| 1. |
- Hess, Timo, et al.
(author)
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Dissecting the genetic heterogeneity of gastric cancer
- 2023
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In: EBioMedicine. - : Elsevier. - 2352-3964. ; 92
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Journal article (peer-reviewed)abstract
- Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
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| 2. |
- Cellini, Andrea, 1991, et al.
(author)
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Directed ultrafast conformational changes accompany electron transfer in a photolyase as resolved by serial crystallography.
- 2024
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In: Nature chemistry. - : Springer Nature. - 1755-4349 .- 1755-4330.
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Journal article (peer-reviewed)abstract
- Charge-transfer reactions in proteins are important for life, such as in photolyases which repair DNA, but the role of structural dynamics remains unclear. Here, using femtosecond X-ray crystallography, we report the structural changes that take place while electrons transfer along a chain of four conserved tryptophans in the Drosophila melanogaster (6-4) photolyase. At femto- and picosecond delays, photoreduction of the flavin by the first tryptophan causes directed structural responses at a key asparagine, at a conserved salt bridge, and by rearrangements of nearby water molecules. We detect charge-induced structural changes close to the second tryptophan from 1 ps to 20 ps, identifying a nearby methionine as an active participant in the redox chain, and from 20 ps around the fourth tryptophan. The photolyase undergoes highly directed and carefully timed adaptations of its structure. This questions the validity of the linear solvent response approximation in Marcus theory and indicates that evolution has optimized fast protein fluctuations for optimal charge transfer.
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| 3. |
- Amare, Azmeraw, 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: Research square. - : Research Square Platform LLC.
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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 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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| 4. |
- 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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| 5. |
- Astermark, Jan, et al.
(author)
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Infrastructural considerations of implementing gene therapy for hemophilia in the Nordic context
- 2023
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In: Therapeutic advances in hematology. - 2040-6207. ; 14
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Journal article (peer-reviewed)abstract
- Background: Despite improvements in hemophilia care, challenges remain, including treatment burden and impaired quality of life. Gene therapy may overcome these. However, its introduction presents a challenge. Objectives: To outline a function-based gene therapy working model describing critical milestones associated with gene therapy handling, administration, and follow-up to facilitate and implement an effective infrastructure for gene therapy introduction. Design: Literature review and consensus discussion among Hemophilia Comprehensive Care centers (HCCCs) in the Nordic region. Methods: Representatives from six HCCCs sought to pinpoint milestones and key stakeholders for site readiness at the pre-, peri-, and post-infusion stages, including authority and genetically modified organism (GMO) product requirements, awareness, medical eligibility, logistics and product handling for infusion, laboratory monitoring, and follow-up. Results: A gene therapy transit map was developed with key stakeholders identified. The approach to prepare the vector will differ between the Nordic centers, but the contracted pharmacy unit will be a key stakeholder. Therefore, a pharmacy checklist for the implementation of gene therapy was developed. For the future, Advanced Therapy Medicinal Product centers will also be implemented. Patients’ expectations, commitments, and concerns need to be addressed repeatedly and education of patients and the expanded health-care professionals team will be the key to successful and optimal clinical management. Eligibility testing according to the product’s summary of product characteristics and frequent follow-up and monitoring post-infusion according to the World Federation of Hemophilia chart will be crucial. Conclusion: The approach to deliver gene therapy in the Nordic region will differ partly between the hemophilia centers, but the defined road map with checklists for the implementation of this advanced therapy will be applicable to all. The map may also serve as a platform for the use of future GMO product options both within and outside the area of hemophilia.
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| 6. |
- Bergkvist, John, et al.
