| 1. |
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| 2. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- de Vries, Paul S., et al.
(författare)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
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Tidskriftsartikel (refereegranskat)abstract
- A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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| 4. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 5. |
- Ablikim, M., et al.
(författare)
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Measurements of (XcJ)-> K+K-K+K- decays
- 2006
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 642:3, s. 197-202
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Tidskriftsartikel (refereegranskat)abstract
- Using 14M psi(2S) events taken with the BESII detector, chi(cJ) -> 2(K+K-) decays are studied. For the four-kaon final state, the branching fractions are B(chi(c0,1,2) ->.2(K+K-)) = (3.48 +/- 0.23 +/- 0.47) x 10(-3), (0.70 +/- 0.13 +/- 0.10) x 10(-3), and (2.17 +/- 0.20 +/- 0.31) x 10(-3). For the phi K+K- final state, the branching fractions, which are measured for the first time, are B(chi(c0,1,2) -> phi K+K-) = (1.03 +/- 0.22 +/- 0.15) x 10(-3), (0.46 +/- 0.16 +/- 0.06) x 10(-3), and (1.67 +/- 0.26 +/- 0.24) x 10(-4). For the phi phi final state, B(chi(c0,2) -> phi phi) = (0.94 +/- 0.21 +/- 0.13) x 10(-3) and (1.70 +/- 0.30 +/- 0.25) x 10(-3).
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| 6. |
- Jang, Seon-Kyeong, et al.
(författare)
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Rare genetic variants explain missing heritability in smoking.
- 2022
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Ingår i: Nature human behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 6:11, s. 1577-1586
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Tidskriftsartikel (refereegranskat)abstract
- Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.
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| 7. |
- A. B. Marçal, L., et al.
(författare)
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Spatially resolved structural and chemical properties of the white layer in machined Inconel 718 super alloy
- 2024
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Ingår i: Materials and Design. - 0264-1275. ; 239
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Tidskriftsartikel (refereegranskat)abstract
- Inconel 718 is one type of nickel-based alloy used for a large range of applications, including gas turbines and aeroengines components. Although mechanical and thermodynamic properties of this material have been deeply studied in the past years, a method able to investigate local properties of the thin white layer formed on the alloy surface after machining remains challenging. Here, a 90 nm X-ray beam is used to probe the local strain, crystal orientation, and chemical composition of grains in the white layer. Data reveals mosaicity induced by the tool during machining. The high spatial resolution, combined with crystal lattice sensitivity, shows that the average grain size is around 30 nm throughout the white layer, while the strain is anisotropic nearest to the surface. Results provide new insights on the basic properties of the white layer in super alloys, revealing important information about the impact of finish machining which might help to explain fatigue and cracking formation on these materials during their usage phase.
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| 8. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 9. |
- Edwards, Robert A., et al.
(författare)
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Global phylogeography and ancient evolution of the widespread human gut virus crAssphage
- 2019
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Ingår i: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 4:10, s. 1727-1736
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Tidskriftsartikel (refereegranskat)abstract
- Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world's countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome.
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| 10. |
- Suarez, M., et al.
(författare)
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Analysis of the upconversion processes of Nd3+ ions in transparent YAG ceramics
- 2014
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Ingår i: Ceramics International. - : Elsevier BV. - 0272-8842 .- 1873-3956. ; 40:10, s. 15951-15956
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Tidskriftsartikel (refereegranskat)abstract
- Optical properties of Nd3+ ions in YAG transparent ceramics have been analysed. The samples were prepared by a high temperature (1650 and 1680 degrees C) sintering followed by hot isostatic pressing (HIP) at 1650 or 1700 degrees C in order to obtain a well-homogeneous diffusion of the ions and functional transparency. The emission and luminescence decay curves from the F-4(3/2) metastable laser level of these samples are very similar to the ones obtained on crystal samples grown with the Czochralski method. However, excitation upconversion spectra obtained detecting at 590 nm for the transparent ceramic samples present important differences compared to the bulk YAG crystal, which can be explained by a change in the upconversion mechanism involved and the different arrangements of the Nd3+ ions in the YAG matrix. The analysis of the upconversion excitation spectra is shown to be a good method to detect the differences between the positions occupied by the Nd3+ ions in different matrices.
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| 11. |
- Swartling, Fredrik Johansson, et al.
