Publikationer från Uppsala Universitet
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Syntaxin 1A transmembrane domain palmitoylation induces a fusogenic conformation
No full textNeurotransmitter release is triggered by the fusion of synaptic vesicles with the plasma membrane, orchestrated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins synaptobrevin 2 (Syb2), syntaxin 1A (Stx1A), and SNAP25. Recent experimental studies showed that Stx1A palmitoylation of C271/C272 promotes spontaneous neurotransmitter release. However, the mechanistic role of SNARE transmembrane domain (TMD) palmitoylation in membrane fusion remains unclear.To investigate the structural and functional implications of TMD palmitoylation, we employed coarse-grained molecular-dynamics simulations with the MARTINI force field. In simulations of individual SNAREs and of SNAP25/ Stx1A (t-SNARE) complexes in a membrane, the palmitoyl chains of Syb2 and Stx1A localize to the membrane midplane, with Stx1A palmitoyl chains bending toward the extracellular leaflet. Nonpalmitoylated Stx1A assumed a conformation where the SNARE domain was lying flat, adhering to the intracellular surface of the membrane. Stx1A dual palmitoylation induced dramatic changes, reducing the tilt of its TMD and stabilizing a more upright conformation of its SNARE domain. This conformation resembles the Stx1A conformation in a t-SNARE complex, providing a potential mechanistic explanation of how Stx1A TMD palmitoylation facilitates early steps in SNARE complex formation and thus promotes spontaneous release.In simulations of the late steps of layers 5-8 SNARE complex zippering in a system of 4 SNARE complexes bridging a 10-nm nanodisc and a planar membrane, fusion pores (FPs) spontaneously opened after a few hundred nanoseconds, preceded by distal-leaflet lipid transfer and followed by FP flickering conductance before FP closure. At this stage, Stx1A TMD palmitoylation delayed lipid transfer and FP formation and decreased FP flicker-open times, whereas the palmitoylation of Syb2 did not affect fusion-pore dynamics. These findings suggest that, after facilitation of priming before FP opening, Stx1A TMD palmitoylation directly affects FP dynamics. These results highlight the essential role of SNARE TMD palmitoylation at multiple stages of neurotransmitter release
Socio-geographical disparities in cardiometabolic multimorbidity in Sweden : an Intersectional Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy (I-MAIHDA)
No full textBackground: Mapping social and geographical disparities in health outcomes helps to identify vulnerable groups that should be targeted for intervention. This study aims to assess the disparities in cardiometabolic multimorbidity, the presence of at least two cardiometabolic diseases (CMD), including type 2 diabetes, heart disease, and stroke, among middle-aged adults across socio-geographical intersectional strata in Sweden. Methods: This cross-sectional study used the first examination (2013-2018) of the Swedish CArdioPulmonary bioImage Study (SCAPIS), with a total sample of 29,093 individuals aged 50-64 years living in six areas in Sweden (Gothenburg, Linköping, Malmö/Lund, Stockholm, Umeå and Uppsala). Cardiometabolic multimorbidity was identified based on self-reported information, the National Patient Register, the Swedish Prescribed Drug Register, and examination of glycaemic status. We constructed ninety-six socio-geographical intersectional strata based on the combination of age (50-59/60-64 years), sex (females/males), education (low/high), country of birth (Swedish/foreign-born), and six geographical areas. Intersectional multilevel analysis of individual heterogeneity and discriminatory accuracy (I-MAIHDA) was used to map the predicted prevalence of cardiometabolic multimorbidity and quantify the variance partition coefficient (VPC) and area under the receiver operating characteristic curve (AUC). Results: 24.4% of the participants had one CMD, and 2.8% had cardiometabolic multimorbidity. Across the six areas, strata of 60-64-year-old males with low education, irrespective of country of birth, had the highest prevalence of cardiometabolic multimorbidity. The highest prevalence was observed in 60-64-year-old foreign-born males with low education in Gothenburg (12.4%, 95% CI 7.1-19.3) and in 60-64-year-old Swedish-born males with low education in Malm & ouml; (8.6%, 95% CI 6.3-11.3). The VPC was high (15.0%, 95% CI 10.5-21.1), indicating the importance of intersectional strata in explaining disparities in cardiometabolic multimorbidity, with an AUC of 0.71 (95% CI 0.70-0.73). Conclusions: By applying an intersectionality framework, our study provides a more nuanced map of disparities in cardiometabolic multimorbidity to inform preventive strategies aligned with proportionate universalism and precision of public health. The heterogeneity and discriminatory accuracy measures suggest the need for universally tailored intervention strategies to prevent cardiometabolic multimorbidity
Sugar beet long-read reference assembly of genotype KWS2320
