| 1. |
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| 2. |
- 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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| 3. |
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| 4. |
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| 5. |
- 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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| 6. |
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| 7. |
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| 8. |
- Adam, A, et al.
(författare)
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Abstracts from Hydrocephalus 2016.
- 2017
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Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 14:Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 9. |
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| 10. |
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| 11. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 12. |
- Ciavola, G., et al.
(författare)
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Status report of the MS-ECRIS construction
- 2007
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Ingår i: High Energy Physics & Nuclear Physics - Chinese Edition. - 0254-3052. ; 31, s. 13-17
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Tidskriftsartikel (refereegranskat)abstract
- The design of each component of the Multipurpose Superconducting ECR Ion Source (MS-ECRIS) has been completed and some items are ready. The magnets and the cryostat are under construction at ACCEL and the commissioning is scheduled for March 2007. The mechanical have been optimized and their construction is under way, the microwave system is under refurbishment and the 65kV power supply is available and upgraded for afterglow operations. Pumping and extraction system were adapted to the EIS testbench of GSI Darmstadt. The description of,each part will be given in the paper along with a schedule of the forthcoming development and experiments.
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| 13. |
- Ciavola, G., et al.
(författare)
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Status report of the multipurpose superconducting electron cyclotron resonance ion source
- 2008
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Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 79:2, s. 02A326-
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Tidskriftsartikel (refereegranskat)abstract
- Intense heavy ion beam production with electron cyclotron resonance (ECR) ion sources is a common requirement for many of the accelerators under construction in Europe and elsewhere. An average increase of about one order of magnitude per decade in the performance of ECR ion sources was obtained up to now since the time of pioneering experiment of R. Geller at CEA, Grenoble, and this trend is not deemed to get the saturation at least in the next decade, according to the increased availability of powerful magnets and microwave generators. Electron density above 1013 cm(-3) and very high current of multiply charged ions are expected with the use of 28 GHz microwave heating and of an adequate plasma trap, with a B-minimum shape, according to the high B mode concept [S. Gammino and G. Ciavola, Plasma Sources Sci. Technol. 5, 19 (1996)]. The MS-ECRIS ion source has been designed following this concept and its construction is underway at GSI, Darmstadt. The project is the result of the cooperation of nine European institutions with the partial funding of EU through the sixth Framework Programme. The contribution of different institutions has permitted to build in 2006-2007 each component at high level of expertise. The description of the major components will be given in the following with a view on the planning of the assembly and commissioning phase to be carried out in fall 2007. An outline of the experiments to be done with the MS-ECRIS source in the next two years will be presented.
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| 14. |
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| 15. |
- Janhunen, P., et al.
(författare)
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Invited Article: Electric solar wind sail : Toward test missions
- 2010
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Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 81:11, s. 111301-
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Tidskriftsartikel (refereegranskat)abstract
- The electric solar wind sail (E-sail) is a space propulsion concept that uses the natural solar wind dynamic pressure for producing spacecraft thrust. In its baseline form, the E-sail consists of a number of long, thin, conducting, and centrifugally stretched tethers, which are kept in a high positive potential by an onboard electron gun. The concept gains its efficiency from the fact that the effective sail area, i.e., the potential structure of the tethers, can be millions of times larger than the physical area of the thin tethers wires, which offsets the fact that the dynamic pressure of the solar wind is very weak. Indeed, according to the most recent published estimates, an E-sail of 1 N thrust and 100 kg mass could be built in the rather near future, providing a revolutionary level of propulsive performance (specific acceleration) for travel in the solar system. Here we give a review of the ongoing technical development work of the E-sail, covering tether construction, overall mechanical design alternatives, guidance and navigation strategies, and dynamical and orbital simulations.
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| 16. |
- Amendola, L., et al.
(författare)
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Cosmology and fundamental physics with the Euclid satellite
- 2018
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Ingår i: Living Reviews in Relativity. - : Springer. - 1433-8351 .- 2367-3613. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Euclid is a European Space Agency medium-class mission selected for launch in 2020 within the cosmic vision 2015–2025 program. The main goal of Euclid is to understand the origin of the accelerated expansion of the universe. Euclid will explore the expansion history of the universe and the evolution of cosmic structures by measuring shapes and red-shifts of galaxies as well as the distribution of clusters of galaxies over a large fraction of the sky. Although the main driver for Euclid is the nature of dark energy, Euclid science covers a vast range of topics, from cosmology to galaxy evolution to planetary research. In this review we focus on cosmology and fundamental physics, with a strong emphasis on science beyond the current standard models. We discuss five broad topics: dark energy and modified gravity, dark matter, initial conditions, basic assumptions and questions of methodology in the data analysis. This review has been planned and carried out within Euclid’s Theory Working Group and is meant to provide a guide to the scientific themes that will underlie the activity of the group during the preparation of the Euclid mission.
