Molecular diagnosis of distal renal tubular acidosis in Tunisian patients: proposed algorithm for Northern Africa populations for the ATP6V1B1, ATP6V0A4 and SCL4A1 genes

Background: Primary distal renal tubular acidosis (dRTA) caused by mutations in the genes that codify for the H+ -ATPase pump subunits is a heterogeneous disease with a poor phenotype-genotype correlation. Up to now, large cohorts of dRTA Tunisian patients have not been analyzed, and molecular defects may differ from those described in other ethnicities. We aim to identify molecular defects present in the ATP6V1B1, ATP6V0A4 and SLC4A1 genes in a Tunisian cohort, according to the following algorithm: first, ATP6V1B1 gene analysis in dRTA patients with sensorineural hearing loss (SNHL) or unknown hearing status. Afterwards, ATP6V0A4 gene study in dRTA patients with normal hearing, and in those without any structural mutation in the ATP6V1B1 gene despite presenting SNHL. Finally, analysis of the SLC4A1 gene in those patients with a negative result for the previous studies. Methods: 25 children (19 boys) with dRTA from 20 families of Tunisian origin were studied. DNAs were extracted by the standard phenol/chloroform method. Molecular analysis was performed by PCR amplification and direct sequencing. Results: In the index cases, ATP6V1B1 gene screening resulted in a mutation detection rate of 81.25%, which increased up to 95% after ATP6V0A4 gene analysis. Three ATP6V1B1 mutations were observed: one frameshift mutation (c.1155dupC; p.Ile386fs), in exon 12; a G to C single nucleotide substitution, on the acceptor splicing site (c.175-1G > C; p.?) in intron 2, and one novel missense mutation (c. 1102G > A; p. Glu368Lys), in exon 11. We also report four mutations in the ATP6V0A4 gene: one single nucleotide deletion in exon 13 (c.1221delG; p. Met408Cysfs* 10); the nonsense c.16C > T; p.Arg6*, in exon 3; and the missense changes c.1739 T > C; p.Met580Thr, in exon 17 and c.2035G > T; p.Asp679Tyr, in exon 19. Conclusion: Molecular diagnosis of ATP6V1B1 and ATP6V0A4 genes was performed in a large Tunisian cohort with dRTA. We identified three different ATP6V1B1 and four different ATP6V0A4 mutations in 25 Tunisian children. One of them, c.1102G > A; p.Glu368Lys in the ATP6V1B1 gene, had not previously been described. Among deaf since childhood patients, 75% had the ATP6V1B1 gene c. 1155dupC mutation in homozygosis. Based on the results, we propose a new diagnostic strategy to facilitate the genetic testing in North Africans with dRTA and SNHL.

Variability in the air-sea interaction patterns and timescales within the south-eastern Bay of Biscay, as observed by HF radar data

Two high-frequency (HF) radar stations were installed on the coast of the south-eastern Bay of Biscay in 2009, providing high spatial and temporal resolution and large spatial coverage of currents in the area for the first time. This has made it possible to quantitatively assess the air-sea interaction patterns and timescales for the period 2009-2010. The analysis was conducted using the Barnett-Preisendorfer approach to canonical correlation analysis (CCA) of reanalysis surface winds and HF radar-derived surface currents. The CCA yields two canonical patterns: the first wind-current interaction pattern corresponds to the classical Ekman drift at the sea surface, whilst the second describes an anticyclonic/cyclonic surface circulation. The results obtained demonstrate that local winds play an important role in driving the upper water circulation. The wind-current interaction timescales are mainly related to diurnal breezes and synoptic variability. In particular, the breezes force diurnal currents in waters of the continental shelf and slope of the south-eastern Bay. It is concluded that the breezes may force diurnal currents over considerably wider areas than that covered by the HF radar, considering that the northern and southern continental shelves of the Bay exhibit stronger diurnal than annual wind amplitudes.

A colorectal cancer genome-wide association study in a Spanish cohort identifies two variants associated with colorectal cancer risk at 1p33 and 8p12

Background: Colorectal cancer (CRC) is a disease of complex aetiology, with much of the expected inherited risk being due to several common low risk variants. Genome-Wide Association Studies (GWAS) have identified 20 CRC risk variants. Nevertheless, these have only been able to explain part of the missing heritability. Moreover, these signals have only been inspected in populations of Northern European origin. Results: Thus, we followed the same approach in a Spanish cohort of 881 cases and 667 controls. Sixty-four variants at 24 loci were found to be associated with CRC at p-values <10-5. We therefore evaluated the 24 loci in another Spanish replication cohort (1481 cases and 1850 controls). Two of these SNPs, rs12080929 at 1p33 (P-replication=0.042; P-pooled=5.523x10(-03); OR (CI95%)=0.866(0.782-0.959)) and rs11987193 at 8p12 (P-replication=0.039; P-pooled=6.985x10(-5); OR (CI95%)=0.786(0.705-0.878)) were replicated in the second Phase, although they did not reach genome-wide statistical significance. Conclusions: We have performed the first CRC GWAS in a Southern European population and by these means we were able to identify two new susceptibility variants at 1p33 and 8p12 loci. These two SNPs are located near the SLC5A9 and DUSP4 loci, respectively, which could be good functional candidates for the association signals. We therefore believe that these two markers constitute good candidates for CRC susceptibility loci and should be further evaluated in other larger datasets. Moreover, we highlight that were these two SNPs true susceptibility variants, they would constitute a decrease in the CRC missing heritability fraction.

