| 1. |
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| 2. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 3. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 4. |
- Alves, Gustavo R., et al.
(författare)
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International Cooperation for Remote Laboratory Use
- 2018
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Ingår i: Contributions to Higher Engineering Education. - Singapore : Springer. - 9789811089176 ; , s. 1-31
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Bokkapitel (refereegranskat)abstract
- Experimenting is fundamental to the training process of all scientists and engineers. While experiments have been traditionally done inside laboratories, the emergence of Information and Communication Technologies added two alternatives accessible anytime, anywhere. These two alternatives are known as virtual and remote laboratories and are sometimes indistinguishably referred as online laboratories. Similarly to other instructional technologies, virtual and remote laboratories require some effort from teachers in integrating them into curricula, taking into consideration several factors that affect their adoption (i.e., cost) and their educational effectiveness (i.e., benefit). This chapter analyzes these two dimensions and sustains the case where only through international cooperation it is possible to serve the large number of teachers and students involved in engineering education. It presents an example in the area of electrical and electronics engineering, based on a remote laboratory named Virtual Instruments System in Reality, and it then describes how a number of European and Latin American institutions have been cooperating under the scope of an Erasmus+ project, for spreading its use in Brazil and Argentina.
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| 5. |
- Arnold, Staci D., et al.
(författare)
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Clinical risks and healthcare utilization of hematopoietic cell transplantation for sickle cell disease in the USA using merged databases
- 2017
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 102:11, s. 1823-1832
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Tidskriftsartikel (refereegranskat)abstract
- Advances in allogeneic hematopoietic cell transplantation for sickle cell disease have improved outcomes, but there is limited analysis of healthcare utilization in this setting. We hypothesized that, compared to late transplantation, early transplantation (at age < 10 years) improves outcomes and decreases healthcare utilization. We performed a retrospective study of children transplanted for sickle cell disease in the USA during 2000-2013 using two large databases. Univariate and Cox models were used to estimate associations of demographics, sickle cell disease severity, and transplant-related variables with mortality and chronic graft-versus-host disease, while Wilcoxon, Kruskal-Wallis, or linear trend tests were applied for the estimates of healthcare utilization. Among 161 patients with a 2-year overall survival rate of 90% (95% confidence interval [CI] 85-95%) mortality was significantly higher in those who underwent late transplantation versus early (hazard ratio (HR) 21, 95% CI 2.8-160.8, P=0.003) and unrelated compared to matched sibling donor transplantation (HR 5.9, 95% CI 1.7-20.2, P=0.005). Chronic graftversus host disease was significantly more frequent among those translanted late (HR 1.9, 95% CI 1.0-3.5, P=0.034) and those who received an unrelated graft (HR 2.5, 95% CI 1.2-5.4; P=0.017). Merged data for 176 patients showed that the median total adjusted transplant cost per patient was $467,747 (range: $344,029-$ 799,219). Healthcare utilization was lower among recipients of matched sibling donor grafts and those with low severity disease compared to those with other types of donor and disease severity types (P<0.001 and P=0.022, respectively); no association was demonstrated with late transplantation (P=0.775). Among patients with 2-year pre-and post-transplant data (n=41), early transplantation was associated with significant reductions in admissions (P<0.001), length of stay (P<0.001), and cost (P=0.008). Early transplant outcomes need to be studied prospectively in young children without severe disease and an available matched sibling to provide conclusive evidence for the superiority of this approach. Reduced post-transplant healthcare utilization inpatient care indicates that transplantation may provide a sustained decrease in healthcare costs over time.
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| 6. |
- Buchbinder, David, et al.
(författare)
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Predictors of Loss to Follow-Up Among Pediatric and Adult Hematopoietic Cell Transplantation Survivors : A Report from the Center for International Blood and Marrow Transplant Research
- 2020
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier. - 1083-8791 .- 1523-6536. ; 26:3, s. 553-561
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Tidskriftsartikel (refereegranskat)abstract
- Follow-up is integral for hematopoietic cell transplantation (HCT) care to ensure surveillance and intervention for complications. We characterized the incidence of and predictors for being lost to follow-up. Two-year survivors of first allogeneic HCT (10,367 adults and 3865 children) or autologous HCT (7291 adults and 467 children) for malignant/nonmalignant disorders between 2002 and 2013 reported to the Center for International Blood and Marrow Transplant Research were selected. The cumulative incidence of being lost to follow-up (defined as having missed 2 consecutive follow-up reporting periods) was calculated. Marginal Cox models (adjusted for center effect) were fit to evaluate predictors. The 10-year cumulative incidence of being lost to follow-up was 13% (95% confidence interval [CI], 12% to 14%) in adult allogeneic HCT survivors, 15% (95% CI, 14% to 16%) in adult autologous HCT survivors, 25% (95% CI, 24% to 27%) in pediatric allogeneic HCT survivors, and 24% (95% CI, 20% to 29%) in pediatric autologous HCT survivors. Factors associated with being lost to follow-up include younger age, nonmalignant disease, public/no insurance (reference: private), residence farther from the tranplantation center, and being unmarried in adult allogeneic HCT survivors; older age and testicular/germ cell tumor (reference: non-Hodgkin lymphoma) in adult autologous HCT survivors; older age, public/no insurance (reference: private), and nonmalignant disease in pediatric allogeneic HCT survivors; and older age in pediatric autologous HCT survivors. Follow-up focusing on minimizing attrition in high-risk groups is needed to ensure surveillance for late effects.
