Dynamical System Parameter Identification using Deep Recurrent Cell Networks

In this paper, we investigate the parameter identification problem in dynamical systems through a deep learning approach. Focusing mainly on second-order, linear time-invariant dynamical systems, the topic of damping factor identification is studied. By utilizing a six-layer deep neural network with different recurrent cells, namely GRUs, LSTMs or BiLSTMs; and by feeding input-output sequence pairs captured from a dynamical system simulator, we search for an effective deep recurrent architecture in order to resolve damping factor identification problem. Our study results show that, although previously not utilized for this task in the literature, bidirectional gated recurrent cells (BiLSTMs) provide better parameter identification results when compared to unidirectional gated recurrent memory cells such as GRUs and LSTM. Thus, indicating that an input-output sequence pair of finite length, collected from a dynamical system and when observed anachronistically, may carry information in both time directions for prediction of a dynamical systems parameter.Comment: Final version published in Journal of Neural Computing and Application

New oncogenic networks regulated by the RNA binding factor CUGBP1 in melanoma

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 13-05-2016Esta tesis tiene embargado el acceso al texto completo hasta el 13-11-2017Melanoma is a prime example of an aggressive tumor that accumulates a plethora of changes in the transcriptome and the proteome. Consequently, distinguishing drivers from inconsequential passenger events has been a main challenge in this disease. Consequently, and despite great progress in identifying (epi)genetic defects accumulated during melanoma progression, the molecular bases underlying the aggressive behavior of this tumor type are not completely understood. RNA binding proteins remain largely unexplored in melanoma. We considered this lack of information of prime relevance as transcripts of nearly all known oncogenes and tumor suppressors may be regulated by alternative splicing and/or controlled by various mechanisms that define mRNA stability and ultimately, competency for translation. Here we show that a screen for all reported mRNA binding proteins (mRBPs) suggested that these genes are not prime targets of mutation or copy number variation. Instead, a customized microarray revealed a series of RBPs overexpressed in melanoma cells when compared to normal melanocytes. Of those factors, we found particularly attractive the CUGBP1/CELF1 protein. First, CUGBP1 is a multifunctional mRBP with a broad spectrum of functions, ranging from the modulation of alternative splicing to modulation of mRNA decay. Secondly, there is little information on comprehensive genome-wide analyses for CUGBP1 in cancer cells, with no previous report in skin cancer. Therefore this PhD thesis was set to address the following unknown aspects of CUGBP1 in melanoma: (i) expression, (ii) functional requirement, and (iii) mechanism of action. In brief, CUGBP1 was found overexpressed in human melanoma cells and tissue specimens. Targeted gene depletion demonstrated that CUGBP1 is required to sustain melanoma cell proliferation. Mechanistically, genome wide human junction arrays, RNA immunoprecipitation followed by sequencing and iTRAQ-MS/MS proteomics assays were utilized and identified novel and direct targets of CUGBP1. Together, these high throughput approaches (to our knowledge the first in class for this gene) uncovered a coordinated network of tumor-associated cell cycle regulators and chromatin remodelers as CUGBP1 targets. Central in this CUGBP1 regulated networks was the oncogene DEK, a feature we validated by targeted gene depletion, cDNA arrays and histological validation in clinical datasets. Mechanistically, CUGBP1 was found to bind to the 3’UTR of DEK stabilizing its mRNA levels and ultimately allowing for an efficient cell proliferation. These results illustrate the power of comprehensive analyses of RNA regulators in the identification of novel malignant features of cancer cells

Metastatic risk and resistance to BRAF inhibitors in melanoma defined by selective allelic loss of ATG5

Melanoma is a paradigm of aggressive tumors with a complex and heterogeneous genetic background. Still, melanoma cells frequently retain developmental traits that trace back to lineage specification programs. In particular, lysosome-associated vesicular trafficking is emerging as a melanoma-enriched lineage dependency. However, the contribution of other lysosomal functions such as autophagy to melanoma progression is unclear, particularly in the context of metastasis and resistance to targeted therapy. Here we mined a broad spectrum of cancers for a meta-analysis of mRNA expression, copy number variation and prognostic value of 13 core autophagy genes. This strategy identified heterozygous loss of ATG5 at chromosome band 6q21 as a distinctive feature of advanced melanomas. Importantly, partial ATG5 loss predicted poor overall patient survival in a manner not shared by other autophagy factors and not recapitulated in other tumor types. This prognostic relevance of ATG5 copy number was not evident for other 6q21 neighboring genes. Melanocyte-specific mouse models confirmed that heterozygous (but not homozygous) deletion of Atg5 enhanced melanoma metastasis and compromised the response to targeted therapy (exemplified by dabrafenib, a BRAF inhibitor in clinical use). Collectively, our results support ATG5 as a therapeutically relevant dose-dependent rheostat of melanoma progression. Moreover, these data have important translational implications in drug design, as partial blockade of autophagy genes may worsen (instead of counteracting) the malignant behavior of metastatic melanomas.M.S.S. is funded by grants from the Spanish Ministry of Economy and Innovation (projects SAF2011-28317, SAF2014-56868-R and RTC-2014-2442-1), as well as a Team Science Award by the Melanoma Research Alliance, and grants from the Worldwide Cancer Research and the Asociacion Espanola Contra el Cancer (AECC). M.G-F was funded by a Juan de la ~ Cierva postdoctoral fellowship from the Spanish Ministry of Education and P.K and M.C. by predoctoral fellowships from Fundación La Caixa

