Primary Coenzyme Q10 Deficiency

open4siCLINICAL CHARACTERISTICS: Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen. DIAGNOSIS/TESTING: The diagnosis of primary CoQ10 deficiency in a proband is established by identification of biallelic pathogenic variants in one of the nine genes encoding proteins directly involved in the synthesis of coenzyme Q10 or by detection of reduced levels of CoQ10 (ubiquinone) in skeletal muscle or reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates. MANAGEMENT: Treatment of manifestations: In individuals with primary CoQ10 deficiency early treatment with high-dose oral CoQ10 supplementation (ranging from 5 to 50 mg/kg/day) can limit disease progression and reverse some manifestations; however, established severe neurologic and/or renal damage cannot be reversed. ACE inhibitors may be used in combination with CoQ10 supplementation in persons with proteinuria; renal transplantation is an option for those with ESRD. Treatment of hypertrophic cardiomyopathy, retinopathy, and sensorineural hearing loss is per usual practice. Prevention of primary manifestations: Supplementation with high-dose oral CoQ10 can prevent progression of the renal disease and onset of neurologic manifestations. Surveillance: Periodic neurologic evaluation, urine analysis (for proteinuria) and renal function tests, ophthalmologic evaluation, and audiometry. Evaluation of relatives at risk: Presymptomatic diagnosis for the purpose of early treatment with CoQ10 supplementation is warranted for relatives at risk. GENETIC COUNSELING: Primary coenzyme Q10 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if the pathogenic variants in a family are known.openSalviati, L; Trevisson, E; Doimo, M; Navas, PSalviati, Leonardo; Trevisson, Eva; Doimo, Mara; Navas, P

Caso práctico integración de la responsabilidad social en la estrategia empresarial

El caso práctico explica cómo se ha integrado, de forma transversal, la Responsabilidad social en la Estrategia de una empresa de economía social, con más de 800 trabajadores. En este contexto, TUSGSAL entiende la RSC como una forma de operar todas las actividades de la organización, y para conseguirlo se plantea implementar la RSC de manera transversal en toda la organización, poniendo el foco en dos aspectos clave: ¿ Desarrollar el Plan de RSC partiendo de la convicción de que el fortalecimiento de la confianza con los grupos de interés, como ventaja competitiva, refuerza la razón de ser de la empresa, le otorga legitimidad para actuar y garantiza su desarrollo futuro. ¿ Integrar el Plan de RSC el sistema integrado de gestión, con el propósito de conseguir que la RSC forme parte de la cultura y de las estrategias que contribuyen a realizar el objeto social de la empresa y, al mismo tiempo esté presente en la gestión cotidiana de TUSGSAL. Además, su integración, se apoya en recursos, procesos y estructuras existentes. El Plan de RSC se enmarca y emana del Plan estratégico 2016-2020 de TUSGSAL y es el resultado del trabajo realizado por un grupo de 25 miembros de la empresa, que participó en talleres diseñados con la finalidad de elaborar dicho Plan. Su puesta en marcha del Plan se centra, finalmente en reflejar, en su ejecución, los Objetivos de Desarrollo Sostenible (ODS).Postprint (author's final draft

Population structure and genetic diversity of the threatened pygmy newt Triturus pygmaeus in a network of natural and artificial ponds

Pond physical characteristics (connectivity, hydroperiod) have shown to be highly relevant in explaining species presence, reproductive success, and survival in breeding-pond amphibians. However, few studies have addressed the influence that these factors may have on the genetic variability of pond populations. We examined genetic variation at 11 microsatellite loci in Iberian endemic, the pygmy newt (Triturus pygmaeus), from 58 breeding ponds in the Doñana National Park (Andalusia), including both temporary ponds and artificially deepened ponds that remain wet during the whole year. Temporary ponds are located in the North part of the region where the surrounding habitat-wet meadows-facilitates the connectivity among populations, whereas the deepest ponds (‘zacallones’) are located in the southern edge embedded in a matrix of unsuitable habitat (thickets and dry underbrush). We investigated genetic diversity and structure within and among ponds. Our results show that both regions (Doñana-North and Doñana-South) are well-differentiated and form two main clusters. We found higher genetic diversity within ponds from the North region, which also exhibited a higher degree of genetic admixture in comparison with populations from the southern edge. Although we found an isolation-by-distance pattern within each cluster, it arose due to the effect of a few isolated ponds located on the edge of each zone, suggesting the existence of substantial gene flow between ponds in the core area. According to our findings, landscape’s permeability to movement (pond connectivity) may constitute a more important factor than hydroperiod length in determining the genetic diversity and viability of pygmy newt populations in this area. Although Doñana populations show a good state, more peripheral and isolated populations present a more worrisome condition as a result of fragmentation and thus, require conservation efforts. Our study provides key insights that could help guide management practices of this threatened and poorly-studied salamander

