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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Weiner, D. J., et al.
(författare)
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Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:7
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
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| 4. |
- Anney, R. J. L., et al.
(författare)
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Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia
- 2017
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Ingår i: Molecular Autism. - : Springer Science and Business Media LLC. - 2040-2392. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) < 1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P= 9 x10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental- related genes such as EXT1, ASTN2, MACROD2, and HDAC4.
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| 8. |
- Bralower, T, et al.
(författare)
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The Habitat of the Nascent Chicxulub Crater
- 2020
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Ingår i: AGU Advances. - : American Geophysical Union (AGU). ; 1
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Tidskriftsartikel (refereegranskat)abstract
- An expanded sedimentary section provides an opportunity to elucidate conditions in the nascent Chicxulub crater during the hours to millennia after the Cretaceous‐Paleogene (K‐Pg) boundary impact. The sediments were deposited by tsunami followed by seiche waves as energy in the crater declined, culminating in a thin hemipelagic marlstone unit that contains atmospheric fallout. Seiche deposits are predominantly composed of calcite formed by decarbonation of the target limestone during impact followed by carbonation in the water column. Temperatures recorded by clumped isotopes of these carbonates are in excess of 70°C, with heat likely derived from the central impact melt pool. Yet, despite the turbidity and heat, waters within the nascent crater basin soon became a viable habitat for a remarkably diverse cross section of the food chain. The earliest seiche layers deposited with days or weeks of the impact contain earliest Danian nannoplankton and dinocyst survivors. The hemipelagic marlstone representing the subsequent years to a few millennia contains a nearly monogeneric calcareous dinoflagellate resting cyst assemblage suggesting deteriorating environmental conditions, with one interpretation involving low light levels in the impact aftermath. At the same horizon, microbial fossils indicate a thriving bacterial community and unique phosphatic fossils including appendages of pelagic crustaceans, coprolites andbacteria‐tunneled fish bone, suggesting that this rapid recovery of the base of the food chain may have supported the survival of larger, higher trophic‐level organisms. The extraordinarily diverse fossil assemblage indicates that the crater was a unique habitat in the immediate impact aftermath, possibly as aresult of heat and nutrients supplied by hydrothermal activity.
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| 12. |
- Horne, B D, et al.
(författare)
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Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy
- 2012
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 107:2, s. 232-240
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Tidskriftsartikel (refereegranskat)abstract
- By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
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| 13. |
- Lenzini, P., et al.
(författare)
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Integration of genetic, clinical, and INR data to refine warfarin dosing
- 2010
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 87:5, s. 572-578
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Tidskriftsartikel (refereegranskat)abstract
- Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.
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| 14. |
- Mahjani, Behrang, et al.
(författare)
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Direct additive genetics and maternal effect contribute to the risk of Tourette disorder
- 2023
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 94:8, s. 638-642
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Risk for Tourette disorder, and chronic motor or vocal tic disorders (referenced here inclusively as CTD), arise from a combination of genetic and environmental factors. While multiple studies have demonstrated the importance of direct additive genetic variation for CTD risk, little is known about the role of cross-generational transmission of genetic risk, such as maternal effect, which is not transmitted via the inherited parental genomes. Here, we partition sources of variation on CTD risk into direct additive genetic effect (narrow-sense heritability) and maternal effect.METHODS: The study population consists of 2 522 677 individuals from the Swedish Medical Birth Register, who were born in Sweden between 1 January 1973 and 31 December 2000, and followed for a diagnosis of CTD through 31 December, 2013. We used generalised linear mixed models to partition the liability of CTD into: direct additive genetic effect, genetic maternal effect and environmental maternal effect.RESULTS: We identified 6227 (0.2%) individuals in the birth cohort with a CTD diagnosis. A study of half-siblings showed that maternal half-siblings had twice higher risk of developing a CTD compared with paternal ones. We estimated 60.7% direct additive genetic effect (95% credible interval, 58.5% to 62.4%), 4.8% genetic maternal effect (95% credible interval, 4.4% to 5.1%) and 0.5% environmental maternal effect (95% credible interval, 0.2% to 7%).CONCLUSIONS: Our results demonstrate genetic maternal effect contributes to the risk of CTD. Failure to account for maternal effect results in an incomplete understanding of the genetic risk architecture of CTD, as the risk for CTD is impacted by maternal effect which is above and beyond the risk from transmitted genetic effect.
