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| 2. |
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| 3. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 4. |
- 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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| 5. |
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| 6. |
- Valassi, E., et al.
(författare)
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High mortality within 90 days of diagnosis in patients with Cushing's syndrome: results from the ERCUSYN registry
- 2019
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 181:5, s. 461-472
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Patients with Cushing's syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality. Methods: In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2-5.5) years. Results: Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment. Conclusion: Mortality rate was highest in patients with ectopic CS. Infectious diseases the commonest cause of death soon after diagnosis, emphasizing the need for careful vigilance at that time, especially in patients presenting with concomitant diabetes mellitus.
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| 7. |
- Sodergren, Erica, et al.
(författare)
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The genome of the sea urchin Strongylocentrotus purpuratus.
- 2006
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 314:5801, s. 941-52
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Tidskriftsartikel (refereegranskat)abstract
- We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus, a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes.
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| 8. |
- Anderson, Cynthia M., et al.
(författare)
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Permanent Genetic Resources added to Molecular Ecology Resources Database 1 December 2009-31 January 2010
- 2010
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Ingår i: Molecular Ecology Resources. - : Wiley. - 1755-098X .- 1755-0998. ; 10:3, s. 576-579
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Tidskriftsartikel (refereegranskat)abstract
- This article documents the addition of 220 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Allanblackia floribunda, Amblyraja radiata, Bactrocera cucurbitae, Brachycaudus helichrysi, Calopogonium mucunoides, Dissodactylus primitivus, Elodea canadensis, Ephydatia fluviatilis, Galapaganus howdenae howdenae, Hoplostethus atlanticus, Ischnura elegans, Larimichthys polyactis, Opheodrys vernalis, Pelteobagrus fulvidraco, Phragmidium violaceum, Pistacia vera, and Thunnus thynnus. These loci were cross-tested on the following species: Allanblackia gabonensis, Allanblackia stanerana, Neoceratitis cyanescens, Dacus ciliatus, Dacus demmerezi, Bactrocera zonata, Ceratitis capitata, Ceratitis rosa, Ceratits catoirii, Dacus punctatifrons, Ephydatia mulleri, Spongilla lacustris, Geodia cydonium, Axinella sp., Ischnura graellsii, Ischnura ramburii, Ischnura pumilio, Pistacia integerrima and Pistacia terebinthus.
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| 9. |
- Andreoni, I., et al.
(författare)
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Follow Up of GW170817 and Its Electromagnetic Counterpart by Australian-Led Observing Programmes
- 2017
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Ingår i: Publications Astronomical Society of Australia. - : Cambridge University Press (CUP). - 1323-3580 .- 1448-6083. ; 34
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Forskningsöversikt (refereegranskat)abstract
- The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement (similar to 2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor.
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| 10. |
- Imanishi, T., et al.
(författare)
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Integrative annotation of 21,037 human genes validated by full-length cDNA clones
- 2004
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 2:6, s. 856-875
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Tidskriftsartikel (refereegranskat)abstract
- The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology.
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| 11. |
- Menkveld, Albert J., et al.
(författare)
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Nonstandard Errors
- 2024
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Ingår i: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390
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Tidskriftsartikel (refereegranskat)abstract
- In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
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| 12. |
- Dujon, B, et al.
(författare)
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The nucleotide sequence of Saccharomyces cerevisiae chromosome XV
- 1997
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 387:6632, s. 98-102
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome XV was one of the last two chromosomes of Saccharomyces cerevisiae to be discovered(1). It is the third-largest yeast chromosome after chromosomes XII and IV, and is very similar in size to chromosome VII. It alone represents 9% of the yeast genome (8% if ribosomal DNA is included). When systematic sequencing of chromosome XV was started, 93 genes or markers were identified, and most of them were mapped(2). However, very little else was known about chromosome XV which, in contrast to shorter chromosomes, had not been the object of comprehensive genetic or molecular analysis. It was therefore decided to start sequencing chromosome XV only in the third phase of the European Yeast Genome Sequencing Programme, after experience was gained on chromosomes III, XI and II (refs 3-5). The sequence of chromosome XV has been determined from a set of partly overlapping cosmid clones derived from a unique yeast strain, and physically mapped at 3.3-kilobase resolution before sequencing. As well as numerous new open reading frames (ORFs) and genes encoding tRNA or small RNA molecules, the sequence of 1,091,283 base pairs confirms the high proportion of orphan genes and reveals a number of ancestral and successive duplications with other yeast chromosomes.
