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Sökning: WFRF:(Cavalli Marco)

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1.
  • 2019
  • Tidskriftsartikel (refereegranskat)
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2.
  • Aad, G, et al. (författare)
  • 2015
  • swepub:Mat__t
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3.
  • Schael, S, et al. (författare)
  • Precision electroweak measurements on the Z resonance
  • 2006
  • Ingår i: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 427:5-6, s. 257-454
  • Forskningsöversikt (refereegranskat)abstract
    • We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron-positron colliders SLC and LEP. The data consist of 17 million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLID experiment using a polarised beam at SLC. The measurements include cross-sections, forward-backward asymmetries and polarised asymmetries. The mass and width of the Z boson, m(Z) and Gamma(Z), and its couplings to fermions, for example the p parameter and the effective electroweak mixing angle for leptons, are precisely measured: m(Z) = 91.1875 +/- 0.0021 GeV, Gamma(Z) = 2.4952 +/- 0.0023 GeV, rho(l) = 1.0050 +/- 0.0010, sin(2)theta(eff)(lept) = 0.23153 +/- 0.00016. The number of light neutrino species is determined to be 2.9840 +/- 0.0082, in agreement with the three observed generations of fundamental fermions. The results are compared to the predictions of the Standard Model (SM). At the Z-pole, electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward-backward asymmetry in b-quark production shows the largest difference with respect to its SM expectation, at the level of 2.8 standard deviations. Through radiative corrections evaluated in the framework of the Standard Model, the Z-pole data are also used to predict the mass of the top quark, m(t) = 173(+10)(+13) GeV, and the mass of the W boson, m(W) = 80.363 +/- 0.032 GeV. These indirect constraints are compared to the direct measurements, providing a stringent test of the SM. Using in addition the direct measurements of m(t) and m(W), the mass of the as yet unobserved SM Higgs boson is predicted with a relative uncertainty of about 50% and found to be less than 285 GeV at 95% confidence level. (c) 2006 Elsevier B.V. All rights reserved.
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4.
  • Aad, G., et al. (författare)
  • 2015
  • Tidskriftsartikel (refereegranskat)
  •  
5.
  • Ahlmér, Anna Klara, et al. (författare)
  • Soil moisture remote-sensing applications for identification of flood-prone areas along transport infrastructure
  • 2018
  • Ingår i: Environmental Earth Sciences. - : Springer. - 1866-6280 .- 1866-6299. ; 77:14
  • Tidskriftsartikel (refereegranskat)abstract
    • The expected increase in precipitation and temperature in Scandinavia, and especially short-time heavy precipitation, will increase the frequency of flooding. Urban areas are the most vulnerable, and specifically, the road infrastructure. The accumulation of large volumes of water and sediments on road-stream intersections gets severe consequences for the road drainage structures. This study integrates the spatial and temporal soil moisture properties into the research about flood prediction methods by a case study of two areas in Sweden, Vastra Gotaland and Varmland, which was affected by severe flooding in August 2014. Soil moisture data are derived from remote-sensing techniques, with a focus on the soil moisture-specific satellites ASCAT and SMOS. Furthermore, several physical catchments descriptors (PCDs) are analyzed and the result shows that larger slopes and drainage density, in general, mean a higher risk of flooding. The precipitation is the same; however, it can be concluded that more precipitation in most cases gives higher soil moisture values. The lack, or the dimensioning, of road drainage structures seems to have a large impact on the flood risk as more sediment and water can be accumulated at the road-stream intersection. The results show that the method implementing soil moisture satellite data is promising for improving the reliability of flooding.
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6.
  • Castillejo-López, Casimiro, et al. (författare)
  • A regulatory element associated to NAFLD in the promoter of DIO1 controls LDL-C, HDL-C and triglycerides in hepatic cells
  • 2024
  • Ingår i: Lipids in Health and Disease. - : BioMed Central (BMC). - 1476-511X. ; 23
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Genome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers.METHODS: CRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants.RESULTS: The candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides.CONCLUSIONS: This comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients.
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7.
  • Cavalli, Marco, et al. (författare)
  • A Multi-Omics Approach to Liver Diseases : Integration of Single Nuclei Transcriptomics with Proteomics and HiCap Bulk Data in Human Liver
  • 2020
  • Ingår i: Omics. - : Mary Ann Liebert Inc. - 1536-2310 .- 1557-8100. ; 24:4, s. 180-194
  • Tidskriftsartikel (refereegranskat)abstract
    • The liver is the largest solid organ and a primary metabolic hub. In recent years, intact cell nuclei were used to perform single-nuclei RNA-seq (snRNA-seq) for tissues difficult to dissociate and for flash-frozen archived tissue samples to discover unknown and rare cell subpopulations. In this study, we performed snRNA-seq of a liver sample to identify subpopulations of cells based on nuclear transcriptomics. In 4282 single nuclei, we detected, on average, 1377 active genes and we identified seven major cell types. We integrated data from 94,286 distal interactions (p < 0.05) for 7682 promoters from a targeted chromosome conformation capture technique (HiCap) and mass spectrometry proteomics for the same liver sample. We observed a reasonable correlation between proteomics and in silico bulk snRNA-seq (r = 0.47) using tissue-independent gene-specific protein abundancy estimation factors. We specifically looked at genes of medical importance. The DPYD gene is involved in the pharmacogenetics of fluoropyrimidine toxicity and some of its variants are analyzed for clinical purposes. We identified a new putative polymorphic regulatory element, which may contribute to variation in toxicity. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and we investigated all known risk genes. We identified a complex regulatory landscape for the SLC2A2 gene with 16 candidate enhancers. Three of them harbor somatic motif breaking and other mutations in HCC in the Pan Cancer Analysis of Whole Genomes dataset and are candidates to contribute to malignancy. Our results highlight the potential of a multi-omics approach in the study of human diseases.
