| 1. |
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| 2. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)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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| 3. |
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| 4. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 5. |
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| 6. |
- Dunham, I, et al.
(författare)
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The DNA sequence of human chromosome 22
- 1999
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 402:6761, s. 489-495
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 8. |
- Chen, DS, et al.
(författare)
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Single cell atlas for 11 non-model mammals, reptiles and birds
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 7083-
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Tidskriftsartikel (refereegranskat)abstract
- The availability of viral entry factors is a prerequisite for the cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Large-scale single-cell screening of animal cells could reveal the expression patterns of viral entry genes in different hosts. However, such exploration for SARS-CoV-2 remains limited. Here, we perform single-nucleus RNA sequencing for 11 non-model species, including pets (cat, dog, hamster, and lizard), livestock (goat and rabbit), poultry (duck and pigeon), and wildlife (pangolin, tiger, and deer), and investigated the co-expression of ACE2 and TMPRSS2. Furthermore, cross-species analysis of the lung cell atlas of the studied mammals, reptiles, and birds reveals core developmental programs, critical connectomes, and conserved regulatory circuits among these evolutionarily distant species. Overall, our work provides a compendium of gene expression profiles for non-model animals, which could be employed to identify potential SARS-CoV-2 target cells and putative zoonotic reservoirs.
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| 9. |
- Dahmen, J., et al.
(författare)
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Osteochondral Lesions of the Tibial Plafond and Ankle Instability With Ankle Cartilage Lesions: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle
- 2022
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Ingår i: Foot & Ankle International. - : SAGE Publications. - 1071-1007 .- 1944-7876. ; 43:3, s. 448-452
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Tidskriftsartikel (refereegranskat)abstract
- Background: An international consensus group of experts was convened to collaboratively advance toward consensus opinions based on the best available evidence on key topics within cartilage repair of the ankle. The purpose of this article is to present the consensus statements on osteochondral lesions of the tibial plafond (OLTP) and on ankle instability with ankle cartilage lesions developed at the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. Methods: Forty-three experts in cartilage repair of the ankle were convened and participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted within 4 working groups focusing on specific topics within cartilage repair of the ankle, after which a comprehensive literature review was performed and the available evidence for each statement was graded. Discussion and debate occurred in cases where statements were not agreed on in unanimous fashion within the working groups. A final vote was then held. Results: A total of 11 statements on OLTP reached consensus. Four achieved unanimous support and 7 reached strong consensus (greater than 75% agreement). A total of 8 statements on ankle instability with ankle cartilage lesions reached consensus during the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. One achieved unanimous support, and seven reached strong consensus (greater than 75% agreement). Conclusions: These consensus statements may assist clinicians in the management of these difficult clinical pathologies.
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Döring, J., et al.
(författare)
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Band terminations in the valence space of 86Zr
- 2000
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Ingår i: Physical Review C - Nuclear Physics. - 0556-2813. ; 61:3, s. 343101-343106
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Tidskriftsartikel (refereegranskat)abstract
- High-spin states in 86Zr up to 30+ and 27- were observed via the 58Ni(32S,4p) reaction at 135 MeV beam energy using the combined GAMMASPHERE and MICROBALL systems. Calculations performed with the configuration-dependent shell-correction approach show that these states are built from six g9/2 neutrons and at most four protons excited from the p1/2,p3/2,f5/2 subshells to the g9/2 subshell at small deformation. The highest observed states at 27- and 30+ are interpreted as band-terminating states with the latter having the highest spin available in the valence space for 86Zr.
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| 15. |
- Feitosa, Mary F., et al.
(författare)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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| 16. |
- Fischer, Alexander W., et al.
(författare)
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Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation
- 2021
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Ingår i: Cell Metabolism. - : Elsevier. - 1550-4131 .- 1932-7420. ; 33:3, s. 547-564.e7
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Tidskriftsartikel (refereegranskat)abstract
- In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid lipase (LAL)-mediated processing. Endothelial cell-specific LAL deficiency results in impaired thermogenic capacity as a consequence of reduced recruitment of brown and brite/beige adipocytes. Mechanistically, TRL processing by LAL induces proliferation of endothelial cells and adipocyte precursors via beta-oxidation-dependent production of reactive oxygen species, which in turn stimulates hypoxia-inducible factor-1α-dependent proliferative responses. In conclusion, this study demonstrates a physiological role for TRL particle uptake into BAT and WAT and establishes endothelial lipoprotein processing as an important determinant of adipose tissue remodeling during thermogenic adaptation.