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| 13. |
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| 14. |
- Andrikopoulos, Petros, et al.
(författare)
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Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide
- 2023
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Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.
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| 15. |
- 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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| 16. |
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| 17. |
- Dorigo, Wouter, et al.
(författare)
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The International Soil Moisture Network : Serving Earth system science for over a decade
- 2021
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Ingår i: Hydrology and Earth System Sciences. - : Copernicus GmbH. - 1027-5606 .- 1607-7938. ; 25:11, s. 5749-5804
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Forskningsöversikt (refereegranskat)abstract
- In 2009, the International Soil Moisture Network (ISMN) was initiated as a community effort, funded by the European Space Agency, to serve as a centralised data hosting facility for globally available in situ soil moisture measurements . The ISMN brings together in situ soil moisture measurements collected and freely shared by a multitude of organisations, harmonises them in terms of units and sampling rates, applies advanced quality control, and stores them in a database. Users can freely retrieve the data from this database through an online web portal (https://ismn.earth/en/, last access: 28 October 2021). Meanwhile, the ISMN has evolved into the primary in situ soil moisture reference database worldwide, as evidenced by more than 3000 active users and over 1000 scientific publications referencing the data sets provided by the network. As of July 2021, the ISMN now contains the data of 71 networks and 2842 stations located all over the globe, with a time period spanning from 1952 to the present. The number of networks and stations covered by the ISMN is still growing, and approximately 70 % of the data sets contained in the database continue to be updated on a regular or irregular basis. The main scope of this paper is to inform readers about the evolution of the ISMN over the past decade, including a description of network and data set updates and quality control procedures. A comprehensive review of the existing literature making use of ISMN data is also provided in order to identify current limitations in functionality and data usage and to shape priorities for the next decade of operations of this unique community-based data repository.
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| 18. |
- Forslund, Sofia K., et al.
(författare)
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Combinatorial, additive and dose-dependent drug–microbiome associations
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 600:7889, s. 500-505
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Tidskriftsartikel (refereegranskat)abstract
- During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1–5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.
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| 19. |
- 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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| 20. |
- Hubert, D., et al.
(författare)
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Ground-based assessment of the bias and long-term stability of 14 limb and occultation ozone profile data records
- 2016
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Ingår i: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 9:6, s. 2497-2534
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Tidskriftsartikel (refereegranskat)abstract
- The ozone profile records of a large number of limb and occultation satellite instruments are widely used to address several key questions in ozone research. Further progress in some domains depends on a more detailed understanding of these data sets, especially of their long-term stability and their mutual consistency. To this end, we made a systematic assessment of 14 limb and occultation sounders that, together, provide more than three decades of global ozone profile measurements. In particular, we considered the latest operational Level-2 records by SAGE II, SAGE III, HALOE, UARS MLS, Aura MLS, POAM II, POAM III, OSIRIS, SMR, GOMOS, MIPAS, SCIAMACHY, ACE-FTS and MAESTRO. Central to our work is a consistent and robust analysis of the comparisons against the ground-based ozonesonde and stratospheric ozone lidar networks. It allowed us to investigate, from the troposphere up to the stratopause, the following main aspects of satellite data quality: long-term stability, overall bias and short-term variability, together with their dependence on geophysical parameters and profile representation. In addition, it permitted us to quantify the overall consistency between the ozone profilers. Generally, we found that between 20 and 40km the satellite ozone measurement biases are smaller than ±5%, the short-term variabilities are less than 5-12% and the drifts are at most ±5%decade-1 (or even ±3%decade-1 for a few records). The agreement with ground-based data degrades somewhat towards the stratopause and especially towards the tropopause where natural variability and low ozone abundances impede a more precise analysis. In part of the stratosphere a few records deviate from the preceding general conclusions; we identified biases of 10% and more (POAM II and SCIAMACHY), markedly higher single-profile variability (SMR and SCIAMACHY) and significant long-term drifts (SCIAMACHY, OSIRIS, HALOE and possibly GOMOS and SMR as well). Furthermore, we reflected on the repercussions of our findings for the construction, analysis and interpretation of merged data records. Most notably, the discrepancies between several recent ozone profile trend assessments can be mostly explained by instrumental drift. This clearly demonstrates the need for systematic comprehensive multi-instrument comparison analyses.
