| 1. |
|
|
| 2. |
- Ramdas, S., et al.
(författare)
-
A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
-
Tidskriftsartikel (refereegranskat)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
|
|
| 3. |
- Sliz, E., et al.
(författare)
-
Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Kanoni, Stavroula, et al.
(författare)
-
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
-
Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
-
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.
|
|
| 8. |
|
|
| 9. |
- Kurki, MI, et al.
(författare)
-
FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
-
Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
|
|
| 10. |
- Polettini, M., et al.
(författare)
-
Decay studies in the A∼225 Po-Fr region from the DESPEC campaign at GSI in 2021
- 2022
-
Ingår i: Il Nuovo Cimento. - : Società Italiana di Fisica. - 2037-4909. ; 45:5
-
Tidskriftsartikel (refereegranskat)abstract
- The HISPEC-DESPEC collaboration aims at investigating the structure of exotic nuclei formed in fragmentation reactions with decay spectroscopy measurements, as part of the FAIR Phase-0 campaign at GSI. This paper reports on first results of an experiment performed in spring 2021, with a focus on beta-decaystudies in the Po-Fr nuclei in the 220 < A <230 island of octupole deformation exploiting the DESPEC setup. Ion-beta correlations and fast-timing techniques are being employed, giving an insight into this difficult-to-reach region.
|
|
| 11. |
- Ahlgren Cederlöf, Ebba, et al.
(författare)
-
Lifetime measurement of the yrast 2+ state in 118Te
- 2023
-
Ingår i: European Physical Journal A. - : Springer. - 1434-6001 .- 1434-601X. ; 59:12
-
Tidskriftsartikel (refereegranskat)abstract
- The electromagnetic transition probabilities of the yrast 2+ states in the midshell Te isotopes, two protons above the closed shell at Sn, are of great importance for the understanding of nuclear collectivity in these isotopes and the role played by the neutron-proton interactions and cross-shell excitations. However, the large uncertainty of the experimental data for the midshell nucleus 118Te and the missing data for 116Te make it difficult to pin down the general trend of the evolution of transition probabilities as a function of the neutron number. In this work, the lifetime of the yrast 2+ state in 118Te was measured, with the aim of reducing the uncertainty of the previous measurement. The result is τ2+ = 7.46(19) ps. In addition, the lifetime of the 4+ state was measured to be τ4+ = 4.25(23) ps. The experimental transition rates are extracted from the measured lifetimes and compared with systematic large-scale shell-model calculations. The trend of the B(E2; 0+ → 2+) values in the midshell area is in good agreement with the calculations and the calculated B4/2 ratio provide evidence for 118Te as a near perfect harmonic vibrator.
|
|
| 12. |
- Devarajan, R., et al.
(författare)
-
Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models
- 2023
-
Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 133:18
-
Tidskriftsartikel (refereegranskat)abstract
- The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and-2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and alpha 6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.
|
|
| 13. |
- Ertoprak, Aysegul, et al.
(författare)
-
Evidence for octupole collectivity in 172Pt
- 2020
-
Ingår i: European Physical Journal A. - : Springer. - 1434-6001 .- 1434-601X. ; 56:2
-
Tidskriftsartikel (refereegranskat)abstract
- Excited states in the extremely neutron-deficient nucleus 172Pt were populated via 96Ru(78Kr,2p) and 92Mo(83Kr,3n) reactions. The level scheme has been extended up to an excitation energy of ~ 5 MeV and tentative spin-parity assignments up to Iπ = 18+. Linear polarization and angular distribution measurements were used to determine the electromagnetic E1 character of the dipole transitions connecting the positive-parity ground-state band with an excited side-band, firmly establishing it as a negative-parity band. The lowest member of this negative-parity structure was firmly assigned spin-parity 3-. In addition, we observed an E3 transition from this 3- state to the ground state, providing direct evidence for octupole collectivity in 172Pt. Large-scale shell model (LSSM) and total Routhian surface (TRS) calculations have been performed, supporting the interpretation of the 3- state as a collective octupole-vibrational state.
|
|
| 14. |
- Fernández, A., et al.
(författare)
-
Mirror energy differences above the 0f7/2 shell: First γ-ray spectroscopy of the Tz=−2 nucleus 56Zn
- 2021
-
Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693. ; 823
-
Tidskriftsartikel (refereegranskat)abstract
- Excited states in 56Zn were populated following one-neutron removal from a 57Zn beam impinging on a Be target at intermediate energies in an experiment conducted at the Radioactive Isotope Beam Factory at RIKEN. Three γ rays were observed and tentatively assigned to the 6+ → 4+ → 2+ → 0+ yrast sequence. This turns 56Zn into the heaviest Tz=−2 nucleus in which excited states are known. The excitation-energy differences between these levels and the isobaric analogue states in the Tz=+2 mirror partner, 56Fe, are compared with large-scale shell-model calculations considering the full pf valence space and various isospin-breaking contributions. This comparison, together with an analysis of the mirror energy differences in the A=58, Tz=±1 pair 58Zn and 58Ni, provides valuable information with respect to the size of the monopole radial and the isovector multipole isospin-breaking terms in the region above doubly-magic 56Ni.
|
|
| 15. |
- Hautakangas, H, et al.
