| 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. |
- 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. |
- 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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| 7. |
- 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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| 8. |
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| 9. |
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| 10. |
- 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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| 11. |
- 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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| 12. |
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| 13. |
- Clark, R M, et al.
(författare)
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Relative deformations of superdeformed bands in Ce-131,Ce-132
- 1996
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 76:19, s. 3510-3513
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Tidskriftsartikel (refereegranskat)abstract
- The quadrupole moments Q(0) of five superdeformed bands in Ce-131,Ce-132 have been established using the Doppler-shift attenuation method; for the first time, we can compare relative deformations of yrast and excited bands in different nuclei to an accuracy of similar or equal to(5-7)%. Four of the five bands have very similar deformations, while the excited band in Ce-131 has a somewhat larger quadrupole moment. Important new information is presented on the shape-driving force of the vi(13/2) orbital, the stability of the second minimum with respect to particle excitations, the relative deformations of identical bands, the nature of the sidefeeding, and the time scale of the decay process.
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| 14. |
- 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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| 15. |
- 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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| 16. |
- Guo, L., et al.
(författare)
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Antiplatelet antibody-induced thrombocytopenia does not correlate with megakaryocyte abnormalities in murine immune thrombocytopenia
- 2018
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475. ; 88:1
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Tidskriftsartikel (refereegranskat)abstract
- Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by increased peripheral immune platelet destruction and megakaryocyte defects in the bone marrow. Although ITP was originally thought to be primarily due to antibody-mediated autoimmunity, it is now clear that T cells also play a significant role in the disease. However, the exact interplay between platelet destruction, megakaryocyte dysfunction and the elements of both humoral and cell-mediated immunity in ITP remains incompletely defined. While most studies have focused on immune platelet destruction in the spleen, an additional possibility is that the antiplatelet antibodies can also destroy bone marrow megakaryocytes. To address this, we negated the effects of T cells by utilizing an in vivo passive ITP model where BALB/c mice were administered various anti-αIIb, anti-β3 or anti-GPIb antibodies or antisera and platelet counts and bone marrow megakaryocytes were enumerated. Our results show that after 24 hours, all the different antiplatelet antibodies/sera induced variable degrees of thrombocytopenia in recipient mice. Compared with naïve control mice, however, histological examination of the bone marrow revealed that only 2 antibody preparations (mouse-anti-mouse β3 sera and an anti- αIIb monoclonal antibody (MWReg30) could affect bone marrow megakaryocyte counts. Our study shows that while most antiplatelet antibodies induce acute thrombocytopenia, the majority of them do not affect the number of megakaryocytes in the bone marrow. This suggests that other mechanisms may be responsible for megakaryocyte abnormalities seen during immune thrombocytopenia.
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| 17. |
- Joss, D T, et al.
(författare)
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Lifetime measurements of a triaxial band in Ce-133
- 1998
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Ingår i: Acta Physica Hungarica A. - 1219-7580 .- 1588-2675. ; 7:1, s. 111-112
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Tidskriftsartikel (refereegranskat)abstract
- The Doppler shift attenuation method has been used to determine the transition quadrupole moment of a triaxial band belonging to the gamma-soft nucleus, Ce-133. Doppler broadened lineshape (DBLS) analysis has revealed the magnitude of the Q(t) value to be similar to 2.4 eb. This contribution provides new information of (i) the transition quadrupole moment of this band (ii) the lifetimes of in-band and sidefeeding transitions and (iii) the relative deformations of coexisting nuclear shapes.
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| 18. |
- Joss, D T, et al.
(författare)
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Lifetime measurements of a triaxial band in Ce-133
- 1998
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 58:6, s. 3219-3222
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Tidskriftsartikel (refereegranskat)abstract
- Lifetimes of states within a triaxial band belonging to;the gamma-soft nucleus Ce-133 have been determined through a Doppler-broadened line shape analysis. A value, Q(t)approximate to 2.2 eb, has been found for the transition quadrupole moment which is considerably smaller than that of superdeformed structures (Q(t)approximate to 7.4 e b) in this mass region. The results are discussed in terms of deformation self-consistent calculations based on the total Routhian surface formalism. [S0556-2813(98)01912-8].
