Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families

A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. (1). The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. (2). However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.

No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF)

The neuregulin-1 gene (NRG1) at chromosome 8p21-22 has been implicated as a schizophrenia susceptibility gene in Icelandic, Scottish, Irish and mixed UK populations. The shared ancestry between these populations led us to investigate the NRG1 polymorphisms and appropriate marker haplotypes for linkage and/or association to schizophrenia in the Irish study of high-density schizophrenia families (ISHDSF). Neither single-point nor multi-point linkage analysis of NRG1 markers gave evidence for linkage independent of our pre-existing findings telomeric on 8p. Analysis of linkage disequilibrium (LD) across the 252 kb interval encompassing the 7 marker core Icelandic/Scottish NRG1 haplotype revealed two separate regions of modest LD, comprising markers SNP8NRG255133, SNP8NRG249130 and SNP8NRG243177 (telomeric) and microsatellites 478B14-428, 420M9-1395, D8S1810 and 420M9-116I12 (centromeric). From single marker analysis by TRANSMIT and FBAT we found no evidence for association with schizophrenia for any marker. Haplotype analysis for the three SNPs in LD region 1 and, separately, the four microsatellites in LD region 2 (analyzed in overlapping 2-marker windows), showed no evidence for overtransmission of specific haplotypes to affected individuals. We therefore conclude that if NRG1 does contain susceptibility alleles for schizophrenia, they impact quite weakly on risk in the ISHDSF.

Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia

Chromosome 5q22-33 is a region where studies have repeatedly found evidence for linkage to schizophrenia. In this report, we took a stepwise approach to systematically map this region in the Irish Study of High Density Schizophrenia Families (ISHDSF, 267 families, 1337 subjects) sample. We typed 289 SNPs in the critical interval of 8 million basepairs and found a 758 kb interval coding for the SPEC2/PDZ-GEF2/ACSL6 genes to be associated with the disease. Using sex and genotype-conditioned transmission disequilibrium test analyses, we found that 19 of the 24 typed markers were associated with the disease and the associations were sex-specific. We replicated these findings with an Irish case-control sample (657 cases and 414 controls), an Irish parent-proband trio sample (187 families, 564 subjects), a German nuclear family sample (211 families, 751 subjects) and a Pittsburgh nuclear family sample (247 families, 729 subjects). In all four samples, we replicated the sex-specific associations at the levels of both individual markers and haplotypes using sex- and genotype-conditioned analyses. Three risk haplotypes were identified in the five samples, and each haplotype was found in at least two samples. Consistent with the discovery of multiple estrogen-response elements in this region, our data showed that the impact of these haplotypes on risk for schizophrenia differed in males and females. From these data, we concluded that haplotypes underlying the SPEC2/PDZ-GEF2/ACSL6 region are associated with schizophrenia. However, due to the extended high LD in this region, we were unable to distinguish whether the association signals came from one or more of these genes.

Environmental Challenges and Physiological Solutions: Comparative Energetic Daily Rhythms of Field Mice Populations from Different Ecosystems

Daily and seasonal variations in physiological characteristics of mammals can be considered adaptations to temporal habitat variables. Across different ecosystems, physiological adjustments are expected to be sensitive to different environmental signals such as changes in photoperiod, temperature or water and food availability; the relative importance of a particular signal being dependent on the ecosystem in question. Energy intake, oxygen consumption (VO) and body temperature (T) daily rhythms were compared between two populations of the broad-toothed field mouse Apodemus mystacinus, one from a Mediterranean and another from a sub-Alpine ecosystem. Mice were acclimated to short-day (SD) 'winter' and long-day (LD) 'summer' photoperiods under different levels of salinity simulating osmotic challenges. Mediterranean mice had higher VO values than sub-Alpine mice. In addition, mice exposed to short days had higher VO values when given water with a high salinity compared with mice exposed to long days. By comparison, across both populations, increasing salinity resulted in a decreased T in SD- but not in LD-mice. Thus, SD-mice may conserve energy by decreasing T during ('winter') conditions which are expected to be cool, whereas LD-mice might do the opposite and maintain a higher T during ('summer') conditions which are expected to be warm. LD-mice behaved to reduce energy expenditure, which might be considered a useful trait during 'summer' conditions. Overall, increasing salinity was a clear signal for Mediterranean-mice with resultant effects on VO and T daily rhythms but had less of an effect on sub-Alpine mice, which were more responsive to changes in photoperiod. Results provide an insight into how different populations respond physiologically to various environmental challenges.