(författare)
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Pleiotropic role for MYCN in medulloblastoma
- 2010
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Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 24:10, s. 1059-1072
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Sonic Hedgehog (SHH) signaling drives a minority of MB, correlating with desmoplastic pathology and favorable outcome. The majority, however, arises independently of SHH and displays classic or large cell anaplastic (LCA) pathology and poor prognosis. To identify common signaling abnormalities, we profiled mRNA, demonstrating misexpression of MYCN in the majority of human MB and negligible expression in normal cerebella. We clarified a role in pathogenesis by targeting MYCN (and luciferase) to cerebella of transgenic mice. MYCN-driven MB showed either classic or LCA pathologies, with Shh signaling activated in approximately 5% of tumors, demonstrating that MYCN can drive MB independently of Shh. MB arose at high penetrance, consistent with a role for MYCN in initiation. Tumor burden correlated with bioluminescence, with rare metastatic spread to the leptomeninges, suggesting roles for MYCN in both progression and metastasis. Transient pharmacological down-regulation of MYCN led to both clearance and senescence of tumor cells, and improved survival. Targeted expression of MYCN thus contributes to initiation, progression, and maintenance of MB, suggesting a central role for MYCN in pathogenesis.
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| 12. |
- Barack, Leor, et al.
(författare)
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Black holes, gravitational waves and fundamental physics : a roadmap
- 2019
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Ingår i: Classical and quantum gravity. - : IOP Publishing. - 0264-9381 .- 1361-6382. ; 36:14
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Forskningsöversikt (refereegranskat)abstract
- The grand challenges of contemporary fundamental physics dark matter, dark energy, vacuum energy, inflation and early universe cosmology, singularities and the hierarchy problem all involve gravity as a key component. And of all gravitational phenomena, black holes stand out in their elegant simplicity, while harbouring some of the most remarkable predictions of General Relativity: event horizons, singularities and ergoregions. The hitherto invisible landscape of the gravitational Universe is being unveiled before our eyes: the historical direct detection of gravitational waves by the LIGO-Virgo collaboration marks the dawn of a new era of scientific exploration. Gravitational-wave astronomy will allow us to test models of black hole formation, growth and evolution, as well as models of gravitational-wave generation and propagation. It will provide evidence for event horizons and ergoregions, test the theory of General Relativity itself, and may reveal the existence of new fundamental fields. The synthesis of these results has the potential to radically reshape our understanding of the cosmos and of the laws of Nature. The purpose of this work is to present a concise, yet comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress. This write-up is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'.
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| 13. |
- Barragan, Antonio, et al.
(författare)
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GABAergic signalling in the immune system
- 2015
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 213:4, s. 819-827
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Forskningsöversikt (refereegranskat)abstract
- The GABAergic system is the main inhibitory neurotransmitter system in the central nervous system (CNS) of vertebrates. Signalling of the transmitter c-aminobutyric acid (GABA) via GABA type A receptor channels or G-protein-coupled type B receptors is implicated in multiple CNS functions. Recent findings have implicated the GABAergic system in immune cell functions, inflammatory conditions and diseases in peripheral tissues. Interestingly, the specific effects may vary between immune cell types, with stage of activation and be altered by infectious agents. GABA/GABA-A receptor-mediated immunomodulatory functions have been unveiled in immune cells, being present in T lymphocytes and regulating the migration of Toxoplasma-infected dendritic cells. The GABAergic system may also play a role in the regulation of brain resident immune cells, the microglial cells. Activation of microglia appears to regulate the function of GABAergic neurotransmission in neighbouring neurones through changes induced by secretion of brain-derived neurotrophic factor. The neurotransmitter-driven immunomodulation is a new but rapidly growing field of science. Herein, we review the present knowledge of the GABA signalling in immune cells of the periphery and the CNS and raise questions for future research.
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| 14. |
- Bhandage, Amol K., 1988-, et al.
(författare)
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GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics
- 2014
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers. - 1662-5102. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Chronic consumption of alcohol by humans has been shown to lead to impairment of executive and cognitive functions. Here, we have studied the mRNA expression of ion channel receptors for glutamate and GABA in the dorsal striatum of post-mortem brains from alcoholics (n = 29) and normal controls (n = 29), with the focus on the caudate nucleus that is associated with the frontal cortex executive functions and automatic thinking and on the putamen area that is linked to motor cortices and automatic movements. The results obtained by qPCR assay revealed significant changes in the expression of specific excitatory ionotropic glutamate and inhibitory GABA-A receptor subunit genes in the caudate but not the putamen. Thus, in the caudate we found reduced levels of mRNAs encoding the GluN2A glutamate receptor and the δ, ε, and ρ2 GABA-A receptor subunits, and increased levels of the mRNAs encoding GluD1, GluD2, and GABA-A γ1 subunits in the alcoholics as compared to controls. Interestingly in the controls, 11 glutamate and 5 GABA-A receptor genes were more prominently expressed in the caudate than the putamen (fold-increase varied from 1.24 to 2.91). Differences in gene expression patterns between the striatal regions may underlie differences in associated behavioral outputs. Our results suggest an altered balance between caudate-mediated voluntarily controlled and automatic behaviors in alcoholics, including diminished executive control on goal-directed alcohol-seeking behavior.
