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Publications

2017

Landscape of X chromosome inactivation across human tissues

Authors
Tukiainen, T; Villani, A; Yen, A; Rivas, MA; Marshall, JL; Satija, R; Aguirre, M; Gauthier, L; Fleharty, M; Kirby, A; Cummings, BB; Castel, SE; Karczewski, KJ; Aguet, F; Byrnes, A; Aguet, F; Ardlie, KG; Cummings, BB; Gelfand, ET; Getz, G; Hadley, K; Handsaker, RE; Huang, KH; Kashin, S; Karczewski, KJ; Lek, M; Li, X; MacArthur, DG; Nedzel, JL; Nguyen, DT; Noble, MS; Segrè, AV; Trowbridge, CA; Tukiainen, T; Abell, NS; Balliu, B; Barshir, R; Basha, O; Battle, A; Bogu, GK; Brown, A; Brown, CD; Castel, SE; Chen, LS; Chiang, C; Conrad, DF; Cox, NJ; Damani, FN; Davis, JR; Delaneau, O; Dermitzakis, ET; Engelhardt, BE; Eskin, E; Ferreira, PG; Frésard, L; Gamazon, ER; Garrido-Martín, D; Gewirtz, ADH; Gliner, G; Gloudemans, MJ; Guigo, R; Hall, IM; Han, B; He, Y; Hormozdiari, F; Howald, C; Kyung Im, H; Jo, B; Yong Kang, E; Kim, Y; Kim-Hellmuth, S; Lappalainen, T; Li, G; Li, X; Liu, B; Mangul, S; McCarthy, MI; McDowell, IC; Mohammadi, P; Monlong, J; Montgomery, SB; Muñoz-Aguirre, M; Ndungu, AW; Nicolae, DL; Nobel, AB; Oliva, M; Ongen, H; Palowitch, JJ; Panousis, N; Papasaikas, P; Park, Y; Parsana, P; Payne, AJ; Peterson, CB; Quan, J; Reverter, F; Sabatti, C; Saha, A; Sammeth, M; Scott, AJ; Shabalin, AA; Sodaei, R; Stephens, M; Stranger, BE; Strober, BJ; Sul, JH; Tsang, EK; Urbut, S; van de Bunt, M; Wang, G; Wen, X; Wright, FA; Xi, HS; Yeger-Lotem, E; Zappala, Z; Zaugg, JB; Zhou, Y; Akey, JM; Bates, D; Chan, J; Chen, LS; Claussnitzer, M; Demanelis, K; Diegel, M; Doherty, JA; Feinberg, AP; Fernando, MS; Halow, J; Hansen, KD; Haugen, E; Hickey, PF; Hou, L; Jasmine, F; Jian, R; Jiang, L; Johnson, A; Kaul, R; Kellis, M; Kibriya, MG; Lee, K; Li, JB; Li, Q; Li, X; Lin, J; Lin, S; Linder, S; Linke, C; Liu, Y; Maurano, MT; Molinie, B; Montgomery, SB; Nelson, J; Neri, FJ; Oliva, M; Park, Y; Pierce, BL; Rinaldi, NJ; Rizzardi, LF; Sandstrom, R; Skol, A; Smith, KS; Snyder, MP; Stamatoyannopoulos, J; Stranger, BE; Tang, H; Tsang, EK; Wang, L; Wang, M; Van Wittenberghe, N; Wu, F; Zhang, R; Nierras, CR; Branton, PA; Carithers, LJ; Guan, P; Moore, HM; Rao, A; Vaught, JB; Gould, SE; Lockart, NC; Martin, C; Struewing, JP; Volpi, S; Addington, AM; Koester, SE; Little, AR; Brigham, LE; Hasz, R; Hunter, M; Johns, C; Johnson, M; Kopen, G; Leinweber, WF; Lonsdale, JT; McDonald, A; Mestichelli, B; Myer, K; Roe, B; Salvatore, M; Shad, S; Thomas, JA; Walters, G; Washington, M; Wheeler, J; Bridge, J; Foster, BA; Gillard, BM; Karasik, E; Kumar, R; Miklos, M; Moser, MT; Jewell, SD; Montroy, RG; Rohrer, DC; Valley, DR; Davis, DA; Mash, DC; Undale, AH; Smith, AM; Tabor, DE; Roche, NV; McLean, JA; Vatanian, N; Robinson, KL; Sobin, L; Barcus, ME; Valentino, KM; Qi, L; Hunter, S; Hariharan, P; Singh, S; Um, KS; Matose, T; Tomaszewski, MM; Barker, LK; Mosavel, M; Siminoff, LA; Traino, HM; Flicek, P; Juettemann, T; Ruffier, M; Sheppard, D; Taylor, K; Trevanion, SJ; Zerbino, DR; Craft, B; Goldman, M; Haeussler, M; Kent, WJ; Lee, CM; Paten, B; Rosenbloom, KR; Vivian, J; Zhu, J; Lappalainen, T; Regev, A; Ardlie, KG; Hacohen, N; MacArthur, DG;

