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| 2. |
- 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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| 3. |
- Allentoft, Morten E., et al.
(författare)
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Population genomics of post-glacial western Eurasia
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
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Tidskriftsartikel (refereegranskat)abstract
- Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
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| 4. |
- Allentoft, Morten E., et al.
(författare)
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100 ancient genomes show repeated population turnovers in Neolithic Denmark
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1–4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5–7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.
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| 5. |
- Watson, Hunna J., et al.
(författare)
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Common Genetic Variation and Age of Onset of Anorexia Nervosa
- 2022
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Ingår i: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.METHODS: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (,13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.RESULTS: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early-and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early -onset AN.CONCLUSIONS: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
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| 6. |
- Sinding, Mikkel-Holger S., et al.
(författare)
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Arctic-adapted dogs emerged at the Pleistocene-Holocene transition
- 2020
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 368:6498
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Tidskriftsartikel (refereegranskat)abstract
- Although sled dogs are one of the most specialized groups of dogs, their origin and evolution has received much less attention than many other dog groups. We applied a genomic approach to investigate their spatiotemporal emergence by sequencing the genomes of 10 modern Greenland sled dogs, an similar to 9500-year-old Siberian dog associated with archaeological evidence for sled technology, and an similar to 33,000-year-old Siberian wolf. We found noteworthy genetic similarity between the ancient dog and modern sled dogs. We detected gene flow from Pleistocene Siberian wolves, but not modern American wolves, to present-day sled dogs. The results indicate that the major ancestry of modern sled dogs traces back to Siberia, where sled dog-specific haplotypes of genes that potentially relate to Arctic adaptation were established by 9500 years ago.
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| 7. |
- Sinding, Mikkel-Holger S., et al.
(författare)
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Population genomics of grey wolves and wolf-like canids in North America
- 2018
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- North America is currently home to a number of grey wolf (Canis lupus) and wolf-like canid populations, including the coyote (Canis latrans) and the taxonomically controversial red, Eastern timber and Great Lakes wolves. We explored their population structure and regional gene flow using a dataset of 40 full genome sequences that represent the extant diversity of North American wolves and wolf-like canid populations. This included 15 new genomes (13 North American grey wolves, 1 red wolf and 1 Eastern timber/Great Lakes wolf), ranging from 0.4 to 15x coverage. In addition to providing full genome support for the previously proposed coyote-wolf admixture origin for the taxonomically controversial red, Eastern timber and Great Lakes wolves, the discriminatory power offered by our dataset suggests all North American grey wolves, including the Mexican form, are monophyletic, and thus share a common ancestor to the exclusion of all other wolves. Furthermore, we identify three distinct populations in the high arctic, one being a previously unidentified "Polar wolf" population endemic to Ellesmere Island and Greenland. Genetic diversity analyses reveal particularly high inbreeding and low heterozygosity in these Polar wolves, consistent with long-term isolation from the other North American wolves.
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| 8. |
- Jensen, Elisabeth Kjær, et al.
(författare)
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A national center for persistent severe pain after groin hernia repair : Five-year prospective data
- 2019
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Ingår i: Medicine. - 0025-7974. ; 98:33
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Tidskriftsartikel (refereegranskat)abstract
- Severe persistent pain after groin hernia repair impairs quality-of-life. Prospective, consecutive cohort study including patients with pain-related impairment of physical and social life. Relevant surgical records were obtained, and examinations were by standardized clinical and neurophysiological tests. Patients demonstrating pain sensitivity to pressure algometry in the operated groin underwent re-surgery, while patients with neuropathic pain received pharmacotherapy. Questionnaires at baseline (Q0) and at the 5-year time point (Q5Y) were used in outcome analyses of pain intensity (numeric rating scale [NRS] 0-10) and pain-related effect on the activity-of-daily-living (Activities Assessment Scale [AAS]). Data are mean (95% CI).Analyses were made in 172/204 (84%) eligible patients. In 54/172 (31%) patients re-surgery (meshectomy/selective neurectomy) was performed, while the remaining 118/172 (69%) patients received pharmacotherapy. In the re-surgery group, activity-related, and average NRS-scores at Q0 were 6.6 (5.6-7.9) and 5.9 (5.6-5.9), respectively. Correspondingly, NRS-scores at Q5Y was 4.1 (3.3-5.1) and 3.1 (2.3-4.0; Q0 vs. Q5Y: P < .0005), respectively. Although both groups experienced a significant improvement in AAS-scores comparing Q0 vs. Q5Y (re-surgery group: 28% (4-43%; P < .0001); pharmacotherapy group: 5% (0-11%; P = .005)) the improvement was significantly larger in the re-surgery group (P = .02).This 5-year cohort study in patients with severe persistent pain after groin hernia repair signals that selection to re-surgery or pharmacotherapy, based on examination of pain sensitivity, is associated with significant improvement in outcome. Analyzing composite endpoints, combining pain and physical function, are novel in exploring interventional effects.ClinicalTrials.gov Identifier NCT03713047.
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| 9. |
- Jensen, Elisabeth Kjær, et al.
(författare)
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Somatosensory Outcomes Following Re-Surgery in Persistent Severe Pain After Groin Hernia Repair : A Prospective Observational Study
- 2023
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Ingår i: Journal of Pain Research. - 1178-7090. ; 16, s. 943-959
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: After groin hernia repair (globally more than 20 million/year) 2–4% will develop persistent severe pain (PSPG). Pain management is challenging and may require multimodal interventions, including re-surgery. Quantitative somatosensory testing (QST) is an investigational psychophysiological tool with the potential to uncover the pathophysiological mechanisms behind the pain, ie, revealing neuropathic or inflammatory components. The primary objective was to examine and describe the underlying pathophysiological changes in the groin areas by QST before and after re-surgery with mesh removal and selective neurectomy. Patients and Methods: Sixty patients with PSPG scheduled for re-surgery and with an inflammatory “component” indicated by blunt pressure algometry were examined in median (95% CI) 7.9 (5.8–11.5) months before and 4.0 (3.5–4.6) months after re-surgery. The QST-analyses included standardized assessments of cutaneous mechanical/thermal detection and pain thresholds. Suprathreshold heat stimuli were applied. Deep tissue sensitivity was tested by pressure algometry. Testing sites were the groin areas and the lower arm. Before/after QST data were z-transformed. Results: Re-surgery resulted in median changes in rest, average, and maximal pain intensity scores of −2.0, −2.5, and −2.0 NRS (0/ 10) units, respectively (P = 0.0001), and proportional increases in various standardized functional scores (P = 0.0001). Compared with the control sites, the cutaneous somatosensory detection thresholds of the painful groin were increased before re-surgery and increased further after re-surgery (median difference: 1.28 z-values; P = 0.001), indicating a successive post-surgical loss of nerve fiber function (“deafferentation”). Pressure algometry thresholds increased after re-surgery (median difference: 0.30 z-values; P = 0.001). Conclusion: In this subset of patients with PSPG who underwent re-surgery, the procedure was associated with improved pain and functional outcomes. While the increase in somatosensory detection thresholds mirrors the surgery-induced cutaneous deafferentation, the increase in pressure algometry thresholds mirrors the removal of the deep “pain generator”. The QST-analyses are useful adjuncts in mechanism-based somatosensory research.
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