| 1. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 2. |
- Machiela, Mitchell J, et al.
(författare)
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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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| 3. |
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| 4. |
- Biggs, Reinette, et al.
(författare)
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Social-ecological change : insights from the Southern African Program on Ecosystem Change and Society
- 2022
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Ingår i: Ecosystems and People. - : Informa UK Limited. - 2639-5908 .- 2639-5916. ; 18:1, s. 447-468
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Tidskriftsartikel (refereegranskat)abstract
- Social-ecological systems (SES) research has emerged as an important area of sustainability science, informing and supporting pressing issues of transformation towards more sustainable, just and equitable futures. To date, much SES research has been done in or from the Global North, where the challenges and contexts for supporting sustainability transformations are substantially different from the Global South. This paper synthesises emerging insights on SES dynamics that can inform actions and advance research to support sustainability transformations specifically in the southern African context. The paper draws on work linked to members of the Southern African Program on Ecosystem Change and Society (SAPECS), a leading SES research network in the region, synthesizing key insights with respect to the five core themes of SAPECS: (i) transdisciplinary and engaged research, (ii) ecosystem services and human well-being, (iii) governance institutions and management practices, (iv) spatial relationships and cross-scale connections, and (v) regime shifts, traps and transformations. For each theme, we focus on insights that are particularly novel, interesting or important in the southern African context, and reflect on key research gaps and emerging frontiers for SES research in the region going forward. Such place-based insights are important for understanding the variation in SES dynamics around the world, and are crucial for informing a context-sensitive global agenda to foster sustainability transformations at local to global scales.
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| 5. |
- Biggs, Reinette, et al.
(författare)
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The Southern African Program on Ecosystem Change and Society : an emergent community of practice
- 2023
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Ingår i: Ecosystems and People. - : Informa UK Limited. - 2639-5908 .- 2639-5916. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Sustainability-focused research networks and communities of practice have emerged as a key response and strategy to build capacity and knowledge to support transformation towards more sustainable, just and equitable futures. This paper synthesises insights from the development of a community of practice on social-ecological systems (SES) research in southern Africa over the past decade, linked to the international Programme on Ecosystem Change and Society (PECS). This community consists of a network of researchers who carry out place-based SES research in the southern African region. They interact through various cross-cutting working groups and also host a variety of public colloquia and student and practitioner training events. Known as the Southern African Program on Ecosystem Change and Society (SAPECS), its core objectives are to: (1) derive new approaches and empirical insights on SES dynamics in the southern African context; (2) have a tangible impact by mainstreaming knowledge into policy and practice; and (3) grow the community of practice engaged in SES research and governance, including researchers, students and practitioners. This paper reflects on experiences in building the SAPECS community, with the aim of supporting the development of similar networks elsewhere in the world, particularly in the Global South.
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| 6. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 7. |
- Deshpande, Shilpa, et al.
(författare)
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A user's manual for the Occupational Circumstances Assessment Interview and Rating Scale
- 2002
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- The OCAIRS provides a structure for gathering, analyzing, and reporting data on the extent and nature of an individual's occupational participation. It can be used with a wide range of clients, and would be appropriate for any adolescent or adult client who has the cognitive and emotional ability to participate in an interview. The OCAIRS provides a structured and theoretically based means of developing interview skills in evaluation and treatment.
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| 8. |
- Forsyth, Kirsty, et al.
(författare)
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The Occupational Circumstances Assessment Interview and Rating Scale Version 4.0, 2005
- 2005
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- The OCAIRS provides a structure for gathering, analyzing, and reporting data on the extent and nature of an individual's occupational participation. It can be used with a wide range of clients, and would be appropriate for any adolescent or adult client who has the cognitive and emotional ability to participate in an interview. The OCAIRS provides a structured and theoretically based means of developing interview skills in evaluation and treatment.
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| 9. |
- Francis, Monika K., et al.
(författare)
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Endocytic membrane turnover at the leading edge is driven by a transient interaction between Cdc42 and GRAF1
- 2015
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Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 128:22, s. 4183-4195
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Tidskriftsartikel (refereegranskat)abstract
- Changes in cell morphology require coordination of plasma membrane turnover and cytoskeleton dynamics, processes that are regulated by Rho GTPases. Here, we describe how a direct interaction between the Rho GTPase Cdc42 and the GTPase activating protein (GAP) GRAF1, facilitate rapid cell surface turnover at the leading edge. Both Cdc42 and GRAF1 were required for fluid phase uptake and regulated the generation of transient GRAF1-coated endocytic carriers, distinct from clathrin coated vesicles. GRAF1 was found to transiently assemble at discrete Cdc42-enriched punctae at the plasma membrane resulting in a corresponding decrease in Cdc42 microdomain association. However, Cdc42 captured in its active state was, via a GAP domain mediated interaction, localised together with GRAF1 on accumulated internal structures derived from the cell surface. Correlative fluorescence and electron tomography microscopy revealed that these structures were clusters of small membrane carriers affected in their endosomal processing. We conclude that a transient interaction between Cdc42 and GRAF1 drives endocytic turnover and controls the transition essential for endosomal maturation of plasma membrane internalised by this mechanism.
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| 10. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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