Uppsala University

Multi-twisted molecules have served as superior prototypes in diverse fields like molecular machines, optical materials, sensors, and so forth. However, it remains challenging to address their persistent room-temperature phosphorescence (pRTP), which limits their further development. Herein, we develop a host–guest energy-transfer relay strategy to improve the phosphorescence lifetime of multi-twisted luminophores by over thousand-fold to realize pRTP, which can be witnessed by the naked eye after removing the excitation light source. Moreover, we employ photoexcitation-induced molecular rearrangement to further prolong the phosphorescence lifetime, which, to the best of our knowledge, is the first example of photoactivation in ordered host–guest systems. Our systems show superior humidity and oxygen resistance, rendering a long-term (at least over 9-12 months) stability of the pRTP properties. By achieving pRTP of multi-twisted luminophores, this work can not only advance the understanding of molecular photophysical mechanisms, but also provide more material choices for time-resolved luminescent events.

Programming by demonstration (PBD) is introduced as family of approaches to teach a computer system new behavior by demonstrating it in the context of a concrete example. References to classical and current PBD systems are given.

We assess fluid intelligence of 6–18 year-old children growing up in families that have fled from Syria and reside in Turkish communities (100 families, 394 individuals). We demonstrate that fluid intelligence of refugee children is related to maternal fluid intelligence and to the amount of time mothers spend reading to their child. These factors stood out in the analysis even when controlling for a large range of other factors such as demographics, parental mental health, parental fluid intelligence, home environment, and a large array of potential enrichment factors.

A prototype CCT dipole magnet developed by a collaboration between Swedish universities, Swedish industry and CERN will be tested at Uppsala University. This 1 m long double-aperture magnet can provide a field strength of 3.3 T at 85 A in a 70 mm aperture with an integrated field of 2.8 Tm. It is intended to replace the current LHC orbit corrector magnets which are reaching the end of their expected life due to the radiation load. The new magnet is designed to handle the radiation dose of the upgrade to the high-luminosity LHC, which will deliver about ten times the current radiation dose. It must therefore be more resistant to radiation and meet strict requirements in terms of electrical insulation while matching the original field quality and self-protective capability, mechanical volume, and maximum excitation current. This paper will present the latest of the design and manufacturing work, including the results of simulations of the mechanical field and the mechanical stress. Details of the various tests performed before machining the parts are also presented.

There are many active substances in Atlantic cod (Gadus morhua) explaining the variety of biological activities. In order to study the immunomodulatory activity and the mechanism of Atlantic cod peptides at the cellular level. In this study, cod peptides were isolated by 80 % ethanol extraction method, the isolated ethanol-soluble cod peptides (CP-ES) were investigated and their immunomodulatory activity was verified. Additionally, CP-ES showed lower molecular weight and more hydrophobic amino acids. CP-ES could promote the proliferation of spleen lymphocytes and T lymphocytes in mice, suggesting that CP-ES may regulate adaptive immunity. It promoted the release of NO and the expression of iNOS, TNF-α, IL-6 and IL-1β genes in macrophages, suggesting that CP-ES may regulate innate immunity. CP-ES could promote the expression of TLR2 gene, and the peptides identified in CP-ES were docked with TLR2 to predict the peptides playing a major role in CP-ES. These results suggested that CP-ES may regulate the immune activity of both innate and adaptive lines.

This study aims to investigate the dietary intervention effect of casein/cyanidin-3-O-glucoside nanoparticles (Cs-C3G) on high-fat-diet (HFD)induced gut microbiota disorders. In HFD-fed C57BL/6mice, Cs-C3G has ameliorated HFD-caused fat accumulation and liver oxidative stress. Cs-C3G as a dietary supplementation can restore the abundance and diversity of gut microbiota with descending the ratio of Firmicutes to Bacteroidetes, increasing some beneficial microorganisms, and reducing some opportunistic pathogenic bacteria. In general, Cs-C3G has a effect on regulating the disturbance of gut microbiota, and then prevents HFD-induced obesity and liver damage.

