Living long and ageing well: is epigenomics the missing link between nature and nurture?

Human longevity is a complex trait and increasingly we understand that both genes and lifestyle interact in the longevity phenotype. Non-genetic factors, including diet, physical activity, health habits, and psychosocial factors contribute approximately 50 % of the variability in human lifespan with another 25 % explained by genetic differences. Family clusters of nonagenarian and centenarian siblings, who show both exceptional age-span and health-span, are likely to have inherited facilitatory gene groups, but also have nine decades of life experiences and behaviours which have interacted with their genetic profiles. Identification of their shared genes is just one small step in the link from genes to their physical and psychological profiles. Behavioural genomics is beginning to demonstrate links to biological mechanisms through regulation of gene expression, which directs the proteome and influences the personal phenotype. Epigenetics has been considered the missing link between nature and nurture. Although there is much that remains to be discovered, this article will discuss some of genetic and environmental factors which appear important in good quality longevity and link known epigenetic mechanisms to themes identified by nonagenarians themselves related to their longevity. Here we suggest that exceptional 90-year old siblings have adopted a range of behaviours and life-styles which have contributed to their ageing-well-phenotype and which link with important public health messages.

Strategic Human Resource Management of Volunteers and the Link to Hospital Patient Satisfaction

This article uses strategic human resource management theory to consider the ways in which volunteers can potentially enhance hospital patient satisfaction. Results of a structural equation modeling analysis of multi-source data on 107 U.S. hospitals show positive associations between hospital strategy, volunteer management practices, volunteer workforce attributes, and patient satisfaction. Although no causality can be assumed, the results shed light on the volunteer–patient satisfaction relationship and have important implications for hospital leaders, volunteer administrators, and future research.

The functional link between HFE and hepcidin- its contribution to iron metabolism regulation

Tese de doutoramento, Biologia (Biologia Molecular), Universidade de Lisboa, Faculdade de Ciências, 2013

Unpacking the Link Between Entrepreneurialism and Employability: an Assessment of the Relationship Between Entrepreneurial Attitudes and Likelihood of Graduate Employment in a Professional Field

Purpose This research investigates the relationship between students’ entrepreneurial attitudes and traits and their classification of employment six months after university graduation. It aims to identify what specific attitudes and traits of entrepreneurial graduates are linked to employability in a professional or managerial field. Design/Methodology The research adopts a quantitative approach to measure the entrepreneurial drive of final-year undergraduate business school students and regresses this measurement against the employment level of the same students six months after their graduation. The employment classification of each respondent was classified as ‘professional/managerial’ or ‘non-professional/non-managerial’, in line with the Standard Occupational Classification (SOC) 2010. Findings The research found that both proactive disposition and achievement motivation were statistically linked to the likelihood of graduates being employed in a professional or managerial position six months after graduation. Originality/Value This research goes beyond existing literature linking entrepreneurship to employability to quantitatively examine what specific attitudes and traits can be linked to employability in recent graduates. By identifying the aspects of entrepreneurialism that have a relationship with employability, more information is available for educators who are designing entrepreneurial education programs and allows for greater focus on aspects that may be of greatest benefit to all students.

RadiaLE: A framework for designing and assessing link quality estimators in wireless sensor networks

Stringent cost and energy constraints impose the use of low-cost and low-power radio transceivers in large-scale wireless sensor networks (WSNs). This fact, together with the harsh characteristics of the physical environment, requires a rigorous WSN design. Mechanisms for WSN deployment and topology control, MAC and routing, resource and mobility management, greatly depend on reliable link quality estimators (LQEs). This paper describes the RadiaLE framework, which enables the experimental assessment, design and optimization of LQEs. RadiaLE comprises (i) the hardware components of the WSN testbed and (ii) a software tool for setting-up and controlling the experiments, automating link measurements gathering through packets-statistics collection, and analyzing the collected data, allowing for LQEs evaluation. We also propose a methodology that allows (i) to properly set different types of links and different types of traffic, (ii) to collect rich link measurements, and (iii) to validate LQEs using a holistic and unified approach. To demonstrate the validity and usefulness of RadiaLE, we present two case studies: the characterization of low-power links and a comparison between six representative LQEs. We also extend the second study for evaluating the accuracy of the TOSSIM 2 channel model.

