| 1. |
- Abelev, Betty, et al.
(författare)
-
Long-range angular correlations on the near and away side in p-Pb collisions at root S-NN=5.02 TeV
- 2013
-
Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 719:1-3, s. 29-41
-
Tidskriftsartikel (refereegranskat)abstract
- Angular correlations between charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV for transverse momentum ranges within 0.5 < P-T,P-assoc < P-T,P-trig < 4 GeV/c. The correlations are measured over two units of pseudorapidity and full azimuthal angle in different intervals of event multiplicity, and expressed as associated yield per trigger particle. Two long-range ridge-like structures, one on the near side and one on the away side, are observed when the per-trigger yield obtained in low-multiplicity events is subtracted from the one in high-multiplicity events. The excess on the near-side is qualitatively similar to that recently reported by the CMS Collaboration, while the excess on the away-side is reported for the first time. The two-ridge structure projected onto azimuthal angle is quantified with the second and third Fourier coefficients as well as by near-side and away-side yields and widths. The yields on the near side and on the away side are equal within the uncertainties for all studied event multiplicity and p(T) bins, and the widths show no significant evolution with event multiplicity or p(T). These findings suggest that the near-side ridge is accompanied by an essentially identical away-side ridge. (c) 2013 CERN. Published by Elsevier B.V. All rights reserved.
|
|
| 2. |
- Amare, Azmeraw, et al.
(författare)
-
Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
- 2023
-
Ingår i: Research square. - : Research Square Platform LLC.
-
Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
|
|
| 3. |
- Amare, Azmeraw T, et al.
(författare)
-
Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
-
Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
-
Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
|
|
| 4. |
- Akram, Talia, et al.
(författare)
-
Aberrant splicing due to a novel RPS7 variant causes Diamond-Blackfan Anemia associated with spontaneous remission and meningocele
- 2020
-
Ingår i: International Journal of Hematology. - : Springer Science and Business Media LLC. - 0925-5710 .- 1865-3774. ; 112:6, s. 894-899
-
Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan Anemia (DBA) is a congenital pure red cell aplasia caused by heterozygous variants in ribosomal protein genes. The hematological features associated with DBA are highly variable and non-hematological abnormalities are common. We report herein on an affected mother and her daughter presenting with transfusion-dependent anemia. The mother showed mild physical abnormalities and entered spontaneous remission at age 13 years. Her daughter was born with occipital meningocele. Exome sequencing of DNA from the mother revealed a heterozygous novel splice site variant (NM_001011.4:c.508-3T > G) in the Ribosomal Protein S7 gene (RPS7) inherited by the daughter. Functional analysis of the RPS7 variant expressed from a mini-gene construct revealed that the exon 7 acceptor splice site was replaced by a cryptic splice resulting in a transcript missing 64 bp of exon 7 (p.Val170Serfs*8). Our study confirms a pathogenic effect of a novel RPS7 variant in DBA associated with spontaneous remission in the mother and meningocele in her daughter, thus adding to the genotype-phenotype correlations in DBA.
|
|
| 5. |
- Alseekh, Saleh, et al.
(författare)
-
Mass spectrometry-based metabolomics: a guide for annotation, quantification and best reporting practices
- 2021
-
Ingår i: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 18:7, s. 747-756
-
Forskningsöversikt (refereegranskat)abstract
- This Perspective, from a large group of metabolomics experts, provides best practices and simplified reporting guidelines for practitioners of liquid chromatography- and gas chromatography-mass spectrometry-based metabolomics. Mass spectrometry-based metabolomics approaches can enable detection and quantification of many thousands of metabolite features simultaneously. However, compound identification and reliable quantification are greatly complicated owing to the chemical complexity and dynamic range of the metabolome. Simultaneous quantification of many metabolites within complex mixtures can additionally be complicated by ion suppression, fragmentation and the presence of isomers. Here we present guidelines covering sample preparation, replication and randomization, quantification, recovery and recombination, ion suppression and peak misidentification, as a means to enable high-quality reporting of liquid chromatography- and gas chromatography-mass spectrometry-based metabolomics-derived data.
|
|
| 6. |
|
|
| 7. |
- Badhai, Jitendra, et al.
(författare)
-
Differential expression of RPS19 5’UTR variants implicated in Diamond-Blackfan anemia
- 2012
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Heterozygous mutations in the ribosomal protein (RP) S19 gene RPS19 are found in about 25% of patients with the congenital erythroblastopenia Diamond-Blackfan anemia (DBA). The RPS19 gene encodes a single RPS19 isoform from three known transcriptional start sites (TSS) with different 5’ untranslated region (UTR). The regulation of RPS19 expression is poorly understood as well as the significance of different 5’UTRs. A few rare sequence variants within the 5’UTR have also been reported in patients with DBA. We determined the transcriptional start sites (TSS) and the tissue distribution of variant 5’UTRs of RPS19. Twenty-nine novel TSS in K562 cells and testis were identified. We then analyzed the relative proportion of three selected 5’UTRs of different length on a panel of primary tissues. The shorter 5’UTR were most abundant in all tissues but with large variations in relative levels of shorter versus longer transcripts. To clarify the effect of different RPS19 5’UTRs on translation we designed and expressed constructs using three 5’UTRs of different length. The short 5’UTR(+35nt.) translate 4-6 folds more efficiently than the two longer variants with 5’UTRs of 382nt. and 467nt., respectively We also introduced DBA associated insertion (c.-149_-148insGCCA, c.-149_-148insAGCC ) and deletion (c.-144_-141delTTTC) variants in the 5’UTR. . Interestingly, the DBA associated 5’UTR sequence variants showed a 20-30% reduction in RPS19 levels when compared to the corresponding w.t. constructs. Our results indicate that the RPS19 gene has a broad range of TSS with tissue specific variations. We also show that sequence variants in the 5’UTR in some DBA patients reduce RPS19 expression with implications for the pathophysiology of the disease.
