| 1. |
- Anney, Richard, et al.
(författare)
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A genome-wide scan for common alleles affecting risk for autism.
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Casey, Jillian P, et al.
(författare)
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A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
- 2012
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Haeger-Eugensson, Marie, et al.
(författare)
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Air Quality Modeling in Dense Urban Areas at Ground Level—CFD, OSM or Gauss?
- 2021
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Ingår i: Springer Proceedings in Complexity. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 2213-8684 .- 2213-8692. ; , s. 265-270
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Konferensbidrag (refereegranskat)abstract
- There is an ongoing intensive urban densification in many cities. The need for advanced modeling methods that realistically simulate dispersion at ground level in complex urban areas have increased. As more modeling is done outside usual model communities, guidelines supporting the selection of suitable models is needed. Dispersion of air pollutants in street canyons is affected by width, height, length and building structure. Studies show that concentration of NO2 in street canyons can become 5-times higher, compared to open conditions. Since Gaussian models cannot simulate dispersion at ground level in dense urban settlements models that include 3D information (buildings) is therefore required, such as CFD or OSM models to obtain realistic results. The purpose of the project is to investigate the effect from building on air quality and giving recommendations to authorities and consultants helping with model choices. This is based on calculations with three different model types, CFD, OSM and Gaussian for four urban environments, from dense to open suburban areas using the same input. Validation was done with continuous measurements of NO2 at each site. The CFD modeling gave best results at all sites, the OSM modeling quality varied between the sites, with slight to about 50% underestimation. The Gaussian modeling generally underestimated the concentration with 50%. The aspect ratio H/W ≥ 0.7 favors development of vortices and lateral dispersion of pollutants in street canyons. It was shown that with at least this aspect ratio locally emitted NO2 frequently becomes at least 2–3 times higher compared an open road case. A methodology has been developed visualized in a flow chart, for help choosing an appropriate model for each environment. Most important factors are; street canyon structure; local concentration level; proximity to high emissions/risk of leakage into calculation area.
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| 4. |
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| 5. |
- Hordoir, Robinson, et al.
(författare)
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Nemo-Nordic 1.0 : a NEMO-based ocean model for the Baltic and North seas - research and operational applications
- 2019
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 12:1, s. 363-386
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Tidskriftsartikel (refereegranskat)abstract
- We present Nemo-Nordic, a Baltic and North Sea model based on the NEMO ocean engine. Surrounded by highly industrialized countries, the Baltic and North seas and their assets associated with shipping, fishing and tourism are vulnerable to anthropogenic pressure and climate change. Ocean models providing reliable forecasts and enabling climatic studies are important tools for the shipping infrastructure and to get a better understanding of the effects of climate change on the marine ecosystems. Nemo-Nordic is intended to be a tool for both short-term and long-term simulations and to be used for ocean forecasting as well as process and climatic studies. Here, the scientific and technical choices within Nemo-Nordic are introduced, and the reasons behind the design of the model and its domain and the inclusion of the two seas are explained. The model's ability to represent barotropic and baroclinic dynamics, as well as the vertical structure of the water column, is presented. Biases are shown and discussed. The short-term capabilities of the model are presented, especially its capabilities to represent sea level on an hourly timescale with a high degree of accuracy. We also show that the model can represent longer timescales, with a focus on the major Baltic inflows and the variability in deep-water salinity in the Baltic Sea.
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| 6. |
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| 7. |
- Pinto, Dalila, et al.
(författare)
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Functional impact of global rare copy number variation in autism spectrum disorders.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Rizoska, Biljana, et al.