Introduction: The purpose of this retrospective clinic chart review study was to determine the potential of a combination therapy (CT) consisting of γ-aminobutyric acid (GABA), a dipeptidyl peptidase-4 inhibitor (DPP-4i), and a proton pump inhibitor (PPI) to improve glycemic control as an adjunct to insulin therapy in patients with type 1 diabetes (T1D). Research design and methods: Nineteen patients with T1D on insulin therapy were treated with additional CT in oral form. Fasting blood glucose (FBG), HbA1c, insulin dose-adjusted HbA1c (IDA-A1c), daily insulin dose, insulin/weight ratio (IWR), and fasting plasma C-peptide were measured after 26-42 weeks of treatments. Results: FBG, HbA1c, IDA-A1c, insulin dose and IWR were all significantly decreased while plasma C-peptide was significantly increased by the CT. Treatment outcomes were further analyzed by separation of the 19 patients into two groups. One group started on the CT within 12 months of insulin treatment (early therapy, 10 patients) and another group started on this therapy only after 12 months of insulin treatment (late therapy, 9 patients). FBG, IDA-A1c, insulin dose, and IWR decreased significantly in both the early and late CT groups, however to a better extent in the early therapy group. Moreover, plasma C-peptide increased significantly only in the early therapy group, and 7 of the 10 patients in this group were able to discontinue insulin treatment while maintaining good glycemic control to study end compared with none of the 9 patients in the late therapy group. Conclusion: These results support the concept that the combination of GABA, a DPP-4i and a PPI as an adjunct to insulin therapy improves glycemic control in patients with T1D, and that the insulin dose required for glycemic control can be reduced or even eliminated in some patients receiving this novel therapy.

Aim: Based on previous qualitative studies, it was hypothesised that dissimilarities in beliefs about illness, which influence healthcare-seeking behaviour, exist between foreign- and native-born persons diagnosed with type 2 diabetes living in Sweden (in the following termed 'Swedish-born'). Background: Beliefs about illness are individual, culturally related, based on knowledge, and guide health-related behaviour, and thus have an impact on health. The question is whether beliefs differ between foreign- and native-born persons diagnosed with type 2 diabetes. No previous comparative studies have been found on this. Based on previous qualitative studies, it was hypothesised that dissimilarities in beliefs about illness, which influence healthcare-seeking behaviour, exist between foreign- and native-born (Swedish) persons diagnosed with type 2 diabetes living in Sweden. Methods: Cross-sectional survey, 138 participants, comprising 69 foreign- and 69 Swedish-born persons aged 33-90 vs 48-91 years. Data were analysed with descriptive and analytic statistics. Findings: Beliefs about illness differed between foreign- and Swedish-born persons concerning causes of diabetes and healthcare-seeking behaviour. Foreign-born persons more often than Swedish-born persons reported uncertainty or lack of knowledge about whether heredity (67% vs 90%, P = 0.002) and pancreatic disease (40% vs 62%, P = 0.037) could cause diabetes. To a higher extent than Swedish-born persons, they reported that emotional stress and anxiety could cause the disease. Furthermore, they claimed they had sought care due to diabetes during the last 6 months to a higher extent than Swedish-born persons (30% vs 4%, P = 0.000).The findings confirmed that dissimilarities in beliefs about illness, including the causes of diabetes and healthcare-seeking behaviour, exist between foreign- and Swedish-born persons with type 2 diabetes.

