| 1. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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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. |
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| 4. |
- 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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| 5. |
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| 6. |
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| 7. |
- Carninci, P, et al.
(författare)
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The transcriptional landscape of the mammalian genome
- 2005
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5740, s. 1559-1563
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Tidskriftsartikel (refereegranskat)abstract
- This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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| 8. |
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| 9. |
- Forrest, ARR, et al.
(författare)
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A promoter-level mammalian expression atlas
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 507:7493, s. 462-
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Tidskriftsartikel (refereegranskat)
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| 10. |
- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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| 11. |
- Kousathanas, A, et al.
(författare)
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Whole-genome sequencing reveals host factors underlying critical COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 607:7917, s. 97-
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Tidskriftsartikel (refereegranskat)abstract
- Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.
- 2011
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:8, s. 753-60
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
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| 16. |
- Ramilowski, JA, et al.
(författare)
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Functional annotation of human long noncoding RNAs via molecular phenotyping
- 2020
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 30:7, s. 1060-1072
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Tidskriftsartikel (refereegranskat)abstract
- Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.
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| 17. |
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| 18. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease and type 2 diabetes.
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:12, s. 4369-77
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms that predispose to hypertension, coronary artery disease (CAD) and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy - a reduction in subcutaneous adipose tissue - it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, coronary artery disease and type 2 diabetes. We aimed to test the hypothesis that common alleles associated with insulin resistance also influence the wider clinical and biochemical profile of monogenic insulin resistance. We selected 19 common genetic variants associated with fasting insulin based measures of insulin resistance. We used hierarchical clustering and results from genome wide association studies of 8 non-disease outcomes of monogenic insulin resistance, to group these variants. We analysed genetic risk scores against disease outcomes including 12,171 T2D cases, 40,365 CAD cases and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle, form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (ß=0.018; p=4x10(-29)), lower HDL cholesterol (ß=-0.020; p=7x10(-37)), greater hepatic steatosis (ß=0.021; p=3x10(-4)) higher alanine transaminase (ß=0.002; p=3x10(-5)), lower SHBG (ß=-0.010; p=9x10(-13)) and lower adiponectin (ß=-0.015; p=2x10(-26)). The same risk alleles were associated with lower BMI (per-allele ß=-0.008; p=7x10(-8)), and increased visceral-to-subcutaneous adipose tissue ratio (ß=-0.015; p=6x10(-7)). Individuals carrying >= 17 fasting insulin raising alleles (5.5% population) were slimmer (0.30 kgm(-2)) but at increased risk of T2D (odds ratio [OR] 1.46, per-allele p=5x10(-13)), CAD (OR 1.12, per-allele p=1x10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg (per-allele p=2x10(-5)), and 0.67 mmHg (per-allele p=2x10(-4)), respectively, compared to individuals carrying <=9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.
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| 19. |
- Evans, A. O., et al.
(författare)
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Magnetic properties of deformed dipole bands in Te-110,Te-112
- 2006
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Ingår i: Physica Scripta. - 0031-8949. ; T125, s. 192-193
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Tidskriftsartikel (refereegranskat)abstract
- A lifetime analysis using the Doppler-shift attenuation method has been performed on the Tellurium isotopes Te-110,Te-112. The experiment was performed using the Gammasphere array in conjunction with the MICROBALL charged-particle detector. Three strongly coupled bands were previously established in Te-110,Te-112 which were observed up to unusually high spins. In the current experiment, it has been possible to extract lifetime measurements using a Doppler broadened lineshape analysis on one of the Delta I = 1 band structures in Te-110. In contrast to similar Delta I = 1 structures in other nuclei in this mass region, the extracted B(M1) values did not rapidly decrease with increasing angular momentum. Instead, the strongly coupled band in Te-110 represents a deformed 1p-1h structure, rather than a weakly deformed structure showing the shears mechanism.
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| 20. |
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| 21. |
- Parry, C. M., et al.
