HpMC: An Energy- Aware Management System for Multi-Level Memory Architectures

DRAM technology faces density and power challenges to increase capacity because of limitations of physical cell design. To overcome these limitations, system designers are exploring alternative solutions that combine DRAM and emerging NVRAM technologies. Previous work on heterogeneous memories focuses, mainly, on two system designs: PCache, a hierarchical, inclusive memory system, and HRank, a flat, non-inclusive memory system. We demonstrate that neither of these designs can universally achieve high performance and energy efficiency across a suite of HPC workloads. In this work, we investigate the impact of a number of multilevel memory designs on the performance, power, and energy consumption of applications. To achieve this goal and overcome the limited number of available tools to study heterogeneous memories, we created HMsim, an infrastructure that enables n-level, heterogeneous memory studies by leveraging existing memory simulators. We, then, propose HpMC, a new memory controller design that combines the best aspects of existing management policies to improve performance and energy. Our energy-aware memory management system dynamically switches between PCache and HRank based on the temporal locality of applications. Our results show that HpMC reduces energy consumption from 13% to 45% compared to PCache and HRank, while providing the same bandwidth and higher capacity than a conventional DRAM system.

Interspecific comparison of estrogen and testosterone concentrations in three species of amphipods (Gammarus duebeni celticus, G. pseudolimnaeus, and G. pulex)

The presence and biological significance of vertebrate-related steroid sex hormones in aquatic invertebrates are poorly understood. We compared the concentrations of estrogen (17β-estradiol) and testosterone between amplexing male and female freshwater amphipods of three species from two continents: Gammarus duebeni celticusLiljeborg, 1852 and G. pulex(L., 1758) from Europe, and G. pseudolimnaeusBousfield, 1958 from North America. All three species were found to have measureable concentrations of both hormones in whole body lysate samples but the concentrations differed between species, with testosterone differing significantly between species only for male amphipods and estradiol differing significantly between species only for female amphipods. Concentrations of both testosterone and estrogen differed between males and females in two of the three species ( G. duebeni celticusand G. pseudolimnaeus). Females had the highest concentration of both hormones in G. duebeni celticusand the lowest concentration of both hormones in G. pseudolimnaeus. These results contribute to a growing body of evidence that these hormones are endogenously produced and biologically relevant in amphipods. Such evidence is particularly important in light of increasing prevalence of endocrine-disrupting compounds in the environment and the central role played by amphipods in aquatic ecosystems.

The cyclin D1 (CCND1) rs9344 G>A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy

Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.

A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor

Ligands targeting G protein-coupled receptors (GPCRs) are currently classified as either orthosteric, allosteric, or dualsteric/bitopic. Here, we introduce a new pharmacological concept for GPCR functional modulation: sequential receptor activation. A hallmark feature of this is a stepwise ligand binding mode with transient activation of a first receptor site followed by sustained activation of a second topographically distinct site. We identify 4-CMTB (2-(4-chlorophenyl)-3-methyl-N-(thiazol-2-yl)butanamide), previously classified as a pure allosteric agonist of the free fatty acid receptor 2, as the first sequential activator and corroborate its two-step activation in living cells by tracking integrated responses with innovative label-free biosensors that visualize multiple signaling inputs in real time. We validate this unique pharmacology with traditional cellular readouts, including mutational and pharmacological perturbations along with computational methods, and propose a kinetic model applicable to the analysis of sequential receptor activation. We envision this form of dynamic agonism as a common principle of nature to spatiotemporally encode cellular information.

Metabolically-inactive glucagon-like peptide-1(9-36)amide confers selective protective actions against post-myocardial infarction remodelling

BACKGROUND: Glucagon-like peptide-1 (GLP-1) therapies are routinely used for glycaemic control in diabetes and their emerging cardiovascular actions have been a major recent research focus. In addition to GLP-1 receptor activation, the metabolically-inactive breakdown product, GLP-1(9-36)amide, also appears to exert notable cardiovascular effects, including protection against acute cardiac ischaemia. Here, we specifically studied the influence of GLP-1(9-36)amide on chronic post-myocardial infarction (MI) remodelling, which is a major driver of heart failure progression.

METHODS: Adult female C57BL/6 J mice were subjected to permanent coronary artery ligation or sham surgery prior to continuous infusion with GLP-1(9-36)amide or vehicle control for 4 weeks.

