| 1. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 2. |
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| 3. |
- Bellenguez, C, et al.
(författare)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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| 8. |
- Fernandez, J. L. Abelleira, et al.
(författare)
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A Large Hadron Electron Collider at CERN
- 2012
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Ingår i: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 39:7
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Akiba, K., et al.
(författare)
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LHC forward physics
- 2016
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Ingår i: Journal of Physics G: Nuclear and Particle Physics. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 43:11
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Tidskriftsartikel (refereegranskat)
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| 10. |
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| 11. |
- Saddiki, H., et al.
(författare)
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Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker-based case-control study
- 2020
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Ingår i: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 17:8
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Tidskriftsartikel (refereegranskat)abstract
- Background The epsilon 4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association betweenAPOEgenotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of beta-amyloid peptide (A, beta-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. Methods and findings This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated withAPOEgenotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least oneAPOE epsilon 4 allele. Compared with non-epsilon 4 carriers, heterozygous epsilon 4 carriers had a 4.6 (95% confidence interval 4.1-5.2;p< 0.001) and epsilon 4/epsilon 4 homozygotes a 25.4 (20.4-31.2;p< 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (pfor interaction < 0.001). The PAF associated with carrying at least one epsilon 4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect ofAPOE epsilon 2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. Conclusions In this study, we found that AD diagnosis based on biomarkers was associated with APOE epsilon 4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect ofAPOE epsilon 4 at the population level. Author summaryWhy was this study done? The epsilon 4 allele of apolipoprotein E () gene () and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The recent development of diagnostic criteria based on biomarkers that reflect brain beta-amyloid and tau lesions (beta-amyloid deposition, pathologic tau, neurodegeneration [A/T/N] classification]) increases homogeneity in diagnosed cases. The strength of association of AD with risk factors can be better determined using biomarker-based AD compared with AD diagnosis based only on clinical criteria because the latter are known to lack specificity as a result of difficulties in ruling out other causes of dementia. What did the researchers do and find? We compared the overall and age-specific association between and AD using a case-control study that included 1,593 AD cases from memory clinics with positive cerebrospinal fluid biomarkers and 11,723 dementia-free controls drawn from two longitudinal cohort studies. The use of a large number of cases and controls allows assessment of whether the association between and AD is dependent on age. Compared with controls, patients with AD were more likely to carry one (odds ratio [OR] = 4.6) or two (OR = 25.3). This association was significantly modified by age, with the strongest association seen between 65 and 70 years of age and weaker associations at the two tails of the age distribution. What do these findings mean? Incorporating biomarkers for diagnosis of AD identified an association with that is apparently greater than has been previously reported using clinical diagnosis of the disease. The impact of on the risk of AD was strongest between the 65 and 70 years of age, earlier than the mean age at diagnosis in this study, which was 72.8 years.
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| 12. |
- Alic, I., et al.
(författare)
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Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26:10, s. 5766-5788
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Tidskriftsartikel (refereegranskat)abstract
- A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of beta-amyloid-(A beta)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar A beta deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical beta and gamma-secretase inhibition. We found that T21 organoids secrete increased proportions of A beta-preventing (A beta 1-19) and A beta-degradation products (A beta 1-20 and A beta 1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in similar to 30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
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| 13. |
- Angeles-Martinez, R., et al.
(författare)
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Transverse Momentum Dependent (TMD) Parton Distribution Functions: Status and Prospects
- 2015
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Ingår i: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 46:12, s. 2501-2534
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Tidskriftsartikel (refereegranskat)abstract
- We review transverse momentum dependent (TMD) parton distribution functions, their application to topical issues in high-energy physics phenomenology, and their theoretical connections with QCD resummation, evolution and factorization theorems. We illustrate the use of TMDs via examples of multi-scale problems in hadronic collisions. These include transverse momentum q(T) spectra of Higgs and vector bosons for low q(T), and azimuthal correlations in the production of multiple jets associated with heavy bosons at large jet masses. We discuss computational tools for TMDs, and present the application of a new tool, TMDLIB, to parton density fits and parameterizations.
