| 1. |
- Wang, Anqi, et al.
(author)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Journal article (peer-reviewed)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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| 2. |
- Chatterjee, S., et al.
(author)
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Protein Paucimannosylation Is an Enriched N-Glycosylation Signature of Human Cancers
- 2019
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In: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 19:21-22
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Journal article (peer-reviewed)abstract
- While aberrant protein glycosylation is a recognized characteristic of human cancers, advances in glycoanalytics continue to discover new associations between glycoproteins and tumorigenesis. This glycomics‐centric study investigates a possible link between protein paucimannosylation, an under‐studied class of human N‐glycosylation [Man1‐3GlcNAc2Fuc0‐1], and cancer. The paucimannosidic glycans (PMGs) of 34 cancer cell lines and 133 tissue samples spanning 11 cancer types and matching non‐cancerous specimens are profiled from 467 published and unpublished PGC‐LC‐MS/MS N‐glycome datasets collected over a decade. PMGs, particularly Man2‐3GlcNAc2Fuc1, are prominent features of 29 cancer cell lines, but the PMG level varies dramatically across and within the cancer types (1.0–50.2%). Analyses of paired (tumor/non‐tumor) and stage‐stratified tissues demonstrate that PMGs are significantly enriched in tumor tissues from several cancer types including liver cancer (p = 0.0033) and colorectal cancer (p = 0.0017) and is elevated as a result of prostate cancer and chronic lymphocytic leukaemia progression (p < 0.05). Surface expression of paucimannosidic epitopes is demonstrated on human glioblastoma cells using immunofluorescence while biosynthetic involvement of N‐acetyl‐β‐hexosaminidase is indicated by quantitative proteomics. This intriguing association between protein paucimannosylation and human cancers warrants further exploration to detail the biosynthesis, cellular location(s), protein carriers, and functions of paucimannosylation in tumorigenesis and metastasis.
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| 3. |
- Buffart, L. M., et al.
(author)
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Effects and moderators of coping skills training on symptoms of depression and anxiety in patients with cancer : Aggregate data and individual patient data meta-analyses
- 2020
-
In: Clinical Psychology Review. - : Elsevier BV. - 0272-7358 .- 1873-7811. ; 80
-
Research review (peer-reviewed)abstract
- PURPOSE: This study evaluated the effects of coping skills training (CST) on symptoms of depression and anxiety in cancer patients, and investigated moderators of the effects.METHODS: Overall effects and intervention-related moderators were studied in meta-analyses of pooled aggregate data from 38 randomized controlled trials (RCTs). Patient-related moderators were examined using linear mixed-effect models with interaction tests on pooled individual patient data (n = 1953) from 15 of the RCTs.RESULTS: CST had a statistically significant but small effect on depression (g = -0.31,95% confidence interval (CI) = -0.40;-0.22) and anxiety (g = -0.32,95%CI = -0.41;-0.24) symptoms. Effects on depression symptoms were significantly larger for interventions delivered face-to-face (p = .003), led by a psychologist (p = .02) and targeted to patients with psychological distress (p = .002). Significantly larger reductions in anxiety symptoms were found in younger patients (pinteraction < 0.025), with the largest reductions in patients <50 years (β = -0.31,95%CI = -0.44;-0.18) and no significant effects in patients ≥70 years. Effects of CST on depression (β = -0.16,95%CI = -0.25;-0.07) and anxiety (β = -0.24,95%CI = -0.33;-0.14) symptoms were significant in patients who received chemotherapy but not in patients who did not (pinteraction < 0.05).CONCLUSIONS: CST significantly reduced symptoms of depression and anxiety in cancer patients, and particularly when delivered face-to-face, provided by a psychologist, targeted to patients with psychological distress, and given to patients who were younger and received chemotherapy.
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| 4. |
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| 5. |
- Butler, P. A., et al.
(author)
-
Evolution of Octupole Deformation in Radium Nuclei from Coulomb Excitation of Radioactive ^{222}Ra and ^{228}Ra Beams
- 2020
-
In: Physical Review Letters. - 1079-7114. ; 124:4
-
Journal article (peer-reviewed)abstract
- There is sparse direct experimental evidence that atomic nuclei can exhibit stable "pear" shapes arising from strong octupole correlations. In order to investigate the nature of octupole collectivity in radium isotopes, electric octupole (E3) matrix elements have been determined for transitions in ^{222,228}Ra nuclei using the method of sub-barrier, multistep Coulomb excitation. Beams of the radioactive radium isotopes were provided by the HIE-ISOLDE facility at CERN. The observed pattern of E3 matrix elements for different nuclear transitions is explained by describing ^{222}Ra as pear shaped with stable octupole deformation, while ^{228}Ra behaves like an octupole vibrator.
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| 6. |
- Butler, P. A., et al.
