| 1. |
- Sliz, E., et al.
(author)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 2. |
- Akkoyun, S., et al.
(author)
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AGATA - Advanced GAmma Tracking Array
- 2012
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In: Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. - : Elsevier BV. - 0168-9002 .- 0167-5087 .- 1872-9576. ; 668, s. 26-58
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Journal article (peer-reviewed)abstract
- The Advanced GAmma Tracking Array (AGATA) is a European project to develop and operate the next generation γ-ray spectrometer. AGATA is based on the technique of γ-ray energy tracking in electrically segmented high-purity germanium crystals. This technique requires the accurate determination of the energy, time and position of every interaction as a γ ray deposits its energy within the detector volume. Reconstruction of the full interaction path results in a detector with very high efficiency and excellent spectral response. The realisation of γ-ray tracking and AGATA is a result of many technical advances. These include the development of encapsulated highly segmented germanium detectors assembled in a triple cluster detector cryostat, an electronics system with fast digital sampling and a data acquisition system to process the data at a high rate. The full characterisation of the crystals was measured and compared with detector- response simulations. This enabled pulse-shape analysis algorithms, to extract energy, time and position, to be employed. In addition, tracking algorithms for event reconstruction were developed. The first phase of AGATA is now complete and operational in its first physics campaign. In the future AGATA will be moved between laboratories in Europe and operated in a series of campaigns to take advantage of the different beams and facilities available to maximise its science output. The paper reviews all the achievements made in the AGATA project including all the necessary infrastructure to operate and support the spectrometer. © 2011 Elsevier B.V. All rights reserved.
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| 3. |
- Tabassum, R, et al.
(author)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Journal article (peer-reviewed)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 4. |
- Romagnoni, A, et al.
(author)
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Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
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Journal article (peer-reviewed)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
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| 5. |
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| 6. |
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| 7. |
- Craddock, Nick, et al.
(author)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Journal article (peer-reviewed)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 8. |
- Chen, Zhishan, et al.
(author)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 9. |
- Tanskanen, T., et al.
(author)
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Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci
- 2018
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In: International Journal of Cancer. - Stockholm : Wiley. - 0020-7136 .- 1097-0215. ; 142:3, s. 540-546
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Journal article (peer-reviewed)abstract
- Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p=2.08 x 10(-4); OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p=1.50 x 10(-9); OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate<0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.
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| 10. |
- Kuisma, H, et al.
(author)
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Parity associates with chromosomal damage in uterine leiomyomas
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 5448-
-
Journal article (peer-reviewed)abstract
- Mechanical forces in a constrained cellular environment were recently established as a facilitator of chromosomal damage. Whether this could contribute to tumorigenesis is not known. Uterine leiomyomas are common neoplasms that display relatively few chromosomal aberrations. We hypothesized that if mechanical forces contribute to chromosomal damage, signs of this could be seen in uterine leiomyomas from parous women. We examined the karyotypes of 1946 tumors, and found a striking overrepresentation of chromosomal damage associated with parity. We then subjected myometrial cells to physiological forces similar to those encountered during pregnancy, and found this to cause DNA breaks and a DNA repair response. While mechanical forces acting in constrained cellular environments may thus contribute to neoplastic degeneration, and genesis of uterine leiomyoma, further studies are needed to prove possible causality of the observed association. No evidence for progression to malignancy was found.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Law, Philip J., et al.
(author)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
-
Journal article (peer-reviewed)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 17. |
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| 18. |
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| 19. |
- Jolma, A, et al.
(author)
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Multiplexed massively parallel SELEX for characterization of human transcription factor binding specificities
- 2010
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In: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 20:6, s. 861-873
-
Journal article (peer-reviewed)abstract
- The genetic code—the binding specificity of all transfer-RNAs—defines how protein primary structure is determined by DNA sequence. DNA also dictates when and where proteins are expressed, and this information is encoded in a pattern of specific sequence motifs that are recognized by transcription factors. However, the DNA-binding specificity is only known for a small fraction of the ∼1400 human transcription factors (TFs). We describe here a high-throughput method for analyzing transcription factor binding specificity that is based on systematic evolution of ligands by exponential enrichment (SELEX) and massively parallel sequencing. The method is optimized for analysis of large numbers of TFs in parallel through the use of affinity-tagged proteins, barcoded selection oligonucleotides, and multiplexed sequencing. Data are analyzed by a new bioinformatic platform that uses the hundreds of thousands of sequencing reads obtained to control the quality of the experiments and to generate binding motifs for the TFs. The described technology allows higher throughput and identification of much longer binding profiles than current microarray-based methods. In addition, as our method is based on proteins expressed in mammalian cells, it can also be used to characterize DNA-binding preferences of full-length proteins or proteins requiring post-translational modifications. We validate the method by determining binding specificities of 14 different classes of TFs and by confirming the specificities for NFATC1 and RFX3 using ChIP-seq. Our results reveal unexpected dimeric modes of binding for several factors that were thought to preferentially bind DNA as monomers.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
- Cajuso, T, et al.