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| 15. |
- Buscaglia, V., et al.
(författare)
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Raman and AFM piezoresponse study of dense BaTiO3 nanocrystalline ceramics
- 2005
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Ingår i: Journal of the European Ceramic Society. - : Elsevier BV. - 0955-2219 .- 1873-619X. ; 25:12, s. 3059-3062
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Tidskriftsartikel (refereegranskat)abstract
- Dense nanocrystalline BaTiO3 (BT) ceramics with grain sizes (GSs) below 100 nm obtained by spark plasma sintering (SPS), were investigated by micro-Raman spectroscopy in order to obtain information about the changes in the local order induced by size effects. The obtained spectra in the range 80-700 K showed the presence of all the crystalline phases of BaTiO3, even in the finest structure (50 nm grain size ceramic), with particularities attributed to the high density of non-ferroelectric grain boundaries. The AFM piezoresponse study incontestably proved the ferroelectric switching at local scale in nanocrystalline BaTiO3 ceramics at room temperature.
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| 16. |
- Clarke, Andrew J., et al.
(författare)
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Non-fullerene acceptor photostability and its impact on organic solar cell lifetime
- 2021
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Ingår i: Cell Reports Physical Science. - : Elsevier. - 2666-3864. ; 2:7
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Tidskriftsartikel (refereegranskat)abstract
- The development of non-fullerene acceptors (NFAs) has facilitated the realization of efficient organic solar cells (OSCs) with minimal burn-in losses and excellent long-term stability. However, the role of NFA molecular structures on device stability remains unclear, limiting commercialization of NFA-based OSCs. Herein, the photostability of 10 OSC devices, fabricated with various NFAs (O-IDTBR, EH-IDTBR, ITIC, and ITIC-M) blended with donor polymers (PTB7-Th, PffBT4T-2OD, and PBDB-T), is investigated. O-IDTBR and EH-IDTBR form highly stable devices with all three polymers, whereas ITIC and ITIC-M devices suffer from burn-in losses and long-term degradation. Conformational instability is found to be responsible for the poor photostability of ITIC and ITIC-M, resulting in poor device stability. Twisting and potential breakage of the chemical bond that links the end group to the main backbone of ITIC and ITIC-M molecules causes undesirable conformational changes. Potential strategies to overcome such detrimental photo-induced conformational changes in NFAs are proposed.
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| 17. |
- Cotman, Andrej Emanuel, et al.
(författare)
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Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold- Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:2, s. 1380-1425
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Tidskriftsartikel (refereegranskat)abstract
- We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aerugi-nosa, which are both on the WHO priority list of antibiotic -resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase II alpha, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.
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| 18. |
- Gao, Feng, et al.
(författare)
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Trap-Induced Losses in Hybrid Photovoltaics
- 2014
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Ingår i: ACS Nano. - : American Chemical Society. - 1936-0851 .- 1936-086X. ; 8:4, s. 3213-3221
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the loss mechanisms in hybrid photovoltaics based on blends of poly(3-hexylthiophene) with CdSe nanocrystals of various sizes. By combining the spectroscopic and electrical measurements on working devices as well as films, we identify that high trap-mediated recombination is responsible for the loss of photogenerated charge carriers in devices with small nanocrystals. In addition, we demonstrate that the reduced open-circuit voltage for devices with small nanocrystals is also caused by the traps.
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| 19. |
- He, Bing, et al.