(författare)
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First evidence for smooth band termination in valence space in the mass 130 region : Spectroscopy of 127La
- 2000
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Ingår i: Physical Review C - Nuclear Physics. - 0556-2813. ; 61:2, s. 213031-213035
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Tidskriftsartikel (refereegranskat)abstract
- High spin states in 127La have been studied using the 32S(100Mo,p4n) reaction at a beam energy of 155 MeV. Gamma rays were detected using the EUROBALL III spectrometer. One of the side bands in 127La is observed to be populated to a spin of 83/2+. These data are compared with cranked Nilsson-Strutinski calculations which suggest that the structure is a smoothly terminating band, in valence space, based upon a π[(g7/2d5/2)5(h11/2)2]⊗ ν[(g7/2d5/2)12(h11/2)6(d3/2s1/2)2] configuration, which can carry a maximum spin of 47.5ℏ. This is the first identification of such a structure in this mass region.
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| 22. |
- Paul, E. S., et al.
(författare)
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Smooth terminating bands in Te-112: Particle-hole induced collectivity
- 2007
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 75:1
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Tidskriftsartikel (refereegranskat)abstract
- The Gammasphere spectrometer, in conjunction with the Microball charged-particle array, was used to investigate high-spin states in Te-112 via Ni-58(Ni-58, 4p gamma) reactions at 240 and 250 MeV. Several smooth terminating bands were established, and lifetime measurements were performed for the strongest one using the Doppler-shift attenuation method. Results obtained in the spin range 18-32h yield a transition quadrupole moment of 4.0 +/- 0.5eb, which corresponds to a quadrupole deformation epsilon(2)=0.26 +/- 0.03; this value is significantly larger than the ground-state deformation of tellurium isotopes. It was also possible to extract a transition quadrupole moment for the yrast band in Xe-114, produced via the 58Ni (58Ni, 2p gamma) reaction. A value of 3.0 +/- 0.5eb was found in the spin range 16-24h, which corresponds to a quadrupole deformation epsilon(2)=0.19 +/- 0.03. Cranked Nilsson-Strutinsky calculations are used to interpret the results.
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| 23. |
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| 24. |
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| 25. |
- Atac, A, et al.
(författare)
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Single-step link of the superdeformed band in Eu-143
- 1996
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Ingår i: ZEITSCHRIFT FUR PHYSIK A-HADRONS AND NUCLEI. - : SPRINGER VERLAG. - 0939-7922. ; 355:4, s. 343-344
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A discrete gamma-ray transition with an energy of 3360.6 keV deexciting the second lowest SD state in Eu-143 has been discovered. It carries 3.2 % of the full intensity of the band and feeds into a nearly spherical state which is above the I = 35/2((+)),
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| 26. |
- Axelsson, A, et al.
(författare)
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Single-step link from yrast SD band in Eu-143
- 1997
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Ingår i: PROGRESS IN PARTICLE AND NUCLEAR PHYSICS. - : PERGAMON PRESS LTD. - 0146-6410. ; 38, s. 51-52
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A discrete gamma-ray transition from the yrast SD band to the region of near-yrast discrete normal-deformed states has been identified in Eu-143. It has an energy of 3360.6 keV and an intensity corresponding to 3.2% of the full intensity of the SD band an
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| 27. |
- Costa, Y, et al.