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| 7. |
- Chazdon, Robin L., et al.
(författare)
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Carbon sequestration potential of second-growth forest regeneration in the Latin American tropics
- 2016
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 2:5
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Tidskriftsartikel (refereegranskat)abstract
- Regrowth of tropical secondary forests following complete or nearly complete removal of forest vegetation actively stores carbon in aboveground biomass, partially counterbalancing carbon emissions from deforestation, forest degradation, burning of fossil fuels, and other anthropogenic sources. We estimate the age and spatial extent of lowland second-growth forests in the Latin American tropics and model their potential aboveground carbon accumulation over four decades. Our model shows that, in 2008, second-growth forests (1 to 60 years old) covered 2.4 million km2 of land (28.1% of the total study area). Over 40 years, these lands can potentially accumulate a total aboveground carbon stock of 8.48 Pg C (petagrams of carbon) in aboveground biomass via low-cost natural regeneration or assisted regeneration, corresponding to a total CO2 sequestration of 31.09 Pg CO2. This total is equivalent to carbon emissions from fossil fuel use and industrial processes in all of Latin America and the Caribbean from 1993 to 2014. Ten countries account for 95% of this carbon storage potential, led by Brazil, Colombia, Mexico, and Venezuela. We model future land-use scenarios to guide national carbon mitigation policies. Permitting natural regeneration on 40% of lowland pastures potentially stores an additional 2.0 Pg C over 40 years. Our study provides information and maps to guide national-level forest-based carbon mitigation plans on the basis of estimated rates of natural regeneration and pasture abandonment. Coupled with avoided deforestation and sustainable forest management, natural regeneration of second-growth forests provides a low-cost mechanism that yields a high carbon sequestration potential with multiple benefits for biodiversity and ecosystem services.
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| 8. |
- Corredor, Zuray, et al.
(författare)
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Loci associated with genomic damage levels in chronic kidney disease patients and controls
- 2020
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Ingår i: Mutation Research - Genetic Toxicology and Environmental Mutagenesis. - : Elsevier BV. - 1383-5718. ; 852
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is a multifactorial disorder with an important genetic component, and several studies have demonstrated potential associations with allelic variants. In addition, CKD patients are also characterized by high levels of genomic damage. Nevertheless, no studies have established relationships between DNA damage, or genomic instability present in CKD patients, and gene polymorphisms. To fill in this gap, the potential role of polymorphisms in genes involved in base excision repair (OGG1, rs1052133; MUTYH, rs3219489; XRCC1, rs25487), nucleotide excision repair (ERCC2/XPD, rs1799793, rs171140, rs13181; ERCC4, rs3136166); phase II metabolism (GSTP1, rs749174; GSTO1, rs2164624; GSTO2, rs156697), and antioxidant enzymes (SOD1, rs17880135, rs1041740, rs202446; SOD2, rs4880; CAT, rs1001179; GPX1, rs17080528; GPX3, rs870406: GPX4, rs713041) were inquired. In addition, some genes involved in CKD (AGT, rs5050; GLO1, rs386572987; SHROOM3, rs17319721) were also evaluated. The genomic damage, the genomic instability, and oxidative damage were evaluated by using the micronucleus and the comet assay in 589 donors (415 CKD patients and 174 controls). Our results showed significant associations between genomic damage and genes directly involved in DNA repair pathways (XRCC1, and ERCC2), and with genes encoding for antioxidant enzymes (SOD1 and GPX1). GSTO2, as a gene involved in phase II metabolism, and MUTYH showed also an association with genomic instability. Interestingly, the three genes associated with CKD (AGT, GLO1, and SHROOM3) showed associations with both the high levels of oxidatively damaged DNA and genomic instability. These results support our view that genomic instability can be considered a biomarker of the CKD status.
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| 9. |
- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 10. |
- Donis, Daphne, et al.