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8.
  • Cavalli, Marco, et al. (författare)
  • Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases
  • 2019
  • Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Several Genome Wide Association Studies (GWAS) have reported variants associated to immune diseases. However, the identified variants are rarely the drivers of the associations and the molecular mechanisms behind the genetic contributions remain poorly understood. ChIP-seq data for TFs and histone modifications provide snapshots of protein-DNA interactions allowing the identification of heterozygous SNPs showing significant allele specific signals (AS-SNPs). AS-SNPs can change a TF binding site resulting in altered gene regulation and are primary candidates to explain associations observed in GWAS and expression studies. We identified 17,293 unique AS-SNPs across 7 lymphoblastoid cell lines. In this set of cell lines we interrogated 85% of common genetic variants in the population for potential regulatory effect and we identified 237 AS-SNPs associated to immune GWAS traits and 714 to gene expression in B cells. To elucidate possible regulatory mechanisms we integrated long-range 3D interactions data to identify putative target genes and motif predictions to identify TFs whose binding may be affected by AS-SNPs yielding a collection of 173 AS-SNPs associated to gene expression and 60 to B cell related traits. We present a systems strategy to find functional gene regulatory variants, the TFs that bind differentially between alleles and novel strategies to detect the regulated genes.
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9.
  • Cavalli, Marco, et al. (författare)
  • Allele-specific transcription factor binding in liver and cervix cells unveils many likely drivers of GWAS signals
  • 2016
  • Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 107:6, s. 248-254
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) point to regions with associated genetic variants but rarely to a specific gene and therefore detailed knowledge regarding the genes contributing to complex traits and diseases remains elusive. The functional role of GWAS-SNPs is also affected by linkage disequilibrium with many variants on the same haplotype and sometimes in the same regulatory element almost equally likely to mediate the effect. Using ChIP-seq data on many transcription factors, we pinpointed genetic variants in HepG2 and HeLa-S3 cell lines which show a genome-wide significant difference in binding between alleles. We identified a collection of 3713 candidate functional regulatory variants many of which are likely drivers of GWAS signals or genetic difference in expression. A recent study investigated many variants before finding the functional ones at the GALNT2 locus, which we found in our genome-wide screen in HepG2. This illustrates the efficiency of our approach.
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10.
  • Cavalli, Marco, et al. (författare)
  • Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression
  • 2016
  • Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 135:5, s. 485-497
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have identified a large number of disease-associated SNPs, but in few cases the functional variant and the gene it controls have been identified. To systematically identify candidate regulatory variants, we sequenced ENCODE cell lines and used public ChIP-seq data to look for transcription factors binding preferentially to one allele. We found 9962 candidate regulatory SNPs, of which 16 % were rare and showed evidence of larger functional effect than common ones. Functionally rare variants may explain divergent GWAS results between populations and are candidates for a partial explanation of the missing heritability. The majority of allele-specific variants (96 %) were specific to a cell type. Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types. Functionally validated SNPs support identification of an SNP in SYNGR1 which may expose to the risk of rheumatoid arthritis and primary biliary cirrhosis, as well as an SNP in the last intron of COG6 exposing to the risk of psoriasis. We propose that by repeating the ChIP-seq experiments of 20 selected transcription factors in three to ten people, the most common polymorphisms can be interrogated for allele-specific binding. Our strategy may help to remove the current bottleneck in functional annotation of the genome.
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11.
  • Cavalli, Marco, et al. (författare)
  • Genetic prevention of hepatitis C virus-induced liver fibrosis by allele-specific downregulation of MERTK
  • 2017
  • Ingår i: Hepatology Research. - : Wiley. - 1386-6346 .- 1872-034X. ; 47:8, s. 826-830
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: Infection by hepatitis C virus (HCV) can result in the development of liver fibrosis and may eventually progress into cirrhosis and hepatocellular carcinoma. However, the molecular mechanisms for this process are not fully known. Several genome-wide association studies have been carried out to pinpoint causative variants in HCV-infected patient cohorts, but these variants are usually not the functional ones. The aim of this study was to identify the regulatory single nucleotide polymorphism associated with the risk of HCV-induced liver fibrosis and elucidate its molecular mechanism.METHODS: We utilized a bioinformatics approach to identify a non-coding regulatory variant, located in an intron of the MERTK gene, based on differential transcription factor binding between the alleles. We validated the results using expression reporter assays and electrophoresis mobility shift assays.RESULTS: Chromatin immunoprecipitation sequencing indicated that transcription factor(s) bind stronger to the A allele of rs6726639. Electrophoresis mobility shift assays supported these findings and suggested that the transcription factor is interferon regulatory factor 1 (IRF1). Luciferase report assays showed lower enhancer activity from the A allele and that IRF1 may act as a repressor.CONCLUSIONS: Treatment of hepatitis C with interferon-α results in increased IRF1 levels and our data suggest that this leads to an allele-specific downregulation of MERTK mediated by an allelic effect on the regulatory element containing the functional rs6726639. This variant also shows the hallmarks for being the driver of the genome-wide association studies for reduced risk of liver fibrosis and non-alcoholic fatty liver disease at MERTK.
