Dynamic power- and failure-aware cloud resources allocation for Sets of independent tasks

Cloud computing is increasingly being adopted in different scenarios, like social networking, business applications, scientific experiments, etc. Relying in virtualization technology, the construction of these computing environments targets improvements in the infrastructure, such as power-efficiency and fulfillment of users’ SLA specifications. The methodology usually applied is packing all the virtual machines on the proper physical servers. However, failure occurrences in these networked computing systems can induce substantial negative impact on system performance, deviating the system from ours initial objectives. In this work, we propose adapted algorithms to dynamically map virtual machines to physical hosts, in order to improve cloud infrastructure power-efficiency, with low impact on users’ required performance. Our decision making algorithms leverage proactive fault-tolerance techniques to deal with systems failures, allied with virtual machine technology to share nodes resources in an accurately and controlled manner. The results indicate that our algorithms perform better targeting power-efficiency and SLA fulfillment, in face of cloud infrastructure failures.

Global-EDF scheduling of multimode real- time systems considering mode independent tasks

Embedded real-time systems often have to support the embedding system in very different and changing application scenarios. An aircraft taxiing, taking off and in cruise flight is one example. The different application scenarios are reflected in the software structure with a changing task set and thus different operational modes. At the same time there is a strong push for integrating previously isolated functionalities in single-chip multicore processors. On such multicores the behavior of the system during a mode change, when the systems transitions from one mode to another, is complex but crucial to get right. In the past we have investigated mode change in multiprocessor systems where a mode change requires a complete change of task set. Now, we present the first analysis which considers mode changes in multicore systems, which use global EDF to schedule a set of mode independent (MI) and mode specific (MS) tasks. In such systems, only the set of MS tasks has to be replaced during mode changes, without jeopardizing the schedulability of the MI tasks. Of prime concern is that the mode change is safe and efficient: i.e. the mode change needs to be performed in a predefined time window and no deadlines may be missed as a function of the mode change.

T cell Maturation and Regulatory T Cell Differentiation:From the Thymus to the Periphery

Immunological tolerance, that is, the failure to mount an immune response to an otherwise immunogenic molecule, is one of the fundamental questions in immunology. The fact that lymphocytes express antigen receptors that are generated randomly and have the potential to recognize any conceivable antigen, adds another puzzle to the physiology of immunological tolerance. The other side of the coin, the general absence of immune responses to self antigens, is ensured by a tight regulation and several selection steps during T and B cell differentiation. One of these processes is the differentiation of regulatory T cells (Treg). While developing in the thymus, T cell clones bearing receptors with high affinity/avidity to antigens present at the time of differentiation may be eliminated by apoptosis or, alternatively, express Foxp3 and become Treg. Treg are key players in the regulation of immunological tolerance since humans and mice with complete loss of function variants of this gene develop fatal autoimmune conditions early in life.(...)