(författare)
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Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes
- 2014
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Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 25:12, s. 2764-2777
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Tidskriftsartikel (refereegranskat)abstract
- Podocin is a key protein of the kidney podocyte slit diaphragm protein complex, an important part of the glomerular filtration barrier. Mutations in the human podocin gene NPHS2 cause familial or sporadic forms of renal disease owing to the disruption of filtration barrier integrity. The exclusive expression of NPHS2 in podocytes reflects its unique function and raises interesting questions about its transcriptional regulation. Here, we further define a 2.5-kb zebrafish nphs2 promoter fragment previously described and identify a 49-bp podocyte-specific transcriptional enhancer using Tol2-mediated G(0) transgenesis in zebrafish. Within this enhancer, we identified a cis-acting element composed of two adjacent DNA-binding sites (FLAT-E and forkhead) bound by transcription factors Lnnx1b and FoxC. In zebrafish, double knockdown of Lmx1b and FoxC orthologs using morpholino doses that caused no or minimal phenotypic changes upon individual knockdown completely disrupted podocyte development in 40% of injected embryos. Co-overexpression of the two genes potently induced endogenous nphs2 expression in zebrafish podocytes. We found that the NPHS2 promoter also contains a cis-acting Lmx1b-FoxC motif that binds LMX1B and FoxC2. Furthermore, a genome-wide search identified several genes that carry the Lmx1b-FoxC motif in their promoter regions. Among these candidates, motif-driven podocyte enhancer activity of CCNC and MEIS2 was functionally analyzed in vivo. Our results show that podocyte expression of some genes is combinatorially regulated by two transcription factors interacting synergistically with a common enhancer. This finding provides insights into transcriptional mechanisms required for normal and pathologic podocyte functions.
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| 20. |
- Jin, Zhe, et al.
(författare)
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Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics
- 2014
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers. - 1662-5102. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The central amygdala (CeA) has a role for mediating fear and anxiety responses. It is also involved in emotional imbalance caused by alcohol abuse and dependence and in regulating relapse to alcohol abuse. Growing evidences suggest that excitatory glutamatergic and inhibitory γ-aminobutyric acid-ergic (GABAergic) transmissions in the CeA are affected by chronic alcohol exposure. Human post-mortem CeA samples from male alcoholics (n = 9) and matched controls (n = 9) were assayed for the expression level of ionotropic glutamate and GABA-A receptors subunit mRNAs using quantitative real-time reverse transcription-PCR (RT-qPCR). Our data revealed that out of the 16 ionotropic glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA1 and GluA4; one kainate receptor subunit GluK2; one NMDA (N-methyl-D-aspartate) receptor subunit GluN2D and one delta receptor subunit GluD2 were significantly decreased in the CeA of alcoholics. In contrast, of the 19 GABA-A receptor subunits, only the mRNA encoding the α2 subunit was significantly down-regulated in the CeA of the alcoholics as compared with control subjects. Our findings imply that the down-regulation of specific ionotropic glutamate and GABA-A receptor subunits in the CeA of alcoholics may represent one of the molecular substrates underlying the new balance between excitatory and inhibitory neurotransmission in alcohol dependence.
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| 21. |
- Jin, Zhe, et al.
(författare)
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Selective Changes of GABA(A) Channel Subunit mRNAs in the Hippocampus and Orbitofrontal Cortex but not in Prefrontal Cortex of Human Alcoholics
- 2012
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol dependence is a common chronic relapsing disorder. The development of alcohol dependence has been associated with changes in brain GABA(A) channel-mediated neurotransmission and plasticity. We have examined mRNA expression of the GABA(A) channel subunit genes in three brain regions in individuals with or without alcohol dependence using quantitative real-time PCR assay. The levels of selective GABA(A) channel subunit mRNAs were altered in specific brain regions in alcoholic subjects. Significant increase in the α1, α4, α5, β1, and γ1 subunit mRNAs in the hippocampal dentate gyrus region, and decrease in the β2 and δ subunit mRNAs in the orbitofrontal cortex were identified whereas no changes in the dorsolateral prefrontal cortex were detected. The data increase our understanding of the role of GABA(A) channels in the development of alcohol dependence.
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| 22. |
- Jin, Zhe, et al.
(författare)
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Selective increases of AMPA, NMDA, and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics
- 2014
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers. - 1662-5102. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Glutamate is the main excitatory transmitter in the human brain. Drugs that affect the glutamatergic signaling will alter neuronal excitability. Ethanol inhibits glutamate receptors. We examined the expression level of glutamate receptor subunit mRNAs in human post-mortem samples from alcoholics and compared the results to brain samples from control subjects. RNA from hippocampal dentate gyrus (HP-DG), orbitofrontal cortex (OFC), and dorso-lateral prefrontal cortex (DL-PFC) samples from 21 controls and 19 individuals with chronic alcohol dependence were included in the study. Total RNA was assayed using quantitative RT-PCR. Out of the 16 glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA2 and GluA3; three kainate receptor subunits GluK2, GluK3 and GluK5 and five NMDA (N-methyl-D-aspartate) receptor subunits GluN1, GluN2A, GluN2C, GluN2D, and GluN3A were significantly increased in the HP-DG region in alcoholics. In the OFC, mRNA encoding the NMDA receptor subunit GluN3A was increased, whereas in the DL-PFC, no differences in mRNA levels were observed. Our laboratory has previously shown that the expression of genes encoding inhibitory GABA-A receptors is altered in the HP-DG and OFC of alcoholics (Jin et al., 2011). Whether the changes in one neurotransmitter system drives changes in the other or if they change independently is currently not known. The results demonstrate that excessive long-term alcohol consumption is associated with altered expression of genes encoding glutamate receptors in a brain region-specific manner. It is an intriguing possibility that genetic predisposition to alcoholism may contribute to these gene expression changes.
