| 1. |
- Abelev, B., et al.
(author)
-
Anisotropic flow of charged hadrons, pions and (anti-)protons measured at high transverse momentum in Pb-Pb collisions at root S-NN=2.76 TeV
- 2013
-
In: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 719:1-3, s. 18-28
-
Journal article (peer-reviewed)abstract
- The elliptic, v(2), triangular, v(3), and quadrangular, v(4), azimuthal anisotropic flow coefficients are measured for unidentified charged particles, pions, and (anti-)protons in Pb-Pb collisions at root S-NN = 2.76 TeV with the ALICE detector at the Large Hadron Collider. Results obtained with the event plane and four-particle cumulant methods are reported for the pseudo-rapidity range vertical bar eta vertical bar < 0.8 at different collision centralities and as a function of transverse momentum, p(T), out to p(T) = 20 GeV/c. The observed non-zero elliptic and triangular flow depends only weakly on transverse momentum for p(T) > 8 GeV/c. The small p(T) dependence of the difference between elliptic flow results obtained from the event plane and four-particle cumulant methods suggests a common origin of flow fluctuations up to p(T) = 8 GeV/c. The magnitude of the (anti-)proton elliptic and triangular flow is larger than that of pions out to at least p(T) = 8 GeV/c indicating that the particle type dependence persists out to high p(T). (c) 2013 CERN. Published by Elsevier B.V. All rights reserved.
|
|
| 2. |
- Abelev, B., et al.
(author)
-
Light vector meson production in pp collisions at root s=7 TeV ALICE Collaboration
- 2012
-
In: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 710:4-5, s. 557-568
-
Journal article (peer-reviewed)abstract
- The ALICE experiment has measured low-mass dimuon production in pp collisions at root s = 7 TeV in the dimuon rapidity region 2.5 < y < 4. The observed dimuon mass spectrum is described as a superposition of resonance decays (eta, rho, omega, eta', phi) into muons and semi-leptonic decays of charmed mesons. The measured production cross sections for omega and phi are sigma(omega)(1 < p(t) < 5 GeV/c. 2.5 < y < 4) = 5.28 +/- 0.54(stat) +/- 0.49(syst) mb and sigma(phi)(1 < p(t) < 5 GeV/c. 2.5 < y < 4) = 0.940 +/- 0.084(stat) +/- 0.076(syst) mb. The differential cross sections d(2)sigma/dy dp(t) are extracted as a function of p(t) for omega and phi. The ratio between the rho and omega cross section is obtained. Results for the phi are compared with other measurements at the same energy and with predictions by models. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved.
|
|
| 3. |
- Abelev, B., et al.
(author)
-
Measurement of event background fluctuations for charged particle jet reconstruction in Pb-Pb collisions at root s(NN)=2.76 TeV
- 2012
-
In: Journal of High Energy Physics. - 1029-8479. ; :3
-
Journal article (peer-reviewed)abstract
- The effect of event background fluctuations on charged particle jet reconstruction in Pb-Pb collisions at root s(NN) = 2.76 TeV has been measured with the ALICE experiment. The main sources of non-statistical fluctuations are characterized based purely on experimental data with an unbiased method, as well as by using single high p(t) particles and simulated jets embedded into real Pb-Pb events and reconstructed with the anti-k(t) jet finder. The influence of a low transverse momentum cut-off on particles used in the jet reconstruction is quantified by varying the minimum track p(t) between 0.15 GeV/c and 2 GeV/c. For embedded jets reconstructed from charged particles with p(t) > 0.15 GeV/c, the uncertainty in the reconstructed jet transverse momentum due to the heavy-ion background is measured to be 11.3 GeV/c (standard deviation) for the 10% most central Pb-Pb collisions, slightly larger than the value of 11.0 GeV/c measured using the unbiased method. For a higher particle transverse momentum threshold of 2 GeV/c, which will generate a stronger bias towards hard fragmentation in the jet finding process, the standard deviation of the fluctuations in the reconstructed jet transverse momentum is reduced to 4.8-5.0 GeV/c for the 10% most central events. A non-Gaussian tail of the momentum uncertainty is observed and its impact on the reconstructed jet spectrum is evaluated for varying particle momentum thresholds, by folding the measured fluctuations with steeply falling spectra.
|
|
| 4. |
|
|
| 5. |
-
- 2019
-
Journal article (peer-reviewed)
|
|
| 6. |
- Palmer, Nicholette D, et al.