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| 17. |
- Hua, Y., et al.
(författare)
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Molecular characteristics of eae-positive clinical Shiga toxin-producing Escherichia coli in Sweden
- 2020
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Ingår i: Emerging microbes & infections. - : Informa UK Limited. - 2222-1751. ; 9:1, s. 2562-2570
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Tidskriftsartikel (refereegranskat)abstract
- Shiga toxin (Stx)-producing Escherichia coli (STEC) can cause a wide range of symptoms from asymptomatic carriage, mild diarrhea to bloody diarrhea (BD) and hemolytic uremic syndrome (HUS). Intimin, encoded by the eae gene, also plays a critical role in STEC pathogenesis. Herein, we investigated the prevalence and genetic diversity of eae among clinical STEC isolates from patients with diarrhea, BD, HUS as well as from asymptomatic STEC-positive individuals in Sweden with whole-genome sequencing. We found that 173 out of 239 (72.4%) of clinical STEC strains were eae positive. Six eae subtypes (epsilon 1, gamma 1, beta 3, theta, zeta and rho) were identified eae and its subtype gamma 1 were significantly overrepresented in O157:H7 strains isolated from BD and HUS patients. epsilon 1 was associated with O121:H19 and O103:H2 strains, and beta 3 to O26:H11 strains. The combination of eae subtype gamma 1 and stx subtype (stx (2) or stx (1)+stx (2)) is more likely to cause severe disease, suggesting the possibility of using eae genotypes in risk assessment of STEC infection. In summary, this study demonstrated a high prevalence of eae in clinical STEC strains and considerable genetic diversity of eae in STEC strains in Sweden from 1994 through 2018, and revealed association between eae subtypes and disease severity.
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| 18. |
- Hua, Y., et al.
(författare)
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Molecular Characterization of the Enterohemolysin Gene (ehxA) in Clinical Shiga Toxin-Producing Escherichia coli Isolates
- 2021
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Ingår i: Toxins. - : MDPI AG. - 2072-6651. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Shiga toxin (Stx)-producing Escherichia coli (STEC) is an important foodborne pathogen with the ability to cause bloody diarrhea (BD) and hemolytic uremic syndrome (HUS). Little is known about enterohemolysin-encoded by ehxA. Here we investigated the prevalence and diversity of ehxA in 239 STEC isolates from human clinical samples. In total, 199 out of 239 isolates (83.26%) were ehxA positive, and ehxA was significantly overrepresented in isolates carrying stx(2a) + stx(2c) (p < 0.001) and eae (p < 0.001). The presence of ehxA was significantly associated with BD and serotype O157:H7. Five ehxA subtypes were identified, among which, ehxA subtypes B, C, and F were overrepresented in eae-positive isolates. All O157:H7 isolates carried ehxA subtype B, which was related to BD and HUS. Three ehxA groups were observed in the phylogenetic analysis, namely, group ? (ehxA subtype A), group II (ehxA subtype B, C, and F), and group (ehxA subtype D). Most BD- and HUS-associated isolates were clustered into ehxA group II, while ehxA group ? was associated with non-bloody stool and individuals >= 10 years of age. The presence of ehxA + eae and ehxA + eae + stx(2) was significantly associated with HUS and O157:H7 isolates. In summary, this study showed a high prevalence and the considerable genetic diversity of ehxA among clinical STEC isolates. The ehxA genotypes (subtype B and phylogenetic group II) could be used as risk predictors, as they were associated with severe clinical symptoms, such as BD and HUS. Furthermore, ehxA, together with stx and eae, can be used as a risk predictor for HUS in STEC infections.
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| 19. |
- Jacobsson, Jesper, 1984-, et al.