(författare)
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Stratification strength and light climate explain variation in chlorophyll a at the continental scale in a European multilake survey in a heatwave summer
- 2021
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Ingår i: Limnology and Oceanography. - : John Wiley & Sons. - 0024-3590 .- 1939-5590. ; 66:12, s. 4314-4333
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Tidskriftsartikel (refereegranskat)abstract
- To determine the drivers of phytoplankton biomass, we collected standardized morphometric, physical, and biological data in 230 lakes across the Mediterranean, Continental, and Boreal climatic zones of the European continent. Multilinear regression models tested on this snapshot of mostly eutrophic lakes (median total phosphorus [TP] = 0.06 and total nitrogen [TN] = 0.7 mg L-1), and its subsets (2 depth types and 3 climatic zones), show that light climate and stratification strength were the most significant explanatory variables for chlorophyll a (Chl a) variance. TN was a significant predictor for phytoplankton biomass for shallow and continental lakes, while TP never appeared as an explanatory variable, suggesting that under high TP, light, which partially controls stratification strength, becomes limiting for phytoplankton development. Mediterranean lakes were the warmest yet most weakly stratified and had significantly less Chl a than Boreal lakes, where the temperature anomaly from the long-term average, during a summer heatwave was the highest (+4 degrees C) and showed a significant, exponential relationship with stratification strength. This European survey represents a summer snapshot of phytoplankton biomass and its drivers, and lends support that light and stratification metrics, which are both affected by climate change, are better predictors for phytoplankton biomass in nutrient-rich lakes than nutrient concentrations and surface temperature.
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| 11. |
- Freitas, Susana N., et al.
(författare)
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The role of hybridisation in the origin and evolutionary persistence of vertebrate parthenogens: a case study of Darevskia lizards
- 2019
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Ingår i: Heredity. - : Springer Science and Business Media LLC. - 0018-067X .- 1365-2540. ; 123, s. 795-808
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Tidskriftsartikel (refereegranskat)abstract
- Obligate parthenogenesis is found in only 0.1% of the vertebrate species, is thought to be relatively short lived and is typically of hybrid origin. However, neither the evolutionary persistence of asexuality in vertebrates, nor the conditions that allow the generation of new parthenogenetic lineages are currently well understood. It has been proposed that vertebrate parthenogenetic lineages arise from hybridisation between two divergent taxa within a specific range of phylogenetic distances (the ‘Balance Hypothesis’). Moreover, parthenogenetic species often maintain a certain level of hybridisation with their closest sexual relatives, potentially generating new polyploid hybrid lineages. Here we address the role of hybridisation in the origin and evolutionary lifespan of vertebrate parthenogens. We use a set of microsatellite markers to characterise the origins of parthenogens in the lizard genus Darevskia, to study the distinctiveness of sexual and asexual taxa currently in sympatry, and to analyse the evolutionary consequences of interspecific hybridisation between asexual females and sexual males. We find that parthenogens result from multiple past hybridisation events between species from specific lineages over a range of phylogenetic distances. This suggests that the Balance Hypothesis needs to allow for lineage-specific effects, as envisaged in the Phylogenetic Constraint Hypothesis. Our results show recurrent backcrossing between sexual and parthenogenic Darevskia but neither gene flow nor formation of new asexual lineages. We suggest that, along with their demographic advantage, parthenogens gain additional leverage to outcompete sexuals in nature when the retention of sexual reproductive machinery allows backcrossing with their sexual ancestors.
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| 12. |
- Gei, Maga, et al.
(författare)
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Legume abundance along successional and rainfall gradients in Neotropical forests
- 2018
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Ingår i: Nature Ecology & Evolution. - : Springer Science and Business Media LLC. - 2397-334X. ; 2:7
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Tidskriftsartikel (refereegranskat)abstract
- The nutrient demands of regrowing tropical forests are partly satisfied by nitrogen-fixing legume trees, but our understanding of the abundance of those species is biased towards wet tropical regions. Here we show how the abundance of Leguminosae is affected by both recovery from disturbance and large-scale rainfall gradients through a synthesis of forest inventory plots from a network of 42 Neotropical forest chronosequences. During the first three decades of natural forest regeneration, legume basal area is twice as high in dry compared with wet secondary forests. The tremendous ecological success of legumes in recently disturbed, water-limited forests is likely to be related to both their reduced leaflet size and ability to fix N2, which together enhance legume drought tolerance and water-use efficiency. Earth system models should incorporate these large-scale successional and climatic patterns of legume dominance to provide more accurate estimates of the maximum potential for natural nitrogen fixation across tropical forests.
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| 13. |
- Gorasso, Vanessa, et al.