(författare)
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Two novel proteins recruited by synaptonemal complex protein 1 (SYCP1) are at the centre of meiosis
- 2005
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Ingår i: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 118:12Pt 12, s. 2755-2762
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Tidskriftsartikel (refereegranskat)abstract
- Completion of meiosis in mammals depends on the formation of the synaptonemal complex, a tripartite structure that physically links homologous chromosomes during prophase I. Several components of the synaptonemal complex are known, including constituents of the cohesin core, the axial/lateral element and the transverse filaments. No protein has previously been identified as an exclusive component of the central element. Mutations in some synaptonemal-complex proteins results in impaired meiosis. In humans, cases of male infertility have been associated with failure to build the synaptonemal complex. To search for new components of the meiotic machinery, we have used data from microarray expression profiling and found two proteins localising solely to the central element of the mammalian synaptonemal complex. These new proteins, SYCE1 and CESC1, interact with the transverse filament protein SYCP1, and their localisation to the central element appears to depend on recruitment by SYCP1. This suggests a role for SYCE1 and CESC1 in synaptonemal-complex assembly, and perhaps also stability and recombination.
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| 28. |
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| 29. |
- Dastani, Zari, et al.
(författare)
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Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals
- 2012
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002607-
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Tidskriftsartikel (refereegranskat)abstract
- Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P=4.5 x 10(-8)-1.2 x 10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3 x 10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p=4.3 x 10(-3), n = 22,044), increased triglycerides (p=2.6 x 10(-14), n = 93,440), increased waist-to-hip ratio (p=1.8 x 10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p=4.4 x 10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p=4.5x10(-13), n = 96,748) and decreased BMI (p= 1.4 x 10(-14), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
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| 30. |
- Dick, FD, et al.
(författare)
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Environmental risk factors for Parkinson's disease and parkinsonism : The Geoparkinson study
- 2007
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Ingår i: Occupational and Environmental Medicine. - : BMJ. - 1351-0711 .- 1470-7926. ; 64:10, s. 666-672
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the associations between Parkinson's disease and other degenerative parkinsonian syndromes and environmental factors in five European countries. Methods: A case-control study of 959 prevalent cases of parkinsonism (767 with Parkinson's disease) and 1989 controls in Scotland, Italy, Sweden, Romania and Malta was carried out. Cases were defined using the United Kingdom Parkinson's Disease Society Brain Bank criteria, and those with drug-induced or vascular parkinsonism or dementia were excluded. Subjects completed an interviewer-administered questionnaire about lifetime occupational and hobby exposure to solvents, pesticides, iron, copper and manganese. Lifetime and average annual exposures were estimated blind to disease status using a job-exposure matrix modified by subjective exposure modelling. Results were analysed using multiple logistic regression, adjusting for age, sex, country, tobacco use, ever knocked unconscious and family history of Parkinson's disease. Results: Adjusted logistic regression analyses showed significantly increased odds ratios for Parkinson's disease/parkinsonism with an exposure-response relationship for pesticides (low vs no exposure, odds ratio (OR) =1.13, 95% Cl 0.82 to 1.57, high vs no exposure, OR =1.41, 95% Cl 1.06 to 1.88) and ever knocked unconscious (once vs never, OR= 1.35, 95% Cl 1.09 to 1.68, more than once vs never, OR = 2.53, 95% Cl 1.78 to 3.59). Hypnotic, anxiolytic or antidepressant drug use for more than 1 year and a family history of Parkinson's disease showed significantly increased odds ratios. Tobacco use was protective (OR = 0.50, 95% Cl 0.42 to 0.60). Analyses confined to subjects with Parkinson's disease gave similar results. Conclusions: The association of pesticide exposure with Parkinson's disease suggests a causative role. Repeated traumatic loss of consciousness is associated with increased risk.
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| 31. |
- Evans, AO, et al.
(författare)
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Magnetic properties of smooth terminating dipole bands in Te-110,Te-112
- 2006
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Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 636:1, s. 25-30
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Tidskriftsartikel (refereegranskat)abstract
- Three strongly coupled sequences have been established in Te-110,Te-112 up to high spins. They are interpreted in terms of deformed structures built on proton 1-particle-1-hole excitations that reach termination at I similar to 40h. This is the first observation of smooth terminating dipole structures in this mass region. Lifetime measurements have allowed the extraction of experimental B(M 1; 1 -> I - 1) and B(E2; I -> I - 2) reduced transition rates for one of the dipole bands in Te-110. The results support the deformed interpretation. (c) 2006 Elsevier B.V. All rights reserved.
