| 1. |
- Archambault, Alexi N., et al.
(författare)
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Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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| 2. |
- Aronsson, Lena, 1959-
(författare)
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När förskolan möter neurovetenskap : Kunskapsteoretiska möten i teori och i praktik
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This doctoral thesis in Early Childhood Education reports on encounters between the theories and practices of Swedish preschool and research-based neuroscience knowledge. Thus, this thesis concerns epistemological encounters and didactic consequences. The scientific problem pertains to the relation between scientifically generated knowledge and educational practices in preschool, with specific attention to the requirement that preschool, as the first level in the Swedish education system, should be based on scientific knowledge and verified experience-based knowledge. The didactic problem emerging from this scientific problem concerns how this might affect the daily practices of responsible preschool teachers and educators at large.The thesis adopts a relational ontology with a multi-epistemological and methodological approach, based primarily on Stengers’ (e.g., 2018) and Mols’ (e.g., 2002) respective scholarship. The aims of the thesis are to investigate, firstly; what is produced in epistemological encounters within and between the research fields of Early Childhood Education and neuroscience. Secondly; what is produced between these fields and preschool didactic practices. The focus for the latter is on the didactic practices relying on the extended language concept in the Swedish preschool curriculum.To explore these aims in more detail, a series of so-called cartography mapping exercises have been conducted. On the one hand, in the analyses of the literature aimed at bringing the two fields together. On the other hand, cartography mapping has been conducted with educators in three preschools collaboratively analyzing their literacy practices. The Deleuze-inspired (Deleuze & Guattari, 1987) methodology of cartography mapping aspire to simultaneously critically deconstruct and productively experiment with underlying lines of thinking emerging from scientific or philosophical problems that concern development and learning, and especially language development and skills of literacy during the preschool years (Lenz Taguchi, 2016a, 2016b).The knowledge that this thesis produces is summarized below. Cartography mapping can be used both as a research method and as a method in pedagogical practice. In addition, cartography mapping can accommodate issues in different epistemologies and in different practices, such as research practice and preschool didactic practice. That is, practices that are related and share an overarching aim, but which are nevertheless not the same. The method reveals the different epistemologies present and how they can operate simultaneously within preschool didactic practice. The results from the thesis support the Swedish preschool curriculum goals which encompasses a dual assignment of learning (group and individual), that require different epistemological and didactic methods to be fulfilled.A preschool practice based on scientific evidence and verified experience-based knowledge thus requires the use of a wide range of theories and epistemologies to guide preschool staff. Hence, the results of this thesis show not just the presence, but also the possibility of developing a multi-epistemological didactic repertoire in preschool development and learning practices.
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| 3. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 4. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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| 5. |
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| 6. |
- Huang, C, et al.
(författare)
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The inhomogeneous structure of water at ambient conditions
- 2009
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Ingår i: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:36, s. 15214-15218
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Tidskriftsartikel (refereegranskat)abstract
- Small-angle X-ray scattering (SAXS) is used to demonstrate the presence of density fluctuations in ambient water on a physical length-scale of approximate to 1 nm; this is retained with decreasing temperature while the magnitude is enhanced. In contrast, the magnitude of fluctuations in a normal liquid, such as CCl4, exhibits no enhancement with decreasing temperature, as is also the case for water from molecular dynamics simulations under ambient conditions. Based on X-ray emission spectroscopy and X-ray Raman scattering data we propose that the density difference contrast in SAXS is due to fluctuations between tetrahedral-like and hydrogen-bond distorted structures related to, respectively, low and high density water. We combine our experimental observations to propose a model of water as a temperature-dependent, fluctuating equilibrium between the two types of local structures driven by incommensurate requirements for minimizing enthalpy (strong near-tetrahedral hydrogen-bonds) and maximizing entropy (non-directional H-bonds and disorder). The present results provide experimental evidence that the extreme differences anticipated in the hydrogen-bonding environment in the deeply supercooled regime surprisingly remain in bulk water even at conditions ranging from ambient up to close to the boiling point.
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| 7. |
- Lenz, Annika, 1980-, et al.
(författare)
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A theoretical study of water clusters : the relation between hydrogen-bond topology and interaction energy from quantum-chemical computations for clusters with up to 22 molecules
- 2005
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : RCS Publishing. - 1463-9076 .- 1463-9084. ; 7, s. 1905-1911
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Tidskriftsartikel (refereegranskat)abstract
- Quantum-chemical calculations of a variety of water clusters with eight, ten and twelve molecules were performed, as well as for selected clusters with up to 22 water molecules. Geometry optimizations were carried out at the B3LYP/cc-pVDZ level and single-point energies were calculated at the B3LYP/aug-cc-pVDZ level for selected clusters. The electronic energies were studied with respect to the geometry of the oxygen arrangement and six different characteristics of the hydrogen-bond arrangement in the cluster. Especially the effect of the placement of the non-hydrogen bonding hydrogens on the interaction energy was studied. Models for the interaction energy with respect to different characteristics of the hydrogen-bond arrangement were derived through least-square fits. The results from the study of the clusters with eight, ten and twelve molecules are used to predict possible low-energy structures for various shapes of clusters with up to 22 molecules.