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| 15. |
- Mahjani, Behrang, et al.
(författare)
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The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum.
- 2022
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 179:3, s. 216-225
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Tidskriftsartikel (refereegranskat)abstract
- Obsessive-compulsive disorder (OCD) is known to be substantially heritable; however, the contribution of genetic variation across the allele frequency spectrum to this heritability remains uncertain. The authors used two new homogeneous cohorts to estimate the heritability of OCD from inherited genetic variation and contrasted the results with those of previous studies.The sample consisted of 2,090 Swedish-born individuals diagnosed with OCD and 4,567 control subjects, all genotyped for common genetic variants, specifically >400,000 single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥0.01. Using genotypes of these SNPs to estimate distant familial relationships among individuals, the authors estimated the heritability of OCD, both overall and partitioned according to MAF bins.Narrow-sense heritability of OCD was estimated at 29% (SE=4%). The estimate was robust, varying only modestly under different models. Contrary to an earlier study, however, SNPs with MAF between 0.01 and 0.05 accounted for 10% of heritability, and estimated heritability per MAF bin roughly followed expectations based on a simple model for SNP-based heritability.These results indicate that common inherited risk variation (MAF ≥0.01) accounts for most of the heritable variation in OCD. SNPs with low MAF contribute meaningfully to the heritability of OCD, and the results are consistent with expectation under the "infinitesimal model" (also referred to as the "polygenic model"), where risk is influenced by a large number of loci across the genome and across MAF bins.
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| 16. |
- Schouten, Stefan, et al.
(författare)
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An interlaboratory study of TEX86 and BIT analysis of sediments, extracts, and standard mixtures
- 2013
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Ingår i: Geochemistry Geophysics Geosystems. - 1525-2027. ; 14:12, s. 5263-5285
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Tidskriftsartikel (refereegranskat)abstract
- Two commonly used proxies based on the distribution of glycerol dialkyl glycerol tetraethers (GDGTs) are the TEX86 (TetraEther indeX of 86 carbon atoms) paleothermometer for sea surface temperature reconstructions and the BIT (Branched Isoprenoid Tetraether) index for reconstructing soil organic matter input to the ocean. An initial round-robin study of two sediment extracts, in which 15 laboratories participated, showed relatively consistent TEX86 values (reproducibility +/- 3-4 degrees C when translated to temperature) but a large spread in BIT measurements (reproducibility +/- 0.41 on a scale of 0-1). Here we report results of a second round-robin study with 35 laboratories in which three sediments, one sediment extract, and two mixtures of pure, isolated GDGTs were analyzed. The results for TEX86 and BIT index showed improvement compared to the previous round-robin study. The reproducibility, indicating interlaboratory variation, of TEX86 values ranged from 1.3 to 3.0 degrees C when translated to temperature. These results are similar to those of other temperature proxies used in paleoceanography. Comparison of the results obtained from one of the three sediments showed that TEX86 and BIT indices are not significantly affected by interlaboratory differences in sediment extraction techniques. BIT values of the sediments and extracts were at the extremes of the index with values close to 0 or 1, and showed good reproducibility (ranging from 0.013 to 0.042). However, the measured BIT values for the two GDGT mixtures, with known molar ratios of crenarchaeol and branched GDGTs, had intermediate BIT values and showed poor reproducibility and a large overestimation of the true (i.e., molar-based) BIT index. The latter is likely due to, among other factors, the higher mass spectrometric response of branched GDGTs compared to crenarchaeol, which also varies among mass spectrometers. Correction for this different mass spectrometric response showed a considerable improvement in the reproducibility of BIT index measurements among laboratories, as well as a substantially improved estimation of molar-based BIT values. This suggests that standard mixtures should be used in order to obtain consistent, and molar-based, BIT values.
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| 17. |
- Spilsbury, Francis, et al.
