| 1. |
- Amare, Azmeraw T, et al.
(author)
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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
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In: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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Journal article (peer-reviewed)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
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| 2. |
- Vanderkelen, I., et al.
(author)
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Global Heat Uptake by Inland Waters
- 2020
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In: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 47:12
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Journal article (peer-reviewed)abstract
- Heat uptake is a key variable for understanding the Earth system response to greenhouse gas forcing. Despite the importance of this heat budget, heat uptake by inland waters has so far not been quantified. Here we use a unique combination of global‐scale lake models, global hydrological models and Earth system models to quantify global heat uptake by natural lakes, reservoirs, and rivers. The total net heat uptake by inland waters amounts to 2.6 ± 3.2 ×1020 J over the period 1900–2020, corresponding to 3.6% of the energy stored on land. The overall uptake is dominated by natural lakes (111.7%), followed by reservoir warming (2.3%). Rivers contribute negatively (‐14%) due to a decreasing water volume. The thermal energy of water stored in artificial reservoirs exceeds inland water heat uptake by a factor ∼10.4. This first quantification underlines that the heat uptake by inland waters is relatively small, but non‐negligible.
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| 3. |
- Golub, Malgorzata, et al.
(author)
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A framework for ensemble modelling of climate change impacts on lakes worldwide : the ISIMIP Lake Sector
- 2022
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In: Geoscientific Model Development. - : Copernicus Publications. - 1991-959X .- 1991-9603. ; 15:11, s. 4597-4623
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Journal article (peer-reviewed)abstract
- Empirical evidence demonstrates that lakes and reservoirs are warming across the globe. Consequently, there is an increased need to project future changes in lake thermal structure and resulting changes in lake biogeochemistry in order to plan for the likely impacts. Previous studies of the impacts of climate change on lakes have often relied on a single model forced with limited scenario-driven projections of future climate for a relatively small number of lakes. As a result, our understanding of the effects of climate change on lakes is fragmentary, based on scattered studies using different data sources and modelling protocols, and mainly focused on individual lakes or lake regions. This has precluded identification of the main impacts of climate change on lakes at global and regional scales and has likely contributed to the lack of lake water quality considerations in policy-relevant documents, such as the Assessment Reports of the Intergovernmental Panel on Climate Change (IPCC). Here, we describe a simulation protocol developed by the Lake Sector of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) for simulating climate change impacts on lakes using an ensemble of lake models and climate change scenarios for ISIMIP phases 2 and 3. The protocol prescribes lake simulations driven by climate forcing from gridded observations and different Earth system models under various representative greenhouse gas concentration pathways (RCPs), all consistently bias-corrected on a 0.5 degrees x 0.5 degrees global grid. In ISIMIP phase 2, 11 lake models were forced with these data to project the thermal structure of 62 well-studied lakes where data were available for calibration under historical conditions, and using uncalibrated models for 17 500 lakes defined for all global grid cells containing lakes. In ISIMIP phase 3, this approach was expanded to consider more lakes, more models, and more processes. The ISIMIP Lake Sector is the largest international effort to project future water temperature, thermal structure, and ice phenology of lakes at local and global scales and paves the way for future simulations of the impacts of climate change on water quality and biogeochemistry in lakes.
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| 4. |
- Huezo-Diaz, P, et al.