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| 19. |
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| 20. |
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| 21. |
- 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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| 22. |
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| 23. |
- Zufferey, Anne, et al.
(författare)
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Mature murine megakaryocytes present antigen-MHC class I molecules to T cells and transfer them to platelets
- 2017
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:20, s. 1773-1785
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Tidskriftsartikel (refereegranskat)abstract
- Megakaryocytes (MKs) are bone marrow-derived cells that are primarily responsible for generating platelets for the maintenance of hemostasis. Although MK can variably express major histocompatibility complex (MHC) class I and II molecules during their differentiation, little is known whether they can elicit nonhemostatic immune functions such as T-cell activation. Here, we demonstrate that mature CD342 MHC class II2 CD411 MKs can endocytose exogenous ovalbumin (OVA) and proteolytically generate its immunogenic peptide ligand, which is crosspresented on their surface in association with MHC class I molecules. This crosspresentation triggered in vitro and in vivo OVA-specific CD81 T-cell activation and proliferation. In addition, the OVA-MHC class I complexes were transferred from MK to pro-platelets upon thrombopoiesis in vitro. MK could also present endogenous MK-associated (CD61) peptides to activate CD61-specific CD81 T cells and mediate immune thrombocytopenia in vivo. These results suggest that, in addition to their hemostatic role, mature MKs can significantly affect antigen-specific CD81 T-cell responses via antigen presentation and are able to spread this immunogenic information through platelets.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Crow, Andrew R., et al.
(författare)
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Treating murine inflammatory diseases with an anti-erythrocyte antibody
- 2019
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:506
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of autoimmune and inflammatory diseases typically involves immune suppression. In an opposite strategy, we show that administration of the highly inflammatory erythrocyte-specific antibody Ter119 into mice remodels the monocyte cellular landscape, leading to resolution of inflammatory disease. Ter119 with intact Fc function was unexpectedly therapeutic in the K/BxN serum transfer model of arthritis. Similarly, it rapidly reversed clinical disease progression in collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis and completely corrected CAIA-induced increase in monocyte Fcγ receptor II/III expression. Ter119 dose-dependently induced plasma chemokines CCL2, CCL5, CXCL9, CXCL10, and CCL11 with corresponding alterations in monocyte percentages in the blood and liver within 24 hours. Ter119 attenuated chemokine production from the synovial fluid and prevented the accumulation of inflammatory cells and complement components in the synovium. Ter119 could also accelerate the resolution of hypothermia and pulmonary edema in an acute lung injury model. We conclude that this inflammatory anti-erythrocyte antibody simultaneously triggers a highly efficient anti-inflammatory effect with broad therapeutic potential.
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| 28. |
- 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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| 29. |
- Fink, R, et al.
(författare)
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Cobalt/copper multilayers studied by perturbed gamma-gamma angular correlation spectroscopy
- 1996
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Ingår i: SURFACE SCIENCE. - : ELSEVIER SCIENCE BV. - 0039-6028. ; 355:1-3, s. 47-62
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Thin films and multilayers of cobalt on Cu(100) and Cu(111) have been studied using the time-differential perturbed gamma-gamma angular correlation (PAC) technique. The In-111 probe isotopes were found to migrate to the surface of the film when new layers
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| 30. |
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| 31. |
- Jongruamklang, Philaiphon, et al.
