A Major Role for Side-Chain Polyglutamine Hydrogen Bonding in Irreversible Ataxin-3 Aggregation

The protein ataxin-3 consists of an N-terminal globular Josephin domain (JD) and an unstructured C-terminal region containing a stretch of consecutive glutamines that triggers the neurodegenerative disorder spinocerebellar ataxia type 3, when it is expanded beyond a critical threshold. The disease results from misfolding and aggregation, although the pathway and structure of the aggregation intermediates are not fully understood. In order to provide insight into the mechanism of the process, we monitored the aggregation of a normal (AT3Q24) ataxin-3, an expanded (AT3Q55) ataxin-3, and the JD in isolation. We observed that all of them aggregated, although the latter did so at a much slower rate. Furthermore, the expanded AT3Q55 displayed a substantially different behavior with respect to the two other variants in that at the latest stages of the process it was the only one that did the following: i) lost its reactivity towards an anti-oligomer antibody, ii) generated SDS-insoluble aggregates, iii) gave rise to bundles of elongated fibrils, and iv) displayed two additional bands at 1604 and 1656 cm−1 in FTIR spectroscopy. Although these were previously observed in other aggregated polyglutamine proteins, no one has assigned them unambiguously, yet. By H/D exchange experiments we show for the first time that they can be ascribed to glutamine side-chain hydrogen bonding, which is therefore the hallmark of irreversibly SDS-insoluble aggregated protein. FTIR spectra also showed that main-chain intermolecular hydrogen bonding preceded that of glutamine side-chains, which suggests that the former favors the latter by reorganizing backbone geometry

A Major Role for Side-Chain Polyglutamine Hydrogen Bonding in Irreversible Ataxin-3 Aggregation

The protein ataxin-3 consists of an N-terminal globular Josephin domain (JD) and an unstructured C-terminal region containing a stretch of consecutive glutamines that triggers the neurodegenerative disorder spinocerebellar ataxia type 3, when it is expanded beyond a critical threshold. The disease results from misfolding and aggregation, although the pathway and structure of the aggregation intermediates are not fully understood. In order to provide insight into the mechanism of the process, we monitored the aggregation of a normal (AT3Q24) ataxin-3, an expanded (AT3Q55) ataxin-3, and the JD in isolation. We observed that all of them aggregated, although the latter did so at a much slower rate. Furthermore, the expanded AT3Q55 displayed a substantially different behavior with respect to the two other variants in that at the latest stages of the process it was the only one that did the following: i) lost its reactivity towards an anti-oligomer antibody, ii) generated SDS-insoluble aggregates, iii) gave rise to bundles of elongated fibrils, and iv) displayed two additional bands at 1604 and 1656 cm−1 in FTIR spectroscopy. Although these were previously observed in other aggregated polyglutamine proteins, no one has assigned them unambiguously, yet. By H/D exchange experiments we show for the first time that they can be ascribed to glutamine side-chain hydrogen bonding, which is therefore the hallmark of irreversibly SDS-insoluble aggregated protein. FTIR spectra also showed that main-chain intermolecular hydrogen bonding preceded that of glutamine side-chains, which suggests that the former favors the latter by reorganizing backbone geometry

Evaluation of production effectiveness in garment companies through key performance indicators

Abstract Key Performance Indicators help an organisation to improve productivity and to evaluate its success. Improved productivity is an essential part of increasing the value-added services that companies can offer to clients and hence their competitiveness. By using Key Performance Indicators, a company can establish baseline figures against a number of important areas. They can be considered like a health check on a company or a diagnosis of where a company can improve its performance. The definition of what they are and how they are measured does not change often, but Key Performance Indicators may change as the organisation's goals change. In this paper we present and discuss the way to establish Key Performance Indicators to evaluate the production effectiveness of garment companies. The KPIs are being tested in several garment companies in Albania and actually implemented in 25 companies. </jats:p

Rhetorical Analysis of the Film A Quiet Place

Title: Rhetorical Analysis of the Film A Quiet Place Author: Joshua Lanier Faculty Mentor: Dr. Monica Shehi Herr Field/Course of Study: Disability and Rhetoric Abstract: In the 2018 horror film, A Quiet Place, (produced by John Krasinski) the audience is introduced to Regan, a deaf girl whose family is fighting for survival after alien creatures with ultra-sensitive hearing come to earth to prey on the human race. Krasinski chose to cast Millicent Simmonds, a deaf actress, in the role of Regan. All of the actors were taught basic ASL (American Sign Language) by Simmonds on set, which Krasinski later commented in an interview with University Wire that his only regret was that he didn’t learn more ASL from Simmonds because “I think there’s no more beautiful language.” The question behind this research is what message does that send the Deaf community? Krasinski, just as the majority of the hearing public, may be unaware of the rhetoric associated with deafness, a disability of which they have a limited knowledge. Although Krasinski undoubtedly did his research before the production of the film, it is difficult to understand the messaging without having experienced at least some degree of deafness. Another viewpoint on this film came from Gabrielle Berry from her paper in the journal Music, Sound, and the Moving Image. Her concern is how “point of audition (POA)” is represented throughout the film, where the audience is immersed in Regan’s in-and-out auditory sensations from her (broken) cochlear device. The viewers are shifted to Regan’s POA as the creature emerges behind her, then quickly jolted into the creature’s hyper-sensitive POA, which startles the audience, producing a type of “jump scare” as the action unfolds. Berry is concerned about the film’s portrayal of a “fantastical conceit and ‘fantasy’ of deafness.” The intent of her paper is to illustrate the “harmonic resonation of the studies of sound, deafness, and disability.” In the film A Quiet Place, we are shown a family that is forced to live their lives in silence, as juxtaposed to the world of (almost) complete silence that Regan lives in daily. In this research paper on the rhetoric associated with the disability of deafness, the messaging to the Deaf community by the portrayal of a deaf character and use of ASL, as well as the messaging associated with the desirability or dependability of cochlear implants comes into question

The Linkage Between Autism Spectrum Disorder and Dup15q Syndrome: A Case Report

Patients diagnosed with autism spectrum disorder (ASD) frequently have a variable presentation and can suffer from underlying conditions, such as Chromosome 15 abnormalities(]) The broad diagnosis of ASD and its debilitating symptoms can overshadow underlying conditions and delay crucial interventions. This report describes a male child who was diagnosed with ASD at the early age of 19 months. Hallmark symptoms seen in this case included lack of social eye contact, lack of joint attention, hand-flapping, and missed motor milestones. Genetic methylation assay revealed a duplication on maternally derived chromosome 15, indicating concurrent 15q11-q13 duplication syndrome (Dup15q). Screening assessments for ASD are an important step in the initial management of developmental abnormalities. However, early genetic screening can lead to a more accurate diagnosis, personalized treatment, and better quality of life in patients with atypical symptoms caused by undiagnosed comorbid conditions