(författare)
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Fish Fingerprinting: Identifying Crude Oil Pollutants using Bicyclic Sesquiterpanes (Bicyclanes) in the Tissues of Exposed Fish
- 2022
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Ingår i: Environmental Toxicology and Chemistry. - : Wiley. - 0730-7268 .- 1552-8618. ; 42:1, s. 7-18
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, we investigated the possibility of identifying the source oils of exposed fish using ratios of bicyclic sesquiterpane (bicyclane) chemical biomarkers. In the event of an oil spill, identification of source oil(s) for assessment, or for litigation purposes, typically uses diagnostic ratios of chemical biomarkers to produce characteristic oil "fingerprints." Although this has been applied in identifying oil residues in sediments, water, and sessile filtering organisms, so far as we are aware this has never been successfully demonstrated for oil-exposed fish. In a 35-day laboratory trial, juvenile Lates calcarifer (barramundi or Asian seabass) were exposed, via the diet (1% w/w), to either a heavy fuel oil or to Montara, an Australian medium crude oil. Two-dimensional gas chromatography with high-resolution mass spectrometry and gas chromatography-mass spectrometry were then used to measure selected ratios of the bicyclanes to examine whether the ratios were statistically reproducibly conserved in the fish tissues. Six diagnostic bicyclane ratios showed high correlation (r(2) > 0.98) with those of each of the two source oils. A linear discriminatory analysis model showed that nine different petroleum products could be reproducibly discriminated using these bicyclane ratios. The model was then used to correctly identify the bicyclane profiles of each of the two exposure oils in the adipose tissue extracts of each of the 18 fish fed oil-enriched diets. From our initial study, bicyclane biomarkers appear to show good potential for providing reliable forensic fingerprints of the sources of oil contamination of exposed fish. Further research is needed to investigate the minimum exposure times required for bicyclane bioaccumulation to achieve detectable concentrations in fish adipose tissues and to determine bicyclane depuration rates once exposure to oil has ceased. Environ Toxicol Chem 2022;00:1-13. (c) 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
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| 18. |
- Stannard, Kimberley A., et al.
(författare)
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Galectin inhibitory disaccharides promote tumour immunity in a breast cancer model
- 2010
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Ingår i: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 299:2, s. 95-110
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Tidskriftsartikel (refereegranskat)abstract
- High level galectin-1 expression results in cancer cell evasion of the immune response, increased tumour survival and aggressive metastases. Using a galectin-1 polyclonal antibody, high levels of galectin-1 protein were shown to be expressed by breast cancer cells established from FVB/N MMTV-c-neu mice as well as by the B16F10 melanoma cell line. In mixed lymphocyte cultures using tumour cells as antigenic stimulators, addition of recombinant galectin-1 dose-dependently inhibited lymphocyte production. Disaccharides were identified that inhibited galectin-1 function and increased growth and activation of CD8+ CTL's killing cancer cells. X-ray crystallographic structures of human galectin-1 in complex with inhibitory disaccharides revealed their mode of binding. Combining galectin-blocking carbohydrates as adjuvants with vaccine immunotherapy in vivo to promote immune responses significantly decreased tumour progression and improved the outcomes for tumour challenged mice. This is the first report showing that suitably selected galectin-1 blocking disaccharides will act as adjuvants promoting vaccine stimulated immune responses against tumours in vivo.
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| 19. |
- Wang, Sheng, et al.
(författare)
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De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis
- 2018
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Ingår i: Cell Reports. - : CELL PRESS. - 2211-1247. ; 24:13, s. 3441-
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Tidskriftsartikel (refereegranskat)abstract
- We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.
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| 20. |
- Zeichner, Sarah S., et al.
(författare)
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Polycyclic aromatic hydrocarbons in samples of Ryugu formed in the interstellar medium
- 2023
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Ingår i: Science. - : AMER ASSOC ADVANCEMENT SCIENCE. - 0036-8075 .- 1095-9203. ; 382:6677, s. 1411-1415
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Tidskriftsartikel (refereegranskat)abstract
- Polycyclic aromatic hydrocarbons (PAHs) contain less than or similar to 20% of the carbon in the interstellar medium. They are potentially produced in circumstellar environments (at temperatures greater than or similar to 1000 kelvin), by (similar to 10 kelvin) interstellar clouds, or by processing of carbon-rich dust grains. We report isotopic properties of PAHs extracted from samples of the asteroid Ryugu and the meteorite Murchison. The doubly-C-13 substituted compositions (Delta 2x(13)C values) of the PAHs naphthalene, fluoranthene, and pyrene are 9 to 51 parts per thousand higher than values expected for a stochastic distribution of isotopes. The Delta 2x(13)C values are higher than expected if the PAHs formed in a circumstellar environment, but consistent with formation in the interstellar medium. By contrast, the PAHs phenanthrene and anthracene in Ryugu samples have Delta 2x(13)C values consistent with formation by higher-temperature reactions.
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| 22. |
- Bum-Erdene, Khuchtumur, et al.
