| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
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| 4. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Bécoulet, A., et al.
(författare)
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Science and technology research and development in support to ITER and the Broader Approach at CEA
- 2013
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 53:10
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Tidskriftsartikel (refereegranskat)abstract
- In parallel to the direct contribution to the procurement phase of ITER and Broader Approach, CEA has initiated research & development programmes, accompanied by experiments together with a significant modelling effort, aimed at ensuring robust operation, plasma performance, as well as mitigating the risks of the procurement phase. This overview reports the latest progress in both fusion science and technology including many areas, namely the mitigation of superconducting magnet quenches, disruption-generated runaway electrons, edge-localized modes (ELMs), the development of imaging surveillance, and heating and current drive systems for steady-state operation. The WEST (W Environment for Steady-state Tokamaks) project, turning Tore Supra into an actively cooled W-divertor platform open to the ITER partners and industries, is presented.
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| 6. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 7. |
- Klonoff, D. C., et al.
(författare)
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A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings
- 2022
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Ingår i: Journal of Diabetes Science and Technology. - : SAGE Publications. - 1932-2968.
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Tidskriftsartikel (refereegranskat)abstract
- Background: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. Methods: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low–glucose and low-glucose hypoglycemia; very high–glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. Results: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. Conclusion: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.
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| 8. |
- Heywood, I., et al.
(författare)
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Inflation of 430-parsec bipolar radio bubbles in the Galactic Centre by an energetic event
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 573:7773, s. 235-237
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Tidskriftsartikel (refereegranskat)abstract
- The Galactic Centre contains a supermassive black hole with a mass of four million Suns1 within an environment that differs markedly from that of the Galactic disk. Although the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings2. Also, although the levels of star formation in the Galactic Centre have been approximately constant over the past few hundred million years, there is evidence of increased short-duration bursts3, strongly influenced by the interaction of the black hole with the enhanced gas density present within the ring-like central molecular zone4 at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200-parsec region is characterized by large amounts of warm molecular gas5, a high cosmic-ray ionization rate6, unusual gas chemistry, enhanced synchrotron emission7,8, and a multitude of radio-emitting magnetized filaments9, the origin of which has not been established. Here we report radio imaging that reveals a bipolar bubble structure, with an overall span of 1 degree by 3 degrees (140 parsecs × 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 × 1052 ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities.
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| 9. |
- Camilo, F., et al.
(författare)
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Revival of the Magnetar PSR J1622-4950: Observations with MeerKAT, Parkes, XMM-Newton, Swift, Chandra, and NuSTAR
- 2018
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 856:2
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Tidskriftsartikel (refereegranskat)abstract
- New radio (MeerKAT and Parkes) and X-ray (XMM-Newton, Swift, Chandra, and NuSTAR) observations of PSR J1622-4950 indicate that the magnetar, in a quiescent state since at least early 2015, reactivated between 2017 March 19 and April 5. The radio flux density, while variable, is approximately 100 larger than during its dormant state. The X-ray flux one month after reactivation was at least 800 larger than during quiescence, and has been decaying exponentially on a 111 19 day timescale. This high-flux state, together with a radio-derived rotational ephemeris, enabled for the first time the detection of X-ray pulsations for this magnetar. At 5%, the 0.3-6 keV pulsed fraction is comparable to the smallest observed for magnetars. The overall pulsar geometry inferred from polarized radio emission appears to be broadly consistent with that determined 6-8 years earlier. However, rotating vector model fits suggest that we are now seeing radio emission from a different location in the magnetosphere than previously. This indicates a novel way in which radio emission from magnetars can differ from that of ordinary pulsars. The torque on the neutron star is varying rapidly and unsteadily, as is common for magnetars following outburst, having changed by a factor of 7 within six months of reactivation.
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| 10. |
- Artigas Soler, María, et al.
(författare)
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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- 2011
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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| 11. |
- Joubert, M., et al.