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| 32. |
- Gizon, J., et al.
(författare)
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Terminating bands in the doubly odd nucleus [Formula Presented]
- 1999
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Ingår i: Physical Review C - Nuclear Physics. - 0556-2813. ; 59:2, s. 570-574
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Tidskriftsartikel (refereegranskat)abstract
- High spin states have been populated in [Formula Presented] using the reaction [Formula Presented] at 130 MeV. The γ rays have been detected with the EUROGAM2 array. The level structure of [Formula Presented] has been investigated. Several bands have been identified and established over a wide range of spin. They are interpreted using the Nilsson-Strutinsky cranking formalism and explained in terms of band terminations. Their configurations are built from the valence particles and valence holes relative to a [Formula Presented] core: [Formula Presented] protons (and [Formula Presented] proton holes) and [Formula Presented] and [Formula Presented] neutrons. After [Formula Presented] is the second heavy nucleus and the first odd-odd nucleus in which configurations in the valence space are followed from low spin up to their termination.
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| 33. |
- Huang-Doran, Isabel, et al.
(författare)
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Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.
- 2016
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Ingår i: JCI insight. - 2379-3708. ; 1:17
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Tidskriftsartikel (refereegranskat)abstract
- Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.
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| 34. |
- Huber, KT, et al.
(författare)
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Replacing cliques by stars in quasi-median graphs
- 2004
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Ingår i: Discrete Applied Mathematics. ; 143:1-3, s. 194-203
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Tidskriftsartikel (refereegranskat)abstract
- For a multi-set Sigma of splits (bipartitions) of a finite set X, we introduce the multi-split graph G(Sigma). This graph is a natural extension of the Buneman graph. Indeed, it is shown that several results pertaining to the Buneman graph extend to the multi-split graph. In addition, in case Sigma is derived from a set R of partitions of X by taking parts together with their complements, we show that the extremal instances where R is either strongly compatible or strongly incompatible are equivalent to G(Sigma) being either a tree or a Cartesian product of star trees, respectively.
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| 35. |
- Jongerius, Ilse, et al.
(författare)
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The Role of Complement in Transfusion-Related Acute Lung Injury
- 2019
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Ingår i: Transfusion Medicine Reviews. - : Elsevier BV. - 0887-7963. ; 33:4, s. 236-242
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Forskningsöversikt (refereegranskat)abstract
- Transfusion-related acute lung injury (TRALI) is a life-threatening complication of acute respiratory distress occurring within 6 hours of blood transfusion. TRALI is one of the leading causes of transfusion-related fatalities and specific therapies are unavailable. Neutrophils are recognized as the major pathogenic cells, whereas T regulatory cells and dendritic cells appear to be important for protection against TRALI. The pathogenesis, however, is complex and incompletely understood. It is frequently postulated that the complement system plays an important role in the TRALI pathogenesis. In this article, we assess the evidence regarding the involvement of complement in TRALI from both human and animal studies. We hypothesize about the potential connection between the complement system and neutrophils in TRALI. Additionally, we draw parallels between TRALI and other acute pulmonary disorders of acute lung injury and acute respiratory distress syndrome regarding the involvement of complement. We conclude that, even though a role for complement in the TRALI pathogenesis seems plausible, studies investigating the role of complement in TRALI are remarkably limited in number and also present conflicting findings. Different types of TRALI animal models, diverse experimental conditions, and the composition of the gastrointestinal microbiota may perhaps all be factors which contribute to these discrepancies. More systematic studies are warranted to shed light on the contribution of the complement cascade in TRALI. The underlying clinical condition of the patient, which influences the susceptibility to TRALI, as well as the transfusion factor (antibody-mediated vs non–antibody-mediated), will be important to take into consideration when researching the contribution of complement. This should significantly increase our understanding of the role of complement in TRALI and may potentially result in promising new treatment strategies.