(författare)
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Investigation into the Feasibility of Thioditaloside as a Novel Scaffold for Galectin-3-Specific Inhibitors
- 2013
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Ingår i: ChemBioChem. - : Wiley. - 1439-4227. ; 14:11, s. 1331-1342
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-3 is extensively involved in metabolic and disease processes, such as cancer metastasis, thus giving impetus for the design of specific inhibitors targeting this -galactose-binding protein. Thiodigalactoside (TDG) presents a scaffold for construction of galectin inhibitors, and its inhibition of galectin-1 has already demonstrated beneficial effects as an adjuvant with vaccine immunotherapy, thereby improving the survival outcome of tumour-challenged mice. A novel approachreplacing galactose with its C2 epimer, taloseoffers an alternative framework, as extensions at C2 permit exploitation of a galectin-3-specific binding groove, thereby facilitating the design of selective inhibitors. We report the synthesis of thioditaloside (TDT) and crystal structures of the galectin-3 carbohydrate recognition domain in complexes with TDT and TDG. The different abilities of galactose and talose to anchor to the protein correlate with molecular dynamics studies, likely explaining the relative disaccharide binding affinities. The feasibility of a TDT scaffold to enable access to a particular galectin-3 binding groove and the need for modifications to optimise such a scaffold for use in the design of potent and selective inhibitors are assessed.
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| 23. |
- Bum-Erdene, Khuchtumur, et al.
(författare)
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Novel Selective Galectin-3 Antagonists Are Cytotoxic to Acute Lymphoblastic Leukemia
- 2022
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:8, s. 5975-5989
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-3 is a β-galactoside-specific, carbohydrate-recognizing protein (lectin) that is strongly implicated in cancer development, metastasis, and drug resistance. Galectin-3 promotes migration and ability to withstand drug treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. Due to high amino acid conservation among galectins and the shallow nature of their glycan-binding site, the design of selective potent antagonists targeting galectin-3 is challenging. Herein, we report the design and synthesis of novel taloside-based antagonists of galectin-3 with enhanced affinity and selectivity. The molecules were optimized by in silico docking, selectivity was established against four galectins, and the binding modes were confirmed by elucidation of X-ray crystal structures. Critically, the specific inhibition of galectin-3-induced BCP-ALL cell agglutination was demonstrated. The compounds decreased the viability of ALL cells even when grown in the presence of protective stromal cells. We conclude that these compounds are promising leads for therapeutics, targeting the tumor-supportive activities of galectin-3 in cancer.
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| 26. |
- Gulick, Sean, P.S., et al.
(författare)
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The first day of the Cenozoic
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : US National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116, s. 19342-19351
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Tidskriftsartikel (refereegranskat)abstract
- Highly expanded Cretaceous–Paleogene (K-Pg) boundary section from the Chicxulub peak ring, recovered by International Ocean Discovery Program (IODP) –International Continental Scientific Drilling Program (ICDP) Expedition 364, provides an unprecedented window into the immediate aftermath of the impact. Site M0077 includes ∼130 m of impact melt rock and suevite deposited the first day of the Cenozoic covered by <1 m of micrite-rich carbonate deposite over subsequent weeks to years. We present an interpreted series of events based on analyses of these drill cores. Within minutes of the impact, centrally uplifted basement rock collapsed outward to forma peak ring capped in melt rock. Within tens of minutes, the peak ring was covered in ∼40 m of brecciated impact melt rock and coarsegrained suevite, including clasts possibly generated by melt–water interactions during ocean resurge. Within an hour, resurge crested the peak ring, depositing a 10-m-thick layer of suevite with increased particle roundness and sorting. Within hours, the full resurge deposit formed through settling and seiches, resulting in an 80-m-thick fining-upward, sorted suevite in the flooded crater. Within a day, the reflected rim-wave tsunami reached the crater, depositing a cross-bedded sand-to-fine gravel layer enriched in polycyclic aromatic hydrocarbons overlain by charcoal fragments. Generation of a deep crater open to the ocean allowed rapid flooding and sediment accumulation rates among the highest known in the geologic record. The high-resolution section provides insight into the impact environmental effects, including charcoal as evidence for impactinduced wildfires and a paucity of sulfur-rich evaporites from the target supporting rapid global cooling and darkness as extinction mechanisms.
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| 28. |
- Liu, D. C., et al.