(author)
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The observation of vibrating pear-shapes in radon nuclei
- 2019
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
-
Journal article (peer-reviewed)abstract
- There is a large body of evidence that atomic nuclei can undergo octupole distortion and assume the shape of a pear. This phenomenon is important for measurements of electric-dipole moments of atoms, which would indicate CP violation and hence probe physics beyond the Standard Model of particle physics. Isotopes of both radon and radium have been identified as candidates for such measurements. Here, we observed the low-lying quantum states in 224Rn and 226Rn by accelerating beams of these radioactive nuclei. We show that radon isotopes undergo octupole vibrations but do not possess static pear-shapes in their ground states. We conclude that radon atoms provide less favourable conditions for the enhancement of a measurable atomic electric-dipole moment.
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| 7. |
- Anney, Richard, et al.
(author)
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A genome-wide scan for common alleles affecting risk for autism.
- 2010
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
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Journal article (peer-reviewed)abstract
- Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
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| 8. |
- Spagnoletti, P., et al.
(author)
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Coulomb excitation of Rn 222
- 2022
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In: Physical Review C. - 2469-9985. ; 105:2
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Journal article (peer-reviewed)abstract
- The nature of quadrupole and octupole collectivity in Rn222 was investigated by determining the electric-quadrupole (E2) and octupole (E3) matrix elements using subbarrier, multistep Coulomb excitation. The radioactive Rn222 beam, accelerated to 4.23 MeV/u, was provided by the HIE-ISOLDE facility at CERN. Data were collected in the Miniball γ-ray spectrometer following the bombardment of two targets, Sn120 and Ni60. Transition E2 matrix elements within the ground-state and octupole bands were measured up to 10ℏ and the results were consistent with a constant intrinsic electric-quadrupole moment, 518(11)efm2. The values of the intrinsic electric-octupole moment for the 0+→3- and 2+→5- transitions were found to be respectively 2360-210+300efm3 and 2300-500+300efm3 while a smaller value, 1200-900+500efm3, was found for the 2+→1- transition. In addition, four excited non-yrast states were identified in this work via γ-γ coincidences.
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| 9. |
- Pinto, Dalila, et al.
(author)
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Functional impact of global rare copy number variation in autism spectrum disorders.
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
-
Journal article (peer-reviewed)abstract
- The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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| 10. |
- Casey, Jillian P, et al.
(author)
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A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
- 2012
-
In: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
-
Journal article (peer-reviewed)abstract
- Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
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| 11. |
- Abrahams, Harriët J. G., et al.
(author)
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Moderators of the effect of psychosocial interventions on fatigue in women with breast cancer and men with prostate cancer : Individual patient data meta-analyses
- 2020
-
In: Psycho-Oncology. - : Wiley. - 1057-9249 .- 1099-1611. ; 29:11, s. 1772-1785
-
Research review (peer-reviewed)abstract
- ObjectivePsychosocial interventions can reduce cancer‐related fatigue effectively. However, it is still unclear if intervention effects differ across subgroups of patients. These meta‐analyses aimed at evaluating moderator effects of (a) sociodemographic characteristics, (b) clinical characteristics, (c) baseline levels of fatigue and other symptoms, and (d) intervention‐related characteristics on the effect of psychosocial interventions on cancer‐related fatigue in patients with non‐metastatic breast and prostate cancer.MethodsData were retrieved from the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) consortium. Potential moderators were studied with meta‐analyses of pooled individual patient data from 14 randomized controlled trials through linear mixed‐effects models with interaction tests. The analyses were conducted separately in patients with breast (n = 1091) and prostate cancer (n = 1008).ResultsStatistically significant, small overall effects of psychosocial interventions on fatigue were found (breast cancer: β = −0.19 [95% confidence interval (95%CI) = −0.30; −0.08]; prostate cancer: β = −0.11 [95%CI = −0.21; −0.00]). In both patient groups, intervention effects did not differ significantly by sociodemographic or clinical characteristics, nor by baseline levels of fatigue or pain. For intervention‐related moderators (only tested among women with breast cancer), statistically significant larger effects were found for cognitive behavioral therapy as intervention strategy (β = −0.27 [95%CI = −0.40; −0.15]), fatigue‐specific interventions (β = −0.48 [95%CI = −0.79; −0.18]), and interventions that only targeted patients with clinically relevant fatigue (β = −0.85 [95%CI = −1.40; −0.30]).ConclusionsOur findings did not provide evidence that any selected demographic or clinical characteristic, or baseline levels of fatigue or pain, moderated effects of psychosocial interventions on fatigue. A specific focus on decreasing fatigue seems beneficial for patients with breast cancer with clinically relevant fatigue.
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| 12. |
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| 13. |
- Downey, Harriet, et al.
(author)
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Training future generations to deliver evidence-based conservation and ecosystem management
- 2021
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In: Ecological Solutions and Evidence. - : Wiley. - 2688-8319. ; 2:1
-
Research review (peer-reviewed)abstract
- 1. To be effective, the next generation of conservation practitioners and managers need to be critical thinkers with a deep understanding of how to make evidence-based decisions and of the value of evidence synthesis.2. If, as educators, we do not make these priorities a core part of what we teach, we are failing to prepare our students to make an effective contribution to conservation practice.3. To help overcome this problem we have created open access online teaching materials in multiple languages that are stored in Applied Ecology Resources. So far, 117 educators from 23 countries have acknowledged the importance of this and are already teaching or about to teach skills in appraising or using evidence in conservation decision-making. This includes 145 undergraduate, postgraduate or professional development courses.4. We call for wider teaching of the tools and skills that facilitate evidence-based conservation and also suggest that providing online teaching materials in multiple languages could be beneficial for improving global understanding of other subject areas.