(författare)
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Burden of disease attributable to risk factors in European countries: a scoping literature review
- 2023
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Ingår i: Archives of Public Health. - 0778-7367 .- 2049-3258. ; 81:1
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Forskningsöversikt (refereegranskat)abstract
- Objectives: Within the framework of the burden of disease (BoD) approach, disease and injury burden estimates attributable to risk factors are a useful guide for policy formulation and priority setting in disease prevention. Considering the important differences in methods, and their impact on burden estimates, we conducted a scoping literature review to: (1) map the BoD assessments including risk factors performed across Europe; and (2) identify the methodological choices in comparative risk assessment (CRA) and risk assessment methods. Methods: We searched multiple literature databases, including grey literature websites and targeted public health agencies websites. Results: A total of 113 studies were included in the synthesis and further divided into independent BoD assessments (54 studies) and studies linked to the Global Burden of Disease (59 papers). Our results showed that the methods used to perform CRA varied substantially across independent European BoD studies. While there were some methodological choices that were more common than others, we did not observe patterns in terms of country, year or risk factor. Each methodological choice can affect the comparability of estimates between and within countries and/or risk factors, since they might significantly influence the quantification of the attributable burden. From our analysis we observed that the use of CRA was less common for some types of risk factors and outcomes. These included environmental and occupational risk factors, which are more likely to use bottom-up approaches for health outcomes where disease envelopes may not be available. Conclusions: Our review also highlighted misreporting, the lack of uncertainty analysis and the under-investigation of causal relationships in BoD studies. Development and use of guidelines for performing and reporting BoD studies will help understand differences, avoid misinterpretations thus improving comparability among estimates.
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| 14. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 15. |
- Honda, Kazufumi, et al.
(författare)
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CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer : a prospective evaluation
- 2019
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Ingår i: International Journal of Cancer. - : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 144:8, s. 1877-1887
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Tidskriftsartikel (refereegranskat)abstract
- Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.
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| 16. |
- Hop, Paul J., et al.
(författare)
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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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| 17. |
- Jallow, Muminatou, et al.
(författare)
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Genome-wide and fine-resolution association analysis of malaria in West Africa.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; , s. 657-665
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
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| 18. |
- Mantzouki, Evanthia, et al.
(författare)
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Temperature Effects Explain Continental Scale Distribution of Cyanobacterial Toxins
- 2018
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Ingår i: Toxins. - : MDPI. - 2072-6651. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Insight into how environmental change determines the production and distribution of cyanobacterial toxins is necessary for risk assessment. Management guidelines currently focus on hepatotoxins (microcystins). Increasing attention is given to other classes, such as neurotoxins (e.g., anatoxin-a) and cytotoxins (e.g., cylindrospermopsin) due to their potency. Most studies examine the relationship between individual toxin variants and environmental factors, such as nutrients, temperature and light. In summer 2015, we collected samples across Europe to investigate the effect of nutrient and temperature gradients on the variability of toxin production at a continental scale. Direct and indirect effects of temperature were the main drivers of the spatial distribution in the toxins produced by the cyanobacterial community, the toxin concentrations and toxin quota. Generalized linear models showed that a Toxin Diversity Index (TDI) increased with latitude, while it decreased with water stability. Increases in TDI were explained through a significant increase in toxin variants such as MC-YR, anatoxin and cylindrospermopsin, accompanied by a decreasing presence of MC-LR. While global warming continues, the direct and indirect effects of increased lake temperatures will drive changes in the distribution of cyanobacterial toxins in Europe, potentially promoting selection of a few highly toxic species or strains.
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| 19. |
- Marchisio, Susana, et al.
(författare)
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Starting the Study of Electronic Circuits with VISIR Viewpoints of college students in a Pilot Test in Argentina
- 2017
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Ingår i: PROCEEDINGS OF 2017 4TH EXPERIMENT@INTERNATIONAL CONFERENCE. - : Institute of Electrical and Electronics Engineers Inc.. - 9781538608104 ; , s. 18-23
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Konferensbidrag (refereegranskat)abstract
- This paper aims at introducing the first intensive use of a remote lab named as VISIR by lecturers and students from Facultad de Ciencias Exactas, Ingeniería y Agrimensura, Universidad Nacional de Rosario. The research was carried under the VISIR + project. It is a pilot test in which 17 students from the third year of an Electronic Engineering degree took part. The pilot test was developed in order to bring forward possible difficulties, assess successes and failures and eventually suggest other possible ways of curricular incorporation of VISIR in the teaching of the Physics of Electronic Devices subject. VISIR was used as a complement to hands-on lab, after the last experimental design activity of basic circuits with bipolar transistor. The students carried out an individual lab work. Then, they were asked to answer an opinion poll made up of 20 items, 1-4 Likert scale. Descriptive statistical analysis and summary of cases were carried out in order to conclude about four dimensions of analysis linked to the students' viewpoint. They are: perceived learnings, VISIR acceptance, perceived teachers' guidance and time and technical restrictions. © 2017 IEEE.
