| 1. |
- Cornillet, Martin, et al.
(författare)
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The Swedish initiative for the study of Primary sclerosing cholangitis (SUPRIM)
- 2024
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Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDespite more than 50 years of research and parallel improvements in hepatology and oncology, there is still today neither a treatment to prevent disease progression in primary sclerosing cholangitis (PSC), nor reliable early diagnostic tools for the associated hepatobiliary cancers. Importantly, the limited understanding of the underlying biological mechanisms in PSC and its natural history not only affects the identification of new drug targets but implies a lack of surrogate markers that hampers the design of clinical trials and the evaluation of drug efficacy. The lack of easy access to large representative well-characterised prospective resources is an important contributing factor to the current situation.MethodsWe here present the SUPRIM cohort, a national multicentre prospective longitudinal study of unselected PSC patients capturing the representative diversity of PSC phenotypes. We describe the 10-year effort of inclusion and follow-up, an intermediate analysis report including original results, and the associated research resource. All included patients gave written informed consent (recruitment: November 2011–April 2016).FindingsOut of 512 included patients, 452 patients completed the five-year follow-up without endpoint outcomes. Liver transplantation was performed in 54 patients (10%) and hepatobiliary malignancy was diagnosed in 15 patients (3%). We draw a comprehensive landscape of the multidimensional clinical and biological heterogeneity of PSC illustrating the diversity of PSC phenotypes. Performances of available predictive scores are compared and perspectives on the continuation of the SUPRIM cohort are provided.InterpretationWe envision the SUPRIM cohort as an open-access collaborative resource to accelerate the generation of new knowledge and independent validations of promising ones with the aim to uncover reliable diagnostics, prognostic tools, surrogate markers, and new treatment targets by 2040.
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| 2. |
- Garvanska, Dimitriya H., et al.
(författare)
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The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions
- 2024
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Ingår i: EMBO Reports. - : Springer Nature. - 1469-221X .- 1469-3178. ; 25:2, s. 902-926
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Tidskriftsartikel (refereegranskat)abstract
- Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1, FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and reduced levels of viral antigen in lungs during the early stages of infection. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins and provides molecular insight into the possible underlying molecular defects in fragile X syndrome.
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| 3. |
- Huss, Linnea, et al.
(författare)
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The Vitamin D Receptor as a Prognostic Marker in Breast Cancer-A Cohort Study
- 2024
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Ingår i: Nutrients. - 2072-6643. ; 16:7, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Previous research has indicated an association between the presence of the vitamin D receptor (VDR) in breast cancer tissue and a favorable prognosis. This study aimed to further evaluate the prognostic potential of VDR located in the nuclear membrane or nucleus (liganded). The VDR protein levels were analyzed using immunohistochemistry in tumor samples from 878 breast cancer patients from Lund, Sweden, included in the Breast Cancer and Blood Study (BCBlood) from October 2002 to June 2012. The follow-up for breast cancer events and overall survival was recorded until 30 June 2019. Univariable and multivariable survival analyses were conducted, both with complete case data and with missing data imputed using multiple imputation by chained equations (MICE). Tumor-specific positive nuclear membrane VDR(num) staining was associated with favorable tumor characteristics and a longer breast cancer free interval (BCFI; HR: 0.64; 95% CI: 0.44-0.95) and overall survival (OS; HR: 0.52; 95% CI: 0.34-0.78). Further analyses indicated that VDRnum status also was predictive of overall survival when investigated in relation to ER status. There were significant interactions between VDR and invasive tumor size (Pinteraction = 0.047), as well as mode of detection (Pinteraction = 0.049). VDRnum was associated with a longer BCFI in patients with larger tumors (HR: 0.36; 95% CI: 0.14-0.93) or clinically detected tumors (HR: 0.28; 95% CI: 0.09-0.83), while no association was found for smaller tumors and screening-detected tumors. Further studies are suggested to confirm our results and to evaluate whether VDR should and could be used as a prognostic and targetable marker in breast cancer diagnostics.
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| 4. |
- Nilsson, Kerstin, et al.
(författare, creator_code:000000023193205X_t)
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Can they Stay or Will They go?