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| 14. |
- Leszczynska, M., et al.
(author)
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Thermal Variation of Structure and Electrical Conductivity in Bi4YbO7.5
- 2013
-
In: Chemistry of Materials. - : American Chemical Society (ACS). - 1520-5002 .- 0897-4756. ; 25:3, s. 326-336
-
Journal article (peer-reviewed)abstract
- The thermal behavior of the oxide ion-conducting solid electrolyte Bi4YbO7.5 was investigated using a combination of variable temperature X-ray and neutron powder diffraction, thermal analysis (DTA and TGA), and ac impedance spectroscopy. The title compound shows a fluorite-type structure throughout the measured temperature range (20-850 degrees C), with a phase separation at ca. 600 degrees C into a cubic delta-type phase and an orthorhombic phase of assumed stoichiometry Bi17Yb7O36. This type of transition is a relatively common feature in bismuth oxide-based systems and can limit their practical application. Here, the transition was carefully studied using isothermal measurements, which showed that it is accompanied by changes in oxide-ion stoichiometry, as well as significant disorder in the oxide ion sublattice in the delta-type phase. These results correlate with the observed electrical behavior. Analysis of the total neutron scattering through reverse Monte Carlo (RMC) modeling reveals details of the coordination environments for both cations. The oxide-ion vacancy distribution seems to be consistent with a favoring of vacancy pairs, although vacancy pairs exhibit the highest frequency as they have the maximum likelihood. A vacancy ordering model based on three vacancies per cell is presented.
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| 15. |
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| 16. |
- Gotz, L., et al.
(author)
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GlycoDigest: a tool for the targeted use of exoglycosidase digestions in glycan structure determination
- 2014
-
In: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 30:21, s. 3131-3133
-
Journal article (peer-reviewed)abstract
- Sequencing oligosaccharides by exoglycosidases, either sequentially or in an array format, is a powerful tool to unambiguously determine the structure of complex N- and O-link glycans. Here, we introduce GlycoDigest, a tool that simulates exoglycosidase digestion, based on controlled rules acquired from expert knowledge and experimental evidence available in GlycoBase. The tool allows the targeted design of glycosidase enzyme mixtures by allowing researchers to model the action of exoglycosidases, thereby validating and improving the efficiency and accuracy of glycan analysis.
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| 17. |
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| 18. |
- Leszczynska, M., et al.
(author)
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Oxide ion distribution, vacancy ordering and electrical behaviour in the Bi3NbO7-Bi3YbO6 pseudo-binary system
- 2014
-
In: Journal of Materials Chemistry A. - : Royal Society of Chemistry (RSC). - 2050-7488 .- 2050-7496. ; 2:43, s. 18624-18634
-
Journal article (peer-reviewed)abstract
- Oxide ion distribution, vacancy ordering and electrical conductivity has been examined in the Nb/Yb double substituted bismuth oxide based system Bi3Nb1-xYbxO7-x, using X-ray and neutron powder diffraction, reverse Monte Carlo modelling of total neutron scattering data and a. c. impedance spectroscopy. Transference number measurements confirm the system to be predominantly ionically conducting above ca. 450 degrees C. Niobium rich compositions show incommensurate ordering of the fluorite subcell, while increasing ytterbium content results in a commensurate fluorite, with fully disordered cation and anion sublattices. Oxide ion distribution shows both compositional and thermal dependencies. The latter is discussed with respect to its effect on the thermal variation of cubic lattice parameter. Substitution of bismuth by niobium and ytterbium in the cation sublattice of bismuth oxide leads to the creation of Frenkel interstitial oxide ions, which increase the tetrahedral vacancy concentration. The high vacancy concentration is confirmed in both Rietveld and RMC analyses of neutron data. Examination of vacancy ordering, in the x - 0.6 composition, indicates a favouring of vacancy pair alignment.
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| 19. |
- Leszczynska, M., et al.
(author)
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Total scattering analysis of cation coordination and vacancy pair distribution in Yb substituted delta-Bi2O3
- 2013
-
In: Journal of Physics Condensed Matter. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 25:45
-
Journal article (peer-reviewed)abstract
- Reverse Monte Carlo (RMC) modelling of neutron total scattering data, combined with conventional Rietveld analysis of x-ray and neutron data, has been used to describe the cation coordination environments and vacancy pair distribution in the oxide ion conducting electrolyte Bi3YbO6. The thermal variation of the cubic fluorite unit cell volume, monitored by variable temperature x-ray and neutron experiments, reveals significant curvature, which is explained by changes in the oxide ion distribution. There is a significant increase in tetrahedral oxide ion vacancy concentration relative to delta-Bi2O3, due to the creation of Frenkel defects associated with the Yb3+ cation. The tetrahedral oxide ion vacancy concentration increases from room temperature to 800 degrees C, but little change is observed in the vacancy pair distribution with temperature. The vacancy pair distributions at both temperatures are consistent with a favouring of vacancy pairs.
