| 1. |
- Bustamante, M., et al.
(författare)
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Dose and time effects of solar-simulated ultraviolet radiation on the in vivo human skin transcriptome
- 2020
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Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 182:6, s. 1458-1468
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Tidskriftsartikel (refereegranskat)abstract
- Background Terrestrial ultraviolet (UV) radiation causes erythema, oxidative stress, DNA mutations and skin cancer. Skin can adapt to these adverse effects by DNA repair, apoptosis, keratinization and tanning.Objectives To investigate the transcriptional response to fluorescent solar-simulated radiation (FSSR) in sun-sensitive human skin in vivo.Methods Seven healthy male volunteers were exposed to 0, 3 and 6 standard erythemal doses (SED). Skin biopsies were taken at 6 h and 24 h after exposure. Gene and microRNA expression were quantified with next generation sequencing. A set of candidate genes was validated by quantitative polymerase chain reaction (qPCR); and wavelength dependence was examined in other volunteers through microarrays.Results The number of differentially expressed genes increased with FSSR dose and decreased between 6 and 24 h. Six hours after 6 SED, 4071 genes were differentially expressed, but only 16 genes were affected at 24 h after 3 SED. Genes for apoptosis and keratinization were prominent at 6 h, whereas inflammation and immunoregulation genes were predominant at 24 h. Validation by qPCR confirmed the altered expression of nine genes detected under all conditions; genes related to DNA repair and apoptosis; immunity and inflammation; pigmentation; and vitamin D synthesis. In general, candidate genes also responded to UVA1 (340-400 nm) and/or UVB (300 nm), but with variations in wavelength dependence and peak expression time. Only four microRNAs were differentially expressed by FSSR.Conclusions The UV radiation doses of this acute study are readily achieved daily during holidays in the sun, suggesting that the skin transcriptional profile of 'typical' holiday makers is markedly deregulated.
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| 2. |
- Sand, M., et al.
(författare)
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Next-generation sequencing of the basal cell carcinoma miRNome and a description of novel microRNA candidates under neoadjuvant vismodegib therapy : an integrative molecular and surgical case study
- 2016
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:2, s. 332-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: MicroRNAs (miRNAs) have been identified as key players in posttranscriptional gene regulation and have a significant impact on basal cell carcinoma (BCC) development. The Sonic hedgehog pathway inhibitor vismodegib has been approved for oral therapy of metastatic or advanced BCC. Here, a high-throughput miRNA sequencing analysis was carried out to identify differentially expressed miRNAs and possible novel miRNA candidates in vismodegib-treated BCC tissue. Additionally, we described our surgical experience with neoadjuvant oral vismodegib therapy. Patients and methods: A punch biopsy (4 mm) from a patient with an extensive cranial BCC under oral vismodegib therapy and a corresponding nonlesional epithelial skin biopsy were harvested. Total RNA was isolated, after which a sequencing cDNA library was prepared, and cluster generation was carried out, which was followed by an ultra-high-throughput miRNA sequencing analysis to indicate the read number of miRNA expression based on miRBase 21. In addition to the identification of differentially expressed miRNAs from RNA sequencing data, additional novel miRNA candidates were determined with a tool for identifying new miRNA sequences (miRDeep2). Results: We identified 33 up-regulated miRNAs (fold change >= 2) and 39 potentially new miRNA candidates (miRDeep scores 0-43.6). A manual sequence analysis of the miRNA candidates on the genomic locus of chromosome 1 with provisional IDs of chr1_1913 and chr1_421 was further carried out and rated as promising (chr1_1913) and borderline (chr1_421). Histopathology revealed skip lesions in clinically healthy appearing skin at the tumor margins, which were the cause of seven re-excisions by micrographic controlled surgery to achieve tumor-free margins. Conclusion: miRNA sequencing revealed novel miRNA candidates that need to be further confirmed in functional Dicer knockout studies. Clinically, on the basis of our surgical experience described here, neoadjuvant vismodegib therapy in BCC appears to impede histopathologic evaluations with effects on surgical therapy. Thus, larger studies are necessary, but are not preferable at this time if other options are available.
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| 3. |
- Ferreira, Pedro G., et al.
(författare)
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Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in the cost-efficiency of sequencing technologies enabled the combined DNA-and RNA-sequencing of human individuals at the population-scale, making genome-wide investigations of the inter-individual genetic impact on gene expression viable. Employing mRNA-sequencing data from the Geuvadis Project and genome sequencing data from the 1000 Genomes Project we show that the computational analysis of DNA sequences around splice sites and poly-A signals is able to explain several observations in the phenotype data. In contrast to widespread assessments of statistically significant associations between DNA polymorphisms and quantitative traits, we developed a computational tool to pinpoint the molecular mechanisms by which genetic markers drive variation in RNA-processing, cataloguing and classifying alleles that change the affinity of core RNA elements to their recognizing factors. The in silico models we employ further suggest RNA editing can moonlight as a splicing-modulator, albeit less frequently than genomic sequence diversity. Beyond existing annotations, we demonstrate that the ultra-high resolution of RNA-Seq combined from 462 individuals also provides evidence for thousands of bona fide novel elements of RNA processing-alternative splice sites, introns, and cleavage sites-which are often rare and lowly expressed but in other characteristics similar to their annotated counterparts.