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12.
  • Cavalli, Marco, et al. (författare)
  • Genome-wide association study of liver enzyme elevation in an extended cohort of rheumatoid arthritis patients starting low-dose methotrexate
  • 2022
  • Ingår i: Pharmacogenomics (London). - : Future Medicine. - 1462-2416 .- 1744-8042. ; 23:15, s. 813-820
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: A follow-up genome-wide association study (GWAS) in an extended cohort of rheumatoid arthritis (RA) patients starting low-dose methotrexate (MTX) treatment was performed to identify further genetic variants associated with alanine aminotransferase (ALT) elevation. Patients & methods: A GWAS was performed on 346 RA patients. Two outcomes within the first 6 months of MTX treatment were assessed: ALT >1.5-times the upper level of normal (ULN) and maximum level of ALT. Results: SPATA9 (rs72783407) was significantly associated with maximum level of ALT (p = 2.58 × 10-8) and PLCG2 (rs60427389) was tentatively associated with ALT >1.5 × ULN. Conclusion: Associations with SNPs in genes related to male fertility (SPATA9) and inflammatory processes (PLCG2) were identified.
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13.
  • Cavalli, Marco, et al. (författare)
  • Looking beyond GWAS : allele-specific transcription factor binding drives the association of GALNT2 to HDL-C plasma levels
  • 2016
  • Ingår i: Lipids in Health and Disease. - : Springer Science and Business Media LLC. - 1476-511X. ; 15
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Plasma levels of high-density lipoprotein cholesterol (HDL-C) have been associated to cardiovascular disease. The high heritability of HDL-C plasma levels has been an incentive for several genome wide association studies (GWASs) which identified, among others, variants in the first intron of the GALNT2 gene strongly associated to HDL-C levels. However, the lead GWAS SNP associated to HDL-C levels in this genomic region, rs4846914, is located outside of transcription factor (TF) binding sites defined by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) experiments in the ENCODE project and is therefore unlikely to be functional. In this study we apply a bioinformatics approach which rely on the premise that ChIP-seq reads can identify allele specific binding of a TF at cell specific regulatory elements harboring allele specific SNPs (AS-SNPs). EMSA and luciferase assays were used to validate the allele specific binding and to test the enhancer activity of the regulatory element harboring the AS-SNP rs4846913 as well as the neighboring rs2144300 which are in high LD with rs4846914. Findings: Using luciferase assays we found that rs4846913 and the neighboring rs2144300 displayed allele specific enhancer activity. We propose that an inhibitor binds preferentially to the rs4846913-C allele with an inhibitory boost from the synergistic binding of other TFs at the neighboring SNP rs2144300. These events influence the transcription level of GALNT2. Conclusions: The results suggest that rs4846913 and rs2144300 drive the association to HDL-C plasma levels through an inhibitory regulation of GALNT2 rather than the reported lead GWAS SNP rs4846914.
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14.
  • Cavalli, Marco, et al. (författare)
  • Novel regulatory variant detected on the VKORC1 haplotype that is associated with warfarin dose
  • 2016
  • Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 17:12, s. 1305-1314
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: Warfarin dose requirement is associated with VKORC1 rs9923231, and we studied whether it is a functional variant.Materials & methods: We selected variants in linkage disequilibrium with rs9923231 that bind transcription factors in an allele-specific way. Representative haplotypes were cloned or constructed, nuclear protein binding and transcriptional activity were evaluated.Results: rs56314408C>T and rs2032915C>T were detected in a liver enhancer in linkage disequilibrium with rs9923231. The rs56314408-rs2032915 C-C haplotype preferentially bound nuclear proteins and had higher transcriptional activity than T-T and the African-specific T-C. A motif for TFAP2A/C was disrupted by rs56314408T. No difference in transcriptional activity was detected for rs9923231G>A.Conclusion: Our results supported an activating role for rs56314408C, while rs9923231G>A had no evidence of being functional.
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15.
  • Cavalli, Marco, et al. (författare)
  • Single Nuclei Transcriptome Analysis of Human Liver with Integration of Proteomics and Capture Hi-C Bulk Tissue Data
  • Tidskriftsartikel (refereegranskat)abstract
    • The liver is the largest solid organ and a primary metabolic hub. In recent years, intact cell nuclei were used to perform single-nuclei RNA-seq (snRNA-seq) for tissues difficult to dissociate and for flash-frozen archived tissue samples to discover unknown and rare cell sub-populations. In this study, we performed snRNA-seq of a liver sample to identify sub-populations of cells based on nuclear transcriptomics. In 4,282 single nuclei we detected on average 1,377 active genes and we identified seven major cell types. We integrated data from 94,286 distal interactions (p<0.05) for 7,682 promoters from a targeted chromosome conformation capture technique (HiCap) and mass spectrometry (MS) proteomics for the same liver sample. We observed a reasonable correlation between proteomics and in silico bulk snRNA-seq (r=0.47) using tissue-independent gene-specific protein abundancy estimation factors. We specifically looked at genes of medical importance. The DPYD gene is involved in the pharmacogenetics of fluoropyrimidines toxicity and some of its variants are analyzed for clinical purposes. We identified a new putative polymorphic regulatory element, which may contribute to variation in toxicity. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and we investigated all known risk genes. We found a complex regulatory network for the SLC2A2 gene with 16 candidate enhancers. Three of them harbor somatic motif breaking and other mutations in HCC in the Pan Cancer Analysis of Whole Genomes dataset and are candidates to contribute to malignancy. Our results highlight the potential of a multi-omics approach in the study of human diseases.
