| 1. |
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| 2. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 4. |
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| 5. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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| 6. |
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| 7. |
- Wang, QBS, et al.
(författare)
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
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Tidskriftsartikel (refereegranskat)abstract
- Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.
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| 17. |
- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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| 18. |
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| 19. |
- Bryois, J., et al.
(författare)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 20. |
- Santangelo, James S., et al.
(författare)
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Global urban environmental change drives adaptation in white clover
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
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Tidskriftsartikel (refereegranskat)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- Watson, H. J., et al.
(författare)
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Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:8
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Tidskriftsartikel (refereegranskat)abstract
- Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness(1), affecting 0.9-4% of women and 0.3% of men(2-4), with twin-based heritability estimates of 50-60%(5). Mortality rates are higher than those in other psychiatric disorders(6), and outcomes are unacceptably poor(7). Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)(8,9) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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| 25. |
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| 26. |
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| 27. |
- Aktas, Özge, 1987-, et al.
(författare)
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First observation of γ-ray transitions in 111Mo
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X.
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Tidskriftsartikel (refereegranskat)abstract
- Excited states in the extremely neutron-rich nuclei 109Mo and 111Mo have been studied following nucleon knock-out reactions. Seven $\gamma$-ray transitions, some of them in prompt mutual coincidence, have been identified for the first time in 11Mo using the DALI2 and MINOS detector systems at the BigRIPS and ZeroDegree electromagnetic fragments separator at the RIBF, RIKEN, Japan. Total Routhian surface (TRS) and Particle- Plus Rotor calculations have been performed to investigate the predicted shape coexistence and its effect on the structure of nuclei in this region of the nuclear chart. Following the results of the calculations, theoretical level schemes are proposed for positive and negative parity states and compared with the experimental findings.
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| 28. |
- Aktas, Özge, et al.
(författare)
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Single-particle structures in 85,87Ge
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X.
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Tidskriftsartikel (refereegranskat)abstract
- Gamma-ray transitions have been identified for the first time in the extremely neutron-rich (N =Z + 25) nucleus 87 Ge following nucleon knockout reactions studied at the RIBF, RIKEN, Japan.New γ-ray transitions from excited states in 85 Ge were also observed and placed in a tentative levelscheme. The exclusive parallel momentum distribution was measured for the 1/2 + state for theneutron knockout reaction leading to 85 Ge which is compared with calculated distorted wave impulseapproximation (DWIA) distributions. The 85,87 Ge results are compared with large-scale shell-modelcalculations and potential energy surface calculations based on the total Routhian surface formalism.
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| 29. |
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| 30. |
- Ogino, K., et al.
(författare)
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Negatively skewed locomotor activity is related to autistic traits and behavioral problems in typically developing children and those with autism spectrum disorders
- 2018
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Ingår i: Frontiers in Human Neuroscience. - : Frontiers Media S.A.. - 1662-5161. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- An important objective for researchers and clinicians is to gain a better understanding of the factors that underlie autism spectrum disorders (ASDs). It is possible that investigating objective and quantitative behavioral phenotypes and their relationship to clinical characteristics, such as autistic traits and other emotional/behavioral problems, might facilitate this process. Given this, in the current study we examined the link between locomotor dynamics and clinical characteristics, including autistic traits and emotional/behavioral problems, in children with ASD (n = 14) and typically developing (TD) children (n = 13). A watch-type actigraph was used to continuously measure locomotor activity which was assessed in terms of mean activity levels and the skewness of activity. Parents assessed quantitative autistic traits using the Japanese version of the Social Responsiveness Scale (SRS) and emotional and behavioral problems using the Japanese version of the Strengths and Difficulties Questionnaire (SDQ). Results showed that among all children, all-day activity was more negatively skewed, suggesting sporadic large all-day “troughs” in activity and was significantly correlated with the SRS social awareness subscale score (ρ = −0.446, p = 0.038). In addition, the more negatively skewed daytime locomotor activity was associated with the SDQ Hyperactivity Inattention subscale score (ρ = −0.493, p = 0.020). The results of this study indicate that investigating locomotor dynamics may provide one way to increase understanding of the neurophysiological mechanisms underlying the clinical characteristics of ASD.
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| 31. |
- Recchia, F., et al.
(författare)
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Isomer spectroscopy in odd–even Ti isotopes : Approaching n = 40
- 2019
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Ingår i: Acta Physica Polonica B. - : Jagellonian University. - 0587-4254 .- 1509-5770. ; 50:3, s. 669-674
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Tidskriftsartikel (refereegranskat)abstract
- Our understanding of the evolution of the shell structure in nuclei far from stability is based on the study of some key nuclei. Nuclei at or next to double shell closures play a special role in this. Presently, a lot of discussion is concentrated on the neutron-rich calcium isotopes, which provide a rich testing ground for various nuclear models with several traditional and new magic numbers. 60 Ca is now almost within reach with the most advanced radioactive beam facilities. In order to investigate the evolution of the shell gap at N = 40, the configuration of states in the odd–even titanium isotopes up to N = 37 ( 59 Ti) have been studied. In order to experimentally access the shell gap at N = 40, it is nowadays within the reach of the most advanced facility the investigation of neutron hole configuration states in odd–even titanium isotopes up to N = 37, in the 59 Ti nucleus. Such states correspond to relatively simple configurations that constitute a challenging testing ground for effective nuclear interactions. The new data obtained in our experiment allows to place the present predictions concerning the shell closure at N = 40 in the calcium region on a more solid ground.