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| 20. |
- Lisacek, F., et al.
(author)
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Databases and associated tools for glycomics and glycoproteomics
- 2017
-
In: High-Throughput Glycomics and Glycoproteomics. Eds: Gordan Lauc & Manfred Wuhrer. - New York : Springer. - 1064-3745. - 9781493964932 - 9781493964918 ; , s. 235-264
-
Book chapter (other academic/artistic)abstract
- The access to biodatabases for glycomics and glycoproteomics has proven to be essential for current glycobiological research. This chapter presents available databases that are devoted to different aspects of glycobioinformatics. This includes oligosaccharide sequence databases, experimental databases, 3D structure databases (of both glycans and glycorelated proteins) and association of glycans with tissue, disease, and proteins. Specific search protocols are also provided using tools associated with experimental databases for converting primary glycoanalytical data to glycan structural information. In particular, researchers using glycoanalysis methods by U/HPLC (GlycoBase), MS (GlycoWorkbench, UniCarb-DB, GlycoDigest), and NMR (CASPER) will benefit from this chapter. In addition we also include information on how to utilize glycan structural information to query databases that associate glycans with proteins (UniCarbKB) and with interactions with pathogens (Sugar Bind). © Springer Science+Business Media New York 2017.
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| 21. |
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| 22. |
- Abrahams-Gessel, Shafika, et al.
(author)
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Improvements in Hypertension Control in the Rural Longitudinal HAALSI Cohort of South African Adults Aged 40 and Older, From 2014 to 2019
- 2023
-
In: American Journal of Hypertension. - : Oxford University Press. - 0895-7061 .- 1941-7225. ; 36:6, s. 324-332
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Over half of the South African adults aged 45 years and older have hypertension but its effective management along the treatment cascade (awareness, treatment, and control) remains poorly understood.METHODS: We compared the prevalence of all stages of the hypertension treatment cascade in the rural HAALSI cohort of older adults at baseline and after four years of follow-up using household surveys and blood pressure data. Hypertension was a mean systolic blood pressure >140 mm Hg or diastolic pressure >90 mm Hg, or current use of anti-hypertension medication. Control was a mean blood pressure <140/90 mm Hg. The effects of sex and age on the treatment cascade at follow-up were assessed. Multivariate Poisson regression models were used to estimate prevalence ratios along the treatment cascade at follow-up.RESULTS: Prevalence along the treatment cascade increased from baseline (B) to follow-up (F): awareness (64.4% vs. 83.6%), treatment (49.7% vs. 73.9%), and control (22.8% vs. 41.3%). At both time points, women had higher levels of awareness (B: 70.5% vs. 56.3%; F: 88.1% vs. 76.7%), treatment (B: 55.9% vs. 41.55; F: 79.9% vs. 64.7%), and control (B: 26.5% vs. 17.9%; F: 44.8% vs. 35.7%). Prevalence along the cascade increased linearly with age for everyone. Predictors of awareness included being female, elderly, or visiting a primary health clinic three times in the previous 3 months, and the latter two also predicted hypertension control.CONCLUSIONS: There were significant improvements in awareness, treatment, and control of hypertension from baseline to follow-up and women fared better at all stages, at both time points.
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| 23. |
- Abrahams, I., et al.
(author)
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A Combined Total Scattering and Simulation Approach to Analyzing Defect Structure in Bi3YO6
- 2010
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In: Chemistry of Materials. - : American Chemical Society (ACS). - 1520-5002 .- 0897-4756. ; 22:15, s. 4435-4445
-
Journal article (peer-reviewed)abstract
- The defect structure and electrical properties of the fast oxide ion-conducting solid electrolyte delta-Bi3YO6 have been studied using a combination of total neutron scattering analysis, energy minimization methods, and AC impedance spectroscopy. Conventional structural analysis using the Rietveld method reveals the oxide ions to be distributed over three crystallographic sites at room temperature, with a small change in this distribution at 800 degrees C. Analysis of short-range correlations using a total neutron scattering approach yields information on Bi and Y coordination environments. Careful analysis of the angular distribution functions derived from reverse Monte Carlo modeling of the total scattering data reveals physical evidence for a predominance of vacancy ordering in this system. This ordering is confirmed as the lowest energy configuration in parallel energy minimization simulations.
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| 24. |
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| 25. |
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| 26. |
- Andersen, Peter M., et al.
(author)
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EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) : revised report of an EFNS task force
- 2012
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 19:3, s. 360-E24
-
Journal article (peer-reviewed)abstract
- Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. Objectives: To provide evidence-based or expert recommendations for the diagnosis and management of ALS based on a literature search and the consensus of an expert panel. Methods: All available medical reference systems were searched, and original papers, meta-analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus. Recommendations: Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non-invasive positive-pressure ventilation also improves survival and quality of life. Maintaining the patient's ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end-of-life care should be discussed early with the patient and carers, respecting the patient's social and cultural background.
