| 1. |
- 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
-
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133 tissue samples spanning 11 cancer types and matching non‐cancerous specimens are profiled from 467 published and unpublished PGC‐LC‐MS/MS N‐glycome datasets collected over a decade.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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| 2. |
- 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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| 3. |
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| 4. |
- Butler, P. A., et al.
(author)
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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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| 5. |
- 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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| 6. |
- Devries, K., et al.
(author)
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Who perpetrates violence against children? A systematic analysis of age-specific and sex-specific data
- 2018
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In: BMJ Paediatr Open. - : BMJ. - 2399-9772. ; 2:1
-
Journal article (peer-reviewed)abstract
- Objective: The epidemiology of violence against children is likely to differ substantially by sex and age of the victim and the perpetrator. Thus far, investment in effective prevention strategies has been hindered by lack of clarity in the burden of childhood violence across these dimensions. We produced the first age-specific and sex-specific prevalence estimates by perpetrator type for physical, sexual and emotional violence against children globally. Design: We used random effects meta-regression to estimate prevalence. Estimates were adjusted for relevant quality covariates, variation in definitions of violence and weighted by region-specific, age-specific and sex-specific population data to ensure estimates reflect country population structures. Data sources: Secondary data from 600 population or school-based representative datasets and 43 publications obtained via systematic literature review, representing 13 830 estimates from 171 countries. Eligibility criteria for selecting studies: Estimates for recent violence against children aged 0-19 were included. Results: The most common perpetrators of physical and emotional violence for both boys and girls across a range of ages are household members, with prevalence often surpassing 50%, followed by student peers. Children reported experiencing more emotional than physical violence from both household members and students. The most common perpetrators of sexual violence against girls aged 15-19 years are intimate partners; however, few data on other perpetrators of sexual violence against children are systematically collected internationally. Few age-specific and sex-specific data are available on violence perpetration by schoolteachers; however, existing data indicate high prevalence of physical violence from teachers towards students. Data from other authority figures, strangers, siblings and other adults are limited, as are data on neglect of children. Conclusions: Without further investment in data generation on violence exposure from multiple perpetrators for boys and girls of all ages, progress towards Sustainable Development Goals 4, 5 and 16 may be slow. Despite data gaps, evidence shows violence from household members, peers in school and for girls, from intimate partners, should be prioritised for prevention. Trial registration number: PROSPERO 2015: CRD42015024315.
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| 7. |
- 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
-
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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| 8. |
- 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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| 9. |
- 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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| 10. |
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| 11. |
- 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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| 12. |
- 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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| 13. |
- Abelein, Axel, et al.
(author)
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The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway
- 2014
-
In: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 19:4-5, s. 623-634
-
Research review (peer-reviewed)abstract
- The amyloid beta (A beta) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditions. Several lines of evidence indicate that the neurotoxic species are the intermediate oligomeric states appearing along the aggregation pathways. This minireview summarizes recent findings, mainly based on solution and solid-state NMR experiments and electron microscopy, which investigate the molecular structures and characteristics of the A beta peptides at different stages along the aggregation pathways. We conclude that a hairpin-like conformation constitutes a common motif for the A beta peptides in most of the described structures. There are certain variations in different hairpin conformations, for example regarding H-bonding partners, which could be one reason for the molecular heterogeneity observed in the aggregated systems. Interacting hairpins are the building blocks of the insoluble fibrils, again with variations in how hairpins are organized in the cross-section of the fibril, perpendicular to the fibril axis. The secondary structure propensities can be seen already in peptide monomers in solution. Unfortunately, detailed structural information about the intermediate oligomeric states is presently not available. In the review, special attention is given to metal ion interactions, particularly the binding constants and ligand structures of A beta complexes with Cu(II) and Zn(II), since these ions affect the aggregation process(es) and are considered to be involved in the molecular mechanisms underlying AD pathology.
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| 14. |
- Abrahams, N., et al.