Dynamics of Streptococcus pneumoniae Serotypes Causing Acute Otitis Media Isolated from Children with Spontaneous Middle-Ear Drainage over a 12-Year Period (1999–2010) in a Region of Northern Spain

10 p.

Association between dietary phylloquinone intake and peripheral metabolic risk markers related to insulin resistance and diabetes in elderly subjects at high cardiovascular risk

Background: Vitamin K has been related to glucose metabolism, insulin sensitivity and diabetes. Because inflammation underlies all these metabolic conditions, it is plausible that the potential role of vitamin K in glucose metabolism occurs through the modulation of cytokines and related molecules. The purpose of the study was to assess the associations between dietary intake of vitamin K and peripheral adipokines and other metabolic risk markers related to insulin resistance and type 2 diabetes mellitus. Methods: Cross-sectional and longitudinal assessments of these associations in 510 elderly participants recruited in the PREDIMED centers of Reus and Barcelona (Spain). We determined 1-year changes in dietary phylloquinone intake estimated by food frequency questionnaires, serum inflammatory cytokines and other metabolic risk markers. Results: In the cross-sectional analysis at baseline no significant associations were found between dietary phylloquinone intake and the rest of metabolic risk markers evaluated, with exception of a negative association with plasminogen activator inhibitor-1. After 1-year of follow-up, subjects in the upper tertile of changes in dietary phylloquinone intake showed a greater reduction in ghrelin (-15.0%), glucose-dependent insulinotropic peptide (-12.9%), glucagon-like peptide-1 (-17.6%), IL-6 (-27.9%), leptin (-10.3%), TNF (-26.9%) and visfatin (-24.9%) plasma concentrations than those in the lowest tertile (all p<0.05). Conclusion: These results show that dietary phylloquinone intake is associated with an improvement of cytokines and other markers related to insulin resistance and diabetes, thus extending the potential protection by dietary phylloquinone on chronic inflammatory diseases.

Contribution of Pannexin1 to Experimental Autoimmune Encephalomyelitis

Pannexin1 (Panx1) is a plasma membrane channel permeable to relatively large molecules, such as ATP. In the central nervous system (CNS) Panx1 is found in neurons and glia and in the immune system in macrophages and T-cells. We tested the hypothesis that Panx1-mediated ATP release contributes to expression of Experimental Autoimmune Encephalomyelitis (EAE), an animal model for multiple sclerosis, using wild-type (WT) and Panx1 knockout (KO) mice. Panx1 KO mice displayed a delayed onset of clinical signs of EAE and decreased mortality compared to WT mice, but developed as severe symptoms as the surviving WT mice. Spinal cord inflammatory lesions were also reduced in Panx1 KO EAE mice during acute disease. Additionally, pharmacologic inhibition of Panx1 channels with mefloquine (MFQ) reduced severity of acute and chronic EAE when administered before or after onset of clinical signs. ATP release and YoPro uptake were significantly increased in WT mice with EAE as compared to WT non-EAE and reduced in tissues of EAE Panx1 KO mice. Interestingly, we found that the P2X7 receptor was upregulated in the chronic phase of EAE in both WT and Panx1 KO spinal cords. Such increase in receptor expression is likely to counterbalance the decrease in ATP release recorded from Panx1 KO mice and thus contribute to the development of EAE symptoms in these mice. The present study shows that a Panx1 dependent mechanism (ATP release and/or inflammasome activation) contributes to disease progression, and that inhibition of Panx1 using pharmacology or gene disruption delays and attenuates clinical signs of EAE.

FTT-MA: A Flexible Time-Triggered Middleware Architecture for Time Sensitive, Resource-Aware AmI Systems

There is an increasing number of Ambient Intelligence (AmI) systems that are time-sensitive and resource-aware. From healthcare to building and even home/office automation, it is now common to find systems combining interactive and sensing multimedia traffic with relatively simple sensors and actuators (door locks, presence detectors, RFIDs, HVAC, information panels, etc.). Many of these are today known as Cyber-Physical Systems (CPS). Quite frequently, these systems must be capable of (1) prioritizing different traffic flows (process data, alarms, non-critical data, etc.), (2) synchronizing actions in several distributed devices and, to certain degree, (3) easing resource management (e.g., detecting faulty nodes, managing battery levels, handling overloads, etc.). This work presents FTT-MA, a high-level middleware architecture aimed at easing the design, deployment and operation of such AmI systems. FTT-MA ensures that both functional and non-functional aspects of the applications are met even during reconfiguration stages. The paper also proposes a methodology, together with a design tool, to create this kind of systems. Finally, a sample case study is presented that illustrates the use of the middleware and the methodology proposed in the paper.

