| 1. |
- Dornelas, M., et al.
(författare)
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BioTIME: A database of biodiversity time series for the Anthropocene
- 2018
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 27:7, s. 760-786
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Tidskriftsartikel (refereegranskat)abstract
- Motivation: The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene. Main types of variables included: The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record. Spatial location and grain: BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km(2) (158 cm(2)) to 100 km(2) (1,000,000,000,000 cm(2)). Time period and grainBio: TIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year. Major taxa and level of measurement: BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.
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| 2. |
- 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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| 3. |
- Boele, H J, et al.
(författare)
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Accessible and reliable neurometric testing in humans using a smartphone platform
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Tests of human brain circuit function typically require fixed equipment in lab environments. We have developed a smartphone-based platform for neurometric testing. This platform, which uses AI models like computer vision, is optimized for at-home use and produces reproducible, robust results on a battery of tests, including eyeblink conditioning, prepulse inhibition of acoustic startle response, and startle habituation. This approach provides a scalable, universal resource for quantitative assays of central nervous system function.
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| 4. |
- Abazajian, Kevork, et al.
(författare)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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| 5. |
- Siddiqui, Mohammad S., et al.
(författare)
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Differential fuel utilization in liver transplant recipients and its relationship with non-alcoholic fatty liver disease
- 2022
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Ingår i: Liver international (Print). - : Wiley. - 1478-3223 .- 1478-3231. ; 42:6, s. 1401-1409
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT). Methods Patients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation). Results The two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p < .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue. Conclusion Reduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT.
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| 6. |
- Ade, Peter, et al.
(författare)
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The Simons Observatory : science goals and forecasts
- 2019
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :2
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Tidskriftsartikel (refereegranskat)abstract
- The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial con figuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping approximate to 10% of the sky to a white noise level of 2 mu K-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of sigma(r) = 0.003. The large aperture telescope will map approximate to 40% of the sky at arcminute angular resolution to an expected white noise level of 6 mu K-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
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| 7. |
- Ferrer, G, et al.
(författare)
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Myeloid-derived suppressor cell subtypes differentially influence T-cell function, T-helper subset differentiation, and clinical course in CLL
- 2021
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 35:11, s. 3163-3175
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Tidskriftsartikel (refereegranskat)abstract
- Cancer pathogenesis involves the interplay of tumor- and microenvironment-derived stimuli. Here we focused on the influence of an immunomodulatory cell type, myeloid-derived suppressor cells (MDSCs), and their lineage-related subtypes on autologous T lymphocytes. Although MDSCs as a group correlated with an immunosuppressive Th repertoire and worse clinical course, MDSC subtypes (polymorphonuclear, PMN-MDSC, and monocytic, M-MDSCs) were often functionally discordant. In vivo, PMN-MDSCs existed in higher numbers, correlated with different Th-subsets, and more strongly associated with poor clinical course than M-MDSCs. In vitro, PMN-MDSCs were more efficient at blocking T-cell growth and promoted Th17 differentiation. Conversely, in vitro M-MDSCs varied in their ability to suppress T-cell proliferation, due to the action of TNFα, and promoted a more immunostimulatory Th compartment. Ibrutinib therapy impacted MDSCs differentially as well, since after initiating therapy, PMN-MDSC numbers progressively declined, whereas M-MDSC numbers were unaffected, leading to a set of less immunosuppressive Th cells. Consistent with this, clinical improvement based on decreasing CLL-cell numbers correlated with the decrease in PMN-MDSCs. Collectively, the data support a balance between PMN-MDSC and M-MDSC numbers and function influencing CLL disease course.
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| 8. |
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| 9. |
- Boucher, A, et al.