(author)
-
A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
-
In: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
-
Journal article (peer-reviewed)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
|
|
| 7. |
- Wessel, Jennifer, et al.
(author)
-
Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Journal article (peer-reviewed)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
|
|
| 8. |
- Pattaro, Cristian, et al.
(author)
-
Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Journal article (peer-reviewed)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
|
|
| 9. |
- Keller, Ulrich B, et al.
(author)
-
Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis.
- 2007
-
In: EMBO J. - 0261-4189. ; 26:10, s. 2562-74
-
Journal article (peer-reviewed)abstract
- Reduced levels of the cyclin-dependent kinase inhibitor p27(Kip1) connote poor prognosis in cancer. In human Burkitt lymphoma and in precancerous B cells and lymphomas arising in Emu-Myc transgenic mice, p27(Kip1) expression is markedly reduced. We show that the transcription of the Cks1 component of the SCF(Skp2) complex that is necessary for p27(Kip1) ubiquitylation and degradation is induced by Myc. Further, Cks1 expression is elevated in precancerous Emu-Myc B cells, and high levels of Cks1 are also a hallmark of Emu-Myc lymphoma and of human Burkitt lymphoma. Finally, loss of Cks1 in Emu-Myc B cells elevates p27(Kip1) levels, reduces proliferation and markedly delays lymphoma development and dissemination of disease. Therefore, Myc suppresses p27(Kip1) expression, accelerates cell proliferation and promotes tumorigenesis at least in part through its ability to selectively induce Cks1.
|
|
| 10. |
- Li, Chen, et al.
(author)
-
Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length
- 2020
-
In: American Journal of Human Genetics. - : CELL PRESS. - 0002-9297 .- 1537-6605. ; 106:3, s. 389-404
-
Journal article (peer-reviewed)abstract
- Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
|
|
| 11. |
- Macsari, Istvan, et al.
(author)
-
3-Oxoisoindoline-1-carboxamides : Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na(V)1.7 with Efficacy in Rat Pain Models
- 2012
-
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:15, s. 6866-6880
-
Journal article (peer-reviewed)abstract
- The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.
|
|
| 12. |
- Saxena, Richa, et al.
(author)
-
Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge
- 2010
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:2, s. 142-148
-
Journal article (peer-reviewed)abstract
- Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).
|
|
| 13. |
- Sehgelmeble, Fernando, et al.
(author)
-
Sulfonimidamides as Sulfonamides Bioisosteres : Rational Evaluation through Synthetic, in Vitro, and in Vivo Studies with γ-Secretase Inhibitors
- 2012
-
In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:3, s. 396-399
-
Journal article (peer-reviewed)abstract
- The proof of the pudding: A proof-of-concept study using γ-secretase inhibitors as a model has shown that sulfonimidamides act as bioisosteres for sulfonamides. Detailed in vitro and in vivo profiling reveal that the sulfonimidamide motif imparts desirable properties such as decreased lipophilicity and plasma protein binding, accompanied by increased solubility. Our data support a wider use of this unique functional group in the design of new pharmacologically active agents.
|
|
| 14. |
- Backman, Helena, et al.