Freeze-Dried Strawberries Lower Serum Cholesterol and Lipid Peroxidation in Adults with Abdominal Adiposity and Elevated Serum Lipids

Dietary flavonoid intake, especially berry flavonoids, has been associated with reduced risks of cardiovascular disease (CVD) in large prospective cohorts. Few clinical studies have examined the effects of dietary berries on CVD risk factors. We examined the hypothesis that freeze-dried strawberries (FDS) improve lipid and lipoprotein profiles and lower biomarkers of inflammation and lipid oxidation in adults with abdominal adiposity and elevated serum lipids. In a randomized dose-response controlled trial, 60 volunteers [5 men and 55 women; aged 49 ± 10 y; BMI: 36 ± 5 kg/m2 (means ± SDs)] were assigned to consume 1 of the following 4 beverages for 12 wk: 1) low-dose FDS (LD-FDS; 25 g/d); 2) low-dose control (LD-C); 3) high-dose FDS (HD-FDS; 50 g/d); and 4) high-dose control (HD-C). Control beverages were matched for calories and total fiber. Blood draws, anthropometrics, blood pressure, and dietary data were collected at screening (0 wk) and after 12-wk intervention. Dose-response analyses revealed significantly greater decreases in serum total and LDL cholesterol and nuclear magnetic resonance (NMR)–derived small LDL particle concentration in HD-FDS [33 ± 6 mg/dL, 28 ± 7 mg/dL, and 301 ± 78 nmol/L, respectively (means ± SEMs)] vs. LD-FDS (−3 ± 11 mg/dL, −3 ± 9 mg/dL, and −28 ± 124 nmol/L, respectively) over 12 wk (0–12 wk; all P < 0.05). Compared with controls, only the decreases in total and LDL cholesterol in HD-FDS remained significant vs. HD-C (0.7 ± 12 and 1.4 ± 9 mg/dL, respectively) over 12 wk (0–12 wk; all P < 0.05). Both doses of strawberries showed a similar decrease in serum malondialdehyde at 12 wk (LD-FDS: 1.3 ± 0.2 μmol/L; HD-FDS: 1.2 ± 0.1 μmol/L) vs. controls (LD-C: 2.1 ± 0.2 μmol/L; HD-C: 2.3 ± 0.2 μmol/L) (P < 0.05). In general, strawberry intervention did not affect any measures of adiposity, blood pressure, glycemia, and serum concentrations of HDL cholesterol and triglycerides, C-reactive protein, and adhesion molecules. Thus, HD-FDS exerted greater effects in lowering serum total and LDL cholesterol and NMR-derived small LDL particles vs. LD-FDS in the 12-wk study. These findings warrant additional investigation in larger trials. This trial was registered at clinicaltrials.gov as NCT01883401.

How to measure the micromaser spectrum in the trapping state regime

We show how our recently proposed scheme for the measurement of the micromaser linewidth, which relates the phase diffusion dynamics of the cavity field to the population statistics of probe atoms, can be applied in the presence of trapping states, where the phase diffusion approximation does not strictly hold. This should allow the observation of the peculiar linewidth oscillations versus atomic pumping which are expected in this regime, and whose origin lies in the quantum nature of the cavity field.

