1. |
- Hudson, Lawrence N, et al.
(författare)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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Ingår i: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
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Tidskriftsartikel (refereegranskat)abstract
- The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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2. |
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3. |
- Drude, Natascha Ingrid, et al.
(författare)
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Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research : a multi-stakeholder workshop report
- 2022
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Ingår i: Translational Medicine Communications. - : Springer Nature. - 2396-832X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solution-oriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory.
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4. |
- John, Juliane, et al.
(författare)
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Redox-controlled reorganization and flavin strain within the ribonucleotide reductase R2b–NrdI complex monitored by serial femtosecond crystallography
- 2022
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Ingår i: eLIFE. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Redox reactions are central to biochemistry and are both controlled by and induce protein structural changes. Here, we describe structural rearrangements and crosstalk within the Bacillus cereus ribonucleotide reductase R2b–NrdI complex, a di-metal carboxylate-flavoprotein system, as part of the mechanism generating the essential catalytic free radical of the enzyme. Femtosecond crystallography at an X-ray free electron laser was utilized to obtain structures at room temperature in defined redox states without suffering photoreduction. Together with density functional theory calculations, we show that the flavin is under steric strain in the R2b–NrdI protein complex, likely tuning its redox properties to promote superoxide generation. Moreover, a binding site in close vicinity to the expected flavin O2 interaction site is observed to be controlled by the redox state of the flavin and linked to the channel proposed to funnel the produced superoxide species from NrdI to the di-manganese site in protein R2b. These specific features are coupled to further structural changes around the R2b–NrdI interaction surface. The mechanistic implications for the control of reactive oxygen species and radical generation in protein R2b are discussed.
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5. |
- John, Juliane, et al.
(författare)
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Redox-controlled reorganization and flavin strain within the ribonucleotide reductase R2b–NrdI complex monitored by serial femtosecond crystallography
- 2022
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Redox reactions are central to biochemistry and are both controlled by and induce protein structural changes. Here, we describe structural rearrangements and crosstalk within the Bacillus cereus ribonucleotide reductase R2b–NrdI complex, a di-metal carboxylate-flavoprotein system, as part of the mechanism generating the essential catalytic free radical of the enzyme. Femtosecond crystallography at an X-ray free electron laser was utilized to obtain structures at room temperature in defined redox states without suffering photoreduction. Together with density functional theory calculations, we show that the flavin is under steric strain in the R2b–NrdI protein complex, likely tuning its redox properties to promote superoxide generation. Moreover, a binding site in close vicinity to the expected flavin O2 interaction site is observed to be controlled by the redox state of the flavin and linked to the channel proposed to funnel the produced superoxide species from NrdI to the di-manganese site in protein R2b. These specific features are coupled to further structural changes around the R2b–NrdI interaction surface. The mechanistic implications for the control of reactive oxygen species and radical generation in protein R2b are discussed.
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6. |
- Lebrette, Hugo, 1986-, et al.
(författare)
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Structure of a ribonucleotide reductase R2 protein radical
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 382:6666, s. 109-113
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Tidskriftsartikel (refereegranskat)abstract
- Aerobic ribonucleotide reductases (RNRs) initiate synthesis of DNA building blocks by generating a free radical within the R2 subunit; the radical is subsequently shuttled to the catalytic R1 subunit through proton-coupled electron transfer (PCET). We present a high-resolution room temperature structure of the class Ie R2 protein radical captured by x-ray free electron laser serial femtosecond crystallography. The structure reveals conformational reorganization to shield the radical and connect it to the translocation path, with structural changes propagating to the surface where the protein interacts with the catalytic R1 subunit. Restructuring of the hydrogen bond network, including a notably short O-O interaction of 2.41 angstroms, likely tunes and gates the radical during PCET. These structural results help explain radical handling and mobilization in RNR and have general implications for radical transfer in proteins.
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7. |
- Liu, Jimmy Z, et al.
(författare)
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Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:6, s. 670-5
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Tidskriftsartikel (refereegranskat)abstract
- Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
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8. |
- Ollila, Hanna M., et al.