Publication
Nature

Abstract
X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

2017

Classifying Heart Sounds Using Images of MFCC and Temporal Features

Authors
Nogueira, DM; Ferreira, CA; Jorge, AM;

Publication
PROGRESS IN ARTIFICIAL INTELLIGENCE (EPIA 2017)

Abstract
Phonocardiogram signals contain very useful information about the condition of the heart. It is a method of registration of heart sounds, which can be visually represented on a chart. By analyzing these signals, early detections and diagnosis of heart diseases can be done. Intelligent and automated analysis of the phonocardiogram is therefore very important, to determine whether the patient's heart works properly or should be referred to an expert for further evaluation. In this work, we use electrocardiograms and phonocardiograms collected simultaneously, from the Physionet challenge database, and we aim to determine whether a phonocardiogram corresponds to a "normal" or "abnormal" physiological state. The main idea is to translate a 1D phonocardiogram signal into a 2D image that represents temporal and Mel-frequency cepstral coefficients features. To do that, we develop a novel approach that uses both features. First we segment the phonocardiogram signals with an algorithm based on a logistic regression hidden semi-Markov model, which uses the electrocardiogram signals as reference. After that, we extract a group of features from the time and frequency domain (Mel-frequency cepstral coefficients) of the phonocardiogram. Then, we combine these features into a two-dimensional time-frequency heat map representation. Lastly, we run a binary classifier to learn a model that discriminates between normal and abnormal phonocardiogram signals. In the experiments, we study the contribution of temporal and Mel-frequency cepstral coefficients features and evaluate three classification algorithms: Support Vector Machines, Convolutional Neural Network, and Random Forest. The best results are achieved when we map both temporal and Mel-frequency cepstral coefficients features into a 2D image and use the Support Vector Machines with a radial basis function kernel. Indeed, by including both temporal and Mel-frequency cepstral coefficients features, we obtain sligthly better results than the ones reported by the challenge participants, which use large amounts of data and high computational power.