Radio link quality estimation in wireless sensor networks: a survey

Radio link quality estimation in Wireless Sensor Networks (WSNs) has a fundamental impact on the network performance and also affects the design of higher-layer protocols. Therefore, for about a decade, it has been attracting a vast array of research works. Reported works on link quality estimation are typically based on different assumptions, consider different scenarios, and provide radically different (and sometimes contradictory) results. This article provides a comprehensive survey on related literature, covering the characteristics of low-power links, the fundamental concepts of link quality estimation in WSNs, a taxonomy of existing link quality estimators, and their performance analysis. To the best of our knowledge, this is the first survey tackling in detail link quality estimation in WSNs. We believe our efforts will serve as a reference to orient researchers and system designers in this area.

F-LQE: a Fuzzy Link Quality Estimator for wireless sensor networks

Radio Link Quality Estimation (LQE) is a fundamental building block for Wireless Sensor Networks, namely for a reliable deployment, resource management and routing. Existing LQEs (e.g. PRR, ETX, Fourbit, and LQI ) are based on a single link property, thus leading to inaccurate estimation. In this paper, we propose F-LQE, that estimates link quality on the basis of four link quality properties: packet delivery, asymmetry, stability, and channel quality. Each of these properties is defined in linguistic terms, the natural language of Fuzzy Logic. The overall quality of the link is specified as a fuzzy rule whose evaluation returns the membership of the link in the fuzzy subset of good links. Values of the membership function are smoothed using EWMA filter to improve stability. An extensive experimental analysis shows that F-LQE outperforms existing estimators.

Fly by data link: feasibility of a relative navigation solution for aviation relying on a future L-band data link

Trabalho final de Mestrado para obtenção do grau de Mestre em Engenharia de Electrónica e Telecomunicações

Primary cilia and the regulation of hedgehog signaling: link to cardiac development

