| 1. |
- Lue, L. F., et al.
(författare)
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Age-Dependent Relationship Between Plasma A beta 40 and A beta 42 and Total Tau Levels in cognitively Normal Subjects
- 2019
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Both amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with Alzheimer's disease (AD). However, the constituents of these hallmarks, amyloid beta (A beta) 40, A beta 42, and total Tau (t-Tau), have been detected in the blood of cognitively normal subjects by using an immunomagnetic reduction (IMR) assay. Whether these levels are age-dependent is not known, and their interrelation remains undefined. We determined the levels of these biomarkers in cognitively normal subjects of different age groups. A total of 391 cognitively normal subjects aged 23-91 were enrolled from hospitals in Asia, Europe, and North America. Healthy cognition was evaluated by NIA-AA guidelines to exclude subjects with mild cognitive impairment (MCI) and AD and by cognitive assessment using the Mini Mental State Examination and Clinical Dementia Rating (CDR). We examined the effect of age on plasma levels of A beta 40, A beta 42, and t-Tau and the relationship between these biomarkers during aging. Additionally, we explored age-related reference intervals for each biomarker. Plasma t-Tau and A beta 42 levels had modest but significant correlations with chronological age (r = 0.127, p = 0.0120 for t-Tau; r = -0.126, p = 0.0128 for A beta 42), ranging from ages 23 to 91. Significant positive correlations were detected between A beta 42 and t-Tau in the groups aged 50 years and older, with Rho values ranging from 0.249 to 0.474. Significant negative correlations were detected between A beta 40 and t-Tau from age 40 to 91 (r ranged from -0.293 to -0.582) and between A beta 40 and A beta 42 in the age groups of 30-39 (r = -0.562, p = 0.0235), 50-59 (r = -0.261, p = 0.0142), 60-69 (r = -0.303, p = 0.0004), and 80-91 (r = 0.459, p = 0.0083). We also provided age-related reference intervals for each biomarker. In this multicenter study, age had weak but significant effects on the levels of A beta 42 and t-Tau in plasma. However, the age group defined by decade revealed the emergence of a relationship between A beta 40, A beta 42, and t-Tau in the 6th and 7th decades. Validation of our findings in a large-scale and longitudinal study is warranted.
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| 2. |
- Verchenko, V. Yu, et al.
(författare)
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Intermetallic solid solution Fe1-xCoxGa3 : Synthesis, structure, NQR study and electronic band structure calculations
- 2012
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Ingår i: Journal of Solid State Chemistry. - : Elsevier BV. - 0022-4596 .- 1095-726X. ; 194, s. 361-368
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Tidskriftsartikel (refereegranskat)abstract
- Unlimited solid solution Fe1-xCoxGa3 was prepared from Ga flux. Its crystal structure was refined for Fe0.5Co0.5Ga3 (P4(2)/mnm, a=6.2436(9), c=6.4654(13), Z=4) and showed no ordering of the metal atoms. A combination of the electronic band structure calculations within the density functional theory (DFT) approach and Ga-69,Ga-71 nuclear quadrupole resonance (NRQ) spectroscopy clearly shows that the Fe-Fe and Co-Co dumbbells are preferred to the Fe-Co dumbbells in the crystals structure. The band structure features a band gap of about 0.4 eV, with the Fermi level crossing peaks of a substantial density of electronic states above the gap for x > 0. The solid solution is metallic for x > 0.025. The study of the nuclear spin-lattice relaxation shows that the rate of the relaxation, 1/T-1, is very sensitive to the Co concentration and correlates well with the square of the density of states at the Fermi level, N-2(E-F).
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| 3. |
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| 4. |
- Futaana, Y, et al.