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| 27. |
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| 28. |
- Benatar, Michael, et al.
(author)
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Preventing amyotrophic lateral sclerosis : insights from pre-symptomatic neurodegenerative diseases
- 2022
-
In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 145:1, s. 27-44
-
Research review (peer-reviewed)abstract
- Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned - more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers - we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.
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| 29. |
- Benatar, Michael, et al.
(author)
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The Miami Framework for ALS and related neurodegenerative disorders : an integrated view of phenotype and biology
- 2024
-
In: Nature Reviews Neurology. - : Springer Nature. - 1759-4758 .- 1759-4766. ; 20:6, s. 364-376
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Research review (peer-reviewed)abstract
- Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.
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| 30. |
- Clabbers, M. T. B., et al.
(author)
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Protein structure determination by electron diffraction using a single three-dimensional nanocrystal
- 2017
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In: Acta Crystallographica Section D. - 2059-7983. ; 73, s. 738-748
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Journal article (peer-reviewed)abstract
- Three-dimensional nanometre-sized crystals of macromolecules currently resist structure elucidation by single-crystal X-ray crystallography. Here, a single nanocrystal with a diffracting volume of only 0.14 mu m(3), i.e. no more than 6 x 10(5) unit cells, provided sufficient information to determine the structure of a rare dimeric polymorph of hen egg-white lysozyme by electron crystallography. This is at least an order of magnitude smaller than was previously possible. The molecular-replacement solution, based on a monomeric polyalanine model, provided sufficient phasing power to show side-chain density, and automated model building was used to reconstruct the side chains. Diffraction data were acquired using the rotation method with parallel beam diffraction on a Titan Krios transmission electron microscope equipped with a novel in-house-designed 1024 x 1024 pixel Timepix hybrid pixel detector for low-dose diffraction data collection. Favourable detector characteristics include the ability to accurately discriminate single high-energy electrons from X-rays and count them, fast readout to finely sample reciprocal space and a high dynamic range. This work, together with other recent milestones, suggests that electron crystallography can provide an attractive alternative in determining biological structures.
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| 31. |
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| 32. |
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| 33. |
- Du Toit, Jacques D., et al.
(author)
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Estimating population level 24-h sodium excretion using spot urine samples in older adults in rural South Africa
- 2023
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In: Journal of Hypertension. - : Wolters Kluwer. - 0263-6352 .- 1473-5598. ; 41:2, s. 280-287
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Journal article (peer-reviewed)abstract
- BACKGROUND: South Africa has introduced regulations to reduce sodium in processed foods. Assessing salt consumption with 24-h urine collection is logistically challenging and expensive. We assess the accuracy of using spot urine samples to estimate 24-h urine sodium (24hrUNa) excretion at the population level in a cohort of older adults in rural South Africa.METHODS: 24hrUNa excretion was measured and compared to that estimated from matched spot urine samples in 399 individuals, aged 40-75 years, from rural Mpumalanga, South Africa. We used the Tanaka, Kawasaki, International Study of Sodium, Potassium, and Blood Pressure (INTERSALT), and Population Mean Volume (PMV) method to predict 24hrUNa at the individual and population level.RESULTS: The population median 24hrUNa excretion from our samples collected in 2017 was 2.6 g (interquartile range: 1.53-4.21) equal to an average daily salt intake of 6.6 g, whereas 65.4% of participants had a salt excretion above the WHO recommended 5 g/day. Estimated population median 24hrUNa derived from the INTERSALT, both with and without potassium, showed a nonsignificant difference of 0.25 g (P = 0.59) and 0.21 g (P = 0.67), respectively. In contrast, the Tanaka, Kawasaki, and PMV formulas were markedly higher than the measured 24hrUNa, with a median difference of 0.51 g (P = 0.004), 0.99 g (P = 0.00), and 1.05 g (P = 0.00) respectively. All formulas however performed poorly when predicting an individual's 24hrUNa.CONCLUSION: In this population, the INTERSALT formulas are a well suited and cost-effective alternative to 24-h urine collection for the evaluation of population median 24hrUNa excretion. This could play an important role for governments and public health agencies in evaluating local salt regulations and identifying at-risk populations.
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| 34. |
- Ferro, Enrico G., et al.