(author)
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Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival
- 2019
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4022-
-
Journal article (peer-reviewed)abstract
- Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We find highly variable retrotransposon activity among tumors and identify recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identify insertions in APC, likely to be tumor-initiating events. Insertions are positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions is independently associated with poor disease-specific survival.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Palin, K, et al.
(author)
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Contribution of allelic imbalance to colorectal cancer
- 2018
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 3664-
-
Journal article (peer-reviewed)abstract
- Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.
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| 29. |
- Palin, Laurianne, et al.
(author)
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Three-dimensional current systems and ionospheric effects associated with small dipolarization fronts
- 2015
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In: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 120:5, s. 3739-3757
-
Journal article (peer-reviewed)abstract
- We present a case study of eight successive plasma sheet (PS) activations (usually referred to as bursty bulk flows or dipolarization fronts), associated with small individual B-ZGSM increases on 31 March 2009 (0200-0900 UT), observed by the Time History of Events and Macroscale Interactions During Substorms mission. This series of events happens during very quiet solar wind conditions, over a period of 7 h preceding a substorm onset at 1230 UT. The amplitude of the dipolarizations increases with time. The low-amplitude dipolarization fronts are associated with few (1 or 2) rapid flux transport events (RFT, E-h > 2 mV/m), whereas the large-amplitude ones encompass many more RFT events. All PS activations are associated with small and localized substorm current wedge (SCW)-like current system signatures, which seems to be the consequence of RFT arrival in the near tail. The associated ground magnetic perturbations affect a larger part of the contracted auroral oval when, in the magnetotail, more RFT are embedded in PS activations (> 5). Dipolarization fronts with very low amplitude, a type usually not included in statistical studies, are of particular interest because we found even those to be associated with clear small SCW-like current system and particle injections at geosynchronous orbit. This exceptional data set highlights the role of flow bursts in the magnetotail and leads to the conclusion that we may be observing the smallest form of a substorm or rather its smallest element. This study also highlights the gradual evolution of the ionospheric current disturbance as the plasma sheet is observed to heat up.
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| 30. |
- Schillings, Audrey, et al.
(author)
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Distribution and Occurrence Frequency of dB/dt Spikes During Magnetic Storms 1980–2020
- 2022
-
In: Space Weather. - : John Wiley & Sons. - 1542-7390. ; 20:5
-
Journal article (peer-reviewed)abstract
- The physical magnetospheric cause for geomagnetically induced currents (GICs) are rapid time-varying magnetic fields (dB/dt), which occur mainly during magnetic substorms and storms. When, where and why exactly such rapid dB/dt may occur is insufficiently understood. We investigated all storms since 1980 and analyzed the negative and positive dB/dt spikes (>|500| nT/min) in the north and east component using a worldwide coverage (SuperMAG). Our analysis confirmed the existence of two dB/dt spikes "hotspots" located in the pre-midnight and in the morning magnetic local time sector, independently of the geographic location of the stations. The associated physical phenomena are probably substorm current wedge onsets and westward traveling surges (WTS) in the evening sector, and wave- or vortex-like current flows in the morning sector known as Omega bands. We observed a spatiotemporal evolution of the negative northern dB/dt spikes. The spikes initially occur in the pre-midnight sector, and then develop in time toward the morning sector. This spatiotemporal sequence is correlated with bursts in the AE index, and can be repeated several times throughout a storm. Finally, we investigated the peak value of Dst and AE during the storm period in comparison with the dB/dt spike occurrence frequency, we did not find any correlation. This result implies that a moderate storm with many spikes can be as (or more) dangerous for ground-based infrastructures than a major storm with fewer dB/dt spikes. Our findings regarding the physical causes and characteristics of dB/dt spikes may help to improve the GIC forecast for the affected regions.
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| 31. |
- Schillings, Audrey, et al.
(author)
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Signatures of wedgelets over Fennoscandia during the St Patrick s Day Storm 2015
- 2023
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In: Journal of Space Weather and Space Climate. - : EDP Sciences. - 2115-7251. ; 13
-
Journal article (peer-reviewed)abstract
- During the long main phase of the St Patrick's Day storm on March 17, 2015, we found three separate enhancements of the westward electrojet. These enhancements are observed in the ionospheric equivalent currents computed using geomagnetic data over Fennoscandia. Using data from the IMAGE magnetometer network, we identified localised field-aligned current (FAC) systems superimposed on the pre-existing ionospheric current system. We suggest that these localised current systems are wedgelets and that they can potentially contribute to a larger-scale structure of a substorm current wedge (SCW). Each wedgelet is associated with a negative BX spike. Each spike is recorded at a higher latitude than the former one and all three are very localised over Fennoscandia. The first spike occurred at 17:34 UT and was observed at Lycksele, R rvik and Nurmij rvi, the second spike was recorded at 17:41 UT and located at Lycksele and R rvik, whereas the last spike occurred at 17:47 UT and was observed at Kevo and Abisko. Simultaneous optical auroral data and electron injections at the geosynchronous orbit indicate that one or more substorms took place in the polar ionosphere at the time of the wedgelets. This study demonstrates the occurrence of small and short-lived structures such as wedgelets at different locations over a short time scale, 15 min in this case.
