| 1. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Akiyama, Kazunori, et al.
(författare)
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First Sagittarius A* Event Horizon Telescope Results. II. EHT and Multiwavelength Observations, Data Processing, and Calibration
- 2022
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
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Tidskriftsartikel (refereegranskat)abstract
- We present Event Horizon Telescope (EHT) 1.3 mm measurements of the radio source located at the position of the supermassive black hole Sagittarius A* (Sgr A*), collected during the 2017 April 5-11 campaign. The observations were carried out with eight facilities at six locations across the globe. Novel calibration methods are employed to account for Sgr A*'s flux variability. The majority of the 1.3 mm emission arises from horizon scales, where intrinsic structural source variability is detected on timescales of minutes to hours. The effects of interstellar scattering on the image and its variability are found to be subdominant to intrinsic source structure. The calibrated visibility amplitudes, particularly the locations of the visibility minima, are broadly consistent with a blurred ring with a diameter of similar to 50 mu as, as determined in later works in this series. Contemporaneous multiwavelength monitoring of Sgr A* was performed at 22, 43, and 86 GHz and at near-infrared and X-ray wavelengths. Several X-ray flares from Sgr A* are detected by Chandra, one at low significance jointly with Swift on 2017 April 7 and the other at higher significance jointly with NuSTAR on 2017 April 11. The brighter April 11 flare is not observed simultaneously by the EHT but is followed by a significant increase in millimeter flux variability immediately after the X-ray outburst, indicating a likely connection in the emission physics near the event horizon. We compare Sgr A*'s broadband flux during the EHT campaign to its historical spectral energy distribution and find that both the quiescent emission and flare emission are consistent with its long-term behavior.
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| 3. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 4. |
- Crawford, Jason, 1975-, et al.
(författare)
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Advanced digital technologies and sustainability assurance
- 2023. - 1
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Ingår i: Auditing Transformation. - London : Routledge. - 9781003411390 ; , s. 180-201
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Bokkapitel (refereegranskat)abstract
- Digitalisation and sustainability have been described as interrelated drivers of change. Audit firms are adopting advanced digital technologies (ADTs) to improve audit quality, and the demand for sustainability assurance is set to increase dramatically as the European Union’s Corporate Sustainability Reporting Directive (CSRD) comes into effect. However, little is known about the actual use of these technologies in sustainability assurance. To help fill this gap, this chapter investigates the use of ADTs in sustainability assurance in Sweden and provides an outlook on how this may evolve in the future. The data includes interviews with regulatory bodies, audit firms, and institutional investors, as well as secondary materials. The chapter finds that ADTs currently play a minor to non-existent role in sustainability assurance engagements performed by large accounting firms in Sweden. The reasons fall within three broader themes: sustainability reporting and assurance regulation, auditor-client dynamics and embedding ADTs, and the emergence of alternative solution providers. In light of the aforementioned developments, this chapter makes a timely and important contribution by identifying and discussing the tensions that exist at the intersection of the inside-out and outside-in approaches to ESG information provision to capital markets and how ADTs are implicated in these tensions.
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| 5. |
- Crawford, Tim, et al.
(författare)
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Specific functions for Mediator complex subunits from different modules in the transcriptional response of Arabidopsis thaliana to abiotic stress
- 2020
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Adverse environmental conditions are detrimental to plant growth and development. Acclimation to abiotic stress conditions involves activation of signaling pathways which often results in changes in gene expression via networks of transcription factors (TFs). Mediator is a highly conserved co-regulator complex and an essential component of the transcriptional machinery in eukaryotes. Some Mediator subunits have been implicated in stress-responsive signaling pathways; however, much remains unknown regarding the role of plant Mediator in abiotic stress responses. Here, we use RNA-seq to analyze the transcriptional response of Arabidopsis thaliana to heat, cold and salt stress conditions. We identify a set of common abiotic stress regulons and describe the sequential and combinatorial nature of TFs involved in their transcriptional regulation. Furthermore, we identify stress-specific roles for the Mediator subunits MED9, MED16, MED18 and CDK8, and putative TFs connecting them to different stress signaling pathways. Our data also indicate different modes of action for subunits or modules of Mediator at the same gene loci, including a co-repressor function for MED16 prior to stress. These results illuminate a poorly understood but important player in the transcriptional response of plants to abiotic stress and identify target genes and mechanisms as a prelude to further biochemical characterization.
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| 6. |
- Crawford, Tim, et al.