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| 32. |
- Wimmer, K., et al.
(författare)
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First spectroscopy of Ti-61 and the transition to the Island of Inversion at N=40
- 2019
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Ingår i: Physics Letters B. - : Elsevier. - 0370-2693 .- 1873-2445. ; 792, s. 16-20
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Tidskriftsartikel (refereegranskat)abstract
- Isomeric states in Ti-59,Ti-61 have been populated in the projectile fragmentation of a 345 AMeV( 238)U beam at the Radioactive Isotope Beam Factory. The decay lifetimes and delayed gamma-ray transitions were measured with the EURICA array. Besides the known isomeric state in Ti-59, two isomeric states in Ti-61 are observed for the first time. Based on the measured lifetimes, transition multipolarities as well as tentative spins and parities are assigned. Large-scale shell model calculations based on the modified LNPS interaction show that both Ti-59 and Ti-61 belong to the Island of Inversion at N = 40 with ground state configurations dominated by particle-hole excitations to the g(9/2 )and d(5/2) orbits.
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| 33. |
- Wimmer, K., et al.
(författare)
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Isomeric states in neutron-rich nuclei near N=40
- 2021
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Ingår i: Physical Review C. - : American Physical Society (APS). - 2469-9985 .- 2469-9993. ; 104:1
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Tidskriftsartikel (refereegranskat)abstract
- Neutron-rich nuclei in the vicinity of the N = 40 island of inversion are characterized by shell evolution and exhibit deformed ground states. In several nuclei isomeric states have been observed and attributed to excitations to the intruder neutron 1g(9/2) orbital. In the present paper we searched for isomeric states in nuclei around N = 40, Z = 22 produced by projectile fragmentation at the Radioactive Isotope Beam Factory. Delayed. rays were detected by the Euroball RIKEN Cluster Array germanium detector array gamma High statistics data allowed for an updated decay scheme of V-60. The lifetime of an isomeric state in V-64 was measured for the first time in the present experiment. A previously unobserved isomeric state was discovered in Sc-58. The measured lifetime suggests a parity changing transition, originating from an odd number of neutrons in the 1g(9/2) orbital. The nature of the isomeric state in Sc-58 is, thus, different from isomers in the less exotic V and Sc nuclei.
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| 34. |
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| 36. |
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| 37. |
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| 38. |
- Springer, W, et al.
(författare)
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Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)
- 2016
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 31:Suppl. S2, s. 282-282
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Konferensbidrag (refereegranskat)abstract
- Objective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype.
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| 41. |
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| 42. |
- Alexandersson, Bjarki, et al.
(författare)
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High-Definition Chromoendoscopy Superior to High-Definition White-Light Endoscopy in Surveillance of Inflammatory Bowel Diseases in a Randomized Trial
- 2020
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-3565 .- 1542-7714. ; 18:9, s. 2101-2107
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: There is debate over the optimal method for colonoscopic surveillance of patients with inflammatory bowel diseases. Guidelines recommend chromoendoscopy, but the value of chromoendoscopy in high-definition colonoscopy has not been proven. Furthermore, the value of random biopsies is controversial. METHODS: We performed a prospective study of 305 patients with ulcerative colitis or Crohn's colitis referred for surveillance colonoscopy at a university hospital in Sweden, from March 2011 through April 2016. Patients randomly assigned to a group that received high-definition chromoendoscopy with indigo carmine (HD-CE; n=152), collection of 32 random biopsies, and targeted biopsies or polypectomies or to a group that received high-definition white light endoscopy (HD-WLE; n=153), collection of 32 random biopsies, and targeted biopsies or polypectomies. The primary endpoint was number of patients with dysplastic lesions. RESULTS: Dysplastic lesions were detected in 17 patients with HD-CE and 7 patients with HD-WLE (P=.032). Dysplasias in random biopsies (n=9760) were detected in 9 patients: 6 (3.9%) in the HD-CE group and 3 (2.0%) in the HD-WLE group (P=.72). Of the 9 patients with dysplasia, 3 patients (33%) had primary sclerosing cholangitis-only 18% of patients (54/305) included in the study had primary sclerosing cholangitis. The number of dysplastic lesions per 10 min of withdrawal time was 0.066 with HD-CE and 0.027 with HD-WLE (P=.056). CONCLUSIONS: In a randomized trial, we found HD-CE with collection of random biopsies to be superior to HD-WLE with random biopsies for detection of dysplasia per colonoscopy. These results support the use of chromoendoscopy for surveillance of patients with inflammatory bowel diseases. ClinicalTrials.gov no: NCT01505842.
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| 43. |
- Ando, T, et al.