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| 17. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 18. |
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| 19. |
- Kainu, T, et al.
(författare)
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Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
- 2000
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 97:17, s. 9603-9608
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Tidskriftsartikel (refereegranskat)abstract
- A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
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| 20. |
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| 21. |
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| 22. |
- Leinonen, V, et al.
(författare)
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Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.
- 2013
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 20:7, s. 1043-52
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: This study determined the correlation between uptake of the amyloid positron emission tomography (PET) imaging agent [(18) F]flutemetamol and amyloid-β measured by immunohistochemical and histochemical staining in a frontal cortical biopsy.METHODS: Fifteen patients with possible normal pressure hydrocephalus (NPH) and previous brain biopsy obtained during intracranial pressure monitoring underwent [18F]flutemetamol PET. Seven of these patients also underwent [11C] Pittsburgh compound B (PiB) PET. [18F]Flutemetamol and [11C]PiB uptake was quantified using standardized uptake value ratio (SUVR) with the cerebellar cortex as a reference region. Tissue amyloid-β was evaluated using the monoclonal antibody 4G8, Thioflavin-S and Bielschowsky silver stain.RESULTS: [18F]Flutemetamol and [11C]PiB SUVRs correlated with biopsy specimen amyloid-β levels contralateral (r = 0.86, P < 0.0001; r = 0.96, P = 0.0008) and ipsilateral (r = 0.82, P = 0.0002; r = 0.87, P = 0.01) to the biopsy site. Association between cortical composite [(18) F]flutemetamol SUVRs and [11C]PiB SUVRs was highly significant (r = 0.97, P = 0.0003).CONCLUSIONS: [18F]Flutemetamol detects brain amyloid-β in vivo with moderate to high sensitivity and high specificity. This agent, therefore, represents a valuable new tool to study and verify the presence of amyloid-β pathology, both in patients with possible NPH and among the wider population.
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| 23. |
- Leinonen, V., et al.
(författare)
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S- F-18 THK-5117-PET and C-11 PIB-PET Imaging in Idiopathic Normal Pressure Hydrocephalus in Relation to Confirmed Amyloid-beta Plaques and Tau in Brain Biopsies
- 2018
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 64:1, s. 171-179
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Tidskriftsartikel (refereegranskat)abstract
- Background: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[F-18] THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[F-18] THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo. Objective: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[F-18] THK-5117, and [C-11] PIB PET against tau and amyloid lesions in brain biopsy. Methods: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF A beta(1-42), total tau, and P-tau(181) measures, underwent brain MRI, [C-11] PIB PET, and S-[F-18] THK-5117 PET imaging. Results: Seven patients had amyloid-beta(A beta, 4G8) plaques, two both A beta and phosphorylated tau (P tau, AT8) and one only P tau in biopsy. As expected, increased brain biopsy A beta was well associated with higher [C-11] PIB uptake in PET. However, S-[F-18] THK-5117 uptake did not show any statistically significant correlation with either brain biopsy P tau or CSF P-tau(181) or total tau. Conclusions: S-[F-18] THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous A beta and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.
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| 24. |
- Malehmir, Alireza, et al.
(författare)
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3D reflection seismic investigation for mine planning and exploration in the Kevitsa Ni-Cu-PGE deposit, northern Finland
- 2011
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- A 3D reflection seismic survey was conducted over an area of about 9 km2 at the Kevitsa Ni-Cu-PGE platinum group elements deposit, northern Finland. The principal objective of the survey was to image major fault and fracture zones at depth. Understanding the geometry of these zones is important for designing a steep open-pit for mining. Initial processing results suggest that the 3D seismic survey has been successful in imaging both gently dipping and steeply dipping reflections as shallow as 50 ms or about 150 m, many of which correlate with fault systems and lithological contacts observed at the surface. Several new target areas can be identified in the seismic data that require further investigations for their mineralization potential.
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| 25. |
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| 26. |
- Walther, G, et al.
