| 1. |
- Dufey, Estefanie, et al.
(författare)
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Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis.
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| 2. |
- Godoy, Patricio, et al.
(författare)
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Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells
- 2015
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 63:4, s. 934-942
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: The differentiation of stem cells to hepatocyte-like cells (HLC) offers the perspective of unlimited supply of human hepatocytes. However, the degree of differentiation of HLC remains controversial. To obtain an unbiased characterization, we performed a transcriptomic study with HLC derived from human embryonic and induced stem cells (ESC, hiPSC) from three different laboratories.METHODS: Genome-wide gene expression profiles of ESC and HLC were compared to freshly isolated and up to 14days cultivated primary human hepatocytes. Gene networks representing successful and failed hepatocyte differentiation, and the transcription factors involved in their regulation were identified.RESULTS: Gene regulatory network analysis demonstrated that HLC represent a mixed cell type with features of liver, intestine, fibroblast and stem cells. The "unwanted" intestinal features were associated with KLF5 and CDX2 transcriptional networks. Cluster analysis identified highly correlated groups of genes associated with mature liver functions (n=1057) and downregulated proliferation associated genes (n=1562) that approach levels of primary hepatocytes. However, three further clusters containing 447, 101, and 505 genes failed to reach levels of hepatocytes. Key TF of two of these clusters include SOX11, FOXQ1, and YBX3. The third unsuccessful cluster, controlled by HNF1, CAR, FXR, and PXR, strongly overlaps with genes repressed in cultivated hepatocytes compared to freshly isolated hepatocytes, suggesting that current in vitro conditions lack stimuli required to maintain gene expression in hepatocytes, which consequently also explains a corresponding deficiency of HLC.CONCLUSIONS: The present gene regulatory network approach identifies key transcription factors which require modulation to improve HLC differentiation.
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| 3. |
- Scaramboni, Caroline, et al.
(författare)
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Characterization of cross-continental PM2.5: Insights into emissions and chemical composition
- 2024
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Ingår i: Atmospheric research. - 0169-8095 .- 1873-2895. ; , s. 107423-107423
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric fine particulate matter (PM2.5) is a critical indicator of air quality, with substantial implications for human health. Understanding the emission sources and chemical composition of PM2.5 is crucial for mitigating possible adverse health effects. This study spans five diverse cities on three continents from north and south hemisphere: Stockholm (Sweden), Kyoto (Japan), Limeira, Ribeirão Preto, and Cáceres (Brazil). Our objective was to assess PM2.5 chemical composition and regional and long-range transport influences to identify the main sources of particulate air pollution at these cities during the winter/dry seasons. All studied cities but Kyoto exhibited PM2.5 levels above World Health Organization (WHO) guidelines, with the Brazilian cities experiencing the highest fine particle pollution levels, implying increased adverse health risks. We observed significant variations in concentrations of polycyclic aromatic compounds (PACs), monosaccharide anhydrides (MAs), and inorganic elements. Limeira exhibited the highest levels of total PACs (median level of 12.4 ng m−3), while Cáceres displayed high variability of PACs, most likely due to episodic regional wildfire events. MA concentrations were significantly higher in Limeira and Ribeirão Preto and together with elevated levels of retene and potassium (K) they suggested a substantial influence of biomass burning. Backward air mass trajectory analysis suggested widespread Amazon and Savanna wildfires along with local fires as main contributors for these sites. All source identification approaches highlighted differences among the cities, with Stockholm and Kyoto showing influence of sources related to traffic emissions, waste burning, and long-range transport, and Brazilian cities traffic, industrial, biogenic, and more evident biomass burning. This cross-continental study provides valuable insights into PM2.5 composition and emission sources, emphasizing the impact of different emissions on air quality. Our findings underscore the importance of local strategies to mitigate air pollution and protect public health, especially in regions where PM2.5 levels consistently exceed recommended guidelines.
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