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  • Klionsky, Daniel J., et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • Ingår i: Autophagy. - : Landes Bioscience. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • Forskningsöversikt (refereegranskat)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
  • Peterlongo, Paolo, et al. (författare)
  • Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
  • 2015
  • Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 24:1, s. 308-316
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
  • Blein, Sophie, et al. (författare)
  • An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.
  • 2015
  • Ingår i: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411 .- 1465-542X. ; 17:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Individuals carrying pathogenic mutations in BRCA1/2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals from different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. Here we test the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
  • Murray, Christopher J. L., et al. (författare)
  • Population and fertility by age and sex for 195 countries and territories, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017
  • 2018
  • Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1995-2051
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardised estimates of mortality. We present single-calendar year and single-year of age estimates of fertility and population by sex with standardised and replicable methods. Methods: We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10–54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10–14 years and 50–54 years was estimated from data on fertility in women aged 15–19 years and 45–49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories. Findings: From 1950 to 2017, TFRs decreased by 49·4% (95% uncertainty interval [UI] 46·4–52·0). The TFR decreased from 4·7 livebirths (4·5–4·9) to 2·4 livebirths (2·2–2·5), and the ASFR of mothers aged 10–19 years decreased from 37 livebirths (34–40) to 22 livebirths (19–24) per 1000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83·8 million people per year since 1985. The global population increased by 197·2% (193·3–200·8) since 1950, from 2·6 billion (2·5–2·6) to 7·6 billion (7·4–7·9) people in 2017; much of this increase was in the proportion of the global population in south Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2·0%; this rate then remained nearly constant until 1970 and then decreased to 1·1% in 2017. Population growth rates in the southeast Asia, east Asia, and Oceania GBD super-region decreased from 2·5% in 1963 to 0·7% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2·7%. The global average age increased from 26·6 years in 1950 to 32·1 years in 2017, and the proportion of the population that is of working age (age 15–64 years) increased from 59·9% to 65·3%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1·0 livebirths (95% UI 0·9–1·2) in Cyprus to a high of 7·1 livebirths (6·8–7·4) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0·08 livebirths (0·07–0·09) in South Korea to 2·4 livebirths (2·2–2·6) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0·3 livebirths (0·3–0·4) in Puerto Rico to a high of 3·1 livebirths (3·0–3·2) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in central, eastern, and western Europe, whereas population growth rates of more than 2·0% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger. Interpretation: Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress. Funding: Bill & Melinda Gates Foundation.
  • Brady, Mark, et al. (författare)
  • Managing soil natural capital: a prudent strategy for adapting to future risks
  • 2017
  • Ingår i: Annals of Operations Research. - : Springer Verlag (Germany). - 0254-5330 .- 1572-9338. ; 255, s. 439-463
  • Tidskriftsartikel (refereegranskat)abstract
    • Farmers are exposed to substantial weather and market related risks. Rational farmers seek to avoid large losses. Future climate change and energy price fluctuations there- foremake adaptating to increased risks particularly important for them. Managing soil natural capital—the capacity of the soil to generate ecosystem services of benefit to farmers—has been proven to generate the double dividend: increasing farm profit and reducing associated risk. In this paper we explore whether managing soil natural capital has a third dividend: reducing the downside risk (increasing the positive skewness of profit). This we refer to as the prudence effect which can be viewed as an adaptation strategy for dealing with future uncertainties through more prudent management of soil natural capital.We do this by devel- oping a dynamic stochastic portfolio model to optimize the stock of soil natural capital—as indicated by soil organic carbon (SOC) content—that considers the mean, variance and skew- ness of profits from arable farming. The SOC state variable can be managed by the farmer only indirectly through the spatial and temporal allocation of land use.We model four cash crops and a grass ley that generates no market return but replenishes SOC. We find that managing soil natural capital can, not only improve farm profit while reducing the risk, but also reduce the downside risk. Prudent adaptation to future risks should therefore consider the impact of current agricultural management practices on the stock of soil natural capital.
  • Brady, Mark, et al. (författare)
  • Optimizing intermediate ecosystem services in agriculture using rules based on landscape composition and configuration indices
  • 2016
  • Ingår i: Ecological Economics. - : Elsevier. - 0921-8009 .- 1873-6106. ; 128, s. 214-223
  • Tidskriftsartikel (refereegranskat)abstract
    • Important intermediate ecosystem services (ES) such as crop pollination and biological control of pests, which underpin the final ES agricultural yields, are mediated by mobile organisms that depend on availability of habitat and its arrangement in the landscape. It has been suggested that landscape-scale management (LSM) of habitat in a multi-farm setting results in higher provisioning of such ES compared to farm-scale management (FSM). However, to achieve the LSM solution, farmers' land-use decisions need to be coordinated. To this end, we develop rules based on novel landscape composition and configuration indices. We model farmers' interdependencies through ES in an agent-based model (ABM) and optimize land use at both the farm and landscape scales for comparison. Our analysis is based on a simple artificial landscape with homogeneous soil quality and uses crop pollination as an illustrative ecosystem service. We consider habitat configuration at the field scale. Our rules demonstrate that the coordinated solution is characterized by a higher degree of habitat availability and a configuration of habitat that is dispersed rather than agglomerated. We tested these rules over a range of assumptions about ecological parameter values and suggest that such rules could be used to improve governance of ES in agricultural landscapes.
  • Brady, Mark V., et al. (författare)
  • Is Passive Farming A Problem for Agriculture in the EU?
