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- Guimond, S. E., et al.
(författare)
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Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction
- 2022
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Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 8:5, s. 527-545
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Tidskriftsartikel (refereegranskat)abstract
- Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.
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- Murphy, M. P., et al.
(författare)
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Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo
- 2022
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Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:6, s. 651-662
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Tidskriftsartikel (refereegranskat)abstract
- Multiple roles of reactive oxygen species (ROS) and their consequences for health and disease are emerging throughout biological sciences. This development has led researchers unfamiliar with the complexities of ROS and their reactions to employ commercial kits and probes to measure ROS and oxidative damage inappropriately, treating ROS (a generic abbreviation) as if it were a discrete molecular entity. Unfortunately, the application and interpretation of these measurements are fraught with challenges and limitations. This can lead to misleading claims entering the literature and impeding progress, despite a well-established body of knowledge on how best to assess individual ROS, their reactions, role as signalling molecules and the oxidative damage that they can cause. In this consensus statement we illuminate problems that can arise with many commonly used approaches for measurement of ROS and oxidative damage, and propose guidelines for best practice. We hope that these strategies will be useful to those who find their research requiring assessment of ROS, oxidative damage and redox signalling in cells and in vivo. Reactive oxygen species (ROS) have important roles in health and disease, but are chemically complex and difficult to measure accurately. This consensus statement proposes guidelines and best practices on the nomenclature and assessment of ROS, oxidative reactions and oxidative damage in cells, tissues and in vivo.
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- Mollehave, L. T., et al.
(författare)
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Register-based information on thyroid diseases in Europe: lessons and results from the EUthyroid collaboration
- 2022
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Ingår i: Endocrine Connections. - : Bioscientifica. - 2049-3614. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveRegisters of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs. DesignRegister-based cross-sectional study. MethodsNational register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated. ResultsRegister data on >= 1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy were found for countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs. ConclusionsThe collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availability and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated. This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.
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- Frassinetti, Lorenzo, et al.
(författare)
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Role of the separatrix density in the pedestal performance in deuterium low triangularity JET-ILW plasmas and comparison with JET-C
- 2021
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Ingår i: Nuclear Fusion. - : IOP Publishing Ltd. - 0029-5515 .- 1741-4326. ; 61:12
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Tidskriftsartikel (refereegranskat)abstract
- A reduction of the pedestal pressure with increasing separatrix density over pedestal density (n (e) (sep)/n (e) (ped)) has been observed in JET. The physics behind this correlation is investigated. The correlation is due to two distinct mechanisms. The increase of n (e) (sep)/n (e) (ped) till approximate to 0.4 shifts the pedestal pressure radially outwards, decreasing the peeling-balloning stability and reducing the pressure height. The effect of the position saturates above n (e) (sep)/n (e) (ped) approximate to 0.4. For higher values, the reduction of the pedestal pressure is ascribed to increased turbulent transport and, likely, to resistive MHD effects. The increase of n (e) (sep)/n (e) (ped) above approximate to 0.4 reduces backward difference n (e) /n (e), increasing eta (e) and the pedestal turbulent transport. This reduces the pressure gradient and the pedestal temperature, producing an increase in the pedestal resistivity. The work suggests that the increase in resistivity might destabilize resistive balloning modes, further reducing the pedestal stability.
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- Ittermann, T., et al.
(författare)
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Standardized Map of Iodine Status in Europe
- 2020
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 30:9
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Tidskriftsartikel (refereegranskat)abstract
- Background:Knowledge about the population's iodine status is important, because it allows adjustment of iodine supply and prevention of iodine deficiency. The validity and comparability of iodine-related population studies can be improved by standardization, which was one of the goals of the EUthyroid project. The aim of this study was to establish the first standardized map of iodine status in Europe by using standardized urinary iodine concentration (UIC) data. Materials and Methods:We established a gold-standard laboratory in Helsinki measuring UIC by inductively coupled plasma mass spectrometry. A total of 40 studies from 23 European countries provided 75 urine samples covering the whole range of concentrations. Conversion formulas for UIC derived from the gold-standard values were established by linear regression models and were used to postharmonize the studies by standardizing the UIC data of the individual studies. Results:In comparison with the EUthyroid gold-standard, mean UIC measurements were higher in 11 laboratories and lower in 10 laboratories. The mean differences ranged from -36.6% to 49.5%. Of the 40 postharmonized studies providing data for the standardization, 16 were conducted in schoolchildren, 13 in adults, and 11 in pregnant women. Median standardized UIC was <100 mu g/L in 1 out of 16 (6.3%) studies in schoolchildren, while in adults 7 out of 13 (53.8%) studies had a median standardized UIC <100 mu g/L. Seven out of 11 (63.6%) studies in pregnant women revealed a median UIC Conclusions:We demonstrate that iodine deficiency is still present in Europe, using standardized data from a large number of studies. Adults and pregnant women, particularly, are at risk for iodine deficiency, which calls for action. For instance, a more uniform European legislation on iodine fortification is warranted to ensure that noniodized salt is replaced by iodized salt more often. In addition, further efforts should be put on harmonizing iodine-related studies and iodine measurements to improve the validity and comparability of results.