(författare)
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Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix (R). Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix (R).
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9. |
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10. |
- Srinivas, Vivek, et al.
(författare)
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High-Resolution XFEL Structure of the Soluble Methane Monooxygenase Hydroxylase Complex with its Regulatory Component at Ambient Temperature in Two Oxidation States
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:33, s. 14249-14266
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Tidskriftsartikel (refereegranskat)abstract
- Soluble methane monooxygenase (sMMO)is a multicomponent metalloenzyme that catalyzes the conversion of methane to methanol at ambient temperature using a nonheme, oxygen-bridged dinuclear iron cluster in the active site. Structural changes in the hydroxylase component (sMMOH) containing the diiron cluster caused by complex formation with a regulatory component (MMOB) and by iron reduction are important for the regulation of O-2 activation and substrate hydroxylation. Structural studies of metalloenzymes using traditional synchrotron-based X-ray crystallography are often complicated by partial X-ray-induced photoreduction of the metal center, thereby obviating determination of the structure of the enzyme in pure oxidation states. Here, microcrystals of the sMMOH:MMOB complex from Methylosinus trichosporium OB3b were serially exposed to X-ray free electron laser (XFEL) pulses, where the <= 35 fs duration of exposure of an individual crystal yields diffraction data before photoreduction-induced structural changes can manifest. Merging diffraction patterns obtained from thousands of crystals generates radiation damage-free, 1.95 angstrom resolution crystal structures for the fully oxidized and fully reduced states of the sMMOH:MMOB complex for the first time. The results provide new insight into the manner by which the diiron cluster and the active site environment are reorganized by the regulatory protein component in order to enhance the steps of oxygen activation and methane oxidation. This study also emphasizes the value of XFEL and serial femtosecond crystallography (SFX) methods for investigating the structures of metalloenzymes with radiation sensitive metal active sites.
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11. |
- Bartsch, Yannic C, et al.
(författare)
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IgG Fc sialylation is regulated during the germinal center reaction upon immunization with different adjuvants
- 2020
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Ingår i: The Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 146:3, s. 652-666
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Effector functions of IgG antibodies (Abs) are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to the protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects.OBJECTIVE: We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction upon immunization of mice with a foreign protein antigen and different adjuvants.METHODS: Mice were analyzed for GC T, B cell and plasma cell responses as well as antigen-specific serum IgG subclass titers and Fc glycosylation patterns.RESULTS: Different adjuvants induce distinct IgG+ GC B cell responses with specific transcriptomes and expression levels of the α2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the T follicular helper (TFH) cell-inducing cytokine IL-6, especially induced by water-in-oil adjuvants and Mycobacterium tuberculosis (Mtb). Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27R-dependent IFNγ+ TFH1 cells, IL-6/IL-23-dependent IL-17A+ TFH17 cells and high TFH/T follicular regulatory (TFR) cell ratios. The two latter were here dependent on Mtb and its cord factor.CONCLUSION: These findings on adjuvant-dependent GC responses and IgG glycosylation programming may aid the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns.
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12. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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13. |
- Bengtsdotter, H., et al.
