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- 2019
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Tidskriftsartikel (refereegranskat)
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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. |
- Herrera-Rivero, Marisol, et al.
(författare)
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Exploring the genetics of lithium response in bipolar disorders.
- 2023
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Ingår i: Research square.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II.We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism.Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
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| 5. |
- Herrera-Rivero, Marisol, et al.
(författare)
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Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.
- 2023
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Ingår i: Research square.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.
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| 6. |
- Balmonte, John Paul, et al.
(författare)
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Sharp contrasts between freshwater and marine microbial enzymatic capabilities, community composition, and DOM pools in a NE Greenland fjord
- 2020
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Ingår i: Limnology and Oceanography. - : WILEY. - 0024-3590 .- 1939-5590. ; 65:1, s. 77-95
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Tidskriftsartikel (refereegranskat)abstract
- Increasing glacial discharge can lower salinity and alter organic matter (OM) supply in fjords, but assessing the biogeochemical effects of enhanced freshwater fluxes requires understanding of microbial interactions with OM across salinity gradients. Here, we examined microbial enzymatic capabilities-in bulk waters (nonsize-fractionated) and on particles (>= 1.6 mu m)-to hydrolyze common OM constituents (peptides, glucose, polysaccharides) along a freshwater-marine continuum within Tyrolerfjord-Young Sound. Bulk peptidase activities were up to 15-fold higher in the fjord than in glacial rivers, whereas bulk glucosidase activities in rivers were twofold greater, despite fourfold lower cell counts. Particle-associated glucosidase activities showed similar trends by salinity, but particle-associated peptidase activities were up to fivefold higher-or, for several peptidases, only detectable-in the fjord. Bulk polysaccharide hydrolase activities also exhibited freshwater-marine contrasts: xylan hydrolysis rates were fivefold higher in rivers, while chondroitin hydrolysis rates were 30-fold greater in the fjord. Contrasting enzymatic patterns paralleled variations in bacterial community structure, with most robust compositional shifts in river-to-fjord transitions, signifying a taxonomic and genetic basis for functional differences in freshwater and marine waters. However, distinct dissolved organic matter (DOM) pools across the salinity gradient, as well as a positive relationship between several enzymatic activities and DOM compounds, indicate that DOM supply exerts a more proximate control on microbial activities. Thus, differing microbial enzymatic capabilities, community structure, and DOM composition-interwoven with salinity and water mass origins-suggest that increased meltwater may alter OM retention and processing in fjords, changing the pool of OM supplied to coastal Arctic microbial communities.
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| 7. |
- Kowal-Bielecka, Otylia, et al.
(författare)
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Update of EULAR recommendations for the treatment of systemic sclerosis
- 2017
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 76, s. 1327-1339
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.
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| 8. |
- Narula, Anant, 1993, et al.
(författare)
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Voltage-based Current Limitation Strategy to Preserve Grid-forming Properties Under Severe Grid Disturbances
- 2023
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Ingår i: IEEE Open Journal of Power Electronics. - 2644-1314. ; 4, s. 176-188
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Tidskriftsartikel (refereegranskat)abstract
- Grid-forming (GFM) converters are a promising solution to enable large scale integration of renewable energy sources into the power system. However, due to the intrinsic voltage-source behaviour of GFM converters, current limitation during large grid disturbances is challenging. This paper presents a novel limitation strategy that preserves the GFM properties of the converter and at the same time effectively limits the converter current to the desired value. Through the limitation of the converter's internal voltage, stable operation even during faults and in case of large frequency disturbances in the grid is achieved. Experimental results show the effectiveness of the proposed current limitation strategy in case of various grid disturbances.
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| 9. |
- Rosen, Gail, et al.
(författare)
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Circuit Implementation of a 2-D Gradient Source Localizer
- 2004
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Ingår i: PROCEEDINGS OF THE IEEE SENSORS 2004, VOLS 1-3. ; , s. 206-206
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Konferensbidrag (refereegranskat)abstract
- Gradient field localization, such as chemical and heat source location, is a complex problem, yet few designs have been proposed. Examples are locating fires, thermal leaks in insulation, explosive vapors, illegal substances, and chemical leaks. In this paper, we propose one 4 sensor stationary array to localize the direction-of-arrival (DOA) of a temperature source and model the approach on our previous biologically-inspired array processing technique. Several variants of the algorithm are shown, and with each degree of sophistication, it significantly reduces the DOA variance caused by noisy measurement conditions. Next, a clean 4/8-sensor version of the array was constructed, and it is shown that sensor cooperation improves the adaptation in diffusive, turbulent, and noisy environments.
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| 10. |
- Rosen, Gail, et al.
(författare)
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Implementation of a Hebbian chemoreceptor model for diffusive source localization
- 2009
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Ingår i: Biosystems (Amsterdam. Print). - : Elsevier BV. - 0303-2647 .- 1872-8324. ; 96:3, s. 223-236
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Tidskriftsartikel (refereegranskat)abstract
- While new approaches to chemical localization have been proposed, animals are still widely used for locating landmines and illegal substances. Existing electronic noses still do not have the necessary sensitivity and accuracy. By modeling a cell's chemical detection system, we can gain insight into the basic "olfactory" system. We use an inspiration from chemotaxis and Hebbian learning to enhance localization and tracking of gradient sources, which can be applied to both chemicals and heat. The eukaryotic receptor clustering model shows improvement over previous prokaryotic chemotaxis-inspired methods that do not take into account receptor clustering. Receptor clustering essentially adapts receptors spatio-temporally. For a mobile simulation. our method locates the source in less convergence time than the other chemotaxis algorithms and insignificantly less time compared to no spatio-temporal filtering (e.g. a single-sensor memoryless case). We then show that local regions of receptor cooperation have the best performance reflecting observations of receptor behavior in biology. To demonstrate the performance of this system in real-time, a stationary 4/8-sensor version of the array is implemented, and the algorithm improves the convergence time, mean, and variance of the Direction-of-Arrival calculation in diffusive, turbulent, and noisy environments.
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