| 1. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Surendran, Praveen, et al.
(author)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Journal article (peer-reviewed)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 7. |
- Evangelou, Evangelos, et al.
(author)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Journal article (peer-reviewed)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 8. |
- Ghara, Raghunath, et al.
(author)
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Constraining the intergalactic medium at z approximate to 9.1 using LOFAR Epoch of Reionization observations
- 2020
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 493:4, s. 4728-4747
-
Journal article (peer-reviewed)abstract
- We derive constraints on the thermal and ionization states of the intergalactic medium (IGM) at redshift approximate to 9.1 using new upper limits on the 21-cm power spectrum measured by the LOFAR radio telescope and a prior on the ionized fraction at that redshift estimated from recent cosmic microwave background (CMB) observations. We have used results from the reionization simulation code GRIZZLY and a Bayesian inference framework to constrain the parameters which describe the physical state of the IGM. We find that, if the gas heating remains negligible, an IGM with ionized fraction greater than or similar to 0.13 and a distribution of the ionized regions with a characteristic size greater than or similar to 8 h(-1) comoving megaparsec (Mpc) and a full width at half-maximum (FWHM) greater than or similar to 16 h(-1) Mpc is ruled out. For an IGM with a uniform spin temperature T-S greater than or similar to 3 K, no constraints on the ionized component can be computed. If the large-scale fluctuations of the signal are driven by spin temperature fluctuations, an IGM with a volume fraction less than or similar to 0.34 of heated regions with a temperature larger than CMB, average gas temperature 7-160 K, and a distribution of the heated regions with characteristic size 3.5-70 h(-1) Mpc and FWHM of less than or similar to 110 h(-1) Mpc is ruled out. These constraints are within the 95 per cent credible intervals. With more stringent future upper limits from LOFAR at multiple redshifts, the constraints will become tighter and will exclude an increasingly large region of the parameter space.
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| 9. |
- Mertens, F. G., et al.
(author)
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Improved upper limits on the 21 cm signal power spectrum of neutral hydrogen at z approximate to 9.1 from LOFAR
- 2020
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 493:2, s. 1662-1685
-
Journal article (peer-reviewed)abstract
- A new upper limit on the 21 cm signal power spectrum at a redshift of z approximate to 9.1 is presented, based on 141 h of data obtained with the Low-Frequency Array (LOFAR). The analysis includes significant improvements in spectrally smooth gain-calibration, Gaussian Process Regression (GPR) foreground mitigation and optimally weighted power spectrum inference. Previously seen 'excess power' due to spectral structure in the gain solutions has markedly reduced but some excess power still remains with a spectral correlation distinct from thermal noise. This excess has a spectral coherence scale of 0.25-0.45 MHz and is partially correlated between nights, especially in the foreground wedge region. The correlation is stronger between nights covering similar local sidereal times. A best 2-sigma upper limit of Delta(2)(21) < (73)(2) mK(2) at k = 0.075 h cMpc(-1) is found, an improvement by a factor approximate to 8 in power compared to the previously reported upper limit. The remaining excess power could be due to residual foreground emission from sources or diffuse emission far away from the phase centre, polarization leakage, chromatic calibration errors, ionosphere, or low-level radiofrequency interference. We discuss future improvements to the signal processing chain that can further reduce or even eliminate these causes of excess power.
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| 10. |
- Wuttke, Matthias, et al.
(author)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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In: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 11. |
- Amiri, M., et al.
(author)
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Periodic activity from a fast radio burst source
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 582:7812, s. 351-355
-
Journal article (peer-reviewed)abstract
- Fast radio bursts (FRBs) are bright, millisecond-duration radio transients originating from sources at extragalactic distances1, the origin of which is unknown. Some FRB sources emit repeat bursts, ruling out cataclysmic origins for those events2–4. Despite searches for periodicity in repeat burst arrival times on timescales from milliseconds to many days2,5–7, these bursts have hitherto been observed to appear sporadically and—although clustered8—without a regular pattern. Here we report observations of a 16.35 ± 0.15 day periodicity (or possibly a higher-frequency alias of that periodicity) from the repeating FRB 180916.J0158+65 detected by the Canadian Hydrogen Intensity Mapping Experiment Fast Radio Burst Project4,9. In 38 bursts recorded from 16 September 2018 to 4 February 2020 utc, we find that all bursts arrive in a five-day phase window, and 50 per cent of the bursts arrive in a 0.6-day phase window. Our results suggest a mechanism for periodic modulation either of the burst emission itself or through external amplification or absorption, and disfavour models invoking purely sporadic processes.
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| 12. |
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| 13. |
- Gan, H., et al.