(författare)
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'Pandem-icons' - exploring the characteristics of highly visible scientists during the Covid-19 pandemic
- 2023
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Ingår i: Jcom-Journal of Science Communication. - : Sissa Medialab Srl. - 1824-2049. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- The Covid-19 pandemic escalated demand for scientific explanations and guidance, creating opportunities for scientists to become publicly visible. In this study, we compared characteristics of visible scientists during the first year of the Covid-19 pandemic (January to December 2020) across 16 countries. We find that the scientists who became visible largely matched socio-cultural criteria that have characterised visible scientists in the past (e.g., age, gender, credibility, public image, involvement in controversies). However, there were limited tendencies that scientists commented outside their areas of expertise. We conclude that the unusual circumstances created by Covid-19 did not change the phenomenon of visible scientists in significant ways.
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| 12. |
- Cronin, M. F., et al.
(författare)
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Developing an Observing Air-Sea Interactions Strategy (OASIS) for the global ocean
- 2022
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Ingår i: Ices Journal of Marine Science. - : Oxford University Press (OUP). - 1054-3139 .- 1095-9289. ; 80:2, s. 367-73
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Tidskriftsartikel (refereegranskat)abstract
- The Observing Air-Sea Interactions Strategy (OASIS) is a new United Nations Decade of Ocean Science for Sustainable Development programme working to develop a practical, integrated approach for observing air-sea interactions globally for improved Earth system (including ecosystem) forecasts, CO2 uptake assessments called for by the Paris Agreement, and invaluable surface ocean information for decision makers. Our "Theory of Change" relies upon leveraged multi-disciplinary activities, partnerships, and capacity strengthening. Recommendations from >40 OceanObs'19 community papers and a series of workshops have been consolidated into three interlinked Grand Ideas for creating #1: a globally distributed network of mobile air-sea observing platforms built around an expanded array of long-term time-series stations; #2: a satellite network, with high spatial and temporal resolution, optimized for measuring air-sea fluxes; and #3: improved representation of air-sea coupling in a hierarchy of Earth system models. OASIS activities are organized across five Theme Teams: (1) Observing Network Design & Model Improvement; (2) Partnership & Capacity Strengthening; (3) UN Decade OASIS Actions; (4) Best Practices & Interoperability Experiments; and (5) Findable-Accessible-Interoperable-Reusable (FAIR) models, data, and OASIS products. Stakeholders, including researchers, are actively recruited to participate in Theme Teams to help promote a predicted, safe, clean, healthy, resilient, and productive ocean.
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| 13. |
- Loth, Daan W, et al.
(författare)
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Genome-wide association analysis identifies six new loci associated with forced vital capacity
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
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Tidskriftsartikel (refereegranskat)abstract
- Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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| 14. |
- McKay, James D., et al.
(författare)
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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
- 2017
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
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Tidskriftsartikel (refereegranskat)abstract
- Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
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| 15. |
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| 16. |
- Ji, Xuemei, et al.
(författare)
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Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
- 2018
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
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| 17. |
- Ji, Xuemei, et al.
(författare)
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Protein-altering germline mutations implicate novel genes related to lung cancer development
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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| 18. |
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| 19. |
- Feuerbacher, M., et al.
(författare)
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The Samson phase, β-Mg2Al3, Revisited
- 2007
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Ingår i: Zeitschrift für Kristallographie. - 0044-2968. ; 222:6, s. 259-288
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Tidskriftsartikel (refereegranskat)
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| 20. |
- Hancock, Dana B, et al.
(författare)
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Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
- 2012
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:12, s. e1003098-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest PJMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
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| 21. |
- Shrine, Nick, et al.
(författare)
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New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:3, s. 481-493
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Tidskriftsartikel (refereegranskat)abstract
- Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
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| 22. |
- Sikdar, S, et al.
(författare)
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Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking
- 2019
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Ingår i: Epigenomics. - : Future Medicine Ltd. - 1750-192X .- 1750-1911. ; 11:13, s. 1487-1500
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.
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| 23. |
- Tang, Wenbo, et al.
(författare)
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Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:7, s. e100776-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 x 10(-7)). In addition, meta-analysis using the five cohorts with >= 3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 x 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
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| 24. |
- Wain, Louise V, et al.
(författare)
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Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:3, s. 416-425
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.
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| 25. |
- Dupin, N., et al.