(författare)
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Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue
- 2004
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 279:26, s. 27263-27271
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Tidskriftsartikel (refereegranskat)abstract
- Hyperlipidemia appears to play an integral role in loss of glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. This impairment can be simulated in vitro by chronic culture of 832/13 insulinoma cells with high concentrations of free fatty acids, or by study of lipid-laden islets from Zucker diabetic fatty rats. Here we show that impaired GSIS is not a simple result of saturation of lipid storage pathways, as adenovirus-mediated overexpression of a cytosolically localized variant of malonyl-CoA decarboxylase in either cellular model results in dramatic lowering of cellular triglyceride stores but no improvement in GSIS. Instead, the glucose-induced increment in "pyruvate cycling" activity ( pyruvate exchange with tricarboxylic acid cycle intermediates measured by C-13 NMR), previously shown to play an important role in GSIS, is completely ablated in concert with profound suppression of GSIS in lipid-cultured 832/13 cells, whereas glucose oxidation is unaffected. Moreover, GSIS is partially restored in both lipid-cultured 832/13 cells and islets from Zucker diabetic fatty rats by addition of a membrane permeant ester of a pyruvate cycling intermediate ( dimethyl malate). We conclude that chronic exposure of islet beta-cells to fatty acids grossly alters a mitochondrial pathway of pyruvate metabolism that is important for normal GSIS.
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| 10. |
- Cantarovich, M, et al.
(författare)
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First global forum on education on organ donation and transplantation for schools.
- 2012
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Ingår i: Pediatric Transplantation. - : Wiley. - 1399-3046 .- 1397-3142.
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Tidskriftsartikel (refereegranskat)abstract
- The Transplantation Society, in collaboration with the Canadian Society of Transplantation, organized a forum on education on ODT for schools. The forum included participants from around the world, school boards, and representatives from different religions. Participants presented on their countries' experience in the area of education on ODT. Working groups discussed about technologies for education, principles for sharing of resources globally, and relationships between education, and health authorities and non-governmental organizations. The forum concluded with a discussion about how to best help existing programs and those wishing to start educational programs on ODT.
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| 11. |
- Chiavaroli, Valentina, et al.
(författare)
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Infants born large-for-gestational-age display slower growth in early infancy, but no epigenetic changes at birth
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the growth patterns of infants born large-for-gestational-age (LGA) from birth to age 1 year compared to those born appropriate-for-gestational-age (AGA). In addition, we investigated possible epigenetic changes associated with being born LGA. Seventy-one newborns were classified by birth weight as AGA (10(th)-90(th) percentile; n = 42) or LGA (>90(th) percentile; n = 29). Post-natal follow-up until age 1 year was performed with clinical assessments at 3, 6, and 12 months. Genome-wide DNA methylation was analysed on umbilical tissue in 19 AGA and 27 LGA infants. At birth, LGA infants had greater weight (p < 0.0001), length (p < 0.0001), ponderal index (p = 0.020), as well as greater head (p < 0.0001), chest (p = 0.044), and abdominal (p = 0.007) circumferences than AGA newborns. LGA infants were still larger at the age of 3 months, but by age 6 months there were no more differences between groups, due to higher length and weight increments in AGA infants between 0 and 6 months (p < 0.0001 and p = 0.002, respectively). Genome-wide analysis showed no epigenetic differences between LGA and AGA infants. Overall, LGA infants had slower growth in early infancy, being anthropometrically similar to AGA infants by 6 months of age. In addition, differences between AGA and LGA newborns were not associated with epigenetic changes.
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| 12. |
- Chofor, Rene, et al.
(författare)
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Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase
- 2015
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 58:7, s. 2988-3001
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Tidskriftsartikel (refereegranskat)abstract
- Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the beta-position of the hydroxamate analogue of 2. While direct addition of a beta-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the longer compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamates methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.
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| 13. |
- De Jong, Wim H., et al.
