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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. |
- Back, Jenny, 1984-, et al.
(författare)
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Psychosocial Predictors of Drop-Out from Organised Sport : A Prospective Study in Adolescent Soccer
- 2022
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Ingår i: International Journal of Environmental Research and Public Health. - Basel : MDPI. - 1661-7827 .- 1660-4601. ; 19:24
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Tidskriftsartikel (refereegranskat)abstract
- In recent years an increased drop-out rate in adolescents' soccer participation has been observed. Given the potentially adverse consequences of drop-out from soccer, more information about risk factors for drop-out is warranted. In the current study, Classification and Regression Tree (CRT) analysis was used to investigate demographic and motivational factors associated with an increased risk of drop-out from adolescent soccer. The results of this study indicate that older age, experiencing less autonomy support from the coach, less intrinsic motivation, being female, and lower socioeconomic status are factors associated with an increased risk of drop-out. An interpretation of the results of this study is that coaches play a central part in creating a sports context that facilitates motivation and continued soccer participation. Based on the findings of the current study we propose that soccer clubs implement theoretically informed coach education programs to help coaches adopt autonomy-supportive coaching strategies.
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| 4. |
- 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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| 5. |
- Ekelund, Rebecka, et al.
(författare)
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Interventions for improving mental health in athletes : a scoping review
- 2023
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Ingår i: International Review of Sport and Exercise Psychology. - Oxon : Routledge. - 1750-984X .- 1750-9858.
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Forskningsöversikt (refereegranskat)abstract
- The aims of this scoping review were to map the current literature on interventions for improving mental health in athletes, identify knowledge gaps, and generate future research questions. The Preferred Reporting Items for Systematic Review and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guided this review. A systematic literature search was conducted in SPORTDiscus, PsycINFO, and SCOPUS and 44 intervention studies met the inclusion criteria. Results showed that 22 studies (50%) implemented cognitive behavioural principles, and the majority of these studies were influenced by various mindfulness programmes. Most studies (93%) included healthy athlete samples, and athletes aged 15–19 were the most examined age group (43%). Only three studies used clinical criteria in their sampling of participants and mediators were examined in two studies. The scarcity of studies examining mediators and subclinical or clinical samples revealed critical knowledge gaps in the literature. Furthermore, the critical appraisal showed that regardless of study design, most studies demonstrated low internal validity. We propose the use of high-quality single-case studies with athletes who experience subclinical or clinical mental health issues, and further investigation of mechanisms of change linking intervention components to outcomes of interest.
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| 6. |
- Gawel, Danuta, et al.
(författare)
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A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases
- 2019
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. Methods: The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. Results: We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. Conclusions: Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.
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| 8. |
- Gustavsson, Andreas, 1982-
(författare)
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Static Execution Time Analysis of Parallel Systems
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The past trend of increasing processor throughput by increasing the clock frequency and the instruction level parallelism is no longer feasible due to extensive power consumption and heat dissipation. Therefore, the current trend in computer hardware design is to expose explicit parallelism to the software level. This is most often done using multiple, relatively slow and simple, processing cores situated on a single processor chip. The cores usually share some resources on the chip, such as some level of cache memory (which means that they also share the interconnect, e.g., a bus, to that memory and also all higher levels of memory). To fully exploit this type of parallel processor chip, programs running on it will have to be concurrent. Since multi-core processors are the new standard, even embedded real-time systems will (and some already do) incorporate this kind of processor and concurrent code.A real-time system is any system whose correctness is dependent both on its functional and temporal behavior. For some real-time systems, a failure to meet the temporal requirements can have catastrophic consequences. Therefore, it is crucial that methods to derive safe estimations on the timing properties of parallel computer systems are developed, if at all possible.This thesis presents a method to derive safe (lower and upper) bounds on the execution time of a given parallel system, thus showing that such methods must exist. The interface to the method is a small concurrent programming language, based on communicating and synchronizing threads, that is formally (syntactically and semantically) defined in the thesis. The method is based on abstract execution, which is itself based on abstract interpretation techniques that have been commonly used within the field of timing analysis of single-core computer systems, to derive safe timing bounds in an efficient (although, over-approximative) way. The thesis also proves the soundness of the presented method (i.e., that the estimated timing bounds are indeed safe) and evaluates a prototype implementation of it.