(författare)
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Using first-principles results to calculate finite-temperature thermodynamic properties of the Nb-Ni mu phase in the Bragg-Williams approximation
- 2006
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Ingår i: Philosophical Magazine. - : Informa UK Limited. - 1478-6435 .- 1478-6443. ; 86:12, s. 1631-1641
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Tidskriftsartikel (refereegranskat)abstract
- Results of first-principles (FP) total energy calculations for 32 different configurations of the mu phase in the binary system Nb-Ni are used in the compound energy formalism (CEF) to model finite-temperature thermodynamic properties. A comparison with Cluster Expansion Hamiltonian-Cluster Variation Method (CEH-CVM) calculations indicates that the CEF describes temperature-dependent site occupancies as well as the CEH-CVM within the temperature range of interest for applications. This suggests that the Bragg-Williams-Gorsky approximation (BWGA) used in the CEF is sufficient to describe site occupancies and thermodynamics of the mu phase. A phase diagram is calculated using the mu phase description derived in the present work together with a previous Calphad description for the other phases of this system. The FP-CEF approach significantly improves the description of the thermodynamic properties as a function of composition compared to the Calphad procedure generally used up to now.
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| 26. |
- Basic, Vladimir T., et al.
(författare)
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Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stress
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Enhanced protein degradation via ubiquitin proteolytic system (UPS) was demonstrated to play an important role in the pathogenesis of cachexia syndrome and muscle wasting in patients with COPD and animal models of the disease. The role of cigarette smoke (CS) exposure in eliciting these abnormalities remains largely unknown. Usp19 is a member of UPS suggested to be involved in progressive muscle wasting in different catabolic conditions. However, factors regulating Usp19 expression, activity and correlation/s with CS-induced muscle atrophy remainunclear.Methods: To address these questions, 129 SvJ mice were exposed to cigarette smoke for 6 months and the gastrocnemius muscles were collected. Expression levels of Usp19 as well as pivotal mediators of ER stress response have been studied using PCR, qPCR, western blot and immunofluorescence. Factors regulating muscle Usp19 expression were studied using in-silico analysis of Usp19 promoter as well as by stimulating C2C12 myocytes with different inducers of ER stress including hypoxia, TNF and tunicamycin. Finally, Usp19 expression was depleted in C2C12 myocytes using specific Usp19 siRNA quadriplex and the expression of pivotal myogenic regulators were analyzed.Results: Usp19 mRNA expression was enhanced in skeletal muscles of CS-exposed mice. Concurrently, ER stress-associated Caspase 12 and Caspase 3 were activated in the CS-exposed group. Analysis of Usp19 promoter sequence revealed binding sites for ER stress response transcription factors such as HSF, STRE1 and AML1-α. Exposure of C2C12 myocytes to tunicamycin but not hypoxia elevated expression levels of Usp19. TNFstimulation elevated Usp19 protein expression but inhibited its RNA transcription in a dose- and time-dependent manner. Finally, Usp19 overexpression in tunicamycin-treated myocytes was accompanied by reduced expression of myosin heavy chain and tropomyosin and their levels were increased after knocking down Usp19 in C2C12 myocytes.Conclusions: In summary, our data demonstrated elevated expression of Usp19 in skeletal muscles of CS-exposed 129 SvJ mice. Moreover, Usp19 overexpression was associated with muscle adaptations to ER stress and suppression of myogenesis. Taken together; our results might provide further insight into molecular mechanisms underlying development and progression of skeletal muscle abnormalities in response to chronic cigarette smoke exposure.
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| 27. |
- Bergman, Lina, 1982, et al.