(författare)
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The Human Stratum Corneum Prevents Small Gold Nanoparticle Penetration and Their Potential Toxic Metabolic Consequences
- 2012
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Ingår i: Journal of Nanomaterials. - : Hindawi Limited. - 1687-4110 .- 1687-4129.
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Tidskriftsartikel (refereegranskat)abstract
- Nanoparticles are being used inmultiple applications, ranging from biomedical and skin care products (e. g., sunscreen) through to industrial manufacturing processes (e. g., water purification). The increase in exposure has led to multiple reports on nanoparticle penetration and toxicity. However, the correlation between nanoparticle size and its penetration without physical/chemical enhancers through the skin is poorly understood-with studies instead focusing primarily on skin penetration under disrupted conditions. In this paper, we investigate the penetration and metabolic effects of 10 nm, 30 nm, and 60 nm gold nanoparticles within viable excised human skin after 24-hour exposure usingmultiphoton tomograph-fluorescence lifetime imaging microscopy. After 24 hour treatment with the 10, 30, and 60 nm gold nanoparticles, there was no significant penetration detected below the stratum corneum. Furthermore, there were no changes in metabolic output (total NAD(P) H) in the viable epidermis posttreatment correlating with lack of penetration of nanoparticles. These results are significant for estimating topical nanoparticle exposure in humans where other model systems may overestimate the exposure of nanoparticles to the viable epidermis. Our data shows that viable human skin resists permeation of small nanoparticles in a size range that has been reported to penetrate deeply in other skin models.
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| 29. |
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| 30. |
- Mahjani, Behrang, et al.
(författare)
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Maternal Effects as Causes of Risk for Obsessive-Compulsive Disorder
- 2020
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 87:12, s. 1045-1051
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: While genetic variation has a known impact on the risk for obsessive-compulsive disorder (OCD), there is also evidence that there are maternal components to this risk. Here, we partitioned sources of variation, including direct genetic and maternal effects, on risk for OCD.METHODS: The study population consisted of 822,843 individuals from the Swedish Medical Birth Register, born in Sweden between January 1, 1982, and December 31, 1990, and followed for a diagnosis of OCD through December 31, 2013. Diagnostic information about OCD was obtained using the Swedish National Patient Register.RESULTS: A total of 7184 individuals in the birth cohort (0.87%) were diagnosed with OCD. After exploring various generalized linear mixed models to fit the diagnostic data, genetic maternal effects accounted for 7.6% (95% credible interval: 6.9%-8.3%) of the total variance in risk for OCD for the best model, and direct additive genetics accounted for 35% (95% credible interval: 32.3%-36.9%). These findings were robust under alternative models.CONCLUSIONS: Our results establish genetic maternal effects as influencing risk for OCD in offspring. We also show that additive genetic effects in OCD are overestimated when maternal effects are not modeled.
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| 32. |
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| 33. |
- Nissen, J, et al.
(författare)
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Diagnostic validity of early-onset obsessive-compulsive disorder in the Danish Psychiatric Central Register: findings from a cohort sample
- 2017
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 7:9, s. e017172-
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Tidskriftsartikel (refereegranskat)abstract
- Employing national registers for research purposes depends on a high diagnostic validity. The aim of the present study was to examine the diagnostic validity of recorded diagnoses of early-onset obsessive-compulsive disorder (OCD) in the Danish Psychiatric Central Register (DPCR).DesignReview of patient journals selected randomly through the DPCR.MethodOne hundred cases of OCD were randomly selected from DPCR. Using a predefined coding scheme based on the Children’s Yale Brown Obsessive Compulsive Scale (CYBOCS), experienced research nurse or child and adolescent psychiatrists assessed each journal to determine the presence/absence of OCD diagnostic criteria. The detailed assessments were reviewed by two senior child and adolescent psychiatrists to determine if diagnostic criteria were met.Primary outcome measurementsPositive predictive value (PPV) was used as the primary outcome measurement.ResultsA total of 3462 children/adolescents received an OCD diagnosis as the main diagnosis between 1 January 1995 and 31 December 2015. The average age at diagnosis was 13.21±2.89 years. The most frequent registered OCD subcode was the combined diagnosis DF42.2. Of the 100 cases we examined, 35 had at least one registered comorbidity. For OCD, the PPV was good (PPV 0.85). Excluding journals with insufficient information, the PPV was 0.96. For the subcode F42.2 the PPV was 0.77. The inter-rater reliability was 0.94. The presence of the CYBOCS in the journal significantly increased the PPV for the OCD diagnosis altogether and for the subcode DF42.2.ConclusionThe validity and reliability of International Classification of Disease 10th revision codes for OCD in the DPCR is generally high. The subcodes for predominant obsessions/predominant compulsions are less certain and should be used with caution. The results apply for both children and adolescents and for both older and more recent cases. Altogether, the study suggests that there is a high validity of the OCD diagnosis in the Danish National Registers.
