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- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)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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- Fox, Siobhan, et al.
(author)
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"Give me the knowledge, and I can do what I want with it, it's my right and my choice" : Triangulated perspectives on the disclosure of young onset dementia
- 2023
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In: Dementia. - : Sage Publications. - 1471-3012 .- 1741-2684. ; 22:8, s. 1757-1775
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Journal article (peer-reviewed)abstract
- IntroductionReceiving a diagnosis of young onset dementia is particularly distressing; the person under 65 years is often in employment, with financial commitments, young children, and an active social life. Some of the stress experienced by younger people experiencing cognitive changes can be reduced by an early and accurate diagnosis, but this is contingent on the timing of disclosure and a process which is sensitive and appropriate to the person. The study aim was to explore experiences of giving and receiving a diagnosis of young onset dementia, by triangulating the perspectives of the key parties involved.MethodsA qualitative design was employed, using semi-structured interviews. Participants (N = 47) included people with young onset dementia (n = 10), family members (n = 12), and health and social care professionals (n = 25). Thematic analysis and triangulation enabled identification of overall themes across different participant groups.ResultsAll participant groups agreed on key aspects of good disclosure practice, with two overarching themes: The optimal conditions for disclosure, and how best to disclose a diagnosis. Positive experiences of disclosure were prefaced on having the appropriate space and time; having a support person present; clearly labelling the diagnosis; providing appropriate information at the right pace. Other findings include recommendations for longer appointment times, offering additional support for young families, and for carers of people with atypical presentations (e.g. frontotemporal dementia).ConclusionMany people with young onset dementia had unsatisfactory disclosure experiences. Health and social care professionals should provide a 'pre-disclosure' appointment, elicit the amount of information the person may want at the point of disclosure of the diagnosis, balance truth and hope, provide contact details for follow-up, and overall be mindful of the individual in front of them. While young onset dementia may be a life-altering diagnosis, a disclosure meeting which is sensitively undertaken can increase the person's agency, coping ability, and ultimately empower them to live well with their diagnosis.
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| 5. |
- Kilty, Caroline, et al.
(author)
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Young onset dementia : implications for employment and finances
- 2023
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In: Dementia. - : Sage Publications. - 1471-3012 .- 1741-2684. ; 22:1, s. 68-84
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Journal article (peer-reviewed)abstract
- Background: People with young onset dementia face unique challenges. Notably, at time of symptom presentation, many people affected by young onset dementia are still employed with significant financial obligations. The aim of this study was to explore the specific impact that young onset dementia has on continued employment and finances and to identify ways to optimise post-diagnostic approaches in this regard.Methods: Purposive sampling, with a maximum variation technique, was used to recruit a small but diverse range of people with young onset dementia in Ireland. In-depth semi-structured interviews were conducted, and data were analysed using Reflexive Thematic Analysis. In total, 22 interviews were conducted with 10 people with young onset dementia and 12 spouses and children. Two themes were constructed: impact of young onset dementia on (I) employment and (II) finances.Findings: Participants' lived accounts showed the devastating effect of a diagnosis of young onset dementia on working life, and the resultant financial, social, and psychological consequences. Participants reported having to leave paid employment early, reported losing contracts and retiring on medical grounds. There were financial implications caused by loss of income, and many additional expenses owing to dementia were incurred. In some families, spouses had to take up employment at the same time as a caring role to mitigate the loss of income, and young children were anxious at the resultant occupational and financial tensions.Conclusion: People diagnosed with young onset dementia encounter significant challenges associated with employment, and individual and family finances. There is a need for more specific information and guidance from healthcare professionals around employment rights, income support and welfare benefits and the pension status for this group of people. Additionally, healthcare professionals should be cognisant of the additional financial burden people face in young onset dementia when advising on services which incur out-of-pocket costs.
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- Lango Allen, Hana, et al.
(author)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Journal article (peer-reviewed)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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- 2019
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Journal article (peer-reviewed)
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