  • Ingår i: Journal of Agricultural Economics. - : Wiley-Blackwell. - 0021-857X .- 1477-9552. ; 68:3, s. 632-650
  • Tidskriftsartikel (refereegranskat)abstract
    • We address a new agricultural policy concern following the decoupling of CAP direct payments in 2005: passive farming, whereby landowners maintain their agricultural area to collect payments without producing commodities. It is claimed that passive farming is hindering agricultural development by 'blocking' access to farmland for expanding farmers. We evaluate the links between the EU's Single Payment Scheme (SPS), passive farming, land use and agricultural development. Following identification of the rational landowners' optimal land-use choice, we evaluate the effects of the SPS using a spatial, agent-based model that simulates farmers' competition for land in a case-study region of Sweden. We show that passive farming does not constrain land from being used in production; on the contrary more land is used than would be the case without the SPS. We conclude that passive farming is not a problem for agriculture, but provides public goods that would otherwise be under provided: preservation of marginal farmland and future food security. However SPS payments on highly productive land inflate land values (capitalisation) and slow structural change, which hinder agricultural development. Consequently CAP goals could be better served by targeting payments on marginal land and phasing out payments to highly productive land.
  • Brady, Mark V., et al. (författare)
  • Roadmap for valuing soil ecosystem services to inform multi-level decision-making in agriculture
  • Ingår i: Sustainability (Switzerland). - : MDPI AG. - 2071-1050. ; 11:19
  • Tidskriftsartikel (refereegranskat)abstract
    • Agricultural soils contribute to human welfare through their generation of manifold ecosystem services such as food security, water quality and climate regulation, but these are degraded by common farming practices. We have developed a roadmap for evaluating the contribution of both private- and public-good ecosystem services generated by agricultural soils to societal welfare. The approach considers the needs of decision-makers at different levels, from farmers to policy-makers. This we achieve through combining production functions-to quantify the impacts of alternative management practices on agricultural productivity and soil ecosystem services-with non-market valuation of changes in public-good ecosystem services and benefit-cost analysis. The results show that the net present value to society of implementing soil-friendly measures are substantial, but negative for farmers in our study region. Although we apply our roadmap to an intensive farming region in Sweden, we believe our results have broad applicability, because farmers do not usually account for the value of public-good ecosystem services. We therefore conclude that market outcomes are not likely to be generating optimal levels of soil ecosystem services from society's perspective. Innovative governance institutions are needed to resolve this market failure to safeguard the welfare of future generations.
  • Brady, Mark V., et al. (författare)
  • Valuing Supporting Soil Ecosystem Services in Agriculture: A Natural Capital Approach
  • 2015
  • Ingår i: Agronomy Journal. - : Wiley-Blackwell. - 0002-1962 .- 1435-0645. ; 107:5, s. 1809-1821
  • Tidskriftsartikel (refereegranskat)abstract
    • Soil biodiversity through its delivery of ecosystem functions and attendant supporting ecosystem services-benefits soil organisms generate for farmers-underpins agricultural production. Yet lack of practical methods to value the long-term effects of current farming practices results, inevitably, in short-sighted management decisions. We present a method for valuing changes in supporting soil ecosystem services and associated soil natural capital-the value of the stock of soil organisms-in agriculture, based on resultant changes in future farm income streams. We assume that a relative change in soil organic C (SOC) concentration is correlated with changes in soil biodiversity and the generation of supporting ecosystem services. To quantify the effects of changes in supporting services on agricultural productivity, we fitted production functions to data from long-term field experiments in Europe and the United States. The different agricultural treatments at each site resulted in significant changes in SOC concentrations with time. Declines in associated services are shown to reduce both maximum yield and fertilizer-use efficiency in the future. The average depreciation of soil natural capital, for a 1% relative reduction in SOC concentration, was 144 (sic) ha(-1) (SD 47 (sic) ha(-1)) when discounting future values to their current value at 3%; the variation was explained by site-specific factors and the current SOC concentration. Moreover, the results show that soil ecosystem services cannot be fully replaced by purchased inputs; they are imperfect substitutes. We anticipate that our results will both encourage and make it possible to include the value of soil natural capital in decisions.
  • de Vries, Franciska T., et al. (författare)
  • Soil food web properties explain ecosystem services across European land use systems
  • 2013
  • Ingår i: Proceedings of the National Academy of Sciences. - : National Acad Sciences. - 1091-6490. ; 110:35, s. 14296-14301
  • Tidskriftsartikel (refereegranskat)abstract
    • Intensive land use reduces the diversity and abundance of many soil biota, with consequences for the processes that they govern and the ecosystem services that these processes underpin. Relationships between soil biota and ecosystem processes have mostly been found in laboratory experiments and rarely are found in the field. Here, we quantified, across four countries of contrasting climatic and soil conditions in Europe, how differences in soil food web composition resulting from land use systems (intensive wheat rotation, extensive rotation, and permanent grassland) influence the functioning of soils and the ecosystem services that they deliver. Intensive wheat rotation consistently reduced the biomass of all components of the soil food web across all countries. Soil food web properties strongly and consistently predicted processes of C and N cycling across land use systems and geographic locations, and they were a better predictor of these processes than land use. Processes of carbon loss increased with soil food web properties that correlated with soil C content, such as earthworm biomass and fungal/bacterial energy channel ratio, and were greatest in permanent grassland. In contrast, processes of N cycling were explained by soil food web properties independent of land use, such as arbuscular mycorrhizal fungi and bacterial channel biomass. Our quantification of the contribution of soil organisms to processes of C and N cycling across land use systems and geographic locations shows that soil biota need to be included in C and N cycling models and highlights the need to map and conserve soil biodiversity across the world.
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