(author)
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CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP
- 2012
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In: Journal of psychopharmacology (Oxford, England). - : SAGE Publications. - 1461-7285 .- 0269-8811. ; 26:3, s. 398-407
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Journal article (peer-reviewed)abstract
- In vitro work shows CYP2C19 and CYP2D6 contribute to the metabolism of escitalopram to its primary metabolite, N-desmethylescitalopram. We report the effect of CYP2C19 and CYP2D6 genotypes on steady state morning concentrations of escitalopram and N-desmethylescitalopram and the ratio of this metabolite to the parent drug in 196 adult patients with depression in GENDEP, a clinical pharmacogenomic trial. Subjects who had one CYP2D6 allele associated with intermediate metabolizer phenotype and one associated with poor metabolizer (i.e. IM/PM genotypic category) had a higher mean logarithm escitalopram concentration than CYP2D6 extensive metabolizers (EMs) ( p = 0.004). Older age was also associated with higher concentrations of escitalopram. Covarying for CYP2D6 and age, we found those homozygous for the CYP2C19*17 allele associated with ultrarapid metabolizer (UM) phenotype had a significantly lower mean escitalopram concentration (2-fold, p = 0.0001) and a higher mean metabolic ratio ( p = 0.0003) than EMs, while those homozygous for alleles conferring the PM phenotype had a higher mean escitalopram concentration than EMs (1.55-fold, p = 0.008). There was a significant overall association between CYP2C19 genotypic category and escitalopram concentration ( p = 0.0003; p = 0.0012 Bonferroni corrected). In conclusion, we have demonstrated an association between CYP2C19 genotype, including the CYP2C19*17 allele, and steady state escitalopram concentration.
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| 5. |
- Mesman, Jorrit P., 1993-, et al.
(author)
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Performance of one-dimensional hydrodynamic lake models during short-term extreme weather events
- 2020
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In: Environmental Modelling & Software. - : Elsevier BV. - 1364-8152 .- 1873-6726. ; 133
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Journal article (peer-reviewed)abstract
- Numerical lake models are useful tools to study hydrodynamics in lakes, and are increasingly applied to extreme weather events. However, little is known about the accuracy of such models during these short-term events. We used high-frequency data from three lakes to test the performance of three one-dimensional (1D) hydrodynamic models (Simstrat, GOTM, GLM) during storms and heatwaves. Models reproduced the overall direction and magnitude of changes during the extreme events, with accurate timing and little bias. Changes in volume-averaged and surface temperatures and Schmidt stability were simulated more accurately than changes in bottom temperature, maximum buoyancy frequency, or mixed layer depth. However, in most cases the model error was higher (30-100%) during extreme events compared to reference periods. As a consequence, while 1D lake models can be used to study effects of extreme weather events, the increased uncertainty in the simulations should be taken into account when interpreting results.
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| 6. |
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| 7. |
- Chotteau, Veronique, 1963-, et al.
(author)
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Study of Alternating Tangential Flow filtration for perfusion and harvest in Chinese Hamster Ovary cells cultivation
- 2010
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In: Proceedings of the Cell Culture Engineering Conference XII, April 25-30, 2010, Banff, Canada.
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Other publication (other academic/artistic)abstract
- Perfusion is a mode of operation where a continuous replacement of the conditioned medium by fresh medium is operated. It has the advantage of allowing high cell densities. This mode of operations is also required for some instable proteins since the cell-free supernatant containing the product of interest is immediately stored at low temperature where the proteolysis is not active. The ATF filtration device, Alternating Tangential Flow, has been designed to perfuse mammalian cell cultivation process and is used (or studied) nowadays for applications like perfusion, medium renewal, harvest, etc. The cell broth circulation back and forward in the filter prevents the filter clogging and the design ensures a low shear not damageable for the cells. A perfusion process operated by ATF filtration and using CHO cells producing a monoclonal antibody was developed in a 2 L bioreactor. The medium did not contain animal derived components. Cell densities above 40 x 106 cells/mL were obtained with a perfusion rate of 2 reactor volume/day. The highest cell density observed was 48 x 106 cells/mL. These high cell densities were challenging for the aeration. Pure oxygen aeration by large bubbles from an open tube resulted in satisfying oxygenation until 25 to 30 x 106 cells/mL but became limiting at higher cell densities due to the low kLa of these bubbles and the small liquid height. At higher cell densities, a porous sparger with pure oxygen was used either alone or in combination with the open tube aeration. Automatic delivery of antifoam C and pluronic counteracted the effect of small bubble foam deleterious for the cells. From an operation point-of-view, the perfusion operated by the ATF device was satisfying, without filter fouling, easy to operate and to adjust in comparison with other separation devices by filtration or acceleration. Finally harvesting by ATF filtration was evaluated in comparison with ‘one-way’ tangential flow filtration, TFF, on an IgG producing CHO fed-batch process produced in 2 L bioreactor. In both operation modes, ATF and TFF, filter fouling occurred after several minutes and the total process time was comparable but an important difference was that the viability drop obtained when using ATF was 15 % while it was 45 % using the TFF.
