| 1. |
- Menden, MP, et al.
(författare)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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| 2. |
- Kleinberger, G., et al.
(författare)
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TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
- 2014
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 6:243
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.
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| 3. |
- Harris, Ted D., et al.
(författare)
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What makes a cyanobacterial bloom disappear? : A review of the abiotic and biotic cyanobacterial bloom loss factors
- 2024
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Ingår i: Harmful Algae. - : Elsevier. - 1568-9883 .- 1878-1470. ; 133
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Forskningsöversikt (refereegranskat)abstract
- Cyanobacterial blooms present substantial challenges to managers and threaten ecological and public health. Although the majority of cyanobacterial bloom research and management focuses on factors that control bloom initiation, duration, toxicity, and geographical extent, relatively little research focuses on the role of loss processes in blooms and how these processes are regulated. Here, we define a loss process in terms of population dynamics as any process that removes cells from a population, thereby decelerating or reducing the development and extent of blooms. We review abiotic (e.g., hydraulic flushing and oxidative stress/UV light) and biotic factors (e.g., allelopathic compounds, infections, grazing, and resting cells/programmed cell death) known to govern bloom loss. We found that the dominant loss processes depend on several system specific factors including cyanobacterial genera -specific traits, in situ physicochemical conditions, and the microbial, phytoplankton, and consumer community composition. We also address loss processes in the context of bloom management and discuss perspectives and challenges in predicting how a changing climate may directly and indirectly affect loss processes on blooms. A deeper understanding of bloom loss processes and their underlying mechanisms may help to mitigate the negative consequences of cyanobacterial blooms and improve current management strategies.
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| 4. |
- Ghatei Kalashami, A., et al.
(författare)
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Correlation of microstructure and strain hardening behavior in the ultrafine-grained Nb-bearing dual phase steels
- 2016
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Ingår i: Materials Science & Engineering. - : Elsevier. - 0921-5093 .- 1873-4936. ; 678, s. 215-226
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Tidskriftsartikel (refereegranskat)abstract
- Ultrafine-grained dual phase (DP) steels with different Nb contents (0.00, 0.06 and 0.12 wt%) were produced by cold-rolling followed by intercritical annealing of ferrite/martensite starting microstructure at 770 °C for different holding times. Scanning electron microscopy, equipped with electron backscattered diffraction (EBSD) detector, nanoindentation and tensile testing were used to characterize microstructural evolutions and their correlations to the strain hardening and fracture behavior. EBSD results confirmed the retardation effect of Nb on recrystallization. It was found that the strains stored in the grains and density of geometrically necessary dislocations (GNDs) were increased with the addition of Nb. Strain hardening analysis showed that plastic deformation of the DP steels occurred in three distinct stages, which based on the EBSD results, nanoindentation and fracture analysis, were controlled by microstructural features such martensite volume fraction and size, density of GNDs and individual ferrite and martensite tensile properties.
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| 5. |
- Ghatei Kalashami, A., et al.
(författare)
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The effect of Nb on texture evolutions of the ultrafine-grained dual-phase steels fabricated by cold rolling and intercritical annealing
- 2017
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Ingår i: Journal of Alloys and Compounds. - : Elsevier. - 0925-8388 .- 1873-4669. ; 694, s. 1026-1035
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Tidskriftsartikel (refereegranskat)abstract
- Dual phase (DP) steels with different amounts of Nb were produced by utilizing cold rolling and intercritical annealing of a ferrite-martensite duplex starting structure. The effects of Nb contents (0.00, 0.06, 0.12 and 0.18 wt%) on microstructure and texture evolutions were studied. Addition of Nb promoted formation of ultra-fine grained structures with the ferrite grain size of about ~1 mm and uniformlydispersed martensite particles. The results showed increasing the fraction of the high angle grain boundaries and formation of {111} fiber components in the microstructures with increasing Nb content. In addition, the texture power was decreased with the addition of Nb, resulting in random texture components
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| 6. |
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| 7. |
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| 8. |
- Morawska, L., et al.
(författare)
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Airborne particles in indoor environment of homes, schools, offices and aged care facilities : The main routes of exposure
- 2017
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120. ; 108, s. 75-83
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Forskningsöversikt (refereegranskat)abstract
- It has been shown that the exposure to airborne particulate matter is one of the most significant environmental risks people face. Since indoor environment is where people spend the majority of time, in order to protect against this risk, the origin of the particles needs to be understood: do they come from indoor, outdoor sources or both? Further, this question needs to be answered separately for each of the PM mass/number size fractions, as they originate from different sources. Numerous studies have been conducted for specific indoor environments or under specific setting. Here our aim was to go beyond the specifics of individual studies, and to explore, based on pooled data from the literature, whether there are generalizable trends in routes of exposure at homes, schools and day cares, offices and aged care facilities. To do this, we quantified the overall 24 h and occupancy weighted means of PM10, PM2.5 and PN - particle number concentration. Based on this, we developed a summary of the indoor versus outdoor origin of indoor particles and compared the means to the WHO guidelines (for PM10 and PM2.5) and to the typical levels reported for urban environments (PN). We showed that the main origins of particle metrics differ from one type of indoor environment to another. For homes, outdoor air is the main origin of PM10 and PM2.5 but PN originate from indoor sources; for schools and day cares, outdoor air is the source of PN while PM10 and PM2.5 have indoor sources; and for offices, outdoor air is the source of all three particle size fractions. While each individual building is different, leading to differences in exposure and ideally necessitating its own assessment (which is very rarely done), our findings point to the existence of generalizable trends for the main types of indoor environments where people spend time, and therefore to the type of prevention measures which need to be considered in general for these environments.
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| 9. |
- Osborn, D. P. S., et al.
(författare)
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Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3
- 2021
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 23:4, s. 787-792
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. Methods Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. Results Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood-onset and sudden cardiac death. We identified a homozygous missense substitution (c.170C>A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G>T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G>A, predicted to result in skipping of exon 5). Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G>T or the missense c.170C>A variants. Minigene assay of the c.482-1G>A variant indicated a splicing defect likely resulting in disruption of the EF-hand Ca2+ binding domains. Conclusions Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function.
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| 10. |
- Ardalan, A., et al.
(författare)
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Post-disaster quality of life among older survivors five years after the Bam earthquake : implications for recovery policy
- 2011
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Ingår i: Ageing & Society. - 0144-686X .- 1469-1779. ; 31:2, s. 179-196
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Tidskriftsartikel (refereegranskat)abstract
- Older people are among the most vulnerable in major disasters. In their aftermath, it is crucial to institute efforts that will maintain a high level of elders' quality of life (QoL). This paper presents QoL assessments of elderly survivors five years after the Bam earthquake in Iran, and evaluates the determinants. A cross-sectional analysis of 210 randomly-selected survivors was carried out in 2008 using the WHOQOL-BREF questionnaire. A comparison of the results with data on the general population showed that experiencing the earthquake may adversely affect psychological dimensions of QoL even five years after, but paradoxically the earthquake resulted in better social relationships in affected communities than in the general population. Lower QoL associated with female gender, higher age, living alone, severe earthquake-related injury, poor quality of living conditions, increased dependency in the activities of daily living, living in an urban area, and being temporarily housed. Recovery experts and donors should carry out long-term monitoring of health status and QoL in disaster-affected communities, with a focus on psychological wellbeing. Intervention programmes that emphasise post-disaster quality of care and satisfactory housing may lead to better QoL of the victims and may shorten the recovery phase.
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