(författare)
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Remote energetic neutral atom imaging of electric potential over a lunar magnetic anomaly
- 2013
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Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 40:2, s. 262-266
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Tidskriftsartikel (refereegranskat)abstract
- The formation of electric potential over lunar magnetized regions is essential for understanding fundamental lunar science, for understanding the lunar environment, and for planning human exploration on the Moon. A large positive electric potential was predicted and detected from single point measurements. Here, we demonstrate a remote imaging technique of electric potential mapping at the lunar surface, making use of a new concept involving hydrogen neutral atoms derived from solar wind. We apply the technique to a lunar magnetized region using an existing dataset of the neutral atom energy spectrometer SARA/CENA on Chandrayaan-1. Electrostatic potential larger than +135 V inside the Gerasimovic anomaly is confirmed. This structure is found spreading all over the magnetized region. The widely spread electric potential can influence the local plasma and dust environment near the magnetic anomaly. Citation: Futaana, Y., S. Barabash, M. Wieser, C. Lue, P. Wurz, A. Vorburger, A. Bhardwaj, and K. Asamura (2013), Remote energetic neutral atom imaging of electric potential over a lunar magnetic anomaly, Geophys. Res. Lett., 40, 262-266, doi:10.1002/grl.50135.
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| 5. |
- Zhao, Lue Ping, et al.
(författare)
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HLA Class II (DR, DQ, DP) Genes Were Separately Associated With the Progression From Seroconversion to Onset of Type 1 Diabetes Among Participants in Two Diabetes Prevention Trials (DPT-1 and TN07)
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Ingår i: Diabetes Care. - 1935-5548.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To explore associations of HLA class II genes (HLAII) with the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D).RESEARCH DESIGN AND METHODS: Next-generation targeted sequencing was used to genotype eight HLAII genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, DPB1) in 1,216 participants from the Diabetes Prevention Trial-1 and Randomized Diabetes Prevention Trial with Oral Insulin sponsored by TrialNet. By the linkage disequilibrium, DQA1 and DQB1 are haplotyped to form DQ haplotypes; DP and DR haplotypes are similarly constructed. Together with available clinical covariables, we applied the Cox regression model to assess HLAII immunogenic associations with the disease progression.RESULTS: 1) The current investigation updated the previously reported genetic associations of DQA1*03:01-DQB1*03:02 (hazard ratio [HR] = 1.25, P = 3.50*10-3) and DQA1*03:03-DQB1*03:01 (HR = 0.56, P = 1.16*10-3), and also uncovered a risk association with DQA1*05:01-DQB1*02:01 (HR = 1.19, P = 0.041). 2) After adjusting for DQ, DPA1*02:01-DPB1*11:01 and DPA1*01:03-DPB1*03:01 were found to have opposite associations with progression (HR = 1.98 and 0.70, P = 0.021 and 6.16*10-3, respectively). 3) DRB1*03:01-DRB3*01:01 and DRB1*03:01-DRB3*02:02, sharing the DRB1*03:01, had opposite associations (HR = 0.73 and 1.44, P = 0.04 and 0.019, respectively), indicating a role of DRB3. Meanwhile, DRB1*12:01-DRB3*02:02 and DRB1*01:03 alone were found to associate with progression (HR = 2.6 and 2.32, P = 0.018 and 0.039, respectively). 4) Through enumerating all heterodimers, it was found that both DQ and DP could exhibit associations with disease progression.CONCLUSIONS: These results suggest that HLAII polymorphisms influence progression from islet autoimmunity to T1D among at-risk subjects with islet autoantibodies.
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| 6. |
- Zhao, Lue Ping, et al.
(författare)
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Oral Insulin Delay of Stage 3 Type 1 Diabetes Revisited in HLA DR4-DQ8 Participants in the TrialNet Oral Insulin Prevention Trial (TN07)
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Ingår i: Diabetes Care. - 1935-5548. ; , s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To explore if oral insulin could delay onset of stage 3 type 1 diabetes (T1D) among patients with stage 1/2 who carry HLA DR4-DQ8 and/or have elevated levels of IA-2 autoantibodies (IA-2As).RESEARCH AND METHODS: Next-generation targeted sequencing technology was used to genotype eight HLA class II genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, and DPB1) in 546 participants in the TrialNet oral insulin preventative trial (TN07). Baseline levels of autoantibodies against insulin (IAA), GAD65 (GADA), and IA-2A were determined prior to treatment assignment. Available clinical and demographic covariables from TN07 were used in this post hoc analysis with the Cox regression model to quantify the preventive efficacy of oral insulin.RESULTS: Oral insulin reduced the frequency of T1D onset among participants with elevated IA-2A levels (HR 0.62; P = 0.012) but had no preventive effect among those with low IA-2A levels (HR 1.03; P = 0.91). High IA-2A levels were positively associated with the HLA DR4-DQ8 haplotype (OR 1.63; P = 6.37 × 10-6) and negatively associated with the HLA DR7-containing DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 extended haplotype (OR 0.49; P = 0.037). Among DR4-DQ8 carriers, oral insulin delayed the progression toward stage 3 T1D onset (HR 0.59; P = 0.027), especially if participants also had high IA-2A level (HR 0.50; P = 0.028).CONCLUSIONS: These results suggest the presence of a T1D endotype characterized by HLA DR4-DQ8 and/or elevated IA-2A levels; for those patients with stage 1/2 disease with such an endotype, oral insulin delays the clinical T1D onset.