In Sweden, people living independently and requiring daily living support can access ‘housing support’, a form of practical, educational, and social support provided by the municipalities. About two-thirds of those receiving this support have neurodevelopmental conditions, primarily autism or ADHD. Many are young adults in the process of adapting to new roles and expectations in different life domains, including education, work, and accommodation. This study aimed to provide a qualitative description of support workers’ views on current practice in housing support for young adults (aged 18 to 29) with neurodevelopmental conditions. Semi-structured telephone interviews were conducted with 34 housing support workers across 19 Swedish regions. An inductive qualitative content analysis approach was used. The interviews depicted a complex service, subject to organizational aspects (roles, responsibilities, availability, and allocation), the joint effort of key players (young adults, relatives, and support workers), and practical aspects of service provision (finding common ground for the work, and delivery of support). Some elements of the service were poorly designed for the target group. The support workers expressed a need for more knowledge about neurodevelopmental conditions, but also described new insights related to remote delivery of support. The results raise important questions about how housing support should be organized and delivered to strike the right balance between support and autonomy, meet specific needs, and ensure equal services across municipalities. Future research should adopt multiple perspectives and approaches, to help translate best practice and available evidence into a flexible and sustainable service.

Background Spirometric small airways obstruction (SAO) is common in the general population. Whether spirometric SAO is associated with respiratory symptoms, cardiometabolic diseases, and quality of life (QoL) is unknown. Methods Using data from the Burden of Obstructive Lung Disease study (N = 21,594), we defined spirometric SAO as the mean forced expiratory flow rate between 25 and 75% of the FVC (FEF25-75) less than the lower limit of normal (LLN) or the forced expiratory volume in 3 s to FVC ratio (FEV3/FVC) less than the LLN. We analysed data on respiratory symptoms, cardiometabolic diseases, and QoL collected using standardised questionnaires. We assessed the associations with spirometric SAO using multivariable regression models, and pooled site estimates using random effects meta-analysis. We conducted identical analyses for isolated spirometric SAO (i.e. with FEV1/FVC ≥ LLN). Results Almost a fifth of the participants had spirometric SAO (19% for FEF25-75; 17% for FEV3/FVC). Using FEF25-75, spirometric SAO was associated with dyspnoea (OR = 2.16, 95% CI 1.77–2.70), chronic cough (OR = 2.56, 95% CI 2.08–3.15), chronic phlegm (OR = 2.29, 95% CI 1.77–4.05), wheeze (OR = 2.87, 95% CI 2.50–3.40) and cardiovascular disease (OR = 1.30, 95% CI 1.11–1.52), but not hypertension or diabetes. Spirometric SAO was associated with worse physical and mental QoL. These associations were similar for FEV3/FVC. Isolated spirometric SAO (10% for FEF25-75; 6% for FEV3/FVC), was also associated with respiratory symptoms and cardiovascular disease. Conclusion Spirometric SAO is associated with respiratory symptoms, cardiovascular disease, and QoL. Consideration should be given to the measurement of FEF25-75 and FEV3/FVC, in addition to traditional spirometry parameters.

The Swedish Childhood Tumor Biobank (BTB) is a nonprofit national infrastructure for collecting tissue samples and genomic data from pediatric patients diagnosed with central nervous system (CNS) and other solid tumors. The BTB is built on a multidisciplinary network established to provide the scientific community with standardized biospecimens and genomic data, thereby improving knowledge of the biology, treatment and outcome of childhood tumors. As of 2022, over 1100 fresh-frozen tumor samples are available for researchers. We present the workflow of the BTB from sample collection and processing to the generation of genomic data and services offered. To determine the research and clinical utility of the data, we performed bioinformatics analyses on next-generation sequencing (NGS) data obtained from a subset of 82 brain tumors and patient blood-derived DNA combined with methylation profiling to enhance the diagnostic accuracy and identified germline and somatic alterations with potential biological or clinical significance. The BTB procedures for collection, processing, sequencing, and bioinformatics deliver high-quality data. We observed that the findings could impact patient management by confirming or clarifying the diagnosis in 79 of the 82 tumors and detecting known or likely driver mutations in 68 of 79 patients. In addition to revealing known mutations in a broad spectrum of genes implicated in pediatric cancer, we discovered numerous alterations that may represent novel driver events and specific tumor entities. In summary, these examples reveal the power of NGS to identify a wide number of actionable gene alterations. Making the power of NGS available in healthcare is a challenging task requiring the integration of the work of clinical specialists and cancer biologists; this approach requires a dedicated infrastructure, as exemplified here by the BTB.