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| 21. |
- Joseph, A, et al.
(författare)
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Metabolic and psychiatric effects of acyl coenzyme A binding protein (ACBP)/diazepam binding inhibitor (DBI)
- 2020
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:7, s. 502-
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Tidskriftsartikel (refereegranskat)abstract
- Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI) is a multifunctional protein with an intracellular action (as ACBP), as well as with an extracellular role (as DBI). The plasma levels of soluble ACBP/DBI are elevated in human obesity and reduced in anorexia nervosa. Accumulating evidence indicates that genetic or antibody-mediated neutralization of ACBP/DBI has anorexigenic effects, thus inhibiting food intake and inducing lipo-catabolic reactions in mice. A number of anorexiants have been withdrawn from clinical development because of their side effects including an increase in depression and suicide. For this reason, we investigated the psychiatric impact of ACBP/DBI in mouse models and patient cohorts. Intravenously (i.v.) injected ACBP/DBI protein conserved its orexigenic function when the protein was mutated to abolish acyl coenzyme A binding, but lost its appetite-stimulatory effect in mice bearing a mutation in the γ2 subunit of the γ-aminobutyric acid (GABA) A receptor (GABAAR). ACBP/DBI neutralization by intraperitoneal (i.p.) injection of a specific mAb blunted excessive food intake in starved and leptin-deficient mice, but not in ghrelin-treated animals. Neither i.v. nor i.p. injected anti-ACBP/DBI antibody affected the behavior of mice in the dark–light box and open-field test. In contrast, ACBP/DBI increased immobility in the forced swim test, while anti-ACBP/DBI antibody counteracted this sign of depression. In patients diagnosed with therapy-resistant bipolar disorder or schizophrenia, ACBP/DBI similarly correlated with body mass index (BMI), not with the psychiatric diagnosis. Patients with high levels of ACBP/DBI were at risk of dyslipidemia and this effect was independent from BMI, as indicated by multivariate analysis. In summary, it appears that ACBP/DBI neutralization has no negative impact on mood and that human depression is not associated with alterations in ACBP/DBI concentrations.
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| 22. |
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| 23. |
- Kowal-Bielecka, Otylia, et al.
(författare)
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Update of EULAR recommendations for the treatment of systemic sclerosis
- 2017
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 76, s. 1327-1339
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.
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| 24. |
- Li, Bo, et al.
(författare)
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Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer
- 2017
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Ingår i: Cancer Research. - 0008-5472. ; 77:14, s. 3834-3845
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Tidskriftsartikel (refereegranskat)abstract
- Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle–related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n ¼ 383) and the METABRIC TNBC dataset (n ¼ 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n ¼ 109) and the METABRIC TNBC cohort (n ¼ 203). The highly specific CDK7 kinase inhibitors, BS-181 and THZ1, each downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment.
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| 25. |
- Mewton, Nathan, et al.
(författare)
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Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients (the CIRCUS trial)
- 2015
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Ingår i: American Heart Journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 169:6, s. 6-766
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Tidskriftsartikel (refereegranskat)abstract
- Background Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients. Methods CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow <= 1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1: 1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in theminutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction. Results Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015. Conclusions The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up.