(author)
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Echocardiographic and Electrocardiographic Abnormalities Among Elderly Adults With Cardiovascular Disease in Rural South Africa
- 2021
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In: Circulation. Cardiovascular Quality and Outcomes. - : NLM (Medline). - 1941-7713 .- 1941-7705. ; 14:11, s. 1175-1186
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Journal article (peer-reviewed)abstract
- BACKGROUND: Sub-Saharan Africa is undergoing an epidemiological transition fueled by the interaction between infectious and cardiovascular diseases. Our cross-sectional study aimed to characterize the spectrum of abnormalities suggesting end-organ damage on ECG and transthoracic echocardiograms (TTE) among older adults with cardiovascular diseases in rural South Africa.METHODS: The prevalence of ECG and TTE abnormalities was estimated; χ2 analyses and multivariable logistic regressions were performed to test their association with sex, hypertension, and other selected comorbidities.RESULTS: Overall, 729 ECGs and 155 TTEs were completed, with 74 participants completing both. ECG evaluation showed high rates of left ventricular hypertrophy (LVH, 36.5%) and T wave abnormalities (13.6%). TTE evaluation showed high rates of concentric LVH (31.6%), with moderate-severe (56.8%) diastolic dysfunction. Participants with hypertension showed more cardiac remodeling on ECG by LVH (45.4% versus 22.1%, P<0.01), and TTE by concentric LVH (42.5% versus 8.2%, P<0.01) and increased left ventricular mass (58.5% versus 20.4%, P<0.0001). In multivariable logistic regression, systolic blood pressure remained significantly associated with LVH on ECG (adjusted odds ratio, 1.03 per mm Hg [95% CI, 1.03-1.04], P<0.0001) and increased left ventricular mass on TTE (adjusted odds ratio, 1.04 per mm Hg [95% CI, 1.01-1.06], P=0.001). Male participants (n=326, 40.2%) were more likely than females (n=484, 59.8%) to show ECG abnormalities like LVH (45% versus 30.8%, P<0.01), whereas females were more likely to show TTE abnormalities like concentric LVH (40.8% versus 13.5%, P<0.01) and increased left ventricular mass (58.4% versus 23.1%, P<0.0001). Similar results were confirmed in multivariable models.CONCLUSIONS: Our findings suggest that cardiovascular diseases are widespread in rural South Africa, with a larger burden of hypertensive heart disease than previously appreciated, and define the severity of end-organ damage that is already underway. Local health systems must adapt to face the growing burden of hypertension, as suboptimal rates of hypertension diagnosis and treatment may dramatically increase the heart failure burden.
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| 35. |
- Lauc, Gordan, et al.
(author)
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Genomics Meets Glycomics-The First GWAS Study of Human N-Glycome Identifies HNF1 alpha as a Master Regulator of Plasma Protein Fucosylation
- 2010
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 6:12, s. e1001256-
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Journal article (peer-reviewed)abstract
- Over half of all proteins are glycosylated, and alterations in glycosylation have been observed in numerous physiological and pathological processes. Attached glycans significantly affect protein function; but, contrary to polypeptides, they are not directly encoded by genes, and the complex processes that regulate their assembly are poorly understood. A novel approach combining genome-wide association and high-throughput glycomics analysis of 2,705 individuals in three population cohorts showed that common variants in the Hepatocyte Nuclear Factor 1 alpha (HNF1 alpha) and fucosyltransferase genes FUT6 and FUT8 influence N-glycan levels in human plasma. We show that HNF1 alpha and its downstream target HNF4 alpha regulate the expression of key fucosyltransferase and fucose biosynthesis genes. Moreover, we show that HNF1 alpha is both necessary and sufficient to drive the expression of these genes in hepatic cells. These results reveal a new role for HNF1 alpha as a master transcriptional regulator of multiple stages in the fucosylation process. This mechanism has implications for the regulation of immunity, embryonic development, and protein folding, as well as for our understanding of the molecular mechanisms underlying cancer, coronary heart disease, and metabolic and inflammatory disorders.
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| 36. |
- Leonard, Hampton L., et al.
(author)
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The IPDGC/GP2 Hackathon - an open science event for training in data science, genomics, and collaboration using Parkinson’s disease data
- 2023
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In: npj Parkinson's Disease. - : Springer Science and Business Media LLC. - 2373-8057. ; 9:1
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Journal article (peer-reviewed)abstract
- Open science and collaboration are necessary to facilitate the advancement of Parkinson’s disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD.
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| 37. |
- Liu, X., et al.
(author)
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A neutron total scattering study of defect structure in Bi3Nb0.5Y0.5O6.5
- 2011
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In: Solid State Ionics. - : Elsevier BV. - 0167-2738. ; 192:1, s. 176-180
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Journal article (peer-reviewed)abstract
- The defect structure of the title compound has been analyzed by reverse Monte Carlo (RMC) modeling of neutron total scattering data. The composition exhibits both diffuse scattering and weak superlattice ordering of the cubic fluorite subcell in neutron diffraction patterns. Combined Rietveld analysis of X-ray and neutron data at room temperature reveals oxide ion scattering on three crystallographic sites. Analysis of the RMC model reveals Bi coordination numbers consistent with stereochemical activity of the Bi 6 s(2) lone pair electrons. Integration of the O-M-O angular distribution function gives an angular ratio consistent with predominantly vacancy ordering in this system.
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| 38. |
- Lu, J., et al.