(author)
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Worldwide prevalence of non-partner sexual violence: a systematic review
- 2014
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In: The Lancet. - 0140-6736. ; 383:9929, s. 1648-1654
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Journal article (peer-reviewed)abstract
- Background: Several highly publicised rapes and murders of young women in India and South Africa have focused international attention on sexual violence. These cases are extremes of the wider phenomenon of sexual violence against women, but the true extent is poorly quantified. We did a systematic review to estimate prevalence. Methods: We searched for articles published from Jan 1, 1998, to Dec 31, 2011, and manually search reference lists and contacted experts to identify population-based data on the prevalence of women's reported experiences of sexual violence from age 15 years onwards, by anyone except intimate partners. We used random effects meta-regression to calculate adjusted and unadjusted prevalence for regions, which we weighted by population size to calculate the worldwide estimate. Findings: We identified 7231 studies from which we obtained 412 estimates covering 56 countries. In 2010 7·2% (95% CI 5·2-9·1) of women worldwide had ever experienced non-partner sexual violence. The highest estimates were in sub-Saharan Africa, central (21%, 95%CI 4·5-37·5) and sub-Saharan Africa, southern (17·4%, 11·4-23·3). The lowest prevalence was for Asia, south (3·3%, 0-8·3). Limited data were available from sub-Saharan Africa, central, North Africa/Middle East, Europe, eastern, and Asia Pacific, high income. Interpretation: Sexual violence against women is common worldwide, with endemic levels seen in some areas, although large variations between settings need to be interpreted with caution because of differences in data availability and levels of disclosure. Nevertheless, our findings indicate a pressing health and human rights concern. Funding: South African Medical Research Council, Sigrid Rausing Trust, WHO. © 2014 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved.
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| 15. |
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| 16. |
- 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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| 17. |
- 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
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In: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
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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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| 18. |
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| 19. |
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| 20. |
- Luo, Jinghui, et al.
(author)
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Alzheimer Peptides Aggregate into Transient Nanoglobules That Nucleate Fibrils
- 2014
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In: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 53:40, s. 6302-6308
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Journal article (peer-reviewed)abstract
- Protein/peptide oligomerization, cross-beta strand fibrillation, and amyloid deposition play a critical role in many diseases, but despite extensive biophysical characterization, the structural and dynamic details of oligomerization and fibrillation of amyloidic peptides/proteins remain to be fully clarified. Here, we simultaneously monitored the atomic, molecular, and mesoscopic states of aggregating Alzheimer's amyloid beta (A beta) peptides over time, using a slow aggregation protocol and a fast aggregation protocol, and determined the cytotoxicity of the intermediate states. We show that in the early stage of fast fibrillation (the lag phase) the A beta peptides coalesced into apparently unstructured globules (15-200 nm in diameter), which slowly grew larger. Then a sharp transition occurred, characterized by the first appearance of single fibrillar structures of approximately >= 100 nm. These fibrils emerged from the globules. Simultaneously, an increase was observed for the cross-beta strand conformation that is characteristic of the fibrils that constitute mature amyloid. The number and size of single fibrils rapidly increased. Eventually, the fibrils coalesced into mature amyloid. Samples from the early lag phase of slow fibrillation conditions were especially toxic to cells, and this toxicity sharply decreased when fibrils formed and matured into amyloid. Our results suggest that the formation of fibrils may protect cells by reducing the toxic structures that appear in the early lag phase of fibrillation.
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| 21. |
- Luo, Jinghui, et al.
(author)
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Cellular Polyamines Promote Amyloid-Beta (A beta) Peptide Fibrillation and Modulate the Aggregation Pathways
- 2013
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In: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 4:3, s. 454-462
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Journal article (peer-reviewed)abstract
- The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (A beta) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric A beta(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 mu M spermine (normal intracellular concentration is similar to 1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce A beta(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of A beta peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.
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| 22. |
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| 23. |
- Luo, Jinghui, et al.