Melanosome transfer between melanocytes and keratinocytes

RESUMO: A pele é o maior órgão do corpo humano e a sua pigmentação é essencial para a sua coloração e proteção contra os efeitos nocivos da radiação ultravioleta (UV). A pigmentação da pele resulta essencialmente de três processos: a síntese e o armazenamento de melanina pelos melanócitos, em organelos especializados denominados melanossomas; o transporte dos melanossomas dentro dos melanócitos; e finalmente, a transferência dos melanossomas para os queratinócitos adjacentes. Nos queratinócitos, a melanina migra para a região perinuclear apical da célula para formar um escudo protetor,responsável pela proteção do DNA dos danos causados pela radiação UV. Os melanócitos estão localizados na camada basal da epiderme e contactam com 30-40 queratinócitos. Em conjunto, estas células formam a “unidade melano-epidérmica”. Apesar dos processos de síntese e transporte de melanina nos melanócitos estarem bastante bem caracterizados, os mecanismos moleculares subjacentes à transferência inter-celular de melanina são menos conhecidos e ainda controversos. Dados preliminares obtidos pelo nosso grupo, que se basearam na observação de amostras de pele humana por microscopia electrónica, indicam que a forma predominante de transferência de melanina na epiderme consiste na exocitose dos melanossomas pelos melanócitos e subsequente endocitose da melanina por queratinócitos. Para além disso sabe-se que as proteínas Rab, que controlam o tráfego membranar, estão envolvidas em várias etapas de pigmentação da pele, nomeadamente na biogénese e no transporte de melanina. Assim, dado o seu papel fundamental nestes processos, questionámo-nos sobre o seu envolvimento na transferência de melanina. Com este trabalho, propomo-nos a expandir o conhecimento atual sobre a transferência de melanina na pele, através do estudo detalhado dos seus mecanismos moleculares, identificando as proteínas Rab que regulam o processo. Pretendemos também confirmar o modelo de exo/endocitose como sendo o mecanismo principal de transferência de melanina. Primeiro, explorámos a regulação da secreção de melanina pelos melanócitos e analisámos o papel de proteínas Rab neste processo. Os resultados foram obtidos recorrendo a um método in vitro, desenvolvido previamente no laboratório, que avalia a quantidade de melanina segregada para o meio de cultura por espectrofotometria, e ainda por microscopia, contando o número de melanossomas transferidos para os queratinócitos. Através de co-culturas de melanócitos e queratinócitos, verificou-se que os queratinócitos estimulam a libertação de melanina dos melanócitos para o meio extra-celular, bem como a sua transferência para os queratinócitos. Além disso, a proteína Rab11b foi identificada como um regulador da exocitose de melanina e da sua transferência para os queratinócitos. De facto, a diminuição da expressão de Rab11b em melanócitos provocou a redução da secreção de melanina estimulada por queratinócitos, bem como da transferência desta. Em segundo lugar, para complementar o nosso estudo, centrámos a nossa investigação na internalização de melanina por queratinócitos. Especificamente, usando uma biblioteca de siRNA, explorámos o envolvimento de proteínas Rab na captação de melanina por queratinócitos. Como primeira abordagem, usámos esferas fluorescentes como substituto de melanina, avaliando os resultados por citometria de fluxo. No entanto, este método revelou-se ineficaz uma vez que a internalização destas esferas é independente do recetor PAR-2 (recetor 2 ativado por protease), que foi previamente descrito como essencial na captação de melanina por queratinócitos Posteriormente, foi desenvolvido um novo protocolo de endocitose baseado em microscopia, usando melanossomas sem a membrana envolvente (melanocores) purificados do meio de cultura de melanócitos, incluindo um programa informático especialmente desenhado para realizar uma análise semi-automatizada. Após internalização, os melanocores acumulam-se na região perinuclear dos queratinócitos, em estruturas que se assemelham ao escudo supranuclear observado na pele humana. Seguidamente, o envolvimento do recetor PAR-2 na captação de melanocores por queratinócitos foi confirmado, utilizando o novo protocolo de endocitose desenvolvido. Para além disso, a necessidade de quatro proteínas Rab foi identificada na internalização de melanocores por queratinócitos. A redução da expressão de Rab1a ou Rab5b em queratinócitos diminuiu significativamente o nível de internalização de melanocores, enquanto o silenciamento da expressão de Rab2a ou Rab14 aumentou a quantidade de melanocores internalizados por estas células. Em conclusão, os resultados apresentados corroboram as observações anteriores, obtidas em amostras de pele humana, e sugerem que o mecanismo de transferência predominante é a exocitose de melanina pelos melanócitos, induzida por queratinócitos, seguida por endocitose pelos queratinócitos. A pigmentação da pele tem implicações tanto ao nível da cosmética, como ao nível médico, relacionadas com foto-envelhecimento e com doenças pigmentares. Assim sendo, ao esclarecer quais os mecanismos moleculares que regulam a transferência de melanina na pele, este trabalho pode conduzir ao desenvolvimento de novas estratégias para modular a pigmentação da pele.