No full textSugar beet (Beta vulgaris ssp. vulgaris) is an important crop plant serving as a major source of sugar, particularly in Europe. Sugar beet research using the genotype KWS2320 has a long-standing history, and many datasets and studies exist that use this genotype as a reference. Here, we present a high-quality genome sequence of sugar beet genotype KWS2320 based on long-read sequencing data as well as an evidence-based gene set employing billions of mRNA (messenger RNA)-seq reads as transcript evidence. The assembly, referred to as RefBeet-3.0, was built using Pacific Biosciences data and was integrated with Bionano optical maps, Oxford Nanopore data, and various additional genomic resources. RefBeet-3.0 comprises 648 Mb in nine pseudochromosomes and further sequences with a total N50 size of 61.5 Mb. The gene set BeetSet-3 consists of 28 271 genes of which 25 824 could be functionally annotated based on sequence homology to orthologous groups. The assembly is highly complete and has a high sequence accuracy in absolute terms and in comparison to existing sugar beet assemblies. RefBeet-3.0 and BeetSet-3 will serve as comprehensive resources for future studies on sugar beet and other plants, as well as for breeding activities
European Integration in a Time of War : Can the EU Gear Up to Face Unprecedent Internal and External Challenges?
No full textIn this chapter, the authors explore how Russia’s large-scale invasion of Ukraine in 2022 has acted as a trigger for a future EU enlargement and how the Union and its member states have taken an inevitable responsibility for future peace and development in Europe. The chapter provides the historical context of EU enlargement, focusing particularly on the 2004 and 2007 Eastern enlargement, which prompted significant discussions about the deepening and widening of the EU. The authors address several challenges the EU faces during the forthcoming enlargement, including the political and economic readiness of the candidate countries, the turbulent geopolitical environment, as well as concerns about the EU’s internal cohesion and its capacity to integrate new members without compromising the Union’s effectiveness. The chapter concludes by outlining the subsequent chapters of the book which, from various perspectives, examine the depth and size of the European Union in a time of war
Evaluation of a person-centred, group-based, culturally appropriate diabetes education model for migrants with type 2 diabetes : a qualitative study
No full textBackground: Diabetes mellitus is a prevalent chronic illness worldwide and largely impacts migrants who have settled in developed countries. In diabetes care, patients play a central role and are natural partners in self-care education for improving health. Upon reviewing the literature, no studies were found that evaluated culturally adapted education models led by a nurse and delivered by a multi-professional team from the perspective of migrants in a group setting. Therefore, this study aims to explore patients' evaluation of the content and implementation of a person-centred, group-based diabetes education model for migrants with type 2 diabetes led by a nurse and delivered by a multi-professional team. Method: Qualitative exploratory study, using semi-structured interviews in focus groups and individually to collect data. Eleven migrants who had participated in an intervention testing the education model aged 45-70, who had been living in Sweden between 4-32 years participated. Inductive qualitative content analysis of data was undertaken. Results: Participants gave a positive picture of their experiences concerning the content and organisation of the person-centred, group-based, culturally adapted diabetes education model. The education sessions were described as providing new and evidence-based knowledge. The multi-professional education staff and the interpreter were perceived as having a professional and familiar approach. They wanted to recommend the education model to others. Conclusions: The study revealed a well-functioning diabetes education model tailored to individual beliefs and cultural aspects. It improved perceived knowledge about type 2 diabetes among migrants, thus increasing self-care behaviour and health. In today's multicultural society, the study offers insights into migrants' feelings, ideas, concerns, knowledge, and experience regarding the content, structure, and outcome of a group-based, culturally adapted diabetes education model that can improve self-care behaviour to promote health and prevent illness. As a result, the education model can be used in primary healthcare as a central and natural partner in self-care education to improve health
An Exploratory Study for Proteomic-Based Markers of Joint Pain and Chronic Back Pain