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| 32. |
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| 33. |
- Grigorenko, E. E., et al.
(author)
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THEMIS observations of the current sheet dynamics in response to the intrusion of the high-velocity plasma flow into the near-Earth magnetotail
- 2014
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In: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 119:8
-
Journal article (peer-reviewed)abstract
- A small separation between Time History of Events and Macroscale Interactions during Substorms (THEMIS) probes allows us to analyze a sudden activation in the near-Earth current sheet (CS) at microscales. The start of the activation coincides with the appearance of an earthward plasma flow and dipolarization front (DF) at THEMIS location. The time sequence of observations of the fast plasma flow and the associated DF by three THEMIS probes denotes their dawnward displacement and the localization of the flow channel in the dawn-dusk direction. The onset of kink perturbations of the CS was generated on the dawn side of the flow. These fluctuations also propagated dawnward and were followed by the CS thinning (L similar to rho(i)) and by the development of tearing instability with transient appearance of a magnetic null point. The region of the unstable CS with a magnetic null point was localized in the X and, possibly, in the Y directions. The CS perturbations were most likely triggered by the intrusion of the fast flow into the ambient plasma in the course of the global dawnward displacement of the flow structure. Although no substorm onset was observed during the CS activation, a ground signature of a pseudobreakup was detected just after the excitement of the tearing mode in the near-Earth tail. Probably the pseudobreakup was caused by a localized diversion of the current, which could result from the disruption of the cross-tail current in a localized region of the near-Earth CS.
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| 34. |
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| 35. |
- Palin, Laurianne, et al.
(author)
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Modulation of the substorm current wedge by bursty bulk flows : 8 September 2002- Revisited
- 2016
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In: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 121:5, s. 4466-4482
-
Journal article (peer-reviewed)abstract
- The ultimate formation mechanism of the substorm current wedge (SCW) remains to date unclear. In this study, we investigate its relationship to plasma flows at substorm onset and throughout the following expansion phase. We revisit the case of 8 September 2002, which has been defined as one of the best textbook examples of a substorm because of its excellent coverage by both spacecraft in the magnetotail and ground-based observatories. We found that a dense sequence of arrival of nightside flux transfer events (NFTEs; which can be understood as the lobe magnetic signature due to a bursty bulk flow travelling earthward in the central plasma sheet) in the near-Earth tail leads to a modulation (and further step-like builtup) of the SCW intensity during the substorm expansion phase. In addition, we found that small SCWs are created also during the growth phase of the event in association with another less intense sequence of NFTEs. The differences between the sequence of NFTEs in the growth and expansion phase are discussed. We conclude that the envelope of the magnetic disturbances which we typically refer to as an intense magnetic substorm is the result of a group or sequence of more intense and more frequent NFTEs.
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| 36. |
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| 37. |
- Roberts, Nick M.W., et al.
(author)
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On the enigmatic mid-Proterozoic: Single-lid versus plate tectonics
- 2022
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In: Earth and Planetary Science Letters. - : Elsevier. - 0012-821X .- 1385-013X. ; 594, s. 1-12
-
Journal article (peer-reviewed)abstract
- The mid-Proterozoic (ca. 1850–850 Ma) is a peculiar period of Earth history in many respects: ophiolites and passive margins of this age are rare, whereas anorthosite and A-type granite suites are abundant; metamorphic rocks typically record high thermobaric (temperature/pressure) ratios, whereas ultrahigh pressure (UHP) rocks are rare; and the abundance of economic mineral deposits features rare porphyry Cu-Au and abundant Ni-Cu and Fe-oxide Cu-Ag (IOCG) deposit types. These collective observations have been used to propose that a stagnant-lid, or single-lid, tectonic regime operated at this time, between periods of plate tectonics in the Paleoproterozoic and Neoproterozoic. In our reappraisal of the mid-Proterozoic geological record, we not only assess the viability of the single-lid hypothesis for each line of evidence, but also that of the plate tectonic alternative. We find that evidence for the single-lid hypothesis is equivocal in all cases, whereas for plate tectonics the evidence is equivocal or supporting.We therefore find no reason to abandon a plate tectonic model for the mid-Proterozoic time period. Instead, we propose that the peculiarities of this enigmatic interval can be reconciled through the combination of two processes working in tandem: secular mantle cooling and the exceptionally long tenure and incomplete breakup of Earth’s first supercontinent, where both of these phenomena had a dramatic effect on lithospheric behaviour and its resulting imprint in the geological record
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| 38. |
- Sahu, B, et al.
(author)
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Human cell transformation by combined lineage conversion and oncogene expression
- 2021
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In: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 40:36, s. 5533-5547
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Journal article (peer-reviewed)abstract
- Cancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis.
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| 39. |
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| 41. |
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