----------------ABSTRACT: Skin pigmentation is achieved through the highly regulated production of the pigment melanin in specialized organelles, termed melanosomes within melanocytes. These are transported from their site of synthesis to the melanocyte periphery before being transferred to keratinocytes where melanin forms a supra-nuclear cap to protect the DNA from UVinduced damage. Together, melanocytes and keratinocytes form a functional complex, termed “epidermal-melanin unit”, that confers color and photoprotective properties to the skin. Skin pigmentation requires three processes: the biogenesis of melanin; its intracelular transport within the melanocyte to the cell periphery; and the melanin transfer to keratinocytes. The first two processes have been extensively characterized. However, despite significant advances that have been made over the past few years, the mechanisms underlying inter-cellular transfer of pigment from melanocytes to keratinocytes remain controversial.Preliminary studies from our group using electron microscopy and human skin samples found evidence for a mechanism of coupled exocytosis-endocytosis. Rab GTPases are master regulators of intracellular trafficking and have already been implicated in several steps of skin pigmentation. Thus, we proposed to explore and characterize the molecular mechanisms of melanin transfer and the role of Rab GTPases in this process. Moreover, we investigated whether the exo/endocytosis model is the main mechanism of melanin transfer. We first focused on melanin exocytosis by melanocytes. Then, we started to investigate the key regulatory Rab proteins involved in this step by establishing an in vitro tissue culture model of melanin secretion. Using co-cultures of melanocytes and keratinocytes, we found that keratinocytes stimulate melanin release and transfer. Moreover, depletion of Rab11b decreases keratinocyte-induced melanin exocytosis by melanocytes. In order to determine whether melanin exocytosis is a predominant mechanism of melanin transfer, the amount of melanin transferred to keratinocytes was then assayed in conditions where melanin exocytosis was inhibited. Indeed, Rab11b depletion resulted in a significant decrease in melanin uptake by keratinocytes. Taken together, these observations suggest that Rab11b mediates melanosome exocytosis from melanocytes and transfer to keratinocytes. To complement and extend our study, we of melanin by keratinocytes. Thus, we aimed to explore the effect of depleting Rab GTPases on melanin uptake and trafficking within keratinocytes. As a first approach, we used fluorescent microspheres as a melanin surrogate. However, the uptake of microspheres was observed to be independent of PAR-2, a receptor that is required for melanin uptakecentred our attention in the internalization of melanin by keratinocytes. Thus, we aimed to explore the effect of depleting Rab GTPases on melanin uptake and trafficking within keratinocytes. As a first approach, we used fluorescent microspheres as a melanin surrogate. However, the uptake of microspheres was observed to be independent of PAR-2, a receptor that is required for melanin uptake.Therefore, we concluded that microspheres were uptaken by keratinocytes through a different pathway than melanin. Subsequently, we developed a microscopy-based endocytosis assay using purified melanocores (melanosomes lacking the limiting membrane) from melanocytes, including a program to perform a semi-automated analysis. Melanocores are taken up by keratinocytes and accumulate in structures in the perinuclear area that resemble the physiological supranuclear cap observed in human skin. We then confirmed the involvement of PAR-2 receptor in the uptake of melanocores by keratinocytes, using the newly developed assay. Furthermore, we identified the role of four Rab GTPases on the uptake of melanocores by keratinocytes. Depletion of Rab1a and Rab5b from keratinocytes significantly reduced the uptake of melanocores, whereas Rab2a, and Rab14 silencing increased the amount the melanocores internalized by XB2 keratinocytes. In conclusion, we present evidence supporting keratinocyte-inducedmelanosome exocytosis from melanocytes, followed by endocytosis of the melanin core by keratinocytes as the predominant mechanism of melanin transfer in skin. Although advances have been made, there is a need for more effective and safer therapies directed at pigmentation disorders and also treatments for cosmetic applications. Hence, the understanding of the above mechanisms of skin pigmentation will lead to a greater appreciation of the molecular machinery underlying human skin pigmentation and could interest the pharmaceutical and cosmetic industries.

