Fruit flies and intellectual disability

Mental retardation-known more commonly nowadays as intellectual disability-is a severe neurological condition affecting up to 3% of the general population. As a result of the analysis of familial cases and recent advances in clinical genetic testing, great strides have been made in our understanding of the genetic etiologies of mental retardation. Nonetheless, no treatment is currently clinically available to patients suffering from intellectual disability. Several animal models have been used in the study of memory and cognition. Established paradigms in Drosophila have recently captured cognitive defects in fly mutants for orthologs of genes involved in human intellectual disability. We review here three protocols designed to understand the molecular genetic basis of learning and memory in Drosophila and the genes identified so far with relation to mental retardation. In addition, we explore the mental retardation genes for which evidence of neuronal dysfunction other than memory has been established in Drosophila. Finally, we summarize the findings in Drosophila for mental retardation genes for which no neuronal information is yet available. All in all, this review illustrates the impressive overlap between genes identified in human mental retardation and genes involved in physiological learning and memory

Clinton F. Thurlow Correspondence

Entries include a print brochure for a motion picture lecture series These United States with a biography of Stiles and photographic images of his Yankee subjects on the U.S. northern coastline, a typed letter that presumably maintains several pseudonyms, returned as from the wife of his editor, on The Sugar Ball Press stationery, typed letters from Stiles on personal stationery with plans to visit the Maine State Library and presenting the second edition of his book, and a typed letter in receipt of the book from the Maine State Library

Exon-Skipping Oligonucleotides Restore Functional Collagen VI by Correcting a Common COL6A1 Mutation in Ullrich CMD

Collagen VI-related congenital muscular dystrophies (COL6-CMDs) are the second most common form of congenital muscular dystrophy. Currently, there is no effective treatment available. COL6-CMDs are caused by recessive or dominant mutations in one of the three genes encoding for the α chains of collagen type VI (COL6A1, COL6A2, and COL6A3). One of the most common mutations in COL6-CMD patients is a de novo deep intronic c.930+189C > T mutation in COL6A1 gene. This mutation creates a cryptic donor splice site and induces incorporation of a novel in-frame pseudo-exon in the mature transcripts. In this study, we systematically evaluated the splice switching approach using antisense oligonucleotides (ASOs) to correct this mutation. Fifteen ASOs were designed using the RNA-tiling approach to target the misspliced pseudo-exon and its flanking sequences. The efficiency of ASOs was evaluated at RNA, protein, and structural levels in skin fibroblasts established from four patients carrying the c.930+189C > T mutation. We identified two additional lead ASO candidates that efficiently induce pseudo-exon exclusion from the mature transcripts, thus allowing for the restoration of a functional collagen VI microfibrillar matrix. Our findings provide further evidence for ASO exon skipping as a therapeutic approach for COL6-CMD patients carrying this common intronic mutation

Reproducibility, bioinformatic analysis and power of the SAGE method to evaluate changes in transcriptome

The serial analysis of gene expression (SAGE) method is used to study global gene expression in cells or tissues in various experimental conditions. However, its reproducibility has not yet been definitively assessed. In this study, we have evaluated the reproducibility of the SAGE method and identified the factors that affect it. The determination coefficient (R(2)) for the reproducibility of SAGE is 0.96. However, there are some factors that can affect the reproducibility of SAGE, such as the replication of concatemers and ditags, the number of sequenced tags and double PCR amplification of ditags. Thus, corrections for these factors must be made to ensure the reproducibility and accuracy of SAGE results. A bioinformatic analysis of SAGE data is also presented in order to eliminate these artifacts. Finally, the current study shows that increasing the number of sequenced tags improves the power of the method to detect transcripts and their regulation by experimental conditions

Fear of reprisal and change agency in the public health and social service system: Protocol for a sequential mixed methods study

Abract Background:   Since they are key witnesses to the systemic difficulties and social inequities experienced by vulnerable patients, health and social service (HSS) professionals and clinical managers must act as change agents. Using their expertise to achieve greater social justice, change agents employ a wide range of actions that span a continuum from the clinical (microsystem) to the societal (macrosystem) sphere and involve actors inside and outside the HSS system. Typically, however, clinical professionals and managers act in a circumscribed manner, that is, within the clinical sphere and with patients and colleagues. Among the hypotheses explaining this reduced scope of action is the fear of reprisal. Little is known about the prevalence of this fear and its complex dynamics. Objective:   The overall aim is to gain a better understanding of the complex dynamic process leading to clinical professionals’ and managers’ fear of reprisal in their change agent actions and senior administrators’ and managers’ determination of wrongdoing. The objectives are (1) to estimate the prevalence of fear of reprisal among clinical professionals and managers; (2) to identify the factors involved in (a) the emergence of this fear among clinical professionals and managers, and (b) the determination of wrongdoing by senior administrators and managers; (3) to describe the process of emergence of (a) the fear of reprisal among clinical professionals and managers, and (b) the determination of wrongdoing by senior administrators and managers; and (4) to document the legal and ethical issues associated with the factors identified (objective 2) and the processes described (objective 3). Methods:   Based on the Exit, Voice, Loyalty, Neglect model, a 3-part sequential mixed methods design will include (1) a web-based survey (objective 1), (2) a qualitative grounded theory design (objectives 2 and 3), and (3) legal and ethical analysis (objective 4). Survey: 77,794 clinical professionals or clinical managers working in the Québec public HSS system will be contacted via email. Data will be analyzed using descriptive statistics. Grounded theory design: for each of the 3 types of participants (clinical professionals, clinical managers, and senior administrators and managers), a theoretical sample of 15 to 30 people will be selected via various strategies. Data will be independently analyzed using constant comparison process. Legal and ethical analysis: situations described by participants will be analyzed using, respectively, applicable legislation and jurisprudence and 2 ethical models. Results:   This ongoing study began in June 2022 and is scheduled for completion by March 2027. Conclusions:   Instead of acting, fear of reprisal could induce clinical professionals to tolerate situations that run counter to their social justice values. To ensure they use their capacities for serving a population that is or could become vulnerable, it is important to know the prevalence of the fear of reprisal and gain a better understanding of its complex dynamics. International Registered Report Identifier (IRRID): PRR1-10.2196/4840

Towards an IT-based Planning Process Alignment: Integrated Route and Location Planning for Small Package Shippers

To increase the efficiency of delivery operations in small package shipping (SPS), numerous optimization models for routeand location planning decisions have been proposed. This operations research view of defining independent problems hastwo major shortcomings: First, most models from literature neglect crucial real-world characteristics, thus making themuseless for small package shippers. Second, business processes for strategic decision making are not well-structured in mostSPS companies and significant cost savings could be generated by an IT-based support infrastructure integrating decisionmaking and planning across the mutually dependent layers of strategic, tactical and operational planning. We present anintegrated planning framework that combines an intelligent data analysis tool, which identifies delivery patterns and changesin customer demand, with location and route planning tools. Our planning approaches extend standard Location Routing andVehicle Routing models by crucial, practically relevant characteristics like the existence of subcontractors on both decisionlevels and the implicit consideration of driver familiarity in route planning