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| 36. |
- LaFosse, D. R., et al.
(författare)
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Collective structures and band termination in 107Sb
- 2000
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Ingår i: Physical Review C - Nuclear Physics. - 0556-2813. ; 62:1
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Tidskriftsartikel (refereegranskat)abstract
- High-spin states in the near proton-dripline nucleus 107Sb have been identified, and collectivity in this nucleus has been observed for the first time in the form of two rotational bands. One of the observed rotational structures is a ΔI = 1 band, and is interpreted as based on a π(g9/2)-1 ⊗ π(g7/2d5/2)2 proton configuration. A second structure has ΔI = 2 character, and is explained as being based on a πh11/2⊗[π(g9/2)-2 ⊗ π(g7/2d5/2)2] proton configuration through comparison with cranked Nilsson-Strutinsky model calculations. The calculations predict that this band terminates at a spin of 79/2 (Latin small letter h with stroke).
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| 37. |
- Leoni, S, et al.
(författare)
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Four independent decay properties in the super-deformed well of Eu-143
- 1997
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Ingår i: PHYSICS LETTERS B. - : ELSEVIER SCIENCE BV. - 0370-2693. ; 409:1-4, s. 71-76
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The flow of gamma-transitions through the superdeformed minimum of Eu-143 is investigated by studying the intensities of four different types of gamma-rays of superdeformed origin, obtained with a variety of gating conditions. They can all be explained ra
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| 38. |
- Nelson, Vivianne S., et al.
(författare)
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Platelets in ITP : Victims in charge of their own fate?
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:11
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Forskningsöversikt (refereegranskat)abstract
- Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The pathophysiological mechanisms leading to low platelet levels in ITP have not been resolved, but at least involve autoantibody-dependent and/or cytotoxic T cell mediated platelet clearance and impaired megakary-opoiesis. In addition, T cell imbalances involving T regulatory cells (Tregs) also appear to play an important role. Intriguingly, over the past years it has become evident that platelets not only mediate hemostasis, but are able to modulate inflammatory and immunological processes upon activation. Platelets, therefore, might play an immuno-modulatory role in the pathogenesis and pathophysiology of ITP. In this respect, we propose several possible pathways in which platelets themselves may participate in the immune response in ITP. First, we will elaborate on how platelets might directly promote inflammation or stimulate immune responses in ITP. Second, we will discuss two ways in which platelet microparticles (PMPs) might contribute to the disrupted immune balance and impaired thrombopoiesis by megakaryocytes in ITP. Importantly, from these insights, new starting points for further research and for the design of potential future therapies for ITP can be envisioned.
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| 39. |
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| 40. |
- Spitalnik, Steven L, et al.
(författare)
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2015 proceedings of the National Heart, Lung, and Blood Institute's State of the Science in Transfusion Medicine symposium
- 2015
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Ingår i: Transfusion. - : Wiley. - 1537-2995 .- 0041-1132. ; 55:9, s. 90-2282
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Forskningsöversikt (refereegranskat)abstract
- On March 25 and 26, 2015, the National Heart, Lung, and Blood Institute sponsored a meeting on the State of the Science in Transfusion Medicine on the National Institutes of Health (NIH) campus in Bethesda, Maryland, which was attended by a diverse group of 330 registrants. The meeting's goal was to identify important research questions that could be answered in the next 5 to 10 years and which would have the potential to transform the clinical practice of transfusion medicine. These questions could be addressed by basic, translational, and/or clinical research studies and were focused on four areas: the three "classical" transfusion products (i.e., red blood cells, platelets, and plasma) and blood donor issues. Before the meeting, four working groups, one for each area, prepared five major questions for discussion along with a list of five to 10 additional questions for consideration. At the meeting itself, all of these questions, and others, were discussed in keynote lectures, small-group breakout sessions, and large-group sessions with open discourse involving all meeting attendees. In addition to the final lists of questions, provided herein, the meeting attendees identified multiple overarching, cross-cutting themes that addressed issues common to all four areas; the latter are also provided. It is anticipated that addressing these scientific priorities, with careful attention to the overarching themes, will inform funding priorities developed by the NIH and provide a solid research platform for transforming the future practice of transfusion medicine.