RESULTS: Infarct size was similar between groups with no effect of GLP-1(9-36)amide on MI-induced cardiac hypertrophy, although modest reduction of in vitro phenylephrine-induced H9c2 cardiomyoblast hypertrophy was observed. Whilst echocardiographic systolic dysfunction post-MI remained unchanged, diastolic dysfunction (decreased mitral valve E/A ratio, increased E wave deceleration rate) was improved by GLP-1(9-36)amide treatment. This was associated with modulation of genes related to extracellular matrix turnover (MMP-2, MMP-9, TIMP-2), although interstitial fibrosis and pro-fibrotic gene expression were unaltered by GLP-1(9-36)amide. Cardiac macrophage infiltration was also reduced by GLP-1(9-36)amide together with pro-inflammatory cytokine expression (IL-1β, IL-6, MCP-1), whilst in vitro studies using RAW264.7 macrophages revealed global potentiation of basal pro-inflammatory and tissue protective cytokines (e.g. IL-1β, TNF-α, IL-10, Fizz1) in the presence of GLP-1(9-36)amide versus exendin-4.

CONCLUSIONS: These data suggest that GLP-1(9-36)amide confers selective protection against post-MI remodelling via preferential preservation of diastolic function, most likely due to modulation of infiltrating macrophages, indicating that this often overlooked GLP-1 breakdown product may exert significant actions in this setting which should be considered in the context of GLP-1 therapy in patients with cardiovascular disease.

F. G. Teixeira e a comunidade matemática europeia nos séculos XIX-XX

Esta dissertação descreve o processo de integração dos matemáticos portugueses na comunidade matemática internacional no final do século XIX e início do século XX, focando-se na vida e obra do matemático Francisco Gomes Teixeira (1851-1933). Tenciona a ser mais um contributo para o reconhecimento nacional e internacional do matemático Gomes Teixeira analisando a sua obra como matemático e organizador científico em Portugal através de fontes, parcialmente ainda não conhecidas. Para esse efeito analisou-se a evolução histórica que ocorreu no mundo científico daquela época, em particular a formação da comunidade matemática através de iniciativas individuais ou coletivas, muitas vezes acompanhadas pela fundação de revistas e elaboração de manuais que contribuíram para a internacionalização e, de certa forma, para uma estandardização do estudo universitário básico. Em particular foi estudada a situação em Portugal, onde o papel de liderança foi assumido por Gomes Teixeira. Mostra-se como Gomes Teixeira, graças ao seu trabalho, ao seu talento como matemático e à sua atividade como organizador académico, conseguiu reduzir significativamente o isolamento científico de Portugal na área da matemática. Estudou-se em extensão a fundação de revistas científicas em diferentes países, acompanhando a sua evolução desde de revistas nacionais até revistas internacionais. Focando-nos no Jornal de Sciencias Matemáticas e Astronómicas, fundado em 1877 por Gomes Teixeira (mais tarde conhecido internacionalmente como Teixeira’s Journal), acompanhamos detalhadamente a sua transformação de uma revista nacional numa revista internacional, sendo esta transformação comum naquela época à maioria de revistas científicas importantes de outros países como, por exemplo, no caso do Jornal de Crelle, do Jornal de Liouville, ou outros. Estudou-se igualmente o reconhecimento a nível internacional, através de referências estrangeiras, da abordagem original de Gomes Teixeira à Análise Infinitesimal patente nos seus manuais. O interesse de Gomes Teixeira pela teoria das funções analíticas e pelos seus diferentes desenvolvimentos em série manifestou-se no grande número de artigos publicados sobre este tema e encontrou reconhecimento justo pela designação de um teorema que completa resultados de Lagrange e de Laurent como Teorema de Teixeira. Na sua análise do mérito científico de Gomes Teixeira esta dissertação restringiu-se conscientemente nesta área da Análise Matemática, uma vez que um estudo abrangente de toda a obra ultrapassasse o nosso objetivo. Foi também discutido o intenso intercâmbio científico levado a cabo por Gomes Teixeira através de correspondência e troca de publicações ou permuta de revistas com os matemáticos de diferentes países. Esta análise permitiu verificar um aumento da popularidade dos matemáticos portugueses através do incremento do número de artigos publicados no estrangeiro durante quase 30 anos. Uma fonte imprescindível nesta análise foi o Jahrbuch über die Fortschritte der Mathematik, cujas referências (em geral na língua alemã e por isso até agora quase nunca usadas na literatura Portuguesa) documentaram as publicações em quase todas as revistas matemáticas durante os anos da sua existência entre 1868 e 1942. Descreve-se a colaboração de Gomes Teixeira com diferentes organizações internacionais e documenta-se o apreço internacional por parte do mundo académico. Novos documentos traçam o processo de eleição como membro da Academia das Ciências Alemã Leopoldina, sob proposta de Georg Cantor e outros matemáticos alemães. Finalmente, incluí-se uma breve descrição das atividades levadas a cabo na Rússia, em Espanha e na Grécia em prol do processo de internacionalização da comunidade matemática europeia tendo em vista uma melhor contextualização do contributo de Gomes Teixeira para a integração de Portugal neste processo.

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.