(författare)
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Ongoing or previous mental disorders predispose to adverse mood reporting during combined oral contraceptive use
- 2018
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Ingår i: European Journal of Contraception and Reproductive Health Care. - : Informa UK Limited. - 1362-5187 .- 1473-0782. ; 23:1, s. 45-51
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Previous studies have emphasised that women with pre-existing mood disorders are more inclined to discontinue hormonal contraceptive use. However, few studies have examined the effects of combined oral contraceptives (COC) on mood in women with previous or ongoing mental disorders. Materials and methods: This is a supplementary analysis of an investigator-initiated, double-blinded, randomised clinical trial during which 202 women were treated with either a COC (1.5mg estradiol and 2.5mg nomegestrolacetate) or placebo during three treatment cycles. The Mini International Neuropsychiatric Interview was used to collect information on previous or ongoing mental disorders. The primary outcome measure was the total change score in five mood symptoms on the Daily Record of Severity of Problems (DRSP) scale in the intermenstrual phase of the treatment cycle. Results: Women with ongoing or previous mood, anxiety or eating disorders allocated to COC had higher total DRSP -scores during the intermenstrual phase of the treatment cycle in comparison with corresponding women randomised to placebo, mean difference 1.3 (95% CI 0.3-2.3). In contrast, among women without mental health problems, no difference in total DRSP -scores between COC- and placebo users was noted. Women with a risk use of alcohol who were randomised to the COC had higher total DRSP -scores than women randomised to placebo, mean difference 2.1 (CI 95% 1.0-3.2). Conclusions: Women with ongoing or previous mental disorders or risk use of alcohol have greater risk of COC-induced mood symptoms. This may be worth noting during family planning and contraceptive counselling.
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14. |
- Brandrud, Marie K., et al.
(författare)
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Phylogenomic relationships of diploids and the origins of allotetraploids in Dactylorhiza (Orchidaceae)
- 2020
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Ingår i: Systematic Biology. - : Oxford University Press (OUP). - 1063-5157 .- 1076-836X. ; 69:1, s. 91-109
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Tidskriftsartikel (refereegranskat)abstract
- Disentangling phylogenetic relationships proves challenging for groups that have evolved recently, especially if there is ongoing reticulation. Although they are in most cases immediately isolated from diploid relatives, sets of sibling allopolyploids often hybridize with each other, thereby increasing the complexity of an already challenging situation. Dactylorhiza (Orchidaceae: Orchidinae) is a genus much affected by allopolyploid speciation and reticulate phylogenetic relationships. Here we use genetic variation at tens of thousands of genomic positions to unravel the convoluted evolutionary history of Dactylorhiza. We first investigate circumscription and relationships of diploid species in the genus using coalescent and maximum likelihood methods, and then group 16 allotetraploids by maximum affiliation to their putative parental diploids, implementing a method based on genotype likelihoods. The direction of hybrid crosses is inferred for each allotetraploid using information from maternally inherited plastid RADseq loci. Starting from age estimates of parental taxa, the relative ages of these allotetraploid entities are inferred by quantifying their genetic similarity to the diploids and numbers of private alleles compared with sibling allotetraploids. Whereas northwestern Europe is dominated by young allotetraploids of postglacial origins, comparatively older allotetraploids are distributed further south, where climatic conditions remained relatively stable during the Pleistocene glaciations. Our bioinformatics approach should prove effective for the study of other naturally occurring, non-model, polyploid plant complexes.
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15. |
- Brandrud, Marie K., et al.
(författare)
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Restriction-site associated DNA sequencing supports a sister group relationship of Nigritella and Gymnadenia (Orchidaceae)
- 2019
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Ingår i: Molecular Phylogenetics and Evolution. - : Elsevier BV. - 1055-7903. ; 136, s. 21-28
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Tidskriftsartikel (refereegranskat)abstract
- The orchid genus Nigritella is closely related to Gymnadenia and has from time to time been merged with the latter. Although Nigritella is morphologically distinct, it has been suggested that the separating characters are easily modifiable and subject to rapid evolutionary change. So far, molecular phylogenetic studies have either given support for the inclusion of Nigritella in Gymnadenia, or for their separation as different genera. To resolve this issue, we analysed data obtained from Restriction-site associated DNA sequencing, RADseq, which provides a large number of SNPs distributed across the entire genome. To analyse samples of different ploidies, we take an analytical approach of building a reduced genomic reference based on de novo RADseq loci reconstructed from diploid accessions only, which we further use to map and call variants across both diploid and polyploid accessions. We found that Nigritella is distinct from Gymnadenia forming a well-supported separate clade, and that genetic diversity within Gymnadenia is high. Within Gymnadenia, taxa characterized by an ITS-E ribotype (G. conopsea s.str. (early flowering) and G. odoratissima), are divergent from taxa characterized by ITS-L ribotype (G. frivaldii, G. densiflora and late flowering G. conopsea). Gymnigritella runei is confirmed to have an allopolyploid origin from diploid Gymnadenia conopsea and tetraploid N. nigra ssp. nigra on the basis of RADseq data. Within Nigritella the aggregation of polyploid members into three clear-cut groups as suggested by allozyme and nuclear microsatellite data was further supported.
