Genetic Variants of Serum Uric Acid and Gout: An Analysis of > 170,000 Individuals

Background/Purpose: Gout is a common and excruciatingly painful inflammatory arthritis caused by hyperuricemia. In addition to various lifestyle risk factors, a substantial genetic predisposition to gout has long been recognized. The Global Urate Genetics Consortium (GUGC) has aimed to comprehensively investigate the genetics of serum uric acid and gout using data from _ 140,000 individuals of European-ancestry, 8,340 individuals of Indian ancestry, 5,820 African-Americans, and 15,286 Japanese. Methods: We performed discovery GWAS meta-analyses of serum urate levels (n_110,347 individuals) followed by replication analyses (n_32,813 different individuals). Our gout analysis involved 3,151 cases and 68,350 controls, including 1,036 incident gout cases that met the American College of Rheumatology Criteria. We also examined the association of gout with fractional excretion of uric acid (n_6,799). A weighted genetic urate score was constructed based on the number of risk alleles across urate-associated loci, and their association with the risk of gout was evaluated. Furthermore, we examined implicated transcript expression in cis (expression quantitative trait loci databases) for potential insights into the gene underlying the association signal. Finally, in order to further identify urate-associated genomic regions, we performed functional network analyses that incorporated prior knowledge on molecular interactions in which the gene products of implicated genes operate. Results: We identified and replicated 28 genome-wide significant loci in association with serum urate (P 5_10_8), including all previously-reported loci as well as 18 novel genetic loci. Unlike the majority of previouslyidentified loci, none of the novel loci appeared to be obvious candidates for urate transport. Rather, they were mapped to genes that encode for purine production, transcription, or growth factors with broad downstream responses. Besides SLC2A9 and ABCG2, no additional regions contained SNPs that differed significantly (P _ 5_10_8) between sexes. Urateincreasing alleles were associated with an increased risk of gout for all loci. The urate genetic risk score (ranging from 10 to 45) was significantly associated with an increased odds of prevalent gout (OR per unit increase, 1.11; 95% CI, 1.09-1.14) and incident gout (OR, 1.10; 95% CI, 1.08-1.13). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. Detailed characterization of the loci revealed associations with transcript expression and the fractional excretion of urate. Network analyses implicated the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. Conclusion: The novel genetic candidates identified in this urate/gout consortium study, the largest to date, highlight the importance of metabolic control of urate production and urate excretion. The modulation by signaling processes that influence metabolic pathways such as glycolysis and the pentose phosphate pathway appear to be central mechanisms underpinned by the novel GWAS candidates. These findings may have implications for further research into urate-lowering drugs to treat and prevent gout.

La investigación sobre El Pirulejo. Una aproximación interdisciplinar

El estudio interdisciplinar que constituye esta obra pone de manifiesto que El Pirulejo es el mejor yacimiento conocido para el conocimiento del Tardiglaciar en las comarcas interiores del sur de la Península Ibérica. El enclave conserva una secuencia muy rica en cantidad, calidad y diversidad de materiales arqueológicos que han permitido un análisis desde múltiples ópticas (cultura material, manifestaciones simbólicas, paleoeconomía, secuencia paleoambiental, etc.).

Análisis del ADN mitocondrial de dos muestras del yacimiento paleolítico de El Pirulejo.

En la presente publicación se presentan los resultados del análisis del ADN mitocondrial (ADNmt) de dos individuos del nivel magdaleniense de El Pirulejo (Córdoba) (Asquerino et al., 1991). Las secuencias obtenidas se encuadran dentro de la variabilidad genética del hombre moderno actual, sin presentar similitud alguna con las secuencias de ADN mitocondrial de neandertal publicadas hasta la fecha. La distribución actual de las variantes mitocondriales encontradas en las dos muestras de El Pirulejo es similar a la encontrada en otros dos individuos Paleolíticos (Caramelli et al., 2003), y coherente con el modelo de expansión del hombre anatómicamente moderno desde África.

The decline in breast cancer mortality in Europe: an update (to 2009).

We updated trends in breast cancer mortality in Europe up to the late 2000's. In the EU, age-adjusted (world standard population) breast cancer mortality rates declined by 6.9% between 2002 and 2006, from 17.9 to 16.7/100,000. The largest falls were in northern European countries, but more recent declines were also observed in central and eastern Europe. In 2007, all major European countries had overall breast cancer rates between 15 and 19/100,000. In relative terms, the declines in mortality were larger at younger age (-11.6% at age 20-49 years between 2002 and 2007 in the EU), and became smaller with advancing age (-6.6% at age 50-69, -5.0% at age 70-79 years). The present report confirms and further quantifies the persisting steady fall in breast cancer mortality in Europe over the last 25-30 years, which is mainly due to advancements in the therapy.