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16.
  • Cavalli, Marco, et al. (författare)
  • Studies of liver tissue identify functional gene regulatory elements associated to gene expression, type 2 diabetes, and other metabolic diseases
  • 2019
  • Ingår i: Human Genomics. - : Springer Science and Business Media LLC. - 1473-9542 .- 1479-7364. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:Genome-wide association studies (GWAS) of diseases and traits have found associations to gene regions but not the functional SNP or the gene mediating the effect. Difference in gene regulatory signals can be detected using chromatin immunoprecipitation and next-gen sequencing (ChIP-seq) of transcription factors or histone modifications by aligning reads to known polymorphisms in individual genomes. The aim was to identify such regulatory elements in the human liver to understand the genetics behind type 2 diabetes and metabolic diseases.Methods: The genome of liver tissue was sequenced using 10X Genomics technology to call polymorphic positions. Using ChIP-seq for two histone modifications, H3K4me3 and H3K27ac, and the transcription factor CTCF, and our established bioinformatics pipeline, we detected sites with significant difference in signal between the alleles.Results:We detected 2329 allele-specific SNPs (AS-SNPs) including 25 associated to GWAS SNPs linked to liver biology, e.g., 4 AS-SNPs at two type 2 diabetes loci. Two hundred ninety-two AS-SNPs were associated to liver gene expression in GTEx, and 134 AS-SNPs were located on 166 candidate functional motifs and most of them in EGR1-binding sites.Conclusions:This study provides a valuable collection of candidate liver regulatory elements for further experimental validation.
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17.
  • Cavalli, Marco, et al. (författare)
  • The Thioesterase ACOT1 as a Regulator of Lipid Metabolism in Type 2 Diabetes Detected in a Multi-Omics Study of Human Liver
  • 2021
  • Ingår i: Omics. - : Mary Ann Liebert. - 1536-2310 .- 1557-8100. ; 25:10, s. 652-659
  • Tidskriftsartikel (refereegranskat)abstract
    • Type 2 diabetes (T2D) is characterized by pathophysiological alterations in lipid metabolism. One strategy to understand the molecular mechanisms behind these abnormalities is to identify cis-regulatory elements (CREs) located in chromatin-accessible regions of the genome that regulate key genes. In this study we integrated assay for transposase-accessible chromatin followed by sequencing (ATAC-seq) data, widely used to decode chromatin accessibility, with multi-omics data and publicly available CRE databases to identify candidate CREs associated with T2D for further experimental validations. We performed high-sensitive ATAC-seq in nine human liver samples from normal and T2D donors, and identified a set of differentially accessible regions (DARs). We identified seven DARs including a candidate enhancer for the ACOT1 gene that regulates the balance of acyl-CoA and free fatty acids (FFAs) in the cytoplasm. The relevance of ACOT1 regulation in T2D was supported by the analysis of transcriptomics and proteomics data in liver tissue. Long-chain acyl-CoA thioesterases (ACOTs) are a group of enzymes that hydrolyze acyl-CoA esters to FFAs and coenzyme A. ACOTs have been associated with regulation of triglyceride levels, fatty acid oxidation, mitochondrial function, and insulin signaling, linking their regulation to the pathogenesis of T2D. Our strategy integrating chromatin accessibility with DNA binding and other types of omics provides novel insights on the role of genetic regulation in T2D and is extendable to other complex multifactorial diseases.
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18.
  • Diamanti, Klev, 1987-, et al. (författare)
  • Integration of whole-body [18F]FDG PET/MRI with non-targeted metabolomics can provide new insights on tissue-specific insulin resistance in type 2 diabetes
  • 2020
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Alteration of various metabolites has been linked to type 2 diabetes (T2D) and insulin resistance. However, identifying significant associations between metabolites and tissue-specific phenotypes requires a multi-omics approach. In a cohort of 42 subjects with different levels of glucose tolerance (normal, prediabetes and T2D) matched for age and body mass index, we calculated associations between parameters of whole-body positron emission tomography (PET)/magnetic resonance imaging (MRI) during hyperinsulinemic euglycemic clamp and non-targeted metabolomics profiling for subcutaneous adipose tissue (SAT) and plasma. Plasma metabolomics profiling revealed that hepatic fat content was positively associated with tyrosine, and negatively associated with lysoPC(P-16:0). Visceral adipose tissue (VAT) and SAT insulin sensitivity (Ki), were positively associated with several lysophospholipids, while the opposite applied to branched-chain amino acids. The adipose tissue metabolomics revealed a positive association between non-esterified fatty acids and, VAT and liver Ki. Bile acids and carnitines in adipose tissue were inversely associated with VAT Ki. Furthermore, we detected several metabolites that were significantly higher in T2D than normal/prediabetes. In this study we present novel associations between several metabolites from SAT and plasma with the fat fraction, volume and insulin sensitivity of various tissues throughout the body, demonstrating the benefit of an integrative multi-omics approach.