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| 20. |
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| 21. |
- Martinez-Montero, Saul, et al.
(författare)
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Design and Divergent Synthesis of Aza Nucleosides from a Chiral Imino Sugar
- 2012
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 77:10, s. 4671-4678
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Tidskriftsartikel (refereegranskat)abstract
- Several novel nucleoside analogues as potential inhibitors of glycosidases and purine nucleoside phosphorylase (PNP) have been synthesized via selective coupling of an appropriate nucleobase at different positions of an orthogonally protected imino sugar as a common precursor. This synthetic strategy offers a straightforward protocol for the assembly of imino sugar containing nucleosides, establishing a new repertoire of molecules as potential therapeutics.
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| 22. |
- Miguel-Blanco, Celia, et al.
(författare)
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The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- New antimalarial therapeutics are needed to ensure that malaria cases continue to be driven down, as both emerging parasite resistance to frontline chemotherapies and mosquito resistance to current insecticides threaten control programmes. Plasmodium, the apicomplexan parasite responsible for malaria, causes disease pathology through repeated cycles of invasion and replication within host erythrocytes (the asexual cycle). Antimalarial drugs primarily target this cycle, seeking to reduce parasite burden within the host as fast as possible and to supress recrudescence for as long as possible. Intense phenotypic drug screening efforts have identified a number of promising new antimalarial molecules. Particularly important is the identification of compounds with new modes of action within the parasite to combat existing drug resistance and suitable for formulation of efficacious combination therapies. Here we detail the antimalarial properties of DDD01034957—a novel antimalarial molecule which is fast-acting and potent against drug resistant strains in vitro, shows activity in vivo, and possesses a resistance mechanism linked to the membrane transporter PfABCI3. These data support further medicinal chemistry lead-optimization of DDD01034957 as a novel antimalarial chemical class and provide new insights to further reduce in vivo metabolic clearance.
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| 23. |
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| 24. |
- Park, Jin Young, et al.
(författare)
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Dietary folate intake and pancreatic cancer risk : Results from the European prospective investigation into cancer and nutrition
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 144:7, s. 1511-1521
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic cancer (PC) has an exceptionally low survival rate and primary prevention strategies are limited. Folate plays an important role in one-carbon metabolism and has been associated with the risk of several cancers, but not consistently with PC risk. We aimed to investigate the association between dietary folate intake and PC risk, using the standardised folate database across 10 European countries. A total of 477,206 participants were followed up for 11 years, during which 865 incident primary PC cases were recorded. Folate intake was energy-adjusted using the residual method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In multivariable analyses stratified by age, sex, study centre and adjusted for energy intake, smoking status, BMI, educational level, diabetes status, supplement use and dietary fibre intake, we found no significant association between folate intake and PC risk: the HR of PC risk for those in the highest quartile of folate intake (>= 353 mu g/day) compared to the lowest (<241 mu g/day) was 0.81 (95% CI: 0.51, 1.31; p(trend) = 0.38). In current smokers, a positive trend was observed in PC risk across folate quartiles [HR = 4.42 (95% CI: 1.05, 18.62) for >= 353 mu g/day vs. <241 mu g/day, p(trend) = 0.01]. Nonetheless, there was no significant interaction between smoking and dietary folate intake (p(interaction) = 0.99). We found no association between dietary folate intake and PC risk in this large European study.
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| 25. |
- Pastor, Susana, et al.
(författare)
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Levels of DNA damage (Micronuclei) in patients suffering from chronic kidney disease. Role of GST polymorphisms
- 2018
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Ingår i: Mutation Research - Genetic Toxicology and Environmental Mutagenesis. - : Elsevier BV. - 1383-5718. ; 836, s. 41-46
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) patients are characterized by the presence of high levels of DNA damage, and a poor response to ionizing radiation. In this study, we proposed that variants in GST genes could explain this fact. One-hundred twenty seven CKD patients and one-hundred forty five controls constituted the studied groups. Micronuclei (MN) frequency was determined in peripheral blood lymphocytes at both basal level, and after challenging the cells with 0.5 Gy of ionizing radiation. The following polymorphisms: GSTP1 (rs749174), GSTO1 (rs2164624), and GSTO2 (rs156697) were evaluated in the two groups. Results indicate that gene variants were distributed differentially between CKD patients and controls. Although GSTO1 and GSTO2 variants were associated with lower levels of MN, this was observed in both CKD patients and controls. When net MN values were determined after irradiation, GSTO1 and GSTO2 variants were also associated with lower MN-frequencies. On the contrary, individuals with the GSTP1 variant showed higher values of induced MN. In conclusion, we have demonstrate that the selected GST polymorphism play a role in the incidence of CKD, and affects the levels of MN. Interestingly, the modulating effects observed on both, the basal and induced levels of DNA damage, are characteristic of the overall population, not only of the CKD patients.