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| 41. |
- Starosta, K., et al.
(författare)
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Smooth band termination at high spin in 113I
- 2001
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Ingår i: Physical Review C - Nuclear Physics. - 0556-2813. ; 64:1, s. 143041-1430419
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Tidskriftsartikel (refereegranskat)abstract
- The 113I nucleus has been studied using the 58Ni(58Ni,3p) reaction at 250 MeV with the Gammasphere/ Microball facility. Gamma-ray three-and four-fold data gated by charged particle combinations were analyzed. Multipolarities of the γ rays were assigned following the angular correlation measurements. The present study is focused on the high spin properties, where the structure is dominated by 2p-2h excitations across the Z=50 gap. Ten decoupled bands showing the features of smooth band termination were observed; three of those bands are linked to known low-spin states, which allows the identification of configurations by direct comparisons with configuration-dependent cranked Nilsson-Strutinsky calculations. The yrast band, which was linked along with the signature partner, was followed up to (101/2+) and ℏω∼1.3 MeV. The other linked band was a negative-parity band observed up to (95/2-). Tentative configurations for the unlinked bands are discussed. Comparisons with the theoretical results suggest that the band built on a configuration involving the neutron i13/2 intruder orbital originating from the N=6 harmonic oscillator subshell was observed in this experiment.
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| 42. |
- Timár, J., et al.
(författare)
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Terminating bands in 98,99,100Ru nuclei : New information on the neutron 2d5/2 and 1g7/2 energy spacing
- 2000
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Ingår i: Physical Review C - Nuclear Physics. - 0556-2813. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- High-spin states of 98,99,100Ru have been populated using the reaction 70Zn(36S, αxn) at 130 MeV. The γ rays have been detected with the EUROGAM-2 array. New high-spin bands have been established in these nuclei and interpreted as terminating configurations using the Nilsson-Strutinsky cranking formalism. These bands were observed up to the predicted terminating states which are built from g9/2 protons and N=3 proton holes combined with d5/2, 87/2, and h11/2 neutrons relative to a 90Zr core. Core-excited configurations with N=3 proton holes have been found to play an important role. The observed high-spin states assigned as terminating show systematic behavior and provide new information on the energy spacing between the 2d5/2 and 1 g7/2 neutron subshells.
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| 43. |
- Van Der Laan, Eveline A.N.Zeeuw, et al.
(författare)
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Biological and structural characterization of murine TRALI antibody reveals increased Fc-mediated complement activation
- 2020
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 4:16, s. 3875-3885
-
Tidskriftsartikel (refereegranskat)abstract
- Transfusion-related acute lung injury (TRALI) remains a leading cause of transfusionrelated deaths. In most cases, anti-leukocyte antibodies in the transfusion product trigger TRALI, but not all anti-leukocyte antibodies cause TRALI. It has been shown that the anti-major histocompatibility complex (MHC) class I antibody 34-1-2S (anti-H-2Kd) causes TRALI in BALB/c mice (MHC class I haplotype H-2Kd), whereas SF1.1.10 (anti-H-2Kd) does not. In C57BL/6 mice (MHC class I haplotype H-2Kb), TRALI only occurs when anti-MHC class I antibody AF6-88.5.5.3 (anti-H-2Kb) is administered together with a high dose of 34-1-2S. It remains unknown which specific antibody characteristics are responsible for eliciting TRALI. We therefore investigated several biological and structural features of 34-1-2S compared with other anti-MHC class I antibodies, which on their own do not cause TRALI: SF1.1.10 and AF6-88.5.5.3. No substantial differences were observed between the TRALIcausing 34-1-2S and the TRALI-resistant SF1.1.10 regarding binding affinity to H-2Kd. Regarding binding affinity to H-2Kb, only AF6-88.5.5.3 potently bound to H-2Kb, whereas 34-1-2S exhibited weak but significant cross-reactivity. Furthermore, the binding affinity to FcgRs as well as the Fc glycan composition seemed to be similar for all antibodies. Similar Fc glycosylation profiles were also observed for human TRALI-causing donor anti-HLA antibodies compared with human anti-HLA antibodies from control donors. 34-1-2S, however, displayed superior complement activation capacity, which was fully Fc dependent and not significantly dependent on Fc glycosylation. We conclude that TRALI induction is not correlated with Fab- A nd Fc-binding affinities for antigen and FcgRs, respectively, nor with the composition of Fc glycans; but increased Fc-mediated complement activation is correlated with TRALI induction.