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| 26. |
- Miguel-Escalada, Irene, et al.
(författare)
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Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:7, s. 1137-1148
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.
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| 27. |
- Molinaro, Antonio, et al.
(författare)
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Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.
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| 28. |
- Pereira, Henrique M., et al.
(författare)
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Scenarios for Global Biodiversity in the 21st Century
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 330:6010, s. 1496-1501
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Forskningsöversikt (refereegranskat)abstract
- Quantitative scenarios are coming of age as a tool for evaluating the impact of future socioeconomic development pathways on biodiversity and ecosystem services. We analyze global terrestrial, freshwater, and marine biodiversity scenarios using a range of measures including extinctions, changes in species abundance, habitat loss, and distribution shifts, as well as comparing model projections to observations. Scenarios consistently indicate that biodiversity will continue to decline over the 21st century. However, the range of projected changes is much broader than most studies suggest, partly because there are major opportunities to intervene through better policies, but also because of large uncertainties in projections.
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| 29. |
- Shrestha, Malakh, et al.
(författare)
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Current status and recommendations for use of the frozen elephant trunk technique: a position paper by the Vascular Domain of EACTS†.
- 2015
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Ingår i: European Journal of Cardio-Thoracic Surgery. - : Oxford University Press (OUP). - 1010-7940 .- 1873-734X. ; 47:5, s. 759-769
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Tidskriftsartikel (refereegranskat)abstract
- The implementation of new surgical techniques offers chances but carries risks. Usually, several years pass before a critical appraisal and a balanced opinion of a new treatment method are available and rely on the evidence from the literature and expert's opinion. The frozen elephant trunk (FET) technique has been increasingly used to treat complex pathologies of the aortic arch and the descending aorta, but there still is an ongoing discussion within the surgical community about the optimal indications. This paper represents a common effort of the Vascular Domain of EACTS together with several surgeons with particular expertise in aortic surgery, and summarizes the current knowledge and the state of the art about the FET technique. The majority of the information about the FET technique has been extracted from 97 focused publications already available in the PubMed database (cohort studies, case reports, reviews, small series, meta-analyses and best evidence topics) published in English.
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| 30. |
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| 31. |
- Sultan, A., et al.
(författare)
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T cell-mediated inflammation in adipose tissue does not cause insulin resistance in hyperlipidemic mice
- 2009
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Ingår i: Circ Res. - 1524-4571 .- 0009-7330. ; 104:8, s. 961-8
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is associated with chronic inflammation in adipose tissue. Proinflammatory cytokines including tumor necrosis factor-alpha and interleukin-6 secreted by adipose tissue during the metabolic syndrome are proposed to cause local and general insulin resistance and promote development of type 2 diabetes. We have used a compound mutant mouse, Apoe(-/-)xCD4dnTGFbR, with dysregulation of T-cell activation, excessive production of proinflammatory cytokines, hyperlipidemia, and atherosclerosis, to dissect the role of inflammation in adipose tissue metabolism. These mice are lean, which avoids confounding effects of concomitant obesity. Expression and secretion of a set of proinflammatory factors including tumor necrosis factor-alpha, interferon-gamma, and monocyte chemoattractant protein-1 was increased in adipose tissue of Apoe(-/-)xCD4dnTGFbR mice, as was the enzyme 11beta-hydroxysteroid dehydrogenase type 1, which converts cortisone to bioactive cortisol. Interleukin-6, which has an inhibitory glucocorticoid response element in its promoter, was not upregulated. In spite of intense local inflammation, insulin sensitivity was not impaired in adipose tissue of Apoe(-/-)xCD4dnTGFbR mice unless exogenous interleukin-6 was administered. In conclusion, T-cell activation causes inflammation in adipose tissue but does not lead to insulin resistance in this tissue in the absence of interleukin-6.
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| 32. |
- Thun, Gian Andri, et al.