Evaluation of Tacotron Based Synthesizers for Spanish and Basque

In this paper, we describe the implementation and evaluation of Text to Speech synthesizers based on neural networks for Spanish and Basque. Several voices were built, all of them using a limited number of data. The system applies Tacotron 2 to compute mel-spectrograms from the input sequence, followed by WaveGlow as neural vocoder to obtain the audio signals from the spectrograms. The limited number of data used for training the models leads to synthesis errors in some sentences. To automatically detect those errors, we developed a new method that is able to find the sentences that have lost the alignment during the inference process. To mitigate the problem, we implemented a guided attention providing the system with the explicit duration of the phonemes. The resulting system was evaluated to assess its robustness, quality and naturalness both with objective and subjective measures. The results reveal the capacity of the system to produce good quality and natural audios.This work was funded by the Basque Government (Project refs. PIBA 2018-035, IT-1355-19). This work is part of the project Grant PID 2019-108040RB-C21 funded by MCIN/AEI/10.13039/ 501100011033

An on-line VAD based on Multi-Normalisation Scoring (MNS) of observation likelihoods

Preprint del artículo públicado online el 31 de mayo 2018Voice activity detection (VAD) is an essential task in expert systems that rely on oral interfaces. The VAD module detects the presence of human speech and separates speech segments from silences and non-speech noises. The most popular current on-line VAD systems are based on adaptive parameters which seek to cope with varying channel and noise conditions. The main disadvantages of this approach are the need for some initialisation time to properly adjust the parameters to the incoming signal and uncertain performance in the case of poor estimation of the initial parameters. In this paper we propose a novel on-line VAD based only on previous training which does not introduce any delay. The technique is based on a strategy that we have called Multi-Normalisation Scoring (MNS). It consists of obtaining a vector of multiple observation likelihood scores from normalised mel-cepstral coefficients previously computed from different databases. A classifier is then used to label the incoming observation likelihood vector. Encouraging results have been obtained with a Multi-Layer Perceptron (MLP). This technique can generalise for unseen noise levels and types. A validation experiment with two current standard ITU-T VAD algorithms demonstrates the good performance of the method. Indeed, lower classification error rates are obtained for non-speech frames, while results for speech frames are similar.This work was partially supported by the EU (ERDF) under grant TEC2015-67163-C2-1-R (RESTORE) (MINECO/ERDF, EU) and by the Basque Government under grant KK-2017/00043 (BerbaOla)

Modelo de duración para conversión de texto a voz en euskera

En este artículo se presenta el trabajo realizado en el modelado de la duración de los fonemas en euskera estándar, para ser utilizado en conversión de texto a voz. El modelado estadístico se ha llevado a cabo mediante árboles binarios de regresión utilizando un corpus de 57.300 fonemas. Se han realizado varios experimentos de predicción testeando diferentes factores de influencia. El resultado obtenido en la predicción de la duración tiene un RMSE de 22.23 ms.This paper presents the modelling of phone durations in standard Basque, to be included in a text-to-speech system. The statistical modelling has been done using binary regression trees and a large corpus containing 57.300 phones. Several experiments have been performed, testing different sets of predicting factors. The result when predicting durations with this model has a RMSE of 22.23 ms.Este trabajo ha sido parcialmente financiado por el Ministerio de Ciencia y Tecnología (TIC2000-1005-C03-03 y TIC2000-1669-C04-03)

Enrichment of Oesophageal Speech: Voice Conversion with Duration-Matched Synthetic Speech as Target

Pathological speech such as Oesophageal Speech (OS) is difficult to understand due to the presence of undesired artefacts and lack of normal healthy speech characteristics. Modern speech technologies and machine learning enable us to transform pathological speech to improve intelligibility and quality. We have used a neural network based voice conversion method with the aim of improving the intelligibility and reducing the listening effort (LE) of four OS speakers of varying speaking proficiency. The novelty of this method is the use of synthetic speech matched in duration with the source OS as the target, instead of parallel aligned healthy speech. We evaluated the converted samples from this system using a collection of Automatic Speech Recognition systems (ASR), an objective intelligibility metric (STOI) and a subjective test. ASR evaluation shows that the proposed system had significantly better word recognition accuracy compared to unprocessed OS, and baseline systems which used aligned healthy speech as the target. There was an improvement of at least 15% on STOI scores indicating a higher intelligibility for the proposed system compared to unprocessed OS, and a higher target similarity in the proposed system compared to baseline systems. The subjective test reveals a significant preference for the proposed system compared to unprocessed OS for all OS speakers, except one who was the least proficient OS speaker in the data set.This project was supported by funding from the European Union’s H2020 research and innovation programme under the MSCA GA 675324 (the ENRICH network: www.enrich-etn.eu (accessed on 25 June 2021)), and the Basque Government (PIBA_2018_1_0035 and IT355-19)