Background Retirement often leads to a more passive lifestyle and may therefore lead to weight gain. This study aims to investigate longitudinal associations between changes in 24-h movement behaviors and BMI and waist circumference in relation to the transition from work to retirement. Methods The study population included 213 retiring public sector workers (mean age 63.5 years, standard deviation 1.1) from the Finnish Retirement and Aging study. Before and after retirement participants wore an Axivity accelerometer on their thigh and filled in a daily log for at least four days to measure daily time spent sleeping, in sedentary behavior (SED), light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA). Also, their body mass index (BMI) and waist circumference were measured repeatedly. Compositional linear regression analysis and isotemporal substitution analysis were used to study associations between one-year changes in 24-h movement behaviors and concurrent changes in BMI and waist circumference. Results An increase in MVPA in relation to sleep, SED and LPA was associated with a decreasing BMI (β = −0.60, p = 0.04) and waist circumference (β = −2.14, p = 0.05) over one year from before retirement to after retirement. In contrast, increasing sleep in relation to SED, LPA and MVPA was associated with an increasing BMI (β = 1.34, p = 0.02). Reallocating 60 min from MVPA to SED or sleep was estimated to increase BMI by on average 0.8–0.9 kg/m² and waist circumference by 3.0 cm during one year. Conclusions During the transition from work to retirement, increasing MVPA was associated with a slight decrease in BMI and waist circumference, whereas increasing sleep was associated with an increasing BMI. Common life transitions, like retirement, should be considered when giving recommendations and guidance for physical activity and sleep.

Colistin heteroresistance (HR) refers to a bacterial population comprised of several subpopulations with different levels of resistance to colistin. In this study, we discuss the classic form of HR, in which a resistant subpopulation exists within a predominantly susceptible population. We investigated the prevalence of colistin HR and its evolution into full resistance among 173 clinical carbapenem-resistant Acinetobacter baumannii isolates and examined the effect of HR on clinical outcomes. To determine HR, we performed population analysis profiling. Our results showed a high prevalence of HR (67.1%). To examine evolution of HR strains into full resistance, the HR strains were grown in colistin-containing broth, transferred onto colistin-containing plates, and colonies on these plates were transferred into colistin-free broth. Many of the HR strains (80.2%) evolved into full resistance, 17.2% reverted to HR, and 2.6% were borderline. We used logistic regression to compare 14-day clinical failure and 14-day mortality between patients infected by HR versus susceptible non-HR carbapenem-resistant A. baumannii. In the subgroup of patients with bacteremia, HR was significantly associated with 14-day mortality. IMPORTANCE To our knowledge, this is the first large-scale study to report on HR in Gram-negative bacteria. We described the prevalence of colistin HR in a large sample of carbapenem-resistant A. baumannii isolates, the evolution of many colistin HR isolates to a resistant phenotype following colistin exposure and withdrawal, and the clinical consequences of colistin HR. We found a high prevalence of HR among clinical carbapenem-resistant A. baumannii isolates; most evolved into a resistant phenotype following colistin exposure and withdrawal. In patients treated with colistin, evolution of HR A. baumannii into full resistance could lead to higher rates of treatment failure and contribute to the reservoir of colistin-resistant pathogens in health care settings.

Escherichia coli coordinates replication and division cycles by initiating replication at a narrow range of cell sizes. By tracking replisomes in individual cells through thousands of division cycles in wild-type and mutant strains, we were able to compare the relative importance of previously described control systems. We found that accurate triggering of initiation does not require synthesis of new DnaA. The initiation size increased only marginally as DnaA was diluted by growth after dnaA expression had been turned off. This suggests that the conversion of DnaA between its active ATP- and inactive ADP-bound states is more important for initiation size control than the total free concentration of DnaA. In addition, we found that the known ATP/ADP converters DARS and datA compensate for each other, although the removal of them makes the initiation size more sensitive to the concentration of DnaA. Only disruption of the regulatory inactivation of DnaA mechanism had a radical impact on replication initiation. This result was corroborated by the finding that termination of one round of replication correlates with the next initiation at intermediate growth rates, as would be the case if RIDA-mediated conversion from DnaA-ATP to DnaA-ADP abruptly stops at termination and DnaA-ATP starts accumulating.