(författare)
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Disease modifying effects of the amyloid-beta protofibril-selective antibody mAb158 in aged Tg2576 transgenic mice
- 2024
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 130
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta (Aβ) peptides, which aggregate to form neocortical plaques in Alzheimer's disease, exist in states that range from soluble monomers and oligomers/protofibrils to insoluble fibrillar amyloid. The present study evaluated the effects of mAb158, a mouse monoclonal antibody version of lecanemab that preferentially binds to soluble Aβ protofibrils, in aged transgenic mice (Tg2576) with Aβ pathology. Female Tg2576 mice (12 months old) received weekly intraperitoneal mAb158 (35 mg/kg) or vehicle for 4 weeks or for 18 weeks, with or without a subsequent 12-week off-treatment period. Aβ protofibril levels were significantly lower in mAb158-treated animals at both 4 and 18 weeks, while longer treatment duration (18 weeks) was required to observe significantly lower Aβ42 levels in insoluble brain fractions and lower Aβ plaque load. Following the off-treatment period, comparison of the vehicle- and mAb158-treated mice demonstrated that the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load remained significantly lower in mAb158-treated animals, as compared with age-matched controls. However, there was a significant increase of brain accumulation of both the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load after treatment cessation. Thus, repeated mAb158 treatment of aged Tg2576 mice first reduced Aβ protofibril levels within 4 weeks of treatment, which then was followed by a reduction of amyloid plaque pathology within 18 weeks of treatment. These effects were maintained 12 weeks after the final dose, indicating that mAb158 had a disease-modifying effect on the Aβ pathology in this mouse model. In addition, brain accumulation of both Aβ protofibril levels and amyloid pathology progressed after discontinuation of the treatment which supports the importance of continued treatment with mAb158 to maintain the effects on Aβ pathology.
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| 9. |
- Wickström, Malin, et al.
(författare)
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The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan
- 2010
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 79:9, s. 1281-1290
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Tidskriftsartikel (refereegranskat)abstract
- The alkylating prodrug of melphalan, J1 (melphalanyl-l-p-fluorophenylalanyl ethyl ester) is currently in early clinical trials. Preclinical studies have shown that J1-mediated cytotoxicity is dependent on hydrolytic activity of tumor cells. In this report we have analyzed potential peptidases and esterases of importance for release of free melphalan from J1. Exposure of tumor cell lines to J1 resulted in a significant increased level of free intracellular melphalan, at least tenfold at Cmax, compared to exposure to melphalan at the same molar concentration. This efficient intracellular delivery could be inhibited in both magnitude and in time by bestatin, a broad spectrum inhibitor of the aminopeptidases, including the metalloproteinase aminopeptidase N (APN, EC 3.4.11.2.), and ebelactone A, an esterase inhibitor. These effects resulted, as expected, in decreased cytotoxic effects of J1. A specific role of APN in hydrolyzing J1 releasing free melphalan was demonstrated in vitro with pure APN enzyme. By using plasmid-based overexpression of APN or down regulation of endogenous APN with siRNA in different tumor cell lines we here confirm the involvement of APN in J1-mediated cytotoxic and apoptotic signaling. In conclusion, this study demonstrates a role of APN in the activation of the melphalan prodrug J1 and subsequently, its cytotoxicity. Given that APN is shown to be overexpressed in several solid tumors our data suggest that J1 may be activated in a tumor selective manner.
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| 10. |
- Winefield, Helen, et al.
(författare)
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Internalized symptoms in adolescence as predictors of mental health in adulthood in the Northern Swedish cohort
- 2013
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Ingår i: Health. - : Scientific Research Publishing, Inc.. - 1949-4998 .- 1949-5005. ; 5:7, s. 1164-1171
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Tidskriftsartikel (refereegranskat)abstract
- Although mental health symptoms in children and adolescents are shown to predict young adult mental health outcomes, long-term prospective studies of childhood cohorts are few. The aim of the present study was to analyze the prospective importance of internalized mental health symptoms in adolescence for internalized symptoms in adulthood. Methods: A communitybased prospective longitudinal cohort provided information by questionnaire about psychological status at age 16 and 43 (n = 1010, representing 94.3% of those still alive). Socio-demographic variables which were indicative of possible childhood adversity (parental class, absence, illness, unemployment, relationship, crowding, number of moves) were treated as confounders and controlled for in ordinal regression. Results: For both women and men, internalizing mental health symptoms reported at 16 significantly predicted the same outcome at 43 years, after controlling for previous adverse environmental conditions (OR = 1.2 for women, 1.3 for men). Conclusion: In this representative cohort studied over 27 years with excellent retention rates, the occurrence of self-reported worry, panic and sadness in mid-adolescence significantly increased the likelihood of similar states in middle adulthood.
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