Evaluation of the welfare impact of regulating mobile termination rates in Portugal

Following the European Commission’s 2009 Recommendation on the Regulatory Treatment of Fixed and Mobile Termination Rates in the EU, the Portuguese regulatory authority (ANACOM) decided to reduce termination prices in mobile networks to their long-run incremental cost (LRIC). Nevertheless, no serious quantitative assessment of the potential effects of this decision was carried out. In this paper, we adapt and calibrate the Harbord and Hoernig (2014) model of the UK mobile telephony market to the Portuguese reality, and simulate the likely impact on consumer surplus, profits and welfare of four different regulatory approaches: pure LRIC, reciprocal termination charges with fixed networks, “bill & keep”, and asymmetric termination rates. Our results show that reducing MTRs does increase social welfare, profits and consumer surplus in the fixed market, but mobile subscribers are seriously harmed by this decision.

Binge eating in binge eating disorder: a break-down of emotion regulatory process?

Current explanatory models for binge eating in binge eating disorder (BED) mostly rely onmodels for bulimianervosa (BN), although research indicates different antecedents for binge eating in BED. This studyinvestigates antecedents and maintaining factors in terms of positive mood, negative mood and tension in asample of 22 women with BED using ecological momentary assessment over a 1-week. Values for negativemood were higher and those for positive mood lower during binge days compared with non-binge days.During binge days, negative mood and tension both strongly and significantly increased and positive moodstrongly and significantly decreased at the first binge episode, followed by a slight though significant, andlonger lasting decrease (negative mood, tension) or increase (positive mood) during a 4-h observation periodfollowing binge eating. Binge eating in BED seems to be triggered by an immediate breakdown of emotionregulation. There are no indications of an accumulation of negative mood triggering binge eating followed byimmediate reinforcing mechanisms in terms of substantial and stable improvement of mood as observed inBN. These differences implicate a further specification of etiological models and could serve as a basis fordeveloping new treatment approaches for BED.

Regulatory RNA binding molecules : implication for diabetes pathogenesis

Le glucose est notre principale source d'énergie. Après un repas, le taux de glucose dans le sang (glycémie) augmente, ce qui entraine la sécrétion d'insuline. L'insuline est une hormone synthétisée au niveau du pancréas par des cellules dites bêta. Elle agit sur différents organes tels que les muscles, le foie ou le tissu adipeux, induisant ainsi le stockage du glucose en vue d'une utilisation future.¦Le diabète est une maladie caractérisée par un taux élevé de glucose dans le sang (hyperglycémie), résultant d'une incapacité de notre corps à utiliser ou à produire suffisamment d'insuline. A long terme, cette hyperglycémie entraîne une détérioration du système cardio-vasculaire ainsi que de nombreuses complications. On distingue principalement deux type de diabète : le diabète de type 1 et le diabète de type 2, le plus fréquent (environ 90% des cas). Bien que ces deux maladies diffèrent sur beaucoup de points, elles partagent quelques similitudes. D'une part, on décèle une diminution de la quantité de cellules bêta. Cette diminution est cependant partielle dans le cas d'un diabète de type 2, et totale dans celui d'un diabète de type 1. D'autre part, la présence dans la circulation de médiateurs de l'inflammation nommés cytokines est décelée aussi bien chez les patients de type 1 que de type 2. Les cytokines sont sécrétées lors d'une inflammation. Elles servent de moyen de communication entre les différents acteurs de l'inflammation et ont pour certaines un effet néfaste sur la survie des cellules bêta.¦L'objectif principal de ma thèse a été d'étudier en détail l'effet de petites molécules régulatrices de l'expression génique, appelées microARNs. Basé sur le fait que de nombreuses publications ont démontré que les microARNs étaient impliqués dans différentes maladies telles que le cancer, j'ai émis l'hypothèse qu'ils pouvaient également jouer un rôle important dans le développement du diabète.¦Nous avons commencé par mettre des cellules bêta en culture en présence de cytokines, imitant ainsi un environnement inflammatoire. Nous avons pu de ce fait identifier les microARNs dont les niveaux d'expression étaient modifiés. A l'aide de méthodes biochimiques, nous avons ensuite observé que la modulation de certains microARNs par les cytokines avaient des effets néfastes sur la cellule bêta : sur sa production et sa sécrétion d'insuline, ainsi que sur sa mort (apoptose). Nous avons en conséquence pu démontrer que ces petites molécules avaient un rôle important à jouer dans le dysfonctionnement des cellules bêta induit par les cytokines, aboutissant au développement du diabète.¦-¦La cellule bêta pancréatique est une cellule endocrine présente dans les îlots de Langerhans, dans le pancréas. L'insuline, une hormone sécrétée par ces cellules, joue un rôle essentiel dans la régulation de la glycémie. Le diabète se développe si le taux d'insuline relâché par les cellules bêta n'est pas suffisant pour couvrir les besoins métaboliques corporels. Le diabète de type 1, qui représente environ 5 à 10% des cas, est une maladie auto-immune qui se caractérise par une réaction inflammatoire déclenchée par notre système immunitaire envers les cellules bêta. La conséquence de cette attaque est une disparition progressive des cellules bêta. Le diabète de type 2 est, quant à lui, largement plus répandu puisqu'il représente environ 90% des cas. Des facteurs à la fois génétiques et environnementaux sont responsables d'une diminution de la sensibilité des tissus métabolisant l'insuline, ainsi que d'une réduction de la sécrétion de l'insuline par les cellules bêta, ce qui a pour conséquence le développement de la maladie. Malgré les différences entre ces deux types de diabète, ils ont pour points communs la présence d'infiltrat immunitaire et la diminution de l'état fonctionnel des cellules bêta.¦Une meilleure compréhension des mécanismes aboutissant à l'altération de la cellule bêta est primordiale, avant de pouvoir développer de nouvelles stratégies thérapeutiques capables de guérir cette maladie. Durant ma thèse, j'ai donc étudié l'implication de petites molécules d'ARN, régulatrices de l'expression génique, appelées microARNs, dans les conditions physiopathologiques qui aboutissent au développement du diabète. J'ai débuté mon étude par l'identification de microARNs dont le niveau d'expression était modifié lorsque les cellules bêta étaient exposées à des conditions favorisant à la fois le développement du diabète de type 1 (cytokines) et celui du diabète de type 2 (palmitate). Nous avons découvert qu'une modification de l'expression des miR-21, -34a et -146a était commune aux deux traitements. Ces changements d'expressions ont également été confirmés dans deux modèles animaux : les souris NOD qui développent un diabète s'apparentant au diabète de type 1 et les souris db/db qui développent plutôt un diabète de type 2. Puis, à l'aide de puces à ADN, nous avons comparé l'expression de microARNs chez des souris NOD pré-diabétiques. Nous avons alors retrouvé des changements au niveau de l'expression des mêmes microARNs mais également au niveau d'une famille de microARNs : les miR-29a, -29b et -29c. De manière artificielle, nous avons ensuite surexprimé ou inhibé en conditions physiopathologiques l'expression de tous ces microARNs et nous nous sommes intéressés à l'impact d'un tel changement sur différentes fonctions de la cellule bêta comme la synthèse et la sécrétion d'insulinè ainsi que leur survie. Nous avons ainsi pu démontrer que les miR-21, -34a, -29a, -29b, -29c avaient un effet délétère sur la sécrétion d'insuline et que la surexpression de tous ces microARNs (excepté le miR-21) favorisait la mort. Finalement, nous avons démontré que la plupart de ces microARNs étaient impliqués dans la régulation d'importantes voies de signalisation responsables de l'apoptose des cellules bêta telles que les voies de NFKB, BCL2 ou encore JNK.¦Par conséquent, nos résultats démontrent que les microARNs ont un rôle important à jouer dans le dysfonctionnement des cellules bêta lors de la mise en place du diabète.

