sensitivity and movement-related sensory behavior. Further, sensory processing subtypes predicted communication competence and maladaptive behavior. The findings of this study lay the foundation for the generation of more specific hypotheses regarding the mechanisms of sensory processing dysfunction in autism, and support the continued use of sensory-based interventions in the remediation of communication and behavioral difficulties in autism
The relationship between sensory processing patterns and behavioural responsiveness in autistic disorder: A pilot study.
No full textLack of evidence for genomic instability in autistic children as measured by the Cytokinesis-Block Micronucleus cytome assay
No full textAutism spectrum disorders are a set of neurodevelopmental disorders that are highly hereditable. Increased genomic instability has been observed in other heritable paediatric neurobiological disorders; therefore, the aim of our study was to test the hypothesis that DNA damage is increased in children with autism and that B vitamin status may explain variations in genome integrity between autistic and normal children. We compared 35 children with autism, 27 of their siblings without autism and 25 age- and gender-matched community controls for genomic stability using the cytokinesis-block micronucleus cytome (CBMN-cyt) assay, B vitamins and homocysteine, as well as autism-related behaviours. It was found that there were no differences in CBMN-cyt biomarkers between the three groups. Vitamin B2 was significantly raised in children with autism and their siblings compared with controls (P = 0.027 and P = 0.016 respectively) but there was no difference in other B vitamins or homocysteine. In conclusion, although replication using a larger cohort is needed, it appears unlikely that genomic instability is a feature of the aetiology of autism. We cannot rule out in utero effects or other types of DNA damage not measured by the CBMN-cyt assay
Innovative approaches to monitor mutant huntingtin and to facilitate its degradation in Huntington's disease models
No full textHuntington’s disease (HD) is a dominant genetic neurodegenerative disease caused by a mutation in the exon 1 of the huntingtin gene. The clinical symptoms, such as motor disturbances (chorea), cognitive decline and psychiatric impairments are usually developed by the patients in mid-life. Mutant huntingtin protein presents an amplification of a polyglutamine repeat at its N-terminus, which induces conformational changes and leads to neurotoxicity, impairment of cell homeostasis and neuronal cell death. The neuropathology of HD is characterized by a progressive degeneration of the brain starting from the striatum and spreading to other regions such as cortex, hypothalamus and cerebellum. In addition to the diffused brain atrophy, HD patients are also affected by multiple peripheral symptoms which contribute to worsening disease progression and eventually lead to death approximately two decades after onset.
The mechanisms leading to the toxicity induced by mutant huntingtin are not well understood. However the acquisition of a misfolded conformation and the formation of intracellular inclusions constituted by shorter fragments of the mutant protein are considered important in the neurodegenerative process.
In my thesis project I have investigated mechanisms to enhance the cellular degradation of mutant huntingtin. A second focus was on the development of an immunoassay to detect and quantify aggregates in HD models.
I analyzed the data obtained form a high through-put screen aimed to identify small molecular weight compounds decreasing mutant huntingtin levels in cells. Among all compounds screened, only inhibitors of heat shock protein 90 (Hsp90) showed a significant effect on mutant huntingtin clearance. I therefore investigated the mechanisms of Hsp90 chaperone inhibition and the reduction of soluble mutant huntigtin levels. Data from biochemical assays demonstrated that mutant huntingtin degradation is enhanced upon compound treatment and that the protein is cleared through the ubiquitin-proteasome system. This was independent from the heat shock response induced after pharmacological Hsp90 inhibition. Co-immunoprecipitation experiments suggested that mutant huntingtin is a client protein of Hsp90. The results were replicated in different cellular models including full length mutant huntingtin expressed from the endogenous locus, thus highlighting the importance of Hsp90 in stabilizing soluble mutant huntingtin and suggesting the possible application of Hsp90 inhibitors as therapies in HD.
In the second project I developed a sensitive method to detect mutant protein aggregates in HD models. To this purpose I implemented the already established time resolved fluorescence resonance energy transfer (TR-FRET) based immunoassay for the detection of soluble mutant and wild-type huntingtin. A mixture of either donor or acceptor fluorophore labeled single monoclonal antibody directed against an epitope exposed on the huntingtin aggregate surface was used. This strategy allowed for energy transfer and therefore a measurable TR-FRET signal, only in presence of mutant aggregated protein. I could demonstrate the sensitivity of the bioassay on a microtiter set up both as a single assay and in a duplex combination with the previously developed TR-FRET assay for soluble huntingtin.
I applied the TR-FRET for aggregated huntingtin to samples from R6/2 and HdhQ150 mice, expressing exon 1 and full length mutant huntingtin, respectively. In brain homogenates from both models there was an age-dependent, inverse correlation between soluble and aggregated mutant huntingtin. These findings supported the importance of the relation between aggregated and soluble protein in disease progression. Furthermore, I detected the inverse correlation also in peripheral tissues of R6/2 mice where the presence of aggregates was previously demonstrated with other methods. An in-depth analysis of R6/2 samples in a combination of TR-FRET and size exclusion chromatography suggested a differential specificity of the two antibody combinations used for different aggregate populations. The TR-FRET method provides a new means to characterize the aggregation process as well as to test the efficacy of possible disease modifying treatments for HD