(author)
-
Decreased COPD prevalence in Sweden after decades of decrease in smoking
- 2020
-
In: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 21
-
Journal article (peer-reviewed)abstract
- BackgroundCOPD has increased in prevalence worldwide over several decades until the first decade after the millennium shift. Evidence from a few recent population studies indicate that the prevalence may be levelling or even decreasing in some areas in Europe. Since the 1970s, a substantial and ongoing decrease in smoking prevalence has been observed in several European countries including Sweden. The aim of the current study was to estimate the prevalence, characteristics and risk factors for COPD in the Swedish general population. A further aim was to estimate the prevalence trend of COPD in Northern Sweden from 1994 to 2009.MethodsTwo large random population samples were invited to spirometry with bronchodilator testing and structured interviews in 2009–2012, one in south-western and one in northern Sweden, n = 1839 participants in total. The results from northern Sweden were compared to a study performed 15 years earlier in the same area and age-span. The diagnosis of COPD required both chronic airway obstruction (CAO) and the presence of respiratory symptoms, in line with the GOLD documents since 2017. CAO was defined as post-bronchodilator FEV1/FVC < 0.70, with sensitivity analyses based on the FEV1/FVC < lower limit of normal (LLN) criterion.ResultsBased on the fixed ratio definition, the prevalence of COPD was 7.0% (men 8.3%; women 5.8%) in 2009–2012. The prevalence of moderate to severe (GOLD ≥ 2) COPD was 3.5%. The LLN based results were about 30% lower. Smoking, occupational exposures, and older age were risk factors for COPD, whereof smoking was the most dominating risk factor. In northern Sweden the prevalence of COPD, particularly moderate to severe COPD, decreased significantly from 1994 to 2009, and the decrease followed a decrease in smoking.ConclusionsThe prevalence of COPD has decreased in Sweden, and the prevalence of moderate to severe COPD was particularly low. The decrease follows a major decrease in smoking prevalence over several decades, but smoking remained the dominating risk factor for COPD.
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
- Heckman, Michael G., et al.
(author)
-
Population-specific Frequencies for LRRK2 Susceptibility Variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium
- 2013
-
In: Movement Disorders. - : Wiley. - 0885-3185. ; 28:12, s. 1740-1744
-
Journal article (peer-reviewed)abstract
- BackgroundVariants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. ConclusionsEstablishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. (c) 2013 International Parkinson and Movement Disorder Society
|
|
| 18. |
- I Siponen, Marina, et al.
(author)
-
Structural Determination of Functional Domains in Early B-cell Factor (EBF) Family of Transcription Factors Reveals Similarities to Rel DNA-binding Proteins and a Novel Dimerization Motif
- 2010
-
In: JOURNAL OF BIOLOGICAL CHEMISTRY. - : The American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 285:34, s. 25875-25879
-
Journal article (peer-reviewed)abstract
- The early B-cell factor (EBF) transcription factors are central regulators of development in several organs and tissues. This protein family shows low sequence similarity to other protein families, which is why structural information for the functional domains of these proteins is crucial to understand their biochemical features. We have used a modular approach to determine the crystal structures of the structured domains in the EBF family. The DNA binding domain reveals a striking resemblance to the DNA binding domains of the Rel homology superfamily of transcription factors but contains a unique zinc binding structure, termed zinc knuckle. Further the EBF proteins contain an IPT/TIG domain and an atypical helix-loop-helix domain with a novel type of dimerization motif. The data presented here provide insights into unique structural features of the EBF proteins and open possibilities for detailed molecular investigations of this important transcription factor family.
|
|
| 19. |
- Jung, Christian, et al.
(author)
-
A comparison of very old patients admitted to intensive care unit after acute versus elective surgery or intervention
- 2019
-
In: Journal of critical care. - : W B SAUNDERS CO-ELSEVIER INC. - 0883-9441 .- 1557-8615. ; 52, s. 141-148
-
Journal article (peer-reviewed)abstract
- Background: We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (80 years; VIP). Predictors of mortality, with special emphasis on frailty, were assessed.Methods: In total, 5063 VIPs were induded in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.Results: Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 +/- 5 vs 7 +/- 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).Conclusions: VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery.
|
|
| 20. |
- Paulson, Linda, 1971, et al.
(author)
-
Comparative genome- and proteome analysis of cerebral cortex from MK-801-treated rats.
