| 1. |
- Galeev, Roman, et al.
(författare)
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Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 14:12, s. 2988-3000
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Tidskriftsartikel (refereegranskat)abstract
- To gain insights into the regulatory mechanisms of hematopoietic stem cells (HSCs), we employed a genome-wide RNAi screen in human cord-blood derived cells and identified candidate genes whose knockdown maintained the HSC phenotype during culture. A striking finding was the identification of members of the cohesin complex (STAG2, RAD21, STAG1, and SMC3) among the top 20 genes from the screen. Upon individual validation of these cohesin genes, we found that their knockdown led to an immediate expansion of cells with an HSC phenotype in vitro. A similar expansion was observed in vivo following transplantation to immunodeficient mice. Transcriptome analysis of cohesin-deficient CD34(+) cells showed an upregulation of HSC-specific genes, demonstrating an immediate shift toward a more stem-cell-like gene expression signature upon cohesin deficiency. Our findings implicate cohesin as a major regulator of HSCs and illustrate the power of global RNAi screens to identify modifiers of cell fate.
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| 2. |
- Habibovic, Azra, et al.
(författare)
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Evaluating interactions with non-existing automated vehicles: three Wizard of Oz approaches
- 2016
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Ingår i: 2016 IEEE Intelligent Vehicles Symposium (IV). - Piscataway, NJ : IEEE. - 9781509018215 - 9781509018222 ; , s. 32-37
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Konferensbidrag (refereegranskat)abstract
- Highly automated test vehicles are rare today, and (independent) researchers have often limited access to them. Also, developing fully functioning system prototypes is time and effort consuming. In this paper, we present three adaptions of the Wizard of Oz technique as a means of gathering data about interactions with highly automated vehicles in early development phases. Two of them address interactions between drivers and highly automated vehicles, while the third one is adapted to address interactions between pedestrians and highly automated vehicles. The focus is on the experimental methodology adaptations and our lessons learned.
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| 3. |
- Jonzen, Jonas, et al.
(författare)
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Skogliga grunddata : digitala kartor för skogsbruket
- 2016
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Ingår i: Fakta. Skog. - 1400-7789.
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Annan publikation (populärvet., debatt m.m.)abstract
- Skogliga grunddata är digitala raster-kartor som beskriver tillståndet i skog och mark. De skogliga variablerna är i huvudsak framtagna genom en sambearbetning av laserdata från Lantmäteriets nationella laserskanning och provytor från Riksskogstaxeringen. De digitala kartorna som beskriver skogsmarken är till stor hjälp för privata skogsägare, skogstjänstemän, myndigheter, m fl. Data är dels tillgängligt för gratis nedladdning, men det finns även möjligheter att titta på kartorna med hjälp av interaktiva webverktyg. Lantmäteriets laserskanning påbörjades 2009 och fortgår än idag. Endast delar av fjällkedjan återstår. Grundtanken med laserskanningen var att få en bra höjdmodell över landet. En bra höjdmodell ger stor nytta vid all samhällsplanering, men är även till hjälp vid klimatanpassning. Riksskogstaxeringen samlar årligen in data om Sveriges skogstillstånd med permanenta och tillfälliga provytor. Dessa provytor är koordinatsatta och är väl spridda över hela landet. I detta projekt har provytor från Riksskogstaxeringen kombinerats med laserdata för att ta fram rasterkartor med uppgifter om virkesvolym, grundyta, medelhöjd, medeldiameter och trädbiomassa.
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| 4. |
- Lunavat, Taral R, et al.
(författare)
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RNAi delivery by exosome-mimetic nanovesicles - Implications for targeting c-Myc in cancer
- 2016
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612. ; 102, s. 231-238
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Tidskriftsartikel (refereegranskat)abstract
- To develop RNA-based therapeutics, it is crucial to create delivery vectors that transport the RNA molecule into the cell cytoplasm. Naturally released exosomes vesicles (also called "Extracellular Vesicles") have been proposed as possible RNAi carriers, but their yield is relatively small in any cell culture system. We have previously generated exosome-mimetic nanovesicles (NV) by serial extrusions of cells through nano-sized filters, which results in 100-times higher yield of extracellular vesicles. We here test 1) whether NV can be loaded with siRNA exogenously and endogenously, 2) whether the siRNA-loaded NV are taken up by recipient cells, and 3) whether the siRNA can induce functional knock-down responses in recipient cells. A siRNA against GFP was first loaded into NV by electroporation, or a c-Myc shRNA was expressed inside of the cells. The NV were efficiently loaded with siRNA with both techniques, were taken up by recipient cells, which resulted in attenuation of target gene expression. In conclusion, our study suggests that exosome-mimetic nanovesicles can be a platform for RNAi delivery to cell cytoplasm.
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| 5. |
- McGinn, Steven, et al.
(författare)
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New Technologies for DNA analysis-A review of the READNA Project.
- 2016
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Ingår i: New Biotechnology. - : Elsevier BV. - 1876-4347 .- 1871-6784.
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Forskningsöversikt (refereegranskat)abstract
- The REvolutionary Approaches and Devices for Nucleic Acid analysis (READNA) project received funding from the European Commission for 4 1/2 years. The objectives of the project revolved around technological developments in nucleic acid analysis. The project partners have discovered, created and developed a huge body of insights into nucleic acid analysis, ranging from improvements and implementation of current technologies to the most promising sequencing technologies that constitute a 3(rd) and 4(th) generation of sequencing methods with nanopores and in situ sequencing, respectively.
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| 6. |
- Muralidharan, Somsundar Veppil, et al.
(författare)
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BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc-induced lymphoma cells.
