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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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- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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- Nguyen, Nadia, et al.
(författare)
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Sexual Partner Types and Incident HIV Infection Among Rural South African Adolescent Girls and Young Women Enrolled in HPTN 068 : A Latent Class Analysis
- 2019
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Ingår i: Journal of Acquired Immune Deficiency Syndromes. - : LIPPINCOTT WILLIAMS & WILKINS. - 1525-4135 .- 1944-7884. ; 82:1, s. 24-33
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sexual partners are the primary source of incident HIV infection among adolescent girls and young women (AGYW) in sub-Saharan Africa. Identifying partner types at greatest risk of HIV transmission could guide the design of tailored HIV prevention interventions. Methods: We conducted a secondary analysis of data from AGYW (aged 13-23 years) enrolled in a randomized controlled trial of cash transfers for HIV prevention in South Africa Annually, AGYW reported behavioral and demographic characteristics of their 3 most recent sexual partners, categorized each partner using prespecified labels, and received HIV testing. We used latent class analysis (LCA) to identify partner types from reported characteristics, and generalized estimating equations to estimate the relationship between both LCA-identified and prespecified partner types and incident HIV infection. Results: Across 2140 AGYW visits, 1034 AGYW made 2968 partner reports and 63 AGYW acquired HIV infection. We identified 5 LCA partner types, which we named monogamous HIV-negative peer partner; one-time protected in-school peer partner; out-ofschool older partner; anonymous out-of-school peer partner; and cohabiting with children in-school peer partner. Compared to AGYW with only monogamous HIV-negative peer partners, AGYW with out-of-school older partners had 2.56 times the annual risk of HIV infection (95% confidence interval: 1.23 to 5.33), whereas AGYW with anonymous out-of-school peer partners had 1.72 times the risk (95% confidence interval: 0.82 to 3.59). Prespecified partner types were not associated with incident HIV. Conclusion: By identifying meaningful combinations of partner characteristics and predicting the corresponding risk of HIV acquisition among AGYW, LCA-identified partner types may provide new insights for the design of tailored HIV prevention interventions.
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