Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two apparently distinct neurodegenerative diseases, the former characterized by selective loss of motor neurons in the brain and spinal cord and the latter characterized by selective atrophy of frontal and temporal lobes. Over the years, however, growing evidence from clinical, pathological and genetic findings has suggested that ALS and FTD belong to the same clinic-pathological spectrum disorder. This concept has been further supported by the identification of the most common genetic cause for both diseases, an aberrantly expanded hexanucleotide repeat GGGGCC/ CCCCGG sequence located in a non-coding region of the gene C9orf72. Three hypotheses have been proposed to explain how this repeats expansion causes diseases: 1) C9orf72 haploinsufficiency-expanded repeats interfere with transcription or translation of the gene, leading to decreased expression of the C9orf72 protein; 2) RNA gain of function-RNA foci formed by sense and antisense transcripts of expanded repeats interact and sequester essential RNA binding proteins, causing neurotoxicity; 3) Repeat associated non-ATG initiated (RAN) translation of expanded sense GGGGCC and antisense CCCCGG repeats produces potential toxic dipeptide repeat protein (DPR). In this review, we assess current evidence supporting or arguing against each proposed mechanism in C9 ALS/FTD disease pathogenesis. Additionally, controversial findings are also discussed. Lastly, we discuss the possibility that the three pathogenic mechanisms are not mutually exclusive and all three might be involved in disease

You Catch More Flies With Honey: Reevaluating the Erroneous Premises of the Military Exception to Title VII

Discrimination is a problem in the military. Though Title VII of the Civil Rights Act prohibits employment discrimination in the “military departments,” courts have held that the statute does not apply to members of the military. The primary justification for this judge-made exception is that Title VII suits might have an adverse effect on military discipline. In their haste to condemn suits for military discrimination, however, courts tend to overlook the negative effects discrimination has on discipline, as well as the positive effects of diversity. This Note calls upon Congress to abrogate the military exception to Title VII; in the alternative, it argues that courts should reconsider the exception in light of discrimination’s true effects. In addition to its eroded policy foundations, the judicial exception to Title VII contradicts the ordinary language of the statute. The term “military departments” naturally includes servicepersons, who are employees, and there is no compelling reason to depart from the statute’s ordinary meaning. The exception is also contrary to the statute’s broad remedial purpose and much of the legislative history surrounding Title VII. The rationales the circuit courts use to conclude that members of the military cannot bring Title VII claims are inconsistent and contradictory, and the exception has resulted in confusion when applied to quasi-military personnel. As such, the military exception to Title VII should be abandoned—left in the past along with other vestiges of discrimination

Making the Abstract Straightforward: A Pilot of Immersive VR in an Allied Health Program of Study

[EN] Emerging technologies in education are offering new tools for teaching and learner engagement. Today’s study and practice can include use of digital technologies far beyond looking at a flat screen: virtual reality, augmented reality, interactive 3D objects and 360 video can provide immersive and impactful teaching and learning. There are a variety of definitions for these “realities” but the overarching impact is one of powerful, immersive, visual learning. Immersive virtual reality in a learner-centric environment can provide more presence and engagement for students, enabling the possibility of enhanced learning experiences relative to conventional classroom practices. This paper presents early results of a pilot study leveraging the possibilities of VR technology in service to an existing program of study in allied health services:graduates surveyed report high degrees of confidence in course materials learned by means of the custom VR components developed, reporting the adjunct course materials substantially helped learners in understanding otherwise difficult to grasp concepts of the course.This project was made possible in part by the Institute of Museum and Library Services through the Library Services and Technology Act.Colegrove, P.; Westergard, T. (2021). Making the Abstract Straightforward: A Pilot of Immersive VR in an Allied Health Program of Study. En 7th International Conference on Higher Education Advances (HEAd'21). Editorial Universitat Politècnica de València. 527-534. https://doi.org/10.4995/HEAd21.2021.13163OCS52753

Examining e-extension: diffusion, disruption, and rate of adoption among Iowa State University Extension and Outreach professionals

The purpose of this study was to assess the perceptions of eXtension held by Iowa Extension professionals and their rate of adoption of the online resource using Rogers\u27s (2003) diffusion of innovations theory and Christensen\u27s (1997) disruptive innovation theory. Specifically, the study looked at Iowa Extension professionals\u27 perceptions and stage of adoption of eXtension. The study also examined the relationship among Iowa Extension professionals\u27 background characteristics and their perceptions of the online resource in addition to whether respondents\u27 perceptions of eXtension predicted stage of adoption. A census survey was disseminated to 975 Iowa State University Extension and Outreach professionals. A final response rate of 44% (n=429) was obtained and included the respondents from the pilot study. The highest number of respondents reported that they were familiar with eXtension--persuasion stage and third stage of adoption (n=139, 32.63%). One quarter of the respondents remained at the no knowledge stage of eXtension (n=109, 25.59%), 16% of respondents were at the knowledge stage (n=68), less than 1% were at the decision stage (n=3), 15% were at the implementation stage (n=65), and 10% were at the highest stage of confirmation (n=42). 75% of Iowa Extension professionals indicated have made a decision to use or not use eXtension in their work. Respondents were shown to have more favorable perceptions of eXtension\u27s perceived relative advantage, accessibility and capacity attributes, while the compatibility, complexity, observability, trialability, affordability, responsiveness, and customization attributes were neutrally perceived. In addition, eXtension was perceived to exhibit only two of the disruptive innovation attributes (accessibility and capacity). The technology was perceived to lack the degree of affordability, responsiveness and customization needed to become a disruptive innovation. As respondents\u27 age, educational attainment and years of employment in Cooperative Extension increased, their perceived trialability of eXtension was also shown to increase. In addition, the perceived attributes of eXtension explained 26% of the variance in membership at one of two levels of adoption--the higher level of adoption or lower level of awareness. The complexity, trialability and customization attributes were shown to have a statistically significant influence on predicting the odds of attaining the higher level of adoption of eXtension

A nine amino acid domain Is essential for mutant prion protein toxicity

Transgenic mice expressing PrP molecules with several different internal deletions display spontaneous neurodegenerative phenotypes that can be dose-dependently suppressed by co-expression of wild-type PrP. Each of these deletions, including the largest one (Δ32–134), retains nine amino acids immediately following the signal peptide cleavage site (residues 23–31; KKRPKPGGW). These residues have been implicated in several biological functions of PrP, including endocytic trafficking and binding of glycosaminoglycans. We report here on our experiments to test the role of this domain in the toxicity of deleted forms of PrP. We find that transgenic mice expressing Δ23–134 PrP display no clinical symptoms or neuropathology, in contrast to mice expressing Δ32–134 PrP, suggesting that residues 23–31 are essential for the toxic phenotype. Using a newly developed cell culture assay, we narrow the essential region to amino acids 23–26, and we show that mutant PrP toxicity is not related to the role of the N-terminal residues in endocytosis or binding to endogenous glycosaminoglycans. However, we find that mutant PrP toxicity is potently inhibited by application of exogenous glycosaminoglycans, suggesting that the latter molecules block an essential interaction between the N-terminus of PrP and a membrane-associated target site. Our results demonstrate that a short segment containing positively charged amino acids at the N-terminus of PrP plays an essential role in mediating PrP-related neurotoxicity. This finding identifies a protein domain that may serve as a drug target for amelioration of prion neurotoxicity