(author)
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Structural, Spectroscopic, and Electrochemical Characterization of Semi-Conducting, Solvated [Pt(NH 3 ) 4 ](TCNQ) 2 ·(DMF) 2 and Non-Solvated [Pt(NH 3 ) 4 ](TCNQ) 2
- 2017
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In: Australian Journal of Chemistry. - 1445-0038 .- 0004-9425. ; 70:9, s. 997-1005
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Journal article (peer-reviewed)abstract
- The demand for catalysts that are highly active and stable for electron-transfer reactions has been boosted by the discovery that [Pt(NH3)4](TCNQF4)2 (TCNQF4≤2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane) is an efficient catalyst. In this work, we prepare and characterize the two related [Pt(NH3)4] 2+ complexes, [Pt(NH3)4](TCNQ)2·(DMF)2 (1) and [Pt(NH3)4] (TCNQ)2 (2). Reaction of [Pt(NH3)4](NO3)2 with LiTCNQ in a mixed solvent (methanol/dimethylformamide, 4:1v/v) gives [Pt(NH3)4] (TCNQ)2·(DMF)2 (1), whereas the same reaction in water affords [Pt(NH3)4](TCNQ)2 (2). 2 has been previously reported. Both 1 and 2 have now been characterized by single-crystal X-ray crystallography, Fourier-transform (FT)IR, Raman and UV-vis spectroscopy, and electrochemistry. Structurally, in 1, the TCNQ1-anions form infinite stacks with a separation between adjacent anions within the stack alternating between 3.12 and 3.42Å. The solvated structure 1 differs from the non-solvated form 2 in that pairs of TCNQ1-anions are clearly displaced from each other. The conductivities of pressed pellets of 1 and 2 are both in the semi-conducting range at room temperature. 2 can be electrochemically synthesized by reduction of a TCNQ-modified electrode in contact with an aqueous solution of [Pt(NH3)4] (NO3)2 via a nucleation growth mechanism. Interestingly, we discovered that 1 and 2 are not catalysts for the ferricyanide and thiosulfate reaction. Li+ and tetraalkylammonium salts of TCNQ1-/2-and TCNQF41-/2-were tested for potential catalytic activity towards ferricyanide and thiosulfate. Only TCNQF41-/2-salts were active, suggesting that the dianion redox level needs to be accessible for efficient catalytic activity and explaining why 1 and 2 are not good catalysts. Importantly, the origin of the catalytic activity of the highly active [Pt(NH3)4](TCNQF4)2 catalyst is now understood, enabling other families of catalysts to be developed for important electron-transfer reactions.
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| 39. |
- Lundstrom, UH, et al.
(author)
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Barriers and opportunities to increase PD incidence and prevalence: Lessons from a European Survey
- 2021
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In: Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. - : SAGE Publications. - 1718-4304 .- 0896-8608. ; 41:6, s. 542-551
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Journal article (peer-reviewed)abstract
- Peritoneal dialysis (PD) remains underutilised and unplanned start of dialysis further diminishes the likelihood of patients starting on PD, although outcomes are equal to haemodialysis (HD). Methods: A survey was sent to members of EuroPD and regional societies presenting a case vignette of a 48-year-old woman not previously known to the nephrology department and who arrives at the emergency department with established end-stage kidney disease (unplanned start), asking which dialysis modality would most likely be chosen at their respective centre. We assessed associations between the modality choices for this case vignette and centre characteristics and PD-related practices. Results: Of 575 respondents, 32.8%, 32.2% and 35.0% indicated they would start unplanned PD, unplanned HD or unplanned HD with intention to educate patient on PD later, respectively. Likelihood for unplanned start of PD was only associated with quality of structure of the pre-dialysis program. Structure of pre-dialysis education program, PD program in general, likelihood to provide education on PD to unplanned starters, good collaboration with the PD access team and taking initiatives to enhance home-based therapies increased the likelihood unplanned patients would end up on PD. Conclusions: Well-structured pre-dialysis education on PD as a modality, good connections to dedicated PD catheter placement teams and additional initiatives to enhance home-based therapies are key to grow PD programs. Centres motivated to grow their PD programs seem to find solutions to do so.
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| 40. |
- Luo, Jinghui, et al.
(author)
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Inhibiting and Reversing Amyloid-β Peptide (1-40) Fibril Formation with Gramicidin S and Engineered Analogues
- 2013
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In: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 19:51, s. 17338-17348
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Journal article (peer-reviewed)abstract
- In Alzheimer's disease, amyloid-β (Aβ) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidin S significantly inhibited Aβ amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidin S, a cyclic decapeptide that adopts a β-sheet conformation, binds to the Aβ peptide hairpin-stacked fibril through β-sheet interactions. This may explain why gramicidin S reduces fibril formation. Analogues of gramicidin S were also tested. An analogue with a potency that was four-times higher than that of the natural product was identified.
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| 41. |
- van der Sluijs, AV, et al.