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19.
  • Diamanti, Klev, 1987-, et al. (författare)
  • Integration of whole-body PET/MRI with non-targeted metabolomics provides new insights into insulin sensitivity of various tissues
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Alteration of various metabolites has been linked to type 2 diabetes (T2D) and insulin resistance. However, identifying significant associations between metabolites and tissue-specific alterations is challenging and requires a multi-omics approach. In this study, we aimed at discovering associations of metabolites from subcutaneous adipose tissue (SAT) and plasma with the volume, the fat fraction (FF) and the insulin sensitivity (Ki) of specific tissues using [18F]FDG PET/MRI.Materials and Methods: In a cohort of 42 subjects with different levels of glucose tolerance (normal, prediabetes and T2D) matched for age and body-mass-index (BMI) we calculated associations between parameters of whole-body FDG PET/MRI during clamp and non-targeted metabolomics profiling for SAT and blood plasma. We also used a rule-based classifier to identify a large collection of prevalent patterns of co-dependent metabolites that characterize non-diabetes (ND) and T2D.Results: The plasma metabolomics profiling revealed that hepatic fat content was positively associated with tyrosine, and negatively associated with lysoPC(P-16:0). Ki in visceral adipose tissue (VAT) and SAT, was positively associated with several species of lysophospholipids while the opposite applied to branched-chain amino acids (BCAA) and their intermediates. The adipose tissue metabolomics revealed a positive association between non-esterified fatty acids and, VAT and liver Ki. On the contrary, bile acids and carnitines in adipose tissue were inversely associated with VAT Ki. Finally, we presented a transparent machine-learning model that predicted ND or T2D in “unseen” data with an accuracy of 78%.Conclusions: Novel associations of several metabolites from SAT and plasma with the FF, volume and insulin senstivity of various tissues throughout the body were discovered using PET/MRI and a new integrative multi-omics approach. A promising computational model that predicted ND and T2D with high certainty, suggested novel non-linear interdependencies of metabolites.
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20.
  • Diamanti, Klev, et al. (författare)
  • Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes
  • 2019
  • Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 9653-
  • Tidskriftsartikel (refereegranskat)abstract
    • Type 2 diabetes (T2D) mellitus is a complex metabolic disease commonly caused by insulin resistance in several tissues. We performed a matched two-dimensional metabolic screening in tissue samples from 43 multi-organ donors. The intra-individual analysis was assessed across five key metabolic tissues (serum, visceral adipose tissue, liver, pancreatic islets and skeletal muscle), and the inter-individual across three different groups reflecting T2D progression. We identified 92 metabolites differing significantly between non-diabetes and T2D subjects. In diabetes cases, carnitines were significantly higher in liver, while lysophosphatidylcholines were significantly lower in muscle and serum. We tracked the primary tissue of origin for multiple metabolites whose alterations were reflected in serum. An investigation of three major stages spanning from controls, to pre-diabetes and to overt T2D indicated that a subset of lysophosphatidylcholines was significantly lower in the muscle of pre-diabetes subjects. Moreover, glycodeoxycholic acid was significantly higher in liver of pre-diabetes subjects while additional increase in T2D was insignificant. We confirmed many previously reported findings and substantially expanded on them with altered markers for early and overt T2D. Overall, the analysis of this unique dataset can increase the understanding of the metabolic interplay between organs in the development of T2D.
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21.
  • Diamanti, Klev, et al. (författare)
  • Maps of context-dependent putative regulatory regions and genomic signal interactions
  • 2016
  • Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 44:19, s. 9110-9120
  • Tidskriftsartikel (refereegranskat)abstract
    • Gene transcription is regulated mainly by transcription factors (TFs). ENCODE and Roadmap Epigenomics provide global binding profiles of TFs, which can be used to identify regulatory regions. To this end we implemented a method to systematically construct cell-type and species-specific maps of regulatory regions and TF-TF interactions. We illustrated the approach by developing maps for five human cell-lines and two other species. We detected similar to 144k putative regulatory regions among the human cell-lines, with the majority of them being similar to 300 bp. We found similar to 20k putative regulatory elements in the ENCODE heterochromatic domains suggesting a large regulatory potential in the regions presumed transcriptionally silent. Among the most significant TF interactions identified in the heterochromatic regions were CTCF and the cohesin complex, which is in agreement with previous reports. Finally, we investigated the enrichment of the obtained putative regulatory regions in the 3D chromatin domains. More than 90% of the regions were discovered in the 3D contacting domains. We found a significant enrichment of GWAS SNPs in the putative regulatory regions. These significant enrichments provide evidence that the regulatory regions play a crucial role in the genomic structural stability. Additionally, we generated maps of putative regulatory regions for prostate and colorectal cancer human cell-lines.
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22.
