Publikationer från Umeå universitet
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Landscapes of missense variant impact for human superoxide dismutase 1
No full textAmyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in superoxide dismutase 1 (SOD1). Diagnosis based on SOD1 sequencing can not only be definitive but can also indicate specific therapies available for SOD1-associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis is limited by the fact that a substantial fraction (currently 26%) of ClinVar SOD1 missense variants are classified as “variants of uncertain significance” (VUSs). Although functional assays can provide strong evidence for clinical variant interpretation, SOD1 assay validation is challenging given the current incomplete and controversial understanding of SOD1-ALS disease mechanism. Using saturation mutagenesis and multiplexed cell-based assays, we measured the functional impact of over 2,000 SOD1 amino acid substitutions on both enzymatic function and protein abundance. The resulting “missense variant-effect maps” not only reflect prior biochemical knowledge of SOD1 but also provide sequence-structure-function insights. Importantly, our variant-abundance assay can discriminate pathogenic missense variation and provides new evidence for 41% of missense variants that had been previously reported as VUSs, offering the potential to identify additional people who would benefit from therapy approved for SOD1-ALS
Predicting Short-Horizon Prepayment Rates using Machine Learning
No full textMortgage prepayment represents a critical challenge for lenders, impacting risk management and pricing strategies. This thesis evaluates whether machine learning models improve three-month prepayment rate forecasts relative to logistic regression and a Cox proportional hazards model. Using monthly loan-level data, containing both fixed and floating rate loans, the models are evaluated on discrimination using ROC-AUC, and on prepayment rate forecasting using MAPE. Permutation importance if performed to identify the most important features. Results indicate that the machine learning models show no distinct increase in performance when predicting the prepayment rate; however, the random forest model achieved the highest ROC-AUC score on both the fixed and floating rate loans. The most important predictor for the floating rate models was the number of months until the next reset, while the floating rate models primarily based their predictions on the spread rate.
Qualitative content analysis : a step-by-step guide for beginners to the method, theories, epistemology, ontology, and rigour
No full textQualitative content analysis (QCA) is a flexible method of analysis, applicable within many epistemologies and on many kinds of data. This makes it suitable as a general introduction to qualitative methods, but students and other beginners sometimes have trouble grasping the associated concepts and ways of thinking. To facilitate their first foray into this new territory, we propose a five-step process of QCA that does not presuppose any foreknowledge of concepts such as levels of abstraction or what coding and categorizing can look like in practice. In our step-by-step guide, we also depart from some staples of QCA, such as likening codes to labels and accepting topic summaries as categories, since this may hamper rather than help beginners’ understanding of the underlying principles. After a concrete how-to section, we offer a brief comparison between QCA and reflexive thematic analysis. To further the pedagogic uses of the article, we also discuss the philosophical underpinnings of the method, focusing on how to handle potential problems of establishing common ground, utterances that contain several ideas, speech acts, and contextuality
Flood pulses as a potential restoration method in Natura 2000 riparian forests along the lower Dalälven region, Sweden
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Synaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson’s disease and dementia with Lewy bodies
No full textGBA is the major risk gene for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), two common α-synucleinopathies with cognitive deficits. Here we investigate the role of mutant GBA in cognitive decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice show cognitive decline but lack PD-like motor deficits or α-synuclein pathology. Conversely, SNCA tg mice display age-related motor deficits, without cognitive abnormalities. Gba-SNCA mice exhibit both cognitive decline and exacerbated motor deficits, accompanied by greater cortical phospho-α-synuclein pathology, especially in layer 5 neurons. Single-nucleus RNA sequencing of the cortex uncovered synaptic vesicle (SV) endocytosis pathway defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via downregulation of genes regulating SV cycle and synapse assembly. Immunohistochemistry and electron microscopy validate these findings. Our results indicate that Gba mutations, while exacerbating pre-existing α-synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through α-synuclein-independent mechanisms, involving dysfunction in SV endocytosis