Diacylglycerol is required for the formation of COPI vesicles in the Golgi-to-ER transport pathway

Diacylglycerol is necessary for trans-Golgi network (TGN) to cell surface transport, but its functional relevance in the early secretory pathway is unclear. Although depletion of diacylglycerol did not affect ER-to-Golgi transport, it led to a redistribution of the KDEL receptor to the Golgi, indicating that Golgi-to-ER transport was perturbed. Electron microscopy revealed an accumulation of COPI-coated membrane profiles close to the Golgi cisternae. Electron tomography showed that the majority of these membrane profiles originate from coated buds, indicating a block in membrane fission. Under these conditions the Golgi-associated pool of ARFGAP1 was reduced, but there was no effect on the binding of coatomer or the membrane fission protein CtBP3/BARS to the Golgi. The addition of 1,2-dioctanoyl-sn-glycerol or the diacylglycerol analogue phorbol 12,13-dibutyrate reversed the effects of endogenous diacylglycerol depletion. Our findings implicate diacylglycerol in the retrograde transport of proteins from Golgi to the ER and suggest that it plays a critical role at a late stage of COPI vesicle formation.

Activation of Srk1 by the Mitogen-activated Protein Kinase Sty1/Spc1 Precedes Its Dissociation from the Kinase and Signals Its Degradation

Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. The Schizosaccharomyces pombe SAPK Sty1/Spc1 orchestrates general changes in gene expression in response to diverse forms of cytotoxic stress. Here we show that Sty1/Spc1 is bound to its target, the Srk1 kinase, when the signaling pathway is inactive. In response to stress, Sty1/Spc1 phosphorylates Srk1 at threonine 463 of the regulatory domain, inducing both activation of Srk1 kinase, which negatively regulates cell cycle progression by inhibiting Cdc25, and dissociation of Srk1 from the SAPK, which leads to Srk1 degradation by the proteasome.

Rugosidade superficial do solo formada por escarificação e influenciada pela erosividade da chuva

A rugosidade superficial do solo é influenciada, entre outros fatores, pelo efeito residual de manejo do solo, pelo tipo de preparo e pela erosividade da chuva e, juntamente com a cobertura do solo por resíduos vegetais, influencia a erosão hídrica. O objetivo deste trabalho foi determinar, entre junho de 2005 e março de 2006, em um Nitossolo Háplico alumínico típico, o efeito de uma operação de escarificador e da erosividade de chuvas sobre a rugosidade superficial, nos seguintes sistemas de manejo do solo: preparo convencional sem cultivo do solo (SCE), preparo convencional com cultivo do solo (PCE), semeadura direta em solo nunca preparado e com resíduos queimados (SQE) e semeadura direta tradicional (STE). Nos tratamentos PCE, SQE e STE, cultivaram-se aveia-preta, soja, ervilhaca comum, milho, aveia-preta, feijão preto, nabo forrageiro, soja, ervilhaca comum, milho e aveia-preta. Aplicaram-se cinco testes de chuva simulada, com 64 mm h-1 e duração de 20, 30, 40, 50 e 60 min cada um. Entre o segundo e o terceiro teste de chuva simulada ocorreram 57 mm de chuva natural; entre o terceiro e o quarto, 21 mm; e entre o quarto e o quinto, 30 mm. Determinou-se a rugosidade superficial imediatamente antes e logo após o preparo do solo com escarificador e imediatamente após cada teste de chuva simulada. A rugosidade original e linear da superfície do solo não foi influenciada pelo manejo, enquanto a rugosidade ao acaso teve essa influência, ao final de um pousio de seis meses. Diferentes sistemas de manejo do solo mantidos em pousio por seis meses resultaram em diferente rugosidade original, linear e ao acaso, quando o solo foi submetido à operação de escarificador. A rugosidade ao acaso foi menos influenciada pela declividade do terreno do que pelas marcas de preparo do solo, tendo diminuído com o aumento da erosividade das chuvas. Essa mesma rugosidade apresentou coeficiente de decaimento temporal semelhante nos sistemas de manejo do solo semeadura direta e preparo convencional.

The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates its Transrepressive Function

Nuclear orphan receptor TLX (NR2E1) functions primarily as a transcriptional repressor and its pivotal role in brain development, glioblastoma, mental retardation and retinopathologies make it an attractive drug target. TLX is expressed in the neural stem cells (NSCs) of the subventricular zone and the hippocampus subgranular zone, regions with persistent neurogenesis in the adult brain, and functions as an essential regulator of NSCs maintenance and self-renewal. Little is known about the TLX social network of interactors and only few TLX coregulators are described. To identify and characterize novel TLX-binders and possible coregulators, we performed yeast-two-hybrid (Y2H) screens of a human adult brain cDNA library using different TLX constructs as baits. Our screens identified multiple clones of Atrophin-1 (ATN1), a previously described TLX interactor. In addition, we identified an interaction with the oncoprotein and zinc finger transcription factor BCL11A (CTIP1/Evi9), a key player in the hematopoietic system and in major blood-related malignancies. This interaction was validated by expression and coimmunoprecipitation in human cells. BCL11A potentiated the transrepressive function of TLX in an in vitro reporter gene assay. Our work suggests that BCL11A is a novel TLX coregulator that might be involved in TLX-dependent gene regulation in the brain.