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| 4. |
- Friedländer, Marc R., 1975-, et al.
(författare)
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How ancient RNA survives and what we can learn from it
- 2024
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Ingår i: Nature reviews. Molecular cell biology. - 1471-0072 .- 1471-0080. ; 25, s. 417-418
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Forskningsöversikt (refereegranskat)abstract
- Although normally transient, RNA can persist postmortem when preserved by cold, desiccation or chemical treatment. In this Comment, we discuss how ancient RNA enables the study of gene expression of (pre)historic viruses, plants and animals going back at least as far as the last Ice Age. Friedlander and Gilbert introduce the study of ancient RNA of viruses, plants and animals, and how it can inform us of (pre)historic gene expression.
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| 5. |
- Fromm, Bastian, et al.
(författare)
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Ancient microRNA profiles of 14,300-yr-old canid samples confirm taxonomic origin and provide glimpses into tissue-specific gene regulation from the Pleistocene
- 2021
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Ingår i: RNA. - : Cold Spring Harbor Laboratory. - 1355-8382 .- 1469-9001. ; 27:3, s. 324-334
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Tidskriftsartikel (refereegranskat)abstract
- DNA sequencing is the current key technology for historic or ancient biological samples and has led to many exciting discoveries in the field of paleogenomics. However, functional insights into tissue identity, cellular composition, or gene regulation cannot be gained from DNA. Recent analyses have shown that, under favorable conditions, RNA can also be sequenced from ancient samples, enabling studies at the transcriptomic and regulatory level. Analyzing ancient RNA data from a Pleistocene canid, we find hundreds of intact microRNAs that are taxonomically informative, show tissue specificity and have functionally predictive characteristics. With an extraordinary age of 14,300 yr, these microRNA sequences are by far the oldest ever reported. The authenticity of the sequences is further supported by (i) the presence of canid/Caniformia-specific sequences that never evolved outside of this Glade, (ii) tissue-specific expression patterns (cartilage, liver, and muscle) that resemble those of modern dogs, and (iii) RNA damage patterns that are clearly distinct from those of fresh samples. By performing computational microRNA-target enrichment analyses on the ancient sequences, we predict microRNA functions consistent with their tissue pattern of expression. For instance, we find a liver-specific microRNA that regulates carbohydrate metabolism and starvation responses in canids. In summary, we show that straightforward paleotranscriptomic microRNA analyses can give functional glimpses into tissue identity, cellular composition, and gene regulatory activity of ancient samples and biological processes that took place in the Pleistocene, thus holding great promise for deeper insights into gene regulation in extinct animals based on ancient RNA sequencing.
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| 6. |
- Lappalainen, Tuuli, et al.
(författare)
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Transcriptome and genome sequencing uncovers functional variation in humans
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 501:7468, s. 506-511
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Tidskriftsartikel (refereegranskat)abstract
- Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project-the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.
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| 7. |
- Mozūraitis, Raimondas, et al.
(författare)
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Male swarming aggregation pheromones increase female attraction and mating success among multiple African malaria vector mosquito species
- 2020
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Ingår i: Nature Ecology & Evolution. - : Nature Research. - 2397-334X. ; 4:10, s. 1395-1401
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating behavioural data indicate that aggregation pheromones may mediate the formation and maintenance of mosquito swarms. However, chemical cues possibly luring mosquitoes to swarms have not been adequately investigated, and the likely molecular incitants of these complex reproductive behaviours remain unknown. Here we show that males of the important malaria vector species Anopheles arabiensis and An. gambiae produce and release aggregation pheromones that attract individuals to the swarm and enhance mating success. We found that males of both species released significantly higher amounts of 3-hydroxy-2-butanone (acetoin), 6-methyl-5-hepten-2-one (sulcatone), octanal, nonanal and decanal during swarming in the laboratory. Feeding males with stable-isotope-labelled glucose revealed that the males produced these five compounds. A blend composed of synthetic analogues to these swarming odours proved highly attractive to virgin males and females of both species under laboratory conditions and substantially increased mating in five African malaria vectors (An. gambiae,An. coluzzii,An. arabiensis,An. merus and An. funestus) in semi-field experiments. Our results not only narrow a conspicuous gap in understanding a vital aspect of the chemical ecology of male mosquitoes but also demonstrate fundamental roles of rhythmic and metabolic genes in the physiology and behavioural regulation of these vectors. These identified aggregation pheromones have great potential for exploitation against these highly dangerous insects. Manipulating such pheromones could increase the efficacy of malaria-vector control programmes.
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