2017

Dynamic landscape and regulation of RNA editing in mammals

Authors
Tan, MH; Li, Q; Shanmugam, R; Piskol, R; Kohler, J; Young, AN; Liu, KI; Zhang, R; Ramaswami, G; Ariyoshi, K; Gupte, A; Keegan, LP; George, CX; Ramu, A; Huang, N; Pollina, EA; Leeman, DS; Rustighi, A; Goh, YPS; Aguet, F; Ardlie, KG; Cummings, BB; Gelfand, ET; Getz, G; Hadley, K; Handsaker, RE; Huang, KH; Kashin, S; Karczewski, KJ; Lek, M; Li, X; MacArthur, DG; Nedzel, JL; Nguyen, DT; Noble, MS; Segrè, AV; Trowbridge, CA; Tukiainen, T; Abell, NS; Balliu, B; Barshir, R; Basha, O; Battle, A; Bogu, GK; Brown, A; Brown, CD; Castel, SE; Chen, LS; Chiang, C; Conrad, DF; Cox, NJ; Damani, FN; Davis, JR; Delaneau, O; Dermitzakis, ET; Engelhardt, BE; Eskin, E; Ferreira, PG; Frésard, L; Gamazon, ER; Garrido-Martín, D; Gewirtz, ADH; Gliner, G; Gloudemans, MJ; Guigo, R; Hall, IM; Han, B; He, Y; Hormozdiari, F; Howald, C; Kyung Im, H; Jo, B; Yong Kang, E; Kim, Y; Kim-Hellmuth, S; Lappalainen, T; Li, G; Li, X; Liu, B; Mangul, S; McCarthy, MI; McDowell, IC; Mohammadi, P; Monlong, J; Montgomery, SB; Muñoz-Aguirre, M; Ndungu, AW; Nicolae, DL; Nobel, AB; Oliva, M; Ongen, H; Palowitch, JJ; Panousis, N; Papasaikas, P; Park, Y; Parsana, P; Payne, AJ; Peterson, CB; Quan, J; Reverter, F; Sabatti, C; Saha, A; Sammeth, M; Scott, AJ; Shabalin, AA; Sodaei, R; Stephens, M; Stranger, BE; Strober, BJ; Sul, JH; Tsang, EK; Urbut, S; van de Bunt, M; Wang, G; Wen, X; Wright, FA; Xi, HS; Yeger-Lotem, E; Zappala, Z; Zaugg, JB; Zhou, Y; Akey, JM; Bates, D; Chan, J; Chen, LS; Claussnitzer, M; Demanelis, K; Diegel, M; Doherty, JA; Feinberg, AP; Fernando, MS; Halow, J; Hansen, KD; Haugen, E; Hickey, PF; Hou, L; Jasmine, F; Jian, R; Jiang, L; Johnson, A; Kaul, R; Kellis, M; Kibriya, MG; Lee, K; Li, JB; Li, Q; Li, X; Lin, J; Lin, S; Linder, S; Linke, C; Liu, Y; Maurano, MT; Molinie, B; Montgomery, SB; Nelson, J; Neri, FJ; Oliva, M; Park, Y; Pierce, BL; Rinaldi, NJ; Rizzardi, LF; Sandstrom, R; Skol, A; Smith, KS; Snyder, MP; Stamatoyannopoulos, J; Stranger, BE; Tang, H; Tsang, EK; Wang, L; Wang, M; Van Wittenberghe, N; Wu, F; Zhang, R; Nierras, CR; Branton, PA; Carithers, LJ; Guan, P; Moore, HM; Rao, A; Vaught, JB; Gould, SE; Lockart, NC; Martin, C; Struewing, JP; Volpi, S; Addington, AM; Koester, SE; Little, AR; Brigham, LE; Hasz, R; Hunter, M; Johns, C; Johnson, M; Kopen, G; Leinweber, WF; Lonsdale, JT; McDonald, A; Mestichelli, B; Myer, K; Roe, B; Salvatore, M; Shad, S; Thomas, JA; Walters, G; Washington, M; Wheeler, J; Bridge, J; Foster, BA; Gillard, BM; Karasik, E; Kumar, R; Miklos, M; Moser, MT; Jewell, SD; Montroy, RG; Rohrer, DC; Valley, DR; Davis, DA; Mash, DC; Undale, AH; Smith, AM; Tabor, DE; Roche, NV; McLean, JA; Vatanian, N; Robinson, KL; Sobin, L; Barcus, ME; Valentino, KM; Qi, L; Hunter, S; Hariharan, P; Singh, S; Um, KS; Matose, T; Tomaszewski, MM; Barker, LK; Mosavel, M; Siminoff, LA; Traino, HM; Flicek, P; Juettemann, T; Ruffier, M; Sheppard, D; Taylor, K; Trevanion, SJ; Zerbino, DR; Craft, B; Goldman, M; Haeussler, M; Kent, WJ; Lee, CM; Paten, B; Rosenbloom, KR; Vivian, J; Zhu, J; Chawla, A; Del Sal, G; Peltz, G; Brunet, A; Conrad, DF; Samuel, CE; O’Connell, MA; Walkley, CR; Nishikura, K; Li, JB;