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| 26. |
- Pinto, Susana, et al.
(författare)
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Respiratory onset in amyotrophic lateral sclerosis : clinical features and spreading pattern
- 2023
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis Group. - 2167-8421 .- 2167-9223. ; 24:1-2, s. 40-44
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Tidskriftsartikel (refereegranskat)abstract
- Objective To describe the clinical features and progression of patients with respiratory onset amyotrophic lateral sclerosis (ALS).Methods: We analyzed the clinical features, including respiratory tests, functional score, noninvasive ventilation (NIV) time and survival of ALS patients with respiratory-onset in our database consisting of 1688 patients. In a subset of 625 ALS patients we analyzed the spreading pattern to other bodily regions.Results: We included 1579 patients with ALS. Sixty-three patients (4%) presented respiratory-onset (79.4% men, mean onset-age 67.7 +/- 8.9yrs). All had predominant LMN involvement, and significant weight loss (>10%) was identified in 38.9%. The respiratory tests were abnormal in these respiratory-onset patients (p < 0.001). ALSFRS-R respiratory subscore was lower in this population (p < 0.001). NIV was adapted in 84.1%, sooner than in the larger group of ALS patients (p < 0.001), and survival from disease onset was shorter (p < 0.001). Respiratory-onset was a predictor of time to NIV (X-2=42.0, p < 0.001) and of survival (X-2=7.1, p = 0.008). The spreading pattern was studied in 18 patients with isolated respiratory-onset. The progression interval to the 2nd region was 4.7 +/- 5.7mo and to a 3rd region 6.1 +/- 8.7mo. Different patterns of spread had no impact on survival.Conclusions: This phenotype is typically seen in emaciated older men with predominant lower motor neuron involvement, and is associated with diaphragm paresis and central respiratory involvement. NIV adaptation is rapid but total survival is shorter than in the other patients. Spreading pattern did not affect time to NIV adaptation or total survival, as NIV support is a modifying treatment in the course of ALS.
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| 27. |
- Pinto, Susana, et al.
(författare)
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Respiratory phenotypes in amyotrophic lateral sclerosis as determined by respiratory questions on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and their relation to respiratory tests
- 2023
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Ingår i: European Journal of Neurology. - : John Wiley & Sons. - 1351-5101 .- 1468-1331. ; 30:6, s. 1594-1599
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Forskningsöversikt (refereegranskat)abstract
- Background and purpose Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). Respiratory symptoms are scored in questions Q10 (dyspnoea) and Q11 (orthopnoea) of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). The association of respiratory test alterations with respiratory symptoms is unclear. Methods Patients with ALS and progressive muscular atrophy were included. We retrospectively recorded demographic data, ALSFRS-R, forced vital capacity (FVC), maximal inspiratory (MIP) and expiratory (MEP) pressures, mouth occlusion pressure at 100 ms, nocturnal oximetry (SpO(2)mean), arterial blood gases, and phrenic nerve amplitude (PhrenAmpl). Three groups were categorized: G1, normal Q10 and Q11; G2, abnormal Q10; and G3, abnormal Q10 and Q11 or only abnormal Q11. A binary logistic regression model explored independent predictors. Results We included 276 patients (153 men, onset age = 62.6 +/- 11.0 years, disease duration = 13.0 +/- 9.6 months, spinal onset in 182) with mean survival of 40.1 +/- 26.0 months. Gender, onset region, and disease duration were similar in G1 (n = 149), G2 (n = 78), and G3 (n = 49). Time to noninvasive ventilation (NIV) was shorter in G3 (p < 0.001), but survival was similar. ALSFRS-R subscores were significantly different (G1>G2>G3, p < 0.001), except for lower limb subscore (p = 0.077). G2 and G3 patients were older than G1 (p < 0.001), and had lower FVC, MIP, MEP, PhrenAmpl, and SpO(2)mean. Independent predictors for G2 were MIP and SpO(2)mean; for G3, the only independent predictor was PhrenAmpl. Conclusions These three distinct ALS phenotypic respiratory categories represent progressive stages of ventilatory dysfunction, supporting ALSFRS-R clinical relevance. Orthopnoea is a severe symptom that should prompt NIV, phrenic nerve response being an independent predictor. Early NIV promotes similar survival for G2 and G3.
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| 28. |
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| 29. |
- Poorter, Lourens, et al.