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| 23. |
- Korol, Sergiy V, et al.
(författare)
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Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells
- 2018
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 30
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Tidskriftsartikel (refereegranskat)abstract
- In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABAA receptors in human islet β cells as biological sensors and reveal that 100-1000nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working. GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABAA receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon-like peptide-1 (GLP-1) but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D) islets, single-channel analysis revealed higher GABA affinity of the receptors. The findings reveal unique GABAA receptors signaling in human islets β cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D.
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| 24. |
- Li, Zhe, et al.
(författare)
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Comparison of the Operation of Polymer/Fullerene, Polymer/Polymer, and Polymer/Nanocrystal Solar Cells: A Transient Photocurrent and Photovoltage Study
- 2011
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Ingår i: Advanced Functional Materials. - : Wiley-VCH Verlag. - 1616-301X .- 1616-3028. ; 21:8, s. 1419-1431
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Tidskriftsartikel (refereegranskat)abstract
- We utilize transient techniques to directly compare the operation of polymer/fullerene, polymer/nanocrystal, and polymer/polymer bulk heterojunction solar cells. For all devices, poly(3-hexylthiophene) (P3HT) is used as the electron donating polymer, in combination with either the fullerene derivative phenyl-C(61)-butyric acid methyl ester (PCBM) in polymer/fullerene cells, CdSe nanoparticles in polymer/nanocrystal cells, or the polyfluorene copolymer poly((9,9-dioctylfluorene)-2,7-diyl-alt-[4,7-bis(3-hexylthien-5-yl)-2,1,3- benzothiadiazole]-2,2-diyl) (F8TBT) in polymer/polymer cells. Transient photocurrent and photovoltage measurements are used to probe the dynamics of charge-separated carriers, with vastly different dynamic behavior observed for polymer/fullerene, polymer/polymer, and polymer/nanocrystal devices on the microsecond to millisecond timescale. Furthermore, by employing transient photocurrent analysis with different applied voltages we are also able to probe the dynamics behavior of these cells from short circuit to open circuit. P3HT/F8TBT and P3HT/CdSe devices are characterized by poor charge extraction of the long-lived carriers attributed to charge trapping. P3HT/PCBM devices, in contrast, show relatively trap-free operation with the variation in the photocurrent decay kinetics with applied bias at low intensity, consistent with the drift of free charges under a uniform electric field. Under solar conditions at the maximum power point, we see direct evidence of bimolecular recombination in the P3HT/PCBM device competing with charge extraction. Transient photovoltage measurements reveal that, at open circuit, photogenerated charges have similar lifetimes in all device types, and hence, the extraction of these long-lived charges is a limiting process in polymer/nanocrystal and polymer/polymer devices.
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| 25. |
- Schank, Jesse R., et al.
(författare)
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Increased Alcohol Consumption in Mice Lacking Sodium Bicarbonate Transporter NBCn1
- 2020
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The previous reports on an addiction vulnerability marker in the human SLC4A7 gene encoding the Na/HCO3 transporter NBCn1 suggest that this pH-regulating protein may affect alcohol-related behavior and response. Here, we examined alcohol consumption and sensitivity to the sedative effects of alcohol in male NBCn1 knockout mice. These mice displayed lower pH in neurons than wildtype controls, determined by intracellular pH in hippocampal neuronal cultures. Neurons from knockout mice had a higher action potential threshold and a more depolarized membrane potential, thus reducing membrane excitability. In a two-bottle free choice procedure, knockout mice consumed more alcohol than controls and consistently increased alcohol consumption after repeated alcohol deprivation periods. Quinine and sucrose preference was similar between genotypes. Knockout mice showed increased propensity for alcohol-induced conditioned place preference. In loss of righting reflex assessment, knockout mice revealed increased sensitivity to alcohol-induced sedation and developed tolerance to the sedation after repeated alcohol administrations. Furthermore, chronic alcohol consumption caused NBCn1 downregulation in the hippocampus and striatum of mice and humans. These results demonstrate an important role of NBCn1 in regulation of alcohol consumption and sensitivity to alcohol-induced sedation.