RESUMO: As células eucarióticas evoluíram um sistema de sinalização complexo que lhes permite responder aos sinais extracelulares e intracelulares. Desta forma, as vias de sinalização são essenciais para a sobrevivência da célula e do organismo, uma vez que regulam processos fundamentais, tais como o desenvolvimento, o crescimento, a imunidade, e a homeostase dos tecidos. A via de transdução de sinal Hedgehog (Hh) envolve o receptor Patched1 (Ptch1), que tem um efeito inibidor sobre a proteína Smoothened (Smo) na ausência dos seus ligandos, as proteínas Sonic hedgehog (Shh). Estas proteínas são reguladores fundamentais do desenvolvimento embrionário, como ilustrado pelas malformações drásticas observadas em embriões humanos e de murganho com perturbações da transdução de sinal da via Hh e que incluem polidactilia, defeitos craniofaciais e malformações ósseas. Igualmente importantes são as consequências da ativação inapropriada da via de sinalização Hh na formação de tumores. Curiosamente, os componentes desta via localizam-se nos cílios primários. Além disso, demonstrou-se que esta localização é crucial para a sinalização através da via Hh. Na presença dos ligandos, Ptch1 é internalizado e destinado a degradação ou sequestrado num compartimento da célula de onde não pode desempenhar o seu papel inibitório. A proteína Arl13b é uma pequena GTPase pertencente à família Arf/Arl da superfamília Ras de pequenas GTPases e foi implicada no síndrome de Joubert, uma ciliopatia caracterizada por ataxia congénita cerebelar, hipotonia, atrso mental e cardiopatia congénita. Murganhos deficientes para Arl13b, chamado hennin (hnn) morrem morrem prematuramente ao dia 13,5 de gestação (E13,5) e exibem anomalias morfológicas nos cílios que levam à interrupção da sinalização Hh. Além disso, a Arl13b está diretamente envolvida na regulação da via Hh, controlando a localização de vários componentes desta via nos cílios primários. Neste trabalho, mostramos que a Arl13b se localiza em circular dorsal ruffles (CDRs), que são estruturas de actina envolvidas em macropinocitose e internalização de recetores, e que regula a sua formação. Além disso, aprofundámos o conhecimento do processo de ativação da via de sinalização Hh, mostrando que as CDRs sequestram seletivamente e internalizam o recetor Ptch1. As CDRs formam-se minutos após ativação da via por ligandos Shh ou pelo agonista de Smo SAG e continuam a ser formadas a partir daí, sugerindo uma indução contínua da reorganização do citoesqueleto de actina quando a via está ativada. Observámos ainda que a inibição da formação de CDRs através do silenciamento de WAVE1, uma proteína necessária para a formação destas estruturas, resulta na diminuição da ativação da via de sinalização Hh. Além disso, o bloqueio da macropinocitose, que se segue ao fecho das CDRs, através do silenciamento de uma proteína necessária para a cisão de macropinossomas, nomeadamente a proteína BARS, tem um efeito semelhante. Estes resultados sugerem que as CDRs e a macropinocitose são necessárias para a ativação da via de sinalização Hh e indicam que esta via de internalização controla os níveis de sinal Hh. Durante o desenvolvimento, as células proliferativas dependem do cílio primário para a transdução de várias vias de sinalização. A via Hh induz a diferenciação do músculo cardíaco. Por conseguinte, os murganhos deficientes na via de sinalização Hh exibem uma variedade de defeitos de lateralidade, incluindo alteração do looping do coração, como pode ser visto em murganhos deficientes para Arl13b. Por conseguinte, investigámos o papel da Arl13b no desenvolvimento do coração. Mostramos que a Arl13b é altamente expressa no coração de embriões de murganho e de murganhos adultos ao nível do mRNA e da proteína. Além disso, o perfil de distribuição da Arl13b no coração segue o dos cílios primários, que são essenciais para o desenvolvimento cardíaco. Corações de murganhos hnn no estadio E12,5 mostram um canal átrio-ventricular aberto, espessamento da camada compacta ventricular e aumento do índice mitótico no ventrículo esquerdo. Além disso, um atraso de 1 a 2 dias no desenvolvimento é observado em corações de murganhos hnn, quando comparados com controlos selvagens no estadio E13,5. Assim, estes resultados sugerem que a Arl13b é necessária para o desenvolvimento embrionário do coração e que defeitos cardíacos podem contribuir para a letalidade embrionária de murganhos hnn. Em suma, foi estabelecido um novo mecanismo para a regulação dos níveis de superfície do recetor Ptch1, que envolve a remodelação do citoesqueleto de actina e a formação de CDRs após a ativação da via de sinalização Hh. Este mecanismo permite um feedback negativo que evita a repressão excessiva da via através da remoção de Ptch1 da superfície da célula. Além disso, determinou-se que uma mutação de perda de função na Arl13b causa defeitos cardíacos durante o desenvolvimento, possivelmente relacionados com a associação dos defeitos em cílios primários e na sinalização Hh, existentes em murganhos deficientes para Arl13b. A via de sinalização Hh tem tido um papel central entre as vias de sinalização, uma vez que a sua regulação é crucial para o funcionamento apropriada da célula. Assim, a descoberta de um novo mecanismo de tráfego através de macropinocitose e CDRs que controla a ativação e repressão da via de sinalização Hh traz novas perspetivas de como esta via pode ser regulada e pode ainda conduzir à identificação de novos alvos e estratégias terapêuticas. --------------------ABSTRACT: Eukaryotic cells have evolved a complex signaling system that allows them to respond to extracellular and intracellular cues. Signaling pathways are essential for cell and organism survival, since they regulate fundamental processes such as development, growth, immunity, and tissue homeostasis. The Hedgehog (Hh) pathway of signal transduction involves the receptor Patched1 (Ptch1), which has an inhibitory effect on Smoothened (Smo) in the absence of its ligands, the Sonic hedgehog (Shh) proteins. These proteins are fundamental regulators of embryonic development, as illustrated by the dramatic malformations seen in human and mouse embryos with perturbed Hh signal transduction that include polydactyly, craniofacial defects and skeletal malformations. Equally important are the consequences of inappropriate activation of the Hh signaling response in tumor formation. Interestingly, the components of this pathway localize to primary cilia. Moreover, it has been shown that this localization is crucial for Hh signaling. However, in the presence of the ligands, Ptch1 is internalized and destined for degradation or sequestered in a cell compartment where it no longer can play its inhibitory role. ADP-ribosylation factor-like (Arl) 13b, a small GTPase belonging to Arf/Arl family of the Ras superfamily of small GTPases has been implicated in Joubert syndrome, a ciliopathy characterized by congenital cerebellar ataxia, hypotonia, intellectual disability and congenital heart disease. Arl13b-deficient mice, called hennin (hnn) die at embryonic day 13.5 (E13.5) and display morphological abnormalities in primary cilia that lead to the disruption of Hh signaling. Furthermore, Arl13b is directly involved in the regulation of Hh signaling by controlling the localization of several components of this pathway to primary cilia. Here, we show that Arl13b localizes to and regulates the formation of circular dorsal rufles (CDRs), which are actin-basedstructures known to be involved in macropinocytosis and receptor internalization. Additionally, we extended the knowledge of the Hh signaling activation process by showing that CDRs selectively sequester and internalize Ptch1 receptors. CDRs are formed minutes after Hh activation by Shh ligands or the Smo agonist SAG and keep being formed thereafter, suggesting a continuous induction of actin reorganization when the pathway is switched on. Importantly, we observed that disruption of CDRs by silencing WAVE1, a protein required for CDR formation, results in down-regulation of Hh signaling activation. Moreover, the blockade of macropinocytosis, which follows CDR closure, through silencing of a protein necessary for the fission of macropinosomes, namely BARS has a similar effect. These results suggest that CDRs and macropinocytosis are necessary for activation of Hh signaling and indicate that this pathway of internalization controls Hh signal levels. During development, proliferating cells rely on the primary cilium for the transduction of several signaling pathways. Hh induces the differentiation of cardiac muscle. Accordingly, Hh-deficient mice display a variety of laterality defects, including alteration of heart looping, as seen in Arl13b-deficient mice. Therefore, we investigated the role of Arl13b in heart development. We show that Arl13b is highly expressed in the heart of both embryonic and adult mice at mRNA and protein levels. Also, Arl13b localization profile mimics that of primary cilia, which have been shown to be essential to early heart development. E12.5 hnn hearts show an open atrioventricular channel, increased thickening of the ventricular compact layer and increased mitotic index in the left ventricle. Moreover, a delay of 1 to 2 days in development is observed in hnn hearts, when compared to wild-type controls at E13.5. Hence, these results suggest that Arl13b is necessary for embryonic heart development and that cardiac defects might contribute to the embryonic lethality of hnn mice. Altogether, we established a novel mechanism for the regulation of Ptch1 surface levels, involving cytoskeleton remodeling and CDR formation upon Hh signaling activation. This mechanism allows a negative feedback loop that prevents excessive repression of the pathway by removing Ptch1 from the cell surface. Additionally, we determined that the Arl13b loss-offunction mutation causes cardiac defects during development, possibly related to the associated ciliary and Hh signaling defects found in Arl13b-deficient mice. Hh signaling has taken a center stage among the signaling pathways since its regulation is crucial for the appropriate output and function of the cell. Hence, the finding of a novel trafficking mechanism through CDRs and macropinocytosis that controls Hh signaling activation and repression brings new insights to how this pathway can be regulated and can lead to the discovery of novel therapeutic targets and strategies.