Blueberry consumption in early life and its effects on allergy, immune biomarkers, and their association with the gut microbiome
No full textBackground/Objectives: The complementary feeding period is a critical window for shaping infant diet, gut microbiota, and immune development. While allergic symptoms often emerge in the first year of life, the effects of specific foods, such fruits, on infant allergy symptoms, inflammation, immunity and associated microbiota remain unclear. This study aimed to assess the impact of daily blueberry consumption during the complementary feeding period on allergy-related symptoms, immune biomarkers, and gut microbiota in breastfed U.S. infants. Methods: In a double-blind, randomized, placebo-controlled trial, infants from the Denver metro area were assigned to receive up to 10 g/day of freeze-dried blueberry powder or an isocaloric placebo from 5 to 12 months of age. Stool, blood, and caregiver-reported allergy-related symptom data were collected at baseline and study end. Results: Of the 76 infants enrolled, 61 completed the study (Blueberry: n = 30; Placebo: n = 31). While more infants in the blueberry group had allergy-related symptoms at baseline, they had significantly different longitudinal symptom trajectories than the placebo (p = 0.05), showing a greater resolution rate of symptoms by study end. Pro-inflammatory serum IL-13 levels were significantly reduced (p = 0.035) and anti-inflammatory IL-10 levels borderline increased (p = 0.052) in the blueberry group. However, changes in allergy symptoms were not significantly associated with IL-10 or IL-13. The relative abundances of Lacticaseibacillus, Blautia, and Peptostreptococcaceae at 12 months were negatively correlated with IL-10, while Lactobacillus, Clostridiaceae, and Megasphaera were positively associated. IL-13 was positively associated with Citrobacter and negatively associated with Anaerostipes and Blautia. Conclusions: The consumptio9n of blueberries as an early complementary food may improve resolution of allergy symptoms, modulate immune biomarkers, and promote beneficial shifts in gut microbiota during infancy. Future research should aim to identify the specific bioactive components of blueberries responsible for these effects and explore the potential of other complementary foods to favorably influence developing biological systems involved in microbiota and immune development
Injuries among students combining academic studies and elite sports
No full textObjective: The purposes of the study were to examine injury incidence among students engaged in elite sports during their first year of study, and to explore factors associated with injury in this population. Methods: Two surveys were carried out one year apart. A total of 243 students responded to the initial baseline survey; 111 also responded to a follow-up survey. The surveys addressed injury events and characteristics, sports participation, experienced stress, relaxation, control during leisure time, and study pace. Results: Prior to commencing their studies, 51% of the athletes had experienced an injury; 54% experienced an injury during their first year of study. A previous injury increased the odds of a new injury (OR = 3.174, p < 0.01). Athletes sustaining an overuse injury prior to studies had higher risk for sustaining a new overuse injury during the first year of studies (OR = 4.312, p < 0.001), while sustaining an acute injury prior to studies did not significantly increase the risk for sustaining a new acute injury. Sex, type of sport, and study pace were not associated with increased odds of injury. Conclusion: A concerning 54% injury incidence was found during the first year of study. A previous injury increased the likelihood of sustaining a new injury. The findings suggest that injury-prevention methods should be focused particularly on students who have been injured in the year before they begin their studies
Are open-identity donors prepared for release of their identity? : long-term follow-up of a national sample of oocyte and sperm donors
No full textSTUDY QUESTION What are the perspectives of oocyte and sperm donors 14-17 years post-donation on the release of their identity and potential contact with donor-conceived offspring (DCO)? SUMMARY ANSWER Most oocyte and sperm donors wanted to be notified about future releases of their identity and were positive towards contact with DCO, but more than half expressed a need for support in relation to potential contact. WHAT IS KNOWN ALREADY Worldwide, an increasing number of individuals conceived by open-identity donation are reaching an age where they may request donor identity. Little is known regarding donors' preparedness for identity-release and potential contact with DCO. STUDY DESIGN, SIZE, DURATION This study is part of the 'Swedish Study on Gamete Donation' (SSGD), a longitudinal multicentre study including oocyte and sperm donors at all clinics performing gamete donation in Sweden. Consecutive recruitment during a 3-year period (2005-2008) resulted in an initial sample of 299 donors (80% response rate). The present study