(författare)
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PROVE-Pre-Eclampsia Obstetric Adverse Events: Establishment of a Biobank and Database for Pre-Eclampsia
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality. The burden of disease lies mainly in low-middle income countries. The aim of this project is to establish a pre-eclampsia biobank in South Africa to facilitate research in the field of pre-eclampsia with a focus on phenotyping severe disease.The approach of our biobank is to collect biological specimens, detailed clinical data, tests, and biophysical examinations, including magnetic resonance imaging (MRI) of the brain, MRI of the heart, transcranial Doppler, echocardiography, and cognitive function tests.Women diagnosed with pre-eclampsia and normotensive controls are enrolled in the biobank at admission to Tygerberg University Hospital (Cape Town, South Africa). Biological samples and clinical data are collected at inclusion/delivery and during the hospital stay. Special investigations as per above are performed in a subset of women. After two months, women are followed up by telephonic interviews. This project aims to establish a biobank and database for severe organ complications of pre-eclampsia in a low-middle income country where the incidence of pre-eclampsia with organ complications is high. The study integrates different methods to investigate pre-eclampsia, focusing on improved understanding of pathophysiology, prediction of organ complications, and potentially future drug evaluation and discovery.
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| 28. |
- Bosse, Yohan, et al.
(författare)
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Transcriptome-wide association study reveals candidate causal genes for lung cancer
- 2020
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:7, s. 1862-1878
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Tidskriftsartikel (refereegranskat)abstract
- We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large‐scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome‐wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never‐ and ever‐smokers). We performed replication analysis using lung data from the Genotype‐Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever‐smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E−99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E−6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3‐adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E−5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.
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| 29. |
- Fluckiger, Aurélie, et al.
(författare)
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Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage
- 2020
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 369:6506, s. 936-942
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae. Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2K(b)-restricted CD8(+) T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
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| 30. |
- Fragoso-Bargas, Nicolas, et al.
(författare)
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Epigenome-wide association study of serum folate in maternal peripheral blood leukocytes
- 2023
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Ingår i: Epigenomics. - : Future Medicine Ltd. - 1750-192X .- 1750-1911. ; 15:1, s. 39-52
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To perform an epigenome-wide association study (EWAS) of serum folate in maternal blood. Methods: Cross-ancestry (Europeans = 302, South Asians = 161) and ancestry-specific EWAS in the EPIPREG cohort were performed, followed by methyl quantitative trait loci analysis and association with cardiometabolic phenotypes. Replication was attempted using maternal folate intake and blood methylation data from the MoBa study and verified if the findings were significant in a previous EWAS of maternal serum folate in cord blood. Results & conclusion: cg19888088 (cross-ancestry) in EBF3, cg01952260 (Europeans) and cg07077240 (South Asians) in HERC3 were associated with serum folate. cg19888088 and cg01952260 were associated with diastolic blood pressure. cg07077240 was associated with variants in CASC15. The findings were not replicated and were not significant in cord blood.
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| 31. |
- Gill, Dipender, et al.
(författare)
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ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels : a Mendelian randomization study
- 2020
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Ingår i: Royal Society Open Science. - : ROYAL SOC. - 2054-5703. ; 7:11
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Tidskriftsartikel (refereegranskat)abstract
- Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 x 10(-4)) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.
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| 32. |
- Joubert, J. M., et al.
(författare)
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Assessment of the niobium-nickel system
- 2004
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Ingår i: Calphad. - : Elsevier BV. - 0364-5916 .- 1873-2984. ; 28:3, s. 299-306
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Tidskriftsartikel (refereegranskat)abstract
- A reassessment of the Nb-Ni system is proposed taking into account new experimental data. According to recent crystallographic work, the g phase has been modelled using three independent sublattices of variable occupation. This has been made possible by including experimental site fractions in the different sublattices as data for parameter optimization. A consistent set of parameters is proposed. Good agreement is obtained between calculated and experimental values for all kinds of data (thermodynamic, crystallographic and phase diagram data).
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| 33. |
- Joubert, J.-M., et al.