- 2024
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Ingår i: Sustaniable Healthy Working life for All Ages. - Basel, Switzerland : MDPI. ; , s. 37-56
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- A larger amount of older people need to participate in working life due to the global demographic change. It is the employer, through the manager, who enables employees to have access to measures in the workplace that facilitate and enable a sustainable extended working life. The aim of this study was to evaluate work life factors associated with managers believing their employees can work versus wanting to work until age 65 or older. This cross-sectional study included 249 managers in the Swedish municipality sector. Logistic regression analysis was used to investigate associations between different univariate estimates and in data modelling using the SwAge-model. The result stated that 79% of managers believed their employees ‘can’ work and 58% of managers believed their employees ‘want to’ work until age 65 or older. Health, physical work environment, skills and competence are associated the strongest to managers believing employees ‘can’ work until age 65 or older. Insufficient social support at work and lacking possibilities for relocations associated the strongest to managers believing employees would not ‘want to’ work until age 65 or older. Though, several countries (especially in Europe) have included in their social policy measures that retirement age be increased after 65, proposing ages approaching 70. When these proposals become laws, through obligation, people will have no choice (if they want to or if they can continue working). However, people’s attitudes to work may be different (especially after the COVID-19 pandemic), and this analysis of the participating managers’ attitudes showed there is a difference between why employees ‘can’ versus ‘want’ to work respectively. Therefore, different strategies may be needed to contribute to employees both being able to and willing to participate in working life until an older age. These findings on managers’ perspectives, regarding whether they believe employees would be able to versus would want to work and the SwAge-model, will hopefully contribute to anincreased understanding of organisational actions and measures in the process of creating a sustainable extended working life and to increase senior employees’ employability.
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| 5. |
- Nilsson Tysklind, Emma, 1986-, et al.
(författare)
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Agonism in a Classroom Discussion on Strindberg's Miss Julie
- 2024
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Ingår i: Democracy & Education. - 1085-3545 .- 2164-7992. ; 32:1
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Tidskriftsartikel (refereegranskat)abstract
- In many parts of the world, researchers and policymakers alike report possible threats to democracy and its institutions. Accounts in the media of hatred and threats aimed at people taking part in public discourse, and of a polarized political debate, raise general questions about the current state and future of democratic dialogue and processes. Solutions are sought, by both research and policy, in the educational context. Some researchers have turned to the agonistic theory proposed by Chantal Mouffe, highlighting the democratic role of conflict and dissent. Empirical research on agonism in education is, however, scarce. In this article, we explore agonistic democratic theory in educational practice, more precisely in a conversation about a literary classic in an upper-secondary Swedish L1 classroom. Based on the analysis of data generated through a teacher-researcher collaboration, we propose six didactic conditions that are fruitful for what we call agonistic literary discussions. Contributing to the debate on how education could meet a possible threat to democracy, we argue that an agonistic approach is a productive path. This approach views democracy as an ongoing process, and it views the classroom as a place where the meaning of democracy can be negotiated.
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| 6. |
- Nilsson Tysklind, Emma, 1986-, et al.
(författare)
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Political emotions in a literature classroom
- 2024
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Ingår i: Pedagogy, Culture & Society. - : ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD. - 1468-1366 .- 1747-5104. ; , s. 1-18
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Tidskriftsartikel (refereegranskat)abstract
- The democratic potential of literature education has often been accentuated. In this article, we draw on Gert Biesta’s subjectification conception of democratic education, and view democracy as a concept open for (re)negotiation in the classroom. We are informed by Chantal Mouffe’s agonistic democratic theory, and its view of dissent as a foundational aspect of democracy, in that the struggle itself constitutes the identities of the opponents. Agonistic proposals for democratic education also pay attention to political emotions in the classroom. We pair agonism with Sara Ahmed’s view of emotion as performative to explore how power, identity and emotions are entangled in a student group and how this entanglement is integrated in the students’ conceptions of democracy. The students were in their last year of upper secondary school in Sweden. We analysed audio recordings from three group interviews with a total of eleven students. The interviews followed a literary discussion about the short story ‘Farangs’ by Rattawut Lapcharoensap, which was video recorded. The analysis shows that students referred to emotion when constructing the collective identities of themselves and their opponents, and that the power relations between these collective identities influenced what literary interpretations were centred in the discussion.
