| 1. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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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.
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| 2. |
- Richards, Stephen, et al.
(författare)
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Genome Sequence of the Pea Aphid Acyrthosiphon pisum
- 2010
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 8:2, s. e1000313-
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Tidskriftsartikel (refereegranskat)abstract
- Aphids are important agricultural pests and also biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and the developmental causes of extreme phenotypic plasticity. Here we present the 464 Mb draft genome assembly of the pea aphid Acyrthosiphon pisum. This first published whole genome sequence of a basal hemimetabolous insect provides an outgroup to the multiple published genomes of holometabolous insects. Pea aphids are host-plant specialists, they can reproduce both sexually and asexually, and they have coevolved with an obligate bacterial symbiont. Here we highlight findings from whole genome analysis that may be related to these unusual biological features. These findings include discovery of extensive gene duplication in more than 2000 gene families as well as loss of evolutionarily conserved genes. Gene family expansions relative to other published genomes include genes involved in chromatin modification, miRNA synthesis, and sugar transport. Gene losses include genes central to the IMD immune pathway, selenoprotein utilization, purine salvage, and the entire urea cycle. The pea aphid genome reveals that only a limited number of genes have been acquired from bacteria; thus the reduced gene count of Buchnera does not reflect gene transfer to the host genome. The inventory of metabolic genes in the pea aphid genome suggests that there is extensive metabolite exchange between the aphid and Buchnera, including sharing of amino acid biosynthesis between the aphid and Buchnera. The pea aphid genome provides a foundation for post-genomic studies of fundamental biological questions and applied agricultural problems.
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| 3. |
- Aze, Tracy, et al.
(författare)
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Identifying anagenesis cladogenesis in the fossil record
- 2013
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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. - 0027-8424 .- 1091-6490. ; 110:32, s. E2946-E2946
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Bernstein, Jonine L., et al.
(författare)
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Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers: A WECARE Study Report
- 2013
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 49:14, s. 2979-2985
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Tidskriftsartikel (refereegranskat)abstract
- Background: Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers. Methods: A population-based, nested case-control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records. Findings: Among women treated with radiation, the mean radiation dose was 1.1 Gy (range = 0.02-6.2 Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR = 4.5, confidence interval, CI = 3.0-6.8), and also among those treated with RT (RR = 1.2, CI = 1.0-1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant. Interpretation: Multiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harbouring deleterious BRCA1/BRCA2 mutations. Funding: All work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178]. (C) 2013 Elsevier Ltd. All rights reserved.
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| 5. |
- Birrell, Duncan, et al.
(författare)
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Shaman : D14.2 - report on demonstration and evaluation activity in the domain of "memory institututions"
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- 1. The report describes the demonstration and evaluation of ISP1, which was designed to demonstrate the potential of the SHAMAN framework for digital preservation in the context of memory institutions and for the research and development community. 2. The demonstration process was carried out by means of presentations based on screen-casts in three locations, Frankfurt, Vilnius and Glasgow. The audiences for the demonstrations consisted persons occupying of a wide range of roles in memory institutions, including senior management, operational level staff and IT support staff. 3. The evaluation is based on the reports of focus groups held in the three locations, together with structured data from self-completed questionnaires, administered on the same occasions. 4. Participants in the focus groups responded favourably to the ideas demonstrated in the presentations. There was particular interest in the choice of mainly open source software and in automation of processes, both of which have cost reduction implications, and in the idea of a digital preservation policy: the majority of participating organizations had no such policy. Participants also drew attention to aspects of preservation which they found lacking in the presentation and which were desirable, specifically: the preservation of font information; working with already obsolete formats; the automatic extraction of necessary metadata; the fact of mixed media archives involving, e.g., film and audio files; support for controlled vocabularies for search and discovery; and demonstration of workflows at a more practical level. 5. The questionnaire results revealed most approval of the retrieval and verification capabilities and less for the ingest processes. Otherwise the results supported the findings from the focus groups in general. There was a division of opinion over the value of the Multivalent browser and the application of grid technology, possibly because of differences in knowledge of these matters. Highest priority was assigned to data migration, access and authentication and bit stream preservation and least to independence standards and search capacity – issues that may be worth further exploration. 6. Evaluation has also been performed to determine the project‟s impact on the R&D community by means of submission and rejection rates of papers to journals and conferences, and bibliometric and Webometric analyses. The results demonstrate that the research outputs from the project are of interest to the R&D community and that the impact of the project as a whole compares favourably with other European projects in the digital preservation area. 7. The evaluation has revealed strengths and shortcomings in the demonstration process, which will influence the development of demonstrators for ISP2 and ISP3. The SHAMAN framework for digital preservation is seen as offering new possibilities and rigorous methods for the field by the practitioners in memory institutions.
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| 6. |
- Borg, Åke, et al.
(författare)
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Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
- 2010
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 31, s. 1200-1240
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Tidskriftsartikel (refereegranskat)abstract
- BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC. (c) 2010 Wiley-Liss, Inc.
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| 7. |
- Dastani, Zari, et al.