(author)
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Modelling managed forest ecosystems in Sweden : An evaluation from the stand to the regional scale
- 2023
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In: Ecological Modelling. - : Elsevier BV. - 0304-3800. ; 477
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Journal article (peer-reviewed)abstract
- Incorporation of a forest management module in the dynamic vegetation model LPJ-GUESS has allowed the study and predictions of management treatment effects on the carbon cycle and on forest ecosystem structure. In this study, LPJ-GUESS is evaluated at the regional scale against observational data from the Swedish National Forest Inventory. Simulated standing volume is compared against observations for the four most common forest types in the country. Furthermore, eddy-covariance flux measurements from the Integrated Carbon Observation System (ICOS) are used to evaluate model predictions of net ecosystem exchange (NEE), gross primary productivity (GPP) and ecosystem respiration (Reco) at the site scale. The model results suggest an adequate representation of standing volume in monocultures of Norway spruce and Scots pine for regional simulations in southern and central Sweden, after an updated parameterization of the species. For northern Sweden, the standing volume in Norway spruce monocultures was overestimated with the updated parameter values. At the stand scale, the model produced mixed results for carbon fluxes when evaluated against eddy-covariance data for two sites, one in central and one in southern Sweden. The interannual variation of GPP was well captured for the central Swedish site, but the modelled average GPP for the period 2015–2019 was overestimated by 9%. For the southern Swedish site, GPP was underestimated by 15% for the corresponding period and the simulated interannual variation was half of the observed. The seasonal estimates of modelled net ecosystem exchange (NEE) deviated from observations and the simulated standing volume was underestimated by 25% for both sites. The results highlight further potential to perform species-specific calibration to capture latitudinal gradients in key ecosystem properties, and to incorporate additional characteristics of site quality which could benefit model accuracy at the scale of individual forest stands, both regarding simulated carbon fluxes and forest stand variables.
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| 7. |
- Bergkvist, John, et al.
(author)
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Modelling managed forest ecosystems in Sweden : Poster presentation
- 2022
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Conference paper (other academic/artistic)abstract
- In this work, the forestry-enabled dynamic vegetation model LPJ-GUESS was used to simulate forest standing volume for the three main regions of Sweden. At the regional scale, the model results were evaluated against observational data from the Swedish National Forest Inventory. Carbon fluxes of net ecosystem exchange (NEE), gross primary productivity (GPP), and ecosystem respiration (Reco) were simulated at the local scale on a daily time step for two sites in Sweden and results were evaluated against data from the Integrated Carbon Observation System (ICOS). The model produced adequate results of standing volume in monocultures of Norway spruce and Scots pine for southern and central Sweden, after an updated parameterization of the species. Stand-scale simulations of carbon fluxes produced mixed results after an evaluation against EC data from ICOS.
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| 8. |
- Christiansen, Iben Maj, 1964-, et al.
(author)
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The crosscurrents of Swedish mathematics teacher education
- 2021
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In: International perspectives on mathematics teacher education. - Waxhaw, NC, USA : Information Age Publishing. - 9781648026317 - 9781648026294 - 9781648026300 ; , s. 9-48
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Book chapter (peer-reviewed)abstract
- As with any programs in teacher education, Swedish mathematics teacher education is influenced by changing political winds, developments in Information and Communication Technology (ICT), culture, history, PISA results, research-based program designs, and a fair amount of passion. Content and outcomes are nationally determined and include the requirement of a strong research foundation, but this is often not how practcing techers work, which exerts its own pull on teacher education. The specific implementations of programs take different forms at the universities that offer mathematics teacher education. In order to provide a comprehensive yet meaningful ntroduction to both the current system and current practices, we describe the overall organization of Swedish mathematics teacher education, and then offer short cases of implemented programs. To ensure inclusivity, the various parts are written by mathematics educators from the respective institutions. In this way, both variation across mathematicas teacher education for diffrent grade levels and variation across different institutions working with the same national directives can be distinguished. Issues such as the academization of teacher education are problematized, as are other forces that constitute the crosscurrents in Swedish mathematics teacher education.
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| 9. |
- Doukani, Asmae, et al.