No full textBackground: Joint pain and chronic back pain are highly prevalent in the aging population and have a large impact on life quality. As the underlying mechanisms are not fully understood, this exploratory cross-sectional study aimed to discover proteins and pathways associated with these two pain conditions in Swedish 70-year-old men. Methods: Plasma proteins (n = 720) were measured in participants from the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 931) using Olink target panels. Participants self-reported current joint pain or continuous back pain during the past year. We used logistic regression with multiple testing adjustments and RIDGE regression (selecting similar to 10% highest-ranking proteins) to identify proteins associated with either joint or chronic back pain, which were then investigated for clusters and pathway enrichments. Results: Out of 931 subjects with protein data, 131 reported joint pain and 31 reported chronic back pain. We identified 19 (significant after multiple testing adjustment) and 25 (nominally significant) highest-ranking proteins associated with joint and chronic back pain, respectively. Enriched pathways included immune responses, inflammation, lipid, coagulation and rheumatoid arthritis pathways. Similar pathways were found for both joint and chronic back pain, even though only two proteins were associated with both these pain conditions. Conclusions: This exploratory proteomics study provides support for systemic inflammation as a common underlying mechanism for joint and chronic back pain. Although similar pathways were found for both pain conditions, the selected proteins differed. Nevertheless, caution is advised due to low sample size and validation in larger studies including both women and men is needed. Significance Statement: Logistic and RIDGE regression analyses indicated that joint pain and chronic back pain were associated with different proteins, which were enriched for similar inflammatory pathways
Combining soft-bodied and three-dimensional fossils to reveal evolutionary modifications in early lingulellotretid brachiopods
No full textLiving lingulide brachiopods are traditionally recognised as representatives of evolutionary conservatism, showing little change in general-morphology from their Cambrian ancestors. However, less attention has been given to their anatomical and ontogenetic modifications since their initial appearance. Among these, lingulellotretids are unique, characterized by their typical elongate pedicle foramen and large pseudointerarea. This study describes exquisitely preserved soft-tissue and phosphatic shells of Lingulellotreta from Cambrian Series 2 deposits in China and Kazakhstan. Biomineralized novelties in Lingulellotreta, including elongate pseudointerarea forming a pouch-like visceral cavity and columnar shell architecture, probably were evolutionarily modified from the unmineralized tubular ancestor Yuganotheca during the Cambrian Explosion. Lingulellotretids, however, faced extinction in the Early Ordovician, exemplifying a short-lived evolutionary experiment with a tubular body form in early brachiopods. Since the early Cambrian, lingulide brachiopods have exhibited a long-term evolutionary trend marked by the reduction of pseudointerarea, reflecting a convergence toward a more efficient body plan that ultimately became dominant in later lineages. The intensification of skeletal defences and the increasing demands of filter feeding within benthic communities likely drove these evolutionary modifications and ecological adjustments, culminating in the development of the distinctive, persistent tongue-shaped body of linguloid brachiopods during the Great Ordovician Biodiversification Event
A New Lutheran Nation : Ideals and Countertypes in The Surgeon’s Stories by Zacharias Topelius
No full textThis study examines how the Finnish-Swedish author, historian, and journalist Zacharias Topelius (1818–1898) formulated ideals and counter-images for Finland as a new Lutheran nation in his historical novel Fältskärns berättelser (The Surgeon’s Stories, 1853–1867). Building on the European tradition of historical fiction initiated by Sir Walter Scott, Topelius used the genre as a means of nation-building, integrating history, religion, and moral ideals into a national narrative. The study demonstrates that Topelius, in Fältskärns berättelser, depicts Finland as a new nation emerging in relation to several religions. However, it is the Lutheran faith that serves as the nation's foundation. In the novel, Topelius emerges as a 19th-century Lutheran author. Through a systematic analysis of Fältskärns berättelser, this study reveals how Topelius employs the Lutheran concept of the household, along with the cultural implications associated with the Table of Duties in Luther’s Small Catechism, as a framework for his nation-building efforts. The household, viewed as the smallest unit of the nation, functions as both a social and spiritual framework, defining gender relations and establishing boundaries on aspects such as fertility and tolerance. The study highlights how Lutheran ideals of shared responsibilities, authority, and care are expressed through the portrayal of men and women as co-regents within the household, illustrating the interplay of masculinity and femininity in the national project. Topelius’ depiction of religious minorities - Catholics, Jews, Muslims, and followers of folk traditions - reveals their exclusion from this Lutheran national framework. Their absence from the household, both symbolically and socially, signifies exclusion from the nation itself. Ultimately, the study argues that Topelius’ Lutheran nation-building continues early modern household-based social structures into the modern era. It highlights the enduring influence of religion in Nordic nation-building and demonstrates that modern Finnish and Nordic identities evolved from, rather than replaced, Lutheran traditions.