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| 26. |
- Smith, Caren E., et al.
(författare)
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Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent
- 2018
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Ingår i: Molecular Nutrition & Food Research. - : Wiley. - 1613-4125. ; 62:3
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Tidskriftsartikel (refereegranskat)abstract
- Scope: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption. Methods and results: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10−7), and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3’ of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10−8) such that each serving of low-fat dairy was associated with 0.225 kg m−2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure. Conclusion: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.
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| 27. |
- Suarez, M., et al.
(författare)
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Effect of freeze-drying treatment on the optical properties of SPS-sintered alumina
- 2013
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Ingår i: Ceramics International. - : Elsevier BV. - 0272-8842 .- 1873-3956. ; 39:6, s. 6669-6672
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Tidskriftsartikel (refereegranskat)abstract
- This study looks at the influence of alumina powder processing on the preparation of transparent alumina by Spark Plasma Sintering (SPS). Zeta potential measurements were carried out on alumina suspensions in order to determine the best dispersion conditions. Stable slurries were submitted to a spray freeze drying process and their sintering behavior was compared with the corresponding non spray freeze dried powders. Transparent alumina samples were successfully prepared from alumina powders by Spark Plasma Sintering. An optical model considering pore and grain size distributions has been developed to obtain information about porosity in dense materials. It was found that the final density and, accordingly, the optical properties were improved when spray freeze dried starting powder was used.
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| 28. |
- Suarez, M., et al.
(författare)
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Hot isostatic pressing of optically active Nd:YAG powders doped by a colloidal processing route
- 2010
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Ingår i: Journal of the European Ceramic Society. - : Elsevier. - 0955-2219 .- 1873-619X. ; 30:6, s. 1489-1494
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Tidskriftsartikel (refereegranskat)abstract
- In this work, 1 at.% Nd doped Yttrium Aluminum Garnet Y(3)Al(5)O(12) (YAG) nano-sized powder prepared by colloidal route was investigated thoroughly concerning agglomeration control and preparation of transparent ceramic by post-HIP. Electrostatic and mechanical deagglomeration process followed by freeze-drying turned out to be an effective method to alleviate agglomeration, yielding a powder with a homogeneous particle size distribution around 100 nm. Transparent Nd:YAG ceramic samples have been successfully prepared by post-HIP without the aid of sintering additives. The optical properties varied markedly with the sintering and hot isostatic pressing conditions used. In-fine transmittance values of 56% at 680 nm and close to 80% in the infrared region were recorded.
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| 29. |
- Wang, Zhe, et al.
(författare)
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Two-step Acceleration of Energetic Electrons at Magnetic Flux Ropes during Turbulent Reconnection
- 2023
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 946:2, s. 67-
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Tidskriftsartikel (refereegranskat)abstract
- Energetic electrons have been frequently observed during magnetic reconnection in the magnetotail. The acceleration process of the energetic electrons is not fully understood. In this paper, we select for a detailed study a case of energetic electron acceleration from the earlier reported interval of turbulent magnetic reconnection in Earth's magnetotail observed by the Magnetospheric Multiscale mission. We use the first-order Taylor expansion method to reconstruct the magnetic topology of electron acceleration sites from the data. We find that the energetic electron fluxes increase inside the flux rope forming in front of the magnetic pileup region. We show that the energetic electrons are produced by a two-step process where two different acceleration mechanisms are successively operating outside and inside the flux rope. First, the thermal electrons are energized in the field-aligned direction inside the magnetic pileup region owing to the Fermi mechanism forming a cigar-like distribution. Second, those energized electrons are further accelerated predominately antiparallel to the magnetic field direction by a parallel electric field inside the flux rope. Our findings provide information for a better understanding of the generation of energetic electrons during turbulent reconnection process.
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| 30. |
- Wen, Bo, et al.
(författare)
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IPeak : An open source tool to combine results from multiple MS/MS search engines
- 2015
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Ingår i: Proteomics. - : Wiley-VCH Verlagsgesellschaft. - 1615-9853 .- 1615-9861. ; 15:17, s. 2916-2920
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Tidskriftsartikel (refereegranskat)abstract
- Liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) is an important technique for detecting peptides in proteomics studies. Here, we present an open source software tool, termed IPeak, a peptide identification pipeline that is designed to combine the Percolator post-processing algorithm and multi-search strategy to enhance the sensitivity of peptide identifications without compromising accuracy. IPeak provides a graphical user interface (GUI) as well as a command-line interface, which is implemented in JAVA and can work on all three major operating system platforms: Windows, Linux/Unix and OS X. IPeak has been designed to work with the mzIdentML standard from the Proteomics Standards Initiative (PSI) as an input and output, and also been fully integrated into the associated mzidLibrary project, providing access to the overall pipeline, as well as modules for calling Percolator on individual search engine result files. The integration thus enables IPeak (and Percolator) to be used in conjunction with any software packages implementing the mzIdentML data standard. IPeak is freely available and can be downloaded under an Apache 2.0 license at https://code.google.com/p/mzidentml-lib/.