(författare)
-
Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles
- 2022
-
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:2, s. 152-
-
Tidskriftsartikel (refereegranskat)abstract
- Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.
|
|
| 16. |
|
|
| 17. |
- Zhang, W., et al.
(författare)
-
Decay spectroscopy of 171,172Os and 171,172,174Ir
- 2023
-
Ingår i: Physical Review C. - : American Physical Society (APS). - 2469-9985 .- 2469-9993. ; 107:1
-
Tidskriftsartikel (refereegranskat)abstract
- We report on a study of the α-decay fine structure and the associated Eα−Eγ correlations in the decays of 171,172Os and 171,172,174Ir. In total, 13 new α-decay energy lines have been resolved, and three new γ-ray transitions have been observed following the new decay branches to 168Re and 167W. The weak α-decay branch from the bandhead of the νi13/2 band in 171Os observed in this work highlights an unusual competition between α, β, and electromagnetic decays from this isomeric state. The nucleus 171Os is therefore one of few nuclei observed to exhibit three different decay modes from the same excited state. The nuclei of interest were produced in 92Mo(83Kr,xpyn) fusion-evaporation reactions at the Accelerator Laboratory of the University of Jyväskylä, Finland. The fusion products were selected using the gas-filled ion separator RITU and their decays were characterized using an array of detectors for charged particles and electromagnetic radiation known as GREAT. Prompt γ-ray transitions were detected and correlated with the decays using the JUROGAM II germanium detector array surrounding the target position. Results obtained from total Routhian surface (TRS) calculations suggest that α-decay fine structure and the associated hindrance factors may be a sensitive probe of even relatively small shape changes between the final states in the daughter nucleus.
|
|
| 18. |
- Zhang, Wei, et al.
(författare)
-
Lifetime measurements of excited states in 169,171,173Os : Persistence of anomalous B(E2) ratios in transitional rare earth nuclei in the presence of a decoupled i13/2 valence neutron
- 2021
-
Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 820
-
Tidskriftsartikel (refereegranskat)abstract
- Lifetimes of low-lying excited states in the νi13/2+ bands of the neutron-deficient osmium isotopes 169,171,173Os have been measured for the first time using the recoil-distance Doppler shift and recoil-isomer tagging techniques. An unusually low value is observed for the ratio B(E2;21/2+→17/2+)/B(E2;17/2+→13/2+) in 169Os, similar to the “anomalously” low values of the ratio B(E2;41+→21+)/B(E2;21+→0gs+) previously observed in several transitional rare-earth nuclides with even numbers of neutrons and protons, including the neighbouring 168,170Os. Furthermore, the evolution of B(E2;21/2+→17/2+)/B(E2;17/2+→13/2+) with increasing neutron number in the odd-mass isotopic chain 169,171,173Os is observed to follow the same trend as observed previously in the even-even Os isotopes. These findings indicate that the possible quantum phase transition from a seniority conserving structure to a collective regime as a function of neutron number suggested for the even-even systems is maintained in these odd-mass osmium nuclei, with the odd valence neutron merely acting as a “spectator”. As for the even-even nuclei, the phenomenon is highly unexpected for nuclei that are not situated near closed shells.
|
|
| 19. |
- Zhao, S., et al.
(författare)
-
Propulsion Calculated by Force and Displacement of Center of Mass in Treadmill Cross-Country Skiing
- 2022
-
Ingår i: Sensors. - : MDPI AG. - 1424-8220. ; 22:7
-
Tidskriftsartikel (refereegranskat)abstract
- This study evaluated two approaches for estimating the total propulsive force on a skier's center of mass (COM) with double-poling (DP) and V2-skating (V2) skiing techniques. We also assessed the accuracy and the stability of each approach by changing the speed and the incline of the treadmill. A total of 10 cross-country skiers participated in this study. Force measurement bindings, pole force sensors, and an eight-camera Vicon system were used for data collection. The coefficient of multiple correlation (CMC) was calculated to evaluate the similarity between the force curves. Mean absolute force differences between the estimated values and the reference value were computed to evaluate the accuracy of each approach. In both DP and V2 techniques, the force-time curves of the forward component of the translational force were similar to the reference value (CMC: 0.832-0.936). The similarity between the force and time curves of the forward component of the ground reaction force (GRF) and the reference value was, however, greater (CMC: 0.879-0.955). Both approaches can estimate the trend of the force-time curve of the propulsive force properly. An approach by calculating the forward component of GRF is a more appropriate method due to a better accuracy.
|
|