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| 34. |
- Raade, G., et al.
(författare)
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Proshchenkoite-(Y) from Russia - a new mineral species in the vicanite group: descriptive data and crystal structure
- 2008
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Ingår i: Mineralogical Magazine. - : Mineralogical Society. - 0026-461X .- 1471-8022. ; 72:5, s. 1071-1082
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Tidskriftsartikel (refereegranskat)abstract
- A REE-bearing fluorosilicate from the Tommot REE-Nb deposit in Yakutia, Russia, described without a name in 1966, is characterized here as a new species, proshchenkoite-(Y), of the vicanite group of borosilicates. Wavelength-dispersive electron probe analyses gave the following empirical formula: (Y3.70REE7.54Ca1.55Na1.16Mn0.77Th0.10Pb0.01)(Sigma 14.83)(Fe0.832+M0.15Ti0.02)(Sigma 1.00)Ca-1.00 (P0.70Si0.26As0.04)(Sigma 1.00)Si6.05B3.20(O34.55F13.45)(Sigma 48). Boron was analysed with a nuclear microprobe method based on the nuclear reaction B-11(p,alpha)2 alpha. The simplified formula is (Y,REE,Ca,Na,Mn)(15) (Fe2+,Mn)Ca(P,Si)Si6B3O34F14. The mineral is trigonal, R3m, with a = 10.7527(7) angstrom, c = 27.4002(18) angstrom, V = 2743.6(6) angstrom(3), Z = 3. The crystal structure was refined to R1 = 0.042 for 1819 observed reflections. Proshchenkoite-(Y) is isostructural with okanoganite-(Y), vicanite-(Ce) and hundholmenite-(Y), and the differences in site occupancies are discussed. The strongest six reflections of the X-ray powder-diffraction pattern [d(obs) in angstrom, (I), (hkl)] are: 4,441, (36), (202); 3.144, (77), (214); 3.028, (45), (009); 2.968, (100), (027); 1.782, (32), (330); and 1.713, (32), (1.2.14). The mineral is optically uniaxial (-) with omega 1.734(2) and epsilon 1.728(2). The Mohs hardness is about 5; density measured on material subject to incipient metarnictization is 4.72 g/cm(3), as compared to D-calc = 4.955 g/cm(3). The result of electron microprobe analyses of alleged okanoganite-(Y) from the type locality in Okanogan County, Washington, USA, is also presented. We find here also that P > Si at one of the sites, whereas the analytical data of Boiocchi et al. (2004) indicate Si > P. Consequently, the mineral we have analysed is the P analogue of okanoganite-(Y), another new species.
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| 35. |
- Raphael, A. P., et al.
(författare)
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Zinc oxide nanoparticle removal from wounded human skin
- 2013
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Ingår i: Nanomedicine. - : Future Medicine Ltd. - 1743-5889 .- 1748-6963. ; 8:11, s. 1751-1761
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Nanoparticle removal from skin is relevant given the concern over topical nanoparticle toxicity. Zinc oxide nanoparticles (ZnO-NPs) are commonly used in sunscreens and their use is currently debated. This study explores the penetration and removal of ZnO-NPs from injured skin. Materials & methods:Ex vivo/in vivo human skin was tape-stripped and/or microneedled followed by ZnO-NP application. After 2 h, treated skin was washed three-times using soapy water. Multiphoton tomography assessed the ZnO-NP signal before and after washing. Results: Washing once removed over 85 and 83% of ZnO-NP signal from ex vivo intact and tape-stripped skin, respectively (p < 0.05) but only 28% (p = 0.5) was removed from puncture sites. A similar trend was found in vivo with removal of 85 and 93% of ZnO-NP signal from intact and tape-stripped skin, respectively (p < 0.05). Conclusion: Washing is effective for the removal of ZnO-NPs from superficial layers of intact and tape-stripped skin, but not from puncture wounds.
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| 36. |
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| 37. |
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