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| 2. |
- Amare, Azmeraw, et al.
(författare)
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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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Ingår i: Research square. - : Research Square Platform LLC.
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder 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=2,367) 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<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
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| 3. |
- Amare, Azmeraw T, et al.
(författare)
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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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Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 5. |
- Kattge, Jens, et al.
(författare)
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TRY plant trait database - enhanced coverage and open access
- 2020
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Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Tidskriftsartikel (refereegranskat)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 6. |
- Behave, A, et al.
(författare)
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Analysis of a natural gas fuelled homogeneous charge compression ignition engine with exhaust gas recirculation using a stochastic reactor model
- 2004
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Ingår i: International Journal of Engine Research. - : SAGE Publications. - 1468-0874 .- 2041-3149. ; 5, s. 93-104
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Tidskriftsartikel (refereegranskat)abstract
- Combustion and emissions formation in a Volvo TD 100 series diesel engine running in a homogeneous charge compression ignition (HCCI) mode and fuelled with natural gas is simulated and compared with measurements for both with and without external exhaust gas recirculation (EGR). A new stochastic approach is introduced to model the convective heat transfer, which accounts for fluctuations and fluid-wall interaction effects. This model is included in a partially stirred plug flow reactor (PaSPFR) approach, a stochastic reactor model (SRM), and is applied to study the effect of EGR on pressure, autoignition timing and emissions of CO and unburned hydrocarbons (HCs). The model accounts for temperature inhomogeneities and includes a detailed chemical mechanism to simulate the chemical reactions within the combustion chamber. Turbulent mixing is described by the interaction by exchange with the mean (IEM) model. A Monte Carlo method with a second-order time-splitting technique is employed to obtain the numerical solution. The model is validated by comparing the simulated in-cylinder pressure history and emissions with measurements taken from Christensen and Johansson (SAE Paper 982454). Excellent agreement is obtained between the peak pressure, ignition timing and CO and HC emissions predicted by the model and those obtained from the measurements for the non-EGR, 38 per cent EGR and 47 per cent EGR cases. A comparison between the pressure profiles for the cases studied reveals that the ignition timing and the peak pressure are dependent on the EGR. With EGR, the peak pressure reduces and the autoignition is delayed. The trend observed in the measured emissions with varying EGR is also predicted correctly by the model.
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| 7. |
- Behave, Amit, et al.
(författare)
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Modelling a Duaul-fuelled Multi-cylinder HCCI Engine Using a PDF based Engine Cycle Simulator
- 2004
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Ingår i: SAE technical paper series. - 0148-7191. ; :No 2004-01-0561
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Operating the HCCI engine with dual fuels with a large difference in auto-ignition characteristics (octane number) is one way to control the HCCI operation. The effect of octane number on combustion, emissions and engine performance in a 6-cylinder SCANIA truck engine, fuelled with n-heptane and isooctane, and running in HCCI mode, are investigated numerically and compared with measurements taken from Olsson et al. To correctly simulate the HCCI engine operation, we implement a probability density function (PDF)-based stochastic reactor model (including detailed chemical kinetics and accounting for inhomogeneities in composition and temperature) coupled with GT-POWER, a 1-D fluid-dynamics-based engine cycle simulator. Such a coupling proves to be ideal for the understanding of the combustion phenomenon as well as the gas dynamics processes intrinsic to the engine cycle. The convective heat transfer in the engine cylinder is modeled as a stochastic jump process and accounts for the fluctuations and fluid-wall interaction effects. Curl's coalescence-dispersion model is used to describe turbulent mixing. A good agreement is observed between the predicted values and measurements for in-cylinder pressure, auto-ignition timing and CO, HC as well as NOx emissions for the base case. The advanced PDF-based engine cycle simulator clearly outperforms the widely used homogeneous model-based full cycle engine simulator. The trends in combustion characteristics such as ignition crank angle degree and combustion duration with respect to varying octane numbers are predicted well as compared to measurements. The integrated model provides reliable predictions for in-cylinder temperature, CO, HC as well as NOx emissions over a wide range of octane numbers studied.
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| 8. |
- Bhave, Amit, et al.
(författare)
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Evaluating the EGR-AFR Operating Range of a HCCI Engine
- 2005
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Ingår i: SAE technical paper series. - 0148-7191. ; :2005-01-0161
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We present a computational tool to develop an exhaust gas recirculation (EGR) - air-fuel ratio (AFR) operating range for homogeneous charge compression ignition (HCCI) engines. A single- cylinder Ricardo E-6 engine running in HCCI mode, with external EGR is simulated using an improved probability density function (PDF)-based engine cycle model. For a base case, the in-cylinder temperature and unburned hydrocarbon emissions predicted by the model show a satisfactory agreement with measurements. Furthermore, the model is applied to develop the operating range for various combustion parameters, emissions and engine parameters with respect to the air-fuel ratio and the amount of EGR used. The model predictions agree reasonably well with the experimental results for various parameters over the entire EGR-AFR operating range thus proving the robustness of the PDF based model. The boundaries of the operating range namely, knocking, partial burn, and misfire are reliably predicted by the model. In particular, the model provides a useful insight into the misfire phenomenon by depicting the cyclic variation in the ignition timing and the in-cylinder temperature profiles. Finally, we investigate two control options, namely heating intake charge and trapping residual burned fraction by negative valve overlap. The effect of these two methods on HCCI combustion and CO, HC and NOdx emissions is studied.
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| 9. |
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| 10. |
- Bohlin, Markus, et al.
(författare)
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Simulation-Based Timing Analysis of Complex Real-Time Systems
- 2009
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Ingår i: 2009 15TH IEEE INTERNATIONAL CONFERENCE ON EMBEDDED AND REAL-TIME COMPUTING SYSTEMS AND APPLICATIONS, PROCEEDINGS. - 9780769537870 ; , s. 321-328
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Konferensbidrag (refereegranskat)abstract
- This paper presents an efficient best-effort approach for simulation-based timing analysis of complex real- time systems. The method can handle in principle any software design that can be simulated, and is based on controlling simulation input using a simple yet novel hill- climbing algorithm. Unlike previous approaches, the new algorithm directly manipulates simulation parameters such as execution times, arrival jitter and input. An evaluation is presented using six different simulation models, and two other simulation methods as reference: Monte Carlo simulation and MABERA. The new method proposed in this paper was 4-11% more accurate while at the same time 42 times faster, on average, than the reference methods.
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