(författare)
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Functional recovery of secondary tropical forests
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 118:49, s. e2003405118-e2003405118
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Tidskriftsartikel (refereegranskat)abstract
- One-third of all Neotropical forests are secondary forests that regrow naturally after agricultural use through secondary succession. We need to understand better how and why succession varies across environmental gradients and broad geographic scales. Here, we analyze functional recovery using community data on seven plant characteristics (traits) of 1,016 forest plots from 30 chronosequence sites across the Neotropics. By analyzing communities in terms of their traits, we enhance understanding of the mechanisms of succession, assess ecosystem recovery, and use these insights to propose successful forest restoration strategies. Wet and dry forests diverged markedly for several traits that increase growth rate in wet forests but come at the expense of reduced drought tolerance, delay, or avoidance, which is important in seasonally dry forests. Dry and wet forests showed different successional pathways for several traits. In dry forests, species turnover is driven by drought tolerance traits that are important early in succession and in wet forests by shade tolerance traits that are important later in succession. In both forests, deciduous and compound-leaved trees decreased with forest age, probably because microclimatic conditions became less hot and dry. Our results suggest that climatic water availability drives functional recovery by influencing the start and trajectory of succession, resulting in a convergence of community trait values with forest age when vegetation cover builds up. Within plots, the range in functional trait values increased with age. Based on the observed successional trait changes, we indicate the consequences for carbon and nutrient cycling and propose an ecologically sound strategy to improve forest restoration success.
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| 30. |
- Poorter, Lourens, et al.
(författare)
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Wet and dry tropical forests show opposite successional pathways in wood density but converge over time
- 2019
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Ingår i: Nature Ecology & Evolution. - : Nature Publishing Group. - 2397-334X. ; 3:6, s. 928-934
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Tidskriftsartikel (refereegranskat)abstract
- Tropical forests are converted at an alarming rate for agricultural use and pastureland, but also regrow naturally through secondary succession. For successful forest restoration, it is essential to understand the mechanisms of secondary succession. These mechanisms may vary across forest types, but analyses across broad spatial scales are lacking. Here, we analyse forest recovery using 1,403 plots that differ in age since agricultural abandonment from 50 sites across the Neotropics. We analyse changes in community composition using species-specific stem wood density (WD), which is a key trait for plant growth, survival and forest carbon storage. In wet forest, succession proceeds from low towards high community WD (acquisitive towards conservative trait values), in line with standard successional theory. However, in dry forest, succession proceeds from high towards low community WD (conservative towards acquisitive trait values), probably because high WD reflects drought tolerance in harsh early successional environments. Dry season intensity drives WD recovery by influencing the start and trajectory of succession, resulting in convergence of the community WD over time as vegetation cover builds up. These ecological insights can be used to improve species selection for reforestation. Reforestation species selected to establish a first protective canopy layer should, among other criteria, ideally have a similar WD to the early successional communities that dominate under the prevailing macroclimatic conditions.
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| 31. |
- Seyed Khoei, Nazlisadat, et al.
(författare)
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Circulating bilirubin levels and risk of colorectal cancer : serological and Mendelian randomization analyses
- 2020
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Ingår i: BMC Medicine. - : Springer Nature. - 1741-7015. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).CONCLUSIONS: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.
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| 32. |
- Thompson, Paul M., et al.
(författare)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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Ingår i: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Tidskriftsartikel (refereegranskat)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 33. |
- Tucker, S., et al.
(författare)
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Improving the mix of institutional and community care for older people with dementia : an application of the balance of care approach in eight European countries
- 2016
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Ingår i: Aging and Mental Health. - Abingdon : Informa UK Limited. - 1360-7863 .- 1364-6915. ; 20:12, s. 1327-1338
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To examine whether the mix of community and institutional long-term care (ILTC) for people with dementia (PwD) in Europe could be improved; assess the economic consequences of providing alternative services for particular groups of ILTC entrants and explore the transnational application of the ‘Balance of Care’ (BoC) approach. Method: A BoC study was undertaken in Estonia, Finland, France, Germany, the Netherlands, Spain, Sweden, and the UK as part of the RightTimePlaceCare project. Drawing on information about 2014 PwD on the margins of ILTC admission, this strategic planning framework identified people whose needs could be met in more than one setting, and compared the relative costs of the possible alternatives. Results: The findings suggest a noteworthy minority of ILTC entrants could be more appropriately supported in the community if enhanced services were available. This would not necessarily require innovative services, but more standard care (including personal and day care), assuming quality was ensured. Potential cost savings were identified in all countries, but community care was not always cheaper than ILTC and the ability to release resources varied between nations. Conclusions: This is believed to be the first transnational application of the BoC approach, and demonstrates its potential to provide a consistent approach to planning across different health and social care systems. Better comparative information is needed on the number of ILTC entrants with dementia, unit costs and outcomes. Nevertheless, the findings offer important evidence on the appropriateness of current provision, and the opportunity to learn from different countries' experience.
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| 34. |
- Ward, Heather A., et al.
