The purpose of this study was to determine what perceptual differences existed between a natural recorded human voice and a synthetic voice that was created to sound like the same voice. This process was meant to mimic the differences between a voice that would be used for Message Banking and a voice that would be created by the ModelTalker system. Forty speech pathology graduate students (mean age = 23 years) rated voices on clarity, naturalness, pleasantness, and overall similarity. Analysis of data showed that the natural human voice was consistently rated as more natural, clear, and pleasant. In addition, participants generally rated the two voices as very different. This demonstrates that, at least in terms of perception, using the method of Message Banking results in a voice that is overall perceived more positively than the voice created using ModelTalker.

Bibliography VÍTEK, Jiří. The effect of physiotherapy on respiratory muscle strength and functional ability in patients with amyotrophic lateral sclerosis. Prague: Charles University, 2nd Faculty of Medicine, Department of Rehabilitation and Sports Medicine, 2017. 132 p. Supervisor prim. MUDr. Ondřej Horáček, Ph.D. Abstract Objectives To determine the effects of intensive physiotherapeutic care in patients with Amyotrophic lateral sclerosis (ALS), with the focus on objective measurement of respiratory functions and functional status. Methods Patients with ALS (n = 21) were non-randomly assigned into two groups. First group (group R) received a 3-week in-patient rehabilitation programme in the Rehabilitation Hospital Beroun. Second group, control group (group K), received a home exercise programme. Patients from both groups underwent spirometry examination and evaluation of functional skills via the Amyotrophic lateral sclerosis functional rating scale revised questionnaire (ALSFRS-R) three weeks apart. Among the spirometry parameters, forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were selected for further evaluation. These parameters are significantly associated with respiratory muscle strength and survival in patients with ALS. Results There were no significant differences in...

No description available.

Bakgrund: Amytrofisk lateralskleros är en obotlig progressiv nervsjukdom som drabbar cirka 200 personer varje år. Sjukdomen innebär att den drabbade successivt förlorar kroppsfunktioner som gör det svårt för personen att klara sitt vardagliga liv, med opåverkade kognitiva förmågor. Än finns inget botemedel utan behandlingen fokuserar på symtomlindring, palliativbehandling och hjälp och stöd i hemmet. Sjuksköterskan ska arbeta utifrån hälso- och sjukvårdslagen med målet att stärka den drabbades livskvalitet och upprätthålla självbestämmanderätten. Syfte: Syftet var att beskriva personers erfarenheter av att leva med Amyotrofisk lateralskleros. Metod: Kvalitativ innehållsanalys med en induktiv ansats baserad på nio bloggar. Resultat: Ur analysen framträdde tre kategorier; Livet begränsas alltmer, oro för framtiden och omöjligt att vara självständig med sju underkategorier. Konklusion: Att få diagnosen påverkar personernas vardag på så sätt att livet begränsas alltmer.  De upplever att deras familjer har en stor betydelse för hur livet upplevs, ger en trygghet samt en vilja att fortsätta leva. Det finns en oro inför framtiden med blandade känslor av dödångest samt hopp och förtvivlan, men trots detta accepterar de sin sjukdom. Personerna får en vardag där det är omöjligt för dem att vara självständiga, med livsavgörande hjälpmedel samt ett beroende av assister. / Background:Amytrophic lateral sclerosis is an incurable progressive nerve disease that affects about 200 people each year. The disease means that the victim gradually loses body functions that make it difficult for the person to cope with his everyday life, with unaffected cognitive abilities. There is no cure but the treatment focuses on treating symptoms, palliative care and support.  The nurse should work on the basis of the health care law with the aim of strengthening the quality of life of the victim and maintaining selfdetermination. Aim: The aim was to describe people’s experiences of living with amyotrophic lateral sclerosis. Method:A qualitative content analysis with an inductive approach based on nine blogs. Results: From the analysis appeared three categories; Life is increasingly limited, worry about the future and impossible to be independent with seven subcategories. Conclusion: Getting the diagnosis affects everyday life so that life gets more limited. They find that their families are importeant for the way life is experiences, providing a sense of security and a willingness to continue life. There is a concern for the future with mixed feelings of death anxiety as well as hope and despair, despite this they accept their illness. People are given a dailey life where it is impossible for them to be independent, with life-giving tools and a dependence on assistants.

A P56S mutation in the VAPB MSP domain is linked to adult-onset amyotrophic lateral sclerosis 8. The objective of this study is to characterize the functional role of VAPB in transport of NE and NPC proteins from the ER to the NE. Over-expression of VAPB-P56S blocked the transport of nucleoporins (Nups) and NE proteins, resulting in their sequestration in dilated cytoplasmic membranes. Simultaneous overexpression of the FFAT motif (two phenylalanines in an acidic track) antagonizes mutant VAPB effects and restores transport to the NE. VAPB function is required for transport to the NE because knockdown of endogenous VAPB recapitulates this phenotype. Moreover, the compartment in which Nups and NE proteins are sequestered and retained was identified as ER-Golgi intermediate compartment (ERGIC). Moreover, a defect in the transport of NE and NPC proteins attenuates nucleocytoplasmic shuttling of the glucocorticoid receptor (GR). Further, VAPB-P56S which is only soluble in SDS was solubilized in the Triton-X-100 fraction similar to VAPB-WT upon co-transfection with the FFAT motif suggesting that FFAT interacts with the insoluble VAPB-P56S protein changing its biophysical properties.

