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| 2. |
- Andersson, Sara B. E., et al.
(author)
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Interlaboratory Validation of Small-Scale Solubility and Dissolution Measurements of Poorly Water-Soluble Drugs
- 2016
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In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 105:9, s. 2864-2872
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Journal article (peer-reviewed)abstract
- The purpose of this study was to investigate the interlaboratory variability in determination of apparent solubility (Sapp) and intrinsic dissolution rate (IDR) using a miniaturized dissolution instrument. Three poorly water-soluble compounds were selected as reference compounds and measured at multiple laboratories using the same experimental protocol. Dissolution was studied in fasted-state simulated intestinal fluid and phosphate buffer (pH 6.5). An additional 6 compounds were used for the development of an IDR measurement guide, which was then validated with 5 compounds. The results clearly showed a need for a standardized protocol including both the experimental assay and the data analysis. Standardization at both these levels decreased the interlaboratory variability. The results also illustrated the difficulties in performing disc IDR on poorly water-soluble drugs because the concentrations reached are typically below the limit of detection. The following guidelines were established: for compounds with Sapp > 1 mg/mL, the disc method is recommended. For compounds with Sapp <100 μg/mL, IDR is recommended to be performed using powder dissolution. Compounds in the interval 100 μg/mL to 1 mg/mL can be analyzed with either of these methods.
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| 3. |
- Antoniou-Kourounioti, Rea L., et al.
(author)
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Temperature Sensing Is Distributed throughout the Regulatory Network that Controls FLC Epigenetic Silencing in Vernalization
- 2018
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In: Cell systems. - : Elsevier BV. - 2405-4712. ; 7:6, s. 643-655
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Journal article (peer-reviewed)abstract
- Many organisms need to respond to complex, noisy environmental signals for developmental decision making. Here, we dissect how Arabidopsis plants integrate widely fluctuating field temperatures over month-long timescales to progressively upregulate VERNALIZATION INSENSITIVE3 (VIN3) and silence FLOWERING LOCUS C (FLC), aligning flowering with spring. We develop a mathematical model for vernalization that operates on multiple timescales-long term (month), short term (day), and current (hour)-and is constrained by experimental data. Our analysis demonstrates that temperature sensing is not localized to specific nodes within the FLC network. Instead, temperature sensing is broadly distributed, with each thermosensory process responding to specific features of the plants' history of exposure to warm and cold. The model accurately predicts FLC silencing in new field data, allowing us to forecast FLC expression in changing climates. We suggest that distributed thermosensing may be a general property of thermoresponsive regulatory networks in complex natural environments.
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| 4. |
- Bengtsson, Caroline, et al.
(author)
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Incident chronic rhinosinusitis is associated with impaired sleep quality: Results of the RhiNE study
- 2019
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In: Journal of Clinical Sleep Medicine. - : American Academy of Sleep Medicine (AASM). - 1550-9389 .- 1550-9397. ; 15:6, s. 899-905
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Journal article (peer-reviewed)abstract
- Study Objectives: Chronic rhinosinusitis (CRS) is a common inflammatory disease of the nasal cavity and paranasal sinuses. Associations between CRS and poor sleep quality have been reported. This 10-year follow-up study investigates possible associations between incident CRS and sleep quality. Methods: A questionnaire was sent to 16,500 individuals in Sweden, Norway, Denmark, Iceland and Estonia in 2000. It included questions on airway diseases, age, sex, body mass index, smoking habits, comorbidities, education and sleep quality. In 2010, a second questionnaire was sent to the same individuals, with a response rate of 53%. A subgroup of 5,145 individuals without nasal symptoms in 2000 was studied. Multiple logistic regression was performed to examine associations between CRS (defined according to the European position paper on rhinosinusitis and nasal polyps epidemiological criteria) at follow-up and sleep quality, with adjustment for potential confounders. Individuals with the respective sleep problem at baseline were excluded. Results: Over 10 years, 141 (2.7%) of the individuals without nasal symptoms in 2000 had developed CRS. CRS was associated with difficulties inducing sleep (adjusted odds ratio 2.81 [95% CI 1.67–4.70]), difficulties maintaining sleep (2.07 [1.35–3.18]), early morning awakening (3.03 [1.91–4.81]), insomnia (2.21 [1.46–3.35]), excessive daytime sleepiness (2.85 [1.79–4.55]), and snoring (3.31 [2.07–5.31]). Three insomnia symptoms at baseline increased the risk of CRS at follow-up by 5.00 (1.93–12.99). Conclusions: Incident CRS is associated with impaired sleep quality and excessive daytime sleepiness. Insomnia symptoms may be a risk factor for the development of CRS. © 2019 American Academy of Sleep Medicine. All rights reserved.
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| 5. |
- Ecke, Frauke, et al.
(author)
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Sublethal Lead Exposure Alters Movement Behavior in Free-Ranging Golden Eagles
- 2017
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In: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 51:10, s. 5729-5736
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Journal article (peer-reviewed)abstract
- Lead poisoning of animals due to ingestion of fragments from lead-based ammunition in carcasses and offal of shot wildlife is acknowledged globally and raises great concerns about potential behavioral effects leading to increased mortality risks. Lead levels in blood were correlated with progress of the moose hunting season. Based on analyses of tracking data, we found that even sublethal lead concentrations in blood (25 ppb, wet weight), can likely negatively affect movement behavior (flight height and movement rate) of free ranging scavenging Golden Eagles (Aquila chrysaetos). Lead levels in liver of recovered post-mortem analyzed eagles suggested that sublethal exposure increases the risk of mortality in eagles. Such adverse effects on animals are probably common worldwide and across species, where game hunting with lead-based ammunition is widespread. Our study highlights lead exposure as a considerably more serious threat to wildlife conservation than previously realized and suggests implementation of bans of lead ammunition for hunting.