(author)
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Cross-interactions between the Alzheimer Disease Amyloid-beta Peptide and Other Amyloid Proteins : A Further Aspect of the Amyloid Cascade Hypothesis
- 2016
-
In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 291:32, s. 16485-16493
-
Research review (peer-reviewed)abstract
- Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-beta (A beta) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between A beta and other amyloid proteins.
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| 24. |
- Luo, Jinghui, et al.
(author)
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Endogenous Polyamines Reduce the Toxicity of Soluble A beta Peptide Aggregates Associated with Alzheimer's Disease
- 2014
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In: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 15:6, s. 1985-1991
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Journal article (peer-reviewed)abstract
- Polyamines promote the formation of the A beta peptide amyloid fibers that are a hallmark of Alzheimer's disease. Here we show that polyamines interact with nonaggregated A beta peptides, thereby reducing the peptide's hydrophobic surface. We characterized the associated conformational change through NMR titrations and molecular dynamics simulations. We found that even low concentrations of spermine, sperimidine, and putrescine fully protected SH-SY5Y (a neuronal cell model) against the most toxic conformational species of AA even at an A beta oligomer concentration that would otherwise kill half of the cells or even more. These observations lead us to conclude that polyamines interfere with the more toxic prefibrillar conformations and might protect cells by promoting the structural transition of A beta toward its less toxic fibrillar state that we reported previously. Since polyamines are present in brain fluid at the concentrations where we observed all these effects, their activity needs to be taken into account in understanding the molecular processes related to the development of Alzheimer's disease.
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| 25. |
- 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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| 26. |
- Luo, Jinghui, et al.
(author)
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Non-chaperone Proteins Can Inhibit Aggregation and Cytotoxicity of Alzheimer Amyloid beta Peptide
- 2014
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 289:40, s. 27766-27775
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Journal article (peer-reviewed)abstract
- Background: A amyloid formation is associated with Alzheimer disease. Results: Non-chaperone proteins prevent amyloid formation and reduce the cytotoxicity of the A peptide. Conclusion: Non-chaperone proteins may affect the onset and development of Alzheimer disease by interfering with A peptide aggregation. Significance: Non-chaperone proteins can function as a chaperone protein to regulate the pathway of the A fibrillation in proteostasis providing a new strategy in the treatment of Alzheimer disease. Many factors are known to influence the oligomerization, fibrillation, and amyloid formation of the A peptide that is associated with Alzheimer disease. Other proteins that are present when A peptides deposit in vivo are likely to have an effect on these aggregation processes. To separate specific versus broad spectrum effects of proteins on A aggregation, we tested a series of proteins not reported to have chaperone activity: catalase, pyruvate kinase, albumin, lysozyme, -lactalbumin, and -lactoglobulin. All tested proteins suppressed the fibrillation of Alzheimer A(1-40) peptide at substoichiometric ratios, albeit some more effectively than others. All proteins bound non-specifically to A, stabilized its random coils, and reduced its cytotoxicity. Surprisingly, pyruvate kinase and catalase were at least as effective as known chaperones in inhibiting A aggregation. We propose general mechanisms for the broad-spectrum inhibition A fibrillation by proteins. The mechanisms we discuss are significant for prognostics and perhaps even for prevention and treatment of Alzheimer disease.
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| 27. |
- Luo, Jinghui, et al.
(author)
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Reciprocal Molecular Interactions between the A beta Peptide Linked to Alzheimer's Disease and Insulin Linked to Diabetes Mellitus Type II
- 2016
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In: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 7:3, s. 269-274
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Journal article (peer-reviewed)abstract
- Clinical studies indicate diabetes mellitus type II (DM) doubles the risk that a patient will also develop Alzheimer's disease (AD). DM is caused by insulin resistance and a relative lack of active insulin. AD is characterized by the deposition of amyloid beta (A beta) peptide fibrils. Prior to fibrillating, A beta forms intermediate, prefibrillar oligomers, which are more cytotoxic than the mature A beta fibrils. Insulin can also form amyloid fibrils. In vivo studies have revealed that insulin promotes the production of A beta, and that soluble A beta competes with insulin for the insulin receptor. Here, we report that monomeric insulin interacted with soluble A beta and that both molecules reciprocally slowed down the aggregation kinetics of the other. Prefibrillar oligomers of A beta that eventually formed in the presence of insulin were less cytotoxic than A beta oligomers formed in the absence of insulin. Mature A beta fibrils induced fibrillation of soluble insulin, but insulin aggregates did not promote A beta fibrillation. Our study indicates that direct molecular interactions between insulin and A beta may contribute to the strong link between DM and AD.