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| 31. |
- Wu, R., et al.
(författare)
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Influence of multiaxial stresses on creep properties of phosphorus alloyed oxygen free copper
- 2010
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Ingår i: Proceedings Of The ASME Pressure Vessels And Piping Conference 2009. - : ASME Press. - 9780791843697 ; , s. 1525-1532
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Konferensbidrag (refereegranskat)abstract
- Phosphorus alloyed oxygen free copper (Cu-OFP) canisters are planned to be used for spent nuclear fuel in Sweden. The copper canisters will be subjected to creep under multiaxial stress states in the repository. Creep tests have therefore been carried out using double notch specimens having a notch acuity of 0.5 in Cu-OFP at 75°C. The creep results from the notched specimens are compared with those from the smooth ones. It shows that the creep lifetime for notched specimens can be estimated to be two orders of magnitude or more longer than that for the smooth ones, indicating notch strengthening for the investigated Cu-OFP material. Metallographic examinations after failure show that pores and creep cavities to a limited extent are observed only adjacent to fracture. To interpret the tests for the notched creep specimens, finite element computations have been performed with a new basic model for primary creep without fitting parameters. The creep strain versus time could be simulated successfully. Initially the stresses at the notches are almost twice as high as in the centre of the specimens. The highest stresses are relaxed rapidly. At the studied temperature 75°C, the creep exponent of Cu-OFP is about 85, thus, deep down in the power-law breakdown regime. This contributes strongly to the homogenous stress distribution across the centre section. Since the redistribution of stresses has taken place before large creep deformation has occurred, the specimens are not notch sensitive in agreement with observations.
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| 32. |
- Xie, Liangqi, et al.
(författare)
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3D ATAC-PALM : super-resolution imaging of the accessible genome
- 2020
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Ingår i: Nature Methods. - : NATURE PUBLISHING GROUP. - 1548-7091 .- 1548-7105. ; 17:4, s. 430-436
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Tidskriftsartikel (refereegranskat)abstract
- 3D ATAC-PALM integrates ATAC with super-resolution imaging for nanoscale views of the accessible genome. When combined with FISH, protein fluorescence and genetic perturbation, the method enables investigation of accessible chromatin in situ. To image the accessible genome at nanometer scale in situ, we developed three-dimensional assay for transposase-accessible chromatin-photoactivated localization microscopy (3D ATAC-PALM) that integrates an assay for transposase-accessible chromatin with visualization, PALM super-resolution imaging and lattice light-sheet microscopy. Multiplexed with oligopaint DNA-fluorescence in situ hybridization (FISH), RNA-FISH and protein fluorescence, 3D ATAC-PALM connected microscopy and genomic data, revealing spatially segregated accessible chromatin domains (ACDs) that enclose active chromatin and transcribed genes. Using these methods to analyze genetically perturbed cells, we demonstrated that genome architectural protein CTCF prevents excessive clustering of accessible chromatin and decompacts ACDs. These results highlight 3D ATAC-PALM as a useful tool to probe the structure and organizing mechanism of the genome.
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| 33. |
- Xing, Zhe, et al.