Water efficiency as a means of reducing carbon emissions in Northern Ireland (NI) Water

The water and sewerage sectors' combined emissions account for just over 1% of total UK emissions, while household water heating accounts for a further 5%. Energy use, particularly electricity, is the largest source of emissions in the sector. Water efficiency measures should therefore result in reduced emissions from a lower demand for water and wastewater treatment and pumping, as well as from decreased domestic water heating. Northern Ireland Water (NI Water) is actively pursuing measures to reduce its carbon footprint. This paper investigated the carbon impacts of implementing a household water efficiency programme in Northern Ireland. Assuming water savings of 59.6 L/prop/day and 15% uptake among households, carbon savings of 0.6% of NI Water's current net operational emissions are achievable from reduced treatment and pumping. Adding the carbon savings from reduced household water heating gives savings equivalent to 6.2% of current net operational emissions. Cost savings to NI Water are estimated as 300,000 per year. The cost of the water efficiency devices is approximately 1.6 million, but may be higher depending on the number of devices distributed relative to the number installed. This paper has shown clear carbon benefits to water efficiency, but further research is needed to examine social and cost impacts. © IWA Publishing 2013.

Low dose effects of ionizing radiation on normal tissue stem cells

In recent years, there has been growing evidence for the involvement of stem cells in cancer initiation. As a result of their long life span, stem cells may have an increased propensity to accumulate genetic damage relative to differentiated cells. Therefore, stem cells of normal tissues may be important targets for radiation-induced carcinogenesis.

Knowledge of the effects of ionizing radiation (IR) on normal stem cells and on the processes involved in carcinogenesis is very limited. The influence of high doses of IR (>5 Gy) on proliferation, cell cycle and induction of senescence has been demonstrated in stem cells. There have been limited studies of the effects of moderate (0.5–5 Gy) and low doses (<0.5 Gy) of IR on stem cells however, the effect of low dose IR (LD-IR) on normal stem cells as possible targets for radiation-induced carcinogenesis has not been studied in any depth. There may also be important parallels between stem cell responses and those of cancer stem cells, which may highlight potential key common mechanisms of their response and radiosensitivity.

This review will provide an overview of the current knowledge of radiation-induced effects on normal stem cells, with particular focus on low and moderate doses of IR.

Release of β-galactosidase from poloxamine/α-cyclodextrin hydrogels

All mammals lose their ability to produce lactase (β-galactosidase), the enzyme that cleaves lactose into galactose and glucose, after weaning. The prevalence of lactase deficiency (LD) spans from 2 to 15% among northern Europeans, to nearly 100% among Asians. Following lactose consumption, people with LD often experience gastrointestinal symptoms such as abdominal pain, bowel distension, cramps and flatulence, or even systemic problems such as headache, loss of concentration and muscle pain. These symptoms vary depending on the amount of lactose ingested, type of food and degree of intolerance. Although those affected can avoid the uptake of dairy products, in doing so, they lose a readily available source of calcium and protein. In this work, gels obtained by complexation of Tetronic 90R4 with α-cyclodextrin loaded with β-galactosidase are proposed as a way to administer the enzyme immediately before or with the lactose-containing meal. Both molecules are biocompatible, can form gels in situ, and show sustained erosion kinetics in aqueous media. The complex was characterized by FTIR that evidenced an inclusion complex between the polyethylene oxide block and α-cyclodextrin. The release profiles of β-galactosidase from two different matrices (gels and tablets) of the in situ hydrogels have been obtained. The influence of the percentage of Tetronic in media of different pH was evaluated. No differences were observed regarding the release rate from the gel matrices at pH 6 (t50 = 105 min). However, in the case of the tablets, the kinetics were faster and they released a greater amount of 90R4 (25%, t50 = 40–50 min). Also, the amount of enzyme released was higher for mixtures with 25% Tetronic. Using suitable mathematical models, the corresponding kinetic parameters have been calculated. In all cases, the release data fit quite well to the Peppas–Sahlin model equation, indicating that the release of β-galactosidase is governed by a combination of diffusion and erosion processes. It has been observed that the diffusion mechanism prevails over erosion during the first 50 minutes, followed by continued release of the enzyme due to the disintegration of the matrix.

238.2T-14 Concrete Thixotropy

Fresh concrete can exhibit different rheological behavior when at rest than when flowing. This difference is due to thixotropy, which can have important consequences for formwork pressure, multi-lift casting, slip-form paving, pumping, and segregation resistance. This TechNote defines thixotropy and distinguishes it from other changes in rheological properties; discusses the origins of, test methods for measuring, and factors affecting thixotropy; and concludes with its applications.

Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

Estudo e aplicação de amplificadores ópticos para suporte a redes banda larga

Esta tese tem como foco principal a análise dos principais tipos de amplificação óptica e algumas de suas aplicações em sistemas de comunicação óptica. Para cada uma das tecnologias abordadas, procurou-se definir o estado da arte bem como identificar as oportunidades de desenvolvimento científico relacionadas. Os amplificadores para os quais foi dirigido alguma atenção neste documento foram os amplificadores em fibra dopada com Érbio (EDFA), os amplificadores a semicondutor (SOA) e os amplificadores de Raman (RA). Este trabalho iniciou-se com o estudo e análise dos EDFA’s. Dado o interesse científico e económico que estes amplificadores têm merecido, apenas poucos nichos de investigação estão ainda em aberto. Dentro destes, focá-mo-nos na análise de diferentes perfis de fibra óptica dopada de forma a conseguir uma optimização do desempenho dessas fibras como sistemas de amplificação. Considerando a fase anterior do trabalho como uma base de modelização para sistemas de amplificação com base em fibra e dopantes, evoluiu-se para amplificadores dopados mas em guias de onda (EDWA). Este tipo de amplificador tenta reduzir o volume físico destes dispositivos, mantendo as suas características principais. Para se ter uma forma de comparação de desempenho deste tipo de amplificador com os amplificadores em fibra, foram desenvolvidos modelos de caixa preta (BBM) e os seus parâmetros afinados por forma a termos uma boa modelização e posterior uso deste tipo de amplificiadores em setups de simulação mais complexos. Depois de modelizados e compreendidos os processo em amplificadores dopados, e com vista a adquirir uma visão global comparativa, foi imperativo passar pelo estudo dos processos de amplificação paramétrica de Raman. Esse tipo de amplificação, sendo inerente, ocorre em todas as bandas de propagação em fibra e é bastante flexível. Estes amplificadores foram inicialmente modelizados, e algumas de suas aplicações em redes passivas de acesso foram estudadas. Em especial uma série de requisitos, como por exemplo, a gama de comprimentos de onda sobre os quais existem amplificação e os altos débitos de perdas de inserção, nos levaram à investigação de um processo de amplificação que se ajustasse a eles, especialmente para buscar maiores capacidades de amplificação (nomeadamente longos alcances – superiores a 100 km – e altas razões de divisão – 1:512). Outro processo investigado foi a possibilidade de flexibilização dos parâmetros de comprimento de onda de ganho sem ter que mudar as caractísticas da bomba e se possível, mantendo toda a referenciação no transmissor. Este processo baseou-se na técnica de clamping de ganho já bastante estudada, mas com algumas modificações importantes, nomeadamente a nível do esquema (reflexão apenas num dos extremos) e da modelização do processo. O processo resultante foi inovador pelo recurso a espalhamentos de Rayleigh e Raman e o uso de um reflector de apenas um dos lados para obtenção de laser. Este processo foi modelizado através das equações de propagação e optimizado, tendo sido demonstrado experimentalmente e validado para diferentes tipos de fibras. Nesta linha, e dada a versatilidade do modelo desenvolvido, foi apresentada uma aplicação mais avançada para este tipo de amplificadores. Fazendo uso da sua resposta ultra rápida, foi proposto e analisado um regenerador 2R e analisada por simulação a sua gama de aplicação tendo em vista a sua aplicação sistémica. A parte final deste trabalho concentrou-se nos amplificadores a semiconductor (SOA). Para este tipo de amplificador, os esforços foram postos mais a nível de aplicação do que a nível de sua modelização. As aplicações principais para estes amplificadores foram baseadas em clamping óptico do ganho, visando a combinação de funções lógicas essenciais para a concepção de um latch óptico com base em componentes discretos. Assim, com base num chip de ganho, foi obtido uma porta lógica NOT, a qual foi caracterizada e demonstrada experimentalmente. Esta foi ainda introduzida num esquema de latching de forma a produzir um bi-estável totalmente óptico, o qual também foi demonstrado e caracterizado. Este trabalho é finalizado com uma conclusão geral relatando os subsistemas de amplificação e suas aplicacações.

