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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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- 2019
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Tidskriftsartikel (refereegranskat)
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- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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- Ding, Xue Bing, et al.
(författare)
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Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:3, s. 411-418
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Tidskriftsartikel (refereegranskat)abstract
- Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease (PD). However, there is no direct evidence in humans to support this role1–5. In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD.
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- Qin, D L, et al.
(författare)
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Research on the reliability and validity of postural workload assessment method and the relation to work-related musculoskeletal disorders of workers
- 2018
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Ingår i: Beijing da xue xue bao. Yi xue ban= Journal of Peking University. Health Sciences. - 1671-167X. ; 50:3, s. 488-494
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To form a new assessment method to evaluate postural workload comprehensively analyzing the dynamic and static postural workload for workers during their work process to analyze the reliability and validity, and to study the relation between workers' postural workload and work-related musculoskeletal disorders (WMSDs).Methods: In the study, 844 workers from electronic and railway vehicle manufacturing factories were selected as subjects investigated by using the China Musculoskeletal Questionnaire (CMQ) to form the postural workload comprehensive assessment method. The Cronbach's α, cluster analysis and factor analysis were used to assess the reliability and validity of the new assessment method. Non-conditional Logistic regression was used to analyze the relation between workers' postural workload and WMSDs.Results: Reliability of the assessment method for postural workload: internal consistency analysis results showed that Cronbach's α was 0.934 and the results of split-half reliability indicated that Spearman-Brown coefficient was 0.881 and the correlation coefficient between the first part and the second was 0.787. Validity of the assessment method for postural workload: the results of cluster analysis indicated that square Euclidean distance between dynamic and static postural workload assessment in the same part or work posture was the shortest. The results of factor analysis showed that 2 components were extracted and the cumulative percentage of variance achieved 65.604%. The postural workload score of the different occupational workers showed significant difference (P<0.05) by covariance analysis. The results of nonconditional Logistic regression indicated that alcohol intake (OR=2.141, 95%CI 1.337-3.428) and obesity (OR=3.408, 95%CI 1.629-7.130) were risk factors for WMSDs. The risk for WMSDs would rise as workers' postural workload rose (OR=1.035, 95%CI 1.022-1.048). There was significant different risk for WMSDs in the different groups of workers distinguished by work type, gender and age. Female workers exhibited a higher prevalence for WMSDs (OR=2.626, 95%CI 1.414-4.879) and workers between 30-40 years of age (OR=1.909, 95%CI 1.237-2.946) as compared with those under 30.Conclusion: This method for comprehensively assessing postural workload is reliable and effective when used in assembling workers, and there is certain relation between the postural workload and WMSDs.
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