(författare)
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Round robin study to evaluate the reconstructed human epidermis (RhE) model as an in vitro skin irritation test for detection of irritant activity in medical device extracts
- 2018
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Ingår i: Toxicology in Vitro. - : Elsevier BV. - 0887-2333 .- 1879-3177. ; 50, s. 439-449
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Tidskriftsartikel (refereegranskat)abstract
- Assessment of skin irritation is an essential component of the safety evaluation of medical devices. OECD Test Guideline 439 describes the use of reconstructed human epidermis (RhE) as an in vitro test system for classification of skin irritation by neat chemicals. An international round robin study was conducted to evaluate the RhE method for determination of skin irritant potential of medical device extracts. Four irritant polymers and three non-irritant controls were obtained or developed that had demonstrated their suitability to act as positive or negative test samples. The RhE tissues (EpiDerm™ and SkinEthic™ RHE) were dosed with 100 μL aliquots of either saline or sesame oil extract. Incubation times were 18 h (EpiDerm™) and 24 h (SkinEthic™ RHE). Cell viability reduction > 50% was indicative of skin irritation. Both the EpiDerm™ and SkinEthic™ RHE tissues were able to correctly identify virtually all of the irritant polymer samples either in the saline, sesame oil or both solvent extracts. Our results indicate that RhE tissue models can detect the presence of strong skin irritants at low levels in dilute medical device polymer extracts. Therefore, these models may be suitable replacements for the rabbit skin irritation test to support the biological evaluation of medical devices.
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| 14. |
- Fang, Li Tai, et al.
(författare)
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Establishing community reference samples, data and call sets for benchmarking cancer mutation detection using whole-genome sequencing
- 2021
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 39:9, s. 1151-1160
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-normal paired DNA samples from a breast cancer cell line and a matched lymphoblastoid cell line enable calibration of clinical sequencing pipelines and benchmarking 'tumor-only' or 'matched tumor-normal' analyses. The lack of samples for generating standardized DNA datasets for setting up a sequencing pipeline or benchmarking the performance of different algorithms limits the implementation and uptake of cancer genomics. Here, we describe reference call sets obtained from paired tumor-normal genomic DNA (gDNA) samples derived from a breast cancer cell line-which is highly heterogeneous, with an aneuploid genome, and enriched in somatic alterations-and a matched lymphoblastoid cell line. We partially validated both somatic mutations and germline variants in these call sets via whole-exome sequencing (WES) with different sequencing platforms and targeted sequencing with >2,000-fold coverage, spanning 82% of genomic regions with high confidence. Although the gDNA reference samples are not representative of primary cancer cells from a clinical sample, when setting up a sequencing pipeline, they not only minimize potential biases from technologies, assays and informatics but also provide a unique resource for benchmarking 'tumor-only' or 'matched tumor-normal' analyses.
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| 15. |
- Leung, Ying-Ying, et al.
(författare)
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Management of Peripheral Arthritis in Patients With Psoriatic Arthritis : An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations
- 2023
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 50:1, s. 119-130
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Forskningsöversikt (refereegranskat)abstract
- Objective We aimed to compile evidence for the efficacy and safety of therapeutic options for the peripheral arthritis domain of psoriatic arthritis (PsA) for the revised 2021 Group in Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations.Methods A working group consisting of clinicians and patient research partners was convened. We reviewed the evidence from new randomized controlled trials (RCTs) for PsA treatment from February 19, 2013, to August 28, 2020. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-informed approach to derive evidence for the classes of therapeutic options for 3 patient groups: (1) naïve to treatment, (2) inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and (3) inadequate response to biologic DMARDs (bDMARDs). Recommendations were derived through consensus meetings.Results The evidence review included 69 RCTs. We derived GRADE evidence for each class of therapeutic options and achieved consensus for the recommendations. For patients naïve to treatment, the working group strongly recommends csDMARDs (methotrexate, sulfasalazine, leflunomide) and phosphodiesterase 4 inhibitors, and emphasizes regular assessment and early escalation to achieve treatment target. bDMARDs (tumor necrosis factor inhibitors [TNFi], interleukin 17 inhibitors [IL-17i], IL-12/23i, IL-23i) and Janus kinase inhibitors (JAKi) are also strongly recommended. For patients with inadequate response to csDMARDs, we strongly recommend TNFi, IL-17i, IL-12/23i, IL-23i, and JAKi. For those who had prior experience with bDMARDs, we strongly recommend a second TNFi, IL-17i, IL-23i, and JAKi. The evidence supporting nonpharmacological interventions was very low. An expert panel conditionally recommends adequate physical activity, smoking cessation, and diet to control weight gain.Conclusion Evidence supporting optimal therapy for the peripheral arthritis domain of PsA was compiled for the revised 2021 GRAPPA treatment recommendations.
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| 16. |
- Lu, Lu, 1984-, et al.