  • Diamanti, Klev, 1987-, et al. (författare)
  • Organ-specific metabolic pathways distinguish prediabetes, type 2 diabetes, and normal tissues
  • 2022
  • Ingår i: Cell Reports Medicine. - : Elsevier BV. - 2666-3791. ; 3:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Environmental and genetic factors cause defects in pancreatic islets driving type 2 diabetes (T2D) together with the progression of multi-tissue insulin resistance. Mass spectrometry proteomics on samples from five key metabolic tissues of a cross-sectional cohort of 43 multi-organ donors provides deep coverage of their proteomes. Enrichment analysis of Gene Ontology terms provides a tissue-specific map of altered biological processes across healthy, prediabetes (PD), and T2D subjects. We find widespread alterations in several relevant biological pathways, including increase in hemostasis in pancreatic islets of PD, increase in the complement cascade in liver and pancreatic islets of PD, and elevation in cholesterol biosynthesis in liver of T2D. Our findings point to inflammatory, immune, and vascular alterations in pancreatic islets in PD that are hypotheses to be tested for potential contributions to hormonal perturbations such as impaired insulin and increased glucagon production. This multi-tissue proteomic map suggests tissue-specific metabolic dysregulations in T2D. © 2022 The Author(s)
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23.
  • Diamanti, Klev, 1987-, et al. (författare)
  • Single nucleus transcriptomics data integration recapitulates the major cell types in human liver
  • 2021
  • Ingår i: Hepatology Research. - : Wiley. - 1386-6346 .- 1872-034X. ; 51:2, s. 233-238
  • Tidskriftsartikel (refereegranskat)abstract
    • Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology Aim: The aim of this study was to explore the benefits of data integration from different platforms for single nucleus transcriptomics profiling to characterize cell populations in human liver. Methods: We generated single-nucleus RNA sequencing data from Chromium 10X Genomics and Drop-seq for a human liver sample. We utilized state of the art bioinformatics tools to undertake a rigorous quality control and to integrate the data into a common space summarizing the gene expression variation from the respective platforms, while accounting for known and unknown confounding factors. Results: Analysis of single nuclei transcriptomes from both 10X and Drop-seq allowed identification of the major liver cell types, while the integrated set obtained enough statistical power to separate a small population of inactive hepatic stellate cells that was not characterized in either of the platforms. Conclusions: Integration of droplet-based single nucleus transcriptomics data enabled identification of a small cluster of inactive hepatic stellate cells that highlights the potential of our approach. We suggest single-nucleus RNA sequencing integrative approaches could be utilized to design larger and cost-effective studies.
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24.
  • Hallberg, Pär, et al. (författare)
  • Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough : a genome-wide association study in a Swedish population
  • 2017
  • Ingår i: Pharmacogenomics (London). - : FUTURE MEDICINE LTD. - 1462-2416 .- 1744-8042. ; 18:3, s. 201-213
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes iden-tified in previous studies. Patients & methods: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 x 10(-8). Results: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 x 10(-8)). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Conclusion: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.
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25.
  • Hallberg, Pär, 1974-, et al. (författare)
  • Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival
  • 2019
  • Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 40, s. 595-604
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.
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26.
  • Kalantari, Zahra, et al. (författare)
  • Flood probability quantification for road infrastructure : Data-driven spatial-statistical approach and case study applications
  • 2017
  • Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 581, s. 386-398
  • Tidskriftsartikel (refereegranskat)abstract
    • Climate-driven increase in the frequency of extreme hydrological events is expected to impose greater strain on the built environment and major transport infrastructure, such as roads and railways. This study develops a data-driven spatial-statistical approach to quantifying and mapping the probability of flooding at critical road-stream intersection locations, where water flow and sediment transport may accumulate and cause serious road damage. The approach is based on novel integration of key watershed and road characteristics, including also measures of sediment connectivity. The approach is concretely applied to and quantified for two specific study case examples in southwest Sweden, with documented road flooding effects of recorded extreme rainfall. The novel contributions of this study in combining a sediment connectivity account with that of soil type, land use, spatial precipitation-runoff variability and road drainage in catchments, and in extending the connectivity measure use for different types of catchments, improve the accuracy of model results for road flood probability.
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27.
  • Karlsson Sundbaum, Johanna, et al. (författare)
  • Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients starting methotrexate
  • 2021
  • Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 22:15, s. 973-982
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results: RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10-8). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA.
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28.
  • Pan, Gang, et al. (författare)
  • Multifaceted regulation of hepatic lipid metabolism by YY1
  • 2021
  • Ingår i: Life Science Alliance. - : LIFE SCIENCE ALLIANCE LLC. - 2575-1077. ; 4:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent studies suggested that dysregulated YY1 plays a pivotal role in many liver diseases. To obtain a detailed view of genes and pathways regulated by YY1 in the liver, we carried out RNA sequencing in HepG2 cells after YY1 knockdown. A rigid set of 2,081 differentially expressed genes was identified by comparing the YY1-knockdown samples (n = 8) with the control samples (n = 14). YY1 knockdown significantly decreased the expression of several key transcription factors and their coactivators in lipid metabolism. This is illustrated by YY1 regulating PPARA expression through binding to its promoter and enhancer regions. Our study further suggest that down-regulation of the key transcription factors together with YY1 knockdown significantly decreased the cooperation between YY1 and these transcription factors at various regulatory regions, which are important in regulating the expression of genes in hepatic lipid metabolism. This was supported by the finding that the expression of SCD and ELOVL6, encoding key enzymes in lipogenesis, were regulated by the cooperation between YY1 and PPARA/RXRA complex over their promoters.
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29.