p62/SQSTM1 Fuels Melanoma Progression by Opposing mRNA Decay of a Selective Set of Pro-metastatic Factors

Modulators of mRNA stability are not well understood in melanoma, an aggressive tumor with complex changes in the transcriptome. Here we report the ability of p62/SQSTM1 to extend mRNA half-life of a spectrum of pro-metastatic factors. These include FERMT2 and other transcripts with no previous links to melanoma. Transcriptomic, proteomic, and interactomic analyses, combined with validation in clinical biopsies and mouse models, identified a selected set of RNA-binding proteins (RBPs) recruited by p62, with IGF2BP1 as a key partner. This p62-RBP interaction distinguishes melanoma from other tumors where p62 controls autophagy or oxidative stress. The relevance of these data is emphasized by follow-up analyses of patient prognosis revealing p62 and FERMT2 as adverse determinants of disease-free survival.M.S.S. is funded by grants from the Spanish Ministry of Economy and Innovation (SAF2014-56868-R; SAF2017-89533-R), the Asociación Española Contra el Cáncer (AECC), TV’13-20131430 (Marato de TV3), the Worldwide Cancer Research, an Established Investigator Award by the Melanoma Research Alliance (MRA), and a L'Oreal-Paris USA-MRA Team Science Award for Women in Scientific Research. M.S.S. also acknowledges a donation from “Fundación Causa Alexandra”, Spain. P.K. was a recipient of a predoctoral fellowship from Fundación La Caixa. E.R.-F. was funded by Fundación Mutua Madrileña (FMM-2013) and was a recipient of a fellowship from ‘‘Fundación Científica de la Asociación Española Contra el Cáncer”. The CNIO Proteomics Unit belongs to ProteoRed, PRB2-ISCIII, supported by grant PT13/0001. J.M. is also supported by Ramon y Cajal Programme (MINECO) RYC-2012-10651. J.L.R.-P. is funded by FIS 2014/173711/02568 and CIBERONC, and P.L.O.-R. by FIS 11/17592014/01784, from the Spanish Ministry of Health

RAB7 Controls Melanoma Progression by Exploiting a Lineage-Specific Wiring of the Endolysosomal Pathway

Although common cancer hallmarks are well established, lineage-restricted oncogenes remain less understood. Here, we report an inherent dependency of melanoma cells on the small GTPase RAB7, identified within a lysosomal gene cluster that distinguishes this malignancy from over 35 tumor types. Analyses in human cells, clinical specimens, and mouse models demonstrated that RAB7 is an early-induced melanoma driver whose levels can be tuned to favor tumor invasion, ultimately defining metastatic risk. Importantly, RAB7 levels and function were independent of MITF, the best-characterized melanocyte lineage-specific transcription factor. Instead, we describe the neuroectodermal master modulator SOX10 and the oncogene MYC as RAB7 regulators. These results reveal a unique wiring of the lysosomal pathway that melanomas exploit to foster tumor progression.M.S.S. is funded by Projects SAF2011-28317 and Consolider RNAREG from the Spanish Ministry of Economy and Innovation, R01CA125017 from the NIH, and a Team Science Award by the Melanoma Research Foundation. J.L.R.-P. and P.O.-R. are funded by grants FIS 11/025685 and FIS 11/1759, respectively, from the Spanish Ministry of Health. J.L.R.-P. was also supported by grant FMM-2008-106 of Fundación Mutua Madrileña, and P.O.-R. by Red Tematica de Investigacion Cooperativa en Cancer. D.A.-C. and E.P.-G. are recipients of Scientists in Training predoctoral fellowships from the Spanish Ministry of Science and Innovation. M.C. and P.K. are funded by predoctoral fellowships of Fundación La Caixa. E.R.-F. is the recipient of a postdoctoral fellowship from Fundación Científica de la Asociación Española Contra el Cáncer, and J.A.J. and H.-W.W. are funded by the American Cancer Society (RSG-12-076-01-LIB)