(författare)
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Transduction with the antioxidant enzyme catalase protects human T cells against oxidative stress
- 2008
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Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 181:12, s. 8382-8390
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Tidskriftsartikel (refereegranskat)abstract
- Patients with diseases characterized by chronic inflammation, caused by infection or cancer, have T cells and NK cells with impaired function. The underlying molecular mechanisms are diverse, but one of the major mediators in this immune suppression is oxidative stress caused by activated monocytes, granulocytes, or myeloid-derived suppressor cells. Reactive oxygen species can seriously hamper the efficacy of active immunotherapy and adoptive transfer of T and NK cells into patients. In this study, we have evaluated whether enhanced expression of the antioxidant enzyme catalase in human T cells can protect them against reactive oxygen species. Human CD4+ and CD8+ T cells retrovirally transduced with the catalase gene had increased intracellular expression and activity of catalase. Catalase transduction made CD4+ T cells less sensitive to H2O2-induced loss-of-function, measured by their cytokine production and ability to expand in vitro following anti-CD3 stimulation. It also enhanced the resistance to oxidative stress-induced cell death after coculture with activated granulocytes, exposure to the oxidized lipid 4-hydroxynonenal, or H2O2. Expression of catalase by CMV-specific CD8+ T cells saved cells from cell death and improved their capacity to recognize CMV peptide-loaded target cells when exposed to H2O2. These findings indicate that catalase-transduced T cells potentially are more efficacious for the immunotherapy of patients with advanced cancer or chronic viral infections.
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| 46. |
- Berk, J.L., et al.
(författare)
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The diflunisal trial : update on study drug tolerance and disease progression
- 2011
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Ingår i: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis. - : Informa UK Limited. - 1744-2818. ; 18:Suppl. 1, s. 191-192
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Familial amyloidotic polyneuropathy (FAP) is a lethal genetic disorder that affects the peripheral and autonomic nervous systems, heart, gastro-intestinal (GI) tract, and soft tissues. Disease progression is increasingly reported following liver transplantation, the only proven treatment for FAP. Small molecule thyroxine mimetics stabilize transthyretin, inhibiting FAP amyloid fibril formation under stringent in vitro conditions. We report on the progress of an international, randomized placebo-controlled study designed to determine the effect of diflunisal, a thyroxine mimetic, on neurologic disease progression in patients with active FAP. Our experience to date indicates diflunisal is well tolerated by this study cohort and that neurologic disease advances more rapidly in FAP than it does in diabetes mellitus.Background: Transthyretin-related familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant genetic disorder that predominantly affects the peripheral nervous system. FAP amyloid fibrils result from the misfolding of transthyretin, a transport protein predominantly produced by the liver. Although liver transplantation effectively treats patients with certain FAP mutations and limited disease, reports increasingly document progressive amyloid deposition following transplantation [1,2]. Alternative treatments are needed. In vitro investigations and a phase I clinical trial have demonstrated that thyroxine and small molecule mimetics, e.g. diflunisal, inhibit tetrameric transthyretin dissociation and suppress amyloid fibril formation [3,4].Methods: To examine the effect of diflunisal on disease progression in FAP, we designed a randomized, placebo controlled, double blind, multicenter international study employing the validated diabetic (DM) polyneuropathy metric, Neurologic Impairment Score + 7 attributes (NIS+7®), as the primary endpoint. A two-point change in NIS+7 correlates with clinically detectable progression of peripheral neuropathy among diabetics [5]. Entry criteria include proven FAP genotype, biopsy-proven amyloid deposits, and peripheral or autonomic neuropathy. Patients with alternate causes of neuropathy, other NSAID use, severe heart or kidney dysfunction, or previous liver transplantion are excluded. Study evaluations occur at entry, 6, 12, and 24 months. Adverse are collected by monthly telephone interviews, diary entries, and study site visit interactions. Relatedness of adverse events to study drug is assigned according to documentation in the investigational brochure, the protocol, the informed consent form; or at the investigator's discretion.Results: To date, 90 subjects have enrolled – 62 men and 28 women with median age 63 years (range 27–76 years). Adverse events tabulated by affected organ systems predominantly involved gastrointestinal events, more often attributed to disease complications than study drug side effects (Table 1). Although rare events, congestive heart failure in two subjects and GI bleeding in another prompted study drug discontinuation. Two disease-related deaths have occurred, both off study drug. Aggregate data from all study subjects (placebo and active drug arms) followed for at least 12 months identified a 3.2 point increase in median NIS+7 summated scores. In contrast, Dyck et al. [6] reported an annual 0.85 point increase in NIS+7 median scores in a large cohort of diabetics with polyneuropathy. Taken together, NIS+7 detected neurologic disease progression in this FAP cohort after 12 months observation. Additionally, NIS+7 measured disease advanced 3.5 times faster in our aggregate FAP study population than previously reported in DM.Conclusions: Diflunisal is well tolerated in FAP patients participating in the study. NIS+7, a composite scoring system, appears to be an effective study instrument for ATTR neuropathy, detecting significant change over 12 months observation. Neurologic disease progresses more rapidly in FAP than DM cohorts. The exact rate of disease progression in untreated FAP subjects detected by NIS+7 awaits unblinding of the data. These data will provide basis for future study design in FAP patients.
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