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16. |
- Brem, Jürgen, et al.
(författare)
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Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
- 2022
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Ingår i: Nature Chemistry. - : Springer Nature. - 1755-4330 .- 1755-4349. ; 14:1, s. 15-24
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Tidskriftsartikel (refereegranskat)abstract
- Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.
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17. |
- Dabkowska, Aleksandra P., et al.
(författare)
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Non-lamellar lipid assembly at interfaces : controlling layer structure by responsive nanogel particles
- 2017
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Ingår i: Interface Focus. - : ROYAL SOC. - 2042-8898 .- 2042-8901. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- Biological membranes do not only occur as planar bilayer structures, but depending on the lipid composition, can also curve into intriguing three-dimensional structures. In order to fully understand the biological implications as well as to reveal the full potential for applications, e.g. for drug delivery and other biomedical devices, of such structures, well-defined model systems are required. Here, we discuss the formation of lipid non-lamellar liquid crystalline (LC) surface layers spin-coated from the constituting lipids followed by hydration of the lipid layer. We demonstrate that hybrid lipid polymer films can be formed with different properties compared with the neat lipid LC layers. The nanostructure and morphologies of the lipid films formed reflect those in the bulk. Most notably, mixed lipid layers, which are composed of glycerol monooleate and diglycerol monooleate with poly(N-isopropylacrylamide) nanogels, can form films of reverse cubic phases that are capable of responding to temperature stimulus. Owing to the presence of the nanogel particles, changing the temperature not only regulates the hydration of the cubic phase lipid films, but also the lateral organization of the lipid domains within the lipid self-assembled film. This opens up the possibility for new nanostructured materials based on lipid-polymer responsive layers.
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18. |
- Desta, Liyew, et al.
(författare)
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Transradial versus trans-femoral access site in high-speed rotational atherectomy in Sweden
- 2022
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 352, s. 45-51
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Tidskriftsartikel (refereegranskat)abstract
- Background: Radial artery is the preferred access site in contemporary percutaneous coronary intervention (PCI). However, limited data exist regarding utilization pattern, safety, and long-term efficacy of transradial artery access (TRA) PCI in heavily calcified lesions using high-speed rotational atherectomy (HSRA). Methods: All patients who underwent HSRA-PCI in Sweden between 2005 and 2016 were included. Outcomes were major adverse cardiac events (MACE, including death, myocardial infarction (MI) or target vessel revascularisation (TVR)), in-hospital bleeding and restenosis. Inverse probability of treatment weighting was used to adjust for the non-randomized access site selection. Results: We included 1479 patients of whom 649 had TRA and 782 transfemoral artery access (TFA) HSRA-PCI. The rate of TRA increased significantly by 18% per year but remained lower in HSRA-PCI (60%) than in the overall PCI population (85%) in 2016. TRA was associated with comparable angiographic success but significantly lower risk for major (adjusted OR 0.16; 95% CI 0.05–0.47) or any in-hospital bleeding (adjusted OR 0.32; 95% CI 0.13–0.78). At one year, the adjusted risk for MACE (HR 0.87; 95% CI 0.67–1.13) and its individual components did not differ between TRA and TFA patients. The risk for restenosis did not significantly differ between TRA and TFA HSRA-PCI treated lesions (adjusted HR 0.92; 95% CI 0.46–1.81). Conclusion: HSRA-PCI by TRA was associated with significantly lower risk for in-hospital bleeding and equivalent long-term efficacy when compared with TFA. Our data support the feasibility and superior safety profile of TRA in HSRA-PCI.
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19. |
- Ellinghaus, David, et al.