(författare)
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Gallstones and incident colorectal cancer in a large pan-European cohort study
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 145:6, s. 1510-1516
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Tidskriftsartikel (refereegranskat)abstract
- Gallstones, a common gastrointestinal condition, can lead to several digestive complications and can result in inflammation. Risk factors for gallstones include obesity, diabetes, smoking and physical inactivity, all of which are known risk factors for colorectal cancer (CRC), as is inflammation. However, it is unclear whether gallstones are a risk factor for CRC. We examined the association between history of gallstones and CRC in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a prospective cohort of over half a million participants from ten European countries. History of gallstones was assessed at baseline using a self‐reported questionnaire. The analytic cohort included 334,986 participants; a history of gallstones was reported by 3,917 men and 19,836 women, and incident CRC was diagnosed among 1,832 men and 2,178 women (mean follow‐up: 13.6 years). Hazard ratios (HR) and 95% confidence intervals (CI) for the association between gallstones and CRC were estimated using Cox proportional hazards regression models, stratified by sex, study centre and age at recruitment. The models were adjusted for body mass index, diabetes, alcohol intake and physical activity. A positive, marginally significant association was detected between gallstones and CRC among women in multivariable analyses (HR = 1.14, 95%CI 0.99–1.31, p = 0.077). The relationship between gallstones and CRC among men was inverse but not significant (HR = 0.81, 95%CI 0.63–1.04, p = 0.10). Additional adjustment for details of reproductive history or waist circumference yielded minimal changes to the observed associations. Further research is required to confirm the nature of the association between gallstones and CRC by sex.
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| 35. |
- Zumarraga, Miren, et al.
(författare)
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Altering the laccase functionality by in vivo assembly of mutant libraries with different mutational spectra
- 2008
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Ingår i: Proteins. - : Wiley. - 0887-3585. ; 71:1, s. 250-260
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Tidskriftsartikel (refereegranskat)abstract
- The generation of diversity for directed protein evolution experiments shows an important bottleneck in the in vitro random mutagenesis protocols. Most Of them are biased towards specific changes that eventually confer a predicted and conservative mutational spectrum, limiting the exploration of the vast protein space. The current work describes a simple methodology to in vivo recombine mutant libraries with different nucleotide bias created by in vitro methods. This in vivo assembly was based on the accurate physiology of Saccharomyces cerevisiae, which as host, provided its high homologous recombination frequency to shuffle the libraries in a nonmutagenic way. The fungal thermophilic laccase from Myceliophthora thermophila expressed in S. cerevisiae was submitted to this protocol under the selective pressure of high concentrations of organic solvents. Mutant 2E9 with similar to 3-fold better kinetics than parent type showed two consecutive amino acid changes (G614D -GGC/GAC- and E615K -GAG/AAG-) because of the in vivo shuffling of the mutant libraries. Both mutations are located in the C-terminal tail that is specifically processed at the Golgi during the maturation of the protein by the Kex2 protease. Notoriously, the oxygen consumption at the T2/T3 trinuclear copper cluster was altered and the catalytic copper at the T1 site was perturbed showing differences in its redox potential and geometry. The change in the isoelectric point of C-terminal extension upon mutations seems to affect the folding of the protein at the posttranslational processing steps providing new insights in the significance of the C-terminal tail for the functionality of the ascomycete laccases.
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| 36. |
- Zumarraga, Miren, et al.
(författare)
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Combinatorial saturation mutagenesis of the Myceliophthora thermophila laccase T2 mutant : the connection between the C-terminal plug and the conserved 509VSG511 tripeptide
- 2008
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Ingår i: Combinatorial chemistry & high throughput screening. - : Bentham Science Publishers Ltd.. - 1386-2073 .- 1875-5402. ; 11:10, s. 807-816
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Tidskriftsartikel (refereegranskat)abstract
- A mutant laccase from the Ascomycete Myceliophthora thermophila has been submitted to iterative cycles of combinatorial satn. mutagenesis through in vivo overlap extension in Saccharomyces cerevisiae. Over 180,000 clones were explored, among which the S510G mutant revealed a direct interaction between the conserved 509VSG511 tripeptide, located in the neighborhood of the T1 site, and the C-terminal plug. The KmO2 value of the mutant increased 1.5-fold, and the electron transfer pathway between the reducing substrate and the T1 copper ion was altered, improving the catalytic efficiency towards non-phenolic and phenolic substrates by about 3- and 8-fold. Although the geometry at the T1 site was perturbed by the mutation, paradoxically the laccase redox potential was not significantly altered. Together, the results obtained in this study suggest that the 509VSG511 tripeptide may play a hitherto unrecognized role in regulating the traffic of oxygen through the C-terminal plug, the latter blocking access to the T2/T3 copper cluster in the native enzyme.
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