  • Pan, Gang, et al. (författare)
  • PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c
  • 2017
  • Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 45:5, s. 2408-2422
  • Tidskriftsartikel (refereegranskat)abstract
    • The FADS1 and FADS2 genes in the FADS cluster encode the rate-limiting enzymes in the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs). Genetic variation in this region has been associated with a large number of diseases and traits many of them correlated to differences in metabolism of PUFAs. However, the causative variants leading to these associations have not been identified. Here we find that the multiallelic rs174557 located in an AluYe5 element in intron 1 of FADS1 is functional and lies within a PATZ1 binding site. The derived allele of rs174557, which is the common variant in most populations, diminishes binding of PATZ1, a transcription factor conferring allele-specific downregulation of FADS1 The PATZ1 binding site overlaps with a SP1 site. The competitive binding between the suppressive PATZ1 and the activating complex of SP1 and SREBP1c determines the enhancer activity of this region, which regulates expression of FADS1.
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30.
  • Pan, Gang, et al. (författare)
  • Polymorphisms rs55710213 and rs56334587 regulate SCD1 expression by modulating HNF4A binding
  • 2021
  • Ingår i: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms. - : Elsevier. - 1874-9399 .- 1876-4320. ; 1864:8
  • Tidskriftsartikel (refereegranskat)abstract
    • The stearoyl-CoA desaturase 1 (SCD1) gene at 10q24.31 encodes the rate limiting enzyme SCD1 that catalyzes the biosynthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids (SFAs). Dysregulated SCD1 activity has been observed in many human diseases including non-alcoholic fatty liver disease (NAFLD), obesity, hypertension, hyperlipidemia, metabolic syndrome and several types of cancer. HNF4A is a central regulator of glucose and lipid metabolism and previous studies suggested that it is deeply involved in regulating the SCD1 activity in the liver. However, the underlying mechanisms on whether and how SCD1 is regulated by HNF4A have not been explored in detail. In this study, we found that HNF4A regulates SCD1 expression by directly binding to the key regulatory regions in the SCD1 locus. Knocking down of HNF4A significantly downregulated the expression of SCD1. Variants rs55710213 and rs56334587 in intron 5 of SCD1 directly reside in a canonical HNF4A binding site. The GG haplotype of rs55710213 and rs56334587 is associated with decreased SCD1 activity by disrupting the binding of HNF4A, which further decreased the enhancer activity and SCD1 expression. In conclusion, our study demonstrated that SCD1 is directly regulated by HNF4A, which may be helpful in the understanding of the altered metabolic pathways in many diseases associated with dysregulated SCD1 or HNF4A or both.
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31.
  • Pan, Gang, et al. (författare)
  • rs953413 Regulates Polyunsaturated Fatty Acid Metabolism by Modulating ELOVL2 Expression
  • 2020
  • Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 23:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Long-chain polyunsaturated fatty acids (LC-PUFAs) influence human health in several areas, including cardiovascular disease, diabetes, fatty liver disease, and cancer. ELOVL2 encodes one of the key enzymes in the in vivo synthesis of LC-PUFAs from their precursors. Variants near ELOVL2 have repeatedly been associated with levels of LC-PUFA-derived metabolites in genome-wide association studies (GWAS), but the mechanisms behind these observations remain poorly defined. In this study, we found that rs953413, located in the first intron of ELOVL2, lies within a functional FOXA and HNF4α cooperative binding site. The G allele of rs953413 increases binding of FOXA1/FOXA2 and HNF4α to an evolutionarily conserved enhancer element, conferring allele-specific upregulation of the rs953413-associated gene ELOVL2. The expression of ELOVL2 was significantly downregulated by both FOXA1 and HNF4α knockdown and CRISPR/Cas9-mediated direct mutation to the enhancer element. Our results suggest that rs953413 regulates LC-PUFAs metabolism by altering ELOVL2 expression through FOXA1/FOXA2 and HNF4α cooperation.
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32.
  • Rahmati, Omid, et al. (författare)
  • Towards quantification of soil conservation performance using sediment connectivity concept at hillslope scale : proposing a new framework for data-scarce regions
  • 2023
  • Ingår i: Journal of Soils and Sediments. - : Springer Science and Business Media LLC. - 1439-0108 .- 1614-7480. ; 23:5, s. 2298-2309
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose Although contour trenching is one of the widely used nature-based solutions for soil conservation around the world, its efficiency has not been quantitatively investigated. This study aimed to scrutinize the performance of the contour trenching program, a nature-based solution and common soil erosion prevention measure in hillslopes of a data-scarce region based on the sediment connectivity approach.Materials and methods Six different hillslopes (A–F) were selected in the Khamsan watershed in Iran, a representative area where contour trenching has been implemented. The sediment connectivity map of each hillslope was generated using the index of connectivity (IC) based on two real scenarios: with (scenario I) and without (scenario II) contour trenching. Two different field-based validation methods were applied on the base of (i) in situ measurements of the sediment depth in contour trenches and Pearson’s correlation analysis, and (ii) field index of connectivity (FIC). The validity of the sediment connectivity results was verified using both validation approaches. The sediment connectivity in two scenarios was compared and the impact of the contour trenching was analyzed. The performance of the contour trenching program was quantitatively determined for each hillslope.Results and discussion The results revealed that contour trenching significantly affected sediment routing and reduced the IC values of all selected hillslopes. The differences in IC value between the two scenarios (∆IC) for hillslopes A, B, C, D, E, and F were found to be 22.6%, 11.27%, 14.69%, 5.83%, 15%, and 7.27%, respectively. Therefore, the spatial pattern of sediment connectivity also differed significantly after implementing contour trenching. Furthermore, Pearson’s correlation coefficients revealed that the sediment connectivity and the sediment depth in contours in all hillslopes had a significant negative relationship, resulting in confirming the validity of the sediment connectivity results for all six hillslopes in the current study.Conclusion Contour trenching significantly reduced the sediment connectivity on all six hillslopes studied. Furthermore, in situ measurements of the sediment depth in contour trenches should be conducted to verify the simulation of sediment connectivity. The proposed methodology can be applied in other data-scarce regions to evaluate the performance of the contour trenching program.