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| 14. |
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| 15. |
- Bringman, S, et al.
(författare)
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Is a dissection balloon beneficial in bilateral, totally extraperitoneal, endoscopic hernioplasty? A randomized, prospective, multicenter study
- 2001
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Ingår i: Surgical Laparoscopy, Endoscopy and Percutaneous Techniques. - 1051-7200 .- 2331-2254. ; 11:5, s. 322-326
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Tidskriftsartikel (refereegranskat)abstract
- Laparoscopic hernioplasty has been criticized because of its technical complexity and increased costs. Disposable dissection balloons can be used to gain the initial working space in totally extraperitoneal endoscopic (TEP) hernioplasty, but this increases its cost. Forty-four men with bilateral, primary or recurrent inguinal hernias were randomized to undergo TEP with or without dissection balloon, There were two conversions to transabdominal preperitoneal hernioplasty, or open herniorrhaphy, in the group with balloon and four in the group without balloon. There was no difference in the postoperative morbidity or operation time between the two groups, and there were no major complications in either group. The recurrence rate was 4.3% in the group with the balloon and 7.1% in the group without the balloon. There were no statistically significant differences between the groups, Although our study population is too small to detect small differences between the groups, it seems that the use of a dissection balloon is not beneficial in a bilateral TEP.
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| 16. |
- Bringman, S., et al.
(författare)
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Is a dissection balloon beneficial in totally extraperitoneal endoscopic hernioplasty (TEP)? A randomized prospective multicenter study
- 2001
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Ingår i: Surgical Endoscopy. - : Springer Science and Business Media LLC. - 0930-2794 .- 1432-2218. ; 15:3, s. 266-270
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Tidskriftsartikel (refereegranskat)abstract
- Background: Laparoscopic hernioplasty has been criticized because of its technical complexity and increased costs. Disposable dissection balloons can be used to facilitate the creation of the initial working space in totally extraperitoneal endoscopic hernioplasty (TEP), but their use adds to the cost of the operation. Methods: A total of 322 men with unilateral, primary, or recurrent inguinal hernias were randomized to undergo TEP with or without a dissection balloon. Results: In the group with the balloon, three of 161 patients (2.5%) required conversion to transabdominal preperitoneal hernioplasty (TAPP), or open herniorraphy, whereas 17 of 161 patients (10.6%) were converted to TAPP or open herniorraphy in the group without the balloon (p = 0.002). The mean operation time was 55 min in the group with the balloon and 63 min in the group without the balloon (p = 0.004). There was no difference between them in postoperative morbidity, and there were no major complications in either group. The recurrence rate was 3.1% in the group with the balloon and 3.7 % in the group without the balloon (p = 0.8). Conclusion: The use of a dissection balloon in TEP reduces the conversion rate and may be especially beneficial early in the learning curve.
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| 17. |
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| 18. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 19. |
- Etcheverry, Sebastian, et al.
(författare)
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Quantum key distribution session with 16-dimensional photonic states
- 2013
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; :3, s. 2316-
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Tidskriftsartikel (refereegranskat)abstract
- The secure transfer of information is an important problem in modern telecommunications. Quantum key distribution (QKD) provides a solution to this problem by using individual quantum systems to generate correlated bits between remote parties, that can be used to extract a secret key. QKD with D-dimensional quantum channels provides security advantages that grow with increasing D. However, the vast majority of QKD implementations has been restricted to two dimensions. Here we demonstrate the feasibility of using higher dimensions for real-world quantum cryptography by performing, for the first time, a fully automated QKD session based on the BB84 protocol with 16-dimensional quantum states. Information is encoded in the single-photon transverse momentum and the required states are dynamically generated with programmable spatial light modulators. Our setup paves the way for future developments in the field of experimental high-dimensional QKD.
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| 20. |
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| 21. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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