Phosphorylation is a ubiquitous post-translation modification that regulates protein function by promoting, inhibiting or modulating protein-protein interactions. Hundreds of thousands of phosphosites have been identified but the vast majority have not been functionally characterised and it remains a challenge to decipher phosphorylation events modulating interactions. We generated a phosphomimetic proteomic peptide-phage display library to screen for phosphosites that modulate short linear motif-based interactions. The peptidome covers ~13,500 phospho-serine/threonine sites found in the intrinsically disordered regions of the human proteome. Each phosphosite is represented as wild-type and phosphomimetic variant. We screened 71 protein domains to identify 248 phosphosites that modulate motif-mediated interactions. Affinity measurements confirmed the phospho-modulation of 14 out of 18 tested interactions. We performed a detailed follow-up on a phospho-dependent interaction between clathrin and the mitotic spindle protein hepatoma-upregulated protein (HURP), demonstrating the essentiality of the phospho-dependency to the mitotic function of HURP. Structural characterisation of the clathrin-HURP complex elucidated the molecular basis for the phospho-dependency. Our work showcases the power of phosphomimetic ProP-PD to discover novel phospho-modulated interactions required for cellular function.

Objective: While the association between obesity and risk of rheumatic disease is well established, the precise causal relation has not been conclusively proved. Here, we estimate the causal effect of body mass index (BMI) on the risk of developing five different rheumatic diseases. Methods: Linear and nonlinear mendelian randomization (MR) were used to estimate the effect of BMI on risk of rheumatic disease, and sex-specific effects were identified. Analyses were performed in 361,952 participants from the UK Biobank cohort for the five rheumatic diseases: rheumatoid arthritis (N=8,381 cases), osteoarthritis (N=87,430), psoriatic arthropathy (N=933), gout (N=13,638), and inflammatory spondylitis (N=4,328). Results: Using linear MR, we found that one standard deviation higher BMI increases the incidence rate for rheumatoid arthritis (IRR=1.52; 95% CI=1.36-1.69), osteoarthritis (IRR=1.49; 1.43-1.55), psoriatic arthropathy (IRR=1.80; 1.31-2.48), gout (IRR=1.73; 1.56-1.92), and inflammatory spondylitis (IRR=1.34; 1.14-1.57) in all individuals. BMI was found to be a stronger risk factor in women compared to men for psoriatic arthropathy (sex-interaction P=3.3×10-4 ) and gout (P=4.3×10-3 ), and the effect on osteoarthritis was stronger in premenopausal compared to postmenopausal women (P=1.8×10-3 ). Nonlinear effects of BMI were identified for osteoarthritis and gout in men, and for gout in women. The nonlinearity for gout was also more extreme in men compared to women (P=0.03). Conclusion: Higher BMI causes an increased risk for rheumatic disease, an effect that is more pronounced in women for both gout and psoriatic arthropathy. The novel sex- and BMI-specific causal effects identified here, give further insight into rheumatic-disease etiology and mark an important step towards personalized medicine. This article is protected by copyright. All rights reserved.