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| 7. |
- Zhao, Lue Ping, et al.
(författare)
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The KAG motif of HLA-DRB1 (beta 71, beta 74, beta 86) predicts seroconversion and development of type 1 diabetes
- 2021
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 69
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Tidskriftsartikel (refereegranskat)abstract
- Background: HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated. Methods: We used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity and identified critical amino acid residues by minimizing local genomic architecture and higher-order interactions. Findings: Three amino acid residues of HLA-DRB1 (beta 71, beta 74, beta 86) were found to be predictive of T1D risk in the population-based study. The " KAG" motif, corresponding to HLA-DRB1x04:01, was most strongly associated with T1D risk ([O]dds [R]atio=3.64, p = 3.19 x 10(-64)). Three less frequent motifs ("EAV", OR = 2.55, p = 0.025; "RAG", OR = 1.93, p = 0.043; and "RAV", OR = 1.56, p = 0.003) were associated with T1D risk, while two motifs ("REG" and "REV") were equally protective (OR = 0.11, p = 4.23 x 10(-4)). In an independent birth cohort of HLA-DR3 and HLA-DR4 subjects, those having the "KAG" motif had increased risk for time-to-seroconversion (Hazard Ratio = 1.74, p = 6.51 x 10(-14)) after adjusting potential confounders. Interpretations: DNA sequence variation in HLA-DRB1 at positions beta 71, beta 74, and beta 86 are non-conservative (beta 74 A -> E, beta 71 E vs K vs R and beta 86 G vs V). They result in substantial differences in peptide antigen anchor pocket preferences at p1, p4 and potentially neighboring regions such as pocket p7. Differential peptide antigen binding is likely to be affected. These sequence substitutions may account for most of the HLA-DR4 contribution to T1D risk as illustrated in two HLA-peptide model complexes of the T1D autoantigens preproinsulin and GAD65. (C) 2021 The Author(s). Published by Elsevier B.V.
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| 8. |
- Zhao, Lue Ping, et al.
(författare)
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The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes
- 2021
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 69
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated.METHODS: We used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity and identified critical amino acid residues by minimizing local genomic architecture and higher-order interactions.FINDINGS: Three amino acid residues of HLA-DRB1 (β71, β74, β86) were found to be predictive of T1D risk in the population-based study. The "KAG" motif, corresponding to HLA-DRB1×04:01, was most strongly associated with T1D risk ([O]dds [R]atio=3.64, p = 3.19 × 10-64). Three less frequent motifs ("EAV", OR = 2.55, p = 0.025; "RAG", OR = 1.93, p = 0.043; and "RAV", OR = 1.56, p = 0.003) were associated with T1D risk, while two motifs ("REG" and "REV") were equally protective (OR = 0.11, p = 4.23 × 10-4). In an independent birth cohort of HLA-DR3 and HLA-DR4 subjects, those having the "KAG" motif had increased risk for time-to-seroconversion (Hazard Ratio = 1.74, p = 6.51 × 10-14) after adjusting potential confounders.INTERPRETATIONS: DNA sequence variation in HLA-DRB1 at positions β71, β74, and β86 are non-conservative (β74 A→E, β71 E vs K vs R and β86 G vs V). They result in substantial differences in peptide antigen anchor pocket preferences at p1, p4 and potentially neighboring regions such as pocket p7. Differential peptide antigen binding is likely to be affected. These sequence substitutions may account for most of the HLA-DR4 contribution to T1D risk as illustrated in two HLA-peptide model complexes of the T1D autoantigens preproinsulin and GAD65.FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases and the Swedish Child Diabetes Foundation and the Swedish Research Council.
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