(author)
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Statistical analysis of the causes of excess variance in the 21 cm signal power spectra obtained with the Low-Frequency Array
- 2022
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 663
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Journal article (peer-reviewed)abstract
- Context. The detection of the 21 cm signal of neutral hydrogen from the Epoch of Reionization (EoR) is challenging due to bright foreground sources, radio frequency interference (RFI), and the ionosphere as well as instrumental effects. Even after correcting for these effects in the calibration step and applying foreground removal techniques, the remaining residuals in the observed 21 cm power spectra are still above the thermal noise, which is referred to as the “excess variance.”Aims. We study a number of potential causes of this excess variance based on 13 nights of data obtained with the Low-Frequency Array (LOFAR).Methods. We focused on the impact of gain errors, the sky model, and ionospheric effects on the excess variance by correlating the relevant parameters such as the gain variance over time or frequency, local sidereal time (LST), diffractive scale, and phase structure–function slope with the level of excess variance.Results. Our analysis shows that the excess variance, at the current level, is neither strongly correlated with gain variance nor the ionospheric parameters. Rather, excess variance has an LST dependence, which is related to the power from the sky. Furthermore, the simulated Stokes I power spectra from bright sources and the excess variance show a similar progression over LST with the minimum power appearing at LST bin 6h to 9h. This LST dependence is also present in sky images of the residual Stokes I of the observations. In very-wide sky images based on one night of observation after direction-dependent calibration, we demonstrate that the extra power comes exactly from the direction of bright and distant sources Cassiopeia A and Cygnus A with the array beam patterns.Conclusions. These results suggest that the level of excess variance in the 21 cm signal power spectra is related to sky effects and, hence, it depends on LST. In particular, very bright and distant sources such as Cassiopeia A and Cygnus A can dominate the effect. This is in line with earlier studies and offers a path forward toward a solution, since the correlation between the sky-related effects and the excess variance is non-negligible.
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| 14. |
- Gehlot, B. K., et al.
(author)
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Degree-scale galactic radio emission at 122 MHz around the North Celestial Pole with LOFAR-AARTFAAC
- 2022
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 662
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Journal article (peer-reviewed)abstract
- Aims. Contamination from bright diffuse Galactic thermal and non-thermal radio emission poses crucial challenges in experiments aiming to measure the 21-cm signal of neutral hydrogen from the cosmic dawn (CD) and Epoch of Reionisation (EoR). If not included in calibration, this diffuse emission can severely impact the analysis and signal extraction in 21-cm experiments. We examine large-scale diffuse Galactic emission at 122 MHz around the North Celestial Pole, using the Amsterdam-ASTRON Radio Transient Facility and Analysis Centre (AARTFAAC-) High Band Antenna (HBA) system.Methods. In this pilot project, we present the first-ever wide-field image produced with a single sub-band of the data recorded with the AARTFAAC-HBA system. We demonstrate two methods, multi-scale CLEAN and shapelet decomposition, to model the diffuse emission revealed in the image. We used angular power spectrum metrics to quantify different components of the emission and compared the performance of the two diffuse structure modelling approaches.Results. We observed that the point sources dominate the angular power spectrum (ℓ(ℓ + 1)Cℓ/2π≡Δ2(ℓ)) of the emission in the field on scales of ℓ ≳ 60 (≲3 degree). The angular power spectrum after subtraction of compact sources is flat within the 20 ≲ ℓ ≲ 200 range, suggesting that the residual power is dominated by the diffuse emission on scales of ℓ ≲ 200. The residual diffuse emission has a brightness temperature variance of Δℓ=1802 = (145.64 ± 13.61) K2 at 122 MHz on angular scales of 1 degree, and it is consistent with a power law following Cℓ ∝ ℓ−2.0 in the 20 ≲ ℓ ≲ 200 range. We also find that, in the current set-up, multi-scale CLEAN is suitable to model the compact and diffuse structures on a wide range of angular scales, whereas the shapelet decomposition method better models the large scales, which are of the order of a few degrees and wider.
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| 15. |
- Hathazi, D., et al.
(author)
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Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
- 2020
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In: Embo Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 39:23
-
Journal article (peer-reviewed)abstract
- Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only similar to 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
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| 16. |
- Joshi, Peter K, et al.
(author)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
-
Journal article (peer-reviewed)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 17. |
- Kraja, Aldi T., et al.
(author)
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New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475000 Individuals
- 2017
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In: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 1942-325X .- 1942-3268. ; 10:5
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Journal article (peer-reviewed)abstract
- Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.Methods and Results - Here, we augment the sample with 140886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, approximate to 475000), and the other in the subset of individuals of European descent (approximate to 423000). Twenty-one SNVs were genome-wide significant (P<5x10(-8) ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
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| 18. |
- Marcote, B., et al.