TTS evaluation campaign with a common spanish database

This paper describes the first TTS evaluation campaign designed for Spanish. Seven research institutions took part in the evaluation campaign and developed a voice from a common speech database provided by the organisation. Each participating team had a period of seven weeks to generate a voice. Next, a set of sentences were released and each team had to synthesise them within a week period. Finally, some of the synthesised test audio files were subjectively evaluated via an online test according to the following criteria: similarity to the original voice, naturalness and intelligibility. Box-plots, Wilcoxon tests and WER have been generated in order to analyse the results. Two main conclusions can be drawn: On the one hand, there is considerable margin for improvement to reach the quality level of the natural voice. On the other hand, two systems get significantly better results than the rest: one is based on statistical parametric synthesis and the other one is a concatenative system that makes use of a sinusoidal model to modify both prosody and smooth spectral joints. Therefore, it seems that some kind of spectral control is needed when building voices with a medium size database for unrestricted domains.Postprint (published version

Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency

Under a Creative Commons license.-- et al.Human COQ6 encodes a monooxygenase which is responsible for the C5-hydroxylation of the quinone ring of coenzyme Q (CoQ). Mutations in COQ6 cause primary CoQ deficiency, a condition responsive to oral CoQ10 supplementation. Treatment is however still problematic given the poor bioavailability of CoQ10. We employed S. cerevisiae lacking the orthologous gene to characterize the two different human COQ6 isoforms and the mutations found in patients. COQ6 isoform a can partially complement the defective yeast, while isoform b, which lacks part of the FAD-binding domain, is inactive but partially stable, and could have a regulatory/inhibitory function in CoQ10 biosynthesis. Most mutations identified in patients, including the frameshift Q461fs478X mutation, retain residual enzymatic activity, and all patients carry at least one hypomorphic allele, confirming that the complete block of CoQ biosynthesis is lethal. These mutants are also partially stable and allow the assembly of the CoQ biosynthetic complex. In fact treatment with two hydroxylated analogues of 4-hydroxybenzoic acid, namely, vanillic acid or 3-4-hydroxybenzoic acid, restored the respiratory growth of yeast δcoq6 cells expressing the mutant huCOQ6-isoa proteins. These compounds, and particularly vanillic acid, could therefore represent an interesting therapeutic option for COQ6 patients.This work has been supported by grants from Telethon Italy, Fondazione CARIPARO, and University of Padova (CPDA123573/12) (to L.S.), the Italian Ministry of Health (GR-2009-1578914) (to E.T.), Région Rhônes-Alpes CIBLE 2009 (to F.P.), Spanish FIS grant PI11-00078 (to P.N.) and Proyecto Excelencia P08-CTS-03988 (to P.N.).Open Access funded by Telethon (Italy).Peer Reviewe

Intelligibility and Listening Effort of Spanish Oesophageal Speech

Communication is a huge challenge for oesophageal speakers, be it for interactions with fellow humans or with digital voice assistants. We aim to quantify these communication challenges (both human-human and human-machine interactions) by measuring intelligibility and Listening Effort (LE) of Oesophageal Speech (OS) in comparison to Healthy Laryngeal Speech (HS). We conducted two listening tests (one web-based, the other in laboratory settings) to collect these measurements. Participants performed a sentence recognition and LE rating task in each test. Intelligibility, calculated as Word Error Rate, showed significant correlation with self-reported LE ratings. Speaker type (healthy or oesophageal) had a major effect on intelligibility and effort. More LE was reported for OS compared to HS even when OS intelligibility was close to HS. Listeners familiar with OS reported less effort when listening to OS compared to nonfamiliar listeners. However, such advantage of familiarity was not observed for intelligibility. Automatic speech recognition scores were higher for OS compared to HS.This project was supported by funding from the EUs H2020 research and innovation programme under the MSCA GA 67532*4 (the ENRICH network: www.enrich-etn.eu), the Spanish Ministry of Economy and Competitiveness with FEDER support (RESTORE project, TEC2015-67163-C2-1-R) and the Basque Government (DL4NLP KK-2019/00045, PIBA_2018_1_0035 and IT355-19)