- 2016
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 35, s. 4689-4697
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Tidskriftsartikel (refereegranskat)abstract
- Inhibiting the bromodomain and extra-terminal (BET) domain family of epigenetic reader proteins has been shown to have potent anti-tumoral activity, which is commonly attributed to suppression of transcription. In this study, we show that two structurally distinct BET inhibitors (BETi) interfere with replication and cell cycle progression of murine Myc-induced lymphoma cells at sub-lethal concentrations when the transcriptome remains largely unaltered. This inhibition of replication coincides with a DNA-damage response and enhanced sensitivity to inhibitors of the upstream replication stress sensor ATR in vitro and in mouse models of B-cell lymphoma. Mechanistically, ATR and BETi combination therapy cause robust transcriptional changes of genes involved in cell death, senescence-associated secretory pathway, NFkB signaling and ER stress. Our data reveal that BETi can potentiate the cell stress and death caused by ATR inhibitors. This suggests that ATRi can be used in combination therapies of lymphomas without the use of genotoxic drugs.Oncogene advance online publication, 25 January 2016; doi:10.1038/onc.2015.521.
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| 7. |
- Nilsson, Jessica, et al.
(författare)
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A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice
- 2016
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Ingår i: Nutrition & Metabolism. - : BioMed Central (BMC). - 1743-7075. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Excess body fat is a major health issue and a risk factor for the development of numerous chronic diseases. Low-carbohydrate diets like the Atkins Diet are popular for rapid weight loss, but the long-term consequences remain the subject of debate. The Scandinavian low-carbohydrate high-fat (LCHF) diet, which has been popular in Scandinavian countries for about a decade, has very low carbohydrate content (~5 E %) but is rich in fat and includes a high proportion of saturated fatty acids. Here we investigated the metabolic and physiological consequences of a diet with a macronutrient composition similar to the Scandinavian LCHF diet and its effects on the organs, tissues, and metabolism of weight stable mice.METHODS: Female C57BL/6J mice were iso-energetically pair-fed for 4 weeks with standard chow or a LCHF diet. We measured body composition using echo MRI and the aerobic capacity before and after 2 and 4 weeks on diet. Cardiac function was assessed by echocardiography before and after 4 weeks on diet. The metabolic rate was measured by indirect calorimetry the fourth week of the diet. Mice were sacrificed after 4 weeks and the organ weight, triglyceride levels, and blood chemistry were analyzed, and the expression of key ketogenic, metabolic, hormonal, and inflammation genes were measured in the heart, liver, and adipose tissue depots of the mice using real-time PCR.RESULTS: The increase in body weight of mice fed a LCHF diet was similar to that in controls. However, while control mice maintained their body composition throughout the study, LCHF mice gained fat mass at the expense of lean mass after 2 weeks. The LCHF diet increased cardiac triglyceride content, impaired cardiac function, and reduced aerobic capacity. It also induced pronounced alterations in gene expression and substrate metabolism, indicating a unique metabolic state.CONCLUSIONS: Pair-fed mice eating LCHF increased their percentage of body fat at the expense of lean mass already after 2 weeks, and after 4 weeks the function of the heart deteriorated. These findings highlight the urgent need to investigate the effects of a LCHF diet on health parameters in humans.
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| 8. |
- Nilsson, Jonas, 1979, et al.
(författare)
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Worst Case Analysis of Automotive Collision Avoidance Systems
- 2016
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Ingår i: IEEE Transactions on Vehicular Technology. - 0018-9545 .- 1939-9359. ; 65:4, s. 1899-1911
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Tidskriftsartikel (refereegranskat)abstract
- Automotive Collision Avoidance (CA) systems help drivers to avoid collisions through autonomous interventions by braking or steering. If the decision to intervene is made too early, the intervention can become a nuisance to the driver and if the decision is made too late, the safety benefits of the intervention will be reduced. The decision to intervene is commonly based on a threat function. The dimensionality of the input state space for the threat function is in general very large making exhaustive evaluation in real vehicles intractable. This paper presents a method for efficient estimation of a conservative bound on CA system performance, i.e. the worst case performance. Closedform expressions are derived for the worst case performance, in terms of early or unnecessary interventions, with regards to longitudinal or lateral prediction and measurement errors. Also, we derive closed-form expressions for robust avoidance scenarios, in which no unnecessary intervention will occur. For a system example, numerical results show how decision timing and robustness depend on scenario and system parameters. The method can be used for e.g. defining system requirements, system verification, system tuning or system sensitivity analysis with regards to scenario variations and sensor measurement errors.
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| 9. |
- Nilsson, Lisa M, 1976, et al.
(författare)
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Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins
- 2016
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 76:8, s. 2376-2383
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Tidskriftsartikel (refereegranskat)abstract
- Agents that trigger cell differentiation are highly efficacious in treating certain cancers, but such approaches are not generally effective in most malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have been used to induce differentiation in experimental systems, but their mechanisms of action and potential range of uses on that basis have not been developed. Here, we show that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical and structural studies revealed an affinity of HMBA for the second bromodomain of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1 induced differentiation of mouse erythroleukemia cells. As expected of a BET inhibitor, HMBA displaced BET proteins from chromatin, caused massive transcriptional changes, and triggered cell-cycle arrest and apoptosis in Myc-induced B-cell lymphoma cells. Furthermore, HMBA exerted anticancer effects in vivo in mouse models of Myc-driven B-cell lymphoma. This study illuminates the function of an early anticancer agent and suggests an intersection with ongoing clinical trials of BET inhibitor, with several implications for predicting patient selection and response rates to this therapy and starting points for generating BD2-selective BET inhibitors. (C) 2016 AACR.
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| 10. |
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