(author)
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A repeating fast radio burst source localized to a nearby spiral galaxy
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 577:7789, s. 190-194
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Journal article (peer-reviewed)abstract
- Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes1,2. Their physical origin remains unknown, but dozens of possible models have been postulated3. Some FRB sources exhibit repeat bursts4–7. Although over a hundred FRB sources have been discovered8, only four have been localized and associated with a host galaxy9–12, and just one of these four is known to emit repeating FRBs9. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source6, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure6 further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.
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| 19. |
- Marouli, Eirini, et al.
(author)
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Rare and low-frequency coding variants alter human adult height
- 2017
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Journal article (peer-reviewed)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 20. |
- Mevius, M., et al.
(author)
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A numerical study of 21-cm signal suppression and noise increase in direction-dependent calibration of LOFAR data
- 2021
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 509:3, s. 3693-3702
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Journal article (peer-reviewed)abstract
- We investigate systematic effects in direction-dependent gain calibration in the context of the Low-Frequency Array (LOFAR) 21-cm Epoch of Reionization (EoR) experiment. The LOFAR EoR Key Science Project aims to detect the 21-cm signal of neutral hydrogen on interferometric baselines of 50–250 λ. We show that suppression of faint signals can effectively be avoided by calibrating these short baselines using only the longer baselines. However, this approach causes an excess variance on the short baselines due to small gain errors induced by overfitting during calibration. We apply a regularized expectation–maximization algorithm with consensus optimization (SAGECAL-CO) to real data with simulated signals to show that overfitting can be largely mitigated by penalising spectrally non-smooth gain solutions during calibration. This reduces the excess power with about a factor of 4 in the simulations. Our results agree with earlier theoretical analysis of this bias-variance trade off and support the gain-calibration approach to the LOFAR 21-cm signal data.
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| 21. |
- Mondal, Rajesh, et al.
(author)
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Tight constraints on the excess radio background at z=9.1 from LOFAR
- 2020
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 498:3, s. 4178-4191
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Journal article (peer-reviewed)abstract
- The ARCADE2 and LWA1 experiments have claimed an excess over the cosmic microwave background (CMB) at low radio frequencies. If the cosmological high-redshift contribution to this radio background is between 0.1 per cent and 22 per cent of the CMB at 1.42 GHz, it could explain the tentative EDGES low-band detection of the anomalously deep absorption in the 21-cm signal of neutral hydrogen. We use the upper limit on the 21-cm signal from the Epoch of Reionization (z = 9.1) based on 141 h of observations with LOFAR to evaluate the contribution of the high-redshift Universe to the detected radio background. Marginalizing over astrophysical properties of star-forming haloes, we find (at 95 per cent CL) that the cosmological radio background can be at most 9.6 per cent of the CMB at 1.42 GHz. This limit rules out strong contribution of the high-redshift Universe to the ARCADE2 and LWA1 measurements. Even though LOFAR places limit on the extra radio background, excess of 0.1-9.6 per cent over the CMB (at 1.42 GHz) is still allowed and could explain the EDGES low-band detection. We also constrain the thermal and ionization state of the gas at z = 9.1, and put limits on the properties of the first star-forming objects. We find that, in agreement with the limits from EDGES high-band data, LOFAR data constrain scenarios with inefficient X-ray sources, and cases where the Universe was ionized by stars in massive haloes only.
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| 22. |
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| 23. |
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| 24. |
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| 26. |
- Turcot, Valerie, et al.
(author)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 27. |
- Acharya, Anshuman, et al.
(author)
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21-cm signal from the Epoch of Reionization : a machine learning upgrade to foreground removal with Gaussian process regression
- 2024
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 527:3, s. 7835-7846
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Journal article (peer-reviewed)abstract
- In recent years, a Gaussian process regression (GPR)-based framework has been developed for foreground mitigation from data collected by the LOw-Frequency ARray (LOFAR), to measure the 21-cm signal power spectrum from the Epoch of Reionization (EoR) and cosmic dawn. However, it has been noted that through this method there can be a significant amount of signal loss if the EoR signal covariance is misestimated. To obtain better covariance models, we propose to use a kernel trained on the grizzly simulations using a Variational Auto-Encoder (VAE)-based algorithm. In this work, we explore the abilities of this machine learning-based kernel (VAE kernel) used with GPR, by testing it on mock signals from a variety of simulations, exploring noise levels corresponding to ≈10 nights (≈141 h) and ≈100 nights (≈1410 h) of observations with LOFAR. Our work suggests the possibility of successful extraction of the 21-cm signal within 2σ uncertainty in most cases using the VAE kernel, with better recovery of both shape and power than with previously used covariance models. We also explore the role of the excess noise component identified in past applications of GPR and additionally analyse the possibility of redshift dependence on the performance of the VAE kernel. The latter allows us to prepare for future LOFAR observations at a range of redshifts, as well as compare with results from other telescopes.