(author)
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Comparison of the Working Alliance in Blended Cognitive Behavioral Therapy and Treatment as Usual for Depression in Europe: Secondary Data Analysis of the E-COMPARED Randomized Controlled Trial
- 2024
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In: Journal of Medical Internet Research. - : JMIR PUBLICATIONS, INC. - 1438-8871. ; 26
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Journal article (peer-reviewed)abstract
- Background: Increasing interest has centered on the psychotherapeutic working alliance as a means of understanding clinical change in digital mental health interventions in recent years. However, little is understood about how and to what extent a digital mental health program can have an impact on the working alliance and clinical outcomes in a blended (therapist plus digital program) cognitive behavioral therapy (bCBT) intervention for depression. Objective: This study aimed to test the difference in working alliance scores between bCBT and treatment as usual (TAU), examine the association between working alliance and depression severity scores in both arms, and test for an interaction between system usability and working alliance with regard to the association between working alliance and depression scores in bCBT at 3 -month assessments. Methods: We conducted a secondary data analysis of the E -COMPARED (European Comparative Effectiveness Research on Blended Depression Treatment versus Treatment -as -usual) trial, which compared bCBT with TAU across 9 European countries. Data were collected in primary care and specialized services between April 2015 and December 2017. Eligible participants aged 18 years or older and diagnosed with major depressive disorder were randomized to either bCBT (n=476) or TAU (n=467). bCBT consisted of 6-20 sessions of bCBT (involving face-to-face sessions with a therapist and an internet-based program). TAU consisted of usual care for depression. The main outcomes were scores of the working alliance (Working Alliance Inventory -Short Revised-Client [WAI-SR-C]) and depressive symptoms (Patient Health Questionnaire -9 [PHQ-9]) at 3 months after randomization. Other variables included system usability scores (System Usability Scale -Client [SUS -C]) at 3 months and baseline demographic information. Data from baseline and 3 -month assessments were analyzed using linear regression models that adjusted for a set of baseline variables. Results: Of the 945 included participants, 644 (68.2%) were female, and the mean age was 38.96 years (IQR 38). bCBT was associated with higher composite WAI-SR-C scores compared to TAU ( B =5.67, 95% CI 4.48-6.86). There was an inverse association between WAI-SR-C and PHQ-9 in bCBT ( B =-0.12, 95% CI -0.17 to -0.06) and TAU ( B =-0.06, 95% CI -0.11 to -0.02), in which as WAI-SR-C scores increased, PHQ-9 scores decreased. Finally, there was a significant interaction between SUS -C and WAI-SR-C with regard to an inverse association between higher WAI-SR-C scores and lower PHQ-9 scores in bCBT ( b =-0.030, 95% CI -0.05 to -0.01; P =.005). Conclusions: To our knowledge, this is the first study to show that bCBT may enhance the client working alliance when compared to evidence -based routine care for depression that services reported offering. The working alliance in bCBT was also associated with clinical improvements that appear to be enhanced by good program usability. Our findings add further weight to the view that the addition of internet-delivered CBT to face-to-face CBT may positively augment experiences of the working alliance.
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| 10. |
- Hederström, Veronica, et al.
(author)
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Do plant ploidy and pollinator tongue length interact to cause low seed yield in red clover?
- 2021
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In: Ecosphere. - : Wiley. - 2150-8925. ; 12:3
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Journal article (peer-reviewed)abstract
- The loss of long-tongued pollinator species and dominance of a few short-tongued generalist species, related to agricultural intensification in recent decades, may have consequences for the quality, quantity, and stability of yields in insect-pollinated crops. Interestingly, the changes in pollinator community coincide with an increase in poor and variable seed yield in red clover, an important crop for green manure and forage production. However, to date we lack a holistic understanding of the factors that drive seed yield in red clover crops. To remedy this, we related plant and pollinator traits to pollinator visitation, behavior, and pollination efficiency in four diploid and five tetraploid red clover cultivars during three years in a common garden setting. Tetraploid cultivars produced 52% fewer seeds and 41% lower seed weight per flower head compared with diploid cultivars. They also had fewer flower heads per plant, larger florets, and lower pollen viability than diploids. Pollinator species with shorter tongues visited diploid cultivars more frequently than tetraploid cultivars. Pollinator species with longer tongues deposited more pollen and showed higher pollination efficiency in terms of seeds produced after single visits. Our results suggest that while both diploid and tetraploid red clover cultivars benefit from the presence of longer-tongued pollinator species, seed yield in tetraploid cultivars may be more sensitive to the loss of these bumble bee species in intensively cultivated agricultural landscapes.
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