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| 8. |
- Lenz, Annika, et al.
(författare)
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A theoretical study of water equilibria: The cluster distribution versus temperature and pressure for (H2O)n, n=1–60, and ice
- 2009
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 131:13, s. 134302-134302-13
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Tidskriftsartikel (refereegranskat)abstract
- The size distribution of water clusters at equilibrium is studied using quantum-chemical calculations in combination with statistical thermodynamics. The necessary energetic data is obtained by quantum-chemical B3LYP computations and through extrapolations from the B3LYP results for the larger clusters. Clusters with up to 60 molecules are included in the equilibrium computations. Populations of different cluster sizes are calculated using both an ideal gas model with noninteracting clusters and a model where a correction for the interaction energy is included analogous to the van der Waals law. In standard vapor the majority of the water molecules are monomers. For the ideal gas model at 1 atm large clusters [56-mer (0–120 K) and 28-mer (100–260 K)] dominate at low temperatures and separate to smaller clusters [21–22-mer (170–280 K) and 4–6-mer (270–320 K) and to monomers (300–350 K)] when the temperature is increased. At lower pressure the transition from clusters to monomers lies at lower temperatures and fewer cluster sizes are formed. The computed size distribution exhibits enhanced peaks for the clusters consisting of 21 and 28 water molecules; these sizes are for protonated water clusters often referred to as magic numbers. If cluster-cluster interactions are included in the model the transition from clusters to monomers is sharper (i.e., occurs over a smaller temperature interval) than when the ideal-gas model is used. Clusters with 20–22 molecules dominate in the liquid region. When a large icelike cluster is included it will dominate for temperatures up to 325 K for the noninteracting clusters model. Thermodynamic properties (Cp, H) were calculated with in general good agreement with experimental values for the solid and gas phase. A formula for the number of H-bond topologies in a given cluster structure is derived. For the 20-mer it is shown that the number of topologies contributes to making the population of dodecahedron-shaped cluster larger than that of a lower-energy fused prism cluster at high temperatures.
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| 9. |
- Lenz, Annika, et al.
(författare)
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Computational studies of the stability of the (H2O)100 nanodrop
- 2010
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Ingår i: Journal of Molecular Structure. - : Elsevier BV. - 0166-1280. ; 944:1-3, s. 163-167
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Tidskriftsartikel (refereegranskat)abstract
- The stability of the (H2O)100 nanodrop, experimentally known from a polyoxomolybdatecrystal structure (Müller et al. Inorg. Chem. Commun., 2003, 6, 52) and other structuresinferred from clathrate structures, are studied by quantum-chemical B3LYP computations.The free energies are compared to the trends for smaller clusters with 15-30 molecules. Forthe small clusters both cage-based structures and denser structures with a larger number of Hbondsobtained by an evolutionary algorithm (Bandow and Hartke, J. Phys. Chem. A, 2006,110, 5809) are used. The dense structures are most often found to be lower in electronicenergy. The cage-based structures, to which the structure of the experimentally found(H2O)100 cluster can be categorized, become more stable when Gibbs free energy is calculatedat 298 K. Additional cage-based clusters in the 35-81 molecular range were constructed forcomparison. The experimental cluster with 100 molecules (C2h/Ci-symmetry for oxygens/allatoms) and the constructed cluster with 42 molecules are found to be lower in energy than aplausible overall trend. The (H2O)42 cluster has an extraordinary high symmetry (S6), evenwhen the hydrogens are considered. The (H2O)100 cluster is the only of the studied clusters forwhich ΔG is negative at 298 K.
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| 10. |
- Lenz, Annika, et al.
(författare)
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Computational study of the catalytic effect of platinum on the decomposition of DNT
- 2012
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Ingår i: International Journal of Quantum Chemistry. - : Wiley-Blackwell. - 0020-7608 .- 1097-461X. ; 112:7, s. 1852-1858
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Tidskriftsartikel (refereegranskat)abstract
- The catalytic decomposition of dinitrotoluene (DNT; 3-4-DNT), a by-product of the explosive trinitrotoluene (trotyl), on a platinum surface is investigated computationally. Reaction paths have been computed for a DNT molecule interacting with a Pt-cluster under varying temperatures using quantum-chemical density functional theory. Two possible initiation steps where DNT split either into nitro-tolyl and NO2, or in nitro-tolyl-oxidanyl and NO, are considered. The energy barrier for the catalytic process is found to decrease significantly for the Pt catalyzed reaction compared with the uncatalyzed reaction.
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