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- Levin, A., et al.
(författare)
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Novel insights into the disease transcriptome of human diabetic glomeruli and tubulointerstitium
- 2020
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Ingår i: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 35:12, s. 2059-2072
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Tidskriftsartikel (refereegranskat)abstract
- Background. Diabetic nephropathy (DN) is the most common cause of end-stage renal disease, affecting similar to 30% of the rapidly growing diabetic population, and strongly associated with cardiovascular risk. Despite this, the molecular mechanisms of disease remain unknown. Methods. RNA sequencing (RNAseq) was performed on paired, micro-dissected glomerular and tubulointerstitial tissue from patients diagnosed with DN [n = 19, 15 males, median (range) age: 61 (30-85) years, chronic kidney disease stages 1-4] and living kidney donors [n = 20, 12 males, median (range) age: 56 (30-70) years]. Results. Principal component analysis showed a clear separation between glomeruli and tubulointerstitium transcriptomes. Differential expression analysis identified 1550 and 4530 differentially expressed genes, respectively (adjusted P < 0.01). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses highlighted activation of inflammation and extracellular matrix (ECM) organization pathways in glomeruli, and immune and apoptosis pathways in tubulointerstitium of DN patients. Specific gene modules were associated with renal function in weighted gene co-expression network analysis. Increased messengerRNA (mRNA) expression of renal damage markers lipocalin 2 (LCN) and hepatitis A virus cellular receptor1 (HAVCR1) in the tubulointerstitial fraction was observed alongside higher urinary concentrations of the corresponding proteins neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in DN patients. Conclusions. Here we present the first RNAseq experiment performed on paired glomerular and tubulointerstitial samples from DN patients. We show that prominent disease-specific changes occur in both compartments, including relevant cellular processes such as reorganization of ECM and inflammation (glomeruli) as well as apoptosis (tubulointerstitium). The results emphasize the potential of utilizing high-throughput transcriptomics to decipher disease pathways and treatment targets in this high-risk patient population.
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- Bertilsson, Johan, et al.
(författare)
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Towards systematic and objective evaluation of police officer performance in stressful situations
- 2020
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Ingår i: Police Practice and Research. - : Informa UK Limited. - 1561-4263 .- 1477-271X. ; 21:6, s. 655-669
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Tidskriftsartikel (refereegranskat)abstract
- To ensure a continuous high standard of police units, it is critical to recruit people who perform well in stressful situations. Today, this selection process includes performing a large series of tests, which still may not objectively reveal a person’s capacity to handle a life-threatening situation when subjected to high levels of stress. To obtain more systematic and objective data, 12 police officers were exposed to six scenarios with varying levels of threat while their heart rate and pupil size were monitored. The scenarios were filmed and six expert evaluators assessed the performance of the police officers according to seven predefined criteria. Four of the scenarios included addressing a moderate threat level task and the scenarios were executed in a rapid sequence. Two further scenarios included a familiar firearm drill performed during high and low threat situations. The results showed that there was a large agreement between the experts in how they judged the performance of the police officers (p < 0.001). Performance increased significantly over tasks in four of the seven evaluation criteria (p ≤ 0.037). There was also a significant effect of pupil size (p = 0.004), but not heart rate, when comparing the different sequential scenarios. Moreover, a high level of threat considerably impaired the motor performance of the police officers during the firearms drill (p = 0.002). Finally, the pupil seemed to systematically dilate more when a threat appeared immediately than with a delay in the scenarios (p = 0.007). We conclude that systematic and quantitative judgments from experts provide valuable and reliable information about the performance of participants in realistic and stressful policing scenarios. Furthermore, objective physiological measures of heart rate and pupil size may help to explain and understand why performance sometimes deteriorates.
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