(author)
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Assisted peritoneal dialysis across Europe: Practice variation and factors associated with availability
- 2021
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In: Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. - : SAGE Publications. - 1718-4304 .- 0896-8608. ; 41:6, s. 533-541
-
Journal article (peer-reviewed)abstract
- In Europe, the number of elderly end-stage kidney disease patients is increasing. Few of those patients receive peritoneal dialysis (PD), as many cannot perform PD autonomously. Assisted PD programmes are available in most European countries, but the percentage of patients receiving assisted PD varies considerably. Hence, we assessed which factors are associated with the availability of an assisted PD programme at a centre level and whether the availability of this programme is associated with proportion of home dialysis patients. Methods: An online survey was sent to healthcare professionals of European nephrology units. After selecting one respondent per centre, the associations were explored by χ 2 tests and (ordinal) logistic regression. Results: In total, 609 respondents completed the survey. Subsequently, 288 respondents from individual centres were identified; 58% worked in a centre with an assisted PD programme. Factors associated with availability of an assisted PD programme were Western European and Scandinavian countries (OR: 5.73; 95% CI: 3.07–10.68), non-academic centres (OR: 2.01; 95% CI: 1.09–3.72) and centres with a dedicated team for education (OR: 2.87; 95% CI: 1.35–6.11). Most Eastern & Central European respondents reported that the proportion of incident and prevalent home dialysis patients was <10% (72% and 63%), while 27% of Scandinavian respondents reported a proportion of >30% for both incident and prevalent home dialysis patients. Availability of an assisted PD programme was associated with a higher incidence (cumulative OR: 1.91; 95% CI: 1.21–3.01) and prevalence (cumulative OR: 2.81; 95% CI: 1.76–4.47) of patients on home dialysis. Conclusions: Assisted PD was more commonly offered among non-academic centres with a dedicated team for education across Europe, especially among Western European and Scandinavian countries where higher incidence and prevalence of home dialysis patients was reported.
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| 42. |
- Wade, Alisha N., et al.
(author)
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Concordance between fasting plasma glucose and HbA1c in the diagnosis of diabetes in black South African adults: A cross-sectional study
- 2021
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In: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 11:6
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Journal article (peer-reviewed)abstract
- Objectives: We investigated concordance between haemoglobin A1c (HbA1c)-defined diabetes and fasting plasma glucose (FPG)-defined diabetes in a black South African population with a high prevalence of obesity.Design: Cross-sectional study.Setting: Rural South African population-based cohort.Participants: 765 black individuals aged 40–70 years and with no history of diabetes.Primary and secondary outcome measures: The primary outcome measure was concordance between HbA1c-defined diabetes and FPG-defined diabetes. Secondary outcome measures were differences in anthropometric characteristics, fat distribution and insulin resistance (measured using Homoeostatic Model Assessment of Insulin Resistance (HOMA-IR)) between those with concordant and discordant HbA1c/FPG classifications and predictors of HbA1c variance.Results: The prevalence of HbA1c-defined diabetes was four times the prevalence of FPG-defined diabetes (17.5% vs 4.2%). Classification was discordant in 15.7% of participants, with 111 individuals (14.5%) having HbA1c-only diabetes (kappa 0.23; 95% CI 0.14 to 0.31). Median body mass index, waist and hip circumference, waist-to-hip ratio, subcutaneous adipose tissue and HOMA-IR in participants with HbA1c-only diabetes were similar to those in participants who were normoglycaemic by both biomarkers and significantly lower than in participants with diabetes by both biomarkers (p<0.05). HOMA-IR and fat distribution explained additional HbA1c variance beyond glucose and age only in women.Conclusions: Concordance was poor between HbA1c and FPG in diagnosis of diabetes in black South Africans, and participants with HbA1c-only diabetes phenotypically resembled normoglycaemic participants. Further work is necessary to determine which of these parameters better predicts diabetes-related morbidities in this population and whether a population-specific HbA1c threshold is necessary.
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| 43. |
- Wallin, Cecilia, et al.
(author)
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Characterization of Mn(II) ion binding to the amyloid-beta peptide in Alzheimer's disease
- 2016
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In: Journal of Trace Elements in Medicine and Biology. - : Elsevier BV. - 0946-672X .- 1878-3252. ; 38, s. 183-193
-
Journal article (peer-reviewed)abstract
- Growing evidence links neurodegenerative diseases to metal exposure. Aberrant metal ion concentrations have been noted in Alzheimer's disease (AD) brains, yet the role of metals in AD pathogenesis remains unresolved. A major factor in AD pathogenesis is considered to be aggregation of and amyloid formation by amyloid-beta (A beta) peptides. Previous studies have shown that A beta displays specific binding to Cu(II) and Zn(II) ions, and such binding has been shown to modulate A beta aggregation. Here, we use nuclear magnetic resonance (NMR) spectroscopy to show that Mn(II) ions also bind to the N-terminal part of the A beta(1-40) peptide, with a weak binding affinity in the milli- to micromolar range. Circular dichroism (CD) spectroscopy, solid state atomic force microscopy (AFM), fluorescence spectroscopy, and molecular modeling suggest that the weak binding of Mn(II) to A beta may not have a large effect on the peptide's aggregation into amyloid fibrils. However, identification of an additional metal ion displaying A beta binding reveals more complex AD metal chemistry than has been previously considered in the literature.
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