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| 44. |
- Zeeuw van der Laan, Eveline A.N., et al.
(författare)
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Evaluation of Platelet Responses in Transfusion-Related Acute Lung Injury (TRALI)
- 2020
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Ingår i: Transfusion Medicine Reviews. - : Elsevier BV. - 0887-7963. ; 34:4, s. 227-233
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Forskningsöversikt (refereegranskat)abstract
- Platelets are versatile cells which are capable of eliciting nonhemostatic immune functions, especially under inflammatory conditions. Depending on the specific setting, platelets may be either protective or pathogenic in acute lung injury and acute respiratory distress syndrome (ARDS). Their role in transfusion-related acute lung injury (TRALI) is less well defined; however, it has been hypothesized that recipient platelets and transfused platelets both play a pathogenic role in TRALI. Overall, despite conflicting findings, it appears that recipient platelets may play a pathogenic role in antibody-mediated TRALI; however, their contribution appears to be limited. It is imperative to first validate the involvement of recipient platelets by standardizing the animal models, methods, reagents, and readouts for lung injury and taking the animal housing environment into consideration. For the involvement of transfused platelets in TRALI, it appears that predominantly lipids such as ceramide in stored platelets are able to induce TRALI in animal models. These studies will also need to be validated, and moreover, the platelet-derived lipid-mediated mechanisms leading to TRALI will need to be investigated.
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| 45. |
- Zeeuw van der Laan, Eveline A.N., et al.
(författare)
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Update on the pathophysiology of transfusion-related acute lung injury
- 2020
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Ingår i: Current Opinion in Hematology. - 1531-7048. ; 27:6, s. 386-391
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE OF REVIEW: The aim of this study was to discuss recent advances regarding the pathogenesis of transfusion-related acute lung injury (TRALI), which highlight the pathogenic role of macrophages. RECENT FINDINGS: TRALI remains a leading cause of transfusion-related fatalities, despite the success of the mitigation strategy, and therapeutic approaches are unavailable. Neutrophils (PMNs) are recognized pathogenic cells in TRALI. Macrophages have previously also been suggested to be pathogenic in mice via binding of C5a to their C5a-receptor, producing reactive oxygen species (ROS), which damages the pulmonary endothelium. Recent work has further highlighted the role of macrophages in the TRALI-pathogenesis. It has been shown that the protein osteopontin (OPN) released by macrophages is critical for pulmonary PMN recruitment in mice suffering from TRALI and that targeting OPN prevents the occurrence of TRALI. Another recent study demonstrated the importance of M1-polarized alveolar macrophages in murine TRALI induction by showing that α1-antitrypsin (AAT) overexpression prevented TRALI in mice through decreasing the polarization of alveolar macrophages towards the M1 phenotype. SUMMARY: Apart from PMNs, macrophages also appear to be important in the pathogenesis of TRALI. Targeting the pathogenic functions of macrophages may be a promising therapeutic strategy to explore in TRALI.
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