Transnational authority in the knowledge-based economy: Who sets the standards of ICT training and certification?

This article examines the extent and limits of nonstate forms of authority in international relations. It analyzes how the information and communication technology (ICT) infrastructure for the tradability of services in a global knowledge-based economy relies on informal regulatory practices for the adjustment of ICT-related skills. By focusing on the challenge that highly volatile and short-lived cycles of demands for this type of knowledge pose for ensuring the right qualification of the labor force, the article explores how companies and associations provide training and certification programs as part of a growing market for educational services setting their own standards. The existing literature on non-conventional forms of authority in the global political economy has emphasized that the consent of actors, subject to informal rules and some form of state support, remains crucial for the effectiveness of those new forms of power. However, analyses based on a limited sample of actors tend toward a narrow understanding of the issues concerned and fail to fully explore the differentiated space in which non state authority is emerging. This article develops a three-dimensional analytical framework that brings together the scope of the issues involved, the range of nonstate actors concerned, and the spatial scope of their authority. The empirical findings highlight the limits of these new forms of nonstate authority and shed light on the role of the state and international governmental organizations in this new context.

Psychometric characteristics of the Spanish version of instruments to measure neck pain disability

Background: The NDI, COM and NPQ are evaluation instruments for disability due to NP. There was no Spanish version of NDI or COM for which psychometric characteristics were known. The objectives of this study were to translate and culturally adapt the Spanish version of the Neck Disability Index Questionnaire (NDI), and the Core Outcome Measure (COM), to validate its use in Spanish speaking patients with non-specific neck pain (NP), and to compare their psychometric characteristics with those of the Spanish version of the Northwick Pain Questionnaire (NPQ).Methods: Translation/re-translation of the English versions of the NDI and the COM was done blindly and independently by a multidisciplinary team. The study was done in 9 primary care Centers and 12 specialty services from 9 regions in Spain, with 221 acute, subacute and chronic patients who visited their physician for NP: 54 in the pilot phase and 167 in the validation phase. Neck pain (VAS), referred pain (VAS), disability (NDI, COM and NPQ), catastrophizing (CSQ) and quality of life (SF-12) were measured on their first visit and 14 days later. Patients' self-assessment was used as the external criterion for pain and disability. In the pilot phase, patients' understanding of each item in the NDI and COM was assessed, and on day 1 test-retest reliability was estimated by giving a second NDI and COM in which the name of the questionnaires and the order of the items had been changed.Results: Comprehensibility of NDI and COM were good. Minutes needed to fill out the questionnaires [median, (P25, P75)]: NDI. 4 (2.2, 10.0), COM: 2.1 (1.0, 4.9). Reliability: [ICC, (95%CI)]: NDI: 0.88 (0.80, 0.93). COM: 0.85 (0.75,0.91). Sensitivity to change: Effect size for patients having worsened, not changed and improved between days 1 and 15, according to the external criterion for disability: NDI: -0.24, 0.15, 0.66; NPQ: -0.14, 0.06, 0.67; COM: 0.05, 0.19, 0.92. Validity: Results of NDI, NPQ and COM were consistent with the external criterion for disability, whereas only those from NDI were consistent with the one for pain. Correlations with VAS, CSQ and SF-12 were similar for NDI and NPQ (absolute values between 0.36 and 0.50 on day 1, between 0.38 and 0.70 on day 15), and slightly lower for COM (between 0.36 and 0.48 on day 1, and between 0.33 and 0.61 on day 15). Correlation between NDI and NPQ: r = 0.84 on day 1, r = 0.91 on day 15. Correlation between COM and NPQ: r = 0.63 on day 1, r = 0.71 on day 15.Conclusion: Although most psychometric characteristics of NDI, NPQ and COM are similar, those from the latter one are worse and its use may lead to patients' evolution seeming more positive than it actually is. NDI seems to be the best instrument for measuring NP-related disability, since its results are the most consistent with patient's assessment of their own clinical status and evolution. It takes two more minutes to answer the NDI than to answer the COM, but it can be reliably filled out by the patient without assistance.