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33.
  • Raine, Amanda, et al. (författare)
  • scSPLAT, a scalable plate-based protocol for single cell WGBS library preparation
  • 2022
  • Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • DNA methylation is a central epigenetic mark that has diverse roles in gene regulation, development, and maintenance of genome integrity. 5 methyl cytosine (5mC) can be interrogated at base resolution in single cells by using bisulfite sequencing (scWGBS). Several different scWGBS strategies have been described in recent years to study DNA methylation in single cells. However, there remain limitations with respect to cost-efficiency and yield. Herein, we present a new development in the field of scWGBS library preparation; single cell Splinted Ligation Adapter Tagging (scSPLAT). scSPLAT employs a pooling strategy to facilitate sample preparation at a higher scale and throughput than previously possible. We demonstrate the accuracy and robustness of the method by generating data from 225 single K562 cells and from 309 single liver nuclei and compare scSPLAT against other scWGBS methods.
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34.
  • Rasmussen, Eva Rye, et al. (författare)
  • Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.
  • 2020
  • Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 20:6, s. 770-783
  • Tidskriftsartikel (refereegranskat)abstract
    • Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10-5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10-8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.
  •  
35.
  • Rydzanicz, Malgorzata, et al. (författare)
  • Variable degree of mosaicism for tetrasomy 18p in phenotypically discordant monozygotic twins-Diagnostic implications
  • 2021
  • Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley-Blackwell. - 2324-9269. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Phenotypically discordant monozygotic twins (PDMZTs) offer a unique opportunity to study post-zygotic genetic variation and provide insights into the linkage between genotype and phenotype. We report a comprehensive analysis of a pair of PDMZTs.Methods: Dysmorphic features and delayed neuro-motor development were observed in the proband, whereas her twin sister was phenotypically normal. Four tissues (blood, skin, hair follicles, and buccal mucosa) from both twins were studied using four complementary methods, including whole-exome sequencing, karyotyping, array CGH, and SNP array.Results: In the proband, tetrasomy 18p affecting all studied tissues except for blood was identified. Karyotyping of fibroblasts revealed isochromosome 18p [i(18p)] in all metaphases. The corresponding analysis of the phenotypically normal sister surprisingly revealed low-level mosaicism (5.4%) for i(18p) in fibroblasts.Conclusion: We emphasize that when mosaicism is suspected, multiple tissues should be studied and we highlight the usefulness of non-invasive sampling of hair follicles and buccal mucosa as a convenient source of non-mesoderm-derived DNA, which complements the analysis of mesoderm using blood. Moreover, low-level mosaic tetrasomy 18p is well tolerated and such low-level mosaicism, readily detected by karyotyping, can be missed by other methods. Finally, mosaicism for low-level tetrasomy 18p might be more common in the general population than it is currently recognized, due to detection limitations.
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36.
  • Umer, Husen M., et al. (författare)
  • A Significant Regulatory Mutation Burden at a High-Affinity Position of the CTCF Motif in Gastrointestinal Cancers
  • 2016
  • Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 37:9, s. 904-913
  • Tidskriftsartikel (refereegranskat)abstract
    • Somatic mutations drive cancer and there are established ways to study those in coding sequences. It has been shown that some regulatory mutations are over-represented in cancer. We develop a new strategy to find putative regulatory mutations based on experimentally established motifs for transcription factors (TFs). In total, we find 1,552 candidate regulatory mutations predicted to significantly reduce binding affinity of many TFs in hepatocellular carcinoma and affecting binding of CTCF also in esophagus, gastric, and pancreatic cancers. Near mutated motifs, there is a significant enrichment of (1) genes mutated in cancer, (2) tumor-suppressor genes, (3) genes in KEGG cancer pathways, and (4) sets of genes previously associated to cancer. Experimental and functional validations support the findings. The strategy can be applied to identify regulatory mutations in any cell type with established TF motifs and will aid identifications of genes contributing to cancer.
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37.
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38.
  • Yalcinkaya, Ahmet, et al. (författare)
  • No link between type I interferon autoantibody positivity and adverse reactions to COVID-19 vaccines
  • 2024
  • Ingår i: NPJ VACCINES. - : Springer Nature. - 2059-0105. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Type I interferons act as gatekeepers against viral infection, and autoantibodies that neutralize these signaling molecules have been associated with COVID-19 severity and adverse reactions to the live-attenuated yellow fever vaccine. On this background, we sought to examine whether autoantibodies against type I interferons were associated with adverse events following COVID-19 vaccination. Our nationwide analysis suggests that type I interferon autoantibodies were not associated with adverse events after mRNA or viral-vector COVID-19 vaccines.
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