(författare)
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Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals
- 2012
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002607-
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Tidskriftsartikel (refereegranskat)abstract
- Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P=4.5 x 10(-8)-1.2 x 10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3 x 10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p=4.3 x 10(-3), n = 22,044), increased triglycerides (p=2.6 x 10(-14), n = 93,440), increased waist-to-hip ratio (p=1.8 x 10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p=4.4 x 10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p=4.5x10(-13), n = 96,748) and decreased BMI (p= 1.4 x 10(-14), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
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| 8. |
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| 9. |
- Hellsmark, Hans, 1974, et al.
(författare)
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Teknologiska innovationssystem inom energiområdet: En praktisk vägledning till identifiering av systemsvagheter som motiverar särskilda politiska åtaganden
- 2014
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Syftet med denna rapport är att illustrera hur ett praktiskt inriktat ramverk, tekno- logiska innovationssystem (TIS), kan användas av analytiker och beslutsfattare vid departement och myndigheter för att analysera strategiskt viktiga teknikområden ?????????????????????????????????????????????????????????????????????????????I rapporten analyseras fem TIS centrerade kring havsbaserad vindkraft, marin energi, ????????????????????????????????????????????????????????????????????????????????????? systemsvagheter som bromsar områdets vidare utveckling, vilka som kan åtgärdas av systemets aktörer och vilka som motiverar särskilda politiska åtaganden. Rapporten utgör därmed ett underlag för att formulera åtgärder för att åstadkomma ökad innova- tion, teknikspridning och industrialisering inom ovan nämnda teknikområden.Studien har även möjliggjort en jämförande analys av likheter och skillnader ???????????????????????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????????????????? mellan områdena – de är starka respektive svaga av olika orsaker. Detta visar att ???????????????????????????????????????????????????????????????????????Samtidigt har områdena gemensamma drag. Systemets aktörer, där även politiska ???????????????????????????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????????- skapsnätverk. Men de har varit sämre på att skapa tidiga nischmarknader som ger utrymme för fortsatt lärande och kostnadsreduktion. Sådana nischer kan ibland skapas av marknadens aktörer, men ofta krävs politiska styrmedel. De behövs för att investeringar i kunskapsutveckling ska kunna nyttiggöras och för att en bred industriell utveckling inom nya områden skall göras möjlig i Sverige.Vidare presenteras lärdomar kring vad en aktiv teknikpolitik innebär. Två huvud- ??????????????????????????????????????????????????????????????????????????????- hällsbygget och därför bör vara ett politikområde bland många samt att den skarpa ??????????????????????????????????????????????????????????????????????????????- ?????????????????????????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????????????? olika faser av innovationssystemets utveckling.För att lyckas med en aktiv teknikpolitik behövs en hög grad av koordinering ??????????????????????????????????????????????????????????????????????? teknikområden så att ”rätt” typ av åtgärder kan sättas in vid ”rätt” tidpunkt av ”rätt” aktör. TIS-ramverket lyfts här fram som en metod för att skapa ett sådant underlag. Slutligen presenteras en metod för projektbedömningar som syftar till att stötta handläggare i utvärderingar av projekt inom nya teknikområden.Rapporten i sin helhet riktar sig särskilt till beslutsfattare och handläggare vid myndigheter, departement och politiker, men även andra organisationer och indi- vider med intresse av att högt ställda klimatmål ska kunna nås samtidigt som en positiv näringslivsutveckling möjliggörs.
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| 10. |
- Malone, Kathleen E, et al.
(författare)
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Population-Based Study of the Risk of Second Primary Contralateral Breast Cancer Associated With Carrying a Mutation in BRCA1 or BRCA2.
- 2010
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 28, s. 2404-2410
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Women with breast cancer diagnosed early in life comprise a substantial portion of those tested for BRCA1/BRCA2 mutations; however, little information is available on the subsequent risks of contralateral breast cancer in mutation carriers. This study assessed the risk of subsequent contralateral breast cancer associated with carrying a BRCA1 or BRCA2 mutation. PATIENTS AND METHODS: In this nested case-control study, patients with contralateral breast cancer diagnosed 1 year or more after a first primary breast cancer (n = 705) and controls with unilateral breast cancer (n = 1,398) were ascertained from an underlying population-based cohort of 52,536 women diagnosed with a first invasive breast cancer before age 55 years. Interviews and medical record reviews were used to collect risk factor and treatment histories. All women were tested for BRCA1/BRCA2 mutations. Relative (rate ratios) and absolute (5- and 10-year cumulative) risks of developing contralateral breast cancer following a first invasive breast cancer were computed. RESULTS: Compared with noncarriers, BRCA1 and BRCA2 mutation carriers had 4.5-fold (95% CI, 2.8- to 7.1-fold) and 3.4-fold (95% CI, 2.0- to 5.8-fold) increased risks of contralateral breast cancer, respectively. The relative risk of contralateral breast cancer for BRCA1 mutation carriers increased as age of first diagnosis decreased. Age-specific cumulative risks are provided for clinical guidance. CONCLUSION: The risks of subsequent contralateral breast cancer are substantial for women who carry a BRCA1/BRCA2 mutation. These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation.
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