(författare)
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Report on challenges for SCIs
- 2021
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report discusses the challenges posed by four types of threats – terrorist attacks, cyber-attacks, extreme weather and social unrest – on the following eight smart critical infrastructure systems:a.ALPHA - Finance (financial system): The analysis focuses on disturbed information flow and disabling/manipulating IT and communication systems, including attacks on the “physical layer” using the example of IEMI/HPEM threats, as well as the software layer.b. BRAVO - Energy supply (system): The analysis focuses on disruption of “smart” energy supply in a “smart city”, caused by natural hazards, in this case flooding, leading to cascading effects and severe consequences for other energy-depending SCIs.c. CHARLIE - Health care (system):Focus of the analysis is on all threats that might cause large increases in the numbers of injuries or sick patients within a densely populated area. This will include indirect impacts, e.g. large numbers of injuries caused by a disaster or terrorist attacks or disease epidemics, but also direct impacts, e.g. service disruptions in critical health infrastructures, such as hospitals, due to attacks or disasters hitting the infrastructure itself.d.DELTA - Transportation (system) – airports: According to the framework situation, threats on Smart Airports will be assessed under circumstances of (i) blocked traffic, (ii) passenger and airplane traffic exceeding capacity (iii) flood.e. ECHO - Industry (in zones in cities) "Industrial Production Plants":The analysis focuses mainly on technological accidents within the refinery complex, but also accidents caused by natural hazards affecting refinery property outside the main refinery complex, e.g. accident on jetty belonging to refinery on the river Danube during unloading/loading oil products from barge to a tank, damages by a gale or storm on process installations (pipes, hoses) resulting in river pollution. Both scenarios could lead to cascading effects for other SCIs in close vicinity.f. FOXTROT - Water supply (systems): The analysis focuses on three cases of local and regional drinking water supply chains, with different kinds of vulnerabilities in terms of climate threats, ICT challenges, security issues and human error.g.GOLF - Urban flood protection (systems): The analysis focuses in the disruption of water and transport caused through tidal and fluvial flooding events.h. HOTEL: City of Helsinki - Flooding underground coal storage. Resilience of the energy infrastructure (city environment).The way this analysis was conducted was by assessing these threats using a 5x5 framework matrix. The two axes of the matrix were phases (understand risks, anticipate/prepare, absorb/withstand, respond/recover, adapt/learn) and dimensions (system/physical, information/data, organizational/business, societal/political, cognitive/decision-making).Each individual matrix block was discussed by subject experts who identified specific challenges and implications for each matrix element and rated its relevance (high, medium, low).In terms of the results, the system/physical dimension received the highest number of important challenges.Overall, the most important singular element was to understand risks in the organizational/business dimension. The least importance was attributed to the adapt/learn phase.
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| 27. |
- Austrin, Per, et al.
(författare)
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Dense Subset Sum may be the hardest
- 2016
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Ingår i: Leibniz International Proceedings in Informatics, LIPIcs. - : Schloss Dagstuhl- Leibniz-Zentrum fur Informatik GmbH, Dagstuhl Publishing. - 9783959770019
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Konferensbidrag (refereegranskat)abstract
- The Subset Sum problem asks whether a given set of n positive integers contains a subset of elements that sum up to a given target t. It is an outstanding open question whether the O∗(2n/2)-time algorithm for Subset Sum by Horowitz and Sahni [J. ACM 1974] can be beaten in the worst-case setting by a "truly faster", O∗(2(0.5-δ)n)-time algorithm, with some constant δ > 0. Continuing an earlier work [STACS 2015], we study Subset Sum parameterized by the maximum bin size β, defined as the largest number of subsets of the n input integers that yield the same sum. For every ∈ > 0 we give a truly faster algorithm for instances with β ≤ 2(0.5-∈)n, as well as instances with β ≥ 20.661n. Consequently, we also obtain a characterization in terms of the popular density parameter n/log2 t: if all instances of density at least 1.003 admit a truly faster algorithm, then so does every instance. This goes against the current intuition that instances of density 1 are the hardest, and therefore is a step toward answering the open question in the affirmative. Our results stem from a novel combinatorial analysis of mixings of earlier algorithms for Subset Sum and a study of an extremal question in additive combinatorics connected to the problem of Uniquely Decodable Code Pairs in information theory.
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| 28. |
- Austrin, Per, et al.