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| 9. |
- Gustavsson, Andreas, 1982-
(författare)
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Static Timing Analysis of Parallel Systems Using Abstract Execution
- 2014
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Power Wall has stopped the past trend of increasing processor throughput by increasing the clock frequency and the instruction level parallelism.Therefore, the current trend in computer hardware design is to expose explicit parallelism to the software level.This is most often done using multiple processing cores situated on a single processor chip.The cores usually share some resources on the chip, such as some level of cache memory (which means that they also share the interconnect, e.g. a bus, to that memory and also all higher levels of memory), and to fully exploit this type of parallel processor chip, programs running on it will have to be concurrent.Since multi-core processors are the new standard, even embedded real-time systems will (and some already do) incorporate this kind of processor and concurrent code.A real-time system is any system whose correctness is dependent both on its functional and temporal output. For some real-time systems, a failure to meet the temporal requirements can have catastrophic consequences. Therefore, it is of utmost importance that methods to analyze and derive safe estimations on the timing properties of parallel computer systems are developed.This thesis presents an analysis that derives safe (lower and upper) bounds on the execution time of a given parallel system.The interface to the analysis is a small concurrent programming language, based on communicating and synchronizing threads, that is formally (syntactically and semantically) defined in the thesis.The analysis is based on abstract execution, which is itself based on abstract interpretation techniques that have been commonly used within the field of timing analysis of single-core computer systems, to derive safe timing bounds in an efficient (although, over-approximative) way.Basically, abstract execution simulates the execution of several real executions of the analyzed program in one go.The thesis also proves the soundness of the presented analysis (i.e. that the estimated timing bounds are indeed safe) and includes some examples, each showing different features or characteristics of the analysis.
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| 10. |
- Hellsmark, Hans, 1974, et al.
(författare)
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Teknologiska innovationssystem inom energiområdet: En praktisk vägledning till identifiering av systemsvagheter som motiverar särskilda politiska åtaganden
- 2014
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Syftet med denna rapport är att illustrera hur ett praktiskt inriktat ramverk, tekno- logiska innovationssystem (TIS), kan användas av analytiker och beslutsfattare vid departement och myndigheter för att analysera strategiskt viktiga teknikområden ?????????????????????????????????????????????????????????????????????????????I rapporten analyseras fem TIS centrerade kring havsbaserad vindkraft, marin energi, ????????????????????????????????????????????????????????????????????????????????????? systemsvagheter som bromsar områdets vidare utveckling, vilka som kan åtgärdas av systemets aktörer och vilka som motiverar särskilda politiska åtaganden. Rapporten utgör därmed ett underlag för att formulera åtgärder för att åstadkomma ökad innova- tion, teknikspridning och industrialisering inom ovan nämnda teknikområden.Studien har även möjliggjort en jämförande analys av likheter och skillnader ???????????????????????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????????????????? mellan områdena – de är starka respektive svaga av olika orsaker. Detta visar att ???????????????????????????????????????????????????????????????????????Samtidigt har områdena gemensamma drag. Systemets aktörer, där även politiska ???????????????????????????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????????- skapsnätverk. Men de har varit sämre på att skapa tidiga nischmarknader som ger utrymme för fortsatt lärande och kostnadsreduktion. Sådana nischer kan ibland skapas av marknadens aktörer, men ofta krävs politiska styrmedel. De behövs för att investeringar i kunskapsutveckling ska kunna nyttiggöras och för att en bred industriell utveckling inom nya områden skall göras möjlig i Sverige.Vidare presenteras lärdomar kring vad en aktiv teknikpolitik innebär. Två huvud- ??????????????????????????????????????????????????????????????????????????????- hällsbygget och därför bör vara ett politikområde bland många samt att den skarpa ??????????????????????????????????????????????????????????????????????????????- ?????????????????????????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????????????? olika faser av innovationssystemets utveckling.För att lyckas med en aktiv teknikpolitik behövs en hög grad av koordinering ??????????????????????????????????????????????????????????????????????? teknikområden så att ”rätt” typ av åtgärder kan sättas in vid ”rätt” tidpunkt av ”rätt” aktör. TIS-ramverket lyfts här fram som en metod för att skapa ett sådant underlag. Slutligen presenteras en metod för projektbedömningar som syftar till att stötta handläggare i utvärderingar av projekt inom nya teknikområden.Rapporten i sin helhet riktar sig särskilt till beslutsfattare och handläggare vid myndigheter, departement och politiker, men även andra organisationer och indi- vider med intresse av att högt ställda klimatmål ska kunna nås samtidigt som en positiv näringslivsutveckling möjliggörs.
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