Designing High Performance Factory Automation Applications on Top of DDS

13 p.

Ca2+ Influx and Tyrosine Kinases Trigger Bordetella Adenylate Cyclase Toxin (ACT) Endocytosis. Cell Physiology and Expression of the CD11b/CD18 Integrin Major Determinants of the Entry Route

Humans infected with Bordetella pertussis, the whooping cough bacterium, show evidences of impaired host defenses. This pathogenic bacterium produces a unique adenylate cyclase toxin (ACT) which enters human phagocytes and catalyzes the unregulated formation of cAMP, hampering important bactericidal functions of these immune cells that eventually cause cell death by apoptosis and/or necrosis. Additionally, ACT permeabilizes cells through pore formation in the target cell membrane. Recently, we demonstrated that ACT is internalised into macrophages together with other membrane components, such as the integrin CD11b/CD18 (CR3), its receptor in these immune cells, and GM1. The goal of this study was to determine whether ACT uptake is restricted to receptor-bearing macrophages or on the contrary may also take place into cells devoid of receptor and gain more insights on the signalling involved. Here, we show that ACT is rapidly eliminated from the cell membrane of either CR3-positive as negative cells, though through different entry routes, which depends in part, on the target cell physiology and characteristics. ACT-induced Ca2+ influx and activation of non-receptor Tyr kinases into the target cell appear to be common master denominators in the different endocytic strategies activated by this toxin. Very importantly, we show that, upon incubation with ACT, target cells are capable of repairing the cell membrane, which suggests the mounting of an anti-toxin cell repair-response, very likely involving the toxin elimination from the cell surface.

Surface Expression and Subunit Specific Control of Steady Protein Levels by the Kv7.2 Helix A-B Linker

12 p.

Cultura y creatividad en la nueva economía urbana: evidencias, discursos y críticas

En la medida en que el papel de los sectores cultural, artístico y creativo en el desarrollo económico y social de las ciudades-región comienza a ser ampliamente reconocido gracias a las progresivas evidencias empíricas recogidas en los últimos años sobre su importante capacidad de dinamismo, innovación y conectividad global, las intervenciones de las diferentes administraciones públicas y agentes privados en este ámbito también han ido en aumento. Una vez que el sector industrial ha declinado de forma drástica y otras actividades terciarias de la economía urbana se encuentran estancadas o en declive (comercio, consultoría, servicios inmobiliarios, etc.), las formas de producción y trabajo cognitivo-culturales son crecientemente señaladas como grandes impulsoras de la regeneración urbana, el posicionamiento global de las ciudades-región, la creación de empleo y la conexión con las vanguardias culturales. Si bien este proceso está facilitando una mayor visibilidad, apoyo y reconocimiento a las industrias y agentes culturales, artísticos y creativos que tradicionalmente han sufrido de forma intensa la precariedad, la baja o inexistente remuneración y la escasa valoración, también está propiciando una irrupción de las lógicas de mercado en ámbitos que hasta el momento han estado parcialmente desmercantilizados. Ello está generando diversas tensiones que afectan de forma destacada a la definición y el papel social y económico de la cultura en las ciudades.

The Influence of the Val158Met Catechol-O-Methyltransferase Polymorphism on the Personality Traits of Bipolar Patients

6 p.

El tráfico de esclavos en la Edad Moderna: destrucción de un mundo, raíces de un conflicto

Antonio Duplá Ansuategui, Piedad Frías Nogales e Iban Zaldúa (editores)

Domain walls collision in Fe-rich and Co-rich glass covered microwires

JEMS 2012 - Joint European Magnetic Symposia edited by Tiberto, P; Affronte, M; Casoli, F; Fernandez, CD; Gubbiotti, G; Marquina, C; Pratt, F; Solzi, M; Tacchi, S; Vavassori, P. 6th Joint European Magnetic Symposia (JEMS) Parma, ITALY SEP 09-14, 2012

Cost effectiveness of a combination of instruments for global warming: a quantitative approach for Spain

Climate change is an important environmental problem and one whose economic implications are many and varied. This paper starts with the presumption that mitigation of greenhouse gases is a necessary policy that has to be designed in a cost effective way. It is well known that market instruments are the best option for cost effectiveness. But the discussion regarding which of the various market instruments should be used, how they may interact and what combinations of policies should be implemented is still open and very lively. In this paper we propose a combination of instruments: the marketable emission permits already in place in Europe for major economic sectors and a CO(2) tax for economic sectors not included in the emissions permit scheme. The study uses an applied general equilibrium model for the Spanish economy to compute the results obtained with the new mix of instruments proposed. As the combination of the market for emission permits and the CO(2) tax admits different possibilities that depend on how the mitigation is distributed among the economic sectors, we concentrate on four possibilities: cost-effective, equalitarian, proportional to emissions, and proportional to output distributions. Other alternatives to the CO(2) tax are also analysed (tax on energy, on oil and on electricity). Our findings suggest that careful, well designed policies are needed as any deviation imposes significant additional costs that increase more than proportionally to the level of emissions reduction targeted by the EU.