Identification and functional analysis of novel pathogenic variants in patients with undiagnosed myopathies

« Myopathie héréditaire » est un terme générique pour les maladies génétiques rares caractérisées par une faiblesse musculaire et une hypotonie avec ou sans atrophie musculaire. Les personnes atteintes d'une forme légère peuvent présenter des contractures, une scoliose, une hyporéflexie ou des caractéristiques dysmorphiques, et les plus sévères peuvent être accompagnées de symptômes cardiaques ou respiratoires pouvant s'avérer mortel. Alors que les méthodes de séquençage de nouvelle génération basées sur l'ADN ont considérablement accéléré la découverte de gènes responsables de maladies rares, de nombreux patients demeurent sans diagnostiques génétiques. L'une des principales raisons de ce problème est le grand nombre de variants de signification inconnue identifiés, où l’impact biologique est peu ou pas connu. Ce mémoire de maîtrise contient trois projets distincts dont l'objectif global est d'augmenter le rendement diagnostique pour les patients atteints de myopathies héréditaires rares. La première étude porte sur trois frères et soeurs atteints d'une dystrophie musculaire non diagnostiquée. Une combinaison de techniques « omic » a été utilisée pour identifier un variant faux-sens dans le gène IARS accompagné d’un déséquilibre allélique spécifique aux tissus musculaires. L’inhibition de iars-1 chez le C. elegans a entraîné une désorganisation progressive du muscle de la paroi corporelle, mais sans perte significative de la motilité. Ainsi, nous avons conclu que iars-1 joue clairement un rôle dans l'organisation des myotubes. La pathogénicité du variant, cependant, nécessite une enquête plus approfondie. La deuxième étude porte sur une femme présentant une myopathie statique congénitale se manifestant par une faiblesse proximale et distale. En utilisant le séquençage de l’ARN, nous avons identifié pour la première fois un profil d'expression génique compatible avec une prédominance des fibres musculaires de type I, focussant l’intérêt sur un variant dans le gène RYR1. La troisième étude englobe une cohorte de vingt-huit patients porteurs de la même mutation RYR1, mais présentant une hétérogénéité clinique significative. Des modèles « knock-in » de C. elegans pour les études deux et trois ont démontrés des changements en transmission synaptique, la durée de vie, la taille corporelle et la locomotion. Ainsi, nous avons conclu que les deux variants identifiés dans RYR1 ont probablement également des conséquences cliniques chez les porteurs humains. En fin de compte, ces études mettent en évidence l'utilité du séquençage de l’ARN en tant qu'outil de diagnostic complémentaire, capable de restreindre la liste de candidats potentiellement pathogéniques, ainsi que le pouvoir du C. elegans en tant que modèles pour des tests rapides et coordonnés de variants candidats.“Hereditary myopathies” is an umbrella term for rare inherited diseases characterized by muscle weakness and hypotonia with or without muscle atrophy. Individuals with a mild affliction may present with contractures, scoliosis, hyporeflexia or dysmorphic features, while those more severely affected may present cardiac or respiratory involvement that could prove deadly. While traditional DNA-based next-generation sequencing techniques have greatly accelerated discovery of genes causing rare diseases, many patients remain without a known genetic cause. The main reason for this diagnostic shortfall is the vast number of variants of unknown significance identified whose biological functions are unknown. This master’s thesis contains three separate projects with an overarching goal to increase the diagnostic yield of patients with rare hereditary myopathies. The first study focuses on three siblings with an undiagnosed muscular dystrophy. A combination of “omic” techniques were used to identify a missense variant as well as a muscle-specific allelic imbalance in the gene IARS leading to the exclusive expression of the mutant allele. Iars-1 knock-down in C. elegans resulted in progressive disorganization of the body wall muscle but with no significant loss of motility. Thus, we concluded that iars-1 likely plays a role in the organization of myotubes. The pathogenicity of the variant, however, requires further investigation. The second study involves a woman with a congenital static myopathy exhibited as proximal and distal weakness. Using RNA-sequencing, we identified for the first time a gene expression profile consistent with type I fiber predominance in the proband which guided the search for the causative RYR1 variant. The third study encompasses a cohort of twenty-eight patients who carry the same RYR1 mutation but display significant clinical heterogeneity. Knock-in models of C. elegans for both studies demonstrated altered synaptic transmission, lifespan, body size and locomotion. Thus, we concluded that both variants identified in RYR1 likely have consequences for human carriers as well. Ultimately, these studies highlight the utility of RNA-seq as a complimentary diagnostic tool capable of narrowing the search for novel pathogenic mutations as well as the value of C. elegans as models for rapid and coordinated testing of candidate variants