(författare)
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Biological Effects of Functionalizing Copolymer Scaffolds with Nanodiamond Particles
- 2013
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Ingår i: Tissue Engineering. Part A. - : Mary Ann Liebert. - 1937-3341 .- 1937-335X. ; 19:15-16, s. 1783-1791
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Tidskriftsartikel (refereegranskat)abstract
- Significant evidence has indicated that poly(L-lactide)-co-(epsilon-caprolactone) [(poly(LLA-co-CL)] scaffolds could be one of the suitable candidates for bone tissue engineering. Oxygen-terminated nanodiamond particles (n-DP) were combined with poly(LLA-co-CL) and revealed to be positive for cell growth. In this study, we evaluated the influence of poly(LLA-co-CL) scaffolds modified by n-DP on attachment, proliferation, differentiation of bone marrow stromal cells (BMSCs) in vitro, and on bone formation using a sheep calvarial defect model. BMSCs were seeded on either poly(LLA-co-CL)-or n-DP-coated scaffolds and incubated for 1 h. Scanning electron microscopy (SEM) and fluorescence microscopy were used in addition to protein and DNA measurements to evaluate cellular attachment on the scaffolds. To determine the effect of n-DP on proliferation of BMSCs, cell/scaffold constructs were harvested after 3 days and evaluated by Bicinchoninic Acid (BCA) protein assay and SEM. In addition, the osteogenic differentiation of cells grown for 2 weeks on the various scaffolds and in a dynamic culture condition was evaluated by real-time RT-PCR. Unmodified and modified scaffolds were implanted into the calvaria of six-year-old sheep. The expression of collagen type I (COL I) and bone morphogenetic protein-2 (BMP-2) after 4 weeks as well as the formation of new bone after 12 and 24 weeks were analyzed by immunohistochemistry and histology. Scaffolds modified with n-DP supported increased cell attachment and the mRNA expression of osteopontin (OPN), bone sialoprotein (BSP), and BMP-2 were significantly increased after 2 weeks of culture. The BMSCs had spread well on the various scaffolds investigated after 3 days in the study with no significant difference in cell proliferation. Furthermore, the in vivo data revealed more positive staining of COLI and BMP-2 in relation to the n-DP-coated scaffolds after 4 weeks and presented more bone formation after 12 and 24 weeks. n-DP modification significantly increased cell attachment and differentiation of BMSCs on poly(LLA-co-CL) scaffolds in vitro and enhanced bone formation in vivo.
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| 34. |
- Xu, Zhe, et al.
(författare)
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Pharmacokinetics and Transport of an Osteogenic Dodecapeptide
- 2020
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Ingår i: Journal of Agricultural and Food Chemistry. - : AMER CHEMICAL SOC. - 0021-8561 .- 1520-5118. ; 68:37, s. 9961-9967
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Tidskriftsartikel (refereegranskat)abstract
- A dodecapeptide with the amino acid sequence of IEELEEELEAER (PIE), identified from Mytilus edulis proteolysis hydrolysates, has shown good bone-forming activity in previous studies. The pharmacokinetics and transport of the PIE peptide in vivo or in vitro were investigated in this study. The results showed that the PIE peptide can be transported into monolayer Caco-2 cells, and the PIE peptide was identified in the serum after the mice reached the highest value of 173.60 +/- 60.30 ng/mL, in which it was quantified by an optimized mass spectrometry method. In addition, the PIE peptide has a promoting effect on the bone morphogenetic protein pathway at the gene and protein levels. According to the distribution of PIE-FITC in ovariectomized mice after orally administrated PIE-FITC, it was confirmed that it can enter the gastrointestinal tract and serum, and reach the bones. Taken together, the PIE peptide can be absorbed well both in vitro and in vivo, and it could promote pre-osteoblast differentiation factors.
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| 35. |
- Zhang, Man, et al.
(författare)
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Highly Efficient Room-Temperature Light-Induced Synthesis of Polymer Dots: A Programming Control Paradigm of Polymer Nanostructurization from Single-Component Precursor
- 2023
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Ingår i: Journal of the American Chemical Society. - : AMER CHEMICAL SOC. - 0002-7863 .- 1520-5126. ; 145:45, s. 24657-24668
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Tidskriftsartikel (refereegranskat)abstract
- Polymer dots (PDs) have raised considerable research interest due to their advantages of designable nanostructures, high biocompatibility, versatile photoluminescent properties, and recyclability as nanophase. However, there remains a lack of in situ, real-time, and noncontact methods for synthesizing PDs. Here we report a rational strategy to synthesize PDs through a well-designed single-component precursor (an asymmetrical donor-acceptor-donor molecular structure) by photoirradiation at ambient temperature. In contrast to thermal processes that normally lack atomic economy, our method is mild and successive, based on an aggregation-promoted sulfonimidization triggered by photoinduced delocalized intrinsic radical cations for polymerization, followed by photooxidation for termination with structural shaping to form PDs. This synthetic approach excludes any external additives, rendering a conversion rate of the precursor exceeding 99%. The prepared PDs, as a single entity, can realize the integration of nanocore luminescence and precursor-transferred luminescence, showing 41.5% of the total absolute luminescence quantum efficiency, which is higher than most reported PD cases. Based on these photoluminescent properties, together with the superior biocompatibility, a unique membrane microenvironmental biodetection could be exemplified. This strategy with programming control of the single precursor can serve as a significant step toward polymer nanomanufacturing with remote control, high-efficiency, precision, and real-time operability.
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