(författare)
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An open-access database and analysis tool for perovskite solar cells based on the FAIR data principles
- 2022
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Ingår i: Nature Energy. - : Springer Nature. - 2058-7546. ; 7:1, s. 107-115
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Tidskriftsartikel (refereegranskat)abstract
- Large datasets are now ubiquitous as technology enables higher-throughput experiments, but rarely can a research field truly benefit from the research data generated due to inconsistent formatting, undocumented storage or improper dissemination. Here we extract all the meaningful device data from peer-reviewed papers on metal-halide perovskite solar cells published so far and make them available in a database. We collect data from over 42,400 photovoltaic devices with up to 100 parameters per device. We then develop open-source and accessible procedures to analyse the data, providing examples of insights that can be gleaned from the analysis of a large dataset. The database, graphics and analysis tools are made available to the community and will continue to evolve as an open-source initiative. This approach of extensively capturing the progress of an entire field, including sorting, interactive exploration and graphical representation of the data, will be applicable to many fields in materials science, engineering and biosciences.
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| 20. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 21. |
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| 22. |
- Lloyd, B., et al.
(författare)
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Overview of physics results from MAST
- 2011
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 51:9, s. 094013 (paper no.)-
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Tidskriftsartikel (refereegranskat)abstract
- Major developments on the Mega Amp Spherical Tokamak (MAST) have enabled important advances in support of ITER and the physics basis of a spherical tokamak (ST) based component test facility (CTF), as well as providing new insight into underlying tokamak physics. For example, L-H transition studies benefit from high spatial and temporal resolution measurements of pedestal profile evolution (temperature, density and radial electric field) and in support of pedestal stability studies the edge current density profile has been inferred from motional Stark effect measurements. The influence of the q-profile and E x B flow shear on transport has been studied in MAST and equilibrium flow shear has been included in gyro-kinetic codes, improving comparisons with the experimental data. H-modes exhibit a weaker q and stronger collisionality dependence of heat diffusivity than implied by IPB98(gamma, 2) scaling, which may have important implications for the design of an ST-based CTF. ELM mitigation, an important issue for ITER, has been demonstrated by applying resonant magnetic perturbations (RMPs) using both internal and external coils, but full stabilization of type-I ELMs has not been observed. Modelling shows the importance of including the plasma response to the RMP fields. MAST plasmas with q > 1 and weak central magnetic shear regularly exhibit a long-lived saturated ideal internal mode. Measured plasma braking in the presence of this mode compares well with neo-classical toroidal viscosity theory. In support of basic physics understanding, high resolution Thomson scattering measurements are providing new insight into sawtooth crash dynamics and neo-classical tearing mode critical island widths. Retarding field analyser measurements show elevated ion temperatures in the scrape-off layer of L-mode plasmas and, in the presence of type-I ELMs, ions with energy greater than 500 eV are detected 20 cm outside the separatrix. Disruption mitigation by massive gas injection has reduced divertor heat loads by up to 70%.
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| 23. |
- Luo, Yang, et al.
(författare)
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Three-dimensional and temperature-dependent electronic structure of the heavy-fermion compound CePt2In7 studied by angle-resolved photoemission spectroscopy
- 2020
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Ingår i: Physical Review B. - : AMER PHYSICAL SOC. - 2469-9950 .- 2469-9969. ; 101:11
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Tidskriftsartikel (refereegranskat)abstract
- The three-dimensional and temperature-dependent electronic structures of the heavy-fermion superconductor CePt2In7 are investigated. Angle-resolved photoemission spectroscopy using variable photon energy establishes the existence of quasi-two- and three-dimensional Fermi surface topologies. Temperature-dependent 4d-4f on-resonance photoemission spectroscopies data reveal that heavy quasiparticle bands begin to form at a temperature well above the characteristic (coherence) temperature T+. The emergence of low-lying crystal electric field excitation may be responsible for the "relocalization" or the precursor to the establishment of heavy electrons coherence in heavy-fermion compounds. These findings provide critical insight into understanding the hybridization in heavy-fermion systems.
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| 24. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)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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| 25. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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