| 1. |
- 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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| 2. |
- Yuan, Shuai, et al.
(författare)
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Continuous Variation of Lattice Dimensions and Pore Sizes in Metal-Organic Frameworks
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:10, s. 4732-4738
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Tidskriftsartikel (refereegranskat)abstract
- The continuous variation of the lattice metric in metal-organic frameworks (MOFs) allows precise control over their chemical and physical properties. This has been realized herein by a series of mixed-linker and Zr-6-cluster-based MOFs, namely, continuously variable MOFs (CVMOFs). Similar to the substitutional solid solutions, organic linkers with different lengths and various ratios were homogeneously incorporated into a framework rather than being allowed to form separate phases or domains, which was manifested by single-crystal X-ray diffraction, powder X-ray diffraction, fluorescence quenching experiments, and molecular simulations. The unit cell dimension, surface area, and pore size of CVMOFs were precisely controlled by adopting different linker sets and linker ratios. We demonstrate that CVMOFs allow the continuous and fine tailoring of cell-edge lengths from 17.83 to 32.63 angstrom, Brunauer-Emmett-Teller (BET) surface areas from 585 to 3791 m(2)g(-1), and pore sizes up to 15.9 angstrom. Furthermore, this synthetic strategy can be applied to other MOF systems with various metal nodes thus allowing for a variety of CVMOFs with unprecedented tunability.
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| 3. |
- He, Tao, et al.
(författare)
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Kinetically Controlled Reticular Assembly of a Chemically Stable Mesoporous Ni(II)-Pyrazolate Metal-Organic Framework
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:31, s. 13491-13499
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Tidskriftsartikel (refereegranskat)abstract
- The application scope of metal-organic frameworks (MOFs) is severely restricted by their weak chemical stability and limited pore size. A robust MOF with large mesopores is highly desired, yet poses a great synthetic challenge. Herein, two chemically stable Ni(II)-pyrazolate MOFs, BUT-32 and -33, were constructed from a conformation-matched elongated pyrazolate ligand through the isoreticular expansion. The two MOFs share the same sodalite-type net, but have different pore sizes due to the network interpenetration in BUT-32. Controlled syntheses of the two MOFs have been achieved through precisely tuning reaction conditions, where the microporous BUT-32 was demonstrated to be a thermodynamically stable product while the mesoporous BUT-33 is kinetically favored. To date, BUT-32 represents the first example of Ni-4-pyrazolate MOF whose structure was unambiguously determined by single-crystal X-ray diffraction. Interestingly, the kinetic product BUT-33 integrates 2.6 nm large mesopores with accessible Ni(II) active sites and remarkable chemical stability even in 4 M NaOH aqueous solution and 1 M Grignard reagent. This MOF thus demonstrated an excellent catalytic performance in carbon-carbon coupling reactions, superior to other Ni(II)-MOFs including BUT-32. These findings highlight the importance of kinetic control in the reticular synthesis of mesoporous MOFs, as well as their superiority in heterogeneous catalysis.
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| 4. |
- Lo, Sheng-Han, et al.
(författare)
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Rapid desolvation-triggered domino lattice rearrangement in a metal-organic framework
- 2020
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Ingår i: Nature Chemistry. - : Springer Science and Business Media LLC. - 1755-4330 .- 1755-4349. ; 12:1, s. 90-97
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Tidskriftsartikel (refereegranskat)abstract
- Topological transitions between considerably different phases typically require harsh conditions to collectively break chemical bonds and overcome the stress caused to the original structure by altering its correlated bond environment. In this work we present a case system that can achieve rapid rearrangement of the whole lattice of a metal-organic framework through a domino alteration of the bond connectivity under mild conditions. The system transforms from a disordered metal-organic framework with low porosity to a highly porous and crystalline isomer within 40s following activation (solvent exchange and desolvation), resulting in a substantial increase in surface area from 725 to 2,749m(2)g(-1). Spectroscopic measurements show that this counter-intuitive lattice rearrangement involves a metastable intermediate that results from solvent removal on coordinatively unsaturated metal sites. This disordered-crystalline switch between two topological distinct metal-organic frameworks is shown to be reversible over four cycles through activation and reimmersion in polar solvents. A disordered metal-organic framework converts into a more porous, crystalline phase within 40s following solvent exchange and desolvation. The rapid domino rearrangement of the whole lattice, which involves carboxylate migration on coordinatively unsaturated metal sites, is accompanied by a substantial increase in surface area.
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| 5. |
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| 6. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2806-2818
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Tidskriftsartikel (refereegranskat)abstract
- Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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