Research indicates that patients consider empathy as a key factor contributing to the quality-of-care. However, ambiguities in the definition of this multidimensional construct complicate definite conclusions to-date. Addressing the challenges in the literature, and using a hypothetical physician-patient interaction which explored patient-perceived differences between expressions of affective empathy, cognitive empathy, compassion and no empathy, this study aimed to test whether lay participants' evaluations of the quality-of-care depend on the type of empathic physician behavior, and on the physician's gender. We conducted a randomized web-based experiment using a 4 (type of empathy) by 2 (physician gender) between-subjects design. Empathy was subdivided into three concepts: first, affective empathy (i.e. feeling with someone); second, cognitive empathy (i.e. understanding); and third, compassion (i.e. feeling for someone and offering support). Perceived quality-of-care was the primary outcome. Compared with non-empathic interactions, quality-of-care was rated higher when physicians reacted cognitively empathic or compassionate (d = 0.71; 0.43 to 1.00 and d = 0.68; 0.38 to 0.98). No significant difference was found between affective empathy and no empathy (d = 0.13; -0.14 to 0.42). The physician's gender was not related with quality-of-care. Aspects of participants' personality but not their age, gender or the number of physician visits were associated with quality-of-care. No interactions were observed. In showing that patients rated quality-of-care higher when physician reactions were described as cognitively empathic and compassionate, as compared with affectively empathic or non-empathic, our findings refine views about the kinds of empathy that are important in patient care with implications for clinical practice, education and communication trainings.

Therapy-resistant disease is a major cause of death in patients with acute lymphoblastic leukemia (ALL). Activation of the MYB oncogene is associated with ALL and leads to uncontrolled neoplastic cell proliferation and blocked differentiation. Here, we used RNA-seq to study the clinical significance of MYB expression and MYB alternative promoter (TSS2) usage in 133 pediatric ALLs. RNA-seq revealed that all cases analyzed overexpressed MYB and demonstrated MYB TSS2 activity. qPCR analyses confirmed the expression of the alternative MYB promoter also in seven ALL cell lines. Notably, high MYB TSS2 activity was significantly associated with relapse (p = 0.007). Moreover, cases with high MYB TSS2 usage showed evidence of therapy-resistant disease with increased expression of ABC multidrug resistance transporter genes (e.g., ABCA2, ABCB5, and ABCC10) and enzymes catalyzing drug degradation (e.g., CYP1A2, CYP2C9, and CYP3A5). Elevated MYB TSS2 activity was further associated with augmented KRAS signaling (p < 0.05) and decreased methylation of the conventional MYB promoter (p < 0.01). Taken together, our results suggest that MYB alternative promoter usage is a novel potential prognostic biomarker for relapse and therapy resistance in pediatric ALL.

Multiple sclerosis is a highly complex and heterogeneous disease. At onset it often presents as a clinically isolated syndrome. Thereafter relapses are followed by periods of remissions, but eventually most patients develop secondary progressive multiple sclerosis. It is widely accepted that autoantibodies are important to the pathogenesis of multiple sclerosis, but hitherto it has been difficult to identify the target of such autoantibodies. As an alternative strategy, cell-based methods of detecting autoantibodies have been developed. The objective of this study was to explore differences in binding of antibodies from sera and CSF of multiple sclerosis patients and controls to oligodendroglial and neuronal cell-lines, related to antibody type, immunoglobulin (IgG/IgM), matrix (serum/CSF) and disease course. The oligodendroglial and neuronal cell-lines were expanded in tissue culture flasks and transferred to 96-well plates at a concentration of 50000 cells/well followed by fixation and blocking with bovine serum albumin. Sera and CSF samples, from healthy controls and multiple sclerosis patients, were incubated with the fixed cells. Epitope binding of immunoglobulins (IgG and IgM) in sera and CSF was detected using biotinylated anti human IgM and IgG followed by avidin conjugated to horseradish peroxidase. Horseradish peroxidase activity was detected with 3,3',5,5'-tetramethylbenzidine substrate. Serum from 76 patients and 30 controls as well as CSF from 62 patients and 32 controls were investigated in the study. The binding was similar between clinically isolated syndrome patients and controls, whereas the largest differences were observed between secondary progressive multiple sclerosis patients and controls. Antibodies from multiple sclerosis patients (all disease course combined) bound more to all investigated cell-lines, irrespectively of matrix type, but binding of immunoglobulin G from CSF to human oligodendroglioma cell-line discriminated best between multiple sclerosis patients and controls with a sensitivity of 93% and a specificity of 96%. The cell-based ELISA was able to discriminate between multiple sclerosis patients and controls with a high degree of accuracy. Disease course was the major determinant for the antibody binding.