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| 7. |
- Stener-Victorin, Elisabet, et al.
(författare)
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Proteomic analysis shows decreased Type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS
- 2024
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Ingår i: eLife. - : eLife Sciences Publications Ltd. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders in women. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead tochanges in protein levels and biological function. Methods: To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Results: Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Conclusions: Our results suggest that hyperandrogenic women with PCOS have higher levels of extramyocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.
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| 8. |
- Willekens, Stefanie M. A., et al.
(författare)
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An MR-based brain template and atlas for optical projection tomography and light sheet fluorescence microscopy in neuroscience
- 2024
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Optical Projection Tomography (OPT) and light sheet fluorescence microscopy (LSFM) are high resolution optical imaging techniques, ideally suited for ex vivo 3D whole mouse brain imaging. Although they exhibit high specificity for their targets, the anatomical detail provided by tissue autofluorescence remains limited.Methods: T1-weighted images were acquired from 19 BABB or DBE cleared brains to create an MR template using serial longitudinal registration. Afterwards, fluorescent OPT and LSFM images were coregistered/normalized to the MR template to create fusion images.Results: Volumetric calculations revealed a significant difference between BABB and DBE cleared brains, leading to develop two optimized templates, with associated tissue priors and brain atlas, for BABB (OCUM) and DBE (iOCUM). By creating fusion images, we identified virus infected brain regions, mapped dopamine transporter and translocator protein expression, and traced innervation from the eye along the optic tract to the thalamus and superior colliculus using cholera toxin B. Fusion images allowed for precise anatomical identification of fluorescent signal in the detailed anatomical context provided by MR.Discussion: The possibility to anatomically map fluorescent signals on magnetic resonance (MR) images, widely used in clinical and preclinical neuroscience, would greatly benefit applications of optical imaging of mouse brain. These specific MR templates for cleared brains enable a broad range of neuroscientific applications integrating 3D optical brain imaging.
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| 9. |
- Willekens, Stefanie M. A., et al.
(författare)
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Optically Cleared Umeå brain template : An MR-based brain template and atlas for optical projection and light sheet fluorescence microscopy
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Optical projection tomography (OPT) and light sheet fluorescence microscopy (LSFM) are high-resolution optical imaging techniques operating in the mm-cm range, ideally suited forex vivo3D whole mouse brain imaging. Although these techniques exhibit high sensitivity and specificity for antibody-labeled targets, the provided anatomical information remains limited. To allow anatomical mapping of fluorescent signal in whole brain, we developed a novel magnetic resonance (MR) – based template with its associated tissue priors and atlas labels, specifically designed for brains subjected to tissue processing protocols required for 3D optical imaging. We investigated the effect of tissue pre-processing and clearing on brain size and morphology and developed optimized templates for BABB/Murrays clear (OCUM) and DBE/iDISCO (iOCUM) cleared brains. By creating optical-(i)OCUM fusion images using our mapping procedure, we localized dopamine transporter and translocator protein expression and tracer innervation from the eye to the lateral geniculate nucleus of thalamus and superior colliculus. These fusion images allowed for precise anatomical identification of fluorescent signal in discrete brain areas. As such, these templates enable applications in a broad range of research areas integrating optical 3D brain imaging by providing an MR template for cleared brains.
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| 10. |
- Bergquist, Annika, et al.
(författare)
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Impact on follow-up strategies in patients with primary sclerosing cholangitis
- 2023
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Ingår i: Liver international (Print). - Chichester, United Kingdom : Wiley-Blackwell Publishing Inc.. - 1478-3223 .- 1478-3231. ; 43:1, s. 127-138
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival.METHODS: We collected retrospective data from 2,975 PSC patients from 27 centers. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from January 1, 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality.RESULTS: A broad variety of different follow-up strategies were reported. All except one center used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centers used scheduled ERCP in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, were 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed.CONCLUSIONS: Follow-up strategies vary considerably across centers. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumor detection and increased endoscopic treatment of asymptomatic benign biliary strictures.
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