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| 28. |
- Luo, Jinghui, et al.
(author)
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The A beta peptide forms non-amyloid fibrils in the presence of carbon nanotubes
- 2014
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In: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3364 .- 2040-3372. ; 6:12, s. 6720-6726
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Journal article (peer-reviewed)abstract
- Carbon nanotubes have specific properties that make them potentially useful in biomedicine and biotechnology. However, carbon nanotubes may themselves be toxic, making it imperative to understand how carbon nanotubes interact with biomolecules such as proteins. Here, we used NMR, CD, and ThT/fluorescence spectroscopy together with AFM imaging to study pH-dependent molecular interactions between single walled carbon nanotubes (SWNTs) and the amyloid-beta (A beta) peptide. The aggregation of the A beta peptide, first into oligomers and later into amyloid fibrils, is considered to be the toxic mechanism behind Alzheimer's disease. We found that SWNTs direct the A beta peptides to form a new class of beta-sheet-rich yet non-amyloid fibrils.
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| 29. |
- 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
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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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| 30. |
- Tiiman, Ann, et al.
(author)
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Specific Binding of Cu(II) Ions to Amyloid-Beta Peptides Bound to Aggregation-Inhibiting Molecules or SDS Micelles Creates Complexes that Generate Radical Oxygen Species
- 2016
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 54:3, s. 971-982
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Journal article (peer-reviewed)abstract
- Aggregation of the amyloid-beta (A beta) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate A beta aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, A beta is found in various cellular locations including membranes. So far, Cu(II)/A beta interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with A beta bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide CP-2 and the Z(A beta 3)(12-58) Y18L Affibody molecule). In all studied systems the A beta N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, A beta was found to bind Cu(II) and Zn(II) with the same ligands and the same K-D as in aqueous solution. ROS was generated in all Cu(II)/A beta complexes. These results indicate that binding of A beta to membranes, drugs, and other entities that do not interact with the A beta N-terminal part, appears not to compromise the N-terminal segment's ability to bind metal ions, nor impede the capacity of N-terminally bound Cu(II) to generate ROS.
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| 31. |
- 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
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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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| 32. |
- Wallin, Cecilia, et al.
(author)
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The Neuronal Tau Protein Blocks in Vitro Fibrillation of the Amyloid-beta (A beta) Peptide at the Oligomeric Stage
- 2018
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 140:26, s. 8138-8146
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Journal article (peer-reviewed)abstract
- In Alzheimer's disease, amyloid-beta (A beta) plaques and tau neurofibrillary tangles are the two pathological hallmarks. The co-occurrence and combined reciprocal pathological effects of A beta and tau protein aggregation have been observed in animal models of the disease. However, the molecular mechanism of their interaction remain unknown. Using a variety of biophysical measurements, we here show that the native full-length tau protein solubilizes the A beta(40) peptide and prevents its fibrillation. The tau protein delays the amyloid fibrillation of the A beta(40) peptide at substoichiometric ratios, showing different binding affinities toward the different stages of the aggregated A beta(40) peptides. The A beta monomer structure remains random coil in the presence of tau, as observed by nuclear magnetic resonance (NMR), circular dichroism (CD) spectroscopy and photoinduced cross-linking methods. We propose a potential interaction mechanism for the influence of tau on A beta fibrillation.
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