(författare)
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Platelets inhibit erythrocyte invasion by Plasmodium falciparum at physiological platelet:erythrocyte ratios
- 2022
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Ingår i: Transfusion Medicine. - : Wiley. - 0958-7578 .- 1365-3148. ; 32:2, s. 168-174
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate the effect of platelet:erythrocyte (P:E) ratios on Plasmodium falciparum erythrocyte invasion.BACKGROUND: Recent reports have shown that platelets are directly involved in the immune response towards P. falciparum during erythrocyte invasion. However, the literature both supports and conflicts with a role for platelets in limiting invasion. Also, the effect of platelet numbers on invasion (parasitemia) has not been thoroughly investigated.METHODS/MATERIALS: The P. falciparum strains FCR3S1.2 and W2mef were cultured with group O erythrocytes. The cultures were synchronised and supplemented with pooled platelets at P:E ratios ranging from 1:100 to 1:2. Parasitemia was measured at 40 h by flow cytometry and by microscopy of blood smears.RESULTS: A linear relationship was observed between reduced invasion and increased platelet numbers at P:E ratios ranging from 1:100 to 1:20. However, this effect was reversed at lower ratios (1:10-1:2). Microscopic evaluation revealed aggregation and attachment of platelets to erythrocytes, but not specifically to parasitised erythrocytes.CONCLUSION: We have shown that under physiological P:E ratios (approx. 1:10-1:40), platelets inhibited P. falciparum invasion in a dose-dependent manner. At ratios of 1:10 and below, platelets did not further increase the inhibitory effect and, although the trend was reversed, inhibition was still maintained.
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| 32. |
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| 33. |
- Kapur, Rick, et al.
(författare)
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Gastrointestinal microbiota contributes to the development of murine transfusion-related acute lung injury
- 2018
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 2:13, s. 1651-1663
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Tidskriftsartikel (refereegranskat)abstract
- Transfusion-related acute lung injury (TRALI) is a syndrome of respiratory distress upon blood transfusion and is the leading cause of transfusion-related fatalities. Whether the gut microbiota plays any role in the development of TRALI is currently unknown. We observed that untreated barrier-free (BF) mice suffered from severe antibody-mediated acute lung injury, whereas the more sterile housed specific pathogen-free (SPF) mice and gut flora-depleted BF mice were both protected from lung injury. The prevention of TRALI in the SPF mice and gut flora-depleted BF mice was associated with decreased plasma macrophage inflammatory protein-2 levels as well as decreased pulmonary neutrophil accumulation. DNA sequencing of amplicons of the 16S ribosomal RNA gene revealed a varying gastrointestinal bacterial composition between BF and SPF mice. BF fecal matter transferred into SPF mice significantly restored TRALI susceptibility in SPF mice. These data reveal a link between the gut flora composition and the development of antibody-mediated TRALI in mice. Assessment of gut microbial composition may help in TRALI risk assessment before transfusion.
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| 34. |
- Kapur, Rick, et al.
(författare)
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T regulatory cells and dendritic cells protect against transfusion-related acute lung injury via IL-10
- 2017
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 129:18, s. 2557-2569
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Tidskriftsartikel (refereegranskat)abstract
- Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related fatalities and is characterized by acute respiratory distress following blood transfusion. Donor antibodies are frequently involved; however, the pathogenesis and protective mechanisms in the recipient are poorly understood, and specific therapies are lacking. Using newly developed murine TRALI models based on injection of anti-major histocompatibility complex class I antibodies, we found CD4+CD25+FoxP3+ T regulatory cells (Tregs) and CD11c+ dendritic cells (DCs) to be critical effectors that protect against TRALI. Treg or DC depletion in vivo resulted in aggravated antibody-mediated acute lung injury within 90 minutes with 60% mortality upon DC depletion. In addition, resistance to antibody-mediated TRALI was associated with increased interleukin-10 (IL-10) levels, and IL-10 levels were found to be decreased in mice suffering from TRALI. Importantly, IL-10 injection completely prevented and rescued the development of TRALI in mice and may prove to be a promising new therapeutic approach for alleviating lung injury in this serious complication of transfusion.
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| 35. |
- Kapur, Rick, et al.