Alternative techniques for Raman amplification in telecommunications

O presente trabalho centra-se no estudo dos amplificadores de Raman em fibra ótica e suas aplicações em sistemas modernos de comunicações óticas. Abordaram-se tópicos específicos como a simulação espacial do amplificador de Raman, a equalização e alargamento do ganho, o uso de abordagens híbridas de amplificação através da associação de amplificadores de Raman em fibra ótica com amplificadores de fibra dopada com Érbio (EDFA) e os efeitos transitórios no ganho dos amplificadores. As actividades realizadas basearam-se em modelos teóricos, sendo os resultados validados experimentalmente. De entre as contribuições mais importantes desta tese, destaca-se (i) o desenvolvimento de um simulador eficiente para amplificadores de Raman que suporta arquitecturas de bombeamento contraprogantes e bidirecionais num contexto com multiplexagem no comprimento de onda (WDM); (ii) a implementação de um algoritmo de alocação de sinais de bombeamento usando a combinação do algoritmo genético com o método de Nelder- Mead; (iii) a apreciação de soluções de amplificação híbridas por associação dos amplificadores de Raman com EDFA em cenários de redes óticas passivas, nomeadamente WDM/TDM-PON com extensão a região espectral C+L; e (iv) a avaliação e caracterização de fenómenos transitórios em amplificadores para tráfego em rajadas/pacotes óticos e consequente desenvolvimento de soluções de mitigação baseadas em técnicas de clamping ótico.

Management and Control of Water Supply Systems

The fast increase in the energy’s price has brought a growing concern about the highly expensive task of transporting water. By creating an hydraulic model of the Water Supply System’s (WSS) network and predicting its behaviour, it is possible to take advantage of the energy’s tariffs, reducing the total cost on pumping activities. This thesis was developed, in association with a technology transfer project called the E-Pumping. It focuses on finding a flexible supervision and control strategy, adaptable to any existent Water Supply System (WSS), as well as forecasting the water demand on a time period chosen by the end user, so that the pumping actions could be planned to an optimum schedule, that minimizes the total operational cost. The OPC protocol, associated to a MySQL database were used to develop a flexible tool of supervision and control, due to their adaptability to function with equipments from various manufacturers, being another integrated modular part of the E-Pumping project. Furthermore, in this thesis, through the study and performance tests of several statistical models based on time series, specifically applied to this problem, a forecasting tool adaptable to any station, and whose model parameters are automatically refreshed at runtime, was developed and added to the project as another module. Both the aforementioned modules were later integrated with an Graphical User Interface (GUI) and installed in a pilot application at the ADDP’s network. The implementation of this software on WSSs across the country will reduce the water supply companies’ running costs, improving their market competition and, ultimately, lowering the water price to the end costumer.

Study of influence of regulatory polymorphisms of expression in development of breast cancer

The human genome has millions of genetics variants that can affect gene expression. These variants are known as cis-regulatory variants and are responsible for intra-species phenotypic differences and individual susceptibility to disease. One of the diseases affected by cis-regulatory variants is breast cancer. Breast cancer is one of the most common cancers, with approximately 4500 new cases each year in Portugal. Breast cancer has many genes mutated and TP53 has been shown to be relevant for this disease. TP53 is one of the most commonly mutated genes in human cancer and it is involved in cell cycle regulation and apoptosis. Previous work by Maia et al has shown that TP53 has differential allelic expression (DAE), which suggests that this gene may be under the influence of cis-regulatory variants. Also, its DAE pattern is totally altered in breast tumours with normal copy number. We hypothesized that cis-regulatory variants affecting TP53 may have a role in breast cancer development and treatment. The present work aims to identify the cis-regulatory variants playing a role in TP53 expression, using in silico, in vitro and in vivo approaches. By bioinformatic tools we have identified candidate cis-regulatory variants and predicted the possible transcription factor binding sites that they affect. By EMSA we studied DNA-protein interactions in this region of TP53. The in silico analysis allowed us to identified three candidate cis-regulatory SNPs which may affect the binding of seven transcription factors. However, the EMSA experiments have not been conclusive and we have not yet confirmed whether any of the identified SNPs are associated with gene expression control of TP53. We will carry out further experiments to validate our findings.