Perspectives on musical care throughout the life course : introducing the musical care international network

In this paper we report on the inaugural meetings of the Musical Care International Network held online in 2022. The term “musical care” is defined by Spiro and Sanfilippo (2022) as “the role of music—music listening as well as music-making—in supporting any aspect of people’s developmental or health needs” (pp. 2–3). Musical care takes varied forms in different cultural contexts and involves people from different disciplines and areas of expertise. Therefore, the Musical Care International Network takes an interdisciplinary and international approach and aims to better reflect the disciplinary, geographic, and cultural diversity relevant to musical care. Forty-two delegates participated in 5 inaugural meetings over 2 days, representing 24 countries and numerous disciplines and areas of practice. Based on the meetings, the aims of this paper are to (1) better understand the diverse practices, applications, contexts, and impacts of musical care around the globe and (2) introduce the Musical Care International Network. Transcriptions of the recordings, alongside notes taken by the hosts, were used to summarise the conversations. The discussions developed ideas in three areas: (a) musical care as context-dependent and social, (b) musical care’s position within the broader research and practice context, and (c) debates about the impact of and evidence for musical care. We can conclude that musical care refers to context-dependent and social phenomena. The term musical care was seen as useful in talking across boundaries while not minimizing individual disciplinary and professional expertise. The use of the term was seen to help balance the importance and place of multiple disciplines, with a role to play in the development of a collective identity. This collective identity was seen as important in advocacy and in helping to shape policy. The paper closes with proposed future directions for the network and its emerging mission statement.The United Kingdom Research and Innovation’s Knowledge Exchange Fund, administered through the Royal College of Music, United Kingdom (2021–2023).http://journals.sagepub.com/home/mnsam2024MusicNon

Perspectives on Musical Care Throughout the Life Course: Introducing the Musical Care International Network

Giorgos Tsiris - ORCID: 0000-0001-9421-412X https://orcid.org/0000-0001-9421-412XIn this paper we report on the inaugural meetings of the Musical Care International Network held online in 2022. The term “musical care” is defined by Spiro and Sanfilippo (2022) as “the role of music—music listening as well as music-making—in supporting any aspect of people's developmental or health needs” (pp. 2–3). Musical care takes varied forms in different cultural contexts and involves people from different disciplines and areas of expertise. Therefore, the Musical Care International Network takes an interdisciplinary and international approach and aims to better reflect the disciplinary, geographic, and cultural diversity relevant to musical care. Forty-two delegates participated in 5 inaugural meetings over 2 days, representing 24 countries and numerous disciplines and areas of practice. Based on the meetings, the aims of this paper are to (1) better understand the diverse practices, applications, contexts, and impacts of musical care around the globe and (2) introduce the Musical Care International Network. Transcriptions of the recordings, alongside notes taken by the hosts, were used to summarise the conversations. The discussions developed ideas in three areas: (a) musical care as context-dependent and social, (b) musical care's position within the broader research and practice context, and (c) debates about the impact of and evidence for musical care. We can conclude that musical care refers to context-dependent and social phenomena. The term musical care was seen as useful in talking across boundaries while not minimizing individual disciplinary and professional expertise. The use of the term was seen to help balance the importance and place of multiple disciplines, with a role to play in the development of a collective identity. This collective identity was seen as important in advocacy and in helping to shape policy. The paper closes with proposed future directions for the network and its emerging mission statement.https://doi.org/10.1177/205920432312005536aheadofprintaheadofprin

Lineage‐specific roles of the cytoplasmic polyadenylation factor CPEB4 in the regulation of oncogenic drivers in melanoma

Nuclear 3’ end‐polyadenylation is essential for the transport, stability and translation of virtually all eukaryotic mRNAs. Poly(A) tail extension can also occur in the cytoplasm, but the transcripts involved are incompletely understood, particularly in cancer. Here we identify a lineage‐specific requirement of the cytoplasmic polyadenylation binding protein 4 (CPEB4) in malignant melanoma. Computational and histological analyses revealed a marked upregulation of CPEB4 at early stages of melanoma progression. Functionally, melanoma cells were found unexpectedly distinct from other tumor cell types in their strict dependency on CPEB4 not only to prevent mitotic aberrations, but to progress through G1/S cell cycle checkpoints. RNA immunoprecipitation, sequencing of bound transcripts and poly(A) length tests uncovered the melanoma drivers MITF and RAB27A within a cohesive network of melanoma‐enriched signaling hubs controlled by CPEB4, a feature validated in clinical biopsies. These results provide new mechanistic links between cytoplasmic polyadenylation and lineage specification in melanoma