Amyotrophic Lateral Sclerosis (ALS) is a fatal, late-onset, progressive neurodegenerative disease. A familial form of ALS, autosomal dominant ALS8, is characterized by a mutation in an ER membrane protein, VAPB. To characterize the role of VAPB in motor neurons, two C. elegans models were generated: one expressing human VAPB-P56S and another with the knockdown of C. elegans VAPB ortholog, VPR-1. Overexpression of human VAPB in DA neurons caused backward locomotion defects, enhanced vulnerability to oxidative stress and premature neuronal death. Knockdown of vpr-1 in C. elegans recapitulated the loss of protein function believed to be associated with human cases of ALS8. It caused backward locomotion defects, such as uncoordination and slowed rates of movement, as well as age-dependent motor neuronal death. In both models, DA6 and DA7 were the most vulnerable motor neurons. Because of the unexpected developmental defects associated with the VAPB transgenic model, the knockdown of vpr-1 may be a better model to recapitulate the human disease. This model provides further support that ALS8 pathogenesis is due to a loss of VAPB protein function and can also be used to test drugs or treatments that may delay the onset of neuronal death.

Microsatellites, or simple tandem repeat sequences, occur naturally in the human genome and have important roles in genome evolution and function. However, the expansion of microsatellites is associated with over two dozen neurological diseases. A common denominator among the majority of these disorders is the expression of expanded tandem repeat-containing RNA, referred to as xtrRNA, which can mediate molecular disease pathology in multiple ways. Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two fatal neurodegenerative diseases with significant clinical, neurological and genetic overlap thus referred to as C9FTD/ALS. Currently, gaps in the study of the underlying disease mechanisms persist, which can aid in the identification of promising therapeutic approaches. Access to simple models of neurological repeat expansion disease is critical for investigating biochemical mechanisms and for early therapeutic discovery. To better understand the molecular pathology of C9FTD/ALS repeat expansion disorder, we cloned GGGGCC repeats, which are the leading genetic cause of C9FTD/ALS. We employed a recursive directional ligation (RDL) technique to build multiple GGGGCC repeat-containing vectors and validated the cloning to facilitate step-by-step characterization of disease mechanisms at the cellular and molecular level using these vectors. In this study, we also differentiated C9FTD/ALS patient-derived induced pluripotent stem cells (iPSCs) to neural stem cells (NSCs) to be used as model systems. The use of iPSCs and NSCs to reveal important insights into the pathogenic mechanisms and to generate multiple neural cell types presents an excellent opportunity for researchers to model neurodegenerative diseases for cell therapy and drug discovery. We further investigated potential nuclear export mechanisms for C9FTD/ALS xtrRNA. The nuclear export mechanisms of xtrRNA in C9FTD/ALS are not well studied. ASOs and siRNAs were employed to knockdown genes of interest to study their involvement in the nuclear export of xtrRNA. We saw promising results on knockdown of TorsinA involved in nuclear export of xtrRNAs, corroborated by a substantial increase in the average number of xtrRNA foci in the nucleus. Our initial study provides evidence that TOR1A may be involved in the nuclear export of aberrant C9FTD/ALS repeat-containing RNAs. Due to the lack of reliable and robust assays to detect RAN translation products, the effect of the knockdown of TorsinA in these cell lines still remains to be explored. But the current study lays the groundwork for a deeper understanding of the less-studied nuclear export mechanisms in C9FTD/ALS and could reveal new therapeutic approaches to selectively block the nuclear export of xtrRNA through the use of RNAi and ASOs. The insights gained from this study will help us understand future events in the xtrRNA life cycle such as repeat translation mechanisms.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22357号 / 医博第4598号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 井上 治久, 教授 伊佐 正, 教授 渡邊 直樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease characterized by motor neuron loss. Although pathological mutations exist in >15 genes, the mechanism(s) underlying ALS are unknown. FUS is one such gene and encodes the nuclear RNA-binding protein (RBP), fused in sarcoma (FUS), which actively shuttles between the nucleus and cytoplasm. Intriguingly, nearly half of the ALS mutations identified in FUS cause this protein to mislocalize, suggesting that FUS localization is relevant to disease. Here, we found that excitotoxicity, a neuronal stress caused by aberrant glutamate signaling, induces the rapid redistribution of FUS and additional disease-linked RBPs from the nucleus to the cytoplasm. As excitotoxicity is pathologically associated with ALS, it was notable that the nuclear egress of FUS was particularly robust. Further, ALS-FUS variants that predominantly localize to the nucleus also undergo redistribution. Thus, we sought to understand the purpose underlying FUS translocation and the potential relevance of this response to disease. As calcium dysregulation is strongly associated with neurodegenerative disorders, we examined the contribution of calcium to FUS egress. In addition to global changes to nucleocytoplasmic transport following excitotoxic insult, we observed that FUS translocation caused by excitotoxicity is calcium mediated. Moreover, we found that dendritic expression of Gria2, a transcript encoding an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit responsible for regulating calcium permeability, is FUS-dependent under conditions of stress. Together, these observations support the premise that FUS has a normal function during excitotoxic stress and that glutamatergic signaling may be dysregulated in FUS-mediated ALS.