(författare)
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The specific heat of Al-based compounds, evaluation of the Neumann-Kopp rule and proposal for a modified Neumann-Kopp rule
- 2023
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Ingår i: Calphad. - : Elsevier BV. - 0364-5916 .- 1873-2984. ; 81
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Tidskriftsartikel (refereegranskat)abstract
- Application of the Neumann-Kopp rule to aluminum containing compounds produces a kink in the specific heat caused by the description of pure aluminum in the SGTE Unary database. Two ways to get rid of this problem are investigated. In a first step, we tried to redefine the description of aluminum above its melting point using a reverse Neumann-Kopp approach. After a systematic review of the experimental Cp data for all the aluminum based compounds, we could evaluate the accuracy of the Neumann-Kopp rule. We could find a nearly systematic overestimation of the Cp of the order of 15%. This makes the use of the reverse Neumann-Kopp approach inapplicable. In a second step, based on this analysis of the available data, we propose another approach consisting in defining the Cp of a compound by a composition average of the Cp of the pure elements, not at the same temperature as in the Neumann-Kopp rule, but rather at a temperature normalized to the melting point of each pure element and the compound. Not only are the results in much better agreement with the experimental data than the conventional Neumann-Kopp rule, but also, there is no longer a need to define the Cp of aluminum above its melting point.
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| 34. |
- Joubert, Jané, et al.
(författare)
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Record-linkage comparison of verbal autopsy and routine civil registration death certification in rural north-east South Africa : 2006-09
- 2014
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 43:6, s. 1945-1958
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Tidskriftsartikel (refereegranskat)abstract
- Background: South African civil registration (CR) provides a key data source for local health decision making, and informs the levels and causes of mortality in data-lacking sub-Saharan African countries. We linked mortality data from CR and the Agincourt Health and Socio-demographic Surveillance System (Agincourt HDSS) to examine the quality of rural CR data. Methods: Deterministic and probabilistic techniques were used to link death data from 2006 to 2009. Causes of death were aggregated into the WHO Mortality Tabulation List 1 and a locally relevant short list of 15 causes. The matching rate was compared with informant-reported death registration. Using the VA diagnoses as reference, misclassification patterns, sensitivity, positive predictive values and cause-specific mortality fractions (CSMFs) were calculated for the short list. Results: A matching rate of 61% [95% confidence interval (CI): 59.2 to 62.3] was attained, lower than the informant-reported registration rate of 85% (CI: 83.4 to 85.8). For the 2264 matched cases, cause agreement was 15% (kappa 0.1083, CI: 0.0995 to 0.1171) for the WHO list, and 23% (kappa 0.1631, CI: 0.1511 to 0.1751) for the short list. CSMFs were significantly different for all but four (tuberculosis, cerebrovascular disease, other heart disease, and ill-defined natural) of the 15 causes evaluated. Conclusion: Despite data limitations, it is feasible to link official CR and HDSS verbal autopsy data. Data linkage proved a promising method to provide empirical evidence about the quality and utility of rural CR mortality data. Agreement of individual causes of death was low but, at the population level, careful interpretation of the CR data can assist health prioritization and planning.
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| 35. |
- Joubert, Johan W., et al.
(författare)
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A matching algorithm to study the evolution of logistics facilities extracted from GPS traces
- 2020
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Ingår i: Transportation Research Procedia. - : Elsevier BV. - 2352-1465. ; 46:2020, s. 237-244
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquity of anonymous GPS data has opened the door to a promising data source in the field of city logistics modelling. From this data the locations of logistics facilities can be extracted and their evolution studied over time. The minimum edge coverproblem, weighted by the Hausdorff distance, is used as a basis for a matching algorithm to study the location of facilities acrosslongitudinal datasets. The efficacy and validity of the algorithm is assessed through the visual inspection of results in three urbanareas across five time instances. Prevalent errors are unpacked and algorithm modifications suggested. This paper makes amethodological contribution to the handling of GPS data for the purpose of city logistics modelling.
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| 36. |
- Macari, F., et al.
(författare)
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TRM6/61 connects PKCα with translational control through tRNAiMet stabilization : impact on tumorigenesis
- 2016
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 35:14, s. 1785-1796
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C [alpha] (PKC[alpha]) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNAiMet), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNAiMet. In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNAiMet-overexpressing cells, PKC[alpha] overexpression decreased tRNAiMet expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAiMet expression with decreased expression of PKC[alpha] mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKC[alpha] tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.
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| 37. |
- Ngassie, Maunick Lefin Koloko, et al.