Monocyte differentiation toward regulatory dendritic cells is not affected by respiratory syncytial virus-induced inflammatory mediators.

Airway epithelial cells were shown to drive the differentiation of monocytes into dendritic cells (DCs) with a suppressive phenotype. In this study, we investigated the impact of virus-induced inflammatory mediator production on the development of DCs. Monocyte differentiation into functional DCs, as reflected by the expression of CD11c, CD123, BDCA-4, and DC-SIGN and the capacity to activate T cells, was similar for respiratory syncytial virus (RSV)-infected and mock-infected BEAS-2B and A549 cells. RSV-conditioned culture media resulted in a partially mature DC phenotype, but failed to up-regulate CD80, CD83, CD86, and CCR7, and failed to release proinflammatory mediators upon Toll-like receptor (TLR) triggering. Nevertheless, these DCs were able to maintain an antiviral response by the release of Type I IFN. Collectively, these data indicate that the airway epithelium maintains an important suppressive DC phenotype under the inflammatory conditions induced by infection with RSV.

Evaluation of the reconstruction limits of a frequency-independent crosshole georadar waveform inversion scheme in the presence of dispersion

Waveform tomographic imaging of crosshole georadar data is a powerful method to investigate the shallow subsurface because of its ability to provide images of pertinent petrophysical parameters with extremely high spatial resolution. All current crosshole georadar waveform inversion strategies are based on the assumption of frequency-independent electromagnetic constitutive parameters. However, in reality, these parameters are known to be frequency-dependent and complex and thus recorded georadar data may show significant dispersive behavior. In this paper, we evaluate synthetically the reconstruction limits of a recently published crosshole georadar waveform inversion scheme in the presence of varying degrees of dielectric dispersion. Our results indicate that, when combined with a source wavelet estimation procedure that provides a means of partially accounting for the frequency-dependent effects through an "effective" wavelet, the inversion algorithm performs remarkably well in weakly to moderately dispersive environments and has the ability to provide adequate tomographic reconstructions.