- 2003
-
In: Journal of neuroscience research. - : Wiley. - 0360-4012 .- 1097-4547. ; 71:4, s. 526-33
-
Journal article (peer-reviewed)abstract
- cDNA microarrays and two-dimensional gel-electrophoresis in combination with mass spectrometry, were used to screen alterations in mRNA and protein levels, respectively, in cerebral cortex of MK-801-treated rats. The rats were divided in two groups; group 1 (short-term treated) and group 2 (long-term treated). In group 1, four genes were up-regulated and five down-regulated. In group 2, seven genes were up-regulated and six down-regulated. In group 1, the levels of one protein was increased and eight proteins reduced. In group 2, the levels of two proteins were increased and four proteins reduced. Several of the altered genes (casein kinase 2, glutamic acid decarboxylase, synaptotagmin, gamma aminobutyric acid [GABA] transporter, creatine kinase, and cytochrome c oxidase) and proteins (superoxide dismutase, hsp 60, hsp 72 and gamma-enolase) have previously been connected to schizophrenia. Alterations of the genes (microglobulin, c-jun proto-oncogene, 40S ribosomal protein S19, adenosine diphosphate (ADP)-ribosylation factors, platelet-derived growth factor, fructose-bisphophate aldolase A, and myelin proteolipid) and the proteins (stathmin, H+-transp. Adenosine triphosphate (ATP) synthase, pyruvate dehydrogenase, beta-actin and alpha-enolase), have not, to our knowledge, earlier been implicated in schizophrenia pathology. Overall, these results with a combined approach of genomics and proteomics add to the validity of subchronic N-methyl-D-aspartate (NMDA)-receptor antagonist treatment as an animal model of schizophrenia.
|
|
| 21. |
- Ross, Owen A., et al.
(author)
-
Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study
- 2011
-
In: Lancet Neurology. - 1474-4465. ; 10:10, s. 898-908
-
Journal article (peer-reviewed)abstract
- Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. Methods LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. Findings 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43, 95% CI 1.15-1.78; p=0.0012) and Asian individuals (A419V, 2.27, 1.35-3.83; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82, 0.72-0.94; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73, 1.20-2.49; p=0.0026), but no association was noted for R1628P (0.62, 0.36-1.07; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4.48, 133-15.09; p=0.012). Interpretation The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. Funding Michael J Fox Foundation and National Institutes of Health.
|
|
| 22. |
|
|
| 23. |
- Steen, Johanna, et al.
(author)
-
Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis
- 2019
-
In: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 71:2, s. 196-209
-
Journal article (peer-reviewed)abstract
- Objective: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity.Methods: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated.Results: Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay.Conclusion: These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.
|
|
| 24. |
- Tedersoo, Leho, et al.
(author)
-
Global patterns in endemicity and vulnerability of soil fungi.
- 2022
-
In: Global change biology. - : Wiley. - 1365-2486 .- 1354-1013. ; 28:22, s. 6696-6710
-
Journal article (peer-reviewed)abstract
- Fungi are highly diverse organisms, which provide multiple ecosystem services. However, compared with charismatic animals and plants, the distribution patterns and conservation needs of fungi have been little explored. Here, we examined endemicity patterns, global change vulnerability and conservation priority areas for functional groups of soil fungi based on six global surveys using a high-resolution, long-read metabarcoding approach. We found that the endemicity of all fungi and most functional groups peaks in tropical habitats, including Amazonia, Yucatan, West-Central Africa, Sri Lanka, and New Caledonia, with a negligible island effect compared with plants and animals. We also found that fungi are predominantly vulnerable to drought, heat and land-cover change, particularly in dry tropical regions with high human population density. Fungal conservation areas of highest priority include herbaceous wetlands, tropical forests, and woodlands. We stress that more attention should be focused on the conservation of fungi, especially root symbiotic arbuscular mycorrhizal and ectomycorrhizal fungi in tropical regions as well as unicellular early-diverging groups and macrofungi in general. Given the low overlap between the endemicity of fungi and macroorganisms, but high conservation needs in both groups, detailed analyses on distribution and conservation requirements are warranted for other microorganisms and soil organisms.
|
|