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| 28. |
- Greig, Bradley, et al.
(author)
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Interpreting LOFAR 21-cm signal upper limits at z ≈ 9.1 in the context of high-z galaxy and reionization observations
- 2021
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 501:1, s. 1-13
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Journal article (peer-reviewed)abstract
- Using the latest upper limits on the 21-cm power spectrum at z approximate to 9.1 from the Low Frequency Array (LOFAR), we explore the regions of parameter space which are inconsistent with the data. We use 21CMMC, a Monte Carlo Markov chain sampler of 21CMFAST which directly forward models the three dimensional (3D) cosmic 21-cm signal in a fully Bayesian framework. We use the astrophysical parametrization from 21CMFAST, which includes mass-dependent star formation rates and ionizing escape fractions as well as soft-band X-ray luminosities to place limits on the properties of the high-z galaxies. Further, we connect the disfavoured regions of parameter space with existing observational constraints on the Epoch of Reionization such as ultra-violet (UV) luminosity functions, background UV photoionization rate, intergalactic medium (IGM) neutral fraction, and the electron scattering optical depth. We find that all models exceeding the 21-cm signal limits set by LOFAR at z approximate to 9.1 are excluded at greater than or similar to 2 sigma by other probes. Finally, we place limits on the IGM spin temperature from LOFAR, disfavouring at 95 per cent confidence spin temperatures below similar to 2.6 K across an IGM neutral fraction range of 0.15 less than or similar to (x) over bar (HI) less than or similar to 0.6. Note, these limits are only obtained from 141 h of data in a single redshift bin. With tighter upper limits, across multiple redshift bins expected in the near future from LOFAR, more viable models will be ruled out. Our approach demonstrates the potential of forward modelling tools such as 21CMMC in combining 21-cm observations with other high-z probes to constrain the astrophysics of galaxies.
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| 29. |
- Lensink, Marc F., et al.
(author)
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Impact of AlphaFold on structure prediction of protein complexes: The CASP15-CAPRI experiment
- 2023
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In: Proteins. - : WILEY. - 0887-3585 .- 1097-0134.
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Journal article (peer-reviewed)abstract
- We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo-trimers, 13 heterodimers including 3 antibody-antigen complexes, and 7 large assemblies. On average similar to 70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target. A total of 21 941 models submitted by these groups and by 15 CAPRI scorer groups were evaluated using the CAPRI model quality measures and the DockQ score consolidating these measures. The prediction performance was quantified by a weighted score based on the number of models of acceptable quality or higher submitted by each group among their five best models. Results show substantial progress achieved across a significant fraction of the 60+ participating groups. High-quality models were produced for about 40% of the targets compared to 8% two years earlier. This remarkable improvement is due to the wide use of the AlphaFold2 and AlphaFold2-Multimer software and the confidence metrics they provide. Notably, expanded sampling of candidate solutions by manipulating these deep learning inference engines, enriching multiple sequence alignments, or integration of advanced modeling tools, enabled top performing groups to exceed the performance of a standard AlphaFold2-Multimer version used as a yard stick. This notwithstanding, performance remained poor for complexes with antibodies and nanobodies, where evolutionary relationships between the binding partners are lacking, and for complexes featuring conformational flexibility, clearly indicating that the prediction of protein complexes remains a challenging problem.
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| 31. |
- Talwelkarshimpi, Mayura, et al.
(author)
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Experimental and theoretical studies of molecular complexes of theophylline with some phenylboronic acids
- 2016
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In: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 6:49, s. 43060-43068
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Journal article (peer-reviewed)abstract
- Molecular complexes of the active pharmaceutical ingredient (API) theophylline, 1 with 4-halophenylboronic acids [4-chlorophenylboronic acid (a), 4-bromophenylboronic acid (b), 4-iodophenylboronic acid (c)], 4-hydroxyphenylboronic acid (d) and 1,4-phenylene-bis-boronic acid (e) have been reported. The complexes were characterized and analysed using the intensity data obtained by X-ray diffraction techniques. All the halo substituted boronic acid complexes are found to be isostructural (1.a, 1.b and 1.c) irrespective of the variations in size and electronegativity of halogen atoms while complexes with non-halogenated boronic acids, 1.d and 1.e, show distinctly different features between themselves as well as with that of 1.a–c, both in two and three-dimensional arrangements. Complexes 1.a–c are noted to be crystallized in the form of sheet structures, which are stacked in three dimensional arrangements, while channels and square grid networks are observed in 1.d and 1.e, respectively. Further the homomeric and heteromeric interactions which occur in the complexes have been analysed by a DFT-D3 method
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| 32. |
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| 33. |
- Teumer, A, et al.
(author)
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Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4130-
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Journal article (peer-reviewed)abstract
- Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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