Change in individual growth rate and its link to gill-net fishing in two sympatric whitefish species

Size-selective fishing is expected to affect traits such as individual growth rate, but the relationship between the fishery-linked selection differentials and the corresponding phenotypic changes is not well understood. We analysed a 25-year monitoring survey of sympatric populations of the two Alpine whitefish Coregonus albellus and C. fatioi. We determined the fishing-induced selection differentials on growth rates, the actual change of growth rates over time, and potential indicators of reproductive strategies that may change over time. We found marked declines in adult growth rate and significant selection differentials that may partly explain the observed declines. However, when comparing the two sympatric species, the selection differentials on adult growth were stronger in C. albellus while the decline in adult growth rate seemed more pronounced in C. fatioi. Moreover, the selection differential on juvenile growth was significant in C. albellus but not in C. fatioi, while a significant reduction in juvenile growth over the last 25 years was only found in C. fatioi. Our results suggest that size-selective fishing affects the genetics for individual growth in these whitefish, and that the link between selection differentials and phenotypic changes is influenced by species-specific factors.

Trigger and data link system for CMS Resistive Plate Chambers at the LHC accelerator

The purpose of the work was to realize a high-speed digital data transfer system for RPC muon chambers in the CMS experiment on CERN’s new LHC accelerator. This large scale system took many years and many stages of prototyping to develop, and required the participation of tens of people. The system interfaces to Frontend Boards (FEB) at the 200,000-channel detector and to the trigger and readout electronics in the control room of the experiment. The distance between these two is about 80 metres and the speed required for the optic links was pushing the limits of available technology when the project was started. Here, as in many other aspects of the design, it was assumed that the features of readily available commercial components would develop in the course of the design work, just as they did. By choosing a high speed it was possible to multiplex the data from some the chambers into the same fibres to reduce the number of links needed. Further reduction was achieved by employing zero suppression and data compression, and a total of only 660 optical links were needed. Another requirement, which conflicted somewhat with choosing the components a late as possible was that the design needed to be radiation tolerant to an ionizing dose of 100 Gy and to a have a moderate tolerance to Single Event Effects (SEEs). This required some radiation test campaigns, and eventually led to ASICs being chosen for some of the critical parts. The system was made to be as reconfigurable as possible. The reconfiguration needs to be done from a distance as the electronics is not accessible except for some short and rare service breaks once the accelerator starts running. Therefore reconfigurable logic is extensively used, and the firmware development for the FPGAs constituted a sizable part of the work. Some special techniques needed to be used there too, to achieve the required radiation tolerance. The system has been demonstrated to work in several laboratory and beam tests, and now we are waiting to see it in action when the LHC will start running in the autumn 2008.