(författare)
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MEPicides : α,β-Unsaturated Fosmidomycin N-acyl Analogsas inhibitors that selectively target DXR from Plasmodium falciparum, the deadliest causative parasite of human Malaria
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Fosmidomycin and FR-9000098 have been confirmed to show parasiticidal activity against Plasmodium falciparum, targeting DXR involved in the MEP pathway. We designed a construct of PfDXR that has successfully been overexpressed in E. coli BL21(DE3) C43, and purified by IMAC and SEC, with the final yield of 1.2 mg/ 8 L culture. PfDXR was concentrated to 20 mg/ml, and co-crystallized with previously tested inhibitors in the FR-9000098 scaffold in the presence of Mn2+. Three FR-9000098 analogues with double-bonded Ca-Cband/or a phenyl ring with various lengths to N1, showed inhibitory activities with IC50s roughly 50 nM. Three crystals were in triclinic P1space group, with similar dimensions in the unit cell (51Å, 56Å, 86Å, 103°, 103°, 101°). All four complex structures have been crystallographically determined at resolutions in the range 1.86 Å, 2.45 Å, 2.13Å, 2.05 Å. Given the high similarity in structures, the initial phases were determined by rigid body refinement with search model PfDXR-FN3 complex, followed by restrained refinement in refmac5. Subsequently, the ligands and surrounding amino acid residues were manually rebuilt with theqdstools in O. the Ca-Cbbonds of the three ligands were altered from a single to double bond based on the structure of FR9000098. In addition, two ligands were extended at the Cdwith a phenyl group, and with the benzyl group connected by two carbons. N-terminal NADPH binding domains from four complexes undergo minor rigid body movement, and more details of conformational changes in the flap region are discussed.
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| 17. |
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| 18. |
- Richards, Stephen, et al.
(författare)
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The genome of the model beetle and pest Tribolium castaneum.
- 2008
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Ingår i: Nature. - 1476-4687. ; 452:7190, s. 949-55
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Tidskriftsartikel (refereegranskat)abstract
- Tribolium castaneum is a representative of earth’s most numerous eukaryotic order, a powerful model organism for the study of generalized insect development, and also an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved an ability to interact with a diverse chemical environment as evidenced by large expansions in odorant and gustatory receptors, as well as p450 and other detoxification enzymes. Developmental patterns in Tribolium are more representative of other arthropods than those found in Drosophila, a fact represented in gene content and function. For one, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, and some are expressed in the growth zone crucial for axial elongation in short germ development. Systemic RNAi in T. castaneum appears to use mechanisms distinct from those found in C. elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.
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| 19. |
- Rothwell, S, et al.
(författare)
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Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 996-1002
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.MethodsWe collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.ResultsWe report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10–5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10–53 and HLA-DRB1*03:01, p=3.25×10–9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10–26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10–11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10–13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10–6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10–64) and position 9 of HLA-B (p=7.03×10–11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.ConclusionsThese findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
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| 20. |
- Singh, Vinayak, et al.
(författare)
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Identification of aminopyrimidine-sulfonamides as potent modulators of Wag31-mediated cell elongation in mycobacteria.
- 2017
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Ingår i: Molecular Microbiology. - : Wiley. - 0950-382X .- 1365-2958. ; 103:1, s. 13-25
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need to discover new anti-tubercular agents with novel mechanisms of action in order to tackle the scourge of drug-resistant tuberculosis. Here, we report the identification of such a molecule - an AminoPYrimidine-Sulfonamide (APYS1) that has potent, bactericidal activity against M. tuberculosis. Mutations in APYS1-resistant M. tuberculosis mapped exclusively to wag31, a gene that encodes a scaffolding protein thought to orchestrate cell elongation. Recombineering confirmed that a Gln201Arg mutation in Wag31 was sufficient to cause resistance to APYS1, however, neither overexpression nor conditional depletion of wag31 impacted M. tuberculosis susceptibility to this compound. In contrast, expression of the wildtype allele of wag31 in APYS1-resistant M. tuberculosis was dominant and restored susceptibility to APYS1 to wildtype levels. Time-lapse imaging and scanning electron microscopy revealed that APYS1 caused gross malformation of the old pole of M. tuberculosis, with eventual lysis. These effects resembled the morphological changes observed following transcriptional silencing of wag31 in M. tuberculosis. These data show that Wag31 is likely not the direct target of APYS1, but the striking phenotypic similarity between APYS1 exposure and genetic depletion of Wag31 in M. tuberculosis suggests that APYS1 might indirectly affect Wag31 through an as yet unknown mechanism.
