| 1. |
- Sliz, E., et al.
(författare)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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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.
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| 2. |
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| 3. |
- Kurki, MI, et al.
(författare)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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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.
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| 4. |
- Saldías, M., et al.
(författare)
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The Vocal Tract in Loud Twang-Like Singing While Producing High and Low Pitches
- 2021
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Ingår i: Journal of Voice. - : Elsevier BV. - 0892-1997 .- 1873-4588. ; 35:5, s. 807.e1-807.e23
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Tidskriftsartikel (refereegranskat)abstract
- Twang-like vocal qualities have been related to a megaphone-like shape of the vocal tract (epilaryngeal tube and pharyngeal narrowing, and a wider mouth opening), low-frequency spectral changes, and tighter and/or increased vocal fold adduction. Previous studies have focused mainly on loud and high-pitched singing, comfortable low-pitched spoken vowels, or are based on modeling and simulation. There is no data available related to twang-like voices in loud, low-pitched singing. Purpose: This study investigates the possible contribution of the lower and upper vocal tract configurations during loud twang-like singing on high and low pitches in a real subject. Methods: One male contemporary commercial music singer produced a sustained vowel [a:] in his habitual speaking pitch (B2) and loudness. The same vowel was also produced in a loud twang-like singing voice on high (G4) and low pitches (B2). Computerized tomography, acoustic analysis, inverse filtering, and audio-perceptual assessments were performed. Results: Both loud twang-like voices showed a megaphone-like shape of the vocal tract, being more notable on the low pitch. Also, low-frequency spectral changes, a peak of sound energy around 3 kHz and increased vocal fold adduction were found. Results agreed with audio-perceptual evaluation. Conclusions: Loud twang-like phonation seems to be mainly related to low-frequency spectral changes (under 2 kHz) and a more compact formant structure. Twang-like qualities seem to require different degrees of twang-related vocal tract adjustments while phonating in different pitches. A wider mouth opening, pharyngeal constriction, and epilaryngeal tube narrowing may be helpful strategies for maximum power transfer and improved vocal economy in loud contemporary commercial music singing and potentially in loud speech. Further studies should focus on vocal efficiency and vocal economy measurements using modeling and simulation, based on real-singers’ data.
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| 5. |
- Oksa, L, et al.
(författare)
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Arginine Methyltransferase PRMT7 Deregulates Expression of RUNX1 Target Genes in T-Cell Acute Lymphoblastic Leukemia
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with no well-established prognostic biomarkers. We examined the expression of protein arginine methyltransferases across hematological malignancies and discovered high levels of PRMT7 mRNA in T-ALL, particularly in the mature subtypes of T-ALL. The genetic deletion of PRMT7 by CRISPR-Cas9 reduced the colony formation of T-ALL cells and changed arginine monomethylation patterns in protein complexes associated with the RNA and DNA processing and the T-ALL pathogenesis. Among them was RUNX1, whose target gene expression was consequently deregulated. These results suggest that PRMT7 plays an active role in the pathogenesis of T-ALL.
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| 6. |
- Peters, Ruth, et al.
(författare)
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An investigation of antihypertensive class, dementia, and cognitive decline: A meta-analysis.
- 2020
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Ingår i: Neurology. - 1526-632X. ; 94:3
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is one of the main modifiable risk factors for dementia. However, there is conflicting evidence regarding the best antihypertensive class for optimizing cognition. Our objective was to determine whether any particular antihypertensive class was associated with a reduced risk of cognitive decline or dementia using comprehensive meta-analysis including reanalysis of original participant data.To identify suitable studies, MEDLINE, Embase, and PsycINFO and preexisting study consortia were searched from inception to December 2017. Authors of prospective longitudinal human studies or trials of antihypertensives were contacted for data sharing and collaboration. Outcome measures were incident dementia or incident cognitive decline (classified using the reliable change index method). Data were separated into mid and late-life (>65 years) and each antihypertensive class was compared to no treatment and to treatment with other antihypertensives. Meta-analysis was used to synthesize data.Over 50,000 participants from 27 studies were included. Among those aged >65 years, with the exception of diuretics, we found no relationship by class with incident cognitive decline or dementia. Diuretic use was suggestive of benefit in some analyses but results were not consistent across follow-up time, comparator group, and outcome. Limited data precluded meaningful analyses in those ≤65 years of age.Our findings, drawn from the current evidence base, support clinical freedom in the selection of antihypertensive regimens to achieve blood pressure goals.The review was registered with the international prospective register of systematic reviews (PROSPERO), registration number CRD42016045454.
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| 9. |
- Pinomaa, T., et al.
(författare)
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The significance of spatial length scales and solute segregation in strengthening rapid solidification microstructures of 316L stainless steel
- 2020
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Ingår i: Acta Materialia. - : Acta Materialia Inc. - 1359-6454 .- 1873-2453. ; 184, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Selective laser melting (SLM) can produce outstanding mechanical properties in 316L stainless steel. Nonetheless, the technique can lead to considerable variation in quality. This reflects an incomplete understanding and control of the process-structure-properties linkage. This paper demonstrates how length-scale informed micromechanical behavior can be linked to solidification microstructures and how these structures depend on SLM process conditions. This linkage is produced by sequential phase field and crystal plasticity simulations. Rapid solidification is described with a recent quantitative phase field model with solute trapping kinetics, where a range of process conditions are considered in terms of thermal gradients and pulling speeds. The predicted morphological transitions (dendritic-cellular-planar) are consistent with experiments, including segregation-free microstructures, which emerge in planar growth conditions. The predicted cell spacing vs. cooling rate data are also consistent with experiments. The simulated cellular structures produced through phase field modeling are then analyzed with a Cosserat crystal plasticity model with calibrated length-scale and hardening effects and with a solid solution strengthening description that depends on the local microsegregation. It is found that the length scale characteristics and solute segregation greatly influence the overall hardening behavior and affect plastic localization and the evolution of geometrically necessary dislocation (GND) type hardening. Our results suggest that the material strength of SLM 316L steel is more sensitive to cell spacing (microstructural length scale) than to the magnitude of solute segregation. Pulling speed (solidification velocity) is identified as the main process condition determining the material micromechanical behavior. Further analysis of idealized polycrystalline structures demonstrated that plastic incompatibilities and subgrain cell interactions with grain boundaries lead to notable strengthening. The presented sequential phase field-crystal plasticity modeling scheme is a proof-of-concept for systematically investigating and discovering new compositions, process conditions and microstructures for SLM.
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