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| 6. |
- Fisher, Rosie A., et al.
(author)
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Vegetation demographics in Earth System Models : A review of progress and priorities
- 2018
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In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 24:1, s. 35-54
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Research review (peer-reviewed)abstract
- Numerous current efforts seek to improve the representation of ecosystem ecology and vegetation demographic processes within Earth System Models (ESMs). These developments are widely viewed as an important step in developing greater realism in predictions of future ecosystem states and fluxes. Increased realism, however, leads to increased model complexity, with new features raising a suite of ecological questions that require empirical constraints. Here, we review the developments that permit the representation of plant demographics in ESMs, and identify issues raised by these developments that highlight important gaps in ecological understanding. These issues inevitably translate into uncertainty in model projections but also allow models to be applied to new processes and questions concerning the dynamics of real-world ecosystems. We argue that stronger and more innovative connections to data, across the range of scales considered, are required to address these gaps in understanding. The development of first-generation land surface models as a unifying framework for ecophysiological understanding stimulated much research into plant physiological traits and gas exchange. Constraining predictions at ecologically relevant spatial and temporal scales will require a similar investment of effort and intensified inter-disciplinary communication.
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| 7. |
- Hepworth, Jo, et al.
(author)
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Absence of warmth permits epigenetic memory of winter in Arabidopsis
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Journal article (peer-reviewed)abstract
- Plants integrate widely fluctuating temperatures to monitor seasonal progression. Here, we investigate the temperature signals in field conditions that result in vernalisation, the mechanism by which flowering is aligned with spring. We find that multiple, distinct aspects of the temperature profile contribute to vernalisation. In autumn, transient cold temperatures promote transcriptional shutdown of Arabidopsis FLOWERING LOCUS C (FLC), independently of factors conferring epigenetic memory. As winter continues, expression of VERNALIZATION INSENSITIVE3 (VIN3), a factor needed for epigenetic silencing, is upregulated by at least two independent thermosensory processes. One integrates long-term cold temperatures, while the other requires the absence of daily temperatures above 15 °C. The lack of spikes of high temperature, not just prolonged cold, is thus the major driver for vernalisation. Monitoring of peak daily temperature is an effective mechanism to judge seasonal progression, but is likely to have deleterious consequences for vernalisation as the climate becomes more variable.
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| 8. |
- Koh, Ara, et al.
(author)
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Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1
- 2018
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In: Cell. - : Elsevier BV. - 0092-8674. ; 175:4
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Journal article (peer-reviewed)abstract
- Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38 gamma MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes.
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| 9. |
- Pape, Kathrine, et al.
(author)
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Agreement of offspring-reported parental smoking status : the RHINESSA generation study
- 2019
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In: BMC Public Health. - : BMC. - 1471-2458. ; 19
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Journal article (peer-reviewed)abstract
- Background: With increasing interest in exposure effects across generations, it is crucial to assess the validity of information given on behalf of others.Aims: To compare adult's report of their parent’s smoking status against parent's own report and examine predictors for discrepant answers.Methods: We studied 7185 offspring (18-51 years) and one of their parents, n = 5307 (27-67 years) participating in the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study. Information about parent's smoking status during offspring's childhood and mother's smoking status during pregnancy was obtained by questionnaires from parents and their offspring. We calculated sensitivity, specificity and Cohen's Kappa [κ] for agreement using parent's own report as the gold standard. We performed logistic regression to examine if offspring's sex, age, educational level, asthma status, own smoking status or parental status, as well as the parent's sex and amount of smoking during childhood predicted disagreement.Results: The sensitivity for offspring's correct report of parent's smoking status during childhood (0-10 years) was 0.82 (95% CI 0.81–0.84), specificity was 0.95 (95% CI 0.95–0.96) and a good agreement was observed, κ = 0.79 (95% CI 0.78–0.80). Offspring's report of mothers' smoking status during pregnancy showed a lower sensitivity, 0.66 (95% CI 0.60–0.71), a slightly lower specificity, 0.92 (95% CI 0.90–0.95) and a good agreement, κ = 0.61 (95% CI 0.55–0.67). In multivariate logistic regression analysis, offspring not having children was a predictor for discrepant answers (odds ratio [OR] 2.11 [95% CI 1.21–3.69]). Low amount of parents' tobacco consumption, < 10 cigarettes/day (OR 2.72 [95% CI 1.71–4.31]) also predicted disagreement compared to ≥10 cigarettes per day, and so did offspring's reports of fathers' smoking status (OR 1.73 [95% CI 1.09–2.74]) compared to mothers' smoking status. Offspring's sex, asthma status, educational level, smoking status or age was not related to discrepant answers.Conclusions: Adults report their parent's smoking status during their childhood, as well as their mothers' smoking status when pregnant with them, quite accurately. In the absence of parents' direct report, offspring's reports could be valuable.
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| 10. |
- van Setten, Jessica, et al.
(author)
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PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
- 2018
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genomewide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are overrepresented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of similar to 105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
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