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| 8. |
- Delorme, Richard, et al.
(author)
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No human tryptophan hydroxylase-2 gene R441H mutation in a large cohort of psychiatric patients and control subjects.
- 2006
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In: Biological Psychiatry. - : Elsevier BV. - 0006-3223. ; 60:2, s. 202-203
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Journal article (peer-reviewed)abstract
- BACKGROUND: It was recently reported that a rare functional variant, R441H, in the human tryptophan hydroxylase-2 gene (hTPH2) could represent an important risk factor for unipolar major depression (UP) since it was originally found in 10% of UP patients (vs. 1.4% in control subjects). METHODS: We explored the occurrence of this variation in patients with affective disorders (n = 646), autism spectrum disorders (n = 224), and obsessive-compulsive disorder (OCD) (n = 201); in healthy volunteers with no psychiatric disorders (n = 246); and in an ethnic panel of control individuals from North Africa, Sub-Saharan Africa, India, China, and Sweden (n = 277). RESULTS: Surprisingly, we did not observe the R441H variant in any of the individuals screened (3188 independent chromosomes). CONCLUSIONS: Our results do not confirm the role of the R441H mutation of the hTPH2 gene in the susceptibility to UP. The absence of the variant from a large cohort of psychiatric patients and control subjects suggests that the findings reported in the original study could be due to a genotyping error or to stratification of the initial population reported. Additional data by other groups should contribute to the clarification of the discrepancy between our results and those previous published.
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| 9. |
- Grant, Luke, et al.
(author)
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Attribution of global lake systems change to anthropogenic forcing
- 2021
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In: Nature Geoscience. - : Springer Nature. - 1752-0894 .- 1752-0908. ; 14:11, s. 849-854
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Journal article (peer-reviewed)abstract
- Lake ecosystems are jeopardized by the impacts of climate change on ice seasonality and water temperatures. Yet historical simulations have not been used to formally attribute changes in lake ice and temperature to anthropogenic drivers. In addition, future projections of these properties are limited to individual lakes or global simulations from single lake models. Here we uncover the human imprint on lakes worldwide using hindcasts and projections from five lake models. Reanalysed trends in lake temperature and ice cover in recent decades are extremely unlikely to be explained by pre-industrial climate variability alone. Ice-cover trends in reanalysis are consistent with lake model simulations under historical conditions, providing attribution of lake changes to anthropogenic climate change. Moreover, lake temperature, ice thickness and duration scale robustly with global mean air temperature across future climate scenarios (+0.9 °C °Cair–1, –0.033 m °Cair–1 and –9.7 d °Cair–1, respectively). These impacts would profoundly alter the functioning of lake ecosystems and the services they provide.
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| 10. |
- Jansen, Joachim, 1989-, et al.
(author)
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Global increase in methane production under future warming of lake bottom waters
- 2022
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In: Global Change Biology. - : John Wiley & Sons. - 1354-1013 .- 1365-2486. ; 28:18, s. 5427-5440
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Journal article (peer-reviewed)abstract
- Lakes are significant emitters of methane to the atmosphere, and thus are important components of the global methane budget. Methane is typically produced in lake sediments, with the rate of methane production being strongly temperature dependent. Local and regional studies highlight the risk of increasing methane production under future climate change, but a global estimate is not currently available. Here, we project changes in global lake bottom temperatures and sediment methane production rates from 1901 to 2099. By the end of the 21st century, lake bottom temperatures are projected to increase globally, by an average of 0.86-2.60 degrees C under Representative Concentration Pathways (RCPs) 2.6-8.5, with greater warming projected at lower latitudes. This future warming of bottom waters will likely result in an increase in methane production rates of 13%-40% by the end of the century, with many low-latitude lakes experiencing an increase of up to 17 times the historical (1970-1999) global average under RCP 8.5. The projected increase in methane production will likely lead to higher emissions from lakes, although the exact magnitude of the emission increase requires more detailed regional studies.
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