L'experiència pilot desenvolupada a partir del projecte d'innovació "La gestió integrada de la qualitat, el medi ambient i la seguretat en la docència experimental dels estudis de grau de les Facultats de Belles Arts"

Es presenta un projecte d'innovació docent, la recerca desevolupada del qual va incorporar aspectes relacionats amb la seguretat i la sostenibilitat dels procediments realitzats als tallers i laboratoris de les Facultats de Belles Arts, aplicant criteris de gestió de qualitat. Els resultats d'aquestes investigacions tenen una extensió social en l'àmbit de les Belles Arts en general. El projecte d'innovació docent va aplicar criteris de gestió de qualitat. La recerca desenvolupada va incorporar aspectes relacionats amb la seguretat i la sostenibilitat dels procediments als tallers i laboratoris de les Facultats de Belles Arts. Els resultats d¿aquestes investigacions tenen una extensió social en l'àmbit de les Belles Arts en general. Amb aquest projecte es va redissenyar un model de procediment normalitzat de treball (PNT) que 11 tallers diferents de les Facultats de BBAA de Barcelona, Conca i València van utilitzar per a elaborar 14 PNT i 3 vídeos de suport. Aquests es van aplicar durant una experiència pilot (curs 2009-2010). El nombre de participants en l¿experiència va ser de 211 alumnes, 15 professors, 10 tècnics de taller, majoritàriament de BBAA de la Universitat de Barcelona. L'experiència pilot va demostrar satisfactòriament la viabilitat de l'aplicació del model de PNT adoptat i els beneficis, de la seva aplicació, orientats a la millora continuada de la qualitat docent i de la investigació. Per concloure el projecte es va elaborar el procediment general (PG) que determina les pautes per a redactar un PNT. Aquest PG va ser aprovat recentment per la CSSMA del Centre2 i es podrà aplicar en el futur en la Facultat de BBAA de Barcelona. Sobre l'experiència s'han realitzat les publicacions pertinents (un llibre i un DVD) i s'ha participat també en dos congressos.

La gestió integrada de la qualitat i la seguretat en la docència: pràctiques de taller i de laboratori als estudis de grau de belles arts

El projecte s'inscriu dins de l'àmbit de la investigació i innovació docent aplicant criteris de gestió de qualitat en els que es tenen molt presents els aspectes relacionats amb la seguretat i la sostenibilitat. El projecte promou la investigació generant models de funcionament i verificant la qualitat dels resultats de la seva aplicació. Des d'aquest punt de vista la recerca incorpora aspectes relacionats amb la seguretat i la sostenibilitat dels procediments, la manipulació de productes i materials, la gestió de residus i el seu reciclatge als tallers i laboratoris de les Facultats de Belles Arts. Els resultats d'aquestes investigacions tenen una extensió social en l'àmbit de les Belles Arts en general. Existeix suficient evidència empírica sobre el deteriorament de la salut i els danys que causen un gran nombre de substàncies, productes i materials utilitzats habitualment en les Belles Arts i es sospita sobre els potencials efectes negatius d'altres productes. A Espanya, també és conegut el limitat desenvolupament en matèria de prevenció laboral, de protecció mediambiental i en paràmetres de sostenibilitat en relació amb l'Espai Europeu i, especialment, al nord d'Europa. Es pot considerar, encara, la tímida i escassament coordinada, encara que progressiva, implantació de mesures orientades a solucionar aquestes deficiències per part de les universitats espanyoles i el seu insuficient finançament. En un context d'elevada sensibilització social i dels mitjans de comunicació sobre els efectes del canvi climàtic i la contaminació els processos de canvi s'han de liderar des d'institucions de rang molt divers. Amb els antecedents esmentats el grup d'investigació advoca per continuar desenvolupant diferents modalitats de recerca, buscant alternatives eficaces en aquest àmbit. Alternatives que contemplin la possible substitució d'uns productes per altres, la reducció d'aquells insubstituïbles, la implantació de procediments de qualitat verificada, l'adopció de mesures de seguretat de naturalesa preventiva o mediambiental, l'exploració de recursos sostenibles, etc. per solucionar en la mesura possible l'esmentada problemàtica.

Seguretat i sostenibilitat: elaboració d'un model de procediment normalitzat de treball (pnt) com a eina docent per a l'autoaprenentatge en els tallers de les Facultats Belles Arts

La implementació dels nous graus requereix la integració dels conceptes i metodologies relacionades amb la seguretat, la prevenció de riscos laborals i la protecció del medi ambient. En aquest context, un equip de professorat de les facultats de Belles Arts (UB, UPV, UCLM) ha desenvolupat un projecte d'innovació docent, una de les parts fonamentals del qual, ha estat la ideació i la creació d'un model de procediment normalitzat de treball (PNT) i la seva aplicació en experiències pilot realitzades en diverses pràctiques als tallers i laboratoris. El PNT s'ha mostrat com una eina bàsica per a l'autoaprenentatge, que, així mateix, garanteix l'adquisició de les competències transversals relacionades amb la seguretat i la sostenibilitat.