(författare)
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Age-associated differences in the human lung extracellular matrix
- 2023
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Ingår i: American Journal of Physiology - Lung Cellular and Molecular Physiology. - 1040-0605. ; 324:5, s. 799-814
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular matrix (ECM) remodeling has been associated with chronic lung diseases. However, information about specific age-associated differences in lung ECM is currently limited. In this study, we aimed to identify and localize age-associated ECM differences in human lungs using comprehensive transcriptomic, proteomic, and immunohistochemical analyses. Our previously identified age-associated gene expression signature of the lung was re-analyzed limiting it to an aging signature based on 270 control patients (37–80 years) and focused on the Matrisome core geneset using geneset enrichment analysis. To validate the age-associated transcriptomic differences on protein level, we compared the age-associated ECM genes (false discovery rate, FDR < 0.05) with a profile of age-associated proteins identified from a lung tissue proteomics dataset from nine control patients (49–76 years) (FDR < 0.05). Extensive immunohistochemical analysis was used to localize and semi-quantify the age-associated ECM differences in lung tissues from 62 control patients (18–82 years). Comparative analysis of transcriptomic and proteomic data identified seven ECM proteins with higher expression with age at both gene and protein levels: COL1A1, COL6A1, COL6A2, COL14A1, FBLN2, LTBP4, and LUM. With immunohistochemistry, we demonstrated higher protein levels with age for COL6A2 in whole tissue, parenchyma, airway wall, and blood vessel, for COL14A1 and LUM in bronchial epithelium, and COL1A1 in lung parenchyma. Our study revealed that higher age is associated with lung ECM remodeling, with specific differences occurring in defined regions within the lung. These differences may affect lung structure and physiology with aging and as such may increase susceptibility to developing chronic lung diseases.
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| 38. |
- Ngwalero, Precious, et al.
(författare)
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Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis
- 2021
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 65:11
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Tidskriftsartikel (refereegranskat)abstract
- Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2, and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used noncompartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 to 2,540 ng/ml in plasma and 16.2 to 5,478 ng/ml in PBMCs, and concentrations of M2 over the 6-month treatment period ranged from 34.3 to 496 ng/ml in plasma and 109.2 to 16,764 ng/ml in PBMCs. Plasma concentrations of bedaquiline were higher than those of M2, but intracellular concentrations of M2 were considerably higher than those of bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratios 1 and 2 months after start of treatment were 0.61 (95% confidence interval [CI]: 0.42 to 0.92) and 1.10 (95% CI: 0.74 to 1.63) for bedaquiline and 12.4 (95% CI: 8.8 to 17.8) and 22.2 (95% CI: 15.6 to 32.3) for M2. The intracellular-plasma ratios for both bedaquiline and M2 were decreased by 54% (95% CI: 24 to 72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting in vitro evidence that M2 is the main inducer of phospholipidosis.
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| 39. |
- Perez, Rosa Jerlerud, et al.
(författare)
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The Zr-Sn binary system : New experimental results and thermodynamic assessment
- 2008
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Ingår i: Calphad. - : Elsevier BV. - 0364-5916 .- 1873-2984. ; 32:3, s. 593-601
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Tidskriftsartikel (refereegranskat)abstract
- The Zr-Sn binary system has been reinvestigated by several experimental techniques: X-ray diffraction, electron probe micro-analysis, mass density and calorimetry measurements. The existence of a miscibility gap inside the homogeneity domain of the eta phase (Zr5Sn3-Zr5Sn4) has been confirmed. It has been also shown that Zr substitution on the Sn sublattice is responsible for the non-stoichiometry of the A15 phase (Zr4Sn). The temperature of the peritectoid reaction beta(Zr)+A15 alpha(Zr) has been determined to be at 1216 K that is 40 degrees below the temperature reported in the literature. All these new experimental data have been taken into account for a new thermodynamic assessment of this system.
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| 40. |
- Visser, Els, et al.
(författare)
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Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus
- 2018
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Ingår i: Journal of Surgical Oncology. - : WILEY. - 0022-4790 .- 1096-9098. ; 117:8, s. 1687-1696
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC. MethodsPatients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared. ResultsOf the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P=0.802) or in-hospital mortality (2% vs 0%, P=0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P=0.013), and higher pathological complete response rates (15% vs 5%, P<0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P=0.645) were found. ConclusionIn this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.
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