(författare)
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Sharper upper bounds for unbalanced Uniquely Decodable Code Pairs
- 2016
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Ingår i: 2016 IEEE International Symposium on Information Theory. - : Institute of Electrical and Electronics Engineers (IEEE). - 9781509018062 ; , s. 335-339
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Konferensbidrag (refereegranskat)abstract
- Two sets A, B subset of {0, 1}(n) form a Uniquely Decodable Code Pair (UDCP) if every pair a is an element of A, b is an element of B yields a distinct sum a + b, where the addition is over Z(n). We show that every UDCP A, B, with vertical bar A vertical bar = 2((1-is an element of)n) and vertical bar B vertical bar = 2(beta n), satisfies beta <= 0.4228 + root is an element of. For sufficiently small is an element of, this bound significantly improves previous bounds by Urbanke and Li [Information Theory Workshop '98] and Ordentlich and Shayevitz [2014, arXiv: 1412.8415], which upper bound beta by 0.4921 and 0.4798, respectively, as is an element of approaches 0.
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| 29. |
- Austrin, Per, et al.
(författare)
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Space-time tradeoffs for subset sum : An improved worst case algorithm
- 2013
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Ingår i: Automata, Languages, and Programming. - Berlin, Heidelberg : Springer. - 9783642392054 ; , s. 45-56
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Konferensbidrag (refereegranskat)abstract
- The technique of Schroeppel and Shamir (SICOMP, 1981) has long been the most efficient way to trade space against time for the Subset Sum problem. In the random-instance setting, however, improved tradeoffs exist. In particular, the recently discovered dissection method of Dinur et al. (CRYPTO 2012) yields a significantly improved space-time tradeoff curve for instances with strong randomness properties. Our main result is that these strong randomness assumptions can be removed, obtaining the same space-time tradeoffs in the worst case. We also show that for small space usage the dissection algorithm can be almost fully parallelized. Our strategy for dealing with arbitrary instances is to instead inject the randomness into the dissection process itself by working over a carefully selected but random composite modulus, and to introduce explicit space-time controls into the algorithm by means of a "bailout mechanism".
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| 30. |
- Austrin, Per, et al.
(författare)
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Subset sum in the absence of concentration
- 2015
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Ingår i: Leibniz International Proceedings in Informatics, LIPIcs. - 9783939897781 ; , s. 48-61
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Konferensbidrag (refereegranskat)abstract
- We study the exact time complexity of the Subset Sum problem. Our focus is on instances that lack additive structure in the sense that the sums one can form from the subsets of the given integers are not strongly concentrated on any particular integer value. We present a randomized algorithm that runs in O (20.3399nB4) time on instances with the property that no value can arise as a sum of more than B different subsets of the n given integers.
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| 31. |
- Barenkamp, Stephen J., et al.
(författare)
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Panel 4 : Report of the Microbiology Panel
- 2017
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Ingår i: Otolaryngology - Head and Neck Surgery. - : Wiley. - 0194-5998 .- 1097-6817. ; 156:4_suppl, s. 51-62
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To perform a comprehensive review of the literature from July 2011 until June 2015 on the virology and bacteriology of otitis media in children. Data Sources: PubMed database of the National Library of Medicine. Review Methods: Two subpanels comprising experts in the virology and bacteriology of otitis media were created. Each panel reviewed the relevant literature in the fields of virology and bacteriology and generated draft reviews. These initial reviews were distributed to all panel members prior to meeting together at the Post-symposium Research Conference of the 18th International Symposium on Recent Advances in Otitis Media, National Harbor, Maryland, in June 2015. A final draft was created, circulated, and approved by all panel members. Conclusions: Excellent progress has been made in the past 4 years in advancing our understanding of the microbiology of otitis media. Numerous advances were made in basic laboratory studies, in animal models of otitis media, in better understanding the epidemiology of disease, and in clinical practice. Implications for Practice: (1) Many viruses cause acute otitis media without bacterial coinfection, and such cases do not require antibiotic treatment. (2) When respiratory syncytial virus, metapneumovirus, and influenza virus peak in the community, practitioners can expect to see an increase in clinical otitis media cases. (3) Biomarkers that predict which children with upper respiratory tract infections will develop otitis media may be available in the future. (4) Compounds that target newly identified bacterial virulence determinants may be available as future treatment options for children with otitis media.
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| 32. |
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| 33. |
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| 34. |
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| 35. |
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| 36. |
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| 37. |
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| 38. |
- Gardberg, M., et al.
(författare)
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FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9, s. e74923-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.
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| 39. |
- Jansen, Iris E, et al.
(författare)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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| 40. |
- Jantti, H, et al.