Refining outcome prediction in traumatic brain injury
No full textTraumatic brain injury (TBI) remains a leading cause of mortality and a major contributor to global disability-adjusted life years in young and middle-aged adults. While animal studies have shown potential, effective pharmacological treatments have failed to materialize in the clinical setting. A primary challenge in TBI research is the inherent heterogeneity of the condition. Outcome prediction models can reduce this complexity by better risk stratification for clinical trials, optimizing resource allocation, and improving prognostic communication with patients and families. TBI outcomes are commonly measured by the Glasgow Outcome Scale Extended (GOSE), an 8-point scale ranging from death (1) to upper good recovery (8). However, current prediction models typically dichotomize this scale into favorable/unfavorable outcomes which limits nuanced prognostication. The primary objective of this thesis was to develop prediction models capable of predicting the full 8-grade GOSE. A secondary objective was to evaluate the integration of machine learning in clinical care, specifically assessing an AI decision support system for detecting intracranial hemorrhage in computed tomography (CT) scans. We found that advanced machine learning methods performed comparably to standard statistical models when limited to admission variables. However, the incorporation of dynamic physiological data captured prognostic signals that static admission models missed, thereby improving prediction accuracy. Regarding the AI diagnostic tool, while it successfully identified most hemorrhages, we observed no significant clinical benefit for the patients. This underscores that in clinical settings, the implementation strategy is as critical as the technology itself. Finally, this thesis emphasizes that predictive models are not static tools. They are sensitive to temporal changes in populations and healthcare protocols. Therefore, future implementation must prioritize the continuous updating and validation of these models
Feasibility of a randomised controlled trial of Healthier Wealthier Families in Sweden: Results from the Ameliorating Child poverty through Connecting Economic Services with child health Services (ACCESS) pilot study
No full textDespite universal measures in Sweden, the proportion of children living in economic hardship is increasing. One strategy to mitigate hardship is integrating financial counselling within healthcare services. This paper describes a pilot randomised controlled trial (RCT) of the ‘Healthier Wealthier Families’ model in which child healthcare nurses screen parents of young children for economic hardship and refer those in need to free budget and debt counselling (BDC). The study was an internal pilot of a two-arm randomised waitlist-control trial with a one-to-one allocation. The intervention arm received BDC immediately after randomisation, while the waitlist-control arm was referred 3 months later. Both arms received a financial guidance book. Assessments were conducted at two points: pre-intervention (T1) and post-intervention (T2; 3 months post-randomisation). The main objective was to assess the feasibility of recruitment, randomisation, data collection, attendance, and adherence to the topic guide. Of 368 screened parents, 111 (30.2%) were eligible, most of whom were identified by two of the five screening questions focused on ‘worrying about running out of money’ and ‘meeting an unexpected cost’. The conversion rate from screening positive to consenting for trial was 18.0% (n=20). Reasons for declining were due to stigma, lack of capacity or already available knowledge and support. The randomisation was effective, with equal distribution between trial arms. No contamination was detected. Eight out of ten participants who were allocated to the intervention attended at least one session; the mean number of sessions was two. Topic guide implementation was inconsistent. There were high completion rates for most measures, except for income. The primary outcome measure of Child Material and Social Deprivation showed a floor effect, with many parents reporting zero ‘enforced lack’ items. Results from the pilot RCT indicate that the screening process identified the anticipated proportion of eligible parents (30.2%), but that three of the screening questions are redundant. The conversion rate was much lower than anticipated, questioning the feasibility of a full-scale RCT. BDC fidelity to protocol could be strengthened with implementation support. Finally, the primary outcome measure should be reconsidered, as well as the way in which participant income is captured.