(författare)
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Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
- 2013
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
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20. |
- Epp, Alexandra, et al.
(författare)
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Sialylation of IgG antibodies inhibits IgG-mediated allergic reactions
- 2018
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 141:1, s. 8-402
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Tidskriftsartikel (refereegranskat)abstract
- In presence of high allergen dosis besides IgE also IgG antibodies can induce allergic reactions, whose severity is dependent on the induced type of IgG Fc glycosylation, what should be considered for new AIT protocols containing new adjuvants.
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21. |
- Haase, Dagmar, et al.
(författare)
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Greening cities - To be socially inclusive? About the alleged paradox of society and ecology in cities
- 2017
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Ingår i: Habitat International. - : Elsevier BV. - 0197-3975 .- 1873-5428. ; 64, s. 41-48
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Tidskriftsartikel (refereegranskat)abstract
- Greening cities, namely installing new parks, rooftop gardens or planting trees along the streets, undoubtedly contributes to an increase in wellbeing and enhances the attractiveness of open spaces in cities. At the same time, we observe an increasing use of greening strategies as ingredients of urban renewal, upgrading and urban revitalization as primarily market-driven endeavours targeting middle class and higher income groups sometimes at the expense of less privileged residents. This paper reflects on the current debate of the social effects of greening using selected examples. We discuss what tradeoffs between social and ecological developments in cities mean for the future debate on greening cities and a socially balanced and inclusive way of developing our cities for various groups of urban dwellers. We conclude that current and future functions and features of greening cities have to be discussed more critically including a greater awareness of social impacts.
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22. |
- Hernandez, Victor Agmo, et al.
(författare)
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The adhesion and spreading of thrombocyte vesicles on electrode surfaces
- 2008
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Ingår i: Bioelectrochemistry. - : Elsevier BV. - 1567-5394 .- 1878-562X. ; 74, s. 210-216
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Tidskriftsartikel (refereegranskat)abstract
- The interaction of thrombocyte vesicles with the surface of metal electrodes, i.e., mercury, gold and gold electrodes modified with self assembled monolayers (SAM), was studied with the help of chronoamperometry, atomic force microscopy, and quartz crystal microbalance measurements. The experimental results show that the interaction of the thrombocyte vesicles with the surface of the electrodes depends on the hydrophobicity of the latter: whereas on very hydrophobic surfaces (mercury and gold functionalized with SAM) the thrombocyte vesicles disintegrate and form a monolayer of lipids. on the less hydrophobic gold surface a bilayer is formed. The chronoamperometric measurements indicate the possibility of future applications to probe membrane properties of thrombocytes. (C) 2008 Elsevier B.V. All rights reserved.
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23. |
- Herold, Nikolas, et al.
(författare)
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Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
- 2017
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
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Tidskriftsartikel (refereegranskat)abstract
- The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
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- Mergenthaler, Philipp, et al.
(författare)
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A functional role of the cyclin-dependent kinase inhibitor 1 (p21(WAF1/CIP1)) for neuronal preconditioning
- 2013
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 33:3, s. 351-355
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxic preconditioning is thought to rely on gene products regulated by hypoxia-inducible factor (HIF)-1. Here, we show that the HIF-1 target gene cyclin-dependent kinase inhibitor 1, p21(WAF1/CIP1), is essential for neuroprotection by hypoxic/aglycemic or erythropoietin preconditioning using wild-type and p21(WAF1/CIP1)-deficient neurons. Furthermore, overexpression of wild-type p21(WAF1/CIP1) or phospho-mutants significantly increased cell death after hypoxia/aglycemia. Moreover, deferoxamine-induced endogenous tolerance did not involve p21(WAF1/CIP1) expression in cortical neurons. Our data suggest that balanced expression and potentially posttranslational regulation of p21(WAF1/CIP1) is required for hypoxic preconditioning. Journal of Cerebral Blood Flow & Metabolism (2013) 33, 351-355; doi:10.1038/jcbfm.2012.213; published online 9 January 2013
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