(författare)
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Thrombopoietin receptor agonist (TPO-RA) treatment raises platelet counts and reduces anti-platelet antibody levels in mice with immune thrombocytopenia (ITP)
- 2020
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Ingår i: Platelets. - : Informa UK Limited. - 0953-7104 .- 1369-1635. ; 31:3, s. 399-402
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Tidskriftsartikel (refereegranskat)abstract
- Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder in which autoantibodies and/or autoreactive T cells destroy platelets and megakaryocytes in the spleen and bone marrow, respectively. Thrombopoietin receptor agonists (TPO-RA e.g. Romiplostim and Eltrombopag) have made a substantial contribution to the treatment of patients with ITP, which are refractory to first-line treatments and approximately 30% demonstrate sustained elevated platelet counts after drug tapering. How TPO-RA induce these sustained responses is not known. We analyzed the efficacy of a murine TPO-RA in a well-established murine model of active ITP. Treatment with TPO-RA (10 ug/kg, based on pilot dose escalation experiments) significantly raised the platelet counts in ITP-mice. Immunomodulation was assessed by measuring serum IgG anti-platelet antibody levels; TPO-RA-treated mice had significantly reduced IgG anti-platelet antibodies despite the increasing platelet counts. These results suggest that TPO-RA is not only an efficacious therapy but also reduces anti-platelet humoral immunity in ITP.
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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. |
- Lotta, Luca A., et al.
(författare)
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Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 17-26
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
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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. |
- 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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| 41. |
- 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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| 42. |
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| 43. |
- SEMPLE, M, et al.
(författare)
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MOSSPAC - A UHV-SYSTEM FOR SURFACE AND THIN-FILM INVESTIGATIONS USING NUCLEAR PROBES
- 1995
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Ingår i: VACUUM. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0042-207X. ; 46:8-10, s. 1049-1052
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A UHV-system constructed for surface, thin film and superlattice measurements, using the time-differential perturbed gamma-gamma angular correlations (DPAC) and Mossbauer spectroscopy techniques, is described. Sample preparation is discussed, particularly
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| 44. |
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| 45. |
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| 46. |
- Slingsby, Martina H.Lundberg, et al.
(författare)
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Sequence-specific 2'-O-methoxyethyl antisense oligonucleotides activate human platelets through glycoprotein VI, triggering formation of platelet-leukocyte aggregates
- 2022
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 107:2, s. 519-531
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Tidskriftsartikel (refereegranskat)abstract
- Antisense oligonucleotides (ASO) are DNA-based, disease-modifying drugs. Clinical trials with 2'-O-methoxyethyl (2'MOE) ASO have shown dose- A nd sequence-specific lowering of platelet counts according to two phenotypes. Phenotype 1 is a moderate (but not clinically severe) drop in platelet count. Phenotype 2 is rare, severe thrombocytopenia. This article focuses on the underlying cause of the more common phenotype 1, investigating the effects of ASO on platelet production and platelet function. Five phosphorothioate ASO were studied: Three 2'MOE sequences; 487660 (no effects on platelet count), 104838 (associated with phenotype 1), and 501861 (effects unknown) and two CpG sequences; 120704 and ODN 2395 (known to activate platelets). Human cord bloodderived megakaryocytes were treated with these ASO to study their effects on proplatelet production. Platelet activation (determined by surface Pselectin) and platelet-leukocyte aggregates were analyzed in ASO-treated blood from healthy human volunteers. None of the ASO inhibited proplatelet production by human megakaryocytes. All the ASO were shown to bind to the platelet receptor glycoprotein VI (KD ∼0.2-1.5 mM). CpG ASO had the highest affinity to glycoprotein VI, the most potent platelet-activating effects and led to the greatest formation of platelet-leukocyte aggregates. 2'MOE ASO 487660 had no detectable platelet effects, while 2'MOE ASOs 104838 and 501861 triggered moderate platelet activation and SYKdependent formation of platelet-leukocyte aggregates. Donors with higher platelet glycoprotein VI levels had greater ASO-induced platelet activation. Sequence-dependent ASO-induced platelet activation and platelet-leukocyte aggregates may explain phenotype 1 (moderate drops in platelet count). Platelet glycoprotein VI levels could be useful as a screening tool to identify patients at higher risk of ASO-induced platelet side effects.
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| 47. |
- 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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| 48. |
- 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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| 49. |
- Yaghootkar, Hanieh, et al.
(författare)
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Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes.
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:10, s. 3589-3598
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Tidskriftsartikel (refereegranskat)abstract
- Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
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