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 355)

This bibliography lists 147 reports, articles and other documents introduced into the NASA Scientific and Technical Information System during October, 1991. Subject coverage includes: aerospace medicine and psychology, life support systems and controlled environments, safety equipment, exobiology and extraterrestrial life, and flight crew behavior and performance

Aerospace medicine and biology: A continuing bibliography with indexes, supplement 184

This bibliography lists 139 reports, articles, and other documents introduced into the NASA scientific and technical information system in August 1978

Aerospace medicine and biology: A continuing bibliography with indexes

This bibliography lists 224 reports, articles and other documents introduced into the NASA scientific and technical information system in February 1984

Fault Diagnosis Of Sensor And Actuator Faults In Multi-Zone Hvac Systems

Globally, the buildings sector accounts for 30% of the energy consumption and more than 55% of the electricity demand. Specifically, the Heating, Ventilation, and Air Conditioning (HVAC) system is the most extensively operated component and it is responsible alone for 40% of the final building energy usage. HVAC systems are used to provide healthy and comfortable indoor conditions, and their main objective is to maintain the thermal comfort of occupants with minimum energy usage. HVAC systems include a considerable number of sensors, controlled actuators, and other components. They are at risk of malfunctioning or failure resulting in reduced efficiency, potential interference with the execution of supervision schemes, and equipment deterioration. Hence, Fault Diagnosis (FD) of HVAC systems is essential to improve their reliability, efficiency, and performance, and to provide preventive maintenance. In this thesis work, two neural network-based methods are proposed for sensor and actuator faults in a 3-zone HVAC system. For sensor faults, an online semi-supervised sensor data validation and fault diagnosis method using an Auto-Associative Neural Network (AANN) is developed. The method is based on the implementation of Nonlinear Principal Component Analysis (NPCA) using a Back-Propagation Neural Network (BPNN) and it demonstrates notable capability in sensor fault and inaccuracy correction, measurement noise reduction, missing sensor data replacement, and in both single and multiple sensor faults diagnosis. In addition, a novel on-line supervised multi-model approach for actuator fault diagnosis using Convolutional Neural Networks (CNNs) is developed for single actuator faults. It is based a data transformation in which the 1-dimensional data are configured into a 2-dimensional representation without the use of advanced signal processing techniques. The CNN-based actuator fault diagnosis approach demonstrates improved performance capability compared with the commonly used Machine Learning-based algorithms (i.e., Support Vector Machine and standard Neural Networks). The presented schemes are compared with other commonly used HVAC fault diagnosis methods for benchmarking and they are proven to be superior, effective, accurate, and reliable. The proposed approaches can be applied to large-scale buildings with additional zones

Papers on anthropology VI

Eelkäija: Tartu Ülikooli toimetised. Antropoloogia-alaseid töid, ISSN 0207-4575http://www.ester.ee/record=b1339521*es

Epidemiologic evidence for asthma and exposure to air toxics: linkages between occupational, indoor, and community air pollution research.