concerns the fifth wave of data collection of the SSGD conducted 14-17 years post-donation, with very high response rates (oocyte donor 83%, sperm donor 92%). Following exclusion of donors who knew the recipients and/or knew that the donation had not resulted in a living child, the final sample comprised 100 oocyte donor and 91 sperm donor. PARTICIPANTS/MATERIALS, SETTING, METHODS Fourteen to seventeen years after having participated in open-identity donation of their gametes, participants completed a postal survey with study-specific questions. Questions concerned preferences related to the release of their identity to DCO, attitudes towards future contact with people conceived from their donations, need for support regarding potential contact, attitudes towards the perceived importance of the genetic link between parent and child, and openness about having donated oocytes or sperm. Chi-square tests, independent t-tests, and Mann-Whitney U-tests were used to compare responses between oocyte and sperm donors. Multinomial logistic regression was used to identify factors associated with donors' attitudes towards future contact with DCO and need for support. Content analysis was used to analyse free-text responses. MAIN RESULTS AND THE ROLE OF CHANCE Almost all oocyte and sperm donors wanted to be notified about requests for their identity (93%). A majority had positive (71%) or neutral (19%) attitudes towards contact with DCO, but a small group was negative (10%), and more than half wanted support related to potential contact (59%). Free-text responses indicated that donors took the interests of both the DCO and their own family members into account when considering future contact. Donors' attitudes towards contact with people conceived from their donations and donors' need for support were not predicted by socio-demographic factors such as donors' gender and legal children, nor by the perceived importance of the genetic parent-child link. While oocyte and sperm donors displayed similar perspectives on most outcomes, oocyte donors were found to be more open about having donated to all people except partners (All P-values <0.05) and sperm donors placed a higher value on the genetic parent-child link (P = 0.005). LIMITATIONS, REASONS FOR CAUTION While the multicentre design and high response rates strengthen the external validity of our findings, the results may not be generalizable to originally anonymous donors. The scope of the qualitative analysis was limited due to the restricted number of free-text responses. An interview format may be needed to further explore donors' thoughts and feelings regarding potential contact with DCO. WIDER IMPLICATIONS OF THE FINDINGS At a time when increasing numbers of donor-conceived people can request donor-identifying information, our finding that donors generally are positive or neutral towards being contacted by DCO is encouraging. Long-term support of open-identity donors should include notification about requests for their identity and access to counselling and information about handling potential future contact with people conceived from their donations
Intraoperative arterial blood flow and stump pressure measurements in internal carotid artery near-occlusion : blood flow and stump pressure in carotid artery near-occlusion
No full textNear-occlusion (NO) with and without full collapse seems to cause low blood flow in symptomatic carotid stenosis. If the stroke mechanism is hypoperfusion in NO, the stump pressure should be low. The aim was to compare and describe stump pressure and blood flow in conventional ≥ 50% stenosis, NO without full collapse, and NO with full collapse. In this prospective single-center study, consecutive patients with symptomatic ≥ 50% carotid stenosis (NASCET grading), undergoing carotid endarterectomy (CEA) were recruited. NO was diagnosed by three blinded observers who reviewed computed tomography angiographies (CTA). Intraoperative measurements of ICA flow before and after CEA and stump pressure were recorded. One hundred and eighty-one patients were included; 116 (64%) had conventional ≥ 50% stenosis, and 66 (36%) had NO. Before CEA, the median ICA flow was significantly lower in NO (90 ml/min) compared to conventional ≥ 50% stenosis (170 mL/min, p < 0.001). In contrast, no difference was observed after CEA (NO 170 mL/min, conventional ≥ 50% stenosis 180 mL/min, p = 0.48). The ICA flow change was significantly higher in NO compared to conventional stenosis (p < 0.001). There was a significant correlation between the distal ICA diameter on CTA and the ICA flow before CEA (r = 0.579, p < 0.001). There were no differences in stump pressure between NO and conventional ≥ 50% stenoses (median 53 (range 41–66) mmHg and median 54 (range 40–67) mmHg, respectively, p = 0.93), nor any correlation between the stump pressure and the distal ICA diameter (r = 0.063, p = 0.41). NO causes low ICA flow, and to our knowledge, this is the first time this causal link between ICA flow and NO is clearly established. Since patients with NO did not have low stump pressure, the mechanism of stroke in NO does not seem to be hypoperfusion