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- 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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- 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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- Cramer, Bradley D., et al.
(författare)
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Paleobiogeography, high-resolution stratigraphy, and the future of Paleozoic biostratigraphy: Fine-scale diachroneity of the Wenlock (Silurian) conodont Kockelella walliseri
- 2010
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Ingår i: Palaeogeography, Palaeoclimatology, Palaeoecology. - : Elsevier BV. - 0031-0182 .- 1872-616X. ; 294:3-4, s. 232-241
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Konferensbidrag (refereegranskat)abstract
- The Wenlock Epoch of the Silurian Period has become one of the chronostratigraphically best-constrained intervals of the Paleozoic. The integration of multiple chronostratigraphic tools, such as conodont and graptolite biostratigraphy, sequence stratigraphy, and delta C-13(carb) chemostratigraphy, has greatly improved global chronostratigraphic correlation and portions of the Wenlock can now be correlated with precision better than +/- 100 kyr. Additionally, such detailed and integrated chronostratigraphy provides an opportunity to evaluate the fidelity of individual chronostratigraphic tools. Here, we use conodont biostratigraphy, sequence stratigraphy and carbon isotope (delta C-13(carb)) chemostratigraphy to demonstrate that the conodont Kockelella walliseri, an important guide fossil for middle and upper Sheinwoodian strata (lower stage of the Wenlock Series), first appears at least one full stratigraphic sequence lower in Laurentia than in Baltica. Rather than serving as a demonstration of the unreliability of conodont biostratigraphy, this example serves to demonstrate the promise of high-resolution Paleozoic stratigraphy. The temporal difference between the two first occurrences was likely less than 1 million years, and although it is conceptually understood that speciation and colonization must have been non-instantaneous events, Paleozoic paleobiogeographic variability on such short timescales (tens to hundreds of kyr) traditionally has been ignored or considered to be of little practical importance. The expansion of high-resolution Paleozoic stratigraphy in the future will require robust biostratigraphic zonations that embrace the integration of multiple chronostratigraphic tools as well as the paleobiogeographic variability in ranges that they will inevitably demonstrate. In addition, a better understanding of the paleobiogeographic migration histories of marine organisms will provide a unique tool for future Paleozoic paleoceanography and paleobiology research. (C) 2010 Elsevier B.V. All rights reserved.
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- Cramer, Bradley D., et al.
(författare)
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Revised correlation of Silurian Provincial Series of North America with global and regional chronostratigraphic units and delta 13C(carb) chemostratigraphy
- 2011
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Ingår i: Lethaia. - : Scandinavian University Press / Universitetsforlaget AS. - 0024-1164. ; 44:2, s. 185-202
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Forskningsöversikt (refereegranskat)abstract
- Recent revisions to the biostratigraphic and chronostratigraphic assignment of strata from the type area of the Niagaran Provincial Series (a regional chronostratigraphic unit) have demonstrated the need to revise the chronostratigraphic correlation of the Silurian System of North America. Recently, the working group to restudy the base of the Wenlock Series has developed an extremely high-resolution global chronostratigraphy for the Telychian and Sheinwoodian stages by integrating graptolite and conodont biostratigraphy with carbonate carbon isotope (delta 13C(carb)) chemostratigraphy. This improved global chronostratigraphy has required such significant chronostratigraphic revisions to the North American succession that much of the Silurian System in North America is currently in a state of flux and needs further refinement. This report serves as an update of the progress on recalibrating the global chronostratigraphic correlation of North American Provincial Series and Stage boundaries in their type area. The revised North American classification is correlated with global series and stages as well as regional classifications used in the United Kingdom, the East Baltic, Australia, China, the Barrandian, and Altaj. Twenty-four potential stage slices, based primarily on graptolite and conodont zones and correlated to the global series and stages, are illustrated alongside a new composite delta 13C(carb) curve for the Silurian. Conodont, graptolite, isotope, New York, Ontario, series, Silurian, stage.
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- van Rheenen, Wouter, et al.
(författare)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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