Publication
Nature

Abstract
Adenosine-to-inosine (A-to-I) RNA editing is a conserved posttranscriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules1. Although many editing sites have recently been discovered2-7, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood8-10. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of nonrepetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis-and trans-regulation of A-to-I editing.

2017

Strategic Challenges of the Portuguese Molds Industry

Authors
Moreira, A; Ferreira, MAMM;

Publication
Handbook of Research on Entrepreneurial Development and Innovation Within Smart Cities - Advances in Environmental Engineering and Green Technologies

Abstract
In a competitive environment shaped by continuous change, the understanding of the different forces that support or hinder the development of an industry, enables more informed, and assertive decision making. As such, following a sectoral system of innovation perspective that takes into account the temporal evolution of its most important events, the main objective of this chapter is to define a set of strategic lines for the sustainable development of the Portuguese molds industry. The study supports set of strategic priorities so that the Portuguese molds industry can embrace both an international favorable position and an entrepreneurial outward looking governance perspective. This chapter proposes that the future outlook will support the diversification to and the penetration of new sectoral markets, associated with a strong international product engineering and development cluster capable of supplying integrated solutions to several international markets.

2017

CERTIFIED ROOMS FOR ELEARNING STUDENTS EVALUATION

Authors
Borges, J; Vaz, C; Amaral, M; Justino, E; Barroso, J; Reis, A;

Publication
INTED2017: 11TH INTERNATIONAL TECHNOLOGY, EDUCATION AND DEVELOPMENT CONFERENCE

Abstract
The University of Tras-os-Montes e Alto Douro is part of a consortium that is providing courses in an e-learning model. In this courses, the students' evaluation requires their physical presence. Currently, the consortium has the general objective of provide evaluation activities in all of the consortium's institutions, independently of the student's Higher Education Institution (HEI) of origin. That way, the student can go through the learning process on-line, using the Learning Management System (LMS), and attend an evaluation activity at the HEI geographically more conveniently located. In pursuing this objective, the consortium is creating a set of specific rooms with the sole purpose of supporting the evaluation of e-learning students. These rooms are located in each one of the HEIs, and equipped with thin personal computers (PC), connected to a local, properly configured, server. These PCs and server will run a customized version of the operating system, in a Virtual Desktop Infrastructure (VDI) model, providing a controlled and safe infrastructure for the usage of the LMS to execute the evaluation activities. In a first phase, it is being created one room in each one of the consortium HEIs. A set of rules and a certification process will be designed, in order to have a standard level of service across all the rooms. Together with the certification process it will also be defined an audit process in order to regularly verify the compliance of the rooms with the previously designed certification standards.

2017

Correlates of adults' participation in sport and frequency of sport

Authors
Oliveira Brochado, A; Brito, PQ; Oliveira Brochado, F;

Publication
SCIENCE & SPORTS

Abstract
The aim of this research is to analyze the correlates of adults' participation in sport and frequency of sport. A hurdle model approach comprising a binary choice regression to model participation in sport and a count model to address frequency of sport was applied to analyze the data obtained from 516 personal interviews in a Portuguese city. Participation in sport and frequent sport are associated with men, younger people, not married and without children under 2 years, nonsmokers and regular drinkers and with good perceived health. However, participation in sport and frequency of sport participation are associated with different levels of perception of the benefits of sport activity. Whereas awareness of the health and enjoyment benefits fosters participation, fitness, socializing and appearance might increase the frequency of sport. Sport communication strategies might play a prominent role in persuading potential participants of the benefits of sport activity and frequency.

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