Transplantation tolerance induced by regulatory T cells: in vivo mechanisms and sites of action.

The mechanisms by which CD4(+)CD25(+)Foxp3(+) T (Treg) cells regulate effector T cells in a transplantation setting and their in vivo homeostasis still remain to be clarified. Using a mouse adoptive transfer model, we analyzed the in vivo expansion, trafficking, and effector function of alloreactive T cells and donor-specific Treg cells, in response to a full-thickness skin allograft. Fluorescent-labeled CD4(+)CD25(-) and antigen-specific Treg cells were transferred alone or co-injected into syngeneic BALB/c-Nude recipients transplanted with skins from (C57BL/6 x BALB/c) F1 donors. Treg cells divided in vivo, migrated and accumulated in the allograft draining lymph nodes as well as within the graft. The co-transfer of Treg cells did not modify the early activation and homing of CD4(+)CD25(-) T cells in secondary lymphoid organs. However, in the presence of Treg cells, alloreactive CD4(+)CD25(-) T cells produced significantly less IFN-gamma and were present in reduced numbers in the secondary lymphoid organs. Furthermore, time-course studies showed that Treg cells were recruited into the allograft at a very early stage after transplantation and effectively prevented the infiltration of effector T cells. In conclusion, suppression of rejection requires the early recruitment to the site of antigenic challenge of donor-specific Treg cells, which then mainly regulate the effector arm of T cell alloresponses.

Methylation profile of TP53 regulatory pathway and mtDNA alterations in breast cancer patients lacking TP53 mutations.

The present study investigated promoter hypermethylation of TP53 regulatory pathways providing a potential link between epigenetic changes and mitochondrial DNA (mtDNA) alterations in breast cancer patients lacking a TP53 mutation. The possibility of using the cancer-specific alterations in serum samples as a blood-based test was also explored. Triple-matched samples (cancerous tissues, matched adjacent normal tissues and serum samples) from breast cancer patients were screened for TP53 mutations, and the promoter methylation profile of P14(ARF), MDM2, TP53 and PTEN genes was analyzed as well as mtDNA alterations, including D-loop mutations and mtDNA content. In the studied cohort, no mutation was found in TP53 (DNA-binding domain). Comparison of P14(ARF) and PTEN methylation patterns showed significant hypermethylation levels in tumor tissues (P < 0.05 and <0.01, respectively) whereas the TP53 tumor suppressor gene was not hypermethylated (P < 0.511). The proportion of PTEN methylation was significantly higher in serum than in the normal tissues and it has a significant correlation to tumor tissues (P < 0.05). mtDNA analysis revealed 36.36% somatic and 90.91% germline mutations in the D-loop region and also significant mtDNA depletion in tumor tissues (P < 0.01). In addition, the mtDNA content in matched serum was significantly lower than in the normal tissues (P < 0.05). These data can provide an insight into the management of a therapeutic approach based on the reversal of epigenetic silencing of the crucial genes involved in regulatory pathways of the tumor suppressor TP53. Additionally, release of significant aberrant methylated PTEN in matched serum samples might represent a promising biomarker for breast cancer.

An introduction to model-independent diffusion magnetic resonance imaging.

ABSTRACT: q-Space-based techniques such as diffusion spectrum imaging, q-ball imaging, and their variations have been used extensively in research for their desired capability to delineate complex neuronal architectures such as multiple fiber crossings in each of the image voxels. The purpose of this article was to provide an introduction to the q-space formalism and the principles of basic q-space techniques together with the discussion on the advantages as well as challenges in translating these techniques into the clinical environment. A review of the currently used q-space-based protocols in clinical research is also provided.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

The Swiss regulatory framework for pædiatric health research

Medical research on minors entails both risks and benefits. Under Swiss law, clinical trials on children, including nontherapeutic drug trials, are permissible. However, ethics committees must systematically verify that all clinical studies have a favorable risk-benefit profile. Additional safeguards are designed to ensure that children are not unnecessarily involved in research and that proper consent is always obtained. Federal Swiss law is undergoing revision to extend these protections beyond clinical trials to a broad array of health research. The Swiss drug agency also seeks to improve the incentives for pharmaceutical firms to develop new paediatric drugs and relevant paediatric drug labels.