TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors

PMCID: PMC4434585.-- et al.The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas.The research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. Work was funded by grants from the Ministerio de Economía y Competitividad (CB07/08/0021, SAF2011-27086, PLE2009-0162 to J.F., BFU2013-41322-P to J.L.G-S.), the Andalusian Government (BIO-396 to J.L.G-S.), the Wellcome Trust (WT088566 and WT097820 to N.A.H., WT101033 to J.F.), the Manchester Biomedical Research Centre, ERC advanced starting grant IMDs (C.H-H.C. and L.V.) and the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre (L.V.). R.E.J. is a Medical Research Council clinical training fellow. The authors are grateful to C. Wright (Vanderbilt University) for zebrafish Pdx1 antiserum, J. Postlethwait (Purdue University) for a Sox9b clone, H. Sasaki (Kumamoto University) for a TEAD–EnR clone, C. Vinod and L. Abi for research nurse assistance, and clinical colleagues at Central Manchester University Hospitals NHS Foundation Trust. The authors thank J. Garcia-Hurtado for technical assistance (IDIBAPS).Peer Reviewe

Una propuesta de adaptación al EEES en el diseño de sistemas embebidos

El Espacio Europeo de Educación Superior (EEES) está suponiendo un cambio importante en la filosofía docente en todas las universidades españolas. Dentro de este ámbito, el aprendizaje colaborativo y, más específicamente, el aprendizaje basado en proyectos (ABP) están siendo considerados como metodologías docentes apropiada en enseñanzas técnicas. En el presente trabajo se describe el proceso llevado a cabo en la incorporación de dicho sistema en el área de tecnología electrónica en la Universidad de Murcia. El estudio se centra en una asignatura concreta orientada al diseño mediante microcontroladores, mostrando la metodología docente empleada, y haciendo énfasis en el trabajo en grupo mediante la realización de un proyecto. Se considera, además, la inclusión de un becario predoctoral FPU en las labores docentes, lo cual complementa la experiencia piloto. Los resultados muestran que la introducción de la nueva metodología es aceptada correctamente.Los autores agradecen al Ministerio de Educación y Ciencia la financiación ofrecida dentro del programa FPU, con la beca AP2005-1437

Defining the Behavior of IoT Devices through the MUD Standard: Review, Challenges, and Research Directions

With the strong development of the Internet of Things (IoT), the definition of IoT devices' intended behavior is key for an effective detection of potential cybersecurity attacks and threats in an increasingly connected environment. In 2019, the Manufacturer Usage Description (MUD) was standardized within the IETF as a data model and architecture for defining, obtaining and deploying MUD files, which describe the network behavioral profiles of IoT devices. While it has attracted a strong interest from academia, industry, and Standards Developing Organizations (SDOs), MUD is not yet widely deployed in real-world scenarios. In this work, we analyze the current research landscape around this standard, and describe some of the main challenges to be considered in the coming years to foster its adoption and deployment. Based on the literature analysis and our own experience in this area, we further describe potential research directions exploiting the MUD standard to encourage the development of secure IoT-enabled scenarios

METALA: a J2EE technology based framework for web mining

In this paper, we discuss the most important aspects of METALA, a software tool for meta-learning that we have developed to perform inductive learning in a distributed and component based fashion. The distribution comes from the use of a well posed distributed application development standard as is J2EE, and the component basis comes from the methodology we developed to integrate new learning algorithms and other software utilities into the system.Keywords: Software architecture, web usage mining, inductive learning, knowledge models, J2EE, XML

Obesity-associated variants within FTO form long-range functional connections with IRX3

PMCID: PMC4113484.-- et al.Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.This work was funded by grants from the National Institutes of Health (DK093972, HL119967, HL114010 and DK020595) to M.A.N. and (MH101820, MH090937 and DK20595) to N.J.C. J.L.G.-S. was funded by grants from the Spanish Ministerio de Economía y Competitividad (BFU2010-14839, CSD2007-00008) and the Andalusian Government (CVI-3488). C.-C.H. was supported by a grant from the Canadian Institute of Health Research. K.-H.K. is supported by a fellowship from the Heart and Stroke Foundation of Canada. S.S. is supported by an NIH postdoctoral training grant (T32HL007381)Peer Reviewe

Towards a Semantic-Aware Collaborative Working Environment

Collaborative Working Environments (CWEs) enable an efficient collaboration between professionals, specially those settled in different locations of a company or stakeholders from different companies. This can be of great help for small and medium enterprises (SMEs), as an effective way to share information. However, it can be difficult for SMEs to have access to a fully integrated CWE providing different tools (e.g., videoconferencing, instant messaging, etc.). Currently, they may define a CWE as a combination of heterogeneous and non-integrated tools which are not able to share information between them. An integrated CWE would provide SMEs with the necessary means to collaborate, making information exchange easier.&nbsp