Outdoor ambient air pollutant exposures in communities are relevant to the acute exacerbation and possibly the onset of asthma. However, the complexity of pollutant mixtures and etiologic heterogeneity of asthma has made it difficult to identify causal components in those mixtures. Occupational exposures associated with asthma may yield clues to causal components in ambient air pollution because such exposures are often identifiable as single-chemical agents (e.g., metal compounds). However, translating occupational to community exposure-response relationships is limited. Of the air toxics found to cause occupational asthma, only formaldehyde has been frequently investigated in epidemiologic studies of allergic respiratory responses to indoor air, where general consistency can be shown despite lower ambient exposures. The specific volatile organic compounds (VOCs) identified in association with occupational asthma are generally not the same as those in studies showing respiratory effects of VOC mixtures on nonoccupational adult and pediatric asthma. In addition, experimental evidence indicates that airborne polycyclic aromatic hydrocarbon (PAH) exposures linked to diesel exhaust particles (DEPs) have proinflammatory effects on airways, but there is insufficient supporting evidence from the occupational literature of effects of DEPs on asthma or lung function. In contrast, nonoccupational epidemiologic studies have frequently shown associations between allergic responses or asthma with exposures to ambient air pollutant mixtures with PAH components, including black smoke, high home or school traffic density (particularly truck traffic), and environmental tobacco smoke. Other particle-phase and gaseous co-pollutants are likely causal in these associations as well. Epidemiologic research on the relationship of both asthma onset and exacerbation to air pollution is needed to disentangle effects of air toxics from monitored criteria air pollutants such as particle mass. Community studies should focus on air toxics expected to have adverse respiratory effects based on biological mechanisms, particularly irritant and immunological pathways to asthma onset and exacerbation

Effect of diesel exhaust particles on allergic reactions and airway responsiveness in ovalbumin-sensitized brown Norway rats

Diesel exhaust particles (DEP) are the major constituent of ambient particulate matter in urban environments and occupational settings. Exposure to DEP in combination with an allergen has been demonstrated to enhance allergen-related airway inflammation, immunoglobulin (Ig) E production, and airway responsiveness (AR) in human and in animal models. However, the mechanisms behind these effects of DEP are not yet fully understood. In this study, we compared the effects of short-term DEP exposure on ovalbumin (OVA)-mediated airway responses under two exposure protocols using an OVA-allergic rat model. Male Brown Norway rats were sensitized to aerosolized OVA (40.5 +/- 6.3 mg/m3) on days 1, 8, and 15, and challenged with OVA on day 29. The rats were exposed to DEP (20 mg/m3) for 4 h/day for 5 consecutive days either before sensitization (protocol A) or before OVA challenge on days 24-28 (protocol B). Control animals received filtered air and aerosolized saline instead of DEP and OVA, respectively. The results showed that DEP exposure (1) elicited an adjuvant effect on OVA-specific IgE and IgG production in serum under both protocols; (2) significantly reduced OVA-induced airway inflammation and lung injury in protocol A, but increased these markers in protocol B; (3) markedly lowered OVA-induced production of nitric oxide, reactive oxygen species, and interleukin (IL)-10 and IL-12 by alveolar macrophages (AM) in protocol A, but increased these parameters in protocol B; (4) significantly lowered the numbers of T cells and their CD4+ and CD8 + subsets in lung-draining lymph nodes in protocol A, but increased these cell counts in protocol B; (5) reduced intracellular glutathione in AM and lymphocytes in both protocols; and (6) enhanced AR of the OVA-sensitized rats to methacholine challenge in protocol B. These results suggest that the effects of DEP on the immune system, including aggravation or exacerbation of asthma, may be greatly influenced by allergic immune status and time of antigen exposure

C-9 and Other Microgravity Simulations

This document represents a summary of medical and scientific evaluations conducted aboard the C-9 and other NASA-sponsored aircraft from June 2008 to June 2009. Included is a general overview of investigations manifested and coordinated by the Human Adaptation and Counter-measures Division. A collection of brief reports that describe tests conducted aboard the NASA-sponsored aircraft follows the overview. Principal investigators and test engineers contributed significantly to the content of the report, describing their particular experiment or hardware evaluation. Although this document follows general guidelines, each report format may vary to accommodate differences in experiment design and procedures. This document concludes with an appendix that provides background information concerning the Reduced Gravity Program. Acknowledgment