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| 21. |
- Sooriyaarachchi, Sanjeewani, et al.
(författare)
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Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with -Arylpropyl Analogues of Fosmidomycin
- 2016
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 11:18, s. 2024-2036
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Tidskriftsartikel (refereegranskat)abstract
- Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the -position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P.falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.
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| 22. |
- Steer, Dylan, et al.
(författare)
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Structure of Lung-Mimetic Multilamellar Bodies with Lipid Compositions Relevant in Pneumonia
- 2018
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 34:25, s. 7561-7574
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Tidskriftsartikel (refereegranskat)abstract
- The hierarchical assembly of lipids, as modulated by composition and environment, plays a significant role in the function of biological membranes and a myriad of diseases. Elevated concentrations of calcium ions and cardiolipin (CL), an anionic tetra-alkyl lipid found in mitochondria and some bacterial cell membranes, have been implicated in pneumonia recently. However, their impact on the physicochemical properties of lipid assemblies in lungs and how it impairs alveoli function is still unknown. We use small- and wide-angle X-ray scattering (S/WAXS) and solid-state nuclear magnetic resonance (ssNMR) to probe the structure and dynamics of lung-mimetic multilamellar bodies (MLBs) in the presence of Ca2+ and CL. We conjecture that CL overexpressed in the hypophase of alveoli strongly affects the structure of lung-lipid bilayers and their stacking in the MLBs. Specifically, S/WAXS data revealed that CL induces significant shrinkage of the water-layer separating the concentric bilayers in multilamellar aggregates. ssNMR measurements indicate that this interbilayer tightening is due to undulation repulsion damping as CL renders the glycerol backbone of the membranes significantly more static. In addition to MLB dehydration, CL promotes intrabilayer phase separation into saturated-rich and unsaturated-rich lipid domains that couple across multiple layers. Expectedly, addition of Ca2+ screens the electrostatic repulsion between negatively charged lung membranes. However, when CL is present, addition of Ca2+ results in an apparent interbilayer expansion likely due to local structural defects. Combining S/WAXS and ssNMR on systems with compositions pertinent to healthy and unhealthy lung membranes, we propose how alteration of the physiochemical properties of MLBs can critically impact the breathing cycle.
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| 23. |
- Tabar, Laszlo, et al.
(författare)
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Effect of Mammography Screening on Mortality by Histological Grade
- 2018
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 27:2, s. 154-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: It has been asserted that mammography screening preferentially benefits those with less aggressive cancers, with lesser or no impact on more rapidly progressing and therefore more life-threatening tumors. Methods: We utilized data from the Swedish Two-County Trial, which randomized 77,080 women ages 40 to 74 to invitation to screening and 55,985 for usual care. We tabulated cancers by histologic grade and then compared mortality from cancers specific to histologic grade between the invited and control group using Poisson regression, with specific interest in the effect on mortality from grade 3 cancers. We used incidence-based mortality from tumors diagnosed within the screening phase of the trial. Finally, we cross-tabulated grade with tumor size and node status, to assess downstaging within tumor grades. Results: There was a major reduction in mortality from grade 3 tumors (RR = 0.65; 95% CI, 0.53-0.80; P < 0.001), and more deaths prevented from grade 3 tumors (n = 95) than grade 1 and 2 tumors combined (n = 48) in the invited group. The proportions of tumors >= 15 mm or larger and node-positive tumors were substantially reduced in the grade 3 tumors in the invited group. Conclusions: The combination of prevention of tumors progressing to grade 3 and detection at smaller sizes and lesser rates of lymph node metastases within grade 3 tumors results in a substantial number of deaths from grade 3 cancers being prevented by invitation to mammographic screening. Impact: Mammography screening prevents deaths from aggressive cancers.
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