|
|
| 8. |
- Badhai, Jitendra, et al.
(författare)
-
Posttranscriptional down-regulation of small ribosomal subunit proteinscorrelates with reduction of 18S rRNA in RPS19 deficiency
- 2009
-
Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 583:12, s. 2049-2053
-
Tidskriftsartikel (refereegranskat)abstract
- Ribosomal protein S19 (RPS19) is mutated in patients with Diamond-Blackfan anemia (DBA). We hypothesized that decreased levels of RPS19 lead to a coordinated down-regulation of other ribosomal (r-)proteins at the subunit level. We show that small interfering RNA (siRNA) knock-down of RPS19 results in a relative decrease of small subunit (SSU) r-proteins (S20, S21 and S24) when compared to large subunit (LSU) r-proteins (L3, L9, L30 and L38). This correlates with a relative decrease in 18S rRNA with respect to 28S rRNA. The r-protein mRNA levels remain relatively unchanged indicating a post transcriptional regulation of r-proteins at the level of subunit formation.
|
|
| 9. |
- Badhai, Jitendra, et al.
(författare)
-
Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond-Blackfan anemia
- 2009
-
Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 1878-2434. ; 1792:10, s. 1036-1042
-
Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan anemia (DBA) is a severe congenital anemia characterized by a specific decrease of erythroid precursors. The disease is also associated with growth retardation, congenital malformations, a predisposition for malignant disease and heterozygous mutations in either of the ribosomal protein (RP) genes RPS7, RPS17, RPS19, RPS24, RPL5, RPL11 and RPL35a. We show herein that primary fibroblasts from DBA patients with truncating mutations in RPS19 or in RPS24 have a marked reduction in proliferative capacity. Mutant fibroblasts are associated with extended cell cycles and normal levels of p53 when compared to w.t. cells. RPS19 mutant fibroblasts accumulate in the G1 phase, whereas the RPS24 mutant cells show an altered progression in the S phase resulting in reduced levels in the G2/M phase. RPS19 deficient cells exhibit reduced levels of Cyclin-E, CDK2 and retinoblastoma (Rb) protein supporting a cell cycle arrest in the G1 phase. In contrast, RPS24 deficient cells show increased levels of the cell cycle inhibitor p21 and a seemingly opposing increase in Cyclin-E, CDK4 and CDK6. In combination, our results show that RPS19 and RPS24 insufficient fibroblasts have an impaired growth caused by distinct blockages in the cell cycle. We suggest this proliferative constraint to be an important contributing mechanism for the complex extra-hematological features observed in DBA.
|
|
| 10. |
- Barrio, Alvaro Martinez, et al.
(författare)
-
Targeted Resequencing and Analysis of the Diamond-Blackfan Anemia Disease Locus RPS19
- 2009
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:7, s. e6172-
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Ribosomal protein S19 gene locus (RPS19) has been linked to two kinds of red cell aplasia, Diamond-Blackfan Anemia (DBA) and Transient Erythroblastopenia in Childhood (TEC). Mutations in RPS19 coding sequences have been found in 25% of DBA patients, but not in TEC patients. It has been suggested that non-coding RPS19 sequence variants contribute to the considerable clinical variability in red cell aplasia. We therefore aimed at identifying non-coding variations associated with DBA or TEC phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: We targeted a region of 19'980 bp encompassing the RPS19 gene in a cohort of 89 DBA and TEC patients for resequencing. We provide here a catalog of the considerable, previously unrecognized degree of variation in this region. We identified 73 variations (65 SNPs, 8 indels) that all are located outside of the RPS19 open reading frame, and of which 67.1% are classified as novel. We hypothesize that specific alleles in non-coding regions of RPS19 could alter the binding of regulatory proteins or transcription factors. Therefore, we carried out an extensive analysis to identify transcription factor binding sites (TFBS). A series of putative interaction sites coincide with detected variants. Sixteen of the corresponding transcription factors are of particular interest, as they are housekeeping genes or show a direct link to hematopoiesis, tumorigenesis or leukemia (e.g. GATA-1/2, PU.1, MZF-1). CONCLUSIONS: Specific alleles at predicted TFBSs may alter the expression of RPS19, modify an important interaction between transcription factors with overlapping TFBS or remove an important stimulus for hematopoiesis. We suggest that the detected interactions are of importance for hematopoiesis and could provide new insights into individual response to treatment.
|
|