(författare)
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Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice
- 2022
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:24
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Tidskriftsartikel (refereegranskat)abstract
- The PSEN1 ΔE9 mutation causes a familial form of Alzheimer’s disease (AD) by shifting the processing of amyloid precursor protein (APP) towards the generation of highly amyloidogenic Aβ42 peptide. We have previously shown that the PSEN1 ΔE9 mutation in human-induced pluripotent stem cell (iPSC)-derived astrocytes increases Aβ42 production and impairs cellular responses. Here, we injected PSEN1 ΔE9 mutant astrosphere-derived glial progenitors into newborn mice and investigated mouse behavior at the ages of 8, 12, and 16 months. While we did not find significant behavioral changes in younger mice, spatial learning and memory were paradoxically improved in 16-month-old PSEN1 ΔE9 glia-transplanted male mice as compared to age-matched isogenic control-transplanted animals. Memory improvement was associated with lower levels of soluble, but not insoluble, human Aβ42 in the mouse brain. We also found a decreased engraftment of PSEN1 ΔE9 mutant cells in the cingulate cortex and significant transcriptional changes in both human and mouse genes in the hippocampus, including the extracellular matrix-related genes. Overall, the presence of PSEN1 ΔE9 mutant glia exerted a more beneficial effect on aged mouse brain than the isogenic control human cells likely as a combination of several factors.
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| 41. |
- Karvonen, H, et al.
(författare)
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Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness
- 2020
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:9, s. 790-
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.
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| 42. |
- Kelloniemi, A., et al.
(författare)
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The Early-Onset Myocardial Infarction Associated PHACTR1 Gene Regulates Skeletal and Cardiac Alpha-Actin Gene Expression
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- The phosphatase and actin regulator 1 (PHACTR1) locus is a very commonly identified hit in genome-wide association studies investigating coronary artery disease and myocardial infarction (MI). However, the function of PHACTR1 in the heart is still unknown. We characterized the mechanisms regulating Phactr1 expression in the heart, used adenoviral gene delivery to investigate the effects of Phactr1 on cardiac function, and analyzed the relationship between MI associated PHACTR1 allele and cardiac function in human subjects. Phactr1 mRNA and protein levels were markedly reduced (60%, P<0.01 and 90%, P<0.001, respectively) at 1 day after MI in rats. When the direct myocardial effects of Phactr1 were studied, the skeletal a-actin to cardiac a-actin isoform ratio was significantly higher (1.5-fold, P<0.05) at 3 days but 40% lower (P<0.05) at 2 weeks after adenovirus-mediated Phactr1 gene delivery into the anterior wall of the left ventricle. Similarly, the skeletal a-actin to cardiac a-actin ratio was lower at 2 weeks in infarcted hearts overexpressing Phactr1. In cultured neonatal cardiac myocytes, adenovirus-mediated Phactr1 overexpression for 48 hours markedly increased the skeletal a-actin to cardiac a-actin ratio, this being associated with an enhanced DNA binding activity of serum response factor. Phactr1 overexpression exerted no major effects on the expression of other cardiac genes or LV structure and function in normal and infarcted hearts during 2 weeks' follow-up period. In human subjects, MI associated PHACTR1 allele was not associated significantly with cardiac function (n = 1550). Phactr1 seems to regulate the skeletal to cardiac a-actin isoform ratio.
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| 48. |
- Koivisto, P, et al.
(författare)
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Factors affecting the preparation of packed capillary columns in supercritical carbon dioxide media
- 1997
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Ingår i: JOURNAL OF MICROCOLUMN SEPARATIONS. - : JOHN WILEY & SONS INC. - 1040-7685. ; 9:2, s. 97-103
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Tidskriftsartikel (refereegranskat)abstract
- In this study, packed capillary columns were prepared using supercritical carbon dioxide as a packing carrier. A factorial design was used to examine the effect that four selected factors have on the packing performance. The investigated factors were: 1)
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| 49. |
- Koivisto, P., et al.
(författare)
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Separation of L-DOPA and four metabolites in plasma using a porous graphitic carbon column in capillary liquid chromatography
- 2002
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Ingår i: Chromatographia. - 0009-5893 .- 1612-1112. ; 55:1-2, s. 39-42
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Tidskriftsartikel (refereegranskat)abstract
- Porous graphitic carbon has been successfully used for the separation of L-DOPA and four metabolites (dopamine, 3,4-dihydroxy-phenyl-acetic acid, homovanillic acid and 3-O-methyl-L-DOPA) and with a volatile mobile phase of relatively high percentage organic modifier (methanol-ammonium formate pH 2.9, 60∶40, v/v). The substances were analysed in plasma. Ultrafiltration was used to remove the proteins from the sample and a coupled column system to enrich and perform on-line sample clean up. Both precolumn and separation column of i. d. 0.2 mm were packed with porous graphitic carbon.
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| 50. |
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