(författare)
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Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels
- 2013
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:8, s. e1003585-
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Tidskriftsartikel (refereegranskat)abstract
- Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs defined by showing minor allele frequencies (MAFs) >5% reached genome-wide significance all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of beta = 20.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis as well as exon-sequencing in a subsample (N = 410) suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only in particular by the well-documented protein inhibitor S and Z (PI S PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001) as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397) associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.
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| 33. |
- van Eerden, Ruben A. G., et al.
(författare)
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Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer
- 2021
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Data from previous work suggests that there is no correlation between systemic (plasma) paclitaxel exposure and efficacy in patients treated for esophageal cancer. In this trial, we investigated ATP-binding cassette efflux transporter expression and intratumoral pharmacokinetics of paclitaxel to identify changes which could be a first sign of chemoresistance.Methods: Patients with esophageal cancer treated with paclitaxel and carboplatin (+/- concomitant radiotherapy) were included. During the first and last cycle of weekly paclitaxel, blood samples and biopsies of esophageal mucosa and tumor tissue were taken. Changes in paclitaxel exposure and expression of ABCB1 (P-glycoprotein) over time were studied in both tumor tissue and normal appearing esophageal mucosa.Results: ABCB1 was significantly higher expressed in tumor tissue compared to esophageal tissue, during both the first and last cycle of paclitaxel (cycle 1: p < 0.01; cycle 5/6: p = 0.01). Interestingly, ABCB1 expression was significantly higher in adenocarcinoma than in squamous cell carcinoma (p < 0.01). During the first cycle, a trend towards a higher intratumoral paclitaxel concentration was observed compared to the esophageal mucosa concentration (RD:43%; 95%CI: -3% to 111% p = 0.07). Intratumoral and plasma paclitaxel concentrations were significantly correlated during the first cycle (AUC(0-48 h): r = 0.72; p < 0.01).Conclusion: Higher ABCB1 expression in tumor tissue, and differences between histological tumor types might partly explain why tumors respond differently to systemic treatment. Resistance by altered intratumoral paclitaxel concentrations could not be demonstrated because the majority of the biopsies taken at the last cycle of paclitaxel did contain a low amount of tumor cells or no tumor.
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| 34. |
- Volkers, Peter, et al.
(författare)
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Recombinant factor VIII products and inhibitor development in previously untreated patients with severe haemophilia A : Combined analysis of three studies
- 2019
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 25:3, s. 398-407
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Standard treatment of congenital haemophilia A is based on replacement therapy with coagulation factor VIII (FVIII) products. A major complication of FVIII therapy is the occurrence of IgG alloantibodies (inhibitors) that neutralize FVIII activity.AIM: The aim of the analysis was estimating the risk of high-titre inhibitor associated with the second-generation full-length product compared to third-generation full-length product and other recombinant FVIII (rFVIII).METHODS: We conducted a combined analysis of individual patient data from three large studies in previously untreated patients (PUPs) with severe haemophilia A.RESULTS: A total of 1109 PUPs were treated from 1993 to 2013 including 787 PUPs treated from 2004 onwards (primary analysis cohort). A total of 322 patients (29.0%) developed an inhibitor, of which 192 (17.3%) a high-titre inhibitor. In the primary analysis set, 29.9% of patients developed an inhibitor and 17.2% a high-titre inhibitor. The combined analysis indicated a lower risk of high-titre inhibitor development for the third-generation rFVIII product compared to the second-generation rFVIII product (primary analysis: adjusted hazard ratio (HR) = 0.72, 95% CI: 0.49 to 1.06). Adjusted HR for all inhibitor development was significantly lower for the third-generation product compared to the second-generation product.CONCLUSION: The trend of an increased risk of inhibitor development in PUPs for one recombinant product illustrates that extrapolation from one recombinant factor VIII product to other products might not be justified.
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| 35. |
- Allum, Felix, et al.