(författare)
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The role of retrograde signals during plant stress responses
- 2018
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Ingår i: Journal of Experimental Botany. - : Oxford University Press. - 0022-0957 .- 1460-2431. ; 69:11, s. 2783-2795
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Forskningsöversikt (refereegranskat)abstract
- Chloroplast and mitochondria not only provide the energy to the plant cell but due to the sensitivity of organellar processes to perturbations caused by abiotic stress, they are also key cellular sensors of environmental fluctuations. Abiotic stresses result in reduced photosynthetic efficiency and thereby reduced energy supply for cellular processes. Thus, in order to acclimate to stress, plants must re-program gene expression and cellular metabolism to divert energy from growth and developmental processes to stress responses. To restore cellular energy homeostasis following exposure to stress, the activities of the organelles must be tightly co-ordinated with the transcriptional re-programming in the nucleus. Thus, communication between the organelles and the nucleus, so-called retrograde signalling, is essential to direct the energy use correctly during stress exposure. Stress-triggered retrograde signals are mediated by reactive oxygen species and metabolites including beta-cyclocitral, MEcPP (2-C-methyl-D-erythritol 2,4-cyclodiphosphate), PAP (3'-phosphoadenosine 5'-phosphate), and intermediates of the tetrapyrrole biosynthesis pathway. However, for the plant cell to respond optimally to environmental stress, these stress-triggered retrograde signalling pathways must be integrated with the cytosolic stress signalling network. We hypothesize that the Mediator transcriptional co-activator complex may play a key role as a regulatory hub in the nucleus, integrating the complex stress signalling networks originating in different cellular compartments.
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| 7. |
- Guinea Diaz, Manuel, et al.
(författare)
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Redox regulation of PEP activity during seedling establishment in Arabidopsis thaliana
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Activation of the plastid-encoded RNA polymerase is tightly controlled and involves a network of phosphorylation and, as yet unidentified, thiol-mediated events. Here, we characterize PLASTID REDOX INSENSITIVE2, a redox-regulated protein required for full PEP-driven transcription. PRIN2 dimers can be reduced into the active monomeric form by thioredoxins through reduction of a disulfide bond. Exposure to light increases the ratio between the monomeric and dimeric forms of PRIN2. Complementation of prin2-2 with different PRIN2 protein variants demonstrates that the monomer is required for light-activated PEP-dependent transcription and that expression of the nuclear-encoded photosynthesis genes is linked to the activity of PEP. Activation of PEP during chloroplast development likely is the source of a retrograde signal that promotes nuclear LHCB expression. Thus, regulation of PRIN2 is the thiol-mediated mechanism required for full PEP activity, with PRIN2 monomerization via reduction by TRXs providing a mechanistic link between photosynthetic electron transport and activation of photosynthetic gene expression.
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| 8. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 9. |
- Milisavljevic, Dan, et al.
(författare)
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MULTI-WAVELENGTH OBSERVATIONS OF SUPERNOVA 2011ei : TIME-DEPENDENT CLASSIFICATION OF TYPE IIb AND Ib SUPERNOVAE AND IMPLICATIONS FOR THEIR PROGENITORS
- 2013
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 767:1, s. 71-
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Tidskriftsartikel (refereegranskat)abstract
- We present X-ray, UV/optical, and radio observations of the stripped-envelope, core-collapse supernova (SN) 2011ei, one of the least luminous SNe IIb or Ib observed to date. Our observations begin with a discovery within similar to 1 day of explosion and span several months afterward. Early optical spectra exhibit broad, Type II-like hydrogen Balmer profiles that subside rapidly and are replaced by Type Ib-like He-rich features on a timescale of one week. High-cadence monitoring of this transition suggests absorption attributable to a high-velocity (greater than or similar to 12,000 km s(-1)) H-rich shell, which is likely present in many Type Ib events. Radio observations imply a shock velocity of v approximate to 0.13 c and a progenitor star average mass-loss rate of (M) over dot approximate to 1.4 x 10(-5) M-circle dot yr(-1) (assuming wind velocity v(w) = 10(3) km s(-1)). This is consistent with independent constraints from deep X-ray observations with Swift-XRT and Chandra. Overall, the multi-wavelength properties of SN 2011ei are consistent with the explosion of a lower-mass (3-4 M-circle dot), compact (R-* less than or similar to 1 x 10(11) cm), He-core star. The star retained a thin hydrogen envelope at the time of explosion, and was embedded in an inhomogeneous circumstellar wind suggestive of modest episodic mass loss. We conclude that SN 2011ei's rapid spectral metamorphosis is indicative of time-dependent classifications that bias estimates of the relative explosion rates for Type IIb and Ib objects, and that important information about a progenitor star's evolutionary state and mass loss immediately prior to SN explosion can be inferred from timely multi-wavelength observations.
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| 10. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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