(författare)
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Coulomb explosion imaging of CH3I and CH2CII photodissociation dynamics
- 2018
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 149:20
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Tidskriftsartikel (refereegranskat)abstract
- The photodissociation dynamics of CH3I and CH2CII at 272 nm were investigated by time-resolved Coulomb explosion imaging, with an intense non-resonant 815nmprobe pulse. Fragment ion momenta over a widem/z range were recorded simultaneously by coupling a velocity map imaging spectrometer with a pixel imaging mass spectrometry camera. For both molecules, delay-dependent pump-probe features were assigned to ultraviolet-induced carbon-iodine bond cleavage followed by Coulomb explosion. Multi-mass imaging also allowed the sequential cleavage of both carbon-halogen bonds in CH2ClI to be investigated. Furthermore, delay-dependent relative fragment momenta of a pair of ions were directly determined using recoil-frame covariance analysis. These results are complementary to conventional velocity map imaging experiments and demonstrate the application of time-resolved Coulomb explosion imaging to photoinduced real-time molecular motion.
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| 36. |
- Artibani, Walter, et al.
(författare)
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EAU Policy on Live Surgery Events.
- 2014
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 66:1, s. 87-97
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Forskningsöversikt (refereegranskat)abstract
- Live surgery is an important part of surgical education, with an increase in the number of live surgery events (LSEs) at meetings despite controversy about their real educational value, risks to patient safety, and conflicts of interest.
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| 37. |
- Atla, Goutham, et al.
(författare)
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Genetic regulation of RNA splicing in human pancreatic islets
- 2022
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1474-760X. ; 23, s. 1-28
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNon-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown.ResultsWe examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3.ConclusionsThese data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.
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| 38. |
- Auer, Gunther, et al.
(författare)
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CELTIC CP5-026 WINNER+, D1.5 Intermediate Report on System Aspect of Advanced RRM
- 2009
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The deliverable describes the second set of best innovations proposed in the framework of the WP1 on system aspect of advanced Radio Resource Management (RRM) approved by the System Group. These concepts consist of promising innovative techniques and include an initial evaluation of the performance and benefits as far as already available. A brief description of each technique together with the relevant state of the art is provided.Moreover, first considerations about the requirements on the system, especially regarding measurements, signalling, architecture and protocols are described. The last set of innovations will be ready for the final deliverable of proof of concept evaluation.
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| 39. |
- Bernatsky, Sasha, et al.
(författare)
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Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma
- 2017
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Ingår i: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE.
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| 40. |
- Berndt, Sonja, I, et al.
(författare)
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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
- 2022
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Ingår i: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:12, s. 2835-2844
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Tidskriftsartikel (refereegranskat)abstract
- Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
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| 41. |
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| 42. |
- Bezem, M., et al.
(författare)
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On generalized algebraic theories and categories with families
- 2021
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Ingår i: Mathematical Structures in Computer Science. - : Cambridge University Press (CUP). - 0960-1295 .- 1469-8072. ; 31:9, s. 1006-1023
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Tidskriftsartikel (refereegranskat)abstract
- We give a syntax independent formulation of finitely presented generalized algebraic theories as initial objects in categories of categories with families (cwfs) with extra structure. To this end, we simultaneously define the notion of a presentation sigma of a generalized algebraic theory and the associated category CwF(sigma) of small cwfs with a sigma-structure and cwf-morphisms that preserve sigma-structure on the nose. Our definition refers to the purely semantic notion of uniform family of contexts, types, and terms in CwF(sigma). Furthermore, we show how to syntactically construct an initial cwf with a sigma-structure. This result can be viewed as a generalization of Birkhoff's completeness theorem for equational logic. It is obtained by extending Castellan, Clairambault, and Dybjer's construction of an initial cwf. We provide examples of generalized algebraic theories for monoids, categories, categories with families, and categories with families with extra structure for some type formers of Martin-Lof type theory. The models of these are internal monoids, internal categories, and internal categories with families (with extra structure) in a small category with families. Finally, we show how to extend our definition to some generalized algebraic theories that are not finitely presented, such as the theory of contextual cwfs.
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| 43. |
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| 44. |
- Bousquet, Jean, et al.
(författare)
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ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice
- 2021
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 76:1, s. 168-190
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Forskningsöversikt (refereegranskat)abstract
- Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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| 45. |
- Brasse, Felix, et al.
(författare)
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Time-resolved inner-shell photoelectron spectroscopy : From a bound molecule to an isolated atom
- 2018
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Ingår i: Physical Review A: covering atomic, molecular, and optical physics and quantum information. - 2469-9926 .- 2469-9934. ; 97:4
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Tidskriftsartikel (refereegranskat)abstract
- Due to its element and site specificity, inner-shell photoelectron spectroscopy is a widely used technique to probe the chemical structure of matter. Here, we show that time-resolved inner-shell photoelectron spectroscopy can be employed to observe ultrafast chemical reactions and the electronic response to the nuclear motion with high sensitivity. The ultraviolet dissociation of iodomethane (CH3I) is investigated by ionization above the iodine 4d edge, using time-resolved inner-shell photoelectron and photoion spectroscopy. The dynamics observed in the photoelectron spectra appear earlier and are faster than those seen in the iodine fragments. The experimental results are interpreted using crystal-field and spin-orbit configuration interaction calculations, and demonstrate that time-resolved inner-shell photoelectron spectroscopy is a powerful tool to directly track ultrafast structural and electronic transformations in gas-phase molecules.
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| 46. |
- Brette, Romain, et al.
(författare)
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Simulation of networks of spiking neurons : A review of tools and strategies
- 2007
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Ingår i: Journal of Computational Neuroscience. - : Springer Science and Business Media LLC. - 0929-5313 .- 1573-6873. ; 23:3, s. 349-398
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Forskningsöversikt (refereegranskat)abstract
- We review different aspects of the simulation of spiking neural networks. We start by reviewing the different types of simulation strategies and algorithms that are currently implemented. We next review the precision of those simulation strategies, in particular in cases where plasticity depends on the exact timing of the spikes. We overview different simulators and simulation environments presently available (restricted to those freely available, open source and documented). For each simulation tool, its advantages and pitfalls are reviewed, with an aim to allow the reader to identify which simulator is appropriate for a given task. Finally, we provide a series of benchmark simulations of different types of networks of spiking neurons, including Hodgkin-Huxley type, integrate-and-fire models, interacting with current-based or conductance-based synapses, using clock-driven or event-driven integration strategies. The same set of models are implemented on the different simulators, and the codes are made available. The ultimate goal of this review is to provide a resource to facilitate identifying the appropriate integration strategy and simulation tool to use for a given modeling problem related to spiking neural networks.
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| 47. |
- Burt, Michael, et al.
(författare)
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Coulomb-explosion imaging of concurrent CH2BrI photodissociation dynamics
- 2017
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Ingår i: Physical Review A: covering atomic, molecular, and optical physics and quantum information. - 2469-9926 .- 2469-9934. ; 96:4
-
Tidskriftsartikel (refereegranskat)abstract
- The dynamics following laser-induced molecular photodissociation of gas-phase CH2BrI at 271.6 nm were investigated by time-resolved Coulomb-explosion imaging using intense near-IR femtosecond laser pulses. The observed delay-dependent photofragment momenta reveal that CH2BrI undergoes C-I cleavage, depositing 65.6% of the available energy into internal product states, and that absorption of a second UV photon breaks the C-Br bond of C(H)2Br. Simulations confirm that this mechanism is consistent with previous data recorded at 248 nm, demonstrating the sensitivity of Coulomb-explosion imaging as a real-time probe of chemical dynamics.
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| 48. |
- Cerhan, James R., et al.
(författare)
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Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:11, s. 1233-1238
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Tidskriftsartikel (refereegranskat